{"schemaVersion":1,"updated":"2026-09-02","nodes":[{"id":"aerobic-exercise","slug":"aerobic-exercise","name":"Aerobic exercise","shortName":"Aerobic","layer":"lifestyle","summary":"Walking, jogging, or other aerobic sessions with a set intensity and a weekly minutes target. Trials assign that work, not daily steps or lifting.","detail":"The SMILE trials put people on a treadmill at 70 to 85 percent of heart-rate reserve. Yu used outdoor walking at the WHO minimums: 150 minutes of moderate work or 75 minutes of vigorous work. That prescribed aerobic work is the variable. Strength sessions, incidental step counts, and calling yourself an active person are different measures.","aliases":["aerobic training","walking program","cardio","supervised exercise"],"unit":"min / week","alsoSearch":["jogging","treadmill walking","moderate-intensity aerobic"]},{"id":"air-pollution","slug":"air-pollution","name":"Ambient air pollution","shortName":"Air pollution","layer":"lifestyle","summary":"Outdoor fine particles and nitrogen dioxide estimated at the home address, often during pregnancy. Indoor cooking smoke and a blood metal are different numbers.","detail":"The papers estimate outdoor concentrations at the address with land-use regression or satellite surfaces. Fine particles (PM2.5) and nitrogen dioxide, a traffic marker, are the usual metrics. The number is the air outside. Blood lead is a body burden, not the same reading.","aliases":["PM2.5","fine particulate matter","NO2","nitrogen dioxide","traffic pollution"],"unit":"µg/m³","alsoSearch":["PM10","land-use regression","ESCAPE"]},{"id":"alcohol-intake","slug":"alcohol-intake","name":"Alcohol intake","shortName":"Alcohol","layer":"lifestyle","summary":"Dose-dependent endocrine and decision disruptor.","detail":"Heavy use lowers T, fragments sleep, and taxes next-day risk and status behavior. Light use is entangled with sociability and class. Do not draw a straight line from 'a drink' to leadership.","aliases":["ethanol"],"unit":"units / week","alsoSearch":["AUD"]},{"id":"ashwagandha","slug":"ashwagandha","name":"Ashwagandha","shortName":"Ashwagandha","layer":"lifestyle","summary":"A standardized extract of Withania somnifera root at a named milligram dose. Trials give the plant on its own, not as a sleep schedule or a mixed adaptogen pack.","detail":"Trials use a standardized root extract and usually report the withanolide fraction on the label. Sleep and stress studies dose the extract as its own bottle. Mixes that add piperine or other herbs are a different product.","aliases":["Withania somnifera","withanolides"],"unit":"mg/day extract","alsoSearch":["KSM-66","Shoden"]},{"id":"bacopa","slug":"bacopa","name":"Bacopa","shortName":"Bacopa","layer":"lifestyle","summary":"Bacopa monnieri extract, often about 300 mg a day for eight to twelve weeks. It is a named plant extract used in cognition trials.","detail":"Trials use a standardized whole-plant extract for weeks and then memory or attention tasks. A polyphenol blend that happens to contain bacopa, or a child ADHD protocol, is a different study.","aliases":["Bacopa monnieri","Brahmi","CDRI 08"],"unit":"mg/day extract","alsoSearch":["bacoside","Bacumen"]},{"id":"berberine","slug":"berberine","name":"Berberine","shortName":"Berberine","layer":"lifestyle","summary":"A plant alkaloid, usually about 500 mg of berberine hydrochloride three times a day. Trials treat that salt as its own dose.","detail":"Trials often use about 1.0 to 1.5 g a day for three to five months in people with metabolic syndrome or type 2 diabetes. A multivitamin, a drink that adds hops, or a protocol paper with no result is not this exposure.","aliases":["berberine hydrochloride","Berberis"],"unit":"mg/day","alsoSearch":["berberine HCl","Coptis","goldenseal alkaloid"]},{"id":"breastfeeding","slug":"breastfeeding","name":"Breastfeeding duration","shortName":"Breastfeeding","layer":"lifestyle","summary":"Months of breastfeeding after birth, exclusive or any. It is a postnatal feeding practice, not famine in the womb or a later diet score.","detail":"The papers ask how long a child was breastfed, or whether feeding was exclusive for a stretch. Prenatal famine is an intrauterine date. Antiepileptic drugs in milk are a different exposure. A diet-quality score in children born very small is not months of milk.","aliases":["exclusive breastfeeding","full breastfeeding","lactation duration","breast milk duration","any breastfeeding"],"unit":"months","alsoSearch":["breastfeeding duration","exclusive breastfeeding","colostrum","lactation"]},{"id":"caffeine","slug":"caffeine","name":"Caffeine intake","shortName":"Caffeine","layer":"lifestyle","summary":"Milligrams of caffeine per day from coffee, tea, or capsules. People take it to stay awake; the atlas tracks the dose.","detail":"Caffeine blocks adenosine receptors. A 150 mg capsule and a strong coffee are the same exposure if the milligrams match. Instant coffee, espresso, and energy drinks are ways to take that dose, not separate variables.","aliases":["caffeine","coffee"],"unit":"mg/day","alsoSearch":["coffee","tea","adenosine"]},{"id":"cardiovascular","slug":"cardiovascular","name":"Major cardiovascular events","shortName":"CV events","layer":"biology","summary":"A first heart attack, stroke, or cardiovascular death. The papers count that composite of events, not a blood-pressure reading.","detail":"The papers count cardiovascular death, myocardial infarction, stroke, and sometimes a hospital stay for unstable angina, heart failure, or a TIA. All-cause death is every recorded death. Insulin resistance is a blood-and-model score. A blood-pressure reading is not this event count.","aliases":["MACE","major adverse cardiovascular events","cardiovascular events","CHD events"],"unit":null,"alsoSearch":["myocardial infarction","stroke","cardiovascular death","unstable angina"]},{"id":"chamomile","slug":"chamomile","name":"Chamomile","shortName":"Chamomile","layer":"lifestyle","summary":"Daily chamomile tea, usually for about two weeks. It is the tea, not a theanine drink or a valerian mix.","detail":"Trials pour a daily chamomile tea for about two weeks and score sleep. A chamomile-plus-theanine drink aimed at menstrual pain, or a multivitamin, is a different mix.","aliases":["Matricaria chamomilla","chamomile tea","German chamomile"],"unit":"cups/day","alsoSearch":["Matricaria recutita","chamomile extract"]},{"id":"chromium","slug":"chromium","name":"Chromium","shortName":"Chromium","layer":"lifestyle","summary":"A chromium salt, usually picolinate, nicotinate, or chloride, at a few hundred micrograms a day. It is that salt alone.","detail":"Trials use a few hundred micrograms a day for six to sixteen weeks, often in people with insulin resistance or type 2 diabetes. Chromium stacked with carnitine, vitamin D, or vitamins C and E is a different mix.","aliases":["chromium picolinate","chromium nicotinate","chromium chloride"],"unit":"μg/day","alsoSearch":["chromium dinicocysteinate","CrPic"]},{"id":"coenzyme-q10","slug":"coenzyme-q10","name":"Coenzyme Q10","shortName":"CoQ10","layer":"lifestyle","summary":"A ubiquinone or ubiquinol capsule. Heart-failure trials often use about 100 mg three times a day on top of usual care.","detail":"Trials in heart failure add about 100 mg three times a day for months or years and watch events or symptoms. A Q10 pack with B and E vitamins, or a workplace stress drink, is a different mix.","aliases":["ubiquinone","ubiquinol","CoQ10"],"unit":"mg/day","alsoSearch":["Q-SYMBIO","ubiquinol-10"]},{"id":"cognitive-performance","slug":"cognitive-performance","name":"Cognitive performance","shortName":"Cognition","layer":"psychology","summary":"Attention, memory, and processing speed on a named lab task. It is not IQ-as-destiny and not a career score.","detail":"Edges here use tasks such as digit span, reaction time, or verbal fluency after a named exposure like iron, sleep, or a supplement. A lab task is not a promotion, and status or income should not ride along inside the score.","aliases":["attention","working memory"],"unit":null,"alsoSearch":["processing speed","fatigue"]},{"id":"contest-outcome","slug":"contest-outcome","name":"Contest outcome (win / loss)","shortName":"Win/loss","layer":"psychology","summary":"Who won the last status-relevant contest. The trigger in winner–loser models.","detail":"Mazur's biosocial model says victory raises T and defeat lowers it, which then biases the next contest. Meta-analyses find a clearer effect in the field than in sterile labs, and a smaller effect than pop-science implies.","aliases":["victory","defeat"],"unit":null,"alsoSearch":["competition"]},{"id":"cortisol","slug":"cortisol","name":"Cortisol","shortName":"Cortisol","layer":"biology","summary":"The main glucocorticoid of the HPA axis. It rises with threat, metabolic load, sleep loss, and social evaluation.","detail":"Calling it the stress hormone oversimplifies. It indexes HPA activation under social-evaluative threat, sleep loss, illness, and circadian phase. In the dual-hormone hypothesis it is the brake: high cortisol is proposed to block or reverse testosterone's link to status-seeking.","aliases":["glucocorticoid","HPA"],"unit":"nmol/L","alsoSearch":["CAR","chronic stress"]},{"id":"creatine","slug":"creatine","name":"Creatine supplementation","shortName":"Creatine","layer":"lifestyle","summary":"Creatine monohydrate taken as a daily powder, usually a few grams. Trials treat that dose as its own exposure, separate from a gym session or a multivitamin.","detail":"Most trials use creatine monohydrate, often with a short loading week and then a smaller daily dose. Inside the body it shows up as phosphocreatine in muscle and as creatine in the brain. Resistance training can change strength on its own; this page is the powder.","aliases":["creatine monohydrate","Cr"],"unit":"g/day","alsoSearch":["phosphocreatine","creatine loading"]},{"id":"curcumin","slug":"curcumin","name":"Curcumin supplementation","shortName":"Curcumin","layer":"lifestyle","summary":"A curcumin extract from turmeric, often about a gram a day. It is the extract, not a saffron mix or a curry habit.","detail":"Trials use a named curcumin extract at about a gram a day and watch mood or inflammation scores. A capsule that pairs curcumin with saffron, or turmeric in food, is a different exposure.","aliases":["turmeric extract","curcuminoids","BCM-95"],"unit":"mg/day","alsoSearch":["Curcuma longa","curcuminoid"]},{"id":"depression","slug":"depression","name":"Depression","shortName":"Depression","layer":"psychology","summary":"Major depressive disorder, or symptom severity on a named scale such as HAM-D or BDI. A bad week and a memory-task score are different objects.","detail":"SMILE used a structured interview plus Hamilton and Beck scores. Brush tracked symptom change in young adults with major depression. Yu required a diagnosis, ongoing medication, and a BDI above 9. Attention and memory tasks sit with cognitive performance. Rank motives sit with status seeking.","aliases":["major depression","MDD","depressive symptoms","HAM-D"],"unit":"HAM-D or BDI score","alsoSearch":["BDI","major depressive disorder","Hamilton depression"]},{"id":"dhea-s","slug":"dhea-s","name":"DHEA-S","shortName":"DHEA-S","layer":"biology","summary":"Adrenal androgen often bundled into 'optimization' panels. Causal behavioral evidence is thin.","detail":"DHEA-S declines with age and correlates with perceived vitality in some observational series. Supplementation trials do not support a reliable effect on status, cognition, or income. Treat it as a biomarker looking for a job.","aliases":["DHEAS","dehydroepiandrosterone sulfate"],"unit":"μmol/L","alsoSearch":["adrenal androgen"]},{"id":"disposable-income","slug":"disposable-income","name":"Disposable income","shortName":"Income","layer":"ses","summary":"Flow of resources after tax. Buys time, health inputs, and mating-market position.","detail":"Income is the master confounder of this atlas. It buys supplements, gym time, sleep, outdoor leisure, private medicine, and dating-app filters. Any observational arrow from a purchasable input to 'success' must first survive income.","aliases":["earnings","wage"],"unit":"currency / year","alsoSearch":["SES"]},{"id":"dominance-strategy","slug":"dominance-strategy","name":"Dominance strategy","shortName":"Dominance","layer":"psychology","summary":"Rank via coercion, intimidation, or formal power. Costly when institutions punish it.","detail":"Dominance works in zero-sum contests and weak-institution settings. In knowledge work it often backfires. Testosterone folklore is almost entirely a dominance story; prestige is the missing half.","aliases":["coercive rank"],"unit":null,"alsoSearch":["aggression","intimidation"]},{"id":"eating-window","slug":"eating-window","name":"Eating window (time-restricted eating)","shortName":"Eating window","layer":"lifestyle","summary":"The hours of the day when calories come in, and where those hours sit on the clock. Time-restricted eating shortens that window.","detail":"A 6-hour dinner-by-3pm schedule and a noon-to-8pm 16:8 are both called time-restricted eating. The clock position is part of what was assigned. Hours asleep and a calorie target are different questions. Trials that hold calories fixed ask something else from trials that let intake fall when the kitchen closes.","aliases":["time-restricted eating","TRE","time-restricted feeding","eTRF","eating window"],"unit":"hours / day","alsoSearch":["early time-restricted feeding","16:8","circadian eating"]},{"id":"education","slug":"education","name":"Educational attainment","shortName":"Education","layer":"ses","summary":"Years or credentials. Confounds health behavior, income, and almost every biomarker.","detail":"Education is both a cause (health literacy, time preference) and a collider (healthy, conscientious people stay in school). Conditioning on it blindly can open or close backdoors depending on the query.","aliases":["schooling","credentials"],"unit":"years or ISCED level","alsoSearch":["human capital"]},{"id":"educational-homogamy","slug":"educational-homogamy","name":"Educational homogamy","shortName":"Homogamy","layer":"psychology","summary":"Assortative mating on education and cognitive class. The quiet successor to strict income hypergamy.","detail":"In high-education markets, couples match on degree and field more tightly than on raw income. That is an incentive story (shared production of household public goods) as much as a biological one.","aliases":["assortative mating"],"unit":null,"alsoSearch":["matching"]},{"id":"employment-status","slug":"employment-status","name":"Employment status","shortName":"Employment","layer":"ses","summary":"In work or not. The outcome most often falsely credited to vitamins.","detail":"Unemployment is a health shock and a selection process. Observational papers that find supplement users 'less unemployed' are almost always looking at Healthy User Bias wearing a lab coat.","aliases":["job holding","occupational class"],"unit":null,"alsoSearch":["unemployment"]},{"id":"estradiol","slug":"estradiol","name":"Estradiol","shortName":"E2","layer":"biology","summary":"Primary estrogen. Relevant to cycle-phase behavior research and to aromatization from testosterone.","detail":"Estradiol is not a side character in male physiology: aromatization links T to E2. Cycle-phase mate-preference effects are contested after the replication wave. Do not import a single-hormone story from either sex.","aliases":["E2","estrogen"],"unit":"pmol/L","alsoSearch":["aromatase"]},{"id":"fenugreek","slug":"fenugreek","name":"Fenugreek","shortName":"Fenugreek","layer":"lifestyle","summary":"Trigonella foenum-graecum seed extract, usually 600 to 1,800 mg a day. It is the named seed, not a gym mix or a testosterone gel.","detail":"Trials use 600 to 1,800 mg a day of a branded seed extract for about twelve weeks and measure testosterone or related scores. A capsule that only claims to block aromatase without naming fenugreek is a different product.","aliases":["Trigonella foenum-graecum","Testofen","methi"],"unit":"mg/day extract","alsoSearch":["Trigozim","fenugreek seed"]},{"id":"ferritin","slug":"ferritin","name":"Ferritin","shortName":"Ferritin","layer":"biology","summary":"Iron store. Deficiency impairs cognition and work capacity; excess is not a performance upgrade.","detail":"Iron-deficiency anemia has a clear clinical path to fatigue and cognitive slowing. That is not a license to treat high ferritin as an executive-function stack. The interesting causal question is correction of deficit, not megadosing.","aliases":["iron stores"],"unit":"μg/L","alsoSearch":["anemia","iron"]},{"id":"fertility","slug":"fertility","name":"Fertility","shortName":"Fertility","layer":"biology","summary":"The chance of a pregnancy, a live birth, an ovulation, or a usable sperm count. A blood testosterone reading is a different measure.","detail":"A trial can count a heartbeat after embryo transfer, a natural pregnancy, a return of bleeding, ovarian volume, or the share of sperm with a normal shape. The object is the event or the gamete, not a hormone panel.","aliases":["pregnancy","live birth","ovulation","sperm morphology","IVF pregnancy"],"unit":"pregnancies per transfer","alsoSearch":["IVF","AMH","semen analysis","PCOS infertility"]},{"id":"formal-power","slug":"formal-power","name":"Formal organizational power","shortName":"Power","layer":"ses","summary":"Command over people or budgets inside an institution.","detail":"Power is not prestige and not income. A senior civil servant and a well-paid IC have different hormones-and-behavior problems. Lab 'leadership' tasks are a long walk from this node.","aliases":["authority","managerial rank"],"unit":null,"alsoSearch":["hierarchy position"]},{"id":"glp1-agonist","slug":"glp1-agonist","name":"GLP-1 receptor agonist","shortName":"GLP-1","layer":"lifestyle","summary":"A prescribed incretin drug: semaglutide, tirzepatide, liraglutide, or dulaglutide. The papers assign a weekly or daily dose.","detail":"These drugs copy gut hormones that slow the stomach, raise insulin when glucose is high, and cut hunger. Tirzepatide also hits the GIP receptor. The object is the assigned pen at a named dose. Weight that falls afterward is a common path, not a second drug.","aliases":["GLP-1 RA","semaglutide","tirzepatide","liraglutide","incretin agonist"],"unit":"mg / week","alsoSearch":["Wegovy","Ozempic","Mounjaro","Zepbound","dulaglutide"]},{"id":"green-tea","slug":"green-tea","name":"Green tea / EGCG","shortName":"Green tea","layer":"lifestyle","summary":"Green tea as a drink, a powder, or an EGCG capsule. Decaffeinated extracts still count; a pure caffeine milligram count does not.","detail":"The catechin named most often is epigallocatechin-3-gallate (EGCG). Decaffeinated extracts still belong here because the trial is dosing tea catechins. A caffeine capsule is a different exposure, and a rye bread or candy that merely contains green tea is a different food.","aliases":["EGCG","green tea extract","catechins"],"unit":"mg/day EGCG or catechins","alsoSearch":["Camellia sinensis","tea polyphenols"]},{"id":"hearing-loss","slug":"hearing-loss","name":"Hearing loss","shortName":"Hearing","layer":"biology","summary":"A measured drop in how well the ear picks up sound, usually a pure-tone average. Age is a nearby cause, not the same score.","detail":"A clinic scores how loud a tone has to be before you hear it. Hearing aids treat that score. Age, vascular disease, and noise sit nearby. The variable here is the audiogram, not the birthday.","aliases":["hearing impairment","audiometric hearing loss","presbycusis"],"unit":"dB HL (pure-tone average)","alsoSearch":["hearing aids","pure-tone average","PTA"]},{"id":"hypergamy-preference","slug":"hypergamy-preference","name":"Income hypergamy preference","shortName":"Hypergamy","layer":"psychology","summary":"Preference for a partner with equal or higher economic rank. Historically female-typical in surveys.","detail":"The modern quantitative nuance is not that women always want richer men. As women's own income and education rise, strict economic hypergamy yields to educational and cultural homogamy (similarity in cognitive class and lifestyle), provided the safety floor is met (Fisman et al. 2006 and later matching studies).","aliases":["marrying up","status hypergamy"],"unit":null,"alsoSearch":["homogamy","assortative mating"]},{"id":"inositol","slug":"inositol","name":"Inositol","shortName":"Inositol","layer":"lifestyle","summary":"Myo-inositol or D-chiro-inositol powder, often 2 g twice a day. It is that powder, not metformin.","detail":"Trials use myo-inositol, sometimes with a little folic acid, for months in metabolic syndrome, polycystic ovary syndrome, or pregnancy. A head-to-head against metformin, or a pack that combines both, is a different product.","aliases":["myo-inositol","D-chiro-inositol","inositol supplement"],"unit":"g/day","alsoSearch":["MI-PG","inositol hexaphosphate"]},{"id":"insulin-resistance","slug":"insulin-resistance","name":"Insulin resistance (HOMA-IR)","shortName":"HOMA-IR","layer":"biology","summary":"How poorly insulin clears glucose, often scored with HOMA-IR from fasting glucose and insulin. It sits between diet, sleep, and long-run metabolic risk.","detail":"HOMA-IR is a common observational score. Lifestyle trials can move it. Arrows from HOMA-IR straight to income or mate choice are almost always tangled with education, body mass, and health-care access.","aliases":["HOMA-IR","insulin"],"unit":"HOMA-IR units","alsoSearch":["metabolic syndrome"]},{"id":"interpersonal-trust","slug":"interpersonal-trust","name":"Interpersonal trust","shortName":"Trust","layer":"psychology","summary":"Willingness to transfer resources to a stranger who can keep them. The trust-game object, not a vibe.","detail":"In the investment/trust game the first mover sends money that is multiplied; the second mover can return some or none. Transfers are the usual behavioral measure of trust. They are not the same as self-reported agreeableness, oxytocin plasma, or 'psychological safety' at work.","aliases":["trust-game transfer","investor transfer"],"unit":"currency units sent","alsoSearch":["trust game","Berg game"]},{"id":"job-strain","slug":"job-strain","name":"Job strain","shortName":"Job strain","layer":"ses","summary":"High job demands with low control. Karasek's score is not having a job, and it is not a wide network.","detail":"Job strain is a questionnaire, usually the Job Content Questionnaire: how much the work asks, and how much say the person has. The Job Demand-Control-Support extension adds workplace support. Effort-reward imbalance is a cousin used on the same pages: high effort, low reward, overcommitment. Employment status on this atlas is in work or not. Social capital is network density. Neither is this score.","aliases":["demand-control","JDCS","work stress","effort-reward imbalance"],"unit":null,"alsoSearch":["Karasek","ERI","job demands","job control"]},{"id":"kidney-disease","slug":"kidney-disease","name":"Kidney disease","shortName":"Kidney","layer":"biology","summary":"A drop in how fast the kidneys filter blood (eGFR), a rise in urine albumin, or a kidney-failure event. A heart attack or stroke is a different count.","detail":"Outcome trials tally a composite: kidney failure (dialysis, a transplant, or eGFR under 15), a large drop in eGFR, or death from kidney or heart causes. The yearly eGFR slope and the albumin-to-creatinine ratio are the continuous reads. The object is the kidney. It is not the three-point heart-event tally on the cardiovascular page.","aliases":["CKD","chronic kidney disease","eGFR decline","albuminuria","kidney failure","nephropathy"],"unit":"events / eGFR slope","alsoSearch":["FLOW trial","major kidney disease events","macroalbuminuria","end-stage kidney disease"]},{"id":"l-theanine","slug":"l-theanine","name":"L-theanine","shortName":"L-theanine","layer":"lifestyle","summary":"The isolated amino acid from tea, usually 50 to 400 mg as a single oral dose. A cup of tea and a theanine-plus-caffeine mix are different drinks.","detail":"Trials give the isolated amino acid and then a reaction-time, attention, or switch task. A cup of tea delivers less theanine along with caffeine and other compounds. Capsules that pair theanine with caffeine are a different drink from theanine alone.","aliases":["theanine","L-theanine","gamma-glutamylethylamide"],"unit":"mg acute","alsoSearch":["suntheanine","tea amino acid"]},{"id":"lead-exposure","slug":"lead-exposure","name":"Blood lead","shortName":"Lead","layer":"biology","summary":"Childhood blood lead, measured in µg/dL. Paint, dust, water, and gasoline are how it gets in; the reading is the blood number.","detail":"The papers draw venous or capillary blood and report lead in micrograms per deciliter. Peak, lifetime average, and concurrent draws are different clocks on the same burden. Paint, pipes, and leaded gasoline are sources. The variable is the blood number.","aliases":["lead exposure","blood lead","PbB","childhood lead","environmental lead"],"unit":"µg/dL","alsoSearch":["blood lead level","Pb exposure","lead poisoning"]},{"id":"leadership-effectiveness","slug":"leadership-effectiveness","name":"Leadership effectiveness","shortName":"Leadership","layer":"psychology","summary":"Rated or revealed ability to coordinate a group. Not the same as being chosen as leader.","detail":"Mehta and Josephs used observer ratings of leader-like behavior in a lab task. That is not CEO performance, promotion velocity, or founder outcomes. The construct leap from 20-minute group tasks to 'success' is where folklore is born.","aliases":["leader emergence"],"unit":null,"alsoSearch":["managerial performance"]},{"id":"light-exposure","slug":"light-exposure","name":"Evening and bright light","shortName":"Evening light","layer":"lifestyle","summary":"Light at the eye in the evening or at night, especially short-wavelength light. Hours outdoors and minutes of scrolling are different clocks.","detail":"Melanopsin cells in the retina read how bright the light is and how much blue is in it. The papers assign evening room light, a screen spectrum, or a light-emitting e-reader against print. Morning sun for vitamin D is time outdoors. Time spent on a phone as content is a different clock from the spectrum at the eye.","aliases":["evening light","blue light","bright light","artificial light at night"],"unit":"lux / spectrum","alsoSearch":["melatonin suppression","blue-enriched","e-reader"]},{"id":"lions-mane","slug":"lions-mane","name":"Lion's mane","shortName":"Lion's mane","layer":"lifestyle","summary":"Hericium erinaceus mushroom extract as a dry powder or a concentrated extract. It is the mushroom dose used in cognition trials.","detail":"Trials use a dry powder or a 10:1 extract for weeks to months and then memory or attention tasks. A kitchen garnish or a mixed herb pack that happens to contain the mushroom is a different product.","aliases":["Hericium erinaceus","Yamabushitake","lion's mane mushroom"],"unit":"mg/day extract","alsoSearch":["erinacine","hericenone"]},{"id":"loneliness","slug":"loneliness","name":"Loneliness","shortName":"Loneliness","layer":"psychology","summary":"The felt gap between the contact a person wants and the contact they have. Living alone and a thin network are different measures.","detail":"Surveys ask whether someone feels left out, isolated, or lacking companionship. That score can rise in a busy house and stay low in a one-person flat. Social capital on this atlas is network density. Depression is a mood disorder on a named scale. Loneliness is the feeling.","aliases":["felt loneliness","perceived isolation","UCLA loneliness"],"unit":null,"alsoSearch":["UCLA Loneliness Scale","lonely","perceived social isolation"]},{"id":"magnesium","slug":"magnesium","name":"Magnesium supplementation","shortName":"Magnesium","layer":"lifestyle","summary":"A magnesium salt or solution that delivers a few hundred milligrams of elemental magnesium a day. Blood magnesium is a lab reading; this page is the assigned dose.","detail":"Trials use oxide, chloride, or another salt at a few hundred milligrams of elemental magnesium a day. Low serum magnesium is common in type 2 diabetes, which is why insulin and sleep trials keep picking the salt. A multivitamin that happens to contain some magnesium is not the same exposure.","aliases":["magnesium oxide","magnesium chloride","oral magnesium"],"unit":"mg/day elemental","alsoSearch":["hypomagnesemia","MgO"]},{"id":"mediterranean-diet","slug":"mediterranean-diet","name":"Mediterranean diet","shortName":"Med diet","layer":"lifestyle","summary":"A food pattern: olive oil, vegetables, fruit, legumes, nuts, fish, and modest wine. Extra-virgin oil and mixed nuts are the PREDIMED supplements.","detail":"PREDIMED scored the pattern on a 14-item Mediterranean Diet Adherence Screener. Points go to olive oil as the main fat, daily fruit and vegetables, weekly legumes, fish, nuts, and sofrito, and to limits on red meat, butter, sweet drinks, and pastry. The pattern here is eaten without a calorie target. Energy-restricted Mediterranean advice plus exercise (PREDIMED-Plus) is a combined program. So is a Mediterranean weight-loss diet on top of a CPAP machine. Ultra-processed intake and an eating window are different diet clocks.","aliases":["MedDiet","Mediterranean dietary pattern","PREDIMED diet","MEDAS diet"],"unit":"MEDAS points (0-14)","alsoSearch":["PREDIMED","extra virgin olive oil","mixed nuts","sofrito"]},{"id":"melatonin","slug":"melatonin","name":"Melatonin supplementation","shortName":"Melatonin","layer":"lifestyle","summary":"A melatonin tablet taken at night, often a 2 mg prolonged-release dose. Evening light and a lab reading of melatonin onset are different measurements.","detail":"The papers assign melatonin at night and then watch sleep latency or sleep quality. Dim-light melatonin onset is a clock reading of when the body starts making melatonin, not this tablet. A multivitamin or a progesterone capsule is a different hormone or bottle.","aliases":["prolonged-release melatonin","PRM"],"unit":"mg/night","alsoSearch":["Circadin","exogenous melatonin"]},{"id":"mindfulness","slug":"mindfulness","name":"Mindfulness-based training","shortName":"Mindfulness","layer":"psychology","summary":"A course that trains attention on present experience without chasing or fighting thoughts. The papers here are MBCT or mindfulness-based CBT, not a personality score.","detail":"MBCT is eight weekly group sessions plus a silent day, from Segal, Williams, and Teasdale. Online programs in the same family mix CBT workbooks with mindfulness videos and a coach. A questionnaire trait score is not the course. A walk belongs with aerobic exercise. Hours in bed belong with sleep duration.","aliases":["MBCT","MBSR","mindfulness-based CBT","mindfulness meditation"],"unit":null,"alsoSearch":["mindfulness-based cognitive therapy","mindfulness-based stress reduction"]},{"id":"mortality","slug":"mortality","name":"All-cause mortality","shortName":"Mortality","layer":"biology","summary":"Death from any cause. The papers count a recorded death, whatever the certificate names.","detail":"Registries and death certificates code a cause. The variable here is the fact of death. Heart disease, cancer, and liver failure all count. A page that only follows one disease is a narrower count. Nothing here is medical advice.","aliases":["all-cause death","all-cause mortality","premature death"],"unit":null,"alsoSearch":["death","survival","cause of death"]},{"id":"muscle-strength","slug":"muscle-strength","name":"Muscle strength","shortName":"Strength","layer":"biology","summary":"How much force a muscle can produce, or the lean mass that usually travels with it. It is an outcome, not the habit of going to the gym.","detail":"Trials report a one-rep max, a predicted 1RM from reps to fatigue, handgrip strength, or lean and fat-free mass. Resistance training is work that may change those numbers. A memory-task score is a different outcome, and water alone can move a lean-mass reading without a stronger contraction.","aliases":["lean mass","fat-free mass","1RM","muscular strength"],"unit":"kg (1RM or FFM)","alsoSearch":["one-rep max","FFM","handgrip"]},{"id":"net-worth","slug":"net-worth","name":"Net worth","shortName":"Wealth","layer":"ses","summary":"Stock of assets minus liabilities. Different incentive object from income.","detail":"Wealth buffers risk and changes mate-search time horizons. Papers that use income as a stand-in for wealth are measuring the wrong stock. Inheritance further breaks any simple biology-to-money arrow.","aliases":["wealth","assets"],"unit":"currency","alsoSearch":["patrimony"]},{"id":"omega3-supplementation","slug":"omega3-supplementation","name":"Omega-3 supplementation","shortName":"Omega-3","layer":"lifestyle","summary":"Capsules or food doses of the marine fats EPA and DHA, from fish oil or algae. Grocery users of fish oil already look healthier on average, so shopping habits are not the claim.","detail":"Cardiometabolic trials assign purified EPA, mixed EPA plus DHA, or a margarine dose and count heart events or triglycerides. Depression trials use EPA-heavy oils against a seed-oil placebo. A promotion or job outcome hung on who buys fish oil is almost always a healthy-user pattern, not a causal arrow from the bottle.","aliases":["fish oil","DHA","EPA"],"unit":"mg/day EPA+DHA","alsoSearch":["PUFA"]},{"id":"outdoor-time","slug":"outdoor-time","name":"Time outdoors","shortName":"Outdoors","layer":"lifestyle","summary":"UV-B exposure, movement, and a SES-coded leisure habit.","detail":"Outdoor time is the hidden common cause of 25(OH)D and of 'having a life that looks healthy'. Desk-bound high earners in high latitudes can be rich and deficient; outdoor workers can be poorer and replete. That is why D is a terrible SES instrument.","aliases":["sun exposure","UV-B"],"unit":"hours / day","alsoSearch":["latitude"]},{"id":"oxytocin","slug":"oxytocin","name":"Oxytocin","shortName":"OT","layer":"biology","summary":"Neuropeptide sold as the trust hormone. The registered replication of the 2005 Nature RCT did not find the main effect.","detail":"Intranasal oxytocin was the 2010s shortcut from a nasal spray to social capital. Kosfeld et al. (2005) reported higher trust-game transfers after OT. Later reviews and a 2020 registered replication (Declerck et al., including original authors) did not recover the headline effect under the original minimal-social-contact condition. Treat OT as a molecule with a replication file, not as a management tool.","aliases":["OT","intranasal oxytocin"],"unit":"IU (intranasal) or pg/mL (plasma)","alsoSearch":["trust game","neuropeptide"]},{"id":"power-pose","slug":"power-pose","name":"Expansive posture (power pose)","shortName":"Power pose","layer":"lifestyle","summary":"Two minutes of expansive stance, claimed to raise T, cut cortisol, and lift risk-taking. The larger replication did not.","detail":"Carney, Cuddy, and Yap (2010) assigned 42 people to expansive versus contractive poses and reported neuroendocrine and risk effects. Ranehill et al. (2015) ran 200 people and found no hormone or risk change. Simmons and Simonsohn (2017) p-curved the supportive set and found it consistent with selective reporting. The TED talk is not an identification strategy.","aliases":["power posing","expansive posture","postural feedback"],"unit":null,"alsoSearch":["Cuddy","wonder woman pose"]},{"id":"prenatal-nutrition","slug":"prenatal-nutrition","name":"Prenatal famine exposure","shortName":"Prenatal famine","layer":"biology","summary":"Exposure to famine while still in the womb, dated by the Dutch Hunger Winter of 1944-1945. It is an intrauterine date, not an adult diet.","detail":"Researchers in the Dutch Famine Birth Cohort mark people by whether they were in utero during the Hunger Winter, and in which trimester. That is a famine date, not a weighed maternal diet. Adult eating window, ultra-processed food, and sleep are later life. This page is intrauterine undernutrition.","aliases":["prenatal undernutrition","intrauterine undernutrition","Dutch Hunger Winter","fetal undernutrition","gestational famine","prenatal famine"],"unit":null,"alsoSearch":["Dutch famine","Hunger Winter","fetal programming","prenatal undernutrition"]},{"id":"prestige-strategy","slug":"prestige-strategy","name":"Prestige strategy","shortName":"Prestige","layer":"psychology","summary":"Rank via skill, knowledge, or valued contribution. Others copy you voluntarily.","detail":"Henrich and Gil-White (2001) argued that prestige is an evolved pathway for cultural learning: we defer to those worth copying. It predicts different endocrine and network signatures than dominance. Most biohacking content never mentions it.","aliases":["freely conferred status"],"unit":null,"alsoSearch":["expertise","cultural learning"]},{"id":"probiotic","slug":"probiotic","name":"Probiotic supplementation","shortName":"Probiotic","layer":"lifestyle","summary":"A live bacterial capsule with one or a few named strains, often Lactobacillus and Bifidobacterium. It is that capsule, not fiber or biotin.","detail":"Trials use one or a few named strains for four to eight weeks and score mood or gut outcomes. Acacia fiber, a probiotic-plus-biotin pack, or a calorie-restriction program is a different product.","aliases":["probiotics","psychobiotic","Lactobacillus"],"unit":"CFU/day","alsoSearch":["Bifidobacterium","gut microbiota","LP299v"]},{"id":"resistance-training","slug":"resistance-training","name":"Resistance training","shortName":"Lifting","layer":"lifestyle","summary":"Progressive strength work. Moves body composition; T responses are acute and small at rest.","detail":"Training raises acute T and GH, improves insulin sensitivity, and changes how others read your body. Chronic basal T elevation in eugonadal adults is not a reliable training effect. The social signal may matter more than the ng/dL.","aliases":["strength training","weights"],"unit":"sessions / week","alsoSearch":["hypertrophy"]},{"id":"rhodiola","slug":"rhodiola","name":"Rhodiola","shortName":"Rhodiola","layer":"lifestyle","summary":"Rhodiola rosea root extract, often the SHR-5 preparation, at a few hundred milligrams a day. It is the plant extract, not sertraline.","detail":"Trials use a standardized rhizome extract for a few weeks in people with mild depression or stress complaints. Sertraline is a prescription drug used as a comparator in some files. A multivitamin that merely lists the plant is not the same exposure.","aliases":["Rhodiola rosea","SHR-5","golden root"],"unit":"mg/day extract","alsoSearch":["roseroot","rhodioloside"]},{"id":"risk-tolerance","slug":"risk-tolerance","name":"Economic risk tolerance","shortName":"Risk","layer":"psychology","summary":"Preference over lotteries, usually measured with Holt–Laury or similar choice lists.","detail":"Risk tolerance in the lab is not the same as 'lives dangerously'. Holt and Laury (2002) gave the field a replicable multiple-price list. Hormonal links to that list are mixed; income and gender composition of the sample matter more than most Twitter threads admit.","aliases":["risk aversion","lottery convexity"],"unit":"Holt–Laury switch point","alsoSearch":["prospect theory"]},{"id":"screen-time","slug":"screen-time","name":"Screen time","shortName":"Screens","layer":"lifestyle","summary":"Hours on a television, console, computer, or phone. Sitting as such and how bright the room is are different clocks.","detail":"People report minutes of media that use a screen. Television, consoles, computers, and phones all count. The object is the clock, not the show. Prolonged sitting is chair time. Evening light is spectrum at the eye.","aliases":["television time","digital media","smartphone use","video games"],"unit":"hours / day","alsoSearch":["television","video games","smartphone","digital media"]},{"id":"sedentary-time","slug":"sedentary-time","name":"Prolonged sitting","shortName":"Sitting","layer":"lifestyle","summary":"Hours of unbroken chair time. The object is sitting that is not interrupted, not a missing gym session.","detail":"Trials park people in a chair for a workday and compare that with the same chair plus a few minutes of walking or standing every half hour. That is not a training program. Aerobic minutes and lifting sessions are different work.","aliases":["uninterrupted sitting","sitting time","sedentary time","chair time"],"unit":"hours / day","alsoSearch":["sitting breaks","interrupt sitting","prolonged sitting"]},{"id":"shift-work","slug":"shift-work","name":"Night / rotating shift work","shortName":"Shift work","layer":"lifestyle","summary":"A work schedule that pushes sleep into the day: night shifts and rotating rosters. Hours in bed on a normal night schedule are a different clock.","detail":"The object is when the clock says you work. A lab can give night and day groups the same nine-hour sleep opportunity and still park night sleep between 8am and 5pm. Short sleep on the sleep page is hours in bed. Nurses, drivers, and volunteers on an assigned night roster count when the work clock moved.","aliases":["night shift","rotating shift","night work"],"unit":null,"alsoSearch":["night shift","rotating roster","circadian misalignment"]},{"id":"sleep-apnea","slug":"sleep-apnea","name":"Obstructive sleep apnea","shortName":"OSA","layer":"biology","summary":"Airway collapse in sleep that stops or shallows breathing. Hours in bed are a different clock.","detail":"The object is obstruction. A lab scores events per hour when it needs a number. A CPAP machine holds the airway open. That is a treatment of the obstruction, not a longer night. Sleep duration and regularity live on the sleep page. Apnoea and apnea are the same word.","aliases":["OSA","OSAS","OSAHS","obstructive sleep apnoea"],"unit":"AHI events / hour","alsoSearch":["CPAP","AHI","sleep-disordered breathing"]},{"id":"sleep-hygiene","slug":"sleep-hygiene","name":"Sleep duration and regularity","shortName":"Sleep","layer":"lifestyle","summary":"How long people sleep and how regular that schedule is. Restriction trials show hormones and insulin can move within a few short nights.","detail":"Partial sleep restriction raises evening cortisol, lowers next-day testosterone in men, and worsens insulin sensitivity within nights. Wearable trackers measure the same clock; they do not create the effect. Hours in bed are not the same as night-shift timing or an apnea count.","aliases":["sleep restriction","circadian"],"unit":"hours / night","alsoSearch":["insomnia"]},{"id":"smoking","slug":"smoking","name":"Cigarette smoking","shortName":"Smoking","layer":"lifestyle","summary":"Combusted tobacco, usually cigarettes. This page counts the habit, not a death certificate and not a lifestyle score.","detail":"People inhale nicotine and the rest of the smoke. Cho read urine cotinine for the last day and NNAL for the last weeks, so the count is not only a questionnaire. Eliasson split men who quit from men who kept smoking, then used a clamp. Nicotine gum and vaping are other products. Secondhand smoke was a covariate in Cho, not this habit.","aliases":["tobacco smoking","current smoking","cigarette use"],"unit":"cigarettes / day","alsoSearch":["cotinine","NNAL","pack-years","smoking cessation"]},{"id":"social-capital","slug":"social-capital","name":"Social capital","shortName":"Network","layer":"ses","summary":"Density and quality of a person's network. A status technology that is not hormonal.","detail":"Network position predicts job finding, mate meeting, and health. It is a classic omitted variable in supplement-and-success studies: people with rich networks both earn more and buy more wellness.","aliases":["network density","weak ties"],"unit":null,"alsoSearch":["Granovetter"]},{"id":"sociosexuality","slug":"sociosexuality","name":"Sociosexuality (SOI-R)","shortName":"SOI-R","layer":"psychology","summary":"Orientation toward uncommitted sex. Measured with Penke and Asendorpf's revised inventory.","detail":"SOI-R separates behavior, attitude, and desire. It is one of the few psychometrics in this atlas with a stable instrument. Hormonal and income correlates exist; they are not destiny and they are sex-differentiated in most samples.","aliases":["SOI","unrestricted mating"],"unit":"SOI-R score","alsoSearch":["mating strategy"]},{"id":"st-johns-wort","slug":"st-johns-wort","name":"St John's wort","shortName":"St John's wort","layer":"lifestyle","summary":"Hypericum perforatum extract, often LI-160 at 900 to 1,500 mg a day. It is the plant extract, not a prescription antidepressant.","detail":"Trials use a named extract such as LI-160 and score depression with Hamilton or similar scales. Sertraline is a prescription drug used as a comparator in some trials. A menopause tea or a multivitamin is a different product.","aliases":["Hypericum perforatum","hypericum","LI-160"],"unit":"mg/day extract","alsoSearch":["hypericin","St. John's wort"]},{"id":"status-seeking","slug":"status-seeking","name":"Status seeking","shortName":"Status","layer":"psychology","summary":"Motivation to gain or defend rank. Can be pursued via dominance or prestige.","detail":"Status seeking is the latent that dual-hormone papers try to predict. It is not aggression. Henrich and Gil-White split the strategy space: force versus freely conferred deference. Collapsing both into 'alpha' is a measurement error.","aliases":["dominance motivation","rank pursuit"],"unit":null,"alsoSearch":["hierarchy","ambition"]},{"id":"t-c-ratio","slug":"t-c-ratio","name":"Testosterone / cortisol ratio","shortName":"T/C","layer":"biology","summary":"Composite used as a proxy for dual-hormone status. A ratio is not a mechanism.","detail":"The T/C ratio appears in popular writing as if it were a single causal knob. It is a derived index. Any association can be driven by T, by cortisol, or by their interaction. Prefer reporting the interaction over the ratio unless the paper pre-registered the ratio.","aliases":["T:C","dual-hormone index"],"unit":"unitless ratio","alsoSearch":["dual-hormone"]},{"id":"tart-cherry","slug":"tart-cherry","name":"Tart cherry","shortName":"Tart cherry","layer":"lifestyle","summary":"Montmorency tart cherry juice or concentrate, often about 240 mL twice a day. It is the juice, not a melatonin tablet.","detail":"Trials use juice or concentrate for one to four weeks and watch sleep or recovery scores. The fruit carries melatonin and anthocyanins. A melatonin tablet or a cherry-plus-blueberry blend is a different product.","aliases":["Montmorency cherry","Prunus cerasus","tart cherry juice"],"unit":"mL/day juice","alsoSearch":["Montmorency","cherry juice","Prunus cerasus"]},{"id":"testosterone","slug":"testosterone","name":"Testosterone","shortName":"T","layer":"biology","summary":"Androgen produced by the HPG axis. Basal levels and acute contest reactivity are not the same construct.","detail":"Total and free testosterone are the most-cited hormones in status and risk folklore. Basal T is a slow trait-like signal; contest T is a minutes-to-hours state. Folk models collapse them into 'more T = more dominance'. The literature treats them separately, and often finds the state change more predictive than the trait.","aliases":["T","serum testosterone","androgen"],"unit":"nmol/L (total) or pg/mL (free)","alsoSearch":["free testosterone","SHBG","HPG axis"]},{"id":"traffic-noise","slug":"traffic-noise","name":"Nighttime transportation noise","shortName":"Traffic noise","layer":"lifestyle","summary":"Outdoor sound from roads, trains, and aircraft at the home, usually as night-time Lnight. Fine particles at the same address are a different reading.","detail":"The papers estimate A-weighted night levels outside the façade, or distance to a road, rail line, or airport contour. Road, rail, and aircraft are the usual sources. The number is sound. Fine particles at the same address are air, not noise.","aliases":["traffic noise","aircraft noise","railway noise","environmental noise"],"unit":"dB Lnight","alsoSearch":["Lnight","road traffic noise","highly sleep disturbed"]},{"id":"ultimatum-rejection","slug":"ultimatum-rejection","name":"Ultimatum rejection","shortName":"UG reject","layer":"psychology","summary":"Willingness to destroy surplus rather than accept an unfair split. A fairness-and-status task.","detail":"The ultimatum game is the workhorse of social neuroendocrinology. Rejection is not 'aggression' in any simple sense; it can be a status-maintenance move. Exogenous T results disagree across labs, sexes, and belief-about-treatment designs.","aliases":["ultimatum game","fairness punishment"],"unit":"rejection rate or minimum acceptable offer","alsoSearch":["bargaining"]},{"id":"ultraprocessed-food","slug":"ultraprocessed-food","name":"Ultra-processed food intake","shortName":"UPF","layer":"lifestyle","summary":"Diet quality marker. Tracks income, time poverty, and metabolic load.","detail":"UPF is both a cause of metabolic damage in feeding trials and a SES symptom. Using it as a moral explanation for other people's hormones skips the budget constraint.","aliases":["junk food","NOVA 4"],"unit":"% of energy","alsoSearch":["diet quality"]},{"id":"valerian","slug":"valerian","name":"Valerian","shortName":"Valerian","layer":"lifestyle","summary":"Valeriana officinalis root extract at a few hundred milligrams, sometimes twice a day. It is the named root, not a multi-herb sleep mix.","detail":"Trials use a concentrated root extract for a few weeks and usually score sleep with a questionnaire or a wrist monitor. A multivitamin or a blend that stacks several sleep herbs is a different product.","aliases":["Valeriana officinalis","valerian root"],"unit":"mg/day extract","alsoSearch":["valerenic acid","valerian extract"]},{"id":"vitamin-d","slug":"vitamin-d","name":"25-hydroxyvitamin D","shortName":"25(OH)D","layer":"biology","summary":"Circulating vitamin D status. Strongly confounded by time outdoors, latitude, adiposity, and wealth.","detail":"Observational catalogs link 25(OH)D to almost every chronic disease and to socioeconomic markers. Mendelian randomization and large RCTs (VITAL) have collapsed most of those claims. Correcting clinical deficiency is a medical act. Treating 25(OH)D as an economic or leadership lever is not supported.","aliases":["vitamin D","calcidiol"],"unit":"nmol/L or ng/mL","alsoSearch":["VDR","sunshine vitamin"]},{"id":"vitamin-supplementation","slug":"vitamin-supplementation","name":"Vitamin / mineral supplementation","shortName":"Vitamins","layer":"lifestyle","summary":"Multivitamins, B-complex, D pills. Purchasable health input.","detail":"Use is a marker of health-seeking and of disposable income. Causal effects on economic outcomes collapse after SES controls, except where a clinical deficiency is being corrected (B12, iron, 25(OH)D in the truly deficient).","aliases":["multivitamin","micronutrient pills"],"unit":null,"alsoSearch":["B12","folate"]},{"id":"wellbeing","slug":"wellbeing","name":"Wellbeing / quality of life","shortName":"Wellbeing","layer":"psychology","summary":"How a person rates daily function and life on a named scale such as IWQOL-Lite or SF-36. A depression score is a different object.","detail":"Obesity trials use the Impact of Weight on Quality of Life questionnaire and the SF-36 physical-functioning scale. Those scores track stairs, work, and self-consciousness about weight. They are not a diagnosis of depression and not a career score.","aliases":["quality of life","IWQOL","HRQOL","physical functioning"],"unit":"IWQOL-Lite-CT or SF-36 score","alsoSearch":["IWQOL-Lite-CT","SF-36","weight-related quality of life"]},{"id":"widowhood","slug":"widowhood","name":"Widowhood","shortName":"Widowhood","layer":"ses","summary":"The death of a spouse. Living alone, a thin network, and the feeling of loneliness are different measures.","detail":"Registries and surveys mark a person as widowed when their husband or wife has died. Elwert and Stahl count that event against people who were still married. Loneliness on this atlas is the felt gap. Social capital is network density. Job strain is a demand-control score. Living alone is a household. Widowhood is the marital event.","aliases":["bereavement","spousal death","widowed","conjugal bereavement"],"unit":null,"alsoSearch":["widowhood effect","spousal bereavement","widow","widower"]},{"id":"youth-fertility-preference","slug":"youth-fertility-preference","name":"Youth / fertility preference in partners","shortName":"Youth pref.","layer":"psychology","summary":"Stated or revealed preference for younger or higher-fertility-cue partners.","detail":"Cross-cultural inventories (Buss 1989) find a male-typical tilt toward youth cues. Speed-dating work shows the tilt is real in revealed choice but is moderated by the chooser's own market position and by the attribute set on the table.","aliases":["age preference","fertility cues"],"unit":null,"alsoSearch":["physical attractiveness"]},{"id":"zinc","slug":"zinc","name":"Zinc","shortName":"Zinc","layer":"lifestyle","summary":"A zinc salt, usually 15 to 45 mg a day. It is that salt, not a folate mix or a multivitamin.","detail":"Trials use zinc sulfate or a similar salt for three to six months. Zinc plus iron and copper in infants, or zinc plus another drug, is a different exposure from zinc alone.","aliases":["zinc sulfate","zinc acetate","zinc supplementation"],"unit":"mg/day","alsoSearch":["ZENITH","elemental zinc"]}],"edges":[{"id":"e-aerobic-insulin","sourceId":"aerobic-exercise","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Gray 2009: +3000 steps/d on 5 d/wk vs no change, n=24+24, 12 wk. Fasting glucose, insulin, inflammatory markers unchanged. Insulin sensitivity null."},"n":48,"summary":"In 48 Glasgow adults, a 12-week pedometer program that added about 3,000 steps a day on five days a week did not change fasting insulin or glucose against a no-change walking control.","mechanism":"Gray randomized 48 adults in Glasgow, mean age 49, to keep their usual walking or to add about 3,000 pedometer steps a day on five days a week. The intervention arm rose from 6,682 to 10,182 steps a day. The control arm stayed near 6,400. Blood at baseline and at 12 weeks was assayed for glucose, insulin, hsCRP, IL-6, soluble IL-6 receptor, TNF-alpha, and the two soluble TNF receptors.\n\nNone of those blood markers moved in either arm. The authors conclude that this community walking dose did not change insulin sensitivity or systemic inflammation.\n\nThe assigned object is walking. Fasting insulin and glucose are the inputs to HOMA-IR. The the record here abstract does not report a HOMA number. Gray did not set a heart-rate range. SMILE-style treadmill sessions are not this trial.","caveats":"Forty-eight people, 11 of them men. Twelve weeks. Community pedometers, not supervised sessions at 70 to 85 percent of heart-rate reserve. The abstract names 48 people.\n\nA null in a sample this size can be a true null for this dose or a miss. The authors report no change in any measured variable. They do not publish an effect size in the abstract.\n\nThis page is not lifting. Waters and Ho sit on the resistance-training edge. It is not unbroken sitting. Dempsey sits on that page. It is not a diet-plus-exercise kitchen sink.\n\nThis is not medical advice and not a walking prescription.","confounders":["sedentary-time","resistance-training","ultraprocessed-food","sleep-hygiene"],"paperIds":["p-pmid-19010347"],"contributions":[{"paperId":"p-pmid-19010347","evidenceGrade":"abstract_only","designNote":"Gray 2009 Prev Med. RCT. Community pedometer walking, Glasgow. Control n=24 (6 men) no change; intervention n=24 (5 men) +3000 steps/d on 5 d/wk, 12 weeks. Glucose, insulin, inflammatory markers unchanged. Insulin sensitivity null. abstract_only. Archive n null; 48 from abstract."}],"featured":false},{"id":"e-alcohol-cognition","sourceId":"alcohol-intake","targetId":"cognitive-performance","relation":"causal_genetic","direction":"forward","polarity":"null_effect","methodology":"mendelian_randomization","confidence":"contested","effect":{"metric":"odds_ratio","value":1,"note":"Campbell two-sample AD IVW OR 1.15 (0.78-1.72). Almeida ADH1B AA/GG OR 1.35 (0.29-6.27). Cui 2SLS drinking-on-MCI b=0.271 (N=235)."},"n":3542,"summary":"Almeida 2014 and Campbell 2024 find no Mendelian randomization effect of adult alcohol on cognitive impairment or Alzheimer disease; Cui 2022, with 235 genotyped rural Chinese adults, finds more drinking and more mild cognitive impairment.","mechanism":"Observational papers have long sold a J-curve: abstainers look worse than moderate drinkers, so a glass looks protective. Sick quitters, education, and who still drinks at 70 sit on that backdoor.\n\nResearchers use a genetic shortcut called Mendelian randomization. It is good at ruling out diet, income, and the decision to stop drinking. It can still be fooled when one gene affects two traits.\n\nAlmeida, Hankey, Yeap, Golledge, and Flicker (2014) used ADH1B rs1229984 in 3542 Australian men aged 65 to 83. The A allele slows ethanol oxidation and, in this sample, cut regular drinking. If alcohol caused later impairment, A carriers should have been safer. They were not. Six years later, 502 men (14.2%) scored 23 or less on the Mini-Mental State Examination. AA versus GG odds ratio 1.35 (95% CI 0.29 to 6.27); GA versus GG 1.05 (0.71 to 1.55). Abstainers and irregular drinkers still looked worse than regular drinkers after adjustment (OR 1.23, 1.00 to 1.51). That is the J-curve. The instrument does not walk it in.\n\nCampbell, Fu, MacDonald, Zawistowski, Bakulski, and Ware (2024) ran two-sample Mendelian randomization of weekly alcohol (Liu 2019, 941,280 people, 59 SNPs, median F 37.8) on late-onset Alzheimer disease (Kunkle 2019: 21,982 cases, 41,944 controls). Inverse-variance weighted odds ratio 1.15 (0.78 to 1.72). Egger, weighted median, and MR-PRESSO were also null. In the 2012 Health and Retirement Study, doubling weekly drinks was not associated with dementia or cognitively impaired, non-dementia once instruments were used. The raw European-ancestry correlation still looked protective (dementia OR 0.62, 0.51 to 0.73).\n\nCui, Si, Zhu, and Zhao (2022) used ALDH2 rs671 in 235 genotyped adults from rural China (mean age 49.7, 78% men, Mini-Cog). Ordinary least squares was null. Two-stage least squares was not: current drinking coefficient 0.271 (0.073 to 0.469) on the mild cognitive impairment indicator; first-stage F 34.88. That file is why confidence is contested.","caveats":"This page is adult alcohol intake and later cognition, mild cognitive impairment, or dementia. It is not prenatal alcohol and a child's school score. That exposure would need their own pages.\n\nAlmeida is older men in Perth, one SNP, no baseline Mini-Mental State Examination, and a healthier returner sample. The A allele is uncommon. The authors say they would need about 196,000 men to call a 35% rise significant. PubMed typed the paper as a randomized trial. The design is Mendelian randomization.\n\nCui genotyped 235 people. Mini-Cog is not a dementia workup. Drinking is the past 30 days. The model is linear on a yes/no outcome. Women drink little in that sample.\n\nCampbell's record here is a medRxiv preprint. The two-sample analysis is the stronger piece. African-ancestry instruments in the Health and Retirement Study were weak. European-ancestry 70-SNP scores were stronger (F 18.71). Mendelian randomization assumes no pleiotropy and a linear lifelong effect. It can miss a threshold in very heavy drinkers, and it does not test a night of intoxication.\n\nThis is not medical advice and not a recommendation to drink, to abstain, or to treat a score.","confounders":["education","sleep-hygiene","disposable-income"],"paperIds":["p-pmid-24553426","p-pmid-36079852","p-pmid-38196582"],"contributions":[{"paperId":"p-pmid-24553426","evidenceGrade":"full_text","designNote":"Almeida 2014. Health in Men Study. 3542 community men 65-83, Perth. ADH1B rs1229984. MMSE<=23 at 5.7y (502/14.2%). AA/GG OR 1.35 (0.29-6.27); GA/GG 1.05 (0.71-1.55). Observational abstainer/irregular vs regular OR 1.23 (1.00-1.51). Archive methodology rct; paper is Mendelian randomization. N from paper (Archive n null). full_text."},{"paperId":"p-pmid-36079852","evidenceGrade":"full_text","designNote":"Cui 2022. Rural China. 1966 surveyed, 235 genotyped (mean age 49.7, 78% men). ALDH2 rs671, Mini-Cog MCI (43%). OLS null. 2SLS drinking b=0.271 (0.073-0.469), F=34.88; frequency b=0.016; ethanol 100g/wk b=0.132. Archive methodology observational; paper is one-sample MR. N=235. full_text."},{"paperId":"p-pmid-38196582","evidenceGrade":"full_text","designNote":"Campbell 2024 medRxiv. Two-sample MR: Liu 2019 drinks/wk n=941280, 59 SNPs, median F 37.8; Kunkle 2019 AD 21982/41944. IVW OR 1.15 (0.78-1.72). One-sample HRS 2012: EA dementia OR 1.37 (0.53-3.51) n=7160; CIND 0.75 (0.47-1.22). Observational EA dementia OR 0.62. Archive methodology observational; paper is MR. full_text."}],"featured":false},{"id":"e-alcohol-cv","sourceId":"alcohol-intake","targetId":"cardiovascular","relation":"causal_genetic","direction":"forward","polarity":"positive","methodology":"mendelian_randomization","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.9,"note":"Holmes 2014: ADH1B A-allele (17% fewer units/week) CHD OR 0.90 (0.84-0.96). More genetically predicted alcohol, more CHD. Millwood stroke RR 1.27-1.58 per 280 g/week; MI null."},"n":261991,"summary":"Holmes 2014 found that a gene variant that cuts weekly drinking by 17 percent also cut the odds of coronary heart disease by 10 percent in 261,991 European adults (odds ratio 0.90, 0.84 to 0.96). Millwood 2019 found genetically predicted drinking raised stroke in Chinese men and left heart attack unmoved.","mechanism":"People who drink a little often look safer than people who drink nothing. Sick quitters, money, and smoking sit on that backdoor.\n\nResearchers use a genetic shortcut called Mendelian randomization. It is good at ruling out diet and income. It can still be fooled when one gene affects two traits.\n\nHolmes, Dale, Zuccolo and colleagues (2014) used ADH1B rs1229984 in 261,991 European adults from 56 studies (20,259 coronary cases, 10,164 strokes). The A-allele cut weekly units by 17.2 percent and cut coronary heart disease (odds ratio 0.90, 0.84 to 0.96). Combined stroke was null. Ischaemic stroke was 0.83 (0.72 to 0.95).\n\nMillwood, Walters, Mei and colleagues (2019) followed 512,715 adults in China for about ten years and genotyped 161,498 for ALDH2 rs671 and ADH1B rs1229984. Self-report was U-shaped. Genotype-predicted male intake was not. Per 280 g a week, haemorrhage relative risk was 1.58 (1.36 to 1.84) and ischaemic stroke 1.27 (1.13 to 1.43). Myocardial infarction was 0.96 (0.78 to 1.18). Women drank little and the same genes did not move events.\n\nLarsson, Burgess, Mason and Michaëlsson (2021) used up to 94 SNPs. Stroke odds per 1-SD log drinks were 1.27 (1.12 to 1.45). Peripheral artery disease was 3.05. Coronary disease was 1.16 (1.00 to 1.36). Smoking-adjusted estimates were weaker.\n\nRosoff, Davey Smith, Mehta, Clarke and Lohoff (2021) found univariable Mendelian randomization raised myocardial infarction (1.24) and coronary disease (1.21). A smoking adjustment attenuated both. They found no protection.\n\nLankester, Zanetti, Ingelsson and Assimes (2021) used ADH1B plus up to 24 SNPs in UK Biobank. An extra daily drink tracked higher pressure, haemorrhagic stroke (2.25, 1.41 to 3.60), and atrial fibrillation (1.26). A heart-attack signal did not hold after pressure. Two-sample work was mostly null. No analysis found protection.","caveats":"This page is adult alcohol intake and later coronary disease or stroke. It is not all-cause death. That pair is the alcohol-and-death page.\n\nHolmes is European and one SNP. Millwood is Chinese men who drink spirits. Women are the negative control. Larsson, Rosoff, and Lankester are mostly European summary statistics and UK Biobank.\n\nMendelian randomization assumes no pleiotropy. Alcohol instruments often travel with smoking. Rosoff's coronary signal shrank after a smoking adjustment. Lankester's heart-attack signal shrank after blood pressure. Millwood's heart-attack estimate is null. Combined stroke in Holmes was null.\n\nThe designs are Mendelian randomization, a genetic shortcut that can still be fooled when one gene affects two traits. N=261,991 is from Holmes.\n\nWood 2018 is an observational pool of current drinkers. Hoek 2022 and Goel 2019 are reviews. Ahmed 2024 is liver fat, not drinks. Hisamatsu 2022 is coronary calcium and a revascularization case-control in Japanese men, not incident events. Bouajila 2024 is a review. Those files stay off this page.\n\nThis is not medical advice and not a recommendation to drink, to abstain, or to treat a number.","confounders":["education","disposable-income","sleep-hygiene","sedentary-time","ultraprocessed-food"],"paperIds":["p-pmid-25011450","p-pmid-30955975","p-pmid-32367730","p-pmid-33275596","p-pmid-34379647"],"contributions":[{"paperId":"p-pmid-25011450","evidenceGrade":"full_text","designNote":"Holmes 2014 BMJ. Identifying IPD MR, 56 studies, 261991 European, ADH1B rs1229984. 20259 CHD, 10164 stroke. A-allele -17.2% units/week; CHD OR 0.90 (0.84-0.96); ischaemic stroke 0.83 (0.72-0.95); combined stroke null. Archive methodology meta_analysis; paper is MR. N from paper (Archive n null). full_text."},{"paperId":"p-pmid-30955975","evidenceGrade":"full_text","designNote":"Millwood 2019 Lancet. CKB 512715, 161498 genotyped ALDH2-rs671 + ADH1B-rs1229984. Genetic male intake per 280 g/week: ICH RR 1.58 (1.36-1.84), ischaemic stroke 1.27 (1.13-1.43), MI 0.96 (0.78-1.18). Women null control. Archive observational; paper is MR. full_text."},{"paperId":"p-pmid-32367730","evidenceGrade":"full_text","designNote":"Larsson 2021 Circ Genom Precis Med. Two-sample MR, up to 94 SNPs. IVW per 1-SD log drinks/week: stroke OR 1.27 (1.12-1.45), PAD 3.05 (1.92-4.85), CAD 1.16 (1.00-1.36). MVMR smoking attenuated. Archive observational; paper is MR. full_text."},{"paperId":"p-pmid-33275596","evidenceGrade":"full_text","designNote":"Rosoff 2021 PLoS Med. SVMR+MVMR, >1.2M GWAS. Alcohol SVMR MI OR 1.24 (1.03-1.50), CHD 1.21 (1.01-1.45); both attenuated after smoking. No cardioprotection. Archive observational; paper is MR. full_text."},{"paperId":"p-pmid-34379647","evidenceGrade":"full_text","designNote":"Lankester 2021 PLoS One. UKB MR, ADH1B + up to 24 SNPs. Per extra drink/day: SBP +2.65 mmHg, haemorrhagic stroke OR 2.25 (1.41-3.60), AF 1.26 (1.07-1.48). MI not held in MVMR. Two-sample mostly null. Archive observational; paper is MR. full_text."}],"featured":false},{"id":"e-alcohol-depression","sourceId":"alcohol-intake","targetId":"depression","relation":"causal_genetic","direction":"forward","polarity":"context_dependent","methodology":"mendelian_randomization","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Wium-Andersen ADH OR 1.11 (0.67-1.83) antidepressants; 4.52 (0.99-20.5) depression hosp/death. Qiu beer IVW OR 1.28, spirits 3.84, MVMR ns. Zhu 2SLS drinker b=-0.127 (n=476)."},"n":68486,"summary":"Three Mendelian randomization files of alcohol on depression disagree: two ADH variants in 68,486 Copenhagen adults are null for antidepressant use, UK Biobank beer and spirits instruments raise major depression until insomnia and smoking enter the model, and ALDH2 plus ADH1B in 476 Chinese adults point the other way.","mechanism":"Observational papers have long sold a J-curve: people who drink a little look less depressed than people who drink nothing, so a glass looks protective. Sick quitters, money, sleep, and who still drinks sit on that backdoor.\n\nResearchers use a genetic shortcut called Mendelian randomization. It is good at ruling out diet, income, and the decision to stop drinking. It can still be fooled when one gene affects two traits.\n\nWium-Andersen, Orsted, Tolstrup, and Nordestgaard genotyped 68,486 Copenhagen adults aged 20 to 100 on ADH1B rs1229984 and ADH1C rs698. The combined genotype raised drinks per day. For hospitalization or death with alcoholism, the causal odds ratio for one extra drink a day was 28.6 (6.47 to 126). That is a different pair. For prescription antidepressants the causal odds ratio was 1.11 (0.67 to 1.83). For hospitalization or death with depression it was 4.52 (0.99 to 20.5). The authors do not claim similar evidence for depression.\n\nZhu, Chen, Si, Li, Chen, and Zhao used ALDH2 rs671 and ADH1B rs1229984 in 476 adults from fifty villages in seven Chinese provinces (mean age 49.4, 74 percent men). Depression was a CESD-10 of 12 or more (9 percent). Two-stage least squares found less depression with more drinking: drinker versus not, b = -0.127 (-0.253 to -0.001), first-stage F 44.5. Occasions in 30 days and grams a week were also negative. Sargan tests did not reject. Cutting heavy or former drinkers did not flip the sign.\n\nQiu, Song, Cao, Tian, Cheng, Sun, Cai, and Wang ran two-sample Mendelian randomization of UK Biobank beverage intake on a major-depression GWAS of 59,851 cases and 113,154 controls. Inverse-variance weighted odds ratios were 1.284 (1.026 to 1.608) for beer and 3.837 (1.993 to 7.387) for spirits. Red wine and white wine were null. When insomnia, smoking, and contraceptive use entered a multivariable model, beer and spirits were no longer independent. Reverse Mendelian randomization did not find major depression moving beer or spirits.","caveats":"This page is adult alcohol intake and later depression or major depressive disorder. It is not alcoholism. Wium-Andersen's strong causal file is hospitalization or death with alcoholism. That pair is not published here.\n\nWium-Andersen used two ADH variants in Copenhagen. The depression hospitalization interval includes 1. Antidepressant use is a prescription, not a structured interview. The paper is Mendelian randomization and is available here only as an abstract.\n\nZhu genotyped 476 people. CESD-10 with a cut of 12 is a screen, not a clinic diagnosis. Women drink little in that sample. The authors name stress relief as a candidate path. That path is not measured. A flushing-response check (n=2,216) was not genotyped.\n\nQiu's alcohol finding is univariable and beverage-specific. The threshold was p below 5 times 10 to the minus 6, not 5 times 10 to the minus 8. Beer and spirits lost the multivariable test. Cheese is a different pair and is not on this page. The European two-sample files do not travel to East Asian ALDH2. Provincial beer and spirit sales against a depression yearbook are not Mendelian randomization.\n\nQiu and Zhu are Mendelian randomization. Sample sizes are taken from the papers. N=68,486, N=476, and the 173,005-person depression GWAS are from the papers.\n\nThis is not medical advice and not a recommendation to drink, to abstain, or to treat a score.","confounders":["education","sleep-hygiene","disposable-income"],"paperIds":["p-pmid-25433705","p-pmid-33193720","p-pmid-39562730"],"contributions":[{"paperId":"p-pmid-25433705","evidenceGrade":"abstract_only","designNote":"Wium-Andersen 2015 IJE. One-sample MR, Copenhagen general pop n=78154, 68486 genotyped, 20-100y. ADH1B rs1229984 + ADH1C rs698. Depression: antidepressant causal OR 1.11 (0.67-1.83); hosp/death 4.52 (0.99-20.5). Alcoholism causal OR 28.6 (not this pair). Archive methodology observational; paper is MR. N from paper (Archive n null). abstract_only."},{"paperId":"p-pmid-33193720","evidenceGrade":"full_text","designNote":"Zhu 2020 Front Genet. One-sample MR, 476 adults, 7 Chinese provinces, mean age 49.4, 74% men. ALDH2 rs671 + ADH1B rs1229984. CESD-10>=12 (9%). 2SLS drinker b=-0.127 (-0.253 to -0.001), F=44.5; occasions b=-0.012, F=28.7; g/wk b=-0.001, F=18.1. Archive methodology observational; paper is MR. N=476. full_text."},{"paperId":"p-pmid-39562730","evidenceGrade":"full_text","designNote":"Qiu 2024 Sci Rep. Two-sample MR. UKB beverage IVs (p<5e-6); MDD IEU 59851/113154. Beer IVW OR 1.284 (1.026-1.608); spirits 3.837 (1.993-7.387); wine ns. MVMR (insomnia, smoking, contraceptives): beer/spirits ns; cheese independent. Reverse MR null. Archive methodology observational; paper is MR. full_text."}],"featured":false},{"id":"e-alcohol-mortality","sourceId":"alcohol-intake","targetId":"mortality","relation":"causal_genetic","direction":"forward","polarity":"positive","methodology":"mendelian_randomization","confidence":"moderate","effect":{"metric":"odds_ratio","value":1.27,"note":"Kassaw 2024: OR 1.27 (1.16-1.39) all-cause death per +8 g/day genetically predicted alcohol. Linear; P for nonlinearity 0.21 or higher. Observational J-curve in the same sample."},"n":278093,"summary":"Kassaw 2024 found a linear Mendelian randomization rise in all-cause death with genetically predicted alcohol in 278,093 white-British UK Biobank adults: odds ratio 1.27 (1.16 to 1.39) per extra 8 grams a day.","mechanism":"Observational papers have long sold a J-curve: people who drink a little look safer than people who drink nothing, so a glass looks protective. Sick quitters, smoking, money, and who is still alive to join a cohort sit on that backdoor.\n\nResearchers use a genetic shortcut called Mendelian randomization. It is good at ruling out diet, income, and the decision to stop drinking. It can still be fooled when one gene affects two traits.\n\nKassaw, Zhou, Mulugeta, Lee, Burgess, and Hyppönen (2024) instrumented habitual grams per day with 94 SNPs from Liu's alcohol GWAS, keeping those that pointed the same way in UK Biobank. The sample was 278,093 unrelated white-British adults aged 37 to 73. Death came from NHS registers through 12 November 2021: 20,834 deaths, median 12.6 years.\n\nLinear Mendelian randomization used a genetic risk score and five summary methods (inverse-variance weighted, Egger, weighted median, weighted mode, MR-PRESSO). Nonlinear Mendelian randomization used the doubly-ranked method in 25 strata, because the gene-to-intake link is stronger where people already drink more.\n\nReported intake against death was J-shaped. Genetically predicted intake was not. Each extra 8 grams a day (one UK unit) raised all-cause death (odds ratio 1.27, 1.16 to 1.39), cardiovascular death (1.30, 1.10 to 1.53), cancer death (1.20, 1.08 to 1.33), and digestive death (2.06, 1.36 to 3.12). Respiratory and COVID-19 death were imprecise. Tests for curvature did not reject a straight line (P of 0.21 or higher on every outcome). Cutting the follow-up before the pandemic did not change the all-cause result.","caveats":"This page is adult alcohol intake and later death from any cause. It is not a heart attack someone survived, not prostate cancer, and not colorectal methylation.\n\nThe sample is white-British UK Biobank. A 5 percent volunteer cohort is healthier than the country. Intake is self-report. The genetic score still associated with smoking and Townsend deprivation; adjusting for both did not move the estimates. Mendelian randomization assumes no pleiotropy and a lifelong linear effect. It can miss a binge, a decade of abstinence, or a threshold in very heavy drinkers.\n\nAn earlier nonlinear Mendelian randomization of alcohol and cardiovascular disease reported a curve, including for all-cause death. Kassaw argues that method assumed a constant gene-to-intake link, which fails here. We take their linear genetic file, not the observational J-curve.\n\nThe design is Mendelian randomization.\n\nHolmes 2014 and Millwood 2019 are vascular events, not all-cause death. Wood 2018 is an observational pool of current drinkers. Those files stay off this page.\n\nThis is not medical advice and not a recommendation to drink, to abstain, or to treat a number.","confounders":["education","disposable-income","sleep-hygiene"],"paperIds":["p-pmid-38508868"],"contributions":[{"paperId":"p-pmid-38508868","evidenceGrade":"full_text","designNote":"Kassaw 2024 IJE. One-sample MR, 278093 white-British UKB, 37-73y. 94 SNPs (Liu 2019). 20834 deaths, median 12.6y. Linear GRS + IVW/Egger/W-median/W-mode/PRESSO. Nonlinear doubly-ranked, 25 strata. All-cause OR 1.27 (1.16-1.39) per 8 g/day; no curvature (P>=0.21). Archive methodology observational; paper is MR. N from paper (Archive n null). full_text."}],"featured":false},{"id":"e-alcohol-sleep","sourceId":"alcohol-intake","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"review","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"One 1.0 g/kg night (0.85 in women) cut TST from 436.6 to 421.3 min and efficiency from 91.2 to 88.0%. REM down, N2 and nocturnal HR up."},"n":null,"summary":"Evening alcohol, 1.0 grams per kilogram in men and 0.85 in women, cut total sleep time from 436.6 to 421.3 minutes and sleep efficiency from 91.2 to 88.0 percent in thirty-one social drinkers on a randomized crossover with overnight PSG.","mechanism":"Pabon, Greenlund, Carter, and de Wit ran a randomized crossover in thirty-one social drinkers, fifteen men and sixteen women, mean age 25. Each person drank alcohol (1.0 g/kg in men, 0.85 in women) or a juice placebo from 8 to 9 pm, a month apart, then slept under PSG from 11 pm to 7 am. Peak breath alcohol was 0.10 percent.\n\nOn alcohol nights, total sleep time was 421.3 minutes against 436.6 on placebo. Sleep efficiency was 88.0 percent against 91.2. REM was 16.5 percent of the night against 20.0. N2 was 54.2 percent against 51.4. Mean nocturnal heart rate was 65.0 against 56.4. Sleep latency, arousals, awakenings, N1, and N3 did not move.\n\nThe drink felt like a sedative. The record was shorter sleep, less REM, more light N2, and a faster heart. Evening sedation tracked the extra N2 (r = 0.5). Those sleep and heart-rate shifts did not track mood or task scores the next morning.\n\nEmanuele and Emanuele reviewed heavy drinking and the male reproductive axis. That paper is here because alcohol is the lifestyle exposure that comes before sleep, not because it recorded a night of PSG. Spiegel, Leproult, and Van Cauter restricted sleep in eleven young men. Evening cortisol rose and glucose tolerance fell. That protocol is the downstream sleep night, not an alcohol-plus-PSG night.","caveats":"Pabon is one high dose on one laboratory night. The sample is thirty-one social drinkers around age 25 who reported a binge in the past six months and no alcohol-use disorder. Women were not on hormonal contraceptives. The authors combined sexes. The lab was quiet. Latency and awakenings did not change. Morning mood shifts were modest. Digit span was better the next morning, which the authors did not treat as a settled benefit.\n\nEmanuele 2001 is a review of the male HPG axis, not a sleep trial. Spiegel 1999 is a restriction protocol in eleven men, not alcohol plus PSG. Heart rate rose on the Pabon night; it is not the target of this edge. These minutes are one trial, not a dose curve for a glass of wine.","confounders":[],"paperIds":["p-emanuele-2001","p-spiegel-1999","p-pmid-35953878"],"contributions":[{"paperId":"p-emanuele-2001","evidenceGrade":"abstract_only","designNote":"Gold review of alcohol and the male HPG axis. Keep p-emanuele-2001. Copy previous.methodology review. Not a PSG trial. abstract_only. Stamp stays causal_direct."},{"paperId":"p-spiegel-1999","evidenceGrade":"abstract_only","designNote":"Sleep-restriction RCT, N=11 men, Lancet. Downstream endocrine protocol, not alcohol-plus-PSG. Keep p-spiegel-1999. abstract_only."},{"paperId":"p-pmid-35953878","evidenceGrade":"full_text","designNote":"RCT, randomized crossover. N=31 social drinkers (15 men, 16 women), mean age 25.3. 1.0 g/kg men, 0.85 g/kg women, 8 to 9 pm, PSG 11 pm to 7 am. TST 436.6 to 421.3 min; efficiency 91.2 to 88.0%; REM 20.0 to 16.5%; N2 51.4 to 54.2%; nocturnal HR 56.4 to 65.0. Archive n:null; N from Table 1. full_text."}],"featured":false},{"id":"e-alcohol-testosterone","sourceId":"alcohol-intake","targetId":"testosterone","relation":"causal_direct","direction":"forward","polarity":"non_linear","methodology":"review","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Heavy chronic use suppresses male T. 0.5 g/kg raised T in 13 men. 40 g/day for 3 weeks lowered it 6.8% in 10 men. Light social use is a different exposure."},"n":null,"summary":"Heavy chronic drinking suppresses male testosterone. A 0.5 g/kg drink raised plasma T in thirteen men. Three weeks of 40 grams a day lowered it 6.8 percent in ten men on a controlled diet. A glass of wine is not a T protocol in reverse.","mechanism":"Emanuele and Emanuele review suppression of GnRH, LH, and testicular testosterone under chronic heavy drinking. In men, that chronic direction is down.\n\nSarkola and Eriksson gave thirteen men 0.5 g/kg alcohol, 10 percent by weight, in a double-blind placebo-controlled crossover. Plasma testosterone rose from 13.5 to 16.0 nmol/L. Androstenedione fell. The testosterone-to-androstenedione ratio rose. A 4-methylpyrazole pretreat, which slowed ethanol clearance by about 37 percent, blocked those shifts. They tie the rise to a change in liver redox state.\n\nSierksma, Sarkola, Eriksson and colleagues ran a diet-controlled crossover in ten middle-aged men and nine postmenopausal women. Dinner was beer or no-alcohol beer for three weeks each. Men received 40 grams of alcohol a day, women 30. Morning fasting testosterone fell 6.8 percent in the men and did not move in the women. Estradiol did not move. DHEA-S rose 16.5 percent; that hormone is not this target.\n\nSarkola, Adlercreutz, Heinonen, and Eriksson studied nine premenopausal women using oral contraceptives. After a week at 0.8 g/kg a day, the acute testosterone rise was still there. Afternoon samples, taken when the women were not intoxicated, showed higher testosterone and androstenedione on alcohol than on placebo. Morning samples did not. They point to hypothalamic-pituitary-adrenal function and to how the liver handles these steroids.","caveats":"The lead paper is a review, not a new trial. The new papers are small crossovers, read from abstracts. Sarkola 2003 is thirteen men and one low dose. Sarkola 2001 is nine women on the pill. Sierksma is ten men and nine postmenopausal women, three weeks, one morning fasting draw.\n\nA 0.5 g/kg rise does not cancel the heavy-use review. Do not cite this edge against a glass of wine without the dose. Sex, binge versus daily, oral contraceptives, and liver disease all matter. Sleep sits on the path. Extra papers do not raise the stamp.","confounders":["sleep-hygiene"],"paperIds":["p-emanuele-2001","p-pmid-12711931","p-pmid-15166654","p-pmid-11566440"],"contributions":[{"paperId":"p-emanuele-2001","evidenceGrade":"abstract_only","designNote":"Gold review. Chronic heavy alcohol suppresses male HPG and T. Keep p-emanuele-2001. Copy previous.methodology review. Do not change methodology to rct. abstract_only. Stamp stays causal_direct."},{"paperId":"p-pmid-12711931","evidenceGrade":"abstract_only","designNote":"RCT, double-blind placebo-controlled crossover. N=13 men. 0.5 g/kg (10% w/v). Plasma T 13.5 to 16.0 nmol/L. Blocked by 4-methylpyrazole. Archive n:null; do not copy. abstract_only. Hang and name the dose. Does not rewrite the heavy-use arrow."},{"paperId":"p-pmid-15166654","evidenceGrade":"abstract_only","designNote":"RCT, randomized diet-controlled crossover. 10 middle-aged men, 9 postmenopausal women. Beer vs no-alcohol beer, 3 weeks. 40 g/day men, 30 g/day women. T fell 6.8% in men; no T effect in women. DHEAS +16.5% is not this target. Archive n:null; N from abstract. abstract_only."},{"paperId":"p-pmid-11566440","evidenceGrade":"abstract_only","designNote":"Placebo-controlled interventional crossover. N=9 premenopausal OC users. 0.8 g/kg/day for 1 week. Acute T elevation; no tolerance. Afternoon T and androstenedione up when not intoxicated. T/androgen is a measured outcome. Archive n:null; do not copy. abstract_only."}],"featured":false},{"id":"e-ashwagandha-cortisol","sourceId":"ashwagandha","targetId":"cortisol","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"percent_change","value":-22.2,"note":"Choudhary 2017: 300 mg BID KSM-66, 8 wk, N=52 (25/25). Serum cortisol 17.25 to 13.41 vs 16.76 to 15.44 μg/dL (P=0.0132). Change -3.83 vs -1.32, P=0.0019. Secondary endpoint."},"n":52,"summary":"Choudhary 2017 found that 300 mg of ashwagandha root extract twice a day for eight weeks lowered morning serum cortisol versus placebo in 52 overweight adults under chronic stress (13.41 versus 15.44 μg per deciliter at week 8, P=0.0132). Cortisol was a secondary endpoint in a weight-and-craving trial.","mechanism":"The authors treat a withanolide extract as an HPA brake. They think a lower serum cortisol number is why food craving and weight moved. This page is the hormone, not the scale.\n\nChoudhary, Bhattacharyya and Joshi (2017) assigned 52 Pune adults, PSS of 20 or more, BMI 25 to 39.9, to 300 mg of KSM-66 (5 percent withanolides) twice a day or matching placebo for eight weeks. Primary endpoints were Perceived Stress Scale and the Food Cravings Questionnaire. Serum cortisol was secondary. Baseline cortisol was 17.25 versus 16.76 μg per deciliter. At week 8 it was 13.41 versus 15.44 (P=0.0132). The change was -3.83 versus -1.32 (P=0.0019), a 22.2 percent drop from baseline on the extract. Tables use 25 people a side.","caveats":"Researchers assigned people to an extract or a control, so this is a trial stamp. Cortisol was not the primary. More papers of the same design do not settle the claim.\n\nThis is a KSM-66 weight-management trial in people already stressed and overweight. A single serum cortisol is not a diurnal curve and not a CAR. The primary objects were a stress questionnaire and food craving.\n\nThis page is not the sleep pair and not a reason to treat a cortisol number.\n\nThis is a journal entry, not medical advice.","confounders":["sleep-hygiene","job-strain","aerobic-exercise"],"paperIds":["p-pmid-27055824"],"contributions":[{"paperId":"p-pmid-27055824","evidenceGrade":"full_text","designNote":"Choudhary 2017 J Evid Based Complementary Altern Med. RCT. 300 mg BID KSM-66 vs placebo, 8 wk, N=52 chronic stress, BMI 25-39.9. Cortisol secondary. Week 8 13.41 vs 15.44 μg/dL P=0.0132. Change -3.83 vs -1.32 P=0.0019. full_text. Archive n null."}],"featured":false},{"id":"e-ashwagandha-sleep","sourceId":"ashwagandha","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Deshpande 2021: 120 mg Shoden 6 wk, N=150/144. Self-report sleep quality +72% vs +29%, P<0.001. Actigraphy SE/TST/SOL/WASO moved. Langade 2021: N=80 healthy+insomnia, 8 wk. SOL and efficiency moved more in insomnia."},"n":150,"summary":"Deshpande 2021 found that 120 mg a day of a standardized ashwagandha extract for six weeks raised self-reported restorative sleep by 72 percent versus 29 percent on placebo among 150 adults with non-restorative sleep, and actigraphy moved efficiency, total sleep, latency, and wake after sleep onset. Langade 2021 found a similar direction in 80 people, stronger in the insomnia arm.","mechanism":"Authors treat a withanolide extract as something that shortens sleep latency and lengthens time asleep. They do not isolate one receptor.\n\nDeshpande, Irani, Balkrishnan and Benny (2021) assigned 150 healthy adults with high non-restorative-sleep scores to 120 mg a day of Shoden ashwagandha or placebo for six weeks. 144 finished. Self-reported sleep quality rose 72 percent on the extract and 29 percent on placebo (P<0.001). Wrist actigraphy favored the extract on sleep efficiency (P<0.01), total sleep time (P<0.001), sleep latency (P<0.01), and wake after sleep onset (P<0.05). The abstract does not publish the minute counts.\n\nLangade, Thakare, Kanchi and Kelgane (2021) assigned 80 people, 40 healthy and 40 with insomnia, to ashwagandha root extract or placebo for eight weeks. Sleep-onset latency, efficiency, total sleep time, and wake after sleep onset moved in both strata and more in the insomnia arm. Repeat-measure ANOVA in insomnia: sleep-onset latency P=0.013. Two-way ANOVA: latency and efficiency P<0.0001. The abstract does not publish the dose in milligrams.","caveats":"Researchers assigned people to a branded extract or placebo, so this is a trial stamp. Both files are short. Extra papers do not settle the claim.\n\nDeshpande's 72 versus 29 percent is a self-report rise, not a 72 percent longer night. Actigraphy moved, but the published abstract does not name the minute changes. The extract is a manufacturer's Shoden product.\n\nLangade mixes healthy sleepers and insomnia. The insomnia slice is forty people. The published abstract does not name the dose.\n\nThis is a journal entry, not medical advice and not a reason to take a root for insomnia.","confounders":["caffeine","alcohol-intake","light-exposure","aerobic-exercise"],"paperIds":["p-pmid-32540634","p-pmid-32818573"],"contributions":[{"paperId":"p-pmid-32540634","evidenceGrade":"abstract_only","designNote":"Deshpande 2021 Sleep Med. RCT. 120 mg/d Shoden vs placebo, 6 wk, N=150 high NRS (144 completers). Self-report quality +72% vs +29% P<0.001. Actigraphy SE P<0.01, TST P<0.001, SOL P<0.01, WASO P<0.05. No minute increments in abstract. abstract_only. Archive n null."},{"paperId":"p-pmid-32818573","evidenceGrade":"abstract_only","designNote":"Langade 2021 J Ethnopharmacol. RCT. Root extract vs placebo, 8 wk, N=80 (40 healthy, 40 insomnia). SOL, SE, TST, WASO moved, more in insomnia. Insomnia SOL P=0.013. Dose not in Archive abstract. abstract_only. Archive n null."}],"featured":false},{"id":"e-ashwagandha-t","sourceId":"ashwagandha","targetId":"testosterone","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Smith 2023: Witholytin 200 mg BID, 12 wk, overweight men and women 40-75. Free T and LH vs placebo in men P=0.048 and 0.002. Primary PSS vs placebo P=0.867. Archive n null."},"n":null,"summary":"Smith 2023 found that 200 mg of Witholytin ashwagandha root extract twice a day for twelve weeks raised free testosterone and luteinizing hormone versus placebo in the men of a trial of overweight adults aged 40 to 75 (P=0.048 and 0.002). The primary stress score did not beat placebo.","mechanism":"Authors treat an ashwagandha root extract as a stress herb that might also move sex hormones. They do not isolate one withanolide.\n\nSmith, Lopresti and Fairchild assigned overweight or mildly obese men and women aged 40 to 75 to 200 mg of Witholytin twice a day or placebo for twelve weeks. Perceived stress fell on both arms and did not differ (P=0.867). Fatigue and heart-rate variability favored ashwagandha. In the men, free testosterone (P=0.048) and luteinizing hormone (P=0.002) rose versus placebo. The abstract does not publish the nanogram increment or the number of men.","caveats":"Researchers assigned people to a root extract or a control, so this is a trial stamp. Testosterone is a secondary slice in the men. More papers of the same design do not settle the claim.\n\nThe primary stress contrast missed. The published abstract does not name a sample size. This is not a lifting stack.\n\nThis is a journal entry, not medical advice and not a reason to take ashwagandha to raise testosterone.","confounders":["sleep-hygiene","alcohol-intake","resistance-training"],"paperIds":["p-pmid-37740662"],"contributions":[{"paperId":"p-pmid-37740662","evidenceGrade":"full_text","designNote":"Smith 2023 J Psychopharmacol. RCT. Witholytin 200 mg BID vs placebo, 12 wk, overweight 40-75. Men: free T P=0.048, LH P=0.002. Primary PSS vs placebo P=0.867. No N in abstract. full_text. Archive n null."}],"featured":false},{"id":"e-bacopa-cognition","sourceId":"bacopa","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Calabrese 2009: 300 mg, 12 wk, 48/54 elderly, AVLT delayed recall vs placebo. Delfan 2024: N=62 MCI, overall MoCA at 2 mo P=0.029. Lopresti 2025: 87/101, primary learning/attention/WM ns."},"n":48,"summary":"Calabrese 2009 found that 300 mg of standardized Bacopa monnieri a day for twelve weeks improved delayed word recall on the Rey Auditory Verbal Learning Test versus placebo in 48 healthy adults aged 65 or older. Lopresti 2025 saw no between-group change on primary learning, attention, or working memory in 87 completers aged 40 to 70.","mechanism":"Authors treat a bacopa extract as a memory aid. They do not isolate one bacoside.\n\nCalabrese, Gregory, Leo and colleagues assigned 54 adults 65 or older without dementia to 300 mg a day or placebo for twelve weeks after a six-week placebo run-in. 48 finished. Delayed recall on the Rey list favored bacopa after a baseline-cognition adjustment. Stroop also moved. Divided attention and a digit task did not.\n\nDelfan, Kordestani-Moghaddam, Gholami and colleagues assigned 62 people with mild cognitive impairment to 160 mg a day or starch for two months. Overall Montreal Cognitive Assessment missed at one month and hit at two (P=0.029). Attention and verbal fluency moved. Sleep did not.\n\nLopresti and Smith assigned 101 adults aged 40 to 70 with self-reported memory complaints to 300 mg of Bacumen or placebo for twelve weeks. 87 finished. Verbal learning, attention, and working memory did not differ (P=0.391, 0.713, 0.610). Stress after a demanding task did.","caveats":"Researchers assigned people to an extract or a control, so this is a trial stamp. Task and age split. More papers of the same design do not settle the claim.\n\nCalabrese is 48 older adults without dementia. Delfan is mild cognitive impairment and a late overall score. Lopresti is the largest file here and missed its three primary tasks.\n\nThis is a journal entry, not medical advice and not a reason to take bacopa for memory.","confounders":["sleep-hygiene","caffeine","alcohol-intake"],"paperIds":["p-pmid-18611150","p-pmid-38538390","p-pmid-41091332"],"contributions":[{"paperId":"p-pmid-18611150","evidenceGrade":"full_text","designNote":"Calabrese 2009 J Altern Complement Med. RCT. 300 mg vs placebo, 12 wk after 6-wk run-in, 48/54 age>=65 no dementia. AVLT delayed recall vs placebo. Stroop moved. DAT/digit ns. full_text. Archive n null."},{"paperId":"p-pmid-38538390","evidenceGrade":"abstract_only","designNote":"Delfan 2024 Explore. RCT. 160 mg vs starch, 2 mo, N=62 MCI. MoCA overall ns at 1 mo, P=0.029 at 2 mo. Attention/fluency moved. Sleep ns. abstract_only. Archive n null."},{"paperId":"p-pmid-41091332","evidenceGrade":"abstract_only","designNote":"Lopresti 2025 Clin Drug Investig. RCT. Bacumen 300 mg vs placebo, 12 wk, 87/101 age 40-70. Primary learning/attention/WM ns. Stress after demand moved. abstract_only. Archive n null."}],"featured":false},{"id":"e-berberine-insulin","sourceId":"berberine","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Perez-Rubio 2014: 500 mg TID, 3 mo, N=24 MetS, Matsuda 2.1 to 3.1. Zhang 2008: 1.0 g/d, 3 mo, N=116 T2D, clamp vs placebo P=0.063. Ruiz-Herrera 2023: HIV MetS pilot, N=36."},"n":24,"summary":"Perez-Rubio 2014 found that 500 mg of berberine three times a day for three months raised the Matsuda insulin-sensitivity index from 2.1 to 3.1 versus placebo in 24 people with metabolic syndrome. Zhang 2008 lowered glucose versus placebo in 116 people with type 2 diabetes; the clamp contrast missed.","mechanism":"Authors treat berberine as an oral glucose-lowering alkaloid. They do not isolate one receptor.\n\nPerez-Rubio, Gonzalez-Ortiz, Martinez-Abundis and colleagues assigned 24 people with metabolic syndrome to 500 mg of berberine hydrochloride or placebo three times a day for three months. The Matsuda index rose from 2.1 to 3.1 (P<0.01). Glucose and insulin areas under the curve fell. Metabolic syndrome remitted in 36 percent (P=0.037).\n\nZhang, Li, Zou and colleagues assigned 116 people with type 2 diabetes and dyslipidemia to 1.0 g of berberine a day or placebo for three months. Fasting and post-load glucose and HbA1c fell versus placebo (P<0.0001). Glucose disposal on a clamp rose after berberine (P=0.037) but not versus placebo (P=0.063).\n\nRuiz-Herrera, Navarro-Lara, Andrade-Villanueva and colleagues assigned 43 adults with HIV, viral suppression, and metabolic syndrome to 500 mg three times a day or placebo for 20 weeks. 36 were analyzed. Weight, body-mass index, and insulin resistance fell.","caveats":"Researchers assigned people to berberine or a control, so this is a trial stamp. The insulin-sensitivity files are small. More papers of the same design do not settle the claim.\n\nPerez-Rubio is 24 people. Zhang's clamp missed versus placebo; the published win is glucose and lipids. Ruiz-Herrera is an HIV pilot.\n\nThis is a journal entry, not medical advice and not a reason to take berberine for insulin resistance.","confounders":["sedentary-time","sleep-hygiene","ultraprocessed-food"],"paperIds":["p-pmid-23808999","p-pmid-18397984","p-pmid-37611246"],"contributions":[{"paperId":"p-pmid-23808999","evidenceGrade":"abstract_only","designNote":"Perez-Rubio 2014 Metab Syndr Relat Disord. RCT. 500 mg TID vs placebo, 3 mo, N=24 MetS. Matsuda 2.1 to 3.1 P<0.01. Glucose/insulin AUC down. MetS remission 36% P=0.037. abstract_only. Archive n null."},{"paperId":"p-pmid-18397984","evidenceGrade":"abstract_only","designNote":"Zhang 2008 JCEM. RCT. 1.0 g/d vs placebo, 3 mo, N=116 T2D+dyslipidemia. Glucose/HbA1c vs placebo P<0.0001. Clamp GDR vs placebo P=0.063. abstract_only. Archive n null."},{"paperId":"p-pmid-37611246","evidenceGrade":"abstract_only","designNote":"Ruiz-Herrera 2023 Int J STD AIDS. RCT. 500 mg TID vs placebo, 20 wk, N=43 HIV+MetS (36 analyzed). Weight, BMI, IR down. HIV population. abstract_only. Archive n null."}],"featured":false},{"id":"e-breastfeeding-cognition","sourceId":"breastfeeding","targetId":"cognitive-performance","relation":"spurious","direction":"forward","polarity":"positive","methodology":"observational","confidence":"low","effect":{"metric":"beta","value":0.09,"note":"Sajjad Generation R: +0.32 IQ/month crude, +0.09 (-0.03 to 0.21) after maternal IQ and SES. Julvez INMA >6mo full BF +7.4 MSCA. Bernard EDEN duration +0.20 FSIQ/month."},"n":3761,"summary":"In three European birth cohorts, longer breastfeeding tracked with higher child IQ on crude models. After maternal IQ, education, and class, Generation R's 0.32 IQ points per month fell to 0.09 and crossed zero. Sabadell's full breastfeeding past six months still sat 7.4 McCarthy points higher. Nobody randomized the feed.","mechanism":"Authors usually name long-chain fats in milk, especially DHA, plus fewer infections and more talk time with the child.\n\nSajjad followed 3,761 Generation R children to a non-verbal IQ test at age 6. Each extra month of breastfeeding looked like 0.32 IQ points (0.20 to 0.44) before family variables. After child factors, parents' lifestyles, sociodemographics, and maternal IQ, the slope was 0.09 (-0.03 to 0.21). The authors say they cannot confirm a benefit.\n\nJulvez assessed 434 INMA children in Sabadell with the McCarthy scales at 4. Full breastfeeding longer than six months still sat 7.4 points above never (2.8 to 12.0) after social class, education, maternal IQ, psychopathology, and colostrum omega-3. The fatty acids themselves were not associated with the scores.\n\nBernard measured colostrum PUFA and WPPSI-III at 5 to 6 in 1,080 EDEN children. Ever versus never breastfeeding was 4.5 full-scale points unadjusted and 1.3 after adjustment (-0.4 to 3.0). Duration still tracked full-scale IQ at 0.20 points per month (0.00 to 0.41) and verbal IQ at 0.31 (0.09 to 0.52). High linoleic acid with low DHA sat lower than high-DHA colostrum.\n\nThe open backdoor is who breastfeeds. Mothers with more schooling and higher IQ do it longer. That path also predicts the child's test.","caveats":"The stamp is smoke because these are birth-cohort observations. A new observational edge publishes as spurious and low. Paper count does not raise it. Nobody assigned breastfeeding at random.\n\nGeneration R is the largest file and the one that measured maternal IQ. Adjustment killed the association. EDEN's ever-versus-never contrast died the same way. INMA kept a long-full-breastfeeding contrast after those covariates. That disagreement is why confidence stays low.\n\nThe tests are different: non-verbal IQ at 6, McCarthy at 4, WPPSI-III at 5 to 6. Full breastfeeding is not the same as any breastfeeding. Colostrum PUFA is a milk chemistry reading, not the duration node.\n\nThis page is not antiepileptic drugs in milk and not diet quality in children born very low birth weight.\n\nThis is not medical advice and not a recommendation to feed a certain number of months.","confounders":["education","disposable-income"],"paperIds":["p-pmid-25700532","p-pmid-24116864","p-pmid-28081886"],"contributions":[{"paperId":"p-pmid-25700532","evidenceGrade":"abstract_only","designNote":"Sajjad 2016 JECH, Generation R. Observational, n=3761, breastfeeding duration → non-verbal IQ at 6. Crude +0.32 (0.20-0.44)/month; adjusted child/SES/lifestyle/maternal IQ +0.09 (-0.03-0.21). Authors cannot confirm benefit. identifying. abstract_only. Archive n null; 3761 from abstract."},{"paperId":"p-pmid-24116864","evidenceGrade":"abstract_only","designNote":"Julvez 2014 DMCN, INMA Sabadell. Observational, n=434, full BF never/≤4/4-6/>6 mo → McCarthy at 4. >6 mo coeff 7.4 (2.8-12.0) after social, psychological, nutritional factors. Maternal IQ/class/education associated; n3 colostrum not. abstract_only. Archive n null; 434 from abstract."},{"paperId":"p-pmid-28081886","evidenceGrade":"abstract_only","designNote":"Bernard 2017 J Pediatr, EDEN. Observational, n=1080, any BF and colostrum PUFA → WPPSI-III at 5-6. Ever vs never FSIQ +4.5 crude, +1.3 (-0.4, 3.0) adjusted. Duration +0.20 FSIQ (0.00-0.41) and +0.31 verbal/month. High LA/low DHA lower IQ. abstract_only. Archive n null; 1080 from abstract."}],"featured":false},{"id":"e-caffeine-mortality","sourceId":"caffeine","targetId":"mortality","relation":"spurious","direction":"forward","polarity":"non_linear","methodology":"meta_analysis","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Li 2020: 21 cohorts, 10,103,115, 3 cups/d vs none/rare all-cause RR 0.87 (0.84-0.89), Pnonlinearity <0.001. U, not a linear drop. Design does not identify."},"n":10103115,"summary":"Li 2020 pooled 21 cohort articles (10,103,115 people, 240,303 deaths) and found a nonlinear inverse between coffee and all-cause death: three cups a day against none or rare sat at relative risk 0.87 (0.84 to 0.89). Tsujimoto 2017 saw the same U in caffeine milligrams. Nobody assigned a dose.","mechanism":"Coffee drinkers tend to smoke more, drink more, and move less. After those habits are named, cohorts often show a U: fewer deaths around a few cups or a mid caffeine dose, then a flatten or a rebound. Authors point at chlorogenic acid and insulin. They do not isolate one path, and they do not agree caffeine is the actor.\n\nLi, Liu, Sun and colleagues (2020) pooled 21 cohort articles, 10,103,115 people, 240,303 deaths. Splines were nonlinear (P < 0.001). Three cups a day versus none or rare: relative risk 0.87 (0.84 to 0.89). The abstract reports a similar inverse for caffeinated coffee and for decaf.\n\nLopez-Garcia, van Dam and Hu (2008) followed 41,736 men and 86,214 women on cumulative coffee. After age, smoking, and diet, all-cause relative risks in women across cups were 1.0, 0.98, 0.93, 0.82, 0.74, and 0.83 at six or more (P for trend < 0.001). Men sat at 1.0, 1.07, 1.02, 0.97, 0.93, and 0.80 (P for trend 0.008). Pooled sexes: 0.86 at two to three cups, 0.79 at four to five, 0.83 at six or more. The inverse ran through cardiovascular death, not cancer. In women on two or more cups a day it sat below 1 in every caffeine quintile. Decaf also tracked a small inverse, mainly in women.\n\nZhou, Ruan and Zhang (2025) followed 46,222 NHANES adults, 7,074 deaths. Total coffee versus none: 0.89 under one cup, 0.84 at one to under two, 0.83 at two to under three, 0.85 at three or more (P-trend 0.004). Splines were nonlinear (P < 0.001). Black coffee 0.86. Low-sugar, low-saturated-fat coffee 0.86. High sugar and cream did not sit below 1. Caffeinated cups tracked the total. Decaf under three cups sat near 1; three or more sat at 0.74.\n\nTsujimoto, Kajio and Sugiyama (2017) followed 17,594 NHANES 1999-2010 adults, 1,310 deaths. Caffeine milligrams versus under 10 mg a day: 0.81 at 10 to 99, 0.63 at 100 to 199, 0.69 at 200 or more. The same U appeared in people who drank under one coffee cup a week. No cardiovascular link.","caveats":"The stamp is smoke because nobody randomized caffeine or coffee against death. These are cohorts and a meta of cohorts. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim.\n\nSmoking sits on the backdoor. In Lopez-Garcia, age-only models in the heaviest drinkers sat above 1. After smoking, the sign flipped. Residual smoking and income, education, and diet remain.\n\nThe exposure here is milligrams. Three of the four files count coffee cups. Li reports a similar inverse for decaf. Lopez-Garcia says the coffee inverse was independent of caffeine. Zhou's inverse was mostly caffeinated cups and mostly black or lightly sweetened coffee. Tsujimoto is the file that isolates milligrams, including in people who barely drank coffee.\n\nZhou 2025 and Tsujimoto 2017 share NHANES. They are not two countries. Li's search closed in November 2017 and likely already holds Lopez-Garcia.\n\nOmitted van Dongen 2017 and the 2020 post-MI review: coffee after a heart attack, not all-cause death in the general population.\n\nOmitted : atrial fibrillation events, not death.\n\nOmitted : all-cause death in French HIV-HCV co-infection.\n\nOmitted : tea in chronic kidney disease.\n\nOmitted : green-tea cups in Vietnam, not a caffeine dose.\n\nOmitted : UK Biobank tea cups. A caffeine-metabolism score was a modifier, not the exposure.\n\nThis is a journal entry, not medical advice and not a reason to drink coffee, to skip cream, or to treat a number.","confounders":["alcohol-intake","aerobic-exercise","disposable-income","education","ultraprocessed-food","sleep-hygiene"],"paperIds":["p-pmid-30786114","p-pmid-18559841","p-pmid-40368300","p-pmid-28697850"],"contributions":[{"paperId":"p-pmid-30786114","evidenceGrade":"abstract_only","designNote":"Li 2020 J Hum Nutr Diet. 21 cohort articles, 10,103,115, 240,303 deaths. 3 cups/d vs none/rare RR 0.87 (0.84-0.89). Pnonlinearity <0.001. Similar inverse caffeinated and decaf. Meta of cohorts. abstract_only. Archive n null."},{"paperId":"p-pmid-18559841","evidenceGrade":"full_text","designNote":"Lopez-Garcia 2008 Ann Intern Med. HPFS 41,736 men + NHS 86,214 women. Cumulative coffee. Women all-cause MV: 0.82 at 2-3, 0.74 at 4-5, 0.83 at ≥6 cups. Independent of caffeine. Decaf also inverse. full_text. Archive n null."},{"paperId":"p-pmid-40368300","evidenceGrade":"full_text","designNote":"Zhou 2025 J Nutr. NHANES 1999-2018 n=46,222, 7,074 deaths. Total coffee 1-<2 cups HR 0.84; 2-<3 0.83; ≥3 0.85. P-nonlinearity <0.001. Black 0.86; LSLF 0.86. full_text. Archive n null."},{"paperId":"p-pmid-28697850","evidenceGrade":"abstract_only","designNote":"Tsujimoto 2017 Mayo Clin Proc. NHANES 1999-2010 n=17,594, 1,310 deaths. Caffeine vs <10 mg/d: HR 0.81 / 0.63 / 0.69 at 10-99 / 100-199 / ≥200 mg. U also if <1 coffee cup/wk. abstract_only. Archive n null."}],"featured":false},{"id":"e-caffeine-sleep","sourceId":"caffeine","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Weibel Sci Rep 2021: nighttime TST, latency, architecture, and subjective quality not different after 9 days of 3x150 mg. J Biol Rhythms: REM latency ~54 vs ~79 min when sleep started ~04:22. Same 20 men."},"n":20,"summary":"In twenty young men, Weibel 2021 found that 450 mg of daytime caffeine a day left nighttime sleep length and stages unchanged, but delayed REM and made waking harder when sleep was pushed into the morning.","mechanism":"Caffeine blocks adenosine A1 and A2A receptors. An evening dose can blunt homeostatic sleep pressure: longer sleep latency, less slow-wave activity. Habitual daytime use can adapt those homeostatic marks.\n\nWeibel, Lin, Landolt, Cajochen, and Reichert ran the same twenty men through caffeine, withdrawal, and placebo. Three 150 mg capsules a day for ten days. Last capsule about eight hours before habitual bedtime.\n\nOn a habitual night (Scientific Reports, 2021), polysomnography did not move total sleep, latency, architecture, or how the night felt. Sigma power between 12 and 16 Hz fell on both caffeine and withdrawal nights. The authors read that as early overnight withdrawal, not deeper sleep. During the ambulatory week, bedtime sat about 25 minutes later on caffeine than on placebo.\n\nThe companion recording (Journal of Biological Rhythms, 2021) started five hours after habitual bedtime, after a one-hour evening nap, around the circadian peak of REM. REM latency rose from about 54 minutes on placebo to about 79 on caffeine. REM accumulated later. Men reported more trouble waking and more tiredness. Total sleep and stages still did not differ.\n\nThe sign depends on when you sleep. A habitual night in good sleepers who already drink coffee is not the same exposure as a delayed night.","caveats":"Twenty men, 18 to 35, habitual 300 to 600 mg a day, good sleepers. No women. One lab, one protocol. The nighttime file lost ten recordings to technical problems. One man was dropped for noncompliance.\n\nThis page is adult daytime caffeine and nighttime or delayed sleep. It is not apnea of prematurity, not oolong tea plus fat oxidation, not caffeine plus zolpidem or trazodone, not slow-release caffeine after two days awake, not a tyrosine-phentermine-amphetamine stack, and not galanga for alertness.\n\nEvening caffeine close to bedtime is a different timing. These capsules stopped in the afternoon. The men already drank coffee; people who quit because it wrecks their sleep are not in the sample.\n\nThis is not medical advice and not a recommendation to drink coffee, to quit, or to treat a number.","confounders":["alcohol-intake"],"paperIds":["p-pmid-33633278","p-pmid-34024173"],"contributions":[{"paperId":"p-pmid-33633278","evidenceGrade":"full_text","designNote":"Weibel 2021 Sci Rep. Double-blind crossover, 20 men 18-35, habitual 300-600 mg/day. 3x150 mg vs withdrawal vs placebo, 10 days. Habitual 8h night, last capsule 8h (caffeine) or 15h (withdrawal) before bed. TST/latency/architecture/LSEQ ns. Sigma 12-16 Hz down. Archive n null; N=20 from paper. full_text."},{"paperId":"p-pmid-34024173","evidenceGrade":"full_text","designNote":"Weibel 2021 J Biol Rhythms. Same 20 men and 3x150 mg protocol. 8h EEG starting ~5h after habitual bedtime (mean 04:22), after 60-min evening nap. REM latency 54 vs 79 min vs placebo/withdrawal. Delayed REM accumulation. Worse LSEQ awakening. TST/architecture ns. Archive n null. full_text."}],"featured":false},{"id":"e-chamomile-sleep","sourceId":"chamomile","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Chang 2016: chamomile tea 2 wk vs usual care, N=80 postnatal PSQS>=16. Physical-symptoms sleep inefficiency P=0.015. Gone at 4-wk post-test. No placebo tea."},"n":80,"summary":"Chang 2016 found that two weeks of chamomile tea lowered a physical-symptoms sleep-inefficiency score versus usual care in 80 Taiwanese postnatal women with poor sleep (P=0.015). The difference was gone two weeks after the tea stopped. There was no placebo drink.","mechanism":"Authors treat chamomile tea as a mild sleep aid. They do not isolate one flavonoid.\n\nChang and Chen assigned 80 postnatal women with a Postpartum Sleep Quality Scale of 16 or higher to two weeks of chamomile tea (n=40) or usual postnatal care (n=40). Assignment was systematic with a random start. The tea arm had lower physical-symptoms-related sleep inefficiency (P=0.015) and lower Edinburgh postnatal depression scores (P=0.020) at two weeks. All three scales were similar at four weeks.","caveats":"Researchers assigned people to a tea or usual care, so this is a trial stamp. The control is usual care, not a placebo drink. More papers of the same design do not settle the claim.\n\nThis is eighty postnatal women in Taiwan and one subscale. The win was gone two weeks after the tea stopped.\n\nThis is a journal entry, not medical advice and not a reason to drink chamomile for insomnia.","confounders":["caffeine","alcohol-intake","light-exposure"],"paperIds":["p-pmid-26483209"],"contributions":[{"paperId":"p-pmid-26483209","evidenceGrade":"abstract_only","designNote":"Chang 2016 J Adv Nurs. RCT. Chamomile tea 2 wk vs usual care, N=80 postnatal PSQS>=16. Sleep-inefficiency subscale P=0.015. EPDS P=0.020. Null at 4 wk. No placebo. abstract_only. Archive n null."}],"featured":false},{"id":"e-chromium-insulin","sourceId":"chromium","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Jamilian 2016: 200 ug, 8 wk, N=64 PCOS, HOMA -0.8 vs +0.9. Kim 2012: N=25 kids, P=.05. Jain 2013: CDNC vs baseline; picolinate ns. Aghdassi 2010: HIV N=46."},"n":64,"summary":"Jamilian 2016 found that 200 micrograms of chromium picolinate a day for eight weeks moved HOMA-IR by -0.8 versus +0.9 on placebo in 64 women with polycystic ovary syndrome (P<0.001). Kim 2012 saw a similar direction in 25 overweight children. Jain 2013's picolinate arm did not.","mechanism":"Authors treat chromium as a trace metal that may help insulin act. They do not isolate one receptor.\n\nJamilian and Asemi assigned 64 women with polycystic ovary syndrome to 200 micrograms of picolinate or placebo for eight weeks. HOMA-IR moved -0.8 versus +0.9 (P<0.001). Insulin and HOMA-B fell. QUICKI rose.\n\nKim, Kim, Park and colleagues assigned 25 overweight children aged 9 to 12 to 400 micrograms of chromium chloride or placebo for six weeks on a shared diet-and-aerobic program. HOMA moved -1.84 versus +0.05 (P=0.05).\n\nJain, Kahlon, Morehead and colleagues finished 74 of 100 people with type 2 diabetes on three months of placebo, picolinate, or chromium dinicocysteinate. Dinicocysteinate lowered HOMA versus baseline (P=0.02). Picolinate did not. Versus-placebo HOMA is not in the abstract.\n\nAghdassi, Arendt, Salit and colleagues finished 46 of 52 HIV-positive adults on 400 micrograms of nicotinate or placebo for 16 weeks. HOMA fell from 4.09 to 3.66 (P=0.004).\n\nLucidi 2006 improved glucose tolerance versus placebo in polycystic ovary syndrome and did not change ovulation.","caveats":"Researchers assigned people to a salt or a control, so this is a trial stamp. Form and population split. More papers of the same design do not settle the claim.\n\nJamilian is eight weeks in polycystic ovary syndrome. Kim is 25 children and a shared aerobic class. Jain's picolinate arm missed; the dinicocysteinate win is versus baseline. Aghdassi is HIV. Lucidi is glucose tolerance, not a HOMA increment.\n\nThis is a journal entry, not medical advice and not a reason to take chromium for insulin resistance.","confounders":["sedentary-time","sleep-hygiene","ultraprocessed-food"],"paperIds":["p-pmid-26279073","p-pmid-21216583","p-pmid-22674882","p-pmid-20163347","p-pmid-16359984"],"contributions":[{"paperId":"p-pmid-26279073","evidenceGrade":"abstract_only","designNote":"Jamilian 2016 Ann Nutr Metab. RCT. Picolinate 200 ug vs placebo, 8 wk, N=64 PCOS. HOMA-IR -0.8 vs +0.9 P<0.001. Insulin/HOMA-B down, QUICKI up. abstract_only. Archive n null."},{"paperId":"p-pmid-21216583","evidenceGrade":"abstract_only","designNote":"Kim 2012 J Nutr Biochem. RCT. CrCl 400 ug vs placebo, 6 wk, N=25 overweight 9-12, shared aerobic/diet. HOMA -1.84 vs +0.05 P=.05. Kids. abstract_only. Archive n null."},{"paperId":"p-pmid-22674882","evidenceGrade":"full_text","designNote":"Jain 2013 Mol Nutr Food Res. RCT. Placebo vs picolinate vs CDNC, 3 mo, 74/100 T2D. CDNC HOMA vs baseline P=0.02. Picolinate ns. No vs-placebo HOMA in abstract. full_text. Archive n null."},{"paperId":"p-pmid-20163347","evidenceGrade":"abstract_only","designNote":"Aghdassi 2010 Curr HIV Res. RCT. 400 ug nicotinate vs placebo, 16 wk, 46/52 HIV HOMA>=2.5. HOMA 4.09 to 3.66 P=0.004. HIV. abstract_only. Archive n null."},{"paperId":"p-pmid-16359984","evidenceGrade":"abstract_only","designNote":"Lucidi 2006 Fertil Steril. RCT. Picolinate 200 ug/d vs placebo, PCOS. Glucose tolerance vs placebo. Ovulation ns. Pilot. abstract_only. Archive n null."}],"featured":false},{"id":"e-cortisol-moderates-t","sourceId":"cortisol","targetId":"leadership-effectiveness","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"observational","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"High cortisol is the proposed brake on T-linked dominance."},"n":null,"summary":"High cortisol is the condition under which 'high T = leader' fails. The internet quote drops this term.","mechanism":"Social-evaluative threat upregulates HPA. In that state, T no longer tracks assertive, leader-like behavior and can track erratic or withdrawn responses instead. Carré and Olmstead emphasize contest-induced T change on top of this basal interaction.","caveats":"Cortisol is time-of-day and context sensitive. A single afternoon assay is a noisy moderator. Chronic vs acute cortisol are different questions.","confounders":["sleep-hygiene","contest-outcome"],"paperIds":["p-mehta-josephs-2010","p-carre-olmstead-2015"],"contributions":[{"paperId":"p-mehta-josephs-2010","evidenceGrade":"abstract_only"},{"paperId":"p-carre-olmstead-2015","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-creatine-cognition","sourceId":"creatine","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"McMorris 2008: 20 g/d 1 wk vs placebo, N=32 elderly. Tasks except backward number recall moved. No scores in abstract. Toniolo 2018: 6 g/d adjunct, N=18 bipolar depression; verbal fluency only."},"n":32,"summary":"McMorris 2008 found that 20 g a day of creatine for one week, after a placebo week, improved random-number, recall, and long-term memory tasks versus continued placebo in 32 older adults, except backward number recall. Toniolo 2018 then found that 6 g a day as an adjunct in 18 people with bipolar depression moved only verbal fluency.","mechanism":"Authors treat creatine as a short-term brain-energy buffer. McMorris tests that in older adults on lab tasks. Toniolo tests it inside a bipolar-depression drug trial.\n\nMcMorris, Mielcarz, Harris, Swain and Howard (2008) split 32 older adults. Fifteen took 5 g of placebo four times a day for a week, then 5 g of creatine four times a day for a week. Seventeen took placebo both weeks. Tasks were random-number generation, forward and backward number and spatial recall, and long-term memory. The abstract says creatine moved every task except backward number recall. It does not publish the scores.\n\nToniolo, Fernandes, Silva, Dias and Lafer (2018) sat Wisconsin Card Sorting, Digit Span, Stroop, Rey-Osterrieth, and FAS verbal fluency at baseline and week 6 in 18 people already in a 6 g creatine-versus-placebo adjunct trial for bipolar depression. Only verbal fluency changed between groups. The other tests did not.","caveats":"Researchers assigned people to a powder or a control, so this is a trial stamp. Both files are small. More papers of the same design do not settle the claim.\n\nMcMorris is one week, thirty-two people, and the record here has no effect sizes. The first week is placebo in the creatine arm. That is not a two-week parallel trial.\n\nToniolo is eighteen people, bipolar depression, already on mood drugs. Verbal fluency moved. Working memory, Stroop, and figure copy did not. That is not a general cognition claim and not a 1RM claim.\n\nMcMorris does not identify lean mass or a lift. This page is not a strength claim.\n\nThis is a journal entry, not medical advice and not a reason to load creatine for a test.","confounders":["sleep-hygiene","aerobic-exercise","resistance-training"],"paperIds":["p-pmid-17828627","p-pmid-27890303"],"contributions":[{"paperId":"p-pmid-17828627","evidenceGrade":"abstract_only","designNote":"McMorris 2008 Aging Neuropsychol Cogn. RCT. Group1 n=15: placebo 20 g/d wk1 then creatine 20 g/d wk2. Group2 n=17: placebo both weeks. Elderly. All tasks except backward number recall. No scores in abstract. No strength outcome. abstract_only. Archive n null."},{"paperId":"p-pmid-27890303","evidenceGrade":"abstract_only","designNote":"Toniolo 2018 J Affect Disord. Nested RCT cognition. 6 g/d creatine adjunct vs placebo, 6 wk, N=18 bipolar depression. FAS verbal fluency improved. WCST, Digit Span, Stroop, Rey-Osterrieth NS. abstract_only. Archive n null."}],"featured":false},{"id":"e-creatine-depression","sourceId":"creatine","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Toniolo 2019 bipolar adjunct. MADRS change ITT P=0.560, d=0.231 NS. Remission MADRS<=12: 52.9% vs 11.1% ITT, OR 9.0, P=0.012. N=35. Two hypomania/mania switches on creatine."},"n":35,"summary":"Toniolo 2019 found that 6 g a day of creatine monohydrate as an add-on for six weeks did not beat placebo on the change in Montgomery-Åsberg score among 35 people already treated for a bipolar depressive episode (P=0.560), while a secondary remission cut (score of 12 or less) favored creatine (52.9 percent versus 11.1 percent).","mechanism":"The authors treat creatine as a mitochondrial add-on in bipolar depression, not as a treatment for ordinary major depression. People stayed on their usual mood drugs.\n\nToniolo, Silva, Fernandes, Amaral, Dias and Lafer (2019) assigned 35 adults with DSM-IV bipolar I or II in a depressive episode to 6 g a day of creatine monohydrate or placebo for six weeks, on top of regular medication. The primary was change in MADRS. Intention-to-treat, the groups did not differ (P=0.560, Cohen's d=0.231). Remission, defined as MADRS of 12 or less at week 6, was 52.9 percent on creatine and 11.1 percent on placebo among the 35 randomized (odds ratio 9.0, P=0.012). Among 23 completers it was 66.7 versus 18.2 percent. Two people on creatine switched to hypomania or mania early.","caveats":"Researchers assigned people to a powder or a control, so this is a trial stamp. This is bipolar depression as an adjunct, not unipolar major depression as a sole treatment. More papers of the same design do not settle the claim.\n\nThe primary MADRS change missed. Remission is a secondary cut on thirty-five people. Two early polarity switches sit on the creatine arm. That is why the sign is context-dependent and the confidence is contested.\n\nThe sister file is verbal fluency in the same trial. It hangs on the creatine-and-cognition page, not here.\n\nThis is a journal entry, not medical advice and not a reason to add creatine to a mood prescription.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise"],"paperIds":["p-pmid-29177955"],"contributions":[{"paperId":"p-pmid-29177955","evidenceGrade":"full_text","designNote":"Toniolo 2019 J Neural Transm. Proof-of-concept RCT. 6 g/d creatine adjunct vs placebo, 6 wk, N=35 bipolar I/II depression on usual meds. MADRS change ITT P=0.560 d=0.231. Remission 52.9% vs 11.1% OR 9.0 P=0.012. 2 mania/hypomania switches. full_text. Archive n null."}],"featured":false},{"id":"e-creatine-strength","sourceId":"creatine","targetId":"muscle-strength","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"percent_change","value":57,"note":"Amiri 2023: 0.1 g/kg + RT 10 wk, N=45, predicted 1RM +57% vs +36% RT. Mihic 2000: 20 g/d 5 d, N=30, FFM 57.4 to 58.3 kg, handgrip ns. Chilibeck 2023: N=237, 1RM ns."},"n":237,"summary":"Assigned creatine raised predicted one-rep strength more than lifting alone in 45 older adults (Amiri 2023) and raised fat-free mass in a five-day load (Mihic 2000), but a two-year postmenopausal trial found no extra one-rep max (Chilibeck 2023).","mechanism":"Authors treat creatine as a phosphocreatine store that lets a muscle do one more hard repetition, or as water that shows up as lean mass. Those are different outcomes.\n\nAmiri and Sheikholeslami-Vatani (2023) assigned 45 older adults to resistance training plus 0.1 g per kg creatine, training plus starch, or no training, for ten weeks. Predicted one-rep strength across seven lifts rose about 57 percent with creatine and 36 percent with training alone.\n\nMihic, MacDonald, McKenzie and Tarnopolsky (2000) assigned 15 men and 15 women to 20 g a day for five days or placebo. Fat-free mass rose from 57.4 to 58.3 kg on creatine and did not move on placebo. Ischemic handgrip did not change. The mass change was larger in men.\n\nChilibeck, Candow, Gordon and colleagues (2023) assigned 237 postmenopausal women to 0.14 g per kg creatine or placebo during two years of lifting and walking. Bench and squat one-rep max rose in both arms and did not differ. Lean tissue mass rose more on creatine only among valid completers (40.8 to 43.1 kg versus 40.4 to 42.0 kg, P=0.046), not in the intent-to-treat set.\n\nMarini, Schincaglia, Candow and Pimentel (2024) assigned 40 people on hemodialysis to 5 g creatine or maltodextrin for a year. Fat-free mass and skeletal-muscle index rose on creatine (P=0.010 and 0.022). Intracellular water rose from 20.2 to 21.0 liters. This file does not publish a strength contrast.","caveats":"Researchers assigned people to creatine or a control, so this is a trial stamp. Signs do not agree. Extra papers do not settle the claim.\n\nAmiri is forty-five people, ten weeks, and a predicted one-rep max, not a tested lift. Training is in both active arms. That is the strength identification.\n\nMihic is five days. Fat-free mass moved. Force did not.\n\nChilibeck is the largest file and the lift is null. Lean mass is a completer slice.\n\nMarini is dialysis and water. A lean-mass number that tracks intracellular water is not a stronger contraction.\n\nThis is a journal entry, not medical advice and not a reason to load creatine for a lift.","confounders":["resistance-training","sleep-hygiene","aerobic-exercise","sedentary-time"],"paperIds":["p-pmid-37206869","p-pmid-10694109","p-pmid-37144634","p-pmid-38474743"],"contributions":[{"paperId":"p-pmid-37206869","evidenceGrade":"full_text","designNote":"Amiri 2023 Front Public Health. RCT. RT+0.1 g/kg Cr vs RT+starch vs control, 10 wk, N=45 older adults. Predicted 1RM (Brzycki) +57% vs +36% RT. Seven lifts. full_text. Archive n null."},{"paperId":"p-pmid-10694109","evidenceGrade":"abstract_only","designNote":"Mihic 2000 Med Sci Sports Exerc. RCT. 20 g/d 5 d vs placebo, N=30 (15M/15W). FFM 57.4 to 58.3 kg vs 54.3 flat. TBM +1.04 kg. Handgrip ns. Men > women. abstract_only. Archive n null."},{"paperId":"p-pmid-37144634","evidenceGrade":"full_text","designNote":"Chilibeck 2023 Med Sci Sports Exerc. RCT. 0.14 g/kg/d vs placebo during RT+walk, 2 y, N=237 postmenopausal. 1RM bench/squat ns. Completer lean 40.8 to 43.1 vs 40.4 to 42.0 P=0.046; ITT ns. full_text. Archive n null."},{"paperId":"p-pmid-38474743","evidenceGrade":"full_text","designNote":"Marini 2024 Nutrients. RCT. 5 g/d vs maltodextrin, 1 y, N=40 hemodialysis. FFM P=0.010, SMMI P=0.022. ICW 20.2 to 21.0 L. No strength contrast in this file. full_text. Archive n null."}],"featured":false},{"id":"e-curcumin-depression","sourceId":"curcumin","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Lopresti 2015: 500 mg BID vs placebo, 8 wk, N=56 MDD. Weeks 0-4 both arms fell. Weeks 4-8 group x time IDS-SR30 P=0.045. Atypical slice stronger. No primary increment in abstract."},"n":56,"summary":"Lopresti 2015 found that 500 mg of curcumin twice a day versus placebo did not separate on the Inventory of Depressive Symptomatology in the first four weeks among 56 adults with major depression, then showed a group-by-time interaction from week 4 to week 8 (P=0.045). The authors call that partial support.","mechanism":"The authors treat curcumin as an anti-inflammatory, monoaminergic, and HPA-axis agent. They do not isolate one path.\n\nLopresti, Maes, Maker, Hood and Drummond (2015) assigned 56 people with major depression to 500 mg of curcumin twice a day or placebo for eight weeks. The primary was the self-rated IDS-SR30. Both arms improved through week 4. From week 4 to week 8 the group-by-time interaction favored curcumin on the total score (F=4.22, P=0.045) and the mood factor (F=6.51, P=0.014). An atypical-depression slice looked larger. The abstract does not publish the point change.","caveats":"Researchers assigned people to an extract or a control, so this is a trial stamp. The separation is a late interaction in fifty-six people. More papers of the same design do not settle the claim.\n\nWeeks 0 to 4 are a shared placebo response. The P=0.045 is weeks 4 to 8. That is why confidence stays contested.\n\nThis is a journal entry, not medical advice.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise"],"paperIds":["p-pmid-25046624"],"contributions":[{"paperId":"p-pmid-25046624","evidenceGrade":"abstract_only","designNote":"Lopresti 2015 J Affect Disord. Identifying RCT. Curcumin 500 mg BID vs placebo, 8 wk, N=56 MDD. IDS-SR30 weeks 0-4 both improved. Weeks 4-8 group x time P=0.045. Mood factor P=0.014. Atypical slice. No increment in abstract. abstract_only. Archive n null."}],"featured":false},{"id":"e-dhea-cognition","sourceId":"dhea-s","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"DAWN: 50 mg DHEA vs placebo for 1 year in 225 healthy adults aged 55 to 85. No between-group change on six cognitive tests (P>.10). Cochrane 2007 review of RCTs: no benefit. van Niekerk 2001: 13 weeks in 46 men, no treatment effect."},"n":225,"summary":"A year of 50 mg DHEA did not move six cognitive tests against placebo in 225 healthy adults aged 55 to 85. A Cochrane review of earlier RCTs and a 13-week crossover in 46 older men also found no cognitive benefit.","mechanism":"DHEA and DHEA-S fall with age. Observational series then tied lower levels to worse memory, and rodent work showed learning gains. The human claim is that a pill restoring youthful DHEA restores cognition.\n\nKritz-Silverstein, von Muhlen, Laughlin, and Bettencourt (DAWN, 2008) tested that claim. Two hundred twenty-five community-dwelling men and women aged 55 to 85, not chosen for low DHEA, took 50 mg oral DHEA or placebo for one year. Circulating DHEA and DHEA-S rose two- to fourfold and stayed there. The battery was the Modified Mini-Mental State Examination, Trail Making B, category fluency, a 15-item Boston Naming Test, and immediate and delayed ten-word list recall. Change over twelve months did not differ by arm (P>.10).\n\nGrimley Evans, Malouf, Huppert, and van Niekerk (Cochrane, 2007) reviewed randomized placebo-controlled trials of DHEA or DHEA-S in people over 50 without dementia. They could not pool. Three trials had adequate parallel-group data. Barnhart 1999 found no cognitive effect at three months. Wolf 1998b gave 75 people aged 59 to 81 two weeks of DHEA; after a stressor, placebo lost selective attention and DHEA lost visual memory recall. van Niekerk 2001 found no cognitive effect. The reviewers wrote that the controlled trials do not support a cognitive benefit.\n\nvan Niekerk, Huppert, and Herbert (2001) ran a double-blind crossover: 50 mg DHEA for 13 weeks then placebo, or the reverse, in 46 men aged 62 to 76. Tests covered speed, attention, and episodic memory. The treatment contrast moved none of the trial outcomes.\n\nParsons, Kratz, Thompson, Stanczyk, and Buckwalter (2006) re-analyzed a six-month, 25 mg trial in twenty postmenopausal women. DHEA raised daytime cortisol. Cortisol did not explain a cognitive drop. The authors infer a direct negative effect. That is a mediation claim in twenty women, not a second year-long null.","caveats":"DAWN enrolled healthy, cognitively intact people. Mean Modified Mini-Mental State was about 96. The authors say a different result in people who are already impaired, clinically depressed, or adrenal-insufficient is an open question. It is not a license to treat a wellness-panel DHEA-S as a cognitive stack.\n\nCompliance was about 95 percent. The authors report power above 0.80 on every cognitive test. Analyses were intent-to-treat. Twenty-three people on DHEA and ten on placebo stopped for adverse events. Those counts do not create a cognitive benefit.\n\nThe Cochrane review is a review of randomized trials. It does not make DAWN more settled. Wolf's visual-memory finding after a lab stressor is one task in one short trial, not a benefit.\n\nvan Niekerk is available here only as an abstract. The abstract names 46 men. Baseline hormone correlations with mood and memory are not the treatment result.\n\nParsons is available here only as an abstract. The cognitive-decrease claim they mediate comes from Kratz's earlier analysis of the same twenty women. Do not read it as a failed replication of DAWN.\n\nThis edge is cognition. Baulieu 2000 sits on DHEA toward status-seeking. Mood and sexual function in DAWN also failed against placebo; they are not this page.","confounders":["vitamin-supplementation","disposable-income","cortisol"],"paperIds":["p-pmid-18482290","p-pmid-16393880","p-pmid-17054283","p-pmid-11403980"],"contributions":[{"paperId":"p-pmid-18482290","evidenceGrade":"full_text","designNote":"Kritz-Silverstein 2008, DAWN. Double-blind RCT, 50 mg oral DHEA vs placebo for 1 year. 110 men and 115 women aged 55 to 85, not selected for low DHEA. Six cognitive tests at baseline and 12 months. No between-group change (P>.10). ITT, power >0.80. full_text."},{"paperId":"p-pmid-16393880","evidenceGrade":"abstract_only","designNote":"Parsons 2006. RCT of 25 mg DHEA vs placebo for 6 months in 20 postmenopausal women (11/9). Mediation re-analysis of Kratz: DHEA raised daytime cortisol; cortisol did not explain a cognitive drop. Authors infer a direct negative effect. abstract_only."},{"paperId":"p-pmid-17054283","evidenceGrade":"full_text","designNote":"Grimley Evans 2007. Cochrane review of RCTs of DHEA/S for cognition in people over 50 without dementia. No pooling. Three adequate parallel-group files: Barnhart 1999 null at 3 months; Wolf 1998b 2-week stressor (visual memory worse on DHEA); van Niekerk 2001 null. Does not raise stamp. full_text."},{"paperId":"p-pmid-11403980","evidenceGrade":"abstract_only","designNote":"van Niekerk, Huppert, Herbert 2001. RCT, double-blind crossover, 50 mg DHEA 13 weeks then placebo or reverse. Abstract: 46 men aged 62-76. Speed, attention, episodic memory. No significant treatment effect on any trial outcome. Archive n:null; 46 from abstract. abstract_only."}],"featured":false},{"id":"e-dhea-status","sourceId":"dhea-s","targetId":"status-seeking","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Replacement moved some aging markers. Rank and ambition were not the endpoints."},"n":280,"summary":"DHEA-S on an optimization panel is not a status intervention.","mechanism":"Baulieu et al. randomized DHEA in older adults and watched hormones, skin, and libido. The folk leap is 'adrenal androgen → drive → rank'. That leap is not in the trial. Age, illness, and who can afford a panel sit on the backdoor of every observational DHEA–success plot.","caveats":"Correcting a documented deficiency is a medical act. Treating DHEA-S as a leadership lever is marketing. No edge from DHEA-S to income is licensed here.","confounders":["disposable-income","vitamin-supplementation"],"paperIds":["p-baulieu-2000"],"contributions":[{"paperId":"p-baulieu-2000","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-dominance-status","sourceId":"dominance-strategy","targetId":"status-seeking","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"theory","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Dominance is one of two technologies for the same latent (rank)."},"n":null,"summary":"Dominance is a means. Status is the end. Folklore treats them as synonyms.","mechanism":"The Henrich–Gil-White split again. Dual-hormone work is mostly about this means. Prestige is the other door into the same room.","caveats":"Conceptual edge. Do not treat it as an identified treatment effect.","confounders":[],"paperIds":["p-henrich-2001"],"contributions":[{"paperId":"p-henrich-2001","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-education-homogamy","sourceId":"education","targetId":"educational-homogamy","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"People meet and match in education-sorted markets. This is one of the least mystical arrows in the atlas."},"n":null,"summary":"Education sorts the rooms where people meet. Homogamy is mostly a market-design fact.","mechanism":"Universities, firms, and cities stratify by credential. Once the meeting technology is stratified, matching on education is the default even if preferences were random. Fisman's intelligence/ambition weights sit on top of that meeting technology.","caveats":"Preferences and markets are entangled. We mark this causal_direct because the meeting-technology path is sufficient; we do not claim a deep preference shock from a diploma.","confounders":["disposable-income","social-capital"],"paperIds":["p-fisman-2006"],"contributions":[{"paperId":"p-fisman-2006","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-estradiol-cycle-pref","sourceId":"estradiol","targetId":"dominance-strategy","relation":"spurious","direction":"forward","polarity":"context_dependent","methodology":"meta_analysis","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Two 2014 meta-analyses disagree on whether cycle shifts exist."},"n":null,"summary":"Cycle-phase 'preference for dominance' is a contested meta-finding, not a hormone dial.","mechanism":"Gildersleeve, Haselton, and Fales (2014) reported ovulatory shifts toward masculine/dominant cues. Wood and colleagues (2014) did not. Estradiol is the usual named mediator. A disagreement this public stays public: both papers sit on this edge.","caveats":"Even the positive meta is not a license to time a negotiation to a luteal calendar. Between-cycle noise, p-hacking risk, and the leap from facial masculinity to 'dominance strategy' as this atlas defines it are all large.","confounders":["sociosexuality","youth-fertility-preference"],"paperIds":["p-gildersleeve-2014","p-wood-2014"],"contributions":[{"paperId":"p-gildersleeve-2014","evidenceGrade":"abstract_only"},{"paperId":"p-wood-2014","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-exercise-depression","sourceId":"aerobic-exercise","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"SMILE II remission 45%/40% vs 31% placebo (p=.057); HAM-D p=.23. Hoffman 1-year: assignment ns; Godin 180 vs 0 min -3.1 HAM-D (observational). Brush gs=0.66. Yu walking vs waitlist p<.001."},"n":202,"summary":"Prescribed walking or jogging reduced depression scores in randomized trials of people with major depression. The programs looked similar to sertraline. Against a placebo pill, SMILE II's HAM-D gap did not reach significance. A year later, assigned arm no longer predicted mood.","mechanism":"The trials assign a heart-rate range and a weekly minutes target. In SMILE that meant three sessions a week, walking or jogging at 70 to 85 percent of heart-rate reserve, thirty minutes after a warm-up. Yu used outdoor walking at the WHO minimums: 150 minutes of moderate work or 75 minutes of vigorous work.\n\nThe authors do not have a settled pathway. Blumenthal's group names self-efficacy, a sense of mastery, and a break from rumination, and they list candidate biology: norepinephrine, the HPA axis, serotonin turnover. Supervised SMILE II patients gained more peak VO2 than home exercisers. Remission did not. A group class is a weak account of the mood change.\n\nBrush measured reward positivity and error-related negativity. Eight weeks of aerobic work beat stretching on symptoms. Both EEG markers stayed put.\n\nA large share of the SMILE II change also appeared on the placebo pill. Attention, weekly check-ins, and the hope of being in a trial sit in those numbers.\n\nHoffman followed the SMILE II cohort for a year after the trial ended. Assigned arm no longer predicted HAM-D or remission. Minutes of moderate or vigorous exercise that people reported on their own sat with lower HAM-D scores up to about three hours a week. The authors say they cannot tell whether exercise kept mood down or better mood kept people exercising.\n\nA later SMILE II read found that high pretreatment state anxiety shrank the depression benefit of the active arms, especially exercise. Anxiety itself is not this page.","caveats":"SMILE randomized 156 adults aged 50 and over with DSM-IV major depression to aerobic exercise, sertraline, or both. No placebo. At 16 weeks the arms did not differ on HAM-D or BDI (P=.67). Medication moved faster at first.\n\nBabyak followed the same 156 to month 10. Remitted exercisers relapsed less than the medication arm (p=.01). Self-exercise in follow-up was observational (OR 0.49).\n\nSMILE II added a placebo pill and a home-exercise arm. 202 adults, mean age 52, 153 women. Remission at 16 weeks: supervised 45 percent, home 40, sertraline 47, placebo 31 (p=.057). HAM-D versus placebo p=.23. The authors put that contrast at about 0.20.\n\nHoffman followed 172 of those 202 for a year after the trial. Assigned arm did not predict HAM-D (p=.73) or remission (p=.96). People who reported about 180 minutes of moderate or vigorous exercise had HAM-D scores 3.1 points lower than people who reported none. The authors say they cannot tell the direction.\n\nBlumenthal 2021 reread 148 SMILE II completers. High pretreatment state anxiety shrank the depression benefit of the active arms on HAM-D (p=.004) and BDI-II (p=.02), more so in exercisers. The STAI drop is anxiety, not this page.\n\nBrush is 66 young adults with a stretching control and is available here only as an abstract. Yu is 35 people with major depression on medication, against a waitlist, also available here only as an abstract.\n\nThis is a journal entry, not medical advice and it is not a reason to stop a prescribed drug.","confounders":["sleep-hygiene","outdoor-time"],"paperIds":["p-pmid-10547175","p-pmid-11020092","p-pmid-17846259","p-pmid-32838817","p-pmid-35579606","p-pmid-21148807","p-pmid-32790020"],"contributions":[{"paperId":"p-pmid-10547175","evidenceGrade":"abstract_only","designNote":"Blumenthal 1999, SMILE. RCT, 156 adults ≥50 with DSM-IV MDD. 16 weeks aerobic (walk/jog, 3×/wk, 70-85% HR reserve) vs sertraline vs both. No placebo. HAM-D and BDI fell in all arms; groups did not differ (P=.67). Medication faster at first. abstract_only. Identifying for the pair."},{"paperId":"p-pmid-11020092","evidenceGrade":"abstract_only","designNote":"Babyak. SMILE 10-month follow-up of the same 156. After 4 months, remission comparable across arms. At 10 months, remitted exercisers relapsed less than medication (p=.01). Continued self-exercise in follow-up: OR 0.49 for a depression diagnosis. That second association is observational. abstract_only."},{"paperId":"p-pmid-17846259","evidenceGrade":"full_text","designNote":"Blumenthal 2007, SMILE II. RCT, 202 adults with MDD, 16 weeks. Supervised aerobic vs home aerobic vs sertraline vs placebo. Remission 45%/40%/47%/31% (p=.057). HAM-D vs placebo p=.23. Fitness rose on exercise; home vs supervised remission did not differ. full_text. Identifying placebo comparison."},{"paperId":"p-pmid-32838817","evidenceGrade":"abstract_only","designNote":"Brush 2022. RCT, 66 young adults with MDD (mean age 20). 8 weeks moderate aerobic (n=35) vs light stretching (n=31), 3×/wk. Greater symptom reduction vs stretching (gs=0.66). RewP and ERN unchanged. Larger baseline RewP predicted response. abstract_only."},{"paperId":"p-pmid-35579606","evidenceGrade":"abstract_only","designNote":"Yu 2023. Pilot RCT, 35 middle-aged/older adults with MDD on medication (BDI>9), 30 completers. 12 weeks, 3×/wk: 150 min moderate walk vs 75 min vigorous walk vs waitlist. Both walking arms lowered BDI vs control (p<.001); MOD vs VIG p=.92. Outdoor groups. abstract_only."},{"paperId":"p-pmid-21148807","evidenceGrade":"full_text","designNote":"Hoffman 2011. SMILE-II 1-year naturalistic follow-up of the same 202 (172 available, 85%). HAM-D and MDD status at 16 months. Assigned arm did not predict HAM-D (p=.73) or remission (p=.96). Godin moderate/vigorous minutes: curvilinear, 180 vs 0 min -3.1 HAM-D (CI -5.1 to -1.2). Authors: cannot tell direction. full_text."},{"paperId":"p-pmid-32790020","evidenceGrade":"full_text","designNote":"Blumenthal 2021. SMILE-II secondary, 148 completers (dropped 14 early responders and 40 missing). Depression endpoints: post-treatment HAMD and BDI-II. Pretreatment STAI modified active-treatment vs placebo on HAMD (p=.004) and BDI-II (p=.02); larger attenuation in exercisers. STAI reduction is anxiety, not this pair. full_text."}],"featured":false},{"id":"e-exercise-mortality","sourceId":"aerobic-exercise","targetId":"mortality","relation":"spurious","direction":"forward","polarity":"negative","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Martinez-Gomez 2024: meeting recommended leisure-time PA, all-cause HR 0.78 (0.77-0.79), 2,011,186. Sign: more activity, less death. Design does not identify."},"n":2011186,"summary":"Martinez-Gomez 2024 pooled 2,011,186 adults in four megacohorts and found that meeting recommended leisure-time activity tracked a 22 percent lower all-cause death rate (hazard ratio 0.78, 0.77 to 0.79). Nobody randomized walking against death.","mechanism":"People who walk more also tend to smoke less, earn more, and sit less. Illness can cut activity and raise later death.\n\nMartinez-Gomez, Luo, Huang and colleagues (2024) pooled NHIS, UK Biobank, China Kadoorie Biobank, and Mei Jau: 2,011,186 adults, 177,436 deaths, median 11.5 years. Leisure-time activity. Meeting the recommended dose, all-cause hazard ratio 0.78 (0.77 to 0.79). Stronger at older ages.\n\nEkelund, Steene-Johannessen, Brown and colleagues (2016) harmonised 13 cohorts, 1,005,791 people, 84,609 deaths. Versus the most active quartile sitting under 4 hours a day, the least active sitting over 8 hours had hazard ratio 1.59 (1.52 to 1.66). The most active sitting over 8 hours were 1.04 (0.99 to 1.10). The paper is an individual-level meta of cohorts.\n\nZhao, Veeranki, Magnussen, and Xi (2020) followed 479,856 NHIS adults. Recommended aerobic activity only: all-cause 0.71 (0.69 to 0.72). Muscle-strengthening only stays off the claim.\n\nLee, Rezende, Joh and colleagues (2022) followed 116,221 Nurses' Health and Health Professionals adults, 47,596 deaths. Meeting vigorous leisure-time minutes versus none: all-cause 0.81 (0.76 to 0.87). Moderate minutes were 19 to 25 percent lower and mixed in lifting.\n\nChang, Zhu, Liu and colleagues (2024) used UK Biobank and NHANES. Replacing 30 minutes of sitting with walking for pleasure: all-cause 0.965 (0.954-0.977).\n\nFeng, Yang, Liang and colleagues (2023) followed 92,139 UK Biobank adults with a wrist accelerometer. More moderate-to-vigorous minutes tracked less all-cause death at any hour. Timing is extra.\n\nStamatakis, Gale, Bauman and colleagues (2020) followed 149,077 in 45 and Up. Among people with no moderate-to-vigorous minutes, sitting over 8 hours versus under 4: all-cause 1.52 (1.13 to 2.03). Meeting the recommendation flattened the slope.\n\nAuthors name fitness, pressure, and insulin. The files do not isolate a path.","caveats":"The stamp is smoke because nobody randomized walking against death. These are cohorts and one individual-level meta of cohorts. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim.\n\nReverse causation sits on the backdoor. Illness cuts activity and raises later death. Healthy-user habits travel with leisure-time walking: income, education, less smoking, less sitting. Residual confounding remains.\n\nThe aerobic page on this site was built for assigned walking or jogging. These files are self-report leisure-time minutes and wrist accelerometers, not SMILE treadmill sessions.\n\nZhao's NHIS wave sits inside Martinez-Gomez's NHIS pool. Chang and Feng share UK Biobank with that pool. They are not four independent samples.\n\nEkelund, Chang, and Stamatakis are joint with sitting. This page is the activity arrow. Sitting is a different question.\n\nOmitted Zhang 2024: diurnal activity and sleep patterns after volume adjustment. Early-morning activity versus midday had hazard ratio 1.36. That is a clock claim, not more activity, less death.\n\nThis is a journal entry, not medical advice and not a walking prescription.","confounders":["disposable-income","education","sedentary-time","ultraprocessed-food","sleep-hygiene","alcohol-intake","resistance-training"],"paperIds":["p-pmid-39570587","p-pmid-27475271","p-pmid-32611588","p-pmid-35876019","p-pmid-39267013","p-pmid-36805455","p-pmid-31023430"],"contributions":[{"paperId":"p-pmid-39570587","evidenceGrade":"full_text","designNote":"Martinez-Gomez 2024 JAMA Netw Open. Identifying pooled cohort, NHIS+UKB+CKB+Mei Jau, 2011186 adults, 177436 deaths, median 11.5 y. Leisure-time PA. Meeting recommended PA, all-cause HR 0.78 (0.77-0.79). Age 20-29: 0.84; 80+: 0.78. Archive n null. N from paper. full_text."},{"paperId":"p-pmid-27475271","evidenceGrade":"abstract_only","designNote":"Ekelund 2016 Lancet. Harmonised IPD meta, 13 cohorts sitting+death, 1005791, 84609 deaths. Vs most active (>35.5 MET-h/wk) sit <4 h: least active sit >8 h HR 1.59 (1.52-1.66); most active sit >8 h 1.04 (0.99-1.10). Archive observational; paper is IPD meta. abstract_only."},{"paperId":"p-pmid-32611588","evidenceGrade":"full_text","designNote":"Zhao 2020 BMJ. NHIS 1997-2014, 479856 adults, 59819 deaths, median 8.75 y. Recommended aerobic only all-cause HR 0.71 (0.69-0.72); muscle-strengthening only 0.89 (off this claim); both 0.60. Archive n null. N from paper. full_text."},{"paperId":"p-pmid-35876019","evidenceGrade":"full_text","designNote":"Lee 2022 Circulation. NHS+HPFS 1988-2018, 116221, 47596 deaths, 30 y. VPA 75-149 min/wk vs none, all-cause HR 0.81 (0.76-0.87). MPA guideline 19-25% lower; MPA mixed walking and some lifting. Archive n null. full_text."},{"paperId":"p-pmid-39267013","evidenceGrade":"full_text","designNote":"Chang 2024 BMC Med. UKB 490659 (36109 deaths) + NHANES 33534 (3057 deaths). Replace 30 min sitting with walking for pleasure, all-cause HR 0.965 (0.954-0.977). Sitting replacement, all-cause identified. Archive n null. full_text."},{"paperId":"p-pmid-36805455","evidenceGrade":"full_text","designNote":"Feng 2023 Nat Commun. UKB accelerometer, 92139, 3088 deaths, median 7 y. MVPA volume associated with lower all-cause at any time of day. Midday-afternoon vs morning timing HR 0.89 is extra. Archive n null. full_text."},{"paperId":"p-pmid-31023430","evidenceGrade":"abstract_only","designNote":"Stamatakis 2020 JACC. 45 and Up, 149077, 8689 deaths, median 8.9 y. Among no MVPA, sit >8 h vs <4 h all-cause HR 1.52 (1.13-2.03). Meeting MVPA recommendation attenuated sitting-death. Archive n null. abstract_only."}],"featured":false},{"id":"e-famine-insulin","sourceId":"prenatal-nutrition","targetId":"insulin-resistance","relation":"spurious","direction":"forward","polarity":"positive","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"de Rooij 2006: +0.4 mmol/l 120-min glucose at 58 (n=699). IVGTT Kg -21%; midgestation disposition index -53% (n=94). Worse glucose after famine. Design does not identify."},"n":699,"summary":"People exposed to the Dutch Hunger Winter in utero had higher 120-minute glucose at age 58, and a smaller IVGTT subsample showed worse glucose tolerance after mid-gestation famine. Nobody randomized a siege.","mechanism":"The authors treat the Hunger Winter as a shock to what the fetus received. Midlife oral glucose tests in the Dutch Famine Birth Cohort show higher 120-minute glucose after prenatal exposure.\n\nde Rooij, Painter, Roseboom and colleagues gave an OGTT to 702 people at age 50 and 699 at age 58, all born as term singletons just before, during, or after the 1944-1945 famine. At 58, famine-exposed people had 0.4 mmol/l higher 120-minute glucose than unexposed peers (95 percent CI 0.1 to 0.7), after sex and BMI. The authors note that the same cohort already had worse glucose tolerance and higher insulin at 50. Glucose and insulin both rose from 50 to 58. The rise was not faster in the exposed group (p=0.28 for glucose, p=0.09 for insulin).\n\nA 94-person intravenous glucose tolerance subsample asked whether that pattern is insulin resistance, a secretion defect, or both. Glucose tolerance (Kg) was 21 percent lower after prenatal famine (95 percent CI -41 to -4). People exposed in mid-gestation had a 53 percent lower disposition index, the product of insulin sensitivity and first-phase insulin response (95 percent CI -126 to -3). Early-gestation exposure pointed the same way and did not reach significance. The authors read the mid- and early-gestation pattern as an insulin secretion defect.\n\nNeither abstract reports HOMA-IR. The measures are 120-minute glucose and insulin, IVGTT Kg, and disposition index. Those sit on this page as the atlas home for glucose-insulin homeostasis.","caveats":"The stamp is smoke because nobody randomized a wartime siege. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim. We do not put a robust-causal stamp on this page without a feeding trial. That is a rule about design, not a claim that prenatal hunger is harmless.\n\nThis is the Roseboom, Ravelli, and de Rooij file. The Hunger Winter bundled food shortage with cold, infection, bombardment, and who was able to conceive or survive to midlife. A siege is not a randomized diet.\n\nBoth papers on this page are available here only as abstracts. The OGTT file is 702 people at 50 and 699 at 58. The IVGTT file is 94 normoglycemic adults from the same cohort. Do not read 94 intravenous tests as a population HOMA-IR.\n\nThe IVGTT authors concluded a secretion defect after mid-gestation famine. This page is insulin resistance as this atlas uses it. The abstracts do not publish a HOMA-IR number.\n\nModels adjust for sex and BMI. Adult BMI can sit on the path from prenatal famine to midlife glucose. Residual confounding remains. Education and later income still sit on who reached the exam and how they lived after the war.\n\nOmitted: Ravelli 1999 (BMI and waist at age 50, not glucose or insulin) and Stein 1995 (third-trimester weight gain and birth size). Those are other pages. We do not open a second page here.\n\nThis is a journal entry, not medical advice.","confounders":["education","disposable-income"],"paperIds":["p-pmid-16470406","p-pmid-16873799"],"contributions":[{"paperId":"p-pmid-16470406","evidenceGrade":"abstract_only","designNote":"de Rooij 2006, Dutch Famine Birth Cohort. Observational. OGTT in 702 at age 50 and 699 at age 58, term singletons born before, during, or after the 1944-1945 famine. Exposed: +0.4 mmol/l 120-min glucose at 58 (95% CI 0.1 to 0.7), adjusted sex and BMI. Rise 50 to 58 not faster in the exposed (p=0.28). abstract_only."},{"paperId":"p-pmid-16873799","evidenceGrade":"abstract_only","designNote":"de Rooij 2006, same cohort, IVGTT subsample, 94 normoglycemic. Observational. Kg -21% (95% CI -41 to -4). Midgestation disposition index -53% (-126 to -3). Early gestation lower, NS. Authors read this as an insulin secretion defect, not a sensitivity defect. abstract_only."}],"featured":false},{"id":"e-fenugreek-t","sourceId":"fenugreek","targetId":"testosterone","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Rao 2017: Testofen 600 mg, 12 wk, N=120, total and free T vs placebo. Lee-Odegard 2024: N=95, saliva T vs placebo; plasma T vs placebo P=0.122. Rao 2020 BPH: T unchanged."},"n":120,"summary":"Rao 2017 found that 600 mg of Testofen fenugreek seed extract a day for twelve weeks raised total and free testosterone versus placebo in 120 healthy men aged 43 to 70. Lee-Odegard 2024 saw a saliva testosterone rise versus placebo in 95 men and missed on plasma. Rao 2020 left testosterone unchanged in men with prostate symptoms.","mechanism":"Authors treat a fenugreek seed extract as a way to raise testosterone. They do not isolate one saponin.\n\nRao, Steels, Inder, Abraham and Vitetta assigned 120 healthy men aged 43 to 70 to 600 mg of Testofen a day or placebo for twelve weeks. Total and free serum testosterone rose versus placebo. Aging Male Symptom scores and some sexual-function items also moved.\n\nLee-Odegard, Gundersen and Drevon assigned 95 men aged 40 to 80 to 0, 600, 1200, or 1800 mg of TrigozimR plus essential nutrients for twelve weeks. Plasma total testosterone and free-testosterone index rose versus baseline and missed versus placebo (P=0.122 and 0.059). Saliva testosterone rose 37.2 percent versus placebo (P=0.042).\n\nRao and Grant assigned 100 men with benign prostate symptoms to 600 mg a day or placebo for twelve weeks. Prostate scores missed. Testosterone, free testosterone, and SHBG did not change.","caveats":"Researchers assigned people to a seed extract or a control, so this is a trial stamp. Brand, matrix, and assay split. More papers of the same design do not settle the claim.\n\nRao 2017 is a branded extract and a symptom scale as the primary. Lee-Odegard tablets also carry essential nutrients; plasma missed versus placebo. Rao 2020 is the same family of extract in men with prostate symptoms and is null on testosterone.\n\nThis is a journal entry, not medical advice and not a reason to take fenugreek to raise testosterone.","confounders":["sleep-hygiene","alcohol-intake","resistance-training"],"paperIds":["p-pmid-26791805","p-pmid-39288153","p-pmid-31828857"],"contributions":[{"paperId":"p-pmid-26791805","evidenceGrade":"abstract_only","designNote":"Rao 2017 Aging Male. RCT. Testofen 600 mg vs placebo, 12 wk, N=120 men 43-70. Total and free T vs placebo. AMS and sexual function moved. abstract_only. Archive n null."},{"paperId":"p-pmid-39288153","evidenceGrade":"full_text","designNote":"Lee-Odegard 2024 PLoS One. RCT. TrigozimR 0/600/1200/1800 mg + nutrients, 12 wk, N=95 men 40-80. Plasma T vs placebo P=0.122. Saliva T vs placebo P=0.042. full_text. Archive n null."},{"paperId":"p-pmid-31828857","evidenceGrade":"abstract_only","designNote":"Rao 2020 Phytother Res. RCT. 600 mg vs placebo, 12 wk, N=100 BPH. IPSS ns. T, free T, SHBG unchanged. abstract_only. Archive n null."}],"featured":false},{"id":"e-ferritin-cognition","sourceId":"ferritin","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Leaving iron deficiency improved named tasks in young women. A food trial and a pilot again tie the gain to a ferritin rise. Berglund 2019: LBW infants, WISC-IV at 7 not different by iron dose."},"n":null,"summary":"Treating iron deficiency in young women can move attention and memory on named tasks. Murray-Kolb and Beard (2007) showed that in a blinded 16-week trial. Two later trials in the same age band again find the gain where ferritin rose. Berglund's infant trial found no WISC-IV difference at age 7.","mechanism":"Murray-Kolb and Beard (2007) gave women aged 18 to 35 either 60 mg of iron a day or a placebo for 16 weeks. One hundred forty-nine sat eight tasks from Detterman's Cognitive Abilities Test at the start. One hundred thirteen came back. Iron-sufficient women were more accurate and faster than women with iron-deficiency anemia. Women who were iron-deficient but not anemic sat in between. After treatment, a rise in serum ferritin tracked a five- to seven-fold gain in task accuracy. A rise in hemoglobin tracked speed.\n\nIron is a cofactor in dopamine synthesis and in myelination. That is the pathway the authors point to. The identified object is leaving a deficit. Climbing a normal ferritin is a different claim.\n\nBlanton (2014) assigned 43 young women to beef or non-beef lunches, 85 grams, three times a week, for 16 weeks. Both lunches raised body iron. The lunch type did not move cognition in a consistent way. Seventeen women whose ferritin rose gained more on planning speed (One Touch Stockings of Cambridge), spatial working memory strategy, and sustained attention (Rapid Visual Information Processing) than the 26 whose ferritin did not. Food iron still belongs here because the measure is iron stores.\n\nLeonard, Chalmers, Collins, and Patterson (2015) ran a pilot. Twenty-four women with latent iron deficiency (ferritin at or below 20 μg/L and hemoglobin above 120 g/L) were randomized to placebo, 60 mg, or 80 mg of iron for 16 weeks. Eight iron-sufficient women took placebo. On the IntegNeuro battery, women whose plasma ferritin rose gained more on Impulsivity and Attention than women whose ferritin did not. The authors say a powered trial would need 26 to 84 women in each iron group.\n\nBerglund and colleagues (2019) randomized 285 marginally low-birth-weight infants (2,000 to 2,500 g) to 0, 1, or 2 mg/kg/day of iron from 6 weeks to 6 months. At age 7, 205 sat the WISC-IV. The abstract reports no significant differences between arms on that scale.","caveats":"These are young women, mostly students. They are not executives with a wellness panel. Excess iron is a different clinical object. Do not read this as high ferritin making leaders.\n\nMurray-Kolb's accuracy claim is a ferritin-responder analysis inside a randomized trial. Hemoglobin responders got speed, not accuracy.\n\nBlanton's randomization was beef versus non-beef, and that contrast failed. The cognition signal sits in who raised ferritin. Verbal free recall went the other way. Blanton treats that as likely an artifact. Forty-three women finished.\n\nLeonard is a pilot. Twenty-five women finished. Iron-deficient and iron-sufficient women did not differ at baseline on the IntegNeuro domains. The randomized treatment contrast reached significance on Impulsivity, not on the full battery. Ferritin improvers versus non-improvers is a post-hoc split. The authors asked for a larger trial.\n\nTwo later trials do not make the first one more settled. They are small, and one is a pilot.\n\nBerglund is low-birth-weight infants followed to age 7, not the young-women deficiency trial. Two hundred five of 285 were assessed. WISC-IV and the Five-to-Fifteen questionnaire did not differ by iron dose. Child Behavior Checklist externalizing scores favored the supplemented children. That is behavior, not this pair. A fourth paper does not make Murray-Kolb more settled.","confounders":["disposable-income","vitamin-supplementation"],"paperIds":["p-murray-kolb-2007","p-pmid-24379009","p-pmid-24959952","p-pmid-28953856"],"contributions":[{"paperId":"p-murray-kolb-2007","evidenceGrade":"abstract_only","designNote":"Murray-Kolb and Beard 2007. Blinded placebo-controlled iron trial, 16 weeks, women 18-35. Detterman CAT, n=149 baseline / 113 completers. Ferritin rise tied to accuracy; hemoglobin rise to speed. Gold paper. abstract_only."},{"paperId":"p-pmid-24379009","evidenceGrade":"full_text","designNote":"Blanton 2014. RCT of beef vs non-beef lunches (85 g, 3x/week, 16 weeks) in 43 young women. Both lunches raised body iron. Ferritin responders (17) improved CANTAB planning speed, SWM strategy, and attention. Lunch type did not. full_text."},{"paperId":"p-pmid-24959952","evidenceGrade":"full_text","designNote":"Leonard et al. 2015. Pilot double-blind RCT. 24 latent iron-deficient women (ferritin <=20 ug/L, Hb >120) randomized to placebo, 60 mg, or 80 mg iron for 16 weeks; 8 iron-sufficient on placebo. 25 completers. IntegNeuro: ferritin improvers gained more on Impulsivity and Attention. Authors: 26-84 per group for a powered trial. full_text."},{"paperId":"p-pmid-28953856","evidenceGrade":"abstract_only","designNote":"Berglund 2019. RCT. 285 marginally LBW (2000-2500 g) infants randomized to 0, 1, or 2 mg/kg/day iron from 6 weeks to 6 months. At 7 years, 205 assessed. No significant differences on WISC-IV or FTF. CBCL externalizing favored supplemented (P=0.045). Archive n:null; N from abstract. abstract_only. Not the young-women deficiency trial."}],"featured":false},{"id":"e-glp1-alcohol","sourceId":"glp1-agonist","targetId":"alcohol-intake","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Klausen 2026 HDD ETD -13.7 pp (CI -22.0 to -5.4), N=108 AUD+obesity. Hendershot 2025 lab grams β -0.48, N=48. Exenatide 2022 primary HDD null."},"n":108,"summary":"In 108 people seeking treatment for alcohol use disorder and obesity, weekly semaglutide 2.4 mg plus usual therapy cut heavy-drinking days by about 14 percentage points versus placebo plus the same therapy (Klausen 2026). An earlier exenatide trial missed that same primary end point.","mechanism":"GLP-1 receptors sit in gut and in reward circuits. The drugs slow the stomach and blunt cue-driven wanting. Authors treat that as a path from an incretin pen to fewer drinks, not only to a smaller waist.\n\nKlausen, Justesen, Pedersen and colleagues (2026) assigned 108 treatment-seeking adults with moderate-to-severe alcohol use disorder and obesity to weekly semaglutide 2.4 mg or saline, both with cognitive behavioural therapy, for 26 weeks. Heavy-drinking days fell 41.1 percentage points on drug versus 26.4 on placebo. Treatment difference -13.7 points (95 percent CI -22.0 to -5.4). abstract_only.\n\nHendershot, Bremmer, Paladino and colleagues (2025) assigned 48 non-treatment-seeking adults with alcohol use disorder to weekly semaglutide, titrated to 1.0 mg, or placebo for 9 weeks. Grams drunk in a laboratory task fell (beta -0.48). Drinks per drinking day fell. Drinks per calendar day did not. full_text.\n\nKlausen 2022 assigned 127 treatment-seeking patients to weekly exenatide 2 mg or placebo for 26 weeks. Heavy-drinking days did not fall in the full sample. Cue reactivity in the ventral striatum did. An obese subgroup drank less. full_text.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. The file is mixed, so confidence stays contested. Paper count does not raise it.\n\nThe 2026 Lancet trial is one centre, 108 people, obesity required, and both arms got therapy. Eighty-one percent finished.\n\nHendershot is 48 people, 9 weeks, and not a treatment-seeking sample. Calendar-day drinks did not move.\n\nExenatide missed the primary end point in the full sample. A later oral semaglutide trial (Schacht 2026, N=50) missed laboratory craving and still cut heavy-drinking days.\n\nDulaglutide cut drinks as a secondary look inside a smoking-cessation trial, not an alcohol-use-disorder trial.\n\nDid not hang the electronic-record association or the Reddit self-report file. Did not hang the narrative review.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["ultraprocessed-food","sedentary-time","depression","disposable-income"],"paperIds":["p-pmid-42070571","p-pmid-39937469","p-pmid-36066977","p-pmid-42522065","p-pmid-37991022"],"contributions":[{"paperId":"p-pmid-42070571","evidenceGrade":"abstract_only","designNote":"Klausen 2026 Lancet. Identifying RCT. Weekly semaglutide 2.4 mg vs saline + CBT both arms. 26 wk. N=108 AUD+obesity. HDD ETD -13.7 pp (CI -22.0 to -5.4) P=0.0015. 88/108 completed. Archive n null. abstract_only."},{"paperId":"p-pmid-39937469","evidenceGrade":"full_text","designNote":"Hendershot 2025 JAMA Psychiatry. Phase 2 RCT. Weekly semaglutide to 1.0 mg vs placebo, 9 wk. N=48 non-treatment-seeking AUD. Lab grams β -0.48 P=0.01. Drinks/drinking day down. Drinks/calendar day NS. Archive n null. full_text."},{"paperId":"p-pmid-36066977","evidenceGrade":"full_text","designNote":"Klausen 2022 JCI Insight. RCT. Weekly exenatide 2 mg vs placebo + CBT, 26 wk. N=127 AUD. Primary HDD NS. Ventral-striatum cue reactivity down. Obese subgroup HDD and intake down. Archive n null. full_text."},{"paperId":"p-pmid-42522065","evidenceGrade":"abstract_only","designNote":"Schacht 2026 Am J Psychiatry. Phase 2 RCT. Oral semaglutide 3 then 7 mg/d vs placebo, 8 wk. N=50 treatment-seeking AUD. Primary lab craving NS. HDD down (b=-0.580). Archive n null. abstract_only."},{"paperId":"p-pmid-37991022","evidenceGrade":"full_text","designNote":"Probst 2023 JCI Insight. Predefined secondary in smoking-cessation RCT. Dulaglutide vs placebo, 12 wk. N=151 baseline drinkers of 255. 29% less alcohol (RE 0.71, CI 0.52-0.97). Not an AUD trial. Archive n null. full_text."}],"featured":false},{"id":"e-glp1-cv","sourceId":"glp1-agonist","targetId":"cardiovascular","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.8,"note":"SELECT HR 0.80 (0.72-0.90) 3-point MACE, N=17604. LEADER HR 0.87 (0.78-0.97), N=9340. PIONEER 6 oral HR 0.79 (0.57-1.11), N=3183, noninferiority."},"n":17604,"summary":"In 17,604 adults with overweight or obesity, established heart disease, and no diabetes, weekly semaglutide 2.4 mg cut a first heart attack, stroke, or cardiovascular death by 20 percent versus placebo (Lincoff 2023). Liraglutide did the same in type 2 diabetes (Marso 2016). Oral semaglutide was not worse for that same count (Husain 2019).","mechanism":"GLP-1 agonists slow the stomach, raise insulin when glucose is high, and cut appetite. Weight, blood pressure, and lipids then fall. Authors also talk about a direct vessel effect: less inflammation, less plaque strain. The trials count events, not a mechanism assay.\n\nLincoff, Brown-Frandsen, Colhoun and colleagues (2023) assigned 17,604 people aged 45 or older with preexisting cardiovascular disease and a BMI of 27 or more, and no diabetes, to weekly semaglutide 2.4 mg or placebo. Mean follow-up was 39.8 months. The primary composite was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Events: 569 of 8803 (6.5 percent) on drug versus 701 of 8801 (8.0 percent) on placebo. Hazard ratio 0.80 (95 percent CI 0.72 to 0.90). abstract_only.\n\nMarso, Daniels, Brown-Frandsen and colleagues (2016) assigned 9340 people with type 2 diabetes and high cardiovascular risk to daily liraglutide or placebo. Median follow-up was 3.8 years. The same three-point composite occurred in 608 of 4668 (13.0 percent) versus 694 of 4672 (14.9 percent). Hazard ratio 0.87 (0.78 to 0.97). Cardiovascular death 0.78 (0.66 to 0.93). full_text.\n\nHusain, Birkenfeld, Donsmark and colleagues (2019) assigned 3,183 people with type 2 diabetes at high cardiovascular risk to daily oral semaglutide or placebo. Median time in the trial was 15.9 months. The trial was built to rule out an 80 percent excess of events, not to prove a cut. Events: 61 of 1591 versus 76 of 1592. Hazard ratio 0.79 (0.57 to 1.11). P less than 0.001 for noninferiority. abstract_only.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. SELECT is secondary prevention in people without diabetes. LEADER is type 2 diabetes at high risk. Neither is a primary-prevention claim in lean people.\n\nPIONEER 6 is the same three-point count under an oral pen. It was a safety trial. The interval for a reduction crosses 1. Follow-up was short.\n\nIn SELECT, 16.6 percent left the drug for an adverse event versus 8.2 percent on placebo. Gut symptoms were the usual reason in both injectables.\n\nA large share of the event drop tracks weight and the usual risk factors. The authors have not isolated a vessel-only path.\n\nDid not hang STEP-HFpEF function, diuretic, NT-proBNP, or NYHA files. Those are symptoms and heart-failure visits, not this three-point count. Did not hang the SELECT HbA1c subgroup, the SELECT death satellite, or the stroke-subtype post-hoc.\n\nDid not hang the LEADER design paper, the baseline calcitonin file, the post-myocardial-infarction satellite, or the heart-failure subgroup.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["ultraprocessed-food","sedentary-time","aerobic-exercise","smoking"],"paperIds":["p-pmid-37952131","p-pmid-27295427","p-pmid-31185157"],"contributions":[{"paperId":"p-pmid-37952131","evidenceGrade":"abstract_only","designNote":"Lincoff 2023 NEJM SELECT. Identifying RCT. Weekly semaglutide 2.4 mg vs placebo. N=17604, age>=45, BMI>=27, established CVD, no diabetes. 3-point MACE HR 0.80 (0.72-0.90). Mean follow-up 39.8 mo. Archive n null. abstract_only."},{"paperId":"p-pmid-27295427","evidenceGrade":"full_text","designNote":"Marso 2016 NEJM LEADER. Identifying RCT. Daily liraglutide vs placebo. N=9340 T2D high CV risk. 3-point MACE HR 0.87 (0.78-0.97). CV death HR 0.78. Median 3.8 y. Archive n null. full_text."},{"paperId":"p-pmid-31185157","evidenceGrade":"abstract_only","designNote":"Husain 2019 NEJM PIONEER 6. Identifying RCT, noninferiority. Daily oral semaglutide vs placebo. N=3183 T2D high CV risk. 3-point MACE 61 vs 76, HR 0.79 (0.57-1.11). Median 15.9 mo. Archive n null. abstract_only."}],"featured":false},{"id":"e-glp1-depression","sourceId":"glp1-agonist","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"STEP 1-3 PHQ-9 ETD -0.56 (CI -0.81 to -0.32) from a floor of ~2. N=3377, no known major psychopathology. Badulescu 2026 MDD: depression severity NS. N=72."},"n":3377,"summary":"In 3,377 adults with overweight or obesity and no known major psychiatric illness, weekly semaglutide 2.4 mg did not raise PHQ-9 depression scores versus placebo (Wadden 2024). A later trial in major depression found no change in symptom severity.","mechanism":"Weight loss can lift mood in people who were not depressed. A gut-hormone effect on reward circuits is also on the table. Spontaneous safety reports raised a suicide scare. The assigned trials count a PHQ-9 or a structured depression scale, not a database of tips.\n\nWadden, Brown, Egebjerg and colleagues (2024) pooled STEP 1, 2, and 3 (68 weeks) and looked at STEP 5 (104 weeks). Adults with overweight or obesity; STEP 2 also had type 2 diabetes. People with recent severe depression were kept out. Baseline PHQ-9 was about 2, no or minimal symptoms. At week 68 the scores were 2.0 on semaglutide and 2.4 on placebo. Treatment difference -0.56 (95 percent CI -0.81 to -0.32). A shift to a worse PHQ-9 band was less common on drug (odds ratio 0.63). On the Columbia scale, 1 percent or fewer reported suicidal ideation or behaviour. full_text.\n\nBadulescu, Gill, Shah and colleagues (2026) assigned 72 adults with major depression, cognitive impairment, and overweight to oral semaglutide 14 mg or placebo for 16 weeks. Depression severity and suicidal ideation did not differ. Executive function, the primary end point, did not move. abstract_only.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. The file is contested. STEP excluded people with recent major depression and started on a PHQ-9 floor of 2. A half-point gap is not an antidepressant claim.\n\nThe 2026 depression trial is 72 people and 16 weeks. Symptom scores did not move.\n\nDid not hang FAERS or VigiBase reports (p-pmid-38087976, p-pmid-39433133): spontaneous tips, no assigned trial.\n\nDid not hang the antidepressant-at-baseline weight look, the Australian dispensing association, or the GRADE diabetes-distress file.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["sleep-hygiene","aerobic-exercise","alcohol-intake","disposable-income"],"paperIds":["p-pmid-39226070","p-pmid-41218611"],"contributions":[{"paperId":"p-pmid-39226070","evidenceGrade":"full_text","designNote":"Wadden 2024 JAMA Intern Med. Post hoc of STEP 1-3 (N=3377) and STEP 5 (N=304) RCTs. Semaglutide 2.4 mg vs placebo. PHQ-9 ETD -0.56. Worse-band OR 0.63. C-SSRS ideation/behaviour <=1%. No known major psychopathology. Archive n null. full_text."},{"paperId":"p-pmid-41218611","evidenceGrade":"abstract_only","designNote":"Badulescu 2026 Med. RCT. Oral semaglutide 14 mg vs placebo, 16 wk, adjunct. N=72 MDD + cognitive impairment + overweight. Depression severity NS. Suicidal ideation NS. Primary executive function NS. Archive n null. abstract_only."}],"featured":false},{"id":"e-glp1-fertility","sourceId":"glp1-agonist","targetId":"fertility","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Salamun 2018 IVF PR/ET 85.7% vs 28.6% (lira+MET vs MET), N=28. Nylander 2018 bleeding ratio +0.14, N=72. Chen 2025 pregnancy 35% vs 15%."},"n":72,"summary":"In 28 infertile obese women with PCOS, twelve weeks of low-dose liraglutide added to metformin, then stopped for four weeks, was followed by more IVF pregnancies per embryo transfer than metformin alone: 85.7 percent versus 28.6 percent (Salamun 2018). The file is small and stacked.","mechanism":"Weight loss can restart ovulation in PCOS. Authors also talk about a direct incretin effect on the ovary and the lining of the womb. The trials count pregnancies, bleeding, ovarian size, or sperm shape. They do not count a testosterone number as the outcome.\n\nSalamun, Jensterle, Janez and Vrtacnik Bokal (2018) assigned 28 infertile obese women with PCOS to metformin or metformin plus liraglutide 1.2 mg a day for 12 weeks, then a 4-week washout, then IVF. Pregnancy per embryo transfer was 85.7 percent versus 28.6 percent (P=0.03). Weight loss was similar. abstract_only.\n\nNylander, Frossing, Clausen and colleagues (2018) assigned 72 women with PCOS to liraglutide 1.8 mg a day or placebo for 26 weeks. The bleeding ratio rose more on drug (between-group 0.14). SHBG rose. Free testosterone and ovarian volume fell. abstract_only.\n\nChen 2025 assigned 100 overweight women with PCOS to semaglutide plus metformin or metformin alone. After the combination phase, natural pregnancy was 35 percent versus 15 percent. full_text.\n\nGregoric 2025 assigned 25 men with obesity, type 2 diabetes, and functional hypogonadism to weekly semaglutide or testosterone undecanoate. Normal sperm shape rose on semaglutide (2 percent to 4 percent). The testosterone arm lost concentration. full_text.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. The file is small, often open-label, and often stacked on metformin, so confidence stays contested.\n\nSalamun is 28 women and a washout before stimulation. Nylander counts bleeding and ovarian volume, not a live birth. Chen stacks semaglutide on metformin. Gregoric compares semaglutide with a testosterone shot that can suppress sperm, in 25 men.\n\nThese drugs are not studied as a treatment to take while pregnant. The IVF trial stopped the pen before stimulation.\n\nDid not hang the GLP-1 versus birth-control-pill proteomic file, the exenatide-dapagliflozin-phentermine stack, or the reviews.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["ultraprocessed-food","insulin-resistance","sedentary-time","aerobic-exercise"],"paperIds":["p-pmid-29703793","p-pmid-28479118","p-pmid-40713699","p-pmid-39511836"],"contributions":[{"paperId":"p-pmid-29703793","evidenceGrade":"abstract_only","designNote":"Salamun 2018 Eur J Endocrinol. Pilot open-label RCT. MET vs MET+lira 1.2 mg, 12 wk, 4-wk washout, then IVF. N=28 obese PCOS infertility. PR/ET 85.7% vs 28.6% P=0.03. Weight loss similar. Archive n null. abstract_only."},{"paperId":"p-pmid-28479118","evidenceGrade":"abstract_only","designNote":"Nylander 2018 RBMO. RCT. Liraglutide 1.8 mg vs placebo, 26 wk. N=72 PCOS. Bleeding ratio +0.14 vs placebo. SHBG up, free T down, ovarian volume -1.6 ml. Archive n null. abstract_only."},{"paperId":"p-pmid-40713699","evidenceGrade":"full_text","designNote":"Chen 2025 Reprod Biol Endocrinol. Open-label RCT. Semaglutide 1 mg QW + MET vs MET, 16 wk, then MET to week 40. N=100 overweight PCOS. Natural pregnancy 35% vs 15%. Archive n null. full_text."},{"paperId":"p-pmid-39511836","evidenceGrade":"full_text","designNote":"Gregoric 2025 DOM. Open-label RCT. Semaglutide 1 mg/wk vs TU 1000 mg. N=25 men T2D+obesity+FH, 24 wk. Normal morphology 2% to 4% on sema P=0.012. TRT cut concentration. Archive n null. full_text."}],"featured":false},{"id":"e-glp1-insulin","sourceId":"glp1-agonist","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"percent_change","value":-24,"note":"SURPASS-2 HOMA2-IR -15.5 to -24.0% tirzepatide vs -5.1% semaglutide 1 mg, N=1879 T2D. Heise 2022 clamp M vs placebo. STEP 1 HOMA-IR vs placebo."},"n":1879,"summary":"In 1,879 people with type 2 diabetes, weekly tirzepatide cut HOMA2 insulin resistance by about 16 to 24 percent, more than weekly semaglutide 1 mg (Frias 2024). A clamp study found the same direction versus placebo (Heise 2022).","mechanism":"These drugs raise insulin when glucose is high and cut glucagon. Weight then falls. Both paths can make insulin work better. A clamp measures that directly. HOMA2-IR is a fasting worksheet.\n\nHeise, Mari, DeVries and colleagues (2022) assigned adults with type 2 diabetes on metformin to weekly tirzepatide 15 mg, semaglutide 1 mg, or placebo for 28 weeks. The primary end point was change in the clamp disposition index versus placebo. Insulin sensitivity (M value) and secretion both moved. abstract_only.\n\nA meal-test look at the same trial (Mather 2024) found a larger gain in model insulin sensitivity on tirzepatide than on semaglutide, with less total insulin secreted for the glucose that remained. abstract_only.\n\nFrias, De Block, Brown and colleagues (2024) looked back at SURPASS-2: 1,879 people assigned to tirzepatide 5, 10, or 15 mg or semaglutide 1 mg for 40 weeks. HOMA2-IR fell 15.5 to 24.0 percent on tirzepatide versus 5.1 percent on semaglutide. full_text.\n\nKosiborod 2023 found HOMA-IR fell more on semaglutide 2.4 mg than on placebo in STEP 1, people with overweight or obesity and no diabetes. full_text.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. The living page is named for HOMA-IR. Heise used a clamp. SURPASS-2 used HOMA2-IR and had no placebo arm.\n\nThese are people with type 2 diabetes (Heise, SURPASS-2) or obesity without diabetes (STEP). The kilograms that fall with the pen carry a large share of the HOMA change.\n\nDid not hang the SELECT adiposity-and-events file (p-pmid-41138739): that is waist and MACE, not HOMA.\n\nDid not hang Chen 2025 (p-pmid-40713699): semaglutide stacked on metformin in PCOS.\n\nDid not hang the SURMOUNT weight-loss-bin HOMA look or the four-trial PCOS meta-analysis.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["ultraprocessed-food","sedentary-time","aerobic-exercise","sleep-hygiene"],"paperIds":["p-pmid-35468322","p-pmid-38795393","p-pmid-38252888","p-pmid-36200477"],"contributions":[{"paperId":"p-pmid-35468322","evidenceGrade":"abstract_only","designNote":"Heise 2022 Lancet D&E. Identifying clamp RCT. Tirzepatide 15 mg vs semaglutide 1 mg vs placebo, 28 wk, T2D on metformin. Primary: clamp disposition index vs placebo. M value (insulin sensitivity) secondary. Archive n null. abstract_only."},{"paperId":"p-pmid-38795393","evidenceGrade":"abstract_only","designNote":"Mather 2024 JCEM. Same NCT03951753 meal-test models. Tirzepatide vs semaglutide vs placebo. Insulin sensitivity up more on tirzepatide (P<.01). ISR AUC down. Archive n null. abstract_only."},{"paperId":"p-pmid-38252888","evidenceGrade":"full_text","designNote":"Frias 2024 JCEM SURPASS-2 post hoc. RCT assignment. Tirzepatide 5/10/15 vs semaglutide 1 mg, 40 wk. N=1879 T2D. HOMA2-IR -15.5 to -24.0% vs -5.1%. No placebo. Archive n null. full_text."},{"paperId":"p-pmid-36200477","evidenceGrade":"full_text","designNote":"Kosiborod 2023 DOM. Exploratory STEP 1/4. Weekly semaglutide 2.4 mg vs placebo. Overweight/obesity, no diabetes. STEP 1 HOMA-IR down vs placebo P<=.001. N=1961 STEP 1. Archive n null. full_text."}],"featured":false},{"id":"e-glp1-kidney","sourceId":"glp1-agonist","targetId":"kidney-disease","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.76,"note":"FLOW HR 0.76 (0.66-0.88) major kidney events, N=3533 T2D+CKD. LEADER renal HR 0.78 (0.67-0.92), N=9340. Kidney-only FLOW 0.79."},"n":3533,"summary":"In 3,533 adults with type 2 diabetes and chronic kidney disease, weekly semaglutide 1.0 mg cut a first major kidney event (kidney failure, a 50 percent drop in eGFR, or death from kidney or heart causes) by 24 percent versus placebo (hazard ratio 0.76; Perkovic 2024). Daily liraglutide cut a similar renal composite (Mann 2017).","mechanism":"The drugs slow the stomach, raise insulin when glucose is high, and cut appetite. Weight, blood pressure, and glucose then fall. Authors also name a kidney-level path: less pressure in the filter and less albumin in the urine. The trials count events and the eGFR slope, not a biopsy.\n\nPerkovic, Tuttle, Rossing and colleagues (2024) assigned 3,533 people with type 2 diabetes and chronic kidney disease to weekly semaglutide 1.0 mg or placebo. Median follow-up was 3.4 years after the trial stopped early. The primary composite was kidney failure (dialysis, a transplant, or eGFR under 15), a 50 percent eGFR drop from baseline, or death from kidney or cardiovascular causes. First events: 331 of 1767 versus 410 of 1766. Hazard ratio 0.76 (95 percent CI 0.66 to 0.88). The kidney-only pieces sat at 0.79 (0.66 to 0.94). The yearly eGFR fall was slower by 1.16 ml per minute per 1.73 m2. abstract_only.\n\nMann, Orsted, Brown-Frandsen and colleagues (2017) reported the prespecified renal secondary of LEADER. 9,340 people with type 2 diabetes and high cardiovascular risk. Daily liraglutide or placebo. Median 3.84 years. The composite was new persistent macroalbuminuria, a persistent doubling of creatinine, end-stage kidney disease, or death from kidney disease. Events: 268 of 4668 versus 337 of 4672. Hazard ratio 0.78 (0.67 to 0.92). The cut was mostly new macroalbuminuria (161 versus 215; 0.74, 0.60 to 0.91). abstract_only.\n\nShaman, Bain, Bakris and colleagues (2022) pooled SUSTAIN 6 and LEADER (12,637 people). Semaglutide or liraglutide cut urine albumin 24 percent versus placebo at two years and slowed a persistent 50 percent eGFR drop (hazard ratio 0.80, 0.66 to 0.97). full_text.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. FLOW stopped early at a planned look. The primary composite includes death from heart causes, not only a kidney certificate.\n\nLEADER's renal count was a prespecified secondary. The cut was mostly new albumin in the urine, not dialysis. The pooled file restacks SUSTAIN 6 and LEADER. It is not a third assignment.\n\nFLOW is type 2 diabetes and established chronic kidney disease. LEADER is type 2 diabetes at high heart risk, not a dedicated kidney trial. Neither is a claim in lean people with healthy kidneys.\n\nGut symptoms were the usual reason people left the drug.\n\nDid not hang the FLOW heart-failure satellite, the mineralocorticoid-receptor subgroup, or the cardiovascular-status split. Those are not a new kidney-event count. Did not hang a 24-week albuminuria trial in 101 people without diabetes, a phase-2 cotadutide file, a journal-club note, or a retrospective in advanced kidney failure.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["smoking","ultraprocessed-food","sedentary-time","aerobic-exercise","cardiovascular"],"paperIds":["p-pmid-38785209","p-pmid-28854085","p-pmid-34903039"],"contributions":[{"paperId":"p-pmid-38785209","evidenceGrade":"abstract_only","designNote":"Perkovic 2024 NEJM FLOW. Identifying RCT. Weekly semaglutide 1.0 mg vs placebo. N=3533 T2D+CKD. Primary kidney composite 331 vs 410, HR 0.76 (0.66-0.88). Kidney-only 0.79. Median 3.4 y. Archive n null. abstract_only."},{"paperId":"p-pmid-28854085","evidenceGrade":"abstract_only","designNote":"Mann 2017 NEJM LEADER renal. Identifying RCT secondary. Daily liraglutide vs placebo. N=9340 T2D. Renal composite 268 vs 337, HR 0.78 (0.67-0.92). Driven by macroalbuminuria. Archive n null. abstract_only."},{"paperId":"p-pmid-34903039","evidenceGrade":"full_text","designNote":"Shaman 2022 Circulation. Pooled SUSTAIN 6 + LEADER n=12637. Albuminuria -24% at 2y. Persistent 50% eGFR drop HR 0.80 (0.66-0.97). Companion, not a third assignment. Archive n null. full_text."}],"featured":false},{"id":"e-glp1-mortality","sourceId":"glp1-agonist","targetId":"mortality","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.81,"note":"SELECT all-cause HR 0.81 (0.71-0.93), 375 vs 458 deaths, N=17604, prespecified secondary. LEADER all-cause HR 0.85 (0.74-0.97), 381 vs 447, N=9340."},"n":17604,"summary":"In SELECT, weekly semaglutide 2.4 mg cut death from any cause versus placebo in 17,604 adults with overweight or obesity and established heart disease (hazard ratio 0.81; Lincoff 2023). Daily liraglutide did the same in type 2 diabetes (Marso 2016).","mechanism":"Fewer heart attacks and strokes mean fewer deaths. Weight, blood pressure, and glucose also fall. The count here is every recorded death, not only a cardiovascular certificate.\n\nLincoff, Brown-Frandsen, Colhoun and colleagues (2023) assigned 17,604 people aged 45 or older with preexisting cardiovascular disease and a BMI of 27 or more, and no diabetes, to weekly semaglutide 2.4 mg or placebo. All-cause death was a prespecified secondary end point. Deaths: 375 of 8803 (4.3 percent) versus 458 of 8801 (5.2 percent). Hazard ratio 0.81 (95 percent CI 0.71 to 0.93). abstract_only.\n\nMarso, Daniels, Brown-Frandsen and colleagues (2016) assigned 9340 people with type 2 diabetes and high cardiovascular risk to daily liraglutide or placebo. Median follow-up was 3.8 years. Death from any cause: 381 of 4668 (8.2 percent) versus 447 of 4672 (9.6 percent). Hazard ratio 0.85 (0.74 to 0.97). full_text.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. All-cause death was a prespecified secondary end point in both trials, not the primary three-point event count.\n\nIn SELECT, cardiovascular death missed the hierarchical P value, so the all-cause hazard ratio is not a confirmatory test. LEADER reported P=0.02 for death from any cause.\n\nSELECT is secondary prevention without diabetes. LEADER is type 2 diabetes at high risk. Neither is a primary-prevention claim in lean people.\n\nGut symptoms drove most dropouts.\n\nDid not hang FLOW kidney, the NASH-cirrhosis file, the MESA allocation paper, or the outcome-trial metas. Those are not a clean assigned death count in SELECT or LEADER.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["smoking","aerobic-exercise","ultraprocessed-food","sedentary-time"],"paperIds":["p-pmid-37952131","p-pmid-27295427"],"contributions":[{"paperId":"p-pmid-37952131","evidenceGrade":"abstract_only","designNote":"Lincoff 2023 NEJM SELECT. Identifying RCT. Weekly semaglutide 2.4 mg vs placebo. N=17604. Prespecified all-cause death 375 vs 458, HR 0.81 (0.71-0.93). Archive n null. abstract_only."},{"paperId":"p-pmid-27295427","evidenceGrade":"full_text","designNote":"Marso 2016 NEJM LEADER. Identifying RCT. Daily liraglutide vs placebo. N=9340 T2D. Prespecified all-cause death 381 vs 447, HR 0.85 (0.74-0.97). Median 3.8 y. Archive n null. full_text."}],"featured":false},{"id":"e-glp1-osa","sourceId":"glp1-agonist","targetId":"sleep-apnea","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"SURMOUNT-OSA AHI ETD -20.0/h trial 1 (CI -25.8 to -14.2), -23.8/h trial 2 (CI -29.6 to -17.9). N=469. 52 wk. Malhotra 2024."},"n":469,"summary":"In two 52-week trials of adults with obesity and moderate-to-severe sleep apnea, weekly tirzepatide cut the apnea-hypopnea index by about 20 to 24 events per hour versus placebo (Malhotra, Grunstein, Fietze 2024).","mechanism":"Tirzepatide copies two gut hormones, GIP and GLP-1. They slow the stomach, raise insulin when glucose is high, and cut appetite. Fat in the tongue and neck then falls as weight falls, and the airway stays open more of the night.\n\nMalhotra, Grunstein, Fietze and colleagues (2024) ran two phase 3 trials in adults with obesity and an apnea-hypopnea index of 15 or more. Trial 1 enrolled people not on a breathing machine. Trial 2 enrolled people who were. Assignment was the highest tolerated weekly tirzepatide, 10 or 15 mg, or placebo, for 52 weeks. The primary end point was change in events per hour of sleep. In trial 1 the treatment difference was -20.0 events per hour (95 percent CI -25.8 to -14.2). In trial 2 it was -23.8 (-29.6 to -17.9). full_text.\n\nA later look at the same trials (Malhotra 2025) found that a home sleep test moved as early as week 4, but the gap versus placebo was not clear until week 20, and the size of the apnea change tracked the weight that was lost. full_text.\n\nFalcon, Xie, Redline and colleagues (2026) split the same file by age, sex, starting AHI, BMI, and neck size. The AHI fall showed up in each slice. abstract_only.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. The two trials are one program in people with obesity and moderate-to-severe apnea. They do not speak for lean people or mild snoring.\n\nA large share of the apnea change tracks weight. The authors have not isolated a direct airway effect.\n\nGut side effects were the usual reason people left. Trial 2 took people off their breathing machine before the sleep tests.\n\nDid not hang Kanu 2025 (p-pmid-40774158): sleep and quality-of-life scores in the same trials, not the event count.\n\nDid not hang the 2026 oral semaglutide liver file (p-pmid-41066034): the title is liver, not apnea.\n\nDid not hang the claims-database semaglutide association (p-pmid-41915556): new-onset billing codes, not an assigned AHI.\n\nDid not hang the Annals journal-club note or the hypoxic-burden commentary.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["ultraprocessed-food","sedentary-time","aerobic-exercise","sleep-hygiene"],"paperIds":["p-pmid-38912654","p-pmid-41135142","p-pmid-42675225"],"contributions":[{"paperId":"p-pmid-38912654","evidenceGrade":"full_text","designNote":"Malhotra 2024 NEJM SURMOUNT-OSA. Identifying RCT, two 52-wk phase 3 trials. Tirzepatide 10/15 mg vs placebo. Moderate-to-severe OSA + obesity. AHI ETD -20.0/h (trial 1, no PAP) and -23.8/h (trial 2, PAP). N=469 from paper. Archive n null. full_text."},{"paperId":"p-pmid-41135142","evidenceGrade":"full_text","designNote":"Malhotra 2025 Sleep Med. Same SURMOUNT-OSA program. Time course and weight association for AHI and hypoxic burden. Home pAHI vs baseline by week 4; vs placebo by week 20. AHI change tracked weight. Archive n null. full_text."},{"paperId":"p-pmid-42675225","evidenceGrade":"abstract_only","designNote":"Falcon 2026 JCSM. Post hoc SURMOUNT-OSA. AHI, hypoxic burden, weight, BP by age, sex, baseline AHI, BMI, neck. AHI down in each slice. 68-79% improved AHI class on drug. Archive n null. abstract_only."}],"featured":false},{"id":"e-glp1-strength","sourceId":"glp1-agonist","targetId":"muscle-strength","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"percent_change","value":-10.9,"note":"SURMOUNT-1 DXA substudy N=160. Lean mass -10.9% tirzepatide vs -2.6% placebo. Fat mass -33.9% vs -8.2%. About 25% of lost weight was lean on both arms."},"n":160,"summary":"In 160 adults with obesity who sat for a DXA scan in SURMOUNT-1, weekly tirzepatide cut lean mass by 10.9 percent versus 2.6 percent on placebo (Look 2025). About a quarter of the lost weight was lean on both arms. Fat mass fell more.","mechanism":"The pen cuts appetite. People eat less. Fat falls. Some lean tissue falls with it, as it does on a diet. That is not a stronger contraction and not a gym session.\n\nLook, Dunn, Kushner and colleagues (2025) scanned 160 of the 2,539 SURMOUNT-1 participants at baseline and week 72. Body weight, fat mass, and lean mass fell more on tirzepatide than on placebo: -21.3, -33.9, and -10.9 percent versus -5.3, -8.2, and -2.6 percent. Of the weight that was lost, about 75 percent was fat and 25 percent was lean on both arms. full_text.\n\nMcCrimmon, Catarig, Frias and colleagues (2021) scanned 178 people with type 2 diabetes in SUSTAIN 8. Weekly semaglutide 1.0 mg and daily canagliflozin 300 mg both trimmed fat and lean mass. Fat fell 3.4 kg versus 2.6 kg. Lean fell 2.3 kg versus 1.5 kg. There was no placebo arm. full_text.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. The living page also covers a one-rep max. These scans are lean mass, not a lift.\n\nLean mass fell because weight fell. The share that was lean matched placebo. Water and glycogen can move a DXA reading without a weaker muscle.\n\nSURMOUNT-1 is obesity without diabetes. SUSTAIN 8 is type 2 diabetes versus an SGLT2 pill, not versus placebo.\n\nDid not hang the parent weight-loss papers (SURMOUNT-1, SURMOUNT-2, STEP 1) or the diabetes-prevention extension: those count kilograms, not lean mass.\n\nDid not hang the apitegromab-plus-tirzepatide stack.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["resistance-training","protein-intake","sedentary-time","aerobic-exercise"],"paperIds":["p-pmid-39996356","p-pmid-31897524"],"contributions":[{"paperId":"p-pmid-39996356","evidenceGrade":"full_text","designNote":"Look 2025 DOM. SURMOUNT-1 DXA substudy. Identifying RCT. Tirzepatide vs placebo, 72 wk. N=160 (124/36). Lean -10.9% vs -2.6%. Fat -33.9% vs -8.2%. ~25% of loss lean both arms. Archive n null. full_text."},{"paperId":"p-pmid-31897524","evidenceGrade":"full_text","designNote":"McCrimmon 2021 Diabetologia. SUSTAIN 8 DXA. RCT. Semaglutide 1 mg vs canagliflozin 300 mg, 52 wk. N=178 T2D (114 in confirmatory). Lean -2.3 vs -1.5 kg. Fat -3.4 vs -2.6 kg. No placebo. Archive n null. full_text."}],"featured":false},{"id":"e-glp1-wellbeing","sourceId":"glp1-agonist","targetId":"wellbeing","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"STEP 1 IWQOL-Lite-CT Physical Function MWPC 51.8% vs 28.3%. SF-36 PF MWPC 39.8% vs 24.1%. Confirmatory secondary. Rubino 2024. OASIS 4 IWQOL PF P<0.001."},"n":1961,"summary":"In the STEP 1 trial of weekly semaglutide 2.4 mg, more people crossed a meaningful threshold on the Impact of Weight on Quality of Life physical-function scale than on placebo: 51.8 percent versus 28.3 percent (Rubino 2024). The same direction showed up on SF-36 physical functioning.","mechanism":"The pen cuts weight. Stairs, work, and self-consciousness about size then get easier to score. That is a quality-of-life scale, not a depression diagnosis.\n\nRubino, Bjorner, Rathor and colleagues (2024) pooled patient-reported scores from STEP 1 to 4. IWQOL-Lite-CT and SF-36 physical functioning were confirmatory secondary end points in STEP 1 and 2 (and SF-36 in STEP 4). More people on semaglutide 2.4 mg than on placebo crossed a meaningful within-person change on IWQOL physical function in STEP 1 (51.8 versus 28.3 percent) and STEP 2 (39.6 versus 29.5 percent). SF-36 physical functioning moved the same way. Other subscales rose numerically except Role Emotional in STEP 2. abstract_only.\n\nWharton, Lingvay, Bogdanski and colleagues (2025) assigned 307 adults with overweight or obesity and no diabetes to daily oral semaglutide 25 mg or placebo for 64 weeks. IWQOL-Lite-CT Physical Function, a confirmatory secondary end point, improved on drug (P less than 0.001). abstract_only.","caveats":"Someone was assigned a pen, so the stamp is an RCT stamp. These scores track weight-related function. They are not a treatment for depression.\n\nA later meta-analysis of the same STEP programme found average SF-36 physical-functioning gains of about 1.7 points, below a 3.7-point within-person threshold. The share who crossed a threshold still favoured the pen.\n\nSTEP 2 is type 2 diabetes; the other STEP files are obesity without diabetes. Gut symptoms were common.\n\nDid not hang the IWQOL validation paper, the oral-versus-injectable indirect comparison, or the Cochrane liraglutide review.\n\nThis page is a journal entry. It is not medical advice and not a reason to start or stop a drug.","confounders":["aerobic-exercise","depression","sedentary-time","disposable-income"],"paperIds":["p-pmid-38698650","p-pmid-40934115"],"contributions":[{"paperId":"p-pmid-38698650","evidenceGrade":"abstract_only","designNote":"Rubino 2024 DOM. STEP 1-4 PROs. Identifying RCT secondaries. Semaglutide 2.4 mg vs placebo, 68 wk. IWQOL-Lite-CT PF MWPC STEP 1 51.8% vs 28.3%. SF-36 PF same direction. Archive n null; STEP 1 N=1961. abstract_only."},{"paperId":"p-pmid-40934115","evidenceGrade":"abstract_only","designNote":"Wharton 2025 NEJM OASIS 4. RCT. Oral semaglutide 25 mg vs placebo, 64 wk. N=307 overweight/obesity, no diabetes. IWQOL-Lite-CT Physical Function confirmatory secondary P<0.001. Archive n null. abstract_only."}],"featured":false},{"id":"e-green-tea-cognition","sourceId":"green-tea","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Wightman 2012: EGCG 135/270 mg, N=27, cognition and mood ns; CBF down at 135 mg. Dietz 2019: matcha vs placebo, N=23, attention/psychomotor speed up. Isolate vs tea matrix."},"n":27,"summary":"Wightman 2012 found that 135 or 270 mg of epigallocatechin gallate did not change computerised cognitive tasks or mood versus placebo in 27 healthy adults, though frontal blood flow fell at the lower dose. Dietz 2019 saw a small attention and psychomotor-speed rise after a matcha drink in 23 people.","mechanism":"Authors treat EGCG as the green-tea catechin that might change blood flow or attention. They do not isolate caffeine from the tea matrix.\n\nWightman, Haskell, Forster, Veasey and Kennedy crossed 27 healthy adults through placebo, 135 mg, and 270 mg of EGCG. After 45 minutes they ran frontal-cortex tasks for 42 minutes. 135 mg lowered oxygenated and total haemoglobin in frontal cortex versus placebo. No cognitive or mood measure moved.\n\nDietz, Dekker and Piqueras-Fiszman crossed 23 people through matcha tea, a matcha bar (4 g powder each), and matched placebos. Basic attention and psychomotor speed improved versus placebo. Other memory tasks barely moved. Mood did not. The drink beat the bar. Single-blind.","caveats":"Researchers assigned people to EGCG or matcha, so this is a trial stamp. An isolated catechin and a caffeinated powder are not the same drink. More papers of the same design do not settle the claim.\n\nWightman is the clean EGCG file and is null on tasks. Dietz is 23 people and single-blind; matcha also carries caffeine and theanine.\n\nThis is a journal entry, not medical advice and not a reason to drink green tea for memory.","confounders":["caffeine","l-theanine","sleep-hygiene"],"paperIds":["p-pmid-22389082","p-pmid-28784536"],"contributions":[{"paperId":"p-pmid-22389082","evidenceGrade":"abstract_only","designNote":"Wightman 2012 Hum Psychopharmacol. Crossover. EGCG 135/270 mg vs placebo, N=27. Frontal CBF down at 135 mg. Cognition and mood ns. abstract_only. Archive n null."},{"paperId":"p-pmid-28784536","evidenceGrade":"abstract_only","designNote":"Dietz 2019 Food Res Int. Single-blind crossover. Matcha tea or bar (4 g) vs placebo, N=23. Attention and psychomotor speed vs placebo. Other tasks thin. Mood ns. abstract_only. Archive n null."}],"featured":false},{"id":"e-green-tea-insulin","sourceId":"green-tea","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Brown 2009 EGCG 400 mg BID, 8 wk, N=88 men: insulin sensitivity NS. Hsu 2011 GTE 1500 mg/d, 16 wk, N=68/80 T2D: HOMA between-group NS. Fukino 2006 powder vs no treatment, N=66: HOMA between-group NS."},"n":88,"summary":"Brown 2009 found that 400 mg of EGCG twice a day for eight weeks did not change insulin sensitivity, insulin secretion, or glucose tolerance versus lactose in 88 overweight or obese men. Hsu 2011 and Fukino 2006 also found no between-group HOMA difference after a green-tea extract or powder.","mechanism":"Authors treat EGCG as a catechin that might make insulin work better. Three assigned contrasts do not find that on a between-group test.\n\nBrown, Lane, Coverly and colleagues (2009) assigned overweight or obese men aged 40 to 65 to 400 mg of EGCG or lactose twice a day for eight weeks (46 versus 42). Oral glucose tolerance, insulin sensitivity, and insulin secretion did not move. Diastolic blood pressure fell 2.68 versus 0.06 mm Hg (P=0.014). That is not this page's outcome.\n\nHsu, Liao, Lin and colleagues (2011) assigned 80 obese adults with type 2 diabetes to 1,500 mg a day of decaffeinated green-tea extract (856 mg EGCG) or placebo for sixteen weeks. 68 finished. No measured variable differed between groups, including HOMA-IR. Within the extract arm, HOMA and insulin fell. That is not the assigned contrast.\n\nFukino, Shimbo, Aoki, Okubo and Iso (2006) asked 66 people with borderline or frank diabetes to add 544 mg of green-tea polyphenols a day as powder, or to do nothing, for two months. HOMA, glucose, HbA1c, and insulin did not differ between groups at two months.","caveats":"Researchers assigned people to a catechin or a powder, so this is a trial stamp. The between-group insulin tests missed. Extra papers do not settle the claim.\n\nFukino has no matching placebo. Hsu's within-group HOMA drop is not the contrast. Brown's blood-pressure and mood notes are not HOMA-IR.\n\nThis page is not a cup of coffee.\n\nThis is a journal entry, not medical advice.","confounders":["ultraprocessed-food","sedentary-time","aerobic-exercise","sleep-hygiene"],"paperIds":["p-pmid-18710606","p-pmid-21649457","p-pmid-16392704"],"contributions":[{"paperId":"p-pmid-18710606","evidenceGrade":"full_text","designNote":"Brown 2009 Br J Nutr. Identifying RCT. EGCG 400 mg BID vs lactose, 8 wk, N=88 overweight/obese men 40-65. Insulin sensitivity, secretion, OGTT NS. DBP -2.68 vs -0.06 mmHg P=0.014. full_text. Archive n null."},{"paperId":"p-pmid-21649457","evidenceGrade":"abstract_only","designNote":"Hsu 2011 Altern Med Rev. RCT. Decaf GTE 1500 mg/d (856 mg EGCG) vs placebo, 16 wk, N=80 obese T2D (68 completers). Between-group HOMA and all variables NS. Within-GTE HOMA/insulin down. abstract_only. Archive n null."},{"paperId":"p-pmid-16392704","evidenceGrade":"abstract_only","designNote":"Fukino 2006 J Nutr Sci Vitaminol. RCT. Green-tea powder 544 mg polyphenols/d vs no treatment, 2 mo, N=66 borderline/diabetes. HOMA, glucose, HbA1c, insulin between-group NS. No placebo. abstract_only. Archive n null."}],"featured":false},{"id":"e-hearing-cognition","sourceId":"hearing-loss","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"ACHIEVE ITT n=977: 3-y global SF −0.200 vs −0.202, diff 0.002 (−0.077 to 0.081), p=0.96. ARIC n=238: 48% less change, diff 0.191 (0.022 to 0.360). De novo n=739 ns."},"n":977,"summary":"In 977 older adults with untreated hearing loss, three years of hearing aids did not slow a global cognition score versus health education; a prespecified ARIC slice of 238 people at higher risk did.","mechanism":"Lin, Pike, Albert and colleagues assigned 977 adults aged 70-84 with untreated hearing loss and no substantial cognitive impairment to hearing aids plus counselling or a health-education control (NCT03243422). Four US sites. Two recruitment streams: 238 from ARIC, 739 healthy volunteers. Mean age 76.8. The primary 3-year change in a global cognition factor score was not different: −0.200 versus −0.202, difference 0.002 (−0.077 to 0.081), p=0.96.\n\nA prespecified split by recruitment source was. In ARIC, hearing intervention cut 3-year cognitive change 48 percent versus control (difference 0.191, 0.022 to 0.360). In the volunteer stream the difference was −0.061 (−0.151 to 0.028). Control participants in ARIC declined 2.7 times faster than volunteers. The signed object is untreated hearing. Aiding hearing is less hearing loss. The total-cohort arrow is a null. The ARIC arrow is a slowdown.\n\nYu, Proctor, Soni and colleagues pooled 50 cohorts (1,548,754 people). Adult-onset hearing loss tracked incident dementia (HR 1.35), MCI (1.29), and unspecified cognitive decline (1.29). Each 10 dB tracked a 16 percent rise in dementia risk. Vascular dementia did not. That association does not raise the stamp.\n\nGrenier, Berr, Goldberg and colleagues scored audiometry and a five-test battery in 62,072 CONSTANCES adults aged 45-69. Mild and disabling loss tracked global impairment (OR 1.10 and 1.24). Hearing-aid use versus unaided disabling loss did not (OR 0.94). Cross-section. It does not raise the stamp.","caveats":"ACHIEVE is unmasked. The control is health education, not a sham aid. The paper names 977 people. The main contrast is the total-cohort 3-year score, which missed. The 48 percent figure lives in 238 ARIC participants, a prespecified sensitivity, not the primary. Do not read ARIC as the main sign.\n\nThe volunteer stream was younger, healthier, and slower to decline. Practice effects on first-time testing are an open story. 88 percent White. Four US sites. Cognitive impairment as a time-to-event endpoint was not different.\n\nYu is cohort association. Residual confounding by vascular disease, education, and who gets an audiogram remains open. Grenier is one-time audiometry in midlife, not a trial of treatment.\n\nBlood lead and ferritin are other biology. This page is a hearing score, not age.\n\nThis is a journal entry, not medical advice and not a reason to buy a hearing aid.","confounders":["education","loneliness","depression","disposable-income"],"paperIds":["p-pmid-37478886","p-pmid-38788800","p-pmid-39352700"],"contributions":[{"paperId":"p-pmid-37478886","evidenceGrade":"full_text","designNote":"Lin 2023 ACHIEVE. Identifying RCT. Hearing aids+counselling vs health education, 3 y, n=977 (490/487), age 70-84, NCT03243422. Primary global SF −0.200 vs −0.202, diff 0.002, p=0.96. ARIC n=238 48% less change, diff 0.191. De novo n=739 ns. Archive n null; N=977 from paper. full_text."},{"paperId":"p-pmid-38788800","evidenceGrade":"abstract_only","designNote":"Yu 2024. 50-cohort meta, N=1,548,754. Incident dementia HR 1.35 (1.26-1.45), MCI 1.29, decline 1.29, ADD 1.56. Per 10 dB HR 1.16. Vascular dementia ns. Observational; does not raise. Archive n null. abstract_only."},{"paperId":"p-pmid-39352700","evidenceGrade":"full_text","designNote":"Grenier 2024 CONSTANCES. Cross-section, n=62,072, age 45-69, PTA + 5-test battery. Mild HL OR 1.10, disabling OR 1.24. HA vs unaided disabling OR 0.94 ns. Named design; does not raise. Archive n null; N from abstract. full_text."}],"featured":false},{"id":"e-income-buys-supplements","sourceId":"disposable-income","targetId":"vitamin-supplementation","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Pills are normal goods. This is the arrow people reverse."},"n":null,"summary":"Money buys bottles. Reverse causation is the whole trick of the wellness-to-wealth genre.","mechanism":"Supplements are inexpensive relative to rent and expensive relative to nothing. Demand rises with income and with health insurance culture. Once this arrow exists, the reverse observational arrow is unidentified.","caveats":"Not an RCT of cash transfers on pill purchases, but the demand curve is not in serious dispute.","confounders":["education"],"paperIds":["p-shrank-2011"],"contributions":[{"paperId":"p-shrank-2011","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-income-hypergamy","sourceId":"disposable-income","targetId":"hypergamy-preference","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Women's preference for affluent partners is real in Fisman; it is not invariant to their own income and education."},"n":400,"summary":"As the income gap closes, strict economic hypergamy yields to educational and cultural homogamy. Incentives, not a frozen instinct.","mechanism":"Fisman et al. (2006): women preferred men from affluent neighborhoods and weighted intelligence heavily. Buss (1989): women stated higher value for earning capacity. The modern reading is a bargaining-and-insurance model: when a woman's own earnings and legal protections rise, the returns to marrying 'up' in money fall and the returns to matching on class and cognition rise.","caveats":"Speed-dating is not a marriage market. Neighborhood affluence is a noisy wealth signal. We do not have an RCT of income on women's preference weights.","confounders":["education","net-worth","social-capital"],"paperIds":["p-fisman-2006","p-buss-1989"],"contributions":[{"paperId":"p-fisman-2006","evidenceGrade":"abstract_only"},{"paperId":"p-buss-1989","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-income-risk","sourceId":"disposable-income","targetId":"risk-tolerance","relation":"spurious","direction":"bidirectional","polarity":"context_dependent","methodology":"observational","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Richer people can afford more risk; risk-tolerant people may sort into higher-variance pay. Both arrows are live."},"n":212,"summary":"Holt–Laury measures the preference. Income changes the budget. Do not call either 'testosterone'.","mechanism":"Holt and Laury showed that the incentive scale itself moves estimated risk aversion. Background wealth should do the same. A T–risk paper that skips wealth is leaking.","caveats":"Lab lists are not portfolio choice. Gender composition of the room changes means.","confounders":["education","net-worth"],"paperIds":["p-holt-laury-2002"],"contributions":[{"paperId":"p-holt-laury-2002","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-income-youth-pref","sourceId":"disposable-income","targetId":"youth-fertility-preference","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Men with more resources state and reveal stronger youth/attractiveness weights; not an identified biological imperative."},"n":10047,"summary":"Richer men can act on a preference that poorer men also often hold. Money changes the feasible set, not necessarily the utility function.","mechanism":"Buss (1989) documents a male-typical stated preference for youth cues. Fisman et al. show attractiveness weights in revealed speed-dating choice. Neither paper identifies a causal income→preference shift that survives market-position controls. The honest edge is: income *expresses* the preference.","caveats":"Stated ≠ revealed. Speed-dating samples are students and young professionals. Cross-cultural surveys are not RCTs of cash transfers.","confounders":["education","formal-power"],"paperIds":["p-buss-1989","p-fisman-2006"],"contributions":[{"paperId":"p-buss-1989","evidenceGrade":"abstract_only"},{"paperId":"p-fisman-2006","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-inositol-insulin","sourceId":"inositol","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Giordano 2011: 2 g BID + diet vs diet+placebo, 6 mo, N=80 postmenopausal MetS, HOMA -75%. D'Anna 2015: open-label, N=220 obese pregnancy, HOMA -1.0 vs +0.1. Formuso 2016: N=137 PCOS vs placebo."},"n":80,"summary":"Giordano 2011 found that 2 g of myo-inositol twice a day plus diet for six months lowered the HOMA insulin-resistance index versus diet plus placebo in 80 postmenopausal women with metabolic syndrome. D'Anna 2015 saw a smaller HOMA drop and less gestational diabetes in 220 obese pregnancies; that file was open-label.","mechanism":"Authors treat myo-inositol as an insulin sensitizer. They do not isolate one isomer as the only actor.\n\nGiordano, Corrado, Santamaria and colleagues assigned 80 postmenopausal women with metabolic syndrome to diet plus 2 g twice a day or diet plus placebo for six months. HOMA, blood pressure, cholesterol, and triglycerides moved versus placebo. The abstract reports a 75 percent HOMA drop on inositol.\n\nD'Anna, Di Benedetto, Scilipoti and colleagues assigned 220 obese pregnant women to 2 g myo-inositol plus folic acid twice a day or folic acid alone from the first trimester. Open-label. Gestational diabetes was 14.0 percent versus 33.6 percent (P=0.001). HOMA changed -1.0 versus +0.1 (P=0.048).\n\nFormuso, Stracquadanio and Ciotta assigned 137 women with polycystic ovary syndrome to myo-inositol, D-chiro-inositol, or placebo for six months. Both inositol arms improved cycle regularity, acne score, and insulin resistance.","caveats":"Researchers assigned people to a powder or a control, so this is a trial stamp. Populations split. More papers of the same design do not settle the claim.\n\nGiordano's 75 percent HOMA drop is one postmenopausal file. D'Anna is open-label pregnancy. Formuso is a three-arm PCOS file without a published HOMA increment in the abstract.\n\nThis is a journal entry, not medical advice and not a reason to take inositol for insulin resistance.","confounders":["sedentary-time","sleep-hygiene","ultraprocessed-food"],"paperIds":["p-pmid-20811299","p-pmid-26241420","p-pmid-25670222"],"contributions":[{"paperId":"p-pmid-20811299","evidenceGrade":"abstract_only","designNote":"Giordano 2011 Menopause. RCT. Myo-inositol 2 g BID + diet vs diet+placebo, 6 mo, N=80 postmenopausal MetS. HOMA vs placebo; abstract -75% on inositol. BP/lipids moved. abstract_only. Archive n null."},{"paperId":"p-pmid-26241420","evidenceGrade":"abstract_only","designNote":"D'Anna 2015 Obstet Gynecol. Open-label RCT. 2 g BID + folate vs folate, N=220 obese pregnancy. GDM 14.0% vs 33.6% P=.001. HOMA -1.0 vs +0.1 P=.048. abstract_only. Archive n null."},{"paperId":"p-pmid-25670222","evidenceGrade":"abstract_only","designNote":"Formuso 2016 Minerva Ginecol. RCT. Myo-inositol vs D-chiro vs placebo, 6 mo, N=137 PCOS. Both inositol arms improved IR, cycles, acne. No HOMA increment in abstract. abstract_only. Archive n null."}],"featured":false},{"id":"e-jobstrain-cortisol","sourceId":"job-strain","targetId":"cortisol","relation":"spurious","direction":"forward","polarity":"context_dependent","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"van der Meij: ERI higher HCC in high-workload n=81; JDCS null. Steptoe +21.7% morning saliva. Herr ΔERI↔ΔHCC β=0.414 n=40. Rudolph MESA AUC ratio 0.10. Signs disagree. Design does not identify."},"n":254,"summary":"Hair cortisol ran higher with effort-reward imbalance among 81 high-workload workers, and morning saliva ran 21.7 percent higher in 48 high-strain teachers, but Karasek job strain tracked a lower diurnal cortisol area in 254 matched MESA adults. Nobody assigned the job.","mechanism":"The authors treat chronic work load as an HPA input. Hair integrates weeks of cortisol. Saliva catches the working day.\n\nSteptoe scored 105 teachers on demand-control a year earlier. At 8:00 to 8:30 on a workday, free cortisol was 21.7 percent higher in the high-strain group after age and negative affect. Later samples and the evening were not higher. The morning bump was larger in teachers who also scored high on anger-out.\n\nvan der Meij compared 81 high-workload workers with 91 on a normal load. Hair cortisol tracked self-report only in the high-load group, and only on effort-reward imbalance: higher when effort was high, reward low, and overcommitment high. Demand, control, and workplace support did not show that link.\n\nHerr followed 40 factory men for a year. Cross-sectional effort-reward and hair cortisol did not line up. Change in effort-reward did line up with change in hair cortisol (beta 0.414).\n\nRudolph modeled 18 saliva samples over three days in employed MESA adults. After propensity matching, 254 people remained. Job strain, high demand and low control, sat with lower salivary levels and a total area about one-tenth that of the low-strain matches (ratio 0.10, 95 percent CI 0.01 to 0.98). The awakening response did not differ.","caveats":"The stamp is smoke because nobody randomized the job. A new observational edge publishes as spurious and low. Paper count does not raise it.\n\nvan der Meij's demand-control-support test was null. The hair signal is effort-reward in the high-workload cell, not in the normal-workload cell.\n\nSteptoe's sample is teachers. Strain was scored a year before the saliva day. One working day. Anger-out is an interaction, not a main effect you can cite alone.\n\nHerr is 40 men. The authors themselves found no cross-sectional link.\n\nRudolph's adults are middle-aged to older, racially and occupationally mixed. The matched high-strain cell is 58 people. The area ratio interval runs from 0.01 to 0.98. Hair and saliva are different clocks. A blunted day curve in older workers is not the same finding as a higher morning sample in teachers or a higher hair value in high-load staff.\n\nThis page is a work-stress questionnaire versus cortisol. It is not employment versus unemployment. It is not a yoga class for burnout, and it is not a scanner speech task in people already burned out.\n\nThis is not medical advice and not a recommendation to change a job, a shift, or a hormone.","confounders":["sleep-hygiene","education","disposable-income","depression","shift-work"],"paperIds":["p-pmid-29331802","p-pmid-10772410","p-pmid-29414027","p-pmid-26905339"],"contributions":[{"paperId":"p-pmid-29331802","evidenceGrade":"abstract_only","designNote":"van der Meij 2018 Psychoneuroendocrinology. Observational hair cortisol, JDCS plus ERI. High-workload n=81, normal n=91. HCC higher with high effort, low reward, high overcommitment in the high-load cell only. JDCS null. abstract_only. Archive n null; 172 from abstract."},{"paperId":"p-pmid-10772410","evidenceGrade":"abstract_only","designNote":"Steptoe 2000 Psychosom Med. Observational. 105 teachers (48 high strain, 57 low), demand/control scored 12 months earlier. Morning saliva 21.7% higher at 8:00-8:30 after age and negative affect. Later samples ns. abstract_only. Archive n null; 105 from abstract."},{"paperId":"p-pmid-29414027","evidenceGrade":"abstract_only","designNote":"Herr 2018 Psychoneuroendocrinology. Observational prospective. 40 male factory workers, ERI and hair cortisol at two times over one year. Cross-section and ΔERI→HCC at t2 ns. ΔERI with ΔHCC β=0.414, SE=0.155, p=0.012. abstract_only. Archive n null; 40 from abstract."},{"paperId":"p-pmid-26905339","evidenceGrade":"full_text","designNote":"Rudolph 2016 AJE, MESA Stress I. Observational, functional mixed model, propensity match. Employed; 341 remained, 254 matched (58 more strain, 196 less). 18 saliva samples over 3 days. Job strain: lower levels, AUC ratio 0.10 (0.01-0.98). CAR ns. full_text. Archive n null; 254 from paper."}],"featured":false},{"id":"e-jobstrain-depression","sourceId":"job-strain","targetId":"depression","relation":"spurious","direction":"forward","polarity":"positive","methodology":"meta_analysis","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Madsen 2018 IPD-Work n=120221, HR 1.27 (1.04-1.55) hospital-treated. Published 6 cohorts n=27461, OR 1.77. Smith 2012 NPHS n=3735, demand rise OR 2.36. Observational. Design does not identify."},"n":120221,"summary":"Madsen 2018's IPD-Work pool of 120,221 employees found a 27 percent higher rate of first hospital-treated depression after job strain (HR 1.27, 1.04 to 1.55). In Smith 2012, 3,735 Canadians free of depression who reported a rise in psychological demands had later depression odds of 2.36. Nobody assigned the job.","mechanism":"Authors treat high demand with low control as a chronic stressor. They name HPA wear, broken sleep, isolation, and less leisure movement. The files score a questionnaire and later count a diagnosis or a PHQ-9. They do not isolate one path.\n\nMadsen, Nyberg, Magnusson Hanson and colleagues (2018) pooled six published cohorts (27,461 people, 914 incident clinical depressions) and 14 unpublished IPD-Work cohorts (120,221 employees, 982 first hospital-treated depressions). Job strain was high demand plus low control against every other combination. Published diagnostic interviews: OR 1.77 (1.47 to 2.13). IPD, age, sex, and cohabitation: HR 1.27 (1.04 to 1.55). A continuous symptom score killed the hospital link (HR 1.03).\n\nBurr, Müller, Rose and colleagues (2021) followed 2,212 German S-MGA employees, 2011/12 to 2017. COPSOQ items mapped to Karasek. PHQ-9 of 10 or more. Strain versus low strain: RR 1.51 (1.03 to 2.23). The joint effect was not larger than the sum (RERI -0.21).\n\nKim, Shin, Oh and colleagues (2021) followed 63,959 Korean employees from a 2012 Kangbuk Samsung exam through 2017, 4,227 incident case-level depressive symptoms. The instrument is the Korean Occupational Stress Scale, not the Karasek quadrant. High job demand tracked new symptoms in men of every age and in women through midlife.\n\nSmith and Bielecky (2012) used 3,735 Canadians in the National Population Health Survey who were free of depression when job scores were taken. An abbreviated Job Content Questionnaire scored control, demands, support, and a demand-to-control ratio. A change counted only if it beat day-to-day noise. Depression two years later was CIDI-SFMD or a first medical diagnosis in the missed year. A rise in psychological demands: adjusted OR 2.36 (1.14 to 4.88). A rise in the strain ratio: 1.24 (0.57 to 2.68). Control and support changes did not. The authors say not to assume a demand-by-control interaction.","caveats":"The stamp stays smoke. Nobody randomized the job. These are cohorts and a meta-analysis of cohorts. Another cohort does not close the backdoor. More papers of the same design do not settle the claim.\n\nBaseline mood sits on the backdoor. People who already feel low report worse jobs and later meet a depression code. Madsen's hospital association vanished after a continuous symptom score. The same file also shows the reverse arrow: symptoms predict later strain.\n\nMadsen's IPD outcome is hospital-treated depression. Most episodes never reach a ward. The published OR 1.77 uses diagnostic interviews and may be inflated by publication bias. The IPD studies are Nordic plus Whitehall. Burr is German employees aged 31 to 60 on social insurance, not civil servants or the self-employed. Kim is one hospital screening program and a Korean stress battery, not Karasek's combination. Smith is a household survey, two demand items, and self-report. A change in the strain ratio itself did not move. The authors cannot tell a real job change from a change in how the job felt. Sample size: N from the papers.\n\nBurr found no extra risk from combining high demand and low control beyond adding the two. Madsen's continuous analysis found low control, not high demand, and no demand-by-control interaction. Passive jobs also sat higher in the IPD. Smith found the demand rise, not the control change.\n\nThis page is not employment versus unemployment. Job loss is a different exposure. It is not long-term sickness absence. Jarroch 2024 asked whether strain modified the path from depression to absence; depression was not the outcome. It is not ovarian cancer. The 2017 work-characteristics file asked about ovarian risk and death. It is not job strain to cortisol. That pair already has its own page.\n\nThis is a journal entry, not medical advice and not a reason to quit a job, to change a shift, or to treat a number.","confounders":["education","disposable-income","sleep-hygiene","alcohol-intake","shift-work"],"paperIds":["p-pmid-28122650","p-pmid-34444078","p-pmid-31797050","p-pmid-22390450"],"contributions":[{"paperId":"p-pmid-28122650","evidenceGrade":"full_text","designNote":"Madsen 2018 Psychol Med. SR+IPD. 6 published n=27461, 914 incident clinical depression, OR 1.77 (1.47-2.13). IPD-Work 14 cohorts n=120221, 982 hospital-treated, HR 1.27 (1.04-1.55). Continuous baseline symptoms HR 1.03. Observational. full_text. Archive n null; N from paper."},{"paperId":"p-pmid-34444078","evidenceGrade":"full_text","designNote":"Burr 2021 IJERPH. S-MGA 2212 German employees 2011/12-2017, mean 5.1 y. COPSOQ demand-control. PHQ-9>=10. Strain vs low-strain RR 1.51 (1.03-2.23). No superadditivity RERI -0.21. Observational. full_text. Archive n null; N from paper."},{"paperId":"p-pmid-31797050","evidenceGrade":"abstract_only","designNote":"Kim 2021 Int Arch Occup Environ Health. Kangbuk Samsung, 63959 Korean employees 2012-2017, 4227 incident depressive symptoms. KOSS, not Karasek quadrant. High job demand associated; insufficient control only midlife men. Observational. abstract_only. Archive n null; N from abstract."},{"paperId":"p-pmid-22390450","evidenceGrade":"full_text","designNote":"Smith 2012 Am J Public Health. Canadian NPHS 2000-04. n=3735 workers 25-60 free of depression at job scores. Abbreviated JCQ. Detectable rise in psychological demands: AOR 2.36 (1.14-4.88). Strain-ratio rise 1.24 (0.57-2.68) ns. Observational. full_text. Archive n null; N from paper."}],"featured":false},{"id":"e-lead-cognition","sourceId":"lead-exposure","targetId":"cognitive-performance","relation":"spurious","direction":"forward","polarity":"negative","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Lanphear: 6.9 IQ points from concurrent 2.4 to 30 µg/dL. Canfield: 4.6 per 10 µg/dL. Reuben 2017: −1.61 IQ at 38 per 5 µg/dL. Sign is inverse. Design does not identify."},"n":1333,"summary":"Higher childhood blood lead tracked lower IQ in Rochester, the Lanphear pool, and Dunedin at age 38 after maternal IQ was in the model. Nobody randomized lead.","mechanism":"Lead can stand in for calcium at the synapse. Animal work shows damage to NMDA signaling, synapse formation, and myelination in developing cortex. The human papers do not isolate that pathway. They report a dose-response on named IQ tests.\n\nCanfield gave the Stanford-Binet at ages 3 and 5 to 172 Rochester children. Jusko gave the same cohort the WPPSI-R at age 6. Lanphear pooled Wechsler scales from seven prospective sites (Boston, Cincinnati, Cleveland, Mexico City, Port Pirie, Rochester, Yugoslavia) in 1,333 children followed from infancy to ages 5 to 10. Concurrent blood lead fit best. The log-linear model estimated a 6.9-point IQ decrement (95 percent CI 4.2 to 9.4) as concurrent lead rose from 2.4 to 30 µg/dL, and 3.9 points (2.4 to 5.3) from 2.4 to 10. The slope was steeper below 7.5 µg/dL than above it.\n\nReuben gave the Dunedin cohort the WAIS-IV at age 38 and again at 45. Blood lead at age 11 (mean 10.99 µg/dL) tracked 1.61 IQ points lower at 38 per 5 µg/dL after maternal IQ, childhood IQ, and childhood SES were in the model (n=533). At 45 the WAIS-IV decrement was 2.07 points per 5 µg/dL (n=564). That is a midlife score on the same construct. SES and social mobility in the 2017 file are not this node.\n\nTaylor measured maternal blood lead at a median of 11 weeks in ALSPAC (mean 3.67 µg/dL) and gave the WPPSI at 4 (348 complete cases) and the WISC-III at 8 (1,823). After maternal education and family covariates, prenatal lead was not associated with child IQ. A sex-by-lead term at age 8 (p=0.033) does not identify. Child blood lead was available in a 235-child overlap and did not moderate. A prenatal null does not flip the childhood sign.","caveats":"The stamp is smoke because nobody randomized lead. The childhood association did not vanish after maternal IQ and home scores were in the model. That is the Canfield/Lanphear file. A new observational edge publishes as spurious and low. Paper count does not raise it. We do not put a robust-causal stamp on this pair without a dosing trial. That is a rule about design, not a claim that lead is harmless.\n\nCanfield and Jusko are one Rochester sample at two ages. Lanphear includes Rochester, so those children appear twice on this page. A 2019 erratum corrected Boston IQ and lead coding. The authors said the headline association held.\n\nThe models adjust for maternal IQ, HOME scores, maternal education, and birth weight. Jusko also put family income and transferrin saturation in the model. Residual confounding remains. Housing quality, nutrition, and parental cognition still sit on the backdoor. Iron deficiency can raise lead absorption and can lower cognition on its own.\n\nThe Rochester children were mostly low-income. Mean full-scale IQ in Jusko was 85. Do not export a child IQ association into a career or income arrow.\n\nReuben 2017 is hung for the WAIS-IV at 38 and for IQ change from the WISC-R, not for NZSEI-06 or downward mobility. Reuben 2021 is hung for the WAIS-IV at 45, not for MRI. The two files are one Dunedin cohort at two ages.\n\nTaylor is maternal blood in pregnancy, not the child's venous lead. The adjusted prenatal association with IQ at 4 and 8 was null. That file does not raise the stamp and does not change the sign.\n\nOmitted: Wright 2021 (arrests), Lanphear 2008 (comment on pesticide confounding), Min 2022 (language and substance use), Kampouri 2024 (lead mixed with cadmium and fluoride), Searle 2015 (Port Pirie review; already in Lanphear). Beckley 2019 and Reuben 2020 stay off this pair.\n\nThis page is a journal entry. It is not medical advice.","confounders":["education","disposable-income","ferritin"],"paperIds":["p-pmid-12700371","p-pmid-16002379","p-pmid-18288325","p-pmid-33201203","p-pmid-28350927","p-pmid-28687448"],"contributions":[{"paperId":"p-pmid-12700371","evidenceGrade":"full_text","designNote":"Canfield 2003, Rochester. Observational, 172 children, Stanford-Binet at 3 and 5. Lifetime average: 4.6 IQ points per 10 µg/dL (P=0.004). Nonlinear: 7.4 points from 1 to 10 µg/dL. Steeper below 10 (n=101 with max <10). Adjusted maternal IQ, HOME. full_text. Same cohort as Jusko."},{"paperId":"p-pmid-16002379","evidenceGrade":"full_text","designNote":"Lanphear 2005, pooled 7 cohorts, 1,333 children, Wechsler IQ at 5-10. Identifying observational file. Concurrent lead, log-linear: 6.9 IQ points from 2.4 to 30 µg/dL (95% CI 4.2-9.4); 3.9 from 2.4 to 10. Steeper below 7.5 (p=0.015). Adjusted site, HOME, birth weight, maternal IQ and education. Includes Rochester. 2019 erratum: Boston coding, conclusions held. full_text."},{"paperId":"p-pmid-18288325","evidenceGrade":"full_text","designNote":"Jusko 2008, Rochester follow-up of Canfield. Observational, 194 at age 6, 174 complete, WPPSI-R. Lifetime average mean 7.2 µg/dL. Inverse FSIQ p=0.006. Lifetime 5-9.9 vs <5: 4.9 FSIQ points (91.3 vs 86.4, p=0.03). Peak associated down to 2.1 µg/dL. Adjusted maternal IQ, HOME, income, transferrin. full_text."},{"paperId":"p-pmid-33201203","evidenceGrade":"full_text","designNote":"Reuben 2021, Dunedin. Observational, blood lead at 11 (mean 10.99 µg/dL), n=564. Hung for WAIS-IV at 45: -2.07 IQ points per 5 µg/dL (95% CI -3.39 to -0.74, P=.002). MRI structure is not this node. full_text."},{"paperId":"p-pmid-28350927","evidenceGrade":"full_text","designNote":"Reuben 2017, Dunedin. Observational, B-Pb at 11 (mean 10.99 µg/dL). Hung for WAIS-IV at 38, n=533 complete: −1.61 IQ per 5 µg/dL fully adjusted (maternal IQ, childhood IQ, childhood SES; 95% CI −2.48 to −0.74). IQ decline vs childhood WISC-R. SES/mobility is not this node. Same cohort as Reuben 2021. full_text."},{"paperId":"p-pmid-28687448","evidenceGrade":"full_text","designNote":"Taylor 2018, ALSPAC. Observational, maternal B-Pb median 11 weeks (mean 3.67 µg/dL). WPPSI at 4 (n=348 complete) and WISC-III at 8 (n=1823). Adjusted models null. Sex-by-lead p=0.033 at 8. Child B-Pb subsample n=235, no moderation. Prenatal maternal draw, still blood lead to IQ. full_text."}],"featured":false},{"id":"e-light-sleep","sourceId":"light-exposure","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Chang 2015: LE-eBook vs print, 12 adults, 4 h × 5 nights. Melatonin −55%. DLMO +1.5 h. Latency 25.7 vs 15.8 min. REM 109 vs 121 min."},"n":12,"summary":"Chang 2015 randomized twelve young adults: five evenings of a light-emitting e-reader versus a printed book delayed dim-light melatonin onset by more than 1.5 hours, suppressed evening melatonin by about 55 percent, and lengthened sleep latency by about ten minutes.","mechanism":"Evening light hits melanopsin cells in the retina. The clock holds melatonin and slips later. Falling asleep takes longer. REM can shrink.\n\nChang, Aeschbach, Duffy and Czeisler (2015) randomized twelve healthy young adults to five nights of an iPad at full brightness or a printed book, four hours before a fixed 22:00 bedtime. Crossover. Evening melatonin fell 55 percent on the e-reader and did not fall on print. Dim-light melatonin onset sat at 22:31 after the e-reader and 21:01 after print. Sleep latency 25.7 versus 15.8 minutes. REM 109 versus 121 minutes.\n\nZerbini, Kantermann and Merrow (2021) randomly assigned 38 adults with social jetlag to orange blue-blocking glasses or clear lenses for two evening weeks. Workday sleep onset advanced 36 minutes in week 1. Dim-light melatonin onset advanced 32 minutes. Social jetlag did not move. Morning curtains in a second randomized study moved neither.\n\nChellappa, Steiner and Cajochen (2014) ran 30 adults through two evening hours at 6500 K, 2500 K, or 3000 K, about 40 lux. Sleep stages did not differ. Frontal slow-wave activity in the first cycle fell after 6500 K.\n\nSanthi, Thorne and Dijk (2012) put 22 adults through six evening spectra. Melatonin rise, sleepiness, and EEG sleep onset varied with the melanopsin-weighted lights.\n\nGreen, Cohen-Zion, Haim and Dagan (2018) assigned 19 adults short- or long-wavelength screen light at 80 or 350 lux from 21:00. Short-wavelength light broke sleep architecture and damped melatonin.\n\nHartstein and LeBourgeois (2022) randomized 36 children aged 3 to 5 to one evening hour at 5 to 5000 lux. Melatonin fell 69 to 99 percent.\n\nGordijn 1999: three days of morning or evening bright light shifted melatonin onset, temperature, wake time, and first REM. Sleep displacement shifted melatonin onset only.\n\nTähkämö 2020 reviewed 128 human files (melatonin 122, REM 13). No pool.","caveats":"Chang is twelve young inpatients. The iPad sat at maximum brightness. The printed book sat in about 1 lux of reflected room light. Bedtime was fixed, so the latency gap understates what people do when they pick their own bedtime. Melatonin numbers are from eleven of the twelve. The paper names 12 people.\n\nZerbini is a field sample with social jetlag, not a sleep lab. The advance faded in week 2. Clear-lens controls still cut some light.\n\nChellappa, Santhi, and Green are small and young. Most of those papers are available here only as abstracts. Green put the light on a computer; the assigned factors were wavelength and intensity.\n\nHartstein is preschool melatonin, not adult sleep stages.\n\nGordijn's sleep-displacement arm is not this page.\n\nTähkämö does not pool and does not settle the claim. More papers of the same design do not settle the claim.\n\nThis page is evening or bright light at the eye. It is not hours outdoors for vitamin D. That pair is the outdoors-and-vitamin-D page. It is not minutes of phone or social media.\n\nThis is a journal entry, not medical advice and not a reason to buy glasses, to dim a screen, or to treat a number.","confounders":["caffeine","alcohol-intake","shift-work","traffic-noise","outdoor-time"],"paperIds":["p-pmid-25535358","p-pmid-30506899","p-pmid-23509952","p-pmid-22017511","p-pmid-28548897","p-pmid-34997782","p-pmid-10476002","p-pmid-30311830"],"contributions":[{"paperId":"p-pmid-25535358","evidenceGrade":"full_text","designNote":"Chang 2015 PNAS. Identifying RCT, randomized crossover, 12 young adults (6F). 5 evenings LE-eBook (iPad max ~32 lux) vs printed book (~1 lux), 4h before fixed 22:00. Melatonin -55% vs none. DLMO 22:31 vs 21:01. Latency 25.65 vs 15.75 min. REM 109 vs 121. TST ns. Archive n null. N=12 from paper. full_text."},{"paperId":"p-pmid-30506899","evidenceGrade":"abstract_only","designNote":"Zerbini 2021 Eur J Neurosci. Field RCT, 38 adults SJL≥1.5h, orange blue-block glasses vs clear lenses, 2 evening weeks after 2-week baseline. Workday sleep onset -36 min week 1. DLMO -32 min week 1. SJL ns. Study 2 morning curtains ns. Archive n null. N=38 from paper. abstract_only."},{"paperId":"p-pmid-23509952","evidenceGrade":"abstract_only","designNote":"Chellappa 2014 J Sleep Res. Balanced crossover, 30 adults 20-31. 2h evening 6500K vs 2500K vs 3000K, ~40 lux wall. Sleep stages first 3 cycles ns. Frontal SWA first cycle down after 6500K. Archive n null. N=30 from abstract. abstract_only."},{"paperId":"p-pmid-22017511","evidenceGrade":"abstract_only","designNote":"Santhi 2012 J Pineal Res. Six-way crossover Clinical Trial, 22 adults 23.1±4.7y. Evening polychromatic spectra, melanopsin vs photopic weighting. Melatonin rise, sleepiness, EEG sleep onset P<0.01. ICC 0.44 individual sensitivity. Archive n null. N=22 from abstract. abstract_only."},{"paperId":"p-pmid-28548897","evidenceGrade":"abstract_only","designNote":"Green 2018 Chronobiol Int. Counterbalanced 2x2, 19 adults 24.3y. Screen 80 vs 350 lux × 460 vs 620 nm, 21:00-23:00 then PSG. SWL disrupted continuity/architecture and damped melatonin more than intensity. Contrast is light, not content. Archive n null. N=19 from abstract. abstract_only."},{"paperId":"p-pmid-34997782","evidenceGrade":"full_text","designNote":"Hartstein 2022 J Pineal Res. RCT, 36 children 3.0-4.9y, 1h evening light randomized to 15 levels 5-5000 lux. Melatonin suppression 69.4-98.7% (mean 85.4%). Lowest quartile 5-40 lux 77.5% vs ~86-89% higher. Archive n null. N=36 from paper. full_text."},{"paperId":"p-pmid-10476002","evidenceGrade":"abstract_only","designNote":"Gordijn 1999 J Sleep Res. Comparative. Bright morning or evening light 3 days, sleep fixed, vs sleep displacement under constant light-dark. Light shifted DLMO, temperature, wake, first REM. Sleep displacement shifted DLMO only. Archive n null. abstract_only."},{"paperId":"p-pmid-30311830","evidenceGrade":"abstract_only","designNote":"Tähkämö 2020 Chronobiol Int. Systematic review, 128 human light-circadian papers. Melatonin 122, REM 13. 39 files n≤10. No pooled estimate. LCA/light-pollution frame. Does not raise the stamp. Archive n null. abstract_only."}],"featured":false},{"id":"e-lions-mane-cognition","sourceId":"lions-mane","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Mori 2009: 3 g/d powder, 16 wk, N=30 MCI, HDS-R vs placebo weeks 8-16; fell after stop. Docherty 2023: 1.8 g, N=41, acute Stroop faster; 28-d stress P=0.051. Surendran 2025: 3 g extract, N=18, global ns."},"n":30,"summary":"Mori 2009 found that 3 g a day of Yamabushitake powder for sixteen weeks raised Revised Hasegawa Dementia Scale scores versus placebo in 30 people with mild cognitive impairment; scores fell after the powder stopped. Docherty 2023 saw a faster Stroop after one 1.8 g dose in 41 young adults and little chronic change.","mechanism":"Authors treat Hericium erinaceus as a source of hericenones and erinacines. They do not isolate one molecule.\n\nMori, Inatomi, Ouchi, Azumi and Tuchida assigned 30 people with mild cognitive impairment to 3 g a day of dry powder or placebo for sixteen weeks. Hasegawa scores rose versus placebo at weeks 8, 12, and 16 and fell four weeks after stopping.\n\nDocherty, Doughty and Smith assigned 41 healthy adults aged 18 to 45 to 1.8 g a day or placebo. One dose sped the Stroop at 60 minutes (P=0.005). After 28 days, stress trended down (P=0.051). Other tasks were null or thin. Pilot.\n\nSurendran, Saye, Jalil and colleagues crossed 18 healthy adults aged 18 to 35 through 3 g of a 10:1 fruiting-body extract and placebo. Global cognition and mood did not move at 90 minutes. A pegboard score did.","caveats":"Researchers assigned people to a mushroom or a control, so this is a trial stamp. The files are small. More papers of the same design do not settle the claim.\n\nMori is 30 people and a dementia screen. Docherty is a pilot with mixed nulls. Surendran is 18 people and one task.\n\nThis is a journal entry, not medical advice and not a reason to take a mushroom for memory.","confounders":["sleep-hygiene","caffeine","alcohol-intake"],"paperIds":["p-pmid-18844328","p-pmid-38004235","p-pmid-40276537"],"contributions":[{"paperId":"p-pmid-18844328","evidenceGrade":"abstract_only","designNote":"Mori 2009 Phytother Res. RCT. Yamabushitake 3 g/d vs placebo, 16 wk, N=30 MCI. HDS-R vs placebo weeks 8/12/16. Fell 4 wk after stop. abstract_only. Archive n null."},{"paperId":"p-pmid-38004235","evidenceGrade":"full_text","designNote":"Docherty 2023 Nutrients. Pilot RCT. 1.8 g vs placebo, N=41 age 18-45. Acute Stroop P=0.005. 28-d stress P=0.051. Other tasks mixed/null. full_text. Archive n null."},{"paperId":"p-pmid-40276537","evidenceGrade":"full_text","designNote":"Surendran 2025 Front Nutr. Acute crossover (Archive observational). 3 g 10:1 extract vs placebo, N=18 age 18-35. Global cognition/mood ns. Pegboard moved. full_text. Archive n null."}],"featured":false},{"id":"e-loneliness-depression","sourceId":"loneliness","targetId":"depression","relation":"spurious","direction":"forward","polarity":"positive","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Hysing 2026: SHoT 2022 T-ILS quintiles to CIDI-5 MDE 2023. n=10460 students 18-35. Highest vs lowest: RR 2.02 women, 2.64 men after age and HSCL. Observational. Archive n null."},"n":10460,"summary":"Hysing 2026 followed 10,460 Norwegian university students: those in the highest fifth of a 2022 Three-Item Loneliness Scale score, against the lowest fifth, had more CIDI major depressive episodes a year later (relative risk 2.02 in women and 2.64 in men after age and baseline Hopkins symptoms).","mechanism":"The authors treat loneliness as a felt gap in companionship, not a head count of friends. They think that gap wears on mood through isolation, left-outness, and a thin campus network. They do not isolate one biological path.\n\nHysing, Petrie, Harvey and Sivertsen (2026) invited every full-time Norwegian student aged 18 to 35 in the 2022 Students' Health and Wellbeing Study. 53,362 answered. 16,418 were drawn for a 2023 diagnostic follow-up. 10,460 completed at least one CIDI 5.0 section. Loneliness was the Three-Item Loneliness Scale in 2022. The outcome was a current major depressive episode on a self-administered CIDI about twelve months later. Students with a 12-month or lifetime episode who were not currently depressed were dropped from the models.\n\nHighest versus lowest loneliness fifth, age only: relative risk 6.45 (5.14 to 8.07). After age and a high Hopkins Symptoms Checklist score: 2.02 (1.58 to 2.63) in women and 2.64 (1.63 to 4.49) in men. The dose ran through lacking companionship, feeling left out, and feeling isolated. Feeling isolated very often versus never sat at 3.51 in men and 2.28 in women after the same adjustment. Below the Hopkins cutoff the top fifth sat at 3.74 (2.66 to 5.28).","caveats":"Nobody assigned loneliness. These are students who answered a survey and then a diagnostic interview. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim.\n\nBaseline mood sits on the backdoor. Adjusting for Hopkins symptoms cut the relative risks by about 70 percent. The authors still cannot rule out reverse flow: depression can make campus feel empty. They omitted people with a past episode who were well at the CIDI, so this page is current 30-day MDE, not a first-ever diagnosis in a depression-free cohort.\n\nThe SHOT response was 35 percent. The CIDI sample was 70.6 percent women, mean age 24, slightly lonelier than invitees who skipped. Follow-up was one year. The T-ILS items are felt isolation. They are not living alone and not a network count.\n\nThis is a journal entry, not medical advice and not a reason to join a group, to treat a number, or to diagnose a friend.","confounders":["sleep-hygiene","alcohol-intake","education","disposable-income","social-capital"],"paperIds":["p-pmid-40962949"],"contributions":[{"paperId":"p-pmid-40962949","evidenceGrade":"full_text","designNote":"Hysing 2026 Soc Psychiatry Psychiatr Epidemiol. SHoT2022 T-ILS then CIDI 5.0 MDE ~12 mo. n=10460 of 16418 invited (SHOT 53362). Highest vs lowest quintile Model 2 (age+HSCL): RR 2.02 (1.58-2.63) women, 2.64 (1.63-4.49) men. Unadjusted RR 6.45. Current 30-day MDE. Observational. full_text. Archive n null; N from paper."}],"featured":false},{"id":"e-loneliness-mortality","sourceId":"loneliness","targetId":"mortality","relation":"spurious","direction":"forward","polarity":"positive","methodology":"meta_analysis","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Wang 2023: loneliness all-cause pooled ES 1.14 (1.08-1.20), 90 cohorts. Nakou 2025 older adults HR 1.14 (1.10-1.18), n=308,948. Sign is more loneliness, more death. Design does not identify."},"n":2205199,"summary":"Wang 2023 pooled 90 prospective cohorts in 2,205,199 adults and found loneliness associated with a 14 percent higher all-cause death risk (effect size 1.14, 1.08 to 1.20). Nobody randomized loneliness.","mechanism":"Loneliness is the feeling that contact falls short of what a person wants. Isolation is a count of contacts. Living alone is a household. The three travel together.\n\nWang, Gao, Han and colleagues (2023) pooled 90 prospective cohorts, 2,205,199 adults aged 18 or older (PROSPERO CRD42022299959). In the general population, loneliness tracked higher all-cause death (pooled effect size 1.14, 1.08 to 1.20) and higher cancer death (1.09, 1.01 to 1.17). Isolation was larger on all-cause death (1.32, 1.26 to 1.39) and also on CVD death (1.34). the record here is The 2.2 million is the whole review.\n\nNakou, Dragioti, Bastas and colleagues (2025) stayed with older adults. Loneliness and all-cause death: 52 studies, 308,948 people, HR 1.14 (1.10 to 1.18). Isolation 1.35. Living alone 1.21. Heterogeneity was high (I-squared 84 percent). A prediction interval ran from 0.89 to 1.46. The Egger test flagged publication bias. Longer follow-up gave a smaller loneliness estimate.\n\nYu, Steptoe, and Chen (2022) followed 35,254 people in the Chinese Longitudinal Healthy Longevity Survey (mean age 86.6) for a median 4.8 years. Isolation tracked death (HR 1.22, 1.18 to 1.25). Loneliness did not after health and low psychological well-being (HR 1.01, 0.98 to 1.04). Under age 80 it did (HR 1.15, 1.05 to 1.26). the record here The paper names N=35,254.\n\nKraav and colleagues (2021) followed 2,588 Finnish men aged 42 to 61 for 23.2 years. Loneliness predicted all-cause death after the full covariate set. Cancer and CVD death moved with loneliness until lifestyle or HPL depression scores went in. Isolation predicted all-cause and injury death. That isolation path ran through loneliness and depression scores. the record here The paper names N=2,588.\n\nAuthors name stress physiology, health behavior, and mood. The files do not isolate one path.","caveats":"The stamp is smoke because nobody randomized loneliness. These are cohorts and metas of cohorts. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim. A larger meta is still observation.\n\nWang's 2.2 million mixes isolation with loneliness. This page is the loneliness arrow. Isolation is a different construct. So is living alone.\n\nReverse causation sits on the backdoor: illness can cut contact and raise both the feeling and later death. Yu's very-old null after health and well-being is that problem in one sample. Nakou's prediction interval crosses 1.\n\nSelf-report scales differ. Residual confounding from income, education, smoking, and drinking remains. Kraav's cause-specific associations moved when depression or lifestyle went in.\n\nThis is a journal entry, not medical advice.","confounders":["social-capital","depression","disposable-income","education","alcohol-intake"],"paperIds":["p-pmid-37337095","p-pmid-39836319","p-pmid-35229887","p-pmid-33939562"],"contributions":[{"paperId":"p-pmid-37337095","evidenceGrade":"abstract_only","designNote":"Wang 2023. Systematic review and meta of 90 prospective cohorts, 2,205,199 adults ≥18. PROSPERO CRD42022299959. Identifying. Loneliness all-cause ES 1.14 (1.08-1.20); cancer 1.09 (1.01-1.17). Isolation all-cause 1.32; CVD 1.34. Archive n null; N from abstract. abstract_only."},{"paperId":"p-pmid-39836319","evidenceGrade":"full_text","designNote":"Nakou 2025. Meta of cohorts, older adults. Loneliness all-cause: 52 studies, 308,948 people, HR 1.14 (1.10-1.18), I² 84%, PI 0.89-1.46, Egger bias. Isolation 1.35. Living alone 1.21. Does not raise the stamp. full_text."},{"paperId":"p-pmid-35229887","evidenceGrade":"abstract_only","designNote":"Yu 2022. CLHLS cohort, 35,254 Chinese adults, mean age 86.6, median 4.8 y, 21,570 deaths. Isolation HR 1.22 (1.18-1.25). Loneliness NS after health and low PWB (HR 1.01); <80 y HR 1.15 (1.05-1.26). Archive n null; N from abstract. abstract_only."},{"paperId":"p-pmid-33939562","evidenceGrade":"abstract_only","designNote":"Kraav 2021. Prospective, 2,588 Finnish men aged 42-61, mean 23.2 y. Loneliness predicted all-cause death after full covariates. Cancer/CVD except after lifestyle or HPL depression. Isolation: all-cause and injury; mediated by loneliness and depression. Archive n null; N=2588 from abstract. abstract_only."}],"featured":false},{"id":"e-magnesium-depression","sourceId":"magnesium","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Tarleton 2017 open-label crossover: PHQ-9 net -6.0 (-7.9 to -4.2) vs no treatment, N=112. Barragán-Rodríguez 2008: Yasavage 11.4 vs 10.9 vs imipramine 50 mg, N=23. No placebo in either."},"n":112,"summary":"Tarleton 2017 found that 248 mg a day of elemental magnesium as chloride, versus no treatment, cut PHQ-9 scores by 6.0 points among 112 primary-care adults with mild-to-moderate depression in an open-label crossover (95% CI -7.9 to -4.2). Barragán-Rodríguez 2008 found a similar drop versus imipramine in 23 older adults with diabetes and low serum magnesium.","mechanism":"Authors treat a magnesium salt as something that might ease a mild depressive episode, perhaps through NMDA or inflammatory paths. Neither file isolates that path, and neither uses a matching placebo.\n\nTarleton, Littenberg, MacLean, Kennedy and Daley (2017) assigned 126 US primary-care adults with a PHQ-9 of 5 to 19 to six weeks of 248 mg elemental magnesium as chloride and six weeks of no treatment, in an open-label blocked crossover. 112 people gave analyzable data. The net PHQ-9 change was -6.0 points (-7.9 to -4.2). GAD-7 sat at -4.5 (-6.6 to -2.4). Adherence by pill count was 83 percent. The authors say the drop showed within two weeks and did not depend on baseline serum magnesium or on being already on an antidepressant.\n\nBarragán-Rodríguez, Rodríguez-Morán and Guerrero-Romero (2008) assigned 23 older adults with type 2 diabetes, serum magnesium under 1.8 mg per deciliter, and a new Yasavage and Brink score of 11 or more to 450 mg of elemental magnesium as chloride solution or 50 mg of imipramine for twelve weeks. End scores were 11.4 versus 10.9 (P=0.27). Serum magnesium rose only on the salt.","caveats":"Researchers assigned people to a salt or a control, so this is a trial stamp. Nobody assigned a matching placebo. More papers of the same design do not settle the claim.\n\nTarleton is open-label against no pill. A six-point PHQ-9 drop against nothing includes expectancy, phone-call attention, and regression to the mean. That is why confidence stays contested.\n\nBarragán-Rodríguez is twenty-three people, older, diabetic, hypomagnesemic, and the comparator is a tricyclic, not placebo. Both arms fell. Equivalence to 50 mg of imipramine is not a placebo-controlled identification.\n\nThis page is not the insulin page. It is not a reason to treat a PHQ-9 with a grocery salt.\n\nThis is a journal entry, not medical advice.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise","insulin-resistance"],"paperIds":["p-pmid-28654669","p-pmid-19271419"],"contributions":[{"paperId":"p-pmid-28654669","evidenceGrade":"full_text","designNote":"Tarleton 2017 PLoS One. Open-label blocked crossover RCT. 248 mg elemental Mg chloride vs no treatment, 6 wk each. N=126 enrolled, 112 analyzable, PHQ-9 5-19. Net PHQ-9 -6.0 (-7.9 to -4.2). GAD-7 -4.5. No placebo. full_text. Archive n null."},{"paperId":"p-pmid-19271419","evidenceGrade":"abstract_only","designNote":"Barragán-Rodríguez 2008 Magnes Res. Equivalence RCT. 450 mg elemental MgCl2 vs imipramine 50 mg, 12 wk, N=23 elderly T2D, Mg<1.8, new Yasavage>=11. End 11.4 vs 10.9 P=0.27. No placebo. abstract_only. Archive n null."}],"featured":false},{"id":"e-magnesium-insulin","sourceId":"magnesium","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Drenthen 2024 clamp M 4.6 vs 4.4, P=0.108, N=14. Heidary 2021 ICU load, HOMA -0.11 vs placebo, N=70. Shahmoradi PCOS IR down. Sadeghian nephropathy IR up."},"n":14,"summary":"Drenthen 2024 found that 15 mmol a day of oral magnesium for six weeks did not change clamp insulin sensitivity versus placebo in 14 adults with insulin-treated type 2 diabetes (M value 4.6 versus 4.4). An intensive-care loading dose then moved HOMA in stress hyperglycemia (Heidary 2021).","mechanism":"Authors treat magnesium as a cofactor in insulin signaling. Raising a low serum number is supposed to make insulin work better. The gold-standard test of that claim is a clamp, not a HOMA worksheet.\n\nDrenthen, de Baaij, Rodwell and colleagues (2024) assigned 14 White adults with insulin-treated type 2 diabetes and serum magnesium at or below 0.79 mmol per liter to 15 mmol a day of oral magnesium or matched placebo for six weeks each, in a blinded crossover. Serum and urine magnesium rose on the salt. The clamp M value was 4.6 versus 4.4 mg per kg per minute (P=0.108).\n\nHeidary, Khalili, Mohammadi, Beigmohammadi and Abdollahi (2021) assigned 70 critically ill people with stress hyperglycemia and no diabetes to 7.5 g of intravenous magnesium sulfate over eight hours or placebo. By day 3, HOMA change was -0.11 versus placebo (95 percent CI -0.19 to -0.01). Adiponectin rose.\n\nShahmoradi, Chiti, Tavakolizadeh and colleagues (2024) assigned 40 women aged 15 to 35 with PCOS to 250 mg a day of magnesium oxide or placebo for two months. Serum insulin (P=0.036) and insulin resistance (P=0.032) fell in the magnesium arm.\n\nSadeghian, Azadbakht, Khalili and colleagues (2020) assigned 80 people with type 2 diabetes, early nephropathy, and low serum magnesium to daily magnesium oxide or placebo for twelve weeks. Insulin resistance was higher on magnesium than on placebo (P=0.04).\n\nRodríguez-Morán, Simental-Mendía, Gamboa-Gómez and Guerrero-Romero (2019) assigned 198 people with metabolic syndrome and serum magnesium under 1.8 mg per deciliter to 382 mg of elemental magnesium as chloride or placebo for sixteen weeks. Fasting glucose fell 12.4 mg per deciliter more on magnesium.","caveats":"Researchers assigned people to a salt or a control, so this is a trial stamp. The only clamp is fourteen people and a null. More papers of the same design do not settle the claim.\n\nDrenthen is insulin-treated type 2 diabetes, six weeks, a crossover. Serum magnesium rose. Sensitivity did not.\n\nHeidary is an intensive-care load, not a daily oral salt, and not diabetes. HOMA moved. A clamp did not.\n\nShahmoradi is PCOS and no published HOMA increment. Sadeghian is diabetic kidney disease and the insulin-resistance change went the other way. Rodríguez-Morán identifies fasting glucose, not HOMA-IR.\n\nThis is a journal entry, not medical advice and not a reason to start or stop a salt.","confounders":["ultraprocessed-food","sedentary-time","aerobic-exercise","sleep-hygiene"],"paperIds":["p-pmid-37922013","p-pmid-37393389","p-pmid-30835085","p-pmid-29793665","p-pmid-29788815"],"contributions":[{"paperId":"p-pmid-37922013","evidenceGrade":"full_text","designNote":"Drenthen 2024 Diabetologia. Identifying clamp RCT, crossover. 15 mmol/d oral Mg vs placebo, 6 wk each, N=14 insulin-treated T2D, serum Mg<=0.79. M value 4.6 vs 4.4 mg/kg/min P=0.108. full_text. Archive n null."},{"paperId":"p-pmid-37393389","evidenceGrade":"abstract_only","designNote":"Shahmoradi 2024 Biol Trace Elem Res. RCT. MgO 250 mg/d vs placebo, 2 mo, N=40 women 15-35 with PCOS. Insulin P=0.036, IR P=0.032 down in Mg arm. No HOMA increment in abstract. abstract_only. Archive n null."},{"paperId":"p-pmid-30835085","evidenceGrade":"abstract_only","designNote":"Sadeghian 2020 Biol Trace Elem Res. RCT. Daily MgO vs placebo, 12 wk, N=80 T2D early nephropathy, low serum Mg. Glycemic indices NS. IR higher on Mg than placebo P=0.04. abstract_only. Archive n null."},{"paperId":"p-pmid-29793665","evidenceGrade":"abstract_only","designNote":"Rodríguez-Morán 2019 Adv Chronic Kidney Dis. RCT. 382 mg elemental Mg chloride vs placebo, 16 wk, N=198 MetS + Mg<1.8. Fasting glucose -12.4 mg/dL. MetS remained 48% vs 77.5%. No HOMA in abstract. abstract_only. Archive n null."},{"paperId":"p-pmid-29788815","evidenceGrade":"abstract_only","designNote":"Heidary 2021 J Intensive Care Med. RCT. IV MgSO4 7.5 g over 8 h vs placebo, N=70 ICU SIH, no diabetes. Day-3 HOMA change -0.11 (CI -0.19 to -0.01). Adiponectin up. abstract_only. Archive n null."}],"featured":false},{"id":"e-magnesium-sleep","sourceId":"magnesium","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Schuster 2025: bisglycinate 250 mg, 4 wk, N=155 poor sleep, ISI -3.9 vs -2.3 P=0.049. Hausenblas 2024: MgT 1 g, 21 d, N=80, deep/REM vs placebo. Nielsen 2011: PSQI improved on both arms."},"n":155,"summary":"Schuster 2025 found that 250 mg of magnesium bisglycinate a day for four weeks lowered the Insomnia Severity Index by 3.9 points versus 2.3 on placebo in 155 adults who reported poor sleep (P=0.049). Hausenblas 2024 saw better deep and REM scores on magnesium L-threonate versus placebo in 80 people.","mechanism":"Authors treat a magnesium salt as a sleep aid. They do not isolate one transporter.\n\nSchuster, Cycelskij, Lopresti and Hahn assigned 155 adults aged 18 to 65 with self-reported poor sleep to 250 mg elemental magnesium as bisglycinate or placebo for four weeks. ISI fell 3.9 versus 2.3 (P=0.049). Other psychological scales did not differ. Hausenblas, Lynch, Hooper and colleagues assigned 80 adults aged 35 to 55 with self-reported sleep problems to 1 g of magnesium L-threonate or placebo for 21 days. Oura deep-sleep and REM scores moved versus placebo. Subjective energy and mood also moved.","caveats":"Researchers assigned people to a salt or a control, so this is a trial stamp. The ISI difference is small. More papers of the same design do not settle the claim.\n\nSchuster is four weeks and P=0.049. Hausenblas is a branded L-threonate and a consumer ring.\n\nThis is a journal entry, not medical advice and not a reason to take magnesium for insomnia.","confounders":["caffeine","alcohol-intake","light-exposure"],"paperIds":["p-pmid-40918053","p-pmid-39252819"],"contributions":[{"paperId":"p-pmid-40918053","evidenceGrade":"full_text","designNote":"Schuster 2025 Nat Sci Sleep. RCT (Archive grade observational). Bisglycinate 250 mg vs placebo, 4 wk, N=155 poor sleep. ISI -3.9 vs -2.3 P=0.049. Other psych ns. full_text. Archive n null."},{"paperId":"p-pmid-39252819","evidenceGrade":"full_text","designNote":"Hausenblas 2024 Sleep Med X. RCT (Archive grade observational). MgT 1 g vs placebo, 21 d, N=80 age 35-55. Deep/REM and some Oura activity vs placebo. full_text. Archive n null."}],"featured":false},{"id":"e-med-insulin","sourceId":"mediterranean-diet","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.48,"note":"PREDIMED-Reus multivariate HR 0.48 (0.27-0.86) pooled MedDiets vs low-fat. 54 T2D events in 418. 2018 household-drop HR 0.47. Incidence, not HOMA."},"n":418,"summary":"In 418 older Spaniards free of diabetes, PREDIMED-Reus assigned a Mediterranean diet with free extra-virgin olive oil or mixed nuts against low-fat advice. After a median four years the pooled Mediterranean arms had about half the new type 2 diabetes (hazard ratio 0.48). The measure is diabetes incidence, not HOMA-IR.","mechanism":"The PREDIMED authors treat the Mediterranean pattern as a high-unsaturated-fat diet: olive oil as the main fat, vegetables, fruit, legumes, nuts, fish, and modest wine, with less red meat, butter, pastry, and sweet drinks. They think that fat swap, plus the phenolics in extra-virgin oil and nuts, improves how insulin works without a calorie deficit. In Reus, weight and leisure activity barely moved.\n\nSalas-Salvadó, Bulló, Babio and colleagues nested a diabetes endpoint in one PREDIMED center. 418 people aged 55 to 80, free of diabetes, high cardiovascular risk. They were assigned to low-fat advice, a Mediterranean diet with a liter of virgin olive oil a week, or the same diet with 30 grams of mixed nuts a day. No calorie target. No exercise program. Diabetes was fasting glucose at or above 7.0 mmol/l or two-hour glucose at or above 11.1 mmol/l after a 75-gram load, confirmed on a second test, by a committee blinded to assignment. Median follow-up was 4.0 years. Fifty-four people developed diabetes. Rates per 1,000 person-years were 24.6 (olive oil), 26.8 (nuts), and 46.6 (control). Multivariate hazard ratios versus control were 0.49 (0.25 to 0.97) for olive oil and 0.48 (0.24 to 0.96) for nuts. Pooled, 0.48 (0.27 to 0.86). Baseline HOMA-IR was recorded in 307 people. It was not the outcome.\n\nMartínez-González, Montero, Ruiz-Canela and colleagues later scored yearly Mediterranean Diet Adherence Screener points in 3,541 PREDIMED participants who started without diabetes. Two extra points on the cumulative average sat with hazard ratio 0.80 (0.70 to 0.92) for new diabetes. Highest versus lowest score (12 to 14 versus under 8) sat at 0.46 (0.25 to 0.83). Adjusting for the randomized arm left 0.82 per two points and 0.48 for the extremes. Two hundred seventy-three incident cases. That is attained adherence inside the same trial, not a second assignment.","caveats":"The insulin page on this site is named for HOMA-IR. PREDIMED-Reus identified new type 2 diabetes. Do not read the stamp as a HOMA change.\n\nReus is one Spanish center, older people at high cardiovascular risk, 54 events. Seventeen percent of scheduled oral glucose tests were refused. Forty-one people had none, so some diagnoses rest on fasting glucose only. The control arm was told to cut fat and mostly did not. Staff who collected diet and weight knew the assignment. Olive oil and nuts were donated by producers.\n\nA 2018 erratum said PREDIMED's individual randomization slipped for at most 14 percent of the whole trial. Reus was not the clinic-assignment site. Twenty-nine Reus household second members (6.9 percent) were put on a spouse's arm. Dropping them left a pooled hazard ratio of 0.47 (0.26 to 0.87).\n\nThe 2023 paper is yearly attained score, not intention-to-treat. Residual confounding remains after adjusting for the arm.\n\nThis is a journal entry, not medical advice and not a reason to buy oil, nuts, or a scorecard.","confounders":["ultraprocessed-food","aerobic-exercise","eating-window","sedentary-time","disposable-income"],"paperIds":["p-pmid-20929998","p-pmid-37775736"],"contributions":[{"paperId":"p-pmid-20929998","evidenceGrade":"full_text","designNote":"PREDIMED-Reus 2011. Identifying RCT. 418 nondiabetic, 55-80, one center. Med+VOO or Med+nuts vs low-fat. No calorie or exercise advice. 54 T2D events, median 4.0 y. Pooled HR 0.48 (0.27-0.86). 2018 erratum: Reus not site D; drop 29 household seconds, HR 0.47. Archive n null; N=418 from paper. full_text. T2D incidence, not HOMA."},{"paperId":"p-pmid-37775736","evidenceGrade":"full_text","designNote":"Martínez-González 2023. Same PREDIMED trial, yearly attained MEDAS in 3541 diabetes-free. Time-varying Cox. +2 MEDAS HR 0.80 (0.70-0.92); 12-14 vs <8 HR 0.46. After randomized arm: 0.82 and 0.48. 273 events. Not ITT. Archive n null; N=3541 from paper. full_text."}],"featured":false},{"id":"e-melatonin-sleep","sourceId":"melatonin","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Luthringer 2009: PRM 2 mg, N=40, age>=55 primary insomnia. SOL -9 min vs placebo P=0.02. Baandrup 2017: PR melatonin add-on in SMI benzo taper. PSG efficiency NS (N=23). Subjective quality improved (N=55)."},"n":40,"summary":"Luthringer 2009 found that 2 mg of prolonged-release melatonin at night shortened polysomnographic sleep-onset latency by 9 minutes versus placebo in 40 people aged 55 or older with primary insomnia (P=0.02). Baandrup 2017 found no change in sleep efficiency when the same kind of tablet was added during benzodiazepine withdrawal in schizophrenia or bipolar disorder.","mechanism":"Authors treat a night-time melatonin tablet as a clock cue that might shorten the wait to sleep. Luthringer tests that in older primary insomnia. Baandrup tests it as an add-on while people with severe mental illness come off a benzodiazepine.\n\nLuthringer, Muzet, Zisapel and Staner (2009) gave 40 patients aged 55 or older with DSM-IV primary insomnia two single-blind placebo weeks, then three double-blind weeks of 2 mg prolonged-release melatonin or placebo, then three withdrawal weeks. At the end of the double-blind period, sleep-onset latency was 9 minutes shorter on melatonin (P=0.02). Half reported a substantial home-sleep improvement versus 15 percent on placebo (P=0.018). Critical flicker fusion was better on melatonin. Sleep architecture was not harmed.\n\nBaandrup, Glenthøj and Jennum (2017) added prolonged-release melatonin or placebo while adults with schizophrenia, schizoaffective disorder, or bipolar disorder tapered long-term benzodiazepines on antipsychotics. One-night polysomnography in 23 people: sleep efficiency did not move. Self-reported sleep quality in 55 people improved. Retention was low.","caveats":"Researchers assigned people to a tablet or a control, so this is a trial stamp. The sign depends on who swallowed it. More papers of the same design do not settle the claim.\n\nLuthringer is forty older people with primary insomnia and a Circadin-style 2 mg tablet. Nine minutes on a lab night is the measured change.\n\nBaandrup is benzodiazepine withdrawal in schizophrenia or bipolar disorder. Objective efficiency missed. Subjective quality moved. The sample is small and leaky. That context is why the polarity is not a simple positive.\n\nThis is a journal entry, not medical advice and not a reason to start a night tablet.","confounders":["light-exposure","caffeine","alcohol-intake"],"paperIds":["p-pmid-19584739","p-pmid-27107670"],"contributions":[{"paperId":"p-pmid-19584739","evidenceGrade":"abstract_only","designNote":"Luthringer 2009 Int Clin Psychopharmacol. Identifying RCT. PRM 2 mg vs placebo, 3 wk double-blind after 2 wk single-blind placebo. N=40 age>=55 primary insomnia. SOL -9 min P=0.02. Home quality 50% vs 15% P=0.018. abstract_only. Archive n null."},{"paperId":"p-pmid-27107670","evidenceGrade":"abstract_only","designNote":"Baandrup 2017 Psychiatry Res. RCT add-on. PR melatonin vs placebo during benzo taper, schizophrenia/schizoaffective/bipolar on antipsychotics. PSG efficiency NS N=23. Subjective quality improved N=55. Low retention. abstract_only. Archive n null."}],"featured":false},{"id":"e-mindfulness-depression","sourceId":"mindfulness","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Cladder-Micus 2019 ITT IDS-SR -3.23 (d=0.35, P=0.09), N=106; MINI remission 41.5% vs 21.6%. Ritvo 2021 ITT BDI-II MD -8.54, P=.01, N=45. Archive n empty."},"n":106,"summary":"Ritvo 2021 found that online mindfulness-based CBT plus monthly psychiatry cut Beck depression scores by 8.54 points versus psychiatry alone in 45 young adults with major depression. Cladder-Micus 2019's MBCT add-on in chronic treatment-resistant depression missed on the IDS-SR in intention-to-treat and still raised partial remission.","mechanism":"MBCT teaches people to notice a familiar train of thought and to let it pass instead of arguing with it. Segal, Williams, and Teasdale built the eight-week group on that idea. Rumination is the named path.\n\nCladder-Micus, Speckens, Vrijsen and colleagues assigned 106 Dutch outpatients with a current DSM-IV episode lasting at least a year, an IDS-SR of 21 or more, and a failed run of both an antidepressant and CBT or IPT. Forty-nine got the standard MBCT course plus usual care. Fifty-seven got usual care. Usual care was whatever the clinic already offered: pills, therapy, a nurse, or day hospital.\n\nAt posttreatment the ITT IDS-SR difference was -3.23 (-6.99 to 0.54, d=0.35, P=0.09). Completers who sat at least four sessions differed by -4.24 (d=0.45, P=0.04). MINI remission, mostly partial, was 41.5 percent versus 21.6 percent (P=0.04). Rumination fell (d=0.39, P=0.04). People who already ruminated above a published clinical mean dropped more on the IDS-SR.\n\nRitvo, Knyahnytska, Pirbaglou and colleagues assigned 45 CAMH outpatients aged 18 to 30 with MINI major depression and a BDI-II of 14 or more. Twenty-two got six months of online CBT-M: 24 workbooks, 56 mindfulness videos, a weekly navigator coach, and a Fitbit, on top of a monthly psychiatry visit. Twenty-three got the monthly visit alone.\n\nThe ITT BDI-II difference was -8.54 (P=.01). QIDS differed by -4.94 (P=.001). A blinded Hamilton rater did not (P=.09). The Nonjudging facet of the FFMQ moved. Anxiety and pain also moved. Those are not this page.","caveats":"Cladder-Micus is open-label and add-on. Assessors who ran the MINI were not blind. A quarter of the MBCT arm sat fewer than four sessions. Full MINI remission was rare (one person versus two). The ITT primary missed. Netherlands, 2013 to 2016. The paper names 106 people.\n\nRitvo is 45 people. The control arm lost 61 percent. The assigned package mixes CBT workbooks, mindfulness videos, coaching, and a step counter. Psychiatrists were not blind. The blinded Hamilton contrast missed. CAMH, Toronto. The paper names 45 people.\n\nThis page is not a walk and not hours in bed. those pages are the exercise-and-depression page and the sleep-and-depression page. More papers of the same design do not settle the claim.\n\nThis is a journal entry, not medical advice and it is not a reason to start or skip a class.","confounders":["sleep-hygiene","aerobic-exercise","alcohol-intake"],"paperIds":["p-pmid-30088834","p-pmid-33688840"],"contributions":[{"paperId":"p-pmid-30088834","evidenceGrade":"full_text","designNote":"Cladder-Micus 2019 Dep Anxiety, pragmatic RCT. MBCT+TAU vs TAU, 106 chronic TRD outpatients (MINI MDD ≥12mo, IDS-SR≥21, prior AD + CBT/IPT). ITT IDS-SR -3.23 (-6.99 to 0.54), d=0.35, P=0.09. MINI remission 41.5% vs 21.6%, P=0.04 (mostly partial). PP d=0.45, P=0.04. 24.5% <4 sessions. Archive n null; 106 from paper. full_text."},{"paperId":"p-pmid-33688840","evidenceGrade":"full_text","designNote":"Ritvo 2021 JMIR, NCT03406052. Online CBT-M + monthly psychiatry vs psychiatry, 45 youth 18-30, MINI MDD, BDI-II≥14. ITT BDI-II MD -8.54, P=.01; QIDS -4.94, P=.001; blinded HDRS -5.52, P=.09. Control dropout 61%. 24 workbooks + 56 videos + coach + Fitbit. Archive n null; 45 from paper. full_text."}],"featured":false},{"id":"e-network-employment","sourceId":"social-capital","targetId":"employment-status","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Weak ties carry job information (Granovetter 1973). LinkedIn PYMK experiments: more weak ties raised job mobility in 20 million members (Rajkumar 2022); inverted-U in tie weakness; industry split."},"n":null,"summary":"Weak ties carry jobs: Granovetter (1973) showed acquaintances bring novel job information, and Rajkumar (2022) tested that claim by randomizing LinkedIn's People You May Know among more than 20 million members over five years.","mechanism":"Close friends share the same pool of news. Acquaintances sit in other clusters. Granovetter (1973) argued that is why a weak tie is the one that tells you about a job you have not already heard of.\n\nRajkumar, Saint-Jacques, Bojinov, Brynjolfsson, and Aral ran large randomized experiments on LinkedIn's People You May Know algorithm, which recommends new connections. The experiments randomly varied how many of those recommendations were weak ties in the networks of more than 20 million members over five years. About 2 billion new ties formed. About 600,000 new jobs appeared. More weak ties raised job mobility.\n\nThey also revised the theory. Tie strength and job transmission form an inverted U: weaker ties moved more jobs up to a point, then further weakness added less. Two ways of measuring a weak tie did not agree. Ties that were moderately weak by number of mutual connections, and the weakest ties by how often people interacted, created the most job mobility. Industry split the result. Weak ties raised job mobility in more digital industries. Strong ties raised it in less digital ones.\n\nWho you know is a hiring channel. That is also why a network is a backdoor in studies that credit a vitamin or another purchasable input for a career.","caveats":"Rajkumar randomized a recommendation algorithm on LinkedIn, not a program that tells people to collect acquaintances. Members of a professional network are already selected. The outcome is job mobility, including job changes by people who already had work. Employment status here means in work or not. Job mobility is the matching Granovetter wrote about. It is not only a switch from unemployed to employed.\n\nThe inverted U and the industry split mean adding ever-weaker ties is not a universal knob. In less digital industries the strong ties did the work.\n\nGranovetter is observational. People befriend people like themselves. Education and money travel with networks outside the LinkedIn experiment.","confounders":["education","disposable-income"],"paperIds":["p-granovetter-1973","p-pmid-36107999"],"contributions":[{"paperId":"p-granovetter-1973","evidenceGrade":"abstract_only","designNote":"Granovetter 1973. Observational: novel job information travels over weak ties. Gold paper. abstract_only."},{"paperId":"p-pmid-36107999","evidenceGrade":"abstract_only","designNote":"Rajkumar et al. 2022. Randomized experiments of LinkedIn People You May Know; varied weak-tie prevalence for >20 million members over 5 years; ~2 billion new ties, ~600,000 new jobs. Outcome job mobility. Paper is a randomized experiment (Archive record lists observational). abstract_only."}],"featured":false},{"id":"e-noise-cv","sourceId":"traffic-noise","targetId":"cardiovascular","relation":"spurious","direction":"forward","polarity":"positive","methodology":"meta_analysis","confidence":"low","effect":{"metric":"odds_ratio","value":1.02,"note":"Fu 2023: road traffic per 10 dB Lden, incident CVD RR 1.020 (1.006-1.035), 23 cohort papers, 18.5M adults. Observational. Design does not identify."},"n":18503167,"summary":"In a 2023 dose-response meta-analysis of 23 cohort papers and 18.5 million adults, mostly in Europe, each extra 10 dB of modelled road-traffic noise (as Lden) sat with a 2 percent higher risk of incident cardiovascular disease (RR 1.020, 1.006 to 1.035). Nobody randomized the street.","mechanism":"Night-time and day-evening-night traffic sound can act as a stressor. The authors think it turns on the hypothalamic-pituitary-adrenal and sympathetic axes, raises adrenaline and cortisol, and, over years, leaves inflammation, oxidative stress, and endothelial dysfunction. Broken sleep is the other named path. The number on this page is outdoor transportation sound, usually converted to Lden. Fine particles at the same address are a different question.\n\nFu, Wang, Yuan and colleagues (2023) pooled 23 cohort papers, 57 analyses, and 18,503,167 adults. Twenty-one papers were European; two were Canadian. They converted LAeq24h, LAeq16h, and Lnight to Lden. Each extra 10 dB of road noise sat with a 2 percent higher risk of incident cardiovascular disease (RR 1.020, 1.006 to 1.035; I-squared 90.6 percent). Aircraft sat at 1.016 (1.000 to 1.032). Railway per 10 dB did not (0.986, 0.968 to 1.004). Highest versus lowest road noise sat at 1.068 (1.023 to 1.115). Stroke with road noise sat at 1.034 (1.026 to 1.043) and heart failure at 1.050 (1.006 to 1.096). The road-and-stroke curve rose to about 62 dB and then flattened. Mean Newcastle-Ottawa score was 8.04.\n\nHao, Zuo, Weng and colleagues (2022) followed 342,566 UK Biobank adults free of cardiovascular disease at baseline and added a cohort meta through April 2021. After adjustment, each extra 10 dB of road noise sat with stroke 1.07 (1.01 to 1.13), cardiovascular disease 1.13 (1.04 to 1.22), and all-cause death 1.08 (1.04 to 1.12). The associations showed in men and not in women. The pooled meta sat at stroke 1.06 (1.02 to 1.11), cardiovascular death 1.03 (1.00 to 1.05), and all-cause death 1.05 (1.02 to 1.07).\n\nBabisch (2008) pooled two cross-sectional and five case-control or cohort studies of road noise and myocardial infarction. Risk did not rise below 60 dB(A) average daytime sound. It rose above that mark. The polynomial fit is the older burden curve.","caveats":"The stamp is smoke because nobody randomized the street. Observation alone cannot close the backdoor, so the stamp stays smoke. A meta-analysis of those cohorts does not raise it. More papers of the same design do not settle the claim.\n\nFu's road-to-disease increment sits on I-squared 90.6 percent. Railway per 10 dB is consistent with a null. The aircraft interval starts at 1.000. Twenty-one of 23 papers are European. Exposure is almost always a model at the façade, not a microphone in the bedroom.\n\nThe same street makes particles. Fu's subgroup that adjusted for air pollution still saw road noise with cardiovascular disease, and a stronger increment when income was in the model. Road noise with myocardial infarction and with atrial fibrillation often lost the association once air pollution was in. Age and income remain open doors: hearing fades, and who can buy a quiet room is not random.\n\nHao's all-cause death is a different question. Fu notes that Hao mixed incidence and death in the stroke pool. The UK Biobank file sits inside Fu's 23 papers.\n\nBabisch is daytime LAeq and infarcts, with a 60 dB floor, in men. It is the older curve, not a trial.\n\nThis page is outdoor transportation sound and incident cardiovascular events. It is not PM2.5 and not a blood-pressure reading.\n\nThis is not medical advice and not a recommendation to move, to close a window, or to treat a number.","confounders":["air-pollution","disposable-income","education","sleep-hygiene"],"paperIds":["p-pmid-37580544","p-pmid-35358546","p-pmid-18270405"],"contributions":[{"paperId":"p-pmid-37580544","evidenceGrade":"full_text","designNote":"Fu 2023 J Urban Health. Identifying dose-response meta. 23 cohort articles (57 studies), n=18503167, Europe 21 + Canada 2, to 4 Apr 2022. Per 10 dB Lden: road CVD RR 1.020 (1.006-1.035) I2=90.6%; aircraft 1.016 (1.000-1.032); railway 0.986 (0.968-1.004). Stroke road 1.034; HF road 1.050. Observational. full_text. Archive n null; 18503167 from paper."},{"paperId":"p-pmid-35358546","evidenceGrade":"abstract_only","designNote":"Hao 2022 Environ Res. UKB n=342566 CVD-free + meta of cohorts to Apr 2021. Per 10 dB: stroke 1.07 (1.01-1.13), CVD 1.13 (1.04-1.22), all-cause death 1.08 (1.04-1.12). Men; women NS. Meta stroke RR 1.06, CVD death 1.03, all-cause 1.05. Observational. abstract_only. Archive n null; 342566 from abstract."},{"paperId":"p-pmid-18270405","evidenceGrade":"abstract_only","designNote":"Babisch 2008 Noise Health. Meta of 2 descriptive + 5 analytical studies. Road day LAeq and myocardial infarction. No rise below 60 dB(A); dose-response above. Polynomial fit for burden calculations. Observational. Does not raise the stamp. abstract_only. Archive n null."}],"featured":false},{"id":"e-noise-sleep","sourceId":"traffic-noise","targetId":"sleep-hygiene","relation":"spurious","direction":"forward","polarity":"negative","methodology":"meta_analysis","confidence":"low","effect":{"metric":"odds_ratio","value":2.52,"note":"Smith 2022: HSD per 10 dB Lnight, noise named. Road OR 2.52 (2.28-2.79); aircraft 2.18; rail 2.97. Unnamed questions: road 1.14. Design does not identify."},"n":173160,"summary":"In a 2022 update of the WHO sleep review, each extra 10 dB of night-time road, rail, or aircraft noise raised the odds of being highly sleep disturbed about two- to three-fold when the question named the noise, across 36 observational studies and 173,160 responses. Nobody randomized the street.","mechanism":"Night-time sound can wake you, cut slow-wave sleep, or make falling asleep harder. The surveys mostly ask whether noise disturbed sleep. When the question names the source, the odds rise with Lnight. When it does not, the association shrinks.\n\nSmith, Cordoza, and Basner updated the WHO 2018 review. They added 11 studies (109,070 responses) to the original 25 (64,090). For questions that named the noise, GRADE was moderate: aircraft OR 2.18, road 2.52, railway 2.97 per 10 dB Lnight. For generic sleep questions, GRADE was low to very low: aircraft 1.52, road 1.14, railway 1.17 (the interval includes 1). At 40 dB the new curves still matched WHO. At high aircraft levels they sat above the old curve.\n\nSchubert asked 5,670 Leipzig adults in LIFE-Adult Wave 2 (2018-2021) the ISO high-sleep-disturbance items, with 2012 façade levels. Road OR 2.86, rail 2.67, aircraft 19.66 per 10 dB Lnight, adjusted for age, sex, and SES. About 2.7 percent were highly disturbed by road, 1.2 percent by rail, 2.0 percent by aircraft. Nobody in that sample sat at 52 dB aircraft or more. The aircraft odds sit on a thin tail.\n\nPerron telephoned 4,336 Montreal adults in 2014. Sleep disturbed by outdoor noise in the past four weeks: 12.4 percent. Road 4.2, aircraft 1.5, rail 1.1. Disturbance rose with LNight from a land-use regression and with proximity to a road, rail line, or airport contour.\n\nPerron 2012 reviewed 12 aircraft-noise papers. Moderate- and high-quality studies reported awakenings, less slow-wave sleep, or more sleep medication. Most of that file is laboratory nights in healthy adults. Pirrera 2010 is a methods review of nocturnal road noise: objective versus subjective sleep, and noise sensitivity as a modifier.","caveats":"The stamp is smoke because nobody randomized the street. A new edge from surveys and reviews publishes as spurious and low. A meta-analysis of those surveys does not raise it. Paper count does not raise it. Perron 2012 writes causal; that language does not mint an RCT.\n\nThe large Smith odds come from questions that already name the noise. Ask about sleep without naming the source and the road OR falls to 1.14. Railway without the prompt is consistent with a null. That is how neighborhood, windows, and who complains get into the answer.\n\nLIFE-Adult used the same named-source ISO items. Exposure is a 2012 map; the questionnaire is 2018 to 2021. People move. Secondary roads are in the road curve, so it is not the WHO road curve. Aircraft OR 19.66 has a wide interval and almost no one at high Lnight.\n\nMontreal is one city, one telephone survey, response 46.8 percent, oversampled near sources. LNight is a land-use regression from two-week samples, not a bedroom microphone.\n\nThis page is outdoor transportation sound and self-reported sleep. It is not PM2.5, not indoor TV, and not a lab restriction protocol.\n\nThis is not medical advice and not a recommendation to move, to close a window, or to treat a number.","confounders":["air-pollution","disposable-income","education"],"paperIds":["p-pmid-35857401","p-pmid-36981810","p-pmid-27529260","p-pmid-22517305","p-pmid-20406712"],"contributions":[{"paperId":"p-pmid-35857401","evidenceGrade":"full_text","designNote":"Smith 2022 EHP. Identifying meta. Update to WHO Basner/McGuire. 11 studies n=109070 responses plus 25 WHO n=64090. Lnight 2300-0700. Noise-named HSD per 10 dB: aircraft OR 2.18 (2.01-2.36), road 2.52 (2.28-2.79), rail 2.97 (2.57-3.43), GRADE moderate. Unnamed: aircraft 1.52, road 1.14, rail 1.17 (0.91-1.49), GRADE low/very low. Archive n null; 173160 from abstract. full_text."},{"paperId":"p-pmid-36981810","evidenceGrade":"full_text","designNote":"Schubert 2023 IJERPH, LIFE-Adult Leipzig. Observational, n=5670 Wave 2 2018-2021, 2012 façade Lnight. ISO HSD (score ≥4). Per 10 dB Lnight: road OR 2.86 (1.92-4.28), rail 2.67 (2.03-3.50), aircraft 19.66 (11.47-33.71). Adjusted age (quadratic), sex, SES. HSD: road 2.7%, rail 1.2%, aircraft 2.0%. full_text. Archive n null; 5670 from paper."},{"paperId":"p-pmid-27529260","evidenceGrade":"full_text","designNote":"Perron 2016 IJERPH (Archive year 2017), Montreal. Observational telephone survey 2014, n=4336 adults, response 46.8%. LUR LNight plus distance to road/rail/airport. Sleep disturbed by outdoor noise past 4 weeks: 12.4%; road 4.2%, aircraft 1.5%, rail 1.1%. Disturbance rose with LNight and proximity. Combined road+rail higher than road only. full_text. Archive n null; 4336 from paper."},{"paperId":"p-pmid-22517305","evidenceGrade":"abstract_only","designNote":"Perron 2012 Noise Health. Systematic review, 12 aircraft-sleep studies to Dec 2010, adults ≥18, objective noise. 4 high, 5 moderate, 3 low quality. Moderate-to-high: awakenings, less SWS, or sleep medication. Authors write causal; mostly lab nights in healthy adults. Does not raise the stamp. abstract_only. Archive n null."},{"paperId":"p-pmid-20406712","evidenceGrade":"abstract_only","designNote":"Pirrera 2010 Environ Int. Narrative review, nocturnal road traffic noise, sleep, and daytime function. Distinguishes objective vs subjective sleep; names noise sensitivity. No pooled OR. Long-term file is mostly cardiovascular, not this node. Does not raise the stamp. abstract_only. Archive n null."}],"featured":false},{"id":"e-omega3-cv","sourceId":"omega3-supplementation","targetId":"cardiovascular","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Bhatt REDUCE-IT HR 0.75 (0.68-0.83), 17.2 vs 22.0%, N=8179. Nicholls STRENGTH HR 0.99 (0.90-1.09), 785 vs 795, N=13078. Kromhout Alpha Omega EPA-DHA HR 1.01 (0.87-1.17), N=4837. Sign depends on bottle."},"n":8179,"summary":"Assigned 4 g a day of icosapent ethyl cut a five-part ischemic composite in 8179 statin-treated adults with high triglycerides (Bhatt 2019, hazard ratio 0.75); the same dose of mixed EPA plus DHA carboxylic acids did not in 13,078 similar adults (Nicholls 2020, 0.99), and about 400 mg of EPA-DHA in margarine did not after a heart attack (Kromhout 2010).","mechanism":"The authors treat marine omega-3 as an anti-inflammatory, triglyceride-lowering fat that might stabilize plaque. Bhatt's bottle is purified EPA as an ethyl ester. Nicholls's bottle mixes EPA and DHA as free fatty acids. Kromhout's margarine is a food-level dose. They do not agree which molecule, which dose, or which comparator does the work.\n\nBhatt, Steg, Miller and colleagues (REDUCE-IT, 2019) assigned 8179 adults on a statin, triglycerides 135 to 499 mg per deciliter, LDL 41 to 100, and either prior cardiovascular disease or diabetes plus other risk, to 4 g a day of icosapent ethyl or mineral-oil placebo. Median follow-up was 4.9 years. A first event in the five-part composite (cardiovascular death, nonfatal infarction, nonfatal stroke, coronary revascularization, or unstable angina) occurred in 17.2 percent on EPA and 22.0 percent on placebo (hazard ratio 0.75, 0.68 to 0.83). The three-part hard composite sat at 0.74 (0.65 to 0.83). Cardiovascular death sat at 0.80 (0.66 to 0.98).\n\nNicholls, Lincoff, Garcia and colleagues (STRENGTH, 2020) assigned 13,078 statin-treated adults with high triglycerides and low HDL in 22 countries to 4 g a day of EPA plus DHA carboxylic acids or corn oil. The trial stopped after 1,384 of a planned 1,600 events. The same five-part composite occurred in 785 (12.0 percent) on omega-3 and 795 (12.2 percent) on corn oil (0.99, 0.90 to 1.09). Gastrointestinal events were 24.7 versus 14.7 percent. New atrial fibrillation was 2.2 versus 1.3 percent.\n\nKromhout, Giltay, Geleijnse and the Alpha Omega group (2010) assigned 4,837 people aged 60 to 80 with a prior infarction to one of four margarines for 40 months. Daily EPA-DHA intake was about 376 mg. A major event occurred in 13.9 percent. EPA-DHA sat at 1.01 (0.87 to 1.17). Plant ALA sat at 0.91 (0.78 to 1.05).","caveats":"Researchers assigned people to a bottle or a control, so this is a trial stamp. The sign is not one sign. Extra papers do not settle the claim.\n\nREDUCE-IT used mineral oil. That placebo can raise LDL and C-reactive protein. STRENGTH used corn oil and saw no event benefit. Whether the gap is EPA versus mixed n-3, ethyl ester versus carboxylic acid, or the comparator, this page does not settle.\n\nBoth large trials enrolled people already on a statin, with high triglycerides. About 71 percent of REDUCE-IT was secondary prevention. STRENGTH was 70 percent diabetes. Alpha Omega was a low margarine dose after a heart attack on modern therapy. None of these is a grocery fish-oil capsule in a healthy adult.\n\nAtrial fibrillation rose on both high-dose bottles. REDUCE-IT also saw more bleeding. Those signals are not the primary count and do not flip the page to a claim that every omega-3 bottle prevents a heart attack.\n\nThis is a journal entry, not medical advice and not a reason to start or stop a capsule.","confounders":["insulin-resistance","sedentary-time","ultraprocessed-food","sleep-hygiene","alcohol-intake"],"paperIds":["p-pmid-30415628","p-pmid-33190147","p-pmid-20929341"],"contributions":[{"paperId":"p-pmid-30415628","evidenceGrade":"abstract_only","designNote":"Bhatt 2019 NEJM REDUCE-IT. Identifying RCT. Icosapent ethyl 4g/d vs mineral oil. 8179 on statin, TG 135-499, LDL 41-100, CVD or DM+risk. Median 4.9y. Primary 17.2% vs 22.0%, HR 0.75 (0.68-0.83). 3-part 0.74. CV death 0.80 (0.66-0.98). abstract_only. Archive n null; 8179 from paper."},{"paperId":"p-pmid-33190147","evidenceGrade":"full_text","designNote":"Nicholls 2020 JAMA STRENGTH. Identifying RCT. EPA+DHA CA 4g/d vs corn oil. 13078 statin, high TG, low HDL, 22 countries. Stopped after 1384/1600 events. Primary 785 (12.0%) vs 795 (12.2%), HR 0.99 (0.90-1.09). GI 24.7 vs 14.7. AF 2.2 vs 1.3. full_text. Archive n null."},{"paperId":"p-pmid-20929341","evidenceGrade":"abstract_only","designNote":"Kromhout 2010 NEJM Alpha Omega. RCT. 4837 aged 60-80, prior MI, 40 mo, 4 margarines. EPA-DHA ~376 mg/d. Primary 13.9%. EPA-DHA HR 1.01 (0.87-1.17). ALA 0.91 (0.78-1.05). Low food dose, not a 4g bottle. abstract_only. Archive n null; 4837 from paper."}],"featured":false},{"id":"e-omega3-depression","sourceId":"omega3-supplementation","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Lespérance 2011: IDS-SR30 MD 1.32 (-0.20 to 2.84), P=0.088, N=432. No-anxiety slice 3.17 (0.89-5.45). Wu 2024 HRSD week 12 13.50 vs 18.53, N=60. Mischoulon 4g response 64% vs 40%, P>0.05."},"n":432,"summary":"Lespérance 2011 found that 1,200 mg a day of EPA-heavy fish oil versus sunflower oil missed the primary Inventory of Depressive Symptomatology contrast among 432 Canadian outpatients in a major depressive episode (adjusted difference 1.32, -0.20 to 2.84); a planned no-anxiety slice moved, and two later pilots of 60 and 61 people do not settle the sign.","mechanism":"Authors treat EPA as an anti-inflammatory fat that might ease a depressive episode. They do not agree on dose, on whether anxiety has to be absent, or on whether C-reactive protein has to be high.\n\nLespérance, Frasure-Smith, St-André and colleagues (2011) assigned 432 Canadian outpatients with a Mini-International major depressive episode lasting at least four weeks to 1,050 mg EPA plus 150 mg DHA a day or sunflower oil (2 percent fish oil) for eight weeks. 40.3 percent were already on an antidepressant. The primary self-report IDS-SR30 difference was 1.32 points (-0.20 to 2.84, P=0.088). Clinician MADRS sat at 0.97 (-0.012 to 1.95, P=0.053). A planned anxiety interaction was significant (P=0.035). In 204 people without a comorbid anxiety disorder the IDS difference was 3.17 (0.89 to 5.45).\n\nWu, Yang, Liu and colleagues (2024) assigned 60 unmedicated Taiwanese adults with DSM major depression and HRSD-21 above 18 to 3.2 g a day (2.1 g EPA, 1.1 g DHA) or soybean oil for twelve weeks. Week-12 Hamilton means were 13.50 versus 18.53 (P=0.010). Response and remission did not differ. Between-group erythrocyte EPA and DHA also did not differ at week 12.\n\nMischoulon, Dunlop, Kinkead and colleagues (2022) assigned 61 unmedicated overweight adults with MDD and hs-CRP at or above 3.0 mg per liter to 1, 2, or 4 g of EPA or placebo for twelve weeks. The prespecified endpoints were inflammatory. In 45 completers, 4 g response on IDS-C30 was 64 percent versus 40 percent on placebo (odds ratio 2.63; all P>0.05).","caveats":"Researchers assigned people to a capsule or a control, so this is a trial stamp. The main result in the only mid-size trial missed. More papers of the same design do not settle the claim.\n\nLespérance is eight weeks, mixed treated and untreated, sunflower oil with a little fish oil as placebo. The no-anxiety slice was planned. It is still a slice.\n\nWu is 60 people, 50 of them women, no other treatment allowed, and a mixed-model treatment-by-time P of 0.045. Categorical response and remission did not move. Red-cell EPA and DHA rose in both arms and did not differ between arms at week 12.\n\nMischoulon is a 61-person dose-finding trial whose primary was inflammation, not mood. The 4 g depression response missed significance. It is not a stack, and it is not a reason to treat C-reactive protein with fish oil.\n\nNone of these files is a grocery capsule in people who are not already depressed. This page is not the heart-event page.\n\nThis is a journal entry, not medical advice and not a reason to start or stop a capsule.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise","insulin-resistance"],"paperIds":["p-pmid-20584525","p-pmid-39519521","p-pmid-36005883"],"contributions":[{"paperId":"p-pmid-20584525","evidenceGrade":"abstract_only","designNote":"Lespérance 2011 J Clin Psychiatry. Identifying RCT. 1050 mg EPA+150 mg DHA vs sunflower, 8 wk, N=432 MDE, 40.3% on AD. IDS-SR30 MD 1.32 (-0.20-2.84) P=0.088. MADRS 0.97 P=0.053. No-anxiety n=204: IDS 3.17 (0.89-5.45). abstract_only. Archive n null."},{"paperId":"p-pmid-39519521","evidenceGrade":"full_text","designNote":"Wu 2024 Nutrients. Pilot RCT monotherapy. 3.2 g (2.1 EPA+1.1 DHA) vs soybean, 12 wk, N=60 unmedicated MDD, HRSD>18. Week 12 HRSD 13.50 vs 18.53 P=0.010. Response/remission NS. RBC EPA/DHA no between-group difference. full_text. Archive n null."},{"paperId":"p-pmid-36005883","evidenceGrade":"abstract_only","designNote":"Mischoulon 2022 J Clin Psychiatry. Dose-finding RCT. 1/2/4 g EPA vs placebo, 12 wk, N=61 unmedicated MDD, BMI>25, hs-CRP>=3. Inflammation primary. 45 completers. 4 g IDS-C30 response 64% vs 40% P>0.05. abstract_only. Archive n null."}],"featured":false},{"id":"e-omega3-employment","sourceId":"omega3-supplementation","targetId":"employment-status","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Same healthy-user structure as multivitamins."},"n":null,"summary":"Fish-oil buyers are not a random sample of the labor force.","mechanism":"Omega-3 use clusters with education, income, and other preventive behaviors. Any raw association with unemployment is the bias, not the oil.","caveats":"This edge is about economic outcomes, not triglycerides. Do not export the verdict to cardiology.","confounders":["disposable-income","education"],"paperIds":["p-shrank-2011"],"contributions":[{"paperId":"p-shrank-2011","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-osa-cognition","sourceId":"sleep-apnea","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Xu 2025: CPAP vs usual care, 148 adults, AHI ≥15, normal cognition. MoCA at 6 mo difference -0.04 (-0.72 to 0.65). Machine did not move the screen."},"n":148,"summary":"Xu 2025 assigned 148 middle-aged adults with moderate-to-severe obstructive sleep apnea and normal cognition to CPAP plus usual care or usual care alone. At six months the Montreal Cognitive Assessment did not differ (difference -0.04, 95% CI -0.72 to 0.65).","mechanism":"Authors treat airway collapse as a source of intermittent hypoxia and fragmented sleep. They expected a machine that holds the airway open to restore cortex and lift named tests.\n\nXu, Liu, Li and colleagues (2025) randomized 148 people with an apnea-hypopnea index of 15 or more and a normal Montreal Cognitive Assessment at five hospitals. CPAP plus best supportive care versus best supportive care. Primary: MoCA at six months. Difference -0.04 (95% CI -0.72 to 0.65). Default-mode connectivity and cortical thickness moved. The screening score did not.\n\nWang, Wang, Tuo and colleagues (2021) pooled 14 randomized trials, 1,926 people. Attention and speed of information processing moved only in the severe-apnea slice (SMD 0.17, 95% CI 0.02 to 0.31). The abstract does not name an overall executive or memory win.\n\nDurtette, Dargent, Gierski and colleagues (2024) pooled 11 randomized trials, 923 adults naive to CPAP with AHI over 10. Trail Making Test B improved (SMD -0.93, 95% CI -1.60 to -0.25). Information processing speed, executive function, and working memory as domains did not. Most trials lasted three months or less.\n\nThe sleep page on this site is hours in bed. This page is obstruction. A CPAP machine treats this source. It is not a longer night.","caveats":"The Xu sample already sat in the normal range. A ceiling can hide a small gain. The machine was open-label against supportive care, not sham. The abstract names 148 people. Evidence grade is\n\nDefault-mode connectivity and cortical thickness are not this page's outcome. This page is the named test.\n\nWang's attention win is a severe-apnea subgroup. Durtette's Trail Making B win is one scale. Neither file rewrites Xu's primary. More papers of the same design do not settle the claim. Both pooled analyses are available here only as abstracts.\n\nOmitted the B10 narrative reviews (public-health burden, geriatric outcomes, cognitive complaints, elderly OSAS). They do not identify a general-adult assigned contrast.\n\nThis page is not HOMA-IR. That pair is the apnea-and-insulin page. It is not a cardiovascular event. That pair is the apnea-and-heart page. It is not hours of sleep. That pair is the sleep-and-attention page.\n\nThis is a journal entry, not medical advice and not a reason to start or stop a machine.","confounders":["sleep-hygiene","depression","education","insulin-resistance","cardiovascular","alcohol-intake","sedentary-time"],"paperIds":["p-pmid-39998447","p-pmid-32310179","p-pmid-39226674"],"contributions":[{"paperId":"p-pmid-39998447","evidenceGrade":"abstract_only","designNote":"Xu 2025 AJRCCM. Identifying RCT, CPAP+BSC vs BSC, 148 middle-aged adults, AHI≥15, normal cognition, 5 hospitals. Primary MoCA at 6 mo: difference -0.04 (-0.72 to 0.65), P=0.91. DMN FC and thickness secondary. Archive n null. N from abstract. abstract_only."},{"paperId":"p-pmid-32310179","evidenceGrade":"abstract_only","designNote":"Wang 2021 J Alzheimers Dis. RCT meta, 14 trials, 1926. Attention/speed SMD 0.17 (0.02-0.31) in severe OSA only. Abstract names no overall executive or memory win. Archive n null. N from abstract. abstract_only."},{"paperId":"p-pmid-39226674","evidenceGrade":"abstract_only","designNote":"Durtette 2024 Sleep Med. RCT meta, 11 trials, 923 adults AHI>10, CPAP-naive. TMT-B SMD -0.93 (-1.60 to -0.25). No global domain effects on speed, executive, working memory. Most ≤3 mo. Archive n null. abstract_only."}],"featured":false},{"id":"e-osa-cv","sourceId":"sleep-apnea","targetId":"cardiovascular","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":1.1,"note":"McEvoy 2016 SAVE: HR 1.10 (0.91-1.32), 229 vs 207 events, N=2717. Peker RICCADSA ITT HR 0.80 (0.46-1.41). Sánchez-de-la-Torre ISAACC HR 0.89 (0.68-1.17)."},"n":2717,"summary":"McEvoy 2016 found that CPAP plus usual care did not change the risk of a composite cardiovascular event versus usual care alone among 2717 adults with moderate-to-severe obstructive sleep apnea and established coronary or cerebrovascular disease (hazard ratio 1.10, 95% CI 0.91 to 1.32).","mechanism":"McEvoy, Antic, Heeley and colleagues assigned 2717 adults aged 45 to 75 with moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to CPAP plus usual care or usual care alone, after a one-week sham-CPAP run-in (SAVE, NCT00738179). Most were men with minimal sleepiness. Mean CPAP use was 3.3 hours a night. The apnea-hypopnea index fell from 29.0 to 3.7 events an hour. After a mean 3.7 years, a primary event (cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or TIA) occurred in 229 people on CPAP (17.0%) and 207 on usual care (15.4%). The hazard ratio was 1.10 (0.91 to 1.32, P=0.34). No single cardiovascular end point moved. Snoring, sleepiness, quality of life, and mood improved. Those are not the primary.\n\nPeker, Glantz, Eulenburg and colleagues assigned 244 people with newly revascularized coronary disease and nonsleepy OSA (AHI at least 15, Epworth under 10) to auto-titrating CPAP or no PAP (RICCADSA, NCT00519597). Median follow-up was 57 months. The composite of repeat revascularization, myocardial infarction, stroke, or cardiovascular death was 18.1% versus 22.1% (hazard ratio 0.80, 0.46 to 1.41, P=0.449). An on-treatment cut at four hours a night is not the assigned contrast.\n\nSánchez-de-la-Torre and colleagues assigned 1264 nonsleepy patients with acute coronary syndrome and OSA at 15 Spanish hospitals to CPAP plus usual care or usual care alone, 633 versus 631 (ISAACC, NCT01335087). Median follow-up was 3.35 years. A composite cardiovascular event occurred in 98 people on CPAP (16%) and 108 on usual care (17%). The hazard ratio was 0.89 (0.68 to 1.17, P=0.40). Mean CPAP use was 2.78 hours a night. A reference group without OSA did not fare differently from usual-care OSA.\n\nThe signed object is obstruction. A machine that holds the airway open is less OSA. When that assignment does not move the event count, more apnea does not identify more events in these samples.","caveats":"SAVE is secondary prevention in people who already have coronary or cerebrovascular disease. Participants had minimal sleepiness. Mean use was 3.3 hours a night. The machine is open-label. The abstract names 2,717 people. Evidence grade is\n\nRICCADSA is one center, 244 people, nonsleepy by Epworth. The intention-to-treat result is null. The paper's adjusted on-treatment analysis (four hours or more) is not the assigned contrast and does not set the sign.\n\nISAACC is acute coronary syndrome, nonsleepy, Spain, open-label. Mean use was 2.78 hours a night. The abstract we have is cut before the primary count. The numbers above are from the published abstract. Blood pressure and Epworth shifts in ISAACC are not this page.\n\nOu 2024 compared a mandibular advancement device with CPAP on 24-hour mean arterial pressure. That is blood pressure, not an event composite. It is not on this page. This page does not add a blood-pressure claim.\n\nThis page is not HOMA-IR. That pair is the apnea-and-insulin page. It is not all-cause death. It is not a reason to start or stop a machine. More papers of the same design do not settle the claim.\n\nThis is a journal entry, not medical advice.","confounders":["insulin-resistance","sedentary-time","ultraprocessed-food","sleep-hygiene","alcohol-intake"],"paperIds":["p-pmid-27571048","p-pmid-26914592","p-pmid-31839558"],"contributions":[{"paperId":"p-pmid-27571048","evidenceGrade":"abstract_only","designNote":"McEvoy 2016 NEJM, SAVE. Identifying RCT. CPAP+usual care vs usual care, 2717 adults 45-75, moderate-severe OSA + CAD/CVD. Mean 3.7y. Primary MACE 229 (17.0%) vs 207 (15.4%), HR 1.10 (0.91-1.32), P=0.34. Mean CPAP 3.3h. AHI 29.0 to 3.7. Sleepiness/QoL not the sign. Archive n null; 2717 from abstract. abstract_only."},{"paperId":"p-pmid-26914592","evidenceGrade":"abstract_only","designNote":"Peker 2016 AJRCCM, RICCADSA. RCT, 122/122 newly revascularized CAD, AHI≥15, ESS<10. Auto-CPAP vs no PAP. Median 57mo. ITT 18.1% vs 22.1%, HR 0.80 (0.46-1.41), P=0.449. On-treatment ≥4h not ITT. Archive n null; 244 from abstract. abstract_only."},{"paperId":"p-pmid-31839558","evidenceGrade":"abstract_only","designNote":"Sánchez-de-la-Torre 2020 Lancet Respir Med, ISAACC. RCT, ACS + nonsleepy OSA, 15 Spanish hospitals. 633 CPAP vs 631 usual care. Median 3.35y. 98 (16%) vs 108 (17%), HR 0.89 (0.68-1.17), P=0.40. Mean CPAP 2.78h. Archive abstract truncated; N and HR from published abstract. abstract_only."}],"featured":false},{"id":"e-osa-insulin","sourceId":"sleep-apnea","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Salord 2016: 2-h glucose -0.5 vs +0.33, HOMA-IR ns, n=80. Iftikhar RCT metas: HOMA-IR -0.44 (2013) and -0.43 (2016) vs sham or no CPAP."},"n":80,"summary":"In 80 adults with severe OSA and morbid obesity, 12 weeks of CPAP improved two-hour glucose versus conservative care. HOMA-IR did not change in that trial. Pooled CPAP trials later found a modest HOMA-IR drop versus sham or no machine.","mechanism":"Salord, Fortuna, Monasterio and colleagues assigned 80 adults with severe obstructive sleep apnea and morbid obesity, none with diabetes, to 12 weeks of CPAP or conservative care (NCT 01029561). Weight loss and activity were similar. HOMA-IR did not move. Impaired glucose tolerance reversed in nine people on CPAP and appeared in none. On conservative care it reversed in five and appeared in five. Two-hour glucose after a load changed more on CPAP (-0.5 ± 1.5 versus +0.33 ± 1.9).\n\nThe authors read that as a peripheral insulin-resistance gain that fasting HOMA missed.\n\nIftikhar, Khan, Das and Magalang pooled five CPAP trials in 244 people without diabetes. HOMA-IR sat 0.44 units lower on CPAP than on sham or no machine (-0.82 to -0.06). I-squared was 0. Iftikhar, Hoyos, Phillips and Magalang updated the RCT pool: HOMA-IR -0.43 (-0.75 to -0.11). Visceral fat and adiponectin did not move. Sixteen case-control files sat 0.51 standardized units higher in OSA. That association does not raise the stamp.\n\nYang, Liu and Yang compared HOMA-IR to each person's baseline. Eight to 24 weeks of CPAP used more than four hours a night cut HOMA-IR by 0.75. Irregular use did not. BMI did not move.\n\nAbud, Salgueiro, Drake and colleagues pooled nine trials in 443 people without diabetes. HOMA-IR fell 0.39 units (-0.69 to -0.08). Fasting glucose did not. GRADE was low. Shang, Zhang, Wang and Han stayed with type 2 diabetes and OSA: seven trials, 691 people. HOMA-IR standardized mean difference -1.05. HbA1c -0.32. Fasting glucose -0.39.\n\nPatruno randomized 31 people with severe OSA to fixed or autoadjusting CPAP for three months. Both machines cut events. HOMA-IR and blood pressure fell on fixed CPAP, not on the autoadjusting machine.\n\nThe signed object is obstruction. A machine that holds the airway open is less OSA. When HOMA-IR or two-hour glucose falls on that machine, more apnea still points to more insulin resistance.\n\nHours in bed sit elsewhere. This page is the blocked airway.","caveats":"Salord is 80 completers, 12 weeks, morbid obesity, severe OSA, no diabetes. Two university hospitals. The main paper is the numbers are from the published abstract. The abstract names 80 people.\n\nHOMA-IR did not move in the main trial. The stamp rests on assigned CPAP versus conservative care and a glucose-tolerance endpoint the authors treat as peripheral insulin resistance. The HOMA drop lives in the pooled trials, not in Salord. Conservative care is not sham CPAP.\n\nPatruno compares two machines. Everybody was treated. It cannot identify untreated OSA.\n\nYang is change from baseline and hours of use, not sham CPAP. They asked for larger randomized trials. Iftikhar 2013 is 83 percent men. Iftikhar 2016 also pools case-control association; that half is not the assigned design. Abud's GRADE is low. Shang is people who already have type 2 diabetes.\n\nWeight is the open backdoor. RICCADSA found insulin resistance improved over a year with BMI change, not with OSA type or CPAP assignment. MIMOSA assigned a Mediterranean weight-loss diet on top of CPAP prescribed to every arm. Neither sits on this page. Dapagliflozin treats glucose and then looks at the apnea index. That is the inverted arrow. Tirzepatide and other GLP-1 or SGLT2 files are not on this page for the same reason.\n\nThis page is not hours in bed. Spiegel and the sleep-restriction trials live on the sleep-and-insulin page. More papers of the same design do not settle the claim.\n\nThis is a journal entry, not medical advice and not a reason to start a machine.","confounders":["sleep-hygiene","ultraprocessed-food","sedentary-time","eating-window"],"paperIds":["p-pmid-26350474","p-pmid-17494789","p-pmid-22492705","p-pmid-23607839","p-pmid-25700870","p-pmid-31518943","p-pmid-33146450"],"contributions":[{"paperId":"p-pmid-26350474","evidenceGrade":"full_text","designNote":"Salord 2016. Identifying RCT. CPAP vs conservative care, 12 w, 80 completers, severe OSA, morbid obesity, no diabetes. NCT 01029561. 2-h glucose -0.5 vs +0.33, P=0.007. IGT reversed 9 vs 5. HOMA-IR ns. Archive n null; N=80 from abstract. full_text front matter."},{"paperId":"p-pmid-17494789","evidenceGrade":"abstract_only","designNote":"Patruno 2007. RCT, 31 severe OSA, 3 months fixed vs auto CPAP. Both cut events. HOMA-IR and BP fell on fixed CPAP only. CRP fell on both. Both arms treated. Archive n null; N=31 from abstract. abstract_only."},{"paperId":"p-pmid-22492705","evidenceGrade":"abstract_only","designNote":"Yang 2013. Meta vs baseline. Effective CPAP >4 h/night, 8-24 w, HOMA-IR -0.75 (-0.96 to -0.53). Irregular use ns. BMI ns. Asks for larger RCTs. Archive n null. abstract_only."},{"paperId":"p-pmid-23607839","evidenceGrade":"full_text","designNote":"Iftikhar 2013. Meta of 5 RCTs, 244 people, 83% men, no diabetes. CPAP vs sham/control HOMA-IR -0.44 (-0.82 to -0.06), I²=0. Archive n null; N=244 from abstract. full_text front matter."},{"paperId":"p-pmid-25700870","evidenceGrade":"full_text","designNote":"Iftikhar 2016. Updated RCT meta: CPAP vs no CPAP HOMA-IR -0.43 (-0.75 to -0.11). VAF and adiponectin ns. 16 case-control SMD 0.51; association does not raise. Archive n null. full_text front matter."},{"paperId":"p-pmid-31518943","evidenceGrade":"abstract_only","designNote":"Abud 2020. Meta of 9 RCTs, 443 non-diabetic OSA. HOMA-IR -0.39 (-0.69 to -0.08), I²=57%, GRADE low. Fasting glucose ns. Title is T2D prevention; hung for HOMA. Archive n null; N=443 from abstract. abstract_only."},{"paperId":"p-pmid-33146450","evidenceGrade":"abstract_only","designNote":"Shang 2021. Meta of 7 RCTs, 691 T2D+OSA, CPAP vs sham or no CPAP. HOMA-IR SMD -1.05 (-1.91 to -0.19). HbA1c SMD -0.32. Fasting glucose SMD -0.39. Archive n null; N=691 from abstract. abstract_only."}],"featured":false},{"id":"e-outdoors-vitd","sourceId":"outdoor-time","targetId":"vitamin-d","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Samefors 2021: outdoor arm 42.5 to 53.5 nmol/L (p=0.011), N=40 analyzed. Control 52.0 to 65.0, not significant. Autier 2014: UV-B cutaneous synthesis is the main natural source."},"n":40,"summary":"Skin makes 25(OH)D from UV-B; Samefors 2021 then showed that encouraging 40 Swedish nursing-home residents outdoors for two summer months raised median serum 25(OH)D from 42.5 to 53.5 nmol/L.","mechanism":"UV-B on uncovered skin turns 7-dehydrocholesterol into previtamin D3. The liver then makes 25(OH)D. That is the main natural source.\n\nAutier, Boniol, Pizot, and Mullie reviewed the observational catalog in 2014. Low 25(OH)D tracks almost every chronic disease. Pill trials do not reproduce those links. Their reading is that low D marks ill health, indoor life, and body fat. The sun pathway is why the marker exists.\n\nSamefors, Tengblad, and Östgren tested that outdoor step. Three nursing homes in Jönköping, 57°N. Two homes were told to get residents outside 20 to 30 minutes between 11 a.m. and 3 p.m. every day for two months in the summer of 2018. The third home lived as usual. Staff reminded the outdoor homes. Everyone kept a diary. Eighteen people in the outdoor arm and 22 in the control arm gave blood before summer. Median 25(OH)D in the outdoor arm rose from 42.5 to 53.5 nmol/L (p=0.011). The control arm went from 52.0 to 65.0 nmol/L without a significant change. After summer the two arms did not differ from each other. About one in six people in each arm was already taking a vitamin D tablet. Fish was on the menu about as often in all three homes.\n\nLatitude, season, melanin, clothing, and hours outside still set most of the number. That is why 25(OH)D tracks lifestyle and class, and why it is a poor instrument for success.","caveats":"Samefors is small and open-label. Homes were the units, not people. Staff knew the assignment. The significant 25(OH)D rise is a within-arm test. After summer the outdoor and control medians were not different. The control arm also lived through a bright Swedish summer. Median age was about 86. Many residents were chairbound. People with severe dementia were not asked. About 17 to 18 percent were already on vitamin D tablets.\n\nThe trial also scored SF-36 mental health. The authors say they cannot tell whether that change came from 25(OH)D, company, or movement. It is not this arrow.\n\nAutier is a review of observational D-and-disease papers and of supplementation trials. It is not a sunlight experiment.\n\nWinter at high latitude, indoor work, and covered skin can make this arrow too weak. That is when a clinician has a job. This page is not a sun prescription and not an argument against treating rickets.","confounders":["disposable-income"],"paperIds":["p-autier-2014","p-pmid-33244559"],"contributions":[{"paperId":"p-autier-2014","evidenceGrade":"abstract_only","designNote":"Autier 2014 systematic review. Observational low 25(OH)D tracks disease; supplementation RCTs do not reproduce those links. Authors read low D as a marker of ill health and indoor life. Cutaneous UV-B is the named natural source. abstract_only. Archive n:null."},{"paperId":"p-pmid-33244559","evidenceGrade":"full_text","designNote":"Samefors 2021 cluster RCT. Jönköping nursing homes, summer 2018. 20 assigned / 18 analyzed outdoor; 22 control. 20-30 min 11-15h daily, 2 months. 25(OH)D 42.5 to 53.5 nmol/L, p=0.011 within outdoor arm; control 52.0 to 65.0 NS; no between-arm difference after. Archive n:null; N=40 from abstract. full_text."}],"featured":false},{"id":"e-oxytocin-trust","sourceId":"oxytocin","targetId":"interpersonal-trust","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Kosfeld 2005 reported higher transfers. Declerck 2020: no MSC main effect (N=677). Krug 2024: no group effect on a hypothetical trust game (N=149). Kroll 2026: no increase; pooled equivalence (n=532) puts the effect in a minimal range."},"n":677,"summary":"Intranasal oxytocin does not raise trusting behavior: a 2026 registered report found no effect in 211 people, and a pooled equivalence test with the 2020 registered replication (532 people) put the leftover effect inside a minimal range.","mechanism":"Kosfeld, Heinrichs, Zak, Fischbacher, and Fehr (2005) reported that intranasal OT raised transfers in a real-stakes trust game. Nave, Camerer, and McCullough (2015) documented small samples, publication bias, and mixed follow-ups. Declerck, Boone, Pauwels, Vogt, and Fehr (2020) pre-registered a 677-person double-blind test with the original minimal-social-contact condition and found no OT effect on trusting behavior there. Exploratory post-hocs are not the registered claim. Krug, Fung, Liu, Treasure and colleagues (2024) randomized 149 female students to 24 IU OT or saline and ran a hypothetical investor game after the spray. Transfers did not differ. Kroll, Schruers, Viechtbauer, Vingerhoets, Seidel, Riedl, and Hernaus (2026) registered a large-scale replication of Kosfeld. Their own trial had 211 people. They found no evidence that the spray increased trusting behavior. Equivalence testing on that sample alone was inconclusive. They then merged their data with Declerck 2020, which they name as n=321, for a pool of 532. In the pool, equivalence testing put the OT effect inside a minimal range: too small, they write, for most lab studies. Baseline trust, reward sensitivity, and punishment sensitivity did not change the result. Another null does not raise the stamp.","caveats":"A contested trial stays on this page. The stamp is smoke for the folk spray-equals-trust arrow, not a claim that oxytocin is biologically inert. Krug's trust game used hypothetical money, no real pay, a deceived counterpart, and a between-subjects contrast run only after the spray. The sample was female university students. Emotion recognition is a different outcome. Kroll is available here only as an abstract. The n=211, the Declerck n=321 they pool, and the pooled n=532 are from that abstract. The sample size on this page stays Declerck's 677. Their own equivalence test was inconclusive. The minimal-range claim is the pooled test. Plasma oxytocin, parenting, and labor are different questions.","confounders":["social-capital"],"paperIds":["p-kosfeld-2005","p-nave-2015","p-declerck-2020","p-pmid-38820421","p-pmid-41880977"],"contributions":[{"paperId":"p-kosfeld-2005","evidenceGrade":"abstract_only"},{"paperId":"p-nave-2015","evidenceGrade":"abstract_only"},{"paperId":"p-declerck-2020","evidenceGrade":"abstract_only"},{"paperId":"p-pmid-38820421","evidenceGrade":"full_text","designNote":"Double-blind 24 IU OT vs saline. 149 female students (76 OT / 73 saline). TASIT-R plus investor game (0-50 hypothetical EMU, no real pay, fake counterpart); trust only post-spray. Trust transfers: no group effect. Archive methodology is observational and n null. Do not copy those. Treat as RCT. N=149. Full text PMC11142561."},{"paperId":"p-pmid-41880977","evidenceGrade":"abstract_only","designNote":"Kroll 2026 registered report, Cortex. Own Kosfeld replication, n=211 from abstract. Pooled with Declerck 2020 (authors name n=321) for n=532. No evidence OT increases trusting behavior. Own equivalence inconclusive; pooled: effect in a minimal range. No moderation by baseline trust, reward or punishment sensitivity. Archive observational / n null; do not copy. abstract_only. PMID 41880977."}],"featured":true},{"id":"e-pm25-cognition","sourceId":"air-pollution","targetId":"cognitive-performance","relation":"spurious","direction":"forward","polarity":"negative","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"ESCAPE n=9482: cognition null at ages 1-6. CHAMACOS n=568: -1.79 FSIQ per 3 µg/m³ pregnancy PM2.5 at 10.5. Sign inverse where IQ is named. Design does not identify."},"n":9482,"summary":"Pregnancy-average outdoor PM2.5 tracked 1.79 fewer full-scale IQ points per 3 µg/m³ at age 10.5 in 568 Salinas Valley children, while six European birth cohorts (9,482 children) found no association between pregnancy air pollution and cognition at ages 1 to 6. Nobody randomized the air.","mechanism":"Particles small enough to reach the alveoli can move into blood. Animal work shows inflammation, microglia activation, and white matter injury after diesel exhaust or fine particles. The human papers do not isolate that path. They estimate outdoor concentrations at the home in pregnancy and later give a named cognitive test.\n\nGuxens pooled GENERATION R, Duisburg, EDEN, GASPII, RHEA, and INMA. Land-use regression at the birth address, back-extrapolated to pregnancy. 9,482 children, tests at ages 1 to 6, random-effects meta-analysis of region-specific models. General cognition and language were not associated with NO2, NOx, PM2.5, PM10, coarse PM, or PM2.5 absorbance. The signal they report is psychomotor: 0.68 points lower per 10 µg/m³ NO2 (95 percent CI -1.25 to -0.11). That motor score is not this node.\n\nHolm estimated outdoor PM2.5 at prenatal addresses in the CHAMACOS cohort in California's Salinas Valley. 568 children sat the WISC-IV at age 10.5 in their dominant language. A 3 µg/m³ higher pregnancy-average PM2.5, about the interquartile range here, tracked 1.79 fewer full-scale IQ points (95 percent CI -2.98 to -0.58) and 1.72 fewer working-memory points. Distributed lags pointed at months 5 to 7. The models included maternal verbal IQ, maternal education, household poverty, and the HOME inventory.","caveats":"The stamp is smoke because nobody randomized the air. A new observational edge publishes as spurious and low. Paper count does not raise it.\n\nGuxens found no association with cognition. The European file is hung for that null, not for the psychomotor decrement. Tests at ages 1 to 6 mix psychologist scores and parent questionnaires. PM was measured in fewer regions than NO2. Back-extrapolation from 2008-2011 campaigns onto 1997-2008 pregnancies can misclassify exposure. Residual confounding by maternal education and neighborhood remains. The authors name traffic noise as an unmeasured companion of NO2.\n\nHolm's sample is low-income farmworker families in one valley. 86 percent of mothers were born in Mexico. Mean pregnancy PM2.5 was 10.6 µg/m³. Agricultural pesticides, flame retardants, and PBDEs have their own IQ files in this cohort. Sensitivity analyses that added those exposures one at a time did not remove the PM2.5 association. Season of birth and years of schooling can over-adjust a seasonal exposure. CHAM2 prenatal addresses were recalled years later.\n\nThis page is pregnancy outdoor air and later childhood cognition. It is not adult ambient exposure, indoor cooking smoke, or blood lead.\n\nThis is not medical advice and not a recommendation to move, to filter a room, or to treat a score.","confounders":["education","disposable-income","outdoor-time"],"paperIds":["p-pmid-25036432","p-pmid-36913239"],"contributions":[{"paperId":"p-pmid-25036432","evidenceGrade":"abstract_only","designNote":"Guxens 2014 Epidemiology (Archive year 2015), ESCAPE. Six European birth cohorts, n=9482, ages 1-6. LUR at birth address, pregnancy back-extrapolation. Cognition and language null for every pollutant. Psychomotor -0.68/10 µg/m³ NO2 is not this node. Archive methodology meta_analysis; identifying design observational. abstract_only. Archive n null; 9482 from paper."},{"paperId":"p-pmid-36913239","evidenceGrade":"full_text","designNote":"Holm 2023 EHP, CHAMACOS. Observational, 568 Salinas Valley children, WISC-IV at 10.5. Prenatal outdoor PM2.5 (ACAG surfaces). 3 µg/m³ pregnancy mean: FSIQ -1.79 (-2.98, -0.58); WMIQ -1.72. Months 5-7. Adjusted maternal verbal IQ, education, poverty, HOME. full_text. Archive n null; 568 from paper."}],"featured":false},{"id":"e-pm25-mortality","sourceId":"air-pollution","targetId":"mortality","relation":"spurious","direction":"forward","polarity":"positive","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Hao 2023 Medicare ~73.4M: PM2.5 mass HR 1.040 (1.039-1.041) per IQR 3.68 µg/m³. Scotland SLS 202,237: HR 1.035 (1.023-1.047) per 1 µg/m³. Chen IBD 4,708: HR 1.14 per IQR. Observational. Design does not identify."},"n":73400000,"summary":"Hao 2023's Medicare cohort of about 73.4 million adults 65 and older found a 4.0 percent higher all-cause death rate per 3.68 µg/m³ of annual PM2.5 (HR 1.040, 1.039 to 1.041). Nobody randomized the air.","mechanism":"Particles small enough to reach the alveoli can enter blood. Authors name lung injury, inflammation, and cardiovascular strain. The files do not isolate one path. They assign outdoor concentrations to a postcode or ZIP code and later count a death.\n\nAbed Al Ahad, Demsar, Sullivan, and Kulu (2023) linked the Scottish Longitudinal Study: 202,237 adults aged 17 and older, 2002 to 2017, 42,415 deaths. Annual NO2, SO2, PM10, and PM2.5 at 1 km² on the residential postcode. All-cause death rose with PM2.5 (HR 1.035, 1.023 to 1.047 per 1 µg/m³) and with PM10, NO2, and SO2. The fullest model added census education, occupation, and urban-rural place.\n\nHao, Wang, Zhu and colleagues (2023) followed about 73.4 million Medicare beneficiaries aged 65 and older in the contiguous United States, 2000 to 2017, 29 million deaths. Yearly PM2.5 mass and six components at the ZIP code, from two prediction surfaces. Per interquartile range of PM2.5 mass (3.68 µg/m³), all-cause HR 1.040 (1.039 to 1.041). Sulfate and ammonium had the largest component HRs per IQR. Models included ZIP-code income, schooling, and Medicaid eligibility.\n\nChen, Dan, Sun and colleagues (2023) followed 4,708 UK Biobank adults who already had inflammatory bowel disease, mean 12 years, 420 deaths. Land-use regression for NOx, NO2, PM10, and PM2.5. Each IQR of PM2.5 tracked all-cause HR 1.14 (1.02 to 1.28). NOx, NO2, and PM10 moved the same way. Enterotomy and gastrointestinal cancer are different outcomes and stay off this page.","caveats":"The stamp is smoke because nobody randomized the air. These are registers and cohorts. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim.\n\nNeighborhood confounding sits on the backdoor. Dirtier air tracks poorer ZIP codes, less schooling, more traffic noise, and different smoking. Hao adjusts ZIP-code income and Medicaid. The Scottish file adjusts education, occupation, and urban-rural class. Residual confounding remains.\n\nHao's sample is Medicare at 65 and older, 84 percent White. The Scottish file is 202,237 adults from a census-linked register. Chen's 4,708 already have IBD. That is not a general-population death rate.\n\nHao's curves for black carbon, organic matter, and dust bent at high levels. This page still names the sign from PM2.5 mass: more particles, more death.\n\nThis is a journal entry, not medical advice and not a reason to move, to buy a filter, or to treat a number.","confounders":["disposable-income","education","traffic-noise","outdoor-time"],"paperIds":["p-pmid-37793592","p-pmid-37074132","p-pmid-37505744"],"contributions":[{"paperId":"p-pmid-37793592","evidenceGrade":"abstract_only","designNote":"Abed Al Ahad 2023 Environ Res. Scottish Longitudinal Study register, 202,237 adults 17+, 2002-2017, 42,415 deaths. Annual PM2.5/PM10/NO2/SO2 at 1 km² postcode. All-cause PM2.5 HR 1.035 (1.023-1.047) per 1 µg/m³ (Model 3). Observational. abstract_only. Archive n null; N from abstract."},{"paperId":"p-pmid-37074132","evidenceGrade":"full_text","designNote":"Hao 2023 Environ Sci Technol. Medicare 65+, contiguous US 2000-2017, ~73.4 million, 29 million deaths. ZIP-code PM2.5 mass + 6 components, two surfaces. Mass HR 1.040 (1.039-1.041) per IQR 3.68 µg/m³. Cox + ZIP SES. Observational. full_text. Archive n null; N from paper."},{"paperId":"p-pmid-37505744","evidenceGrade":"full_text","designNote":"Chen 2023 EHP. UK Biobank IBD, 4,708, mean 12 y, 420 deaths. LUR NOx/NO2/PM10/PM2.5. All-cause per IQR: PM2.5 HR 1.14 (1.02-1.28); NO2 1.16; PM10 1.15; NOx 1.10. Enterotomy and GI cancer are not this pair. Observational. full_text. Archive n null; N from paper."}],"featured":false},{"id":"e-pose-risk","sourceId":"power-pose","targetId":"risk-tolerance","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Carney 2010 reported more risk-taking. Ranehill 2015 (N=200) and Barel 2024 (N=92) found no main effect of pose."},"n":200,"summary":"Expansive posture is not a Holt–Laury intervention. The later RCTs are nulls on the gambling choice.","mechanism":"Carney, Cuddy, and Yap (2010) used a single-trial gamble after two minutes of pose and reported more risk-taking in the expansive condition. Ranehill et al. (2015) measured risk-taking in a larger mixed-sex sample and found no difference. Barel, Shahrabani, Mahagna and colleagues (2024; PMID 39633430) randomly assigned 92 young adults to high- or low-power poses and used another single-trial gamble. Pose did not move the choice. If a pose changed risk, it would still not identify status or income. It does not clear the first gate.","caveats":"Self-reported feelings of power are a different outcome. Barel also reports that, among high-power posers only, a cortisol drop tracked the risky choice. That is a moderator inside a null main effect, not identification. Their task was one roll for 40 shekels, not a Holt–Laury list. This edge is the gambling claim.","confounders":["status-seeking","cortisol"],"paperIds":["p-carney-2010","p-ranehill-2015","p-pmid-39633430"],"contributions":[{"paperId":"p-carney-2010","evidenceGrade":"abstract_only"},{"paperId":"p-ranehill-2015","evidenceGrade":"abstract_only"},{"paperId":"p-pmid-39633430","evidenceGrade":"full_text","designNote":"RCT, N=92. Null main effect of pose on a single-trial gamble. Cortisol-by-pose interaction is not identification. Do not copy Archive observational / n=null. Full text PMC11619626."}],"featured":false},{"id":"e-pose-testosterone","sourceId":"power-pose","targetId":"testosterone","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Carney 2010 reported a T rise. Ranehill 2015 (N=200) and Barel 2024 (N=92) found none."},"n":200,"summary":"Two minutes in a stance does not identify an androgen change. The larger RCTs are nulls. The TED talk is not a protocol.","mechanism":"Carney, Cuddy, and Yap (2010) assigned expansive versus contractive poses and reported higher T, lower cortisol, and more risk-taking. Ranehill et al. (2015) used the same logic in a larger sample and saw no hormone movement. Simmons and Simonsohn (2017) p-curved the supportive set and found it consistent with selective reporting. Barel, Shahrabani, Mahagna and colleagues (2024; PMID 39633430) randomly assigned 92 young adults to high- or low-power poses. Testosterone did not move. Felt power did not move. The folk mechanism is that a pose changes endocrine state and endocrine state changes rank. It never clears the first step.","caveats":"Cuddy, Schultz, and Fosse (2018) p-curved a wider postural-feedback set and disagreed on subjective feelings. That debate is about self-report, not about T as a leadership stack. Barel's 92 adults were 30 men, 32 women on oral contraceptives, and 30 midluteal women. They report a cortisol drop tied to a gambling choice among high-power posers, and an estradiol rise in the contraceptive group. Those are other hormones and another outcome. This edge is the testosterone claim.","confounders":["status-seeking","cortisol"],"paperIds":["p-carney-2010","p-ranehill-2015","p-simmons-2017","p-pmid-39633430"],"contributions":[{"paperId":"p-carney-2010","evidenceGrade":"abstract_only"},{"paperId":"p-ranehill-2015","evidenceGrade":"abstract_only"},{"paperId":"p-simmons-2017","evidenceGrade":"abstract_only"},{"paperId":"p-pmid-39633430","evidenceGrade":"full_text","designNote":"RCT, N=92. Null on testosterone and felt power. Do not copy Archive observational / n=null. Full text PMC11619626."}],"featured":true},{"id":"e-power-youth-pref","sourceId":"formal-power","targetId":"youth-fertility-preference","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Power and income are bundled in the folk story. The papers measure markets, not org charts."},"n":null,"summary":"Command over people is not a separately identified cause of youth preference. It usually arrives with money.","mechanism":"Buss and Fisman do not randomize formal authority. Any raw power–preference link is entangled with income, age, and the rooms executives enter. Marked smoke until a design separates them.","caveats":"A clean identification would need a shock to rank that is not a shock to pay. We do not have one in the seed.","confounders":["disposable-income","education"],"paperIds":["p-buss-1989","p-fisman-2006"],"contributions":[{"paperId":"p-buss-1989","evidenceGrade":"abstract_only"},{"paperId":"p-fisman-2006","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-prestige-leadership","sourceId":"prestige-strategy","targetId":"leadership-effectiveness","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"theory","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"In knowledge groups, prestige should beat dominance as a leadership technology."},"n":null,"summary":"If people follow you because you are worth copying, the group gets coordination without fear. That is a different hormone story.","mechanism":"Henrich and Gil-White (2001): prestige is an adaptation for cultural learning. Leaders who hold rank by skill should show different contest dynamics than leaders who hold rank by threat. Dual-hormone papers that ignore this split are measuring a mash-up.","caveats":"A theory paper, not a field experiment on CEOs. Included because the missing construct is the error in the folk model.","confounders":["formal-power","social-capital"],"paperIds":["p-henrich-2001"],"contributions":[{"paperId":"p-henrich-2001","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-probiotic-depression","sourceId":"probiotic","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Kazemi 2020: L. helveticus+B. longum, 8 wk, 81/110 MDD, BDI 17.39 to 9.1 vs 18.18 to 15.55. Akkasheh 2016: N=40, BDI -5.7 vs -1.5. Sempach 2024: N=43, 4 wk, secondary."},"n":81,"summary":"Kazemi 2020 found that eight weeks of Lactobacillus helveticus and Bifidobacterium longum lowered the Beck Depression Inventory from 17.39 to 9.1 versus 18.18 to 15.55 on placebo in 81 completers with major depression. Akkasheh 2016 saw a similar Beck drop in 40 people.","mechanism":"Authors treat named gut strains as a way to change mood. They do not isolate one metabolite.\n\nKazemi, Noorbala, Azam, Eskandari and Djafarian assigned 110 people with major depression to probiotic, prebiotic, or placebo for eight weeks. 81 finished. Beck scores fell from 17.39 to 9.1 on probiotic versus 18.18 to 15.55 on placebo (P=0.042). The prebiotic arm did not beat placebo.\n\nAkkasheh, Kashani-Poor, Tajabadi-Ebrahimi and colleagues assigned 40 people with major depression to a three-strain capsule (L. acidophilus, L. casei, B. bifidum) or placebo for eight weeks. Beck scores moved -5.7 versus -1.5 (P=0.001). Insulin, HOMA-IR, and hs-CRP also fell.\n\nSempach, Doll, Limbach and colleagues re-analyzed 43 people from a four-week probiotic-plus-usual-care trial (19 probiotic, 24 placebo). This file is immune and ghrelin. The abstract names a depression drop from the same assignment.","caveats":"Researchers assigned people to a capsule or a control, so this is a trial stamp. Strains and durations differ. More papers of the same design do not settle the claim.\n\nKazemi is 81 completers and a Beck score. Akkasheh is 40 people. Sempach is a secondary immune file; the depression claim sits in the parent sentence.\n\nThis is a journal entry, not medical advice and not a reason to take a probiotic for depression.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise"],"paperIds":["p-pmid-29731182","p-pmid-26706022","p-pmid-39048549"],"contributions":[{"paperId":"p-pmid-29731182","evidenceGrade":"abstract_only","designNote":"Kazemi 2020 Clin Nutr. RCT. L. helveticus+B. longum vs prebiotic vs placebo, 8 wk, 81/110 MDD. BDI 17.39 to 9.1 vs 18.18 to 15.55 P=0.042. abstract_only. Archive n null."},{"paperId":"p-pmid-26706022","evidenceGrade":"abstract_only","designNote":"Akkasheh 2016 Nutrition. RCT. 3-strain vs placebo, 8 wk, N=40 MDD. BDI -5.7 vs -1.5 P=0.001. Insulin/HOMA/hs-CRP down. abstract_only. Archive n null."},{"paperId":"p-pmid-39048549","evidenceGrade":"full_text","designNote":"Sempach 2024 Transl Psychiatry. Secondary of 4-wk probiotic+TAU RCT, N=43 (19/24). Immune/ghrelin file. Abstract names depression drop from same assignment. full_text. Archive n null."}],"featured":false},{"id":"e-q10-cv","sourceId":"coenzyme-q10","targetId":"cardiovascular","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"contested","effect":{"metric":"odds_ratio","value":0.5,"note":"Mortensen 2015 Q-SYMBIO: 100 mg TID, 2 y, N=420 HF. MACE 15% vs 26%, HR 0.50. Morisco 1994: 2 mg/kg/d, 1 y, N=641. Hospitalized 73 vs 118."},"n":641,"summary":"Mortensen 2015 found that 100 mg of coenzyme Q10 three times a day for two years halved a first major heart-failure event versus placebo in 420 people (15 percent versus 26 percent; hazard ratio 0.50). Morisco 1994 had already cut hospitalizations for worsening failure in 641 people on 2 mg per kg a day.","mechanism":"Authors treat coenzyme Q10 as a mitochondrial cofactor that is low in failing heart muscle. They do not isolate one downstream path.\n\nMortensen, Rosenfeldt, Kumar and colleagues assigned 420 people with moderate to severe heart failure to 100 mg three times a day or placebo for two years on top of standard therapy (Q-SYMBIO). Short-term NYHA class, six-minute walk, and NT-proBNP did not change at 16 weeks. By two years, a first major adverse cardiovascular event had occurred in 15 percent versus 26 percent (HR 0.50, 0.32 to 0.80, P=0.003). Cardiovascular death was 9 percent versus 16 percent. All-cause death was 10 percent versus 18 percent. NYHA class improved at two years.\n\nMortensen, Rosenfeldt and Filipiak re-analyzed the European subgroup. Major events were 9 percent versus 27 percent (P=0.001). Ejection fraction also moved in that slice. Same assignment.\n\nMorisco, Trimarco and Condorelli (1994) assigned 641 people with NYHA class III or IV failure to 2 mg per kg a day or placebo for one year. Hospitalization for worsening failure was 73 versus 118. Pulmonary edema episodes were 20 versus 51. Cardiac asthma episodes were 97 versus 198.","caveats":"Researchers assigned people to a capsule or a control, so this is a trial stamp. These are heart-failure trials, not a general-population event trial. More papers of the same design do not settle the claim.\n\nShort-term Q-SYMBIO endpoints missed. The two-year win is events and later NYHA. The European paper is the same randomization, not a second trial. Morisco counts hospitalizations and acute failure episodes, not a modern MACE composite.\n\nThis is a journal entry, not medical advice and not a reason to take coenzyme Q10 after a heart diagnosis.","confounders":["sedentary-time","sleep-apnea","smoking"],"paperIds":["p-pmid-25282031","p-pmid-30835327","p-pmid-8241697"],"contributions":[{"paperId":"p-pmid-25282031","evidenceGrade":"abstract_only","designNote":"Mortensen 2015 JACC Heart Fail. Q-SYMBIO RCT. 100 mg TID vs placebo, 2 y, N=420 moderate-severe HF. MACE 15% vs 26%, HR 0.50 (0.32-0.80) P=0.003. 16-wk endpoints ns. abstract_only. Archive n null."},{"paperId":"p-pmid-30835327","evidenceGrade":"full_text","designNote":"Mortensen 2020 Cardiol J. European Q-SYMBIO subgroup. Same assignment. MACE 9% vs 27% P=0.001. LVEF moved in this slice. Not a second trial. full_text. Archive n null."},{"paperId":"p-pmid-8241697","evidenceGrade":"abstract_only","designNote":"Morisco 1994 Clin Investig. RCT. 2 mg/kg/d vs placebo, 1 y, N=641 NYHA III-IV. Hospitalized 73 vs 118 P<0.001. Pulmonary edema 20 vs 51. Cardiac asthma 97 vs 198. abstract_only. Archive n null."}],"featured":false},{"id":"e-ratio-is-not-a-knob","sourceId":"t-c-ratio","targetId":"status-seeking","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"A ratio can be moved by either hormone. It is a headline, not a mechanism."},"n":null,"summary":"T/C is a derived index. Stamp it smoke unless the paper pre-registered the ratio and showed the interaction.","mechanism":"Mehta and Josephs argued for an interaction, not a sacred ratio. Popular writing collapsed that into T/C optimization. Any association can be T, cortisol, or both. Prefer the two-hormone story on the dual-hormone edges.","caveats":"Some papers do pre-register the ratio. Those still need the same confounders as the interaction.","confounders":["testosterone","cortisol"],"paperIds":["p-mehta-josephs-2010","p-mehta-prasad-2015"],"contributions":[{"paperId":"p-mehta-josephs-2010","evidenceGrade":"abstract_only"},{"paperId":"p-mehta-prasad-2015","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-rhodiola-depression","sourceId":"rhodiola","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Mao 2015: HAM-D -5.1 rhodiola vs -4.6 placebo vs -8.2 sertraline, groups P=0.79, N=57. Darbinyan 2008 SHR-5 340/680 mg vs placebo, N=89, authors report HAMD improved on both doses not placebo."},"n":57,"summary":"Mao 2015 found that twelve weeks of Rhodiola rosea extract did not beat placebo on Hamilton change among 57 adults with mild-to-moderate major depression (-5.1 versus -4.6; groups P=0.79). Darbinyan 2008 reported that SHR-5 at 340 or 680 mg a day did move Hamilton scores versus placebo in 89 people.","mechanism":"Authors treat a rhodiola extract as a mild antidepressant with a better side-effect story than an SSRI. Mao tests that against sertraline and placebo. Darbinyan tests two SHR-5 doses against placebo.\n\nMao, Xie, Zee, Soeller, Li, Rockwell and Amsterdam (2015) assigned 57 people to standardized R. rosea, sertraline, or placebo for twelve weeks. Mixed-effects models found no group difference on HAM-D (P=0.79), BDI (P=0.28), or CGI (P=0.17). HAM-D change was -8.2 on sertraline, -5.1 on rhodiola, and -4.6 on placebo. Adverse events were 63.2, 30.0, and 16.7 percent (P=0.012).\n\nDarbinyan, Aslanyan, Amroyan, Gabrielyan, Malmström and Panossian (2008) assigned 89 people with DSM-IV mild-to-moderate depression and HAMD 21 to 31 to SHR-5 340 mg (n=31), 680 mg (n=29), or placebo (n=29) for six weeks. The abstract says overall depression, insomnia, emotional instability, and somatization improved on both doses and not on placebo. It does not publish the Hamilton increment.","caveats":"Researchers assigned people to an extract or a control, so this is a trial stamp. The cleaner US trial missed. More papers of the same design do not settle the claim.\n\nMao is fifty-seven people and a failed three-way contrast. Sertraline moved more and hurt more. That is a risk-benefit sentence, not a Hamilton identification.\n\nDarbinyan is SHR-5 from the extract's developers. The published abstract does not name the point change. Ross 2015 is a nursing-practice write-up of that file, not a second trial. It is not on this page.\n\nThis is a journal entry, not medical advice.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise"],"paperIds":["p-pmid-25837277","p-pmid-17990195"],"contributions":[{"paperId":"p-pmid-25837277","evidenceGrade":"full_text","designNote":"Mao 2015 Phytomedicine. Identifying RCT. R. rosea vs sertraline vs placebo, 12 wk, N=57 mild-moderate MDD. HAM-D groups P=0.79. Change -5.1 vs -8.2 vs -4.6. AE 30% vs 63% vs 17% P=0.012. full_text. Archive n null."},{"paperId":"p-pmid-17990195","evidenceGrade":"abstract_only","designNote":"Darbinyan 2008 Nord J Psychiatry. RCT. SHR-5 340 mg (n=31) or 680 mg (n=29) vs placebo (n=29), 6 wk, HAMD 21-31. Authors: both doses improved HAMD, placebo did not. No increment in abstract. abstract_only. Archive n null."}],"featured":false},{"id":"e-screen-cognition","sourceId":"screen-time","targetId":"cognitive-performance","relation":"spurious","direction":"forward","polarity":"context_dependent","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Soares: positive WM association in men, null in women. McMath: more screen minutes, poorer toddler BRIEF-P (β 0.257). Signs disagree."},"n":3625,"summary":"In 3,625 Pelotas cohort members, more television and games at 11 and more computer time at 11 and 15 tracked with better Digit Span backward scores at 22 in men, and with nothing in women. In 356 Illinois toddlers, more daily screen minutes tracked with worse parent-rated executive function. Nobody assigned the screens.","mechanism":"Authors usually name displacement of sleep and play, plus content that rewards fast, shallow processing. Soares found the opposite of that story in men.\n\nSoares followed 3,625 members of the 1993 Pelotas birth cohort. Screen time was self-reported television, video games, and computer use at 11, 15, and 18. Working memory was Digit Span backward at 22. In men, television and video game time at 11 and computer time at 11 and 15 sat with better working memory. Those paths ran through IQ at 18. In women the associations were null. The authors had hypothesized harm.\n\nMcMath assessed 356 STRONG Kids 2 toddlers at 24 months. Parents reported minutes of screen media on the Common Sense Media survey and rated everyday executive function on the BRIEF-P. The title frames AAP screen-time and physical-activity guidelines together. The identified contrast on this page is screen time. In a path model that also entered physical activity, fruit and vegetable servings, and sugar-sweetened drinks, more daily screen minutes sat with poorer overall executive function (β 0.257, 0.118 to 0.384), inhibitory self-control, cognitive flexibility, and emergent metacognition. Those continuous associations survived a multiple-comparison correction. Meeting the less-than-60-minute guideline sat with better overall executive function before that correction and did not after it. Daily physical activity sat with better metacognition only in the guideline model. Weight-for-length did not mediate.\n\nThe open backdoor is who sits a child in front of a screen, who owns the devices, and who fills in both the minutes and the rating. Sleep, sitting, and class travel with the clock.","caveats":"Nobody assigned screen time. These are cohort observations. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim.\n\nSoares is available here only as an abstract. Sample size: 3,625 is from the abstract. A positive association in men is not a trial of games. Content, device, and sex all split.\n\nMcMath is parent report on both sides in a mostly white, high-SES Illinois sample. Mean screen time was 98 minutes a day. Sixty-seven percent of toddlers met more than one AAP guideline, so behaviors cluster. After Benjamini-Hochberg correction the guideline associations died; the continuous minutes associations did not. This is not a trial of taking the tablet away.\n\nThis is a journal entry, not medical advice and not a reason to set a minutes target.","confounders":["sleep-hygiene","disposable-income","education","sedentary-time"],"paperIds":["p-pmid-33725639","p-pmid-36027980"],"contributions":[{"paperId":"p-pmid-33725639","evidenceGrade":"abstract_only","designNote":"Soares 2021 J Psychiatr Res, 1993 Pelotas. Observational longitudinal, n=3625 from abstract. Self-report TV, video game, computer at 11, 15, 18 to Digit Span backward at 22. Men: TV and games at 11, computer at 11 and 15 positive on WM, mediated by IQ at 18. Women null. identifying. abstract_only. Archive n null."},{"paperId":"p-pmid-36027980","evidenceGrade":"full_text","designNote":"McMath 2022 J Pediatr, STRONG Kids 2. Observational, n=356 from paper (abstract 352). Parent Common Sense Media minutes and BRIEF-P at 24 mo. Continuous screen minutes to poorer overall EF β 0.257 (0.118-0.384); ISC 0.231; flexibility 0.217; metacognition 0.257; survived BH. Under-60-min guideline weaker. PA separate. full_text. Archive n null."}],"featured":false},{"id":"e-shift-insulin","sourceId":"shift-work","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"percent_change","value":25,"note":"Bescos clamp M -25.6±7.4% after 4 assigned night shifts (8 paired); day ns (5). IVGTT glucose AUC +13.7% night. Drivers: higher HOMA-IR on night and early-morning vs day."},"n":17,"summary":"Four assigned night shifts with a nine-hour sleep opportunity reduced clamp insulin sensitivity about 25 percent in healthy adults. Matched day-shift controls did not move.","mechanism":"Bescos, Boden, Jackson, and colleagues assigned a night clock or a day clock in a Victoria University lab. Night sleep sat between 8am and 5pm. Day sleep sat between 10pm and 7am. Both groups had a nine-hour opportunity. Food was each person's usual meals, prepared on site. A 30-minute outdoor walk stood in for the commute.\n\nAfter four night shifts the clamp M value fell about 26 percent. Glucose area under an intravenous test rose about 14 percent. Fasting glucose ticked up. The day-shift group did not show those changes. Muscle Akt and TBC1D4 still answered insulin. Mitochondrial respiration did not move. Melatonin timing and hair-follicle clock genes across the wake period stayed put.\n\nThe authors read the hit as when people were awake, ate, and slept, not as lost hours or a shifted master clock. Night-shift participants ate more at the first work meal, midnight, than day-shift participants did at 10am. Sleep diaries showed about 25 minutes less sleep on nights, not a significant gap.\n\nA later workplace file in professional drivers found higher HOMA-IR on night and early-morning rosters than on days.","caveats":"Bescos assigned the roster. They did not randomize it. They matched groups on age, sex, BMI, and activity so they would not run a crossover with two clamps and two biopsies each. The page label says randomized trial because that is the design class for an assigned schedule. The paper says non-randomised.\n\nClamp pairs were eight night and five day. All eight night-shift clamps were lower afterward. The authors say they lacked power for a between-group contrast after the roster. Seventeen healthy non-shift-workers, mean age 26. Four days. The main paper is available here only as an abstract. The abstract names 17 people.\n\nThe driver file is a workplace exam, not an assignment. HOMA-IR sat higher on nights and early mornings. Who takes those rosters is still open.\n\nHours in bed are a different page. This page is the clock. Buxton 2012 mixed short sleep with a 28-hour day and lives on the sleep-insulin edge.\n\nThis is a journal entry, not medical advice and not a reason to change a roster.","confounders":["sleep-hygiene","eating-window","ultraprocessed-food"],"paperIds":["p-pmid-29356345","p-pmid-35527601"],"contributions":[{"paperId":"p-pmid-29356345","evidenceGrade":"abstract_only","designNote":"Bescos 2019. Assigned night (sleep 08:00-17:00, n=9) vs day (22:00-07:00, n=8), 4 days, 9-h opportunity. Non-randomised, matched age/sex/BMI/activity. Clamp M -25.6±7.4% night (8 paired); day ns (5). IVGTT glucose AUC +13.7% night. Archive observational / n null; N=17 from abstract. abstract_only."},{"paperId":"p-pmid-35527601","evidenceGrade":"abstract_only","designNote":"Sadeghniiat-Haghighi 2022. Occupational exam, 177 day vs 175 night vs 101 early-morning professional drivers. Night and early-morning HOMA-IR higher; MetS higher in night workers. Shift work associated with HOMA-IR after covariates. Observational. Archive n null; N=453 from abstract. abstract_only."}],"featured":false},{"id":"e-sitting-insulin","sourceId":"sedentary-time","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"percent_change","value":36,"note":"Dempsey 2017: insulin iAUC 3,293 SIT vs 2,104 LW and 2,066 SRA (~36% lower with breaks). Yates walking −16.3 mU/L vs sit; standing null."},"n":24,"summary":"In 24 adults with type 2 diabetes, an 8-hour day of unbroken sitting produced a higher postprandial insulin curve than the same day with 3-minute walking or simple resistance breaks every half hour.","mechanism":"Dempsey sat 24 inactive adults with type 2 diabetes for 8 hours, or sat them and stood them up every 30 minutes for 3 minutes of light walking or simple resistance (half-squats, calf raises, gluteal contractions, knee raises). Meals were the same. Insulin incremental area fell from 3,293 to 2,104 (walking) and 2,066 (resistance) picomoles per hour per liter. Glucose incremental area fell from 24.2 to 14.8 and 14.7. Both P less than 0.001.\n\nYates assigned 60 older South Asian and White European adults a 7.5-hour sit, the same sit plus 5 minutes of standing every 30 minutes, or 5 minutes of light walking. Walking lowered postprandial insulin 16.3 mU/L. The drop was larger in South Asians (22.4) than in White Europeans (10.3). Standing did not move insulin, glucose, or triglycerides.\n\nWheeler added a 30-minute moderate walk to an 8-hour sit in 67 older adults with obesity. Exercise then sit cut insulin total area 18 percent. Exercise then 3-minute light walks every half hour cut it 25 percent. The extra 9 percent is the sitting-break increment on top of a training-like bout. People with higher HOMA2-IR dropped insulin more.\n\nA 2018 pool of three crossover days (62 people, including the 2017 type 2 sample) found the sitting-versus-breaks gap in glucose and insulin grew as fasting insulin and surrogate insulin resistance got worse.\n\nMuscle that is not asked to contract takes up less of a meal's glucose. The pancreas then puts out more insulin. Yates's standing-null says getting off the chair is not enough if the legs do not work.","caveats":"These are one-day laboratory assignments with standardized meals, not years of desk work. The stamp is the assigned sit-versus-break contrast. It is not a claim that a gym program is sitting inverted.\n\nDempsey 2017 is 24 people and is available here only as an abstract. Mean age 62. Type 2 diabetes, not insulin-treated. Yates is 65 to 79. Wheeler is 67 on average, overweight to obese; 16 percent had impaired fasting glucose. Freire did not report insulin in the published abstract; it is here for the glucose area. Larsen is eight adults with type 1 diabetes on pumps. Glucose incremental area did not differ (P=0.086). Insulin incremental area was higher with breaks even though the pump was standardized. The authors read a better glucose-to-insulin ratio. That file does not flip the sign.\n\nThe 2018 pool includes the 2017 type 2 sample. Those 24 people appear twice on this page.\n\nThis is a journal entry, not medical advice and not a reason to buy a standing desk.","confounders":["aerobic-exercise","resistance-training","ultraprocessed-food","sleep-hygiene"],"paperIds":["p-pmid-27208318","p-pmid-30403772","p-pmid-29431272","p-pmid-33308235","p-pmid-31310990","p-pmid-39506625"],"contributions":[{"paperId":"p-pmid-27208318","evidenceGrade":"abstract_only","designNote":"Dempsey 2017. Randomized crossover, 24 inactive overweight/obese adults with T2D. 8-h SIT vs 3-min light walking or simple resistance every 30 min. Insulin iAUC 3,293 vs 2,104 and 2,066; glucose iAUC 24.2 vs 14.8 and 14.7 (all P<0.001). Identifying. Archive n null; N=24 from abstract. abstract_only."},{"paperId":"p-pmid-30403772","evidenceGrade":"full_text","designNote":"Yates 2020. Randomized acute crossover, 30 older South Asians and 30 White Europeans, 65-79. 7.5-h sit vs 5-min standing or light walking every 30 min. Walking: insulin −16.3 mU/L (SA 22.4, WE 10.3). Standing null on insulin, glucose, triglycerides. NCT02453204. full_text."},{"paperId":"p-pmid-29431272","evidenceGrade":"abstract_only","designNote":"Dempsey 2018. Pooled 3 randomized crossover lab days, n=62 (2 NGT/IGT, 1 T2D not on insulin). Sitting-vs-breaks gap in postprandial glucose and insulin grew with worse fasting insulin and surrogate IR. Includes the 2017 T2D sample. Archive n null; N=62 from abstract. abstract_only."},{"paperId":"p-pmid-33308235","evidenceGrade":"full_text","designNote":"Wheeler 2021. Randomized crossover, 67 older adults with obesity (65 completers of all 3). 8-h SIT vs 30-min moderate walk then sit vs walk then 3-min light walks every 30 min. Insulin tAUC −18% and −25% vs SIT; breaks beat exercise-then-sit 9%. HOMA2-IR predicted a larger drop. full_text."},{"paperId":"p-pmid-31310990","evidenceGrade":"abstract_only","designNote":"Freire 2019. Crossover, 25 adults with excess body fat. 10-h sit vs LV-HIIE then sit vs 5-min walk every 20 min. Glucose iAUC lower with walking breaks vs sit (β −35.3 mg/dL·10 h). Insulin not in the Archive abstract. Hung for glucose. Archive n null; N=25 from abstract. abstract_only."},{"paperId":"p-pmid-39506625","evidenceGrade":"abstract_only","designNote":"Larsen 2025. Randomized crossover pilot, 8 adults with T1D on CSII. 6-h sit vs 3-min simple resistance every 30 min. Glucose iAUC ns (P=0.086). Insulin iAUC higher with breaks; glucose/insulin ratio lower. SiSP higher at dinner. Does not flip the sign. Archive n null; N=8 from abstract. abstract_only."}],"featured":false},{"id":"e-sjw-depression","sourceId":"st-johns-wort","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"HDTSG 2002: HAM-D change -8.68 Hypericum vs -9.20 placebo, P=0.59, N=340. Full response 23.9% vs 31.9%. Sertraline also missed primary. Moreno 2006 ITT NS, N=72; OC remission lowest on Hypericum."},"n":340,"summary":"The Hypericum Depression Trial (Davidson 2002) found that LI-160 St John's wort did not beat placebo on eight-week Hamilton change among 340 US outpatients with major depression and a baseline score of at least 20 (-8.68 versus -9.20, P=0.59). Sertraline, the active comparator, also missed that primary.","mechanism":"Authors treat a hypericin-standardized extract as an antidepressant. The main US trial does not find a Hamilton move versus placebo.\n\nDavidson, Gadde, Fairbank and the Hypericum Depression Trial Study Group (2002) assigned 340 adults at 12 US clinics to H. perforatum LI-160 (900 to 1,500 mg), sertraline (50 to 100 mg), or placebo for eight weeks. HAM-D change: placebo -9.20, Hypericum -8.68 (P=0.59), sertraline -10.53 (P=0.18 versus placebo). Full response: 31.9, 23.9, and 24.8 percent. Sertraline beat placebo on a secondary CGI improvement item.\n\nMoreno, Teng, Almeida and Tavares (2006) assigned 72 Brazilian outpatients with mild-to-moderate depression to Hypericum 900 mg, fluoxetine 20 mg, or placebo for eight weeks. Intention-to-treat scores did not differ. In observed cases, remission was 12 percent on Hypericum, 34.6 percent on fluoxetine, and 45 percent on placebo (P=0.016).","caveats":"Researchers assigned people to an extract or a control, so this is a trial stamp. The main result missed. Extra papers do not settle the claim.\n\nHDTSG is a failed assay: sertraline also missed the Hamilton primary. That is why confidence stays contested. It is still the cleanest Hypericum-versus-placebo contrast in major depression in the files on this page.\n\nMoreno's observed-case remission puts Hypericum below placebo. That does not turn this page into a harm claim. It is a small third arm.\n\nThis is a journal entry, not medical advice and not a reason to start or skip an extract.","confounders":["sleep-hygiene","alcohol-intake","aerobic-exercise"],"paperIds":["p-pmid-11939866","p-pmid-16612487"],"contributions":[{"paperId":"p-pmid-11939866","evidenceGrade":"abstract_only","designNote":"HDTSG / Davidson 2002 JAMA. Identifying RCT. LI-160 900-1500 mg vs sertraline 50-100 vs placebo, 8 wk, N=340 MDD HAM-D>=20. HAM-D change -8.68 vs -9.20 P=0.59. Full response 23.9% vs 31.9%. Sertraline also missed primary. abstract_only. Archive n null."},{"paperId":"p-pmid-16612487","evidenceGrade":"abstract_only","designNote":"Moreno 2006 Rev Bras Psiquiatr. RCT. Hypericum 900 vs fluoxetine 20 vs placebo, 8 wk, N=72 mild-moderate. ITT NS. OC remission 12% Hypericum vs 34.6% fluoxetine vs 45% placebo P=0.016. abstract_only. Archive n null."}],"featured":false},{"id":"e-sleep-cognition","sourceId":"sleep-hygiene","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"meta_analysis","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Lim-Dinges meta: acute deprivation cuts vigilance and WM. Zimmerman N=65: 6-wk 7-9 h beat practice on WM and flanker. Santisteban: 6 nights minus 1 h cut WM, not attention. Lo N=56: 7 nights of 5 h TIB cut PVT and n-back."},"n":null,"summary":"Lim and Dinges's 2010 meta of short-term deprivation shows losses on vigilance and working memory. Santisteban's 2019 adult week and Lo's 2016 adolescent week then lose working memory; Lo also loses vigilance. Zimmerman's 2024 habit trial moves the same tasks.","mechanism":"Lim and Dinges (2010) pooled short-term deprivation studies. Vigilance and working memory fell. The identified object is hours asleep. This atlas will not let that smuggle income, mate value, or a title.\n\nZimmerman and colleagues (2024) ran a randomized crossover in sixty-five adults who already slept 7 to 9 hours. Two six-week conditions: keep habitual bed and wake times, or delay bedtime by 1.5 hours. They used the NIH Toolbox and scored each endpoint against the first baseline so practice would not be mistaken for a sleep effect. List Sorting working memory and the Flanker task rose after the habitual weeks beyond that practice gain. After the short weeks they did not. Processing speed rose in both arms. Card-sort flexibility did not move.\n\nSantisteban, Brown, Ouimet, and Gruber (2019) cut one hour from habitual nights for six nights against a lamp with no known effect. Working memory capacity improved from baseline in the lamp arm and did not in the short-sleep arm. Sustained attention, response inhibition, and decision making did not change in either arm.\n\nLo, Ong, Leong, Gooley, and Chee (2016) randomized fifty-six adolescents aged 15 to 19, from top high schools and not habitual short sleepers, in a boarding school. After three 9-hour nights, one arm had seven nights of 5-hour time in bed and the other kept 9 hours. A battery ran three times a day. Psychomotor Vigilance lapses rose night after night in the short arm. Verbal 1-back and 3-back sensitivity fell. Practice gains on mental arithmetic and symbol-digit were smaller than in the 9-hour arm. After two 9-hour recovery nights, vigilance and sleepiness were still worse than baseline, and processing speed still lagged the controls.\n\nThe four papers are not the same exposure. The meta is acute deprivation. Zimmerman is six weeks of a modest bedtime delay. Santisteban is a one-hour adult week. Lo is a hard adolescent week. All still name time asleep.","caveats":"The meta is acute lab protocols, not a career trial. Recovery sleep reverses much of that deficit. Chronic restriction and shift work are related exposures, not that estimate.\n\nZimmerman is sixty-five completers, mean age about 36, 89 percent women, already 7-to-9-hour sleepers without a diagnosed sleep disorder. Scores after the short arm did not fall below baseline; they failed to show the practice gain seen after habitual nights. Women using hormonal contraception were excluded.\n\nSantisteban is available here only as an abstract. The placebo was a lamp. Working memory was the task that moved. Attention, inhibition, and decision making did not. The abstract names 93 adults, mean age about 24, and does not name a sample size in the record we hold.\n\nLo is fifty-six adolescents in a Singapore boarding school after the school year. Thirty were on 5-hour nights and 26 on 9-hour nights. The short arm woke two hours earlier and went to bed two hours later, so tests sat after a longer wake. They were not habitual short sleepers. Mood and sleepiness are not this page. Two recovery nights did not restore vigilance.\n\nNone of these papers is a reason to prescribe a bedtime.","confounders":["alcohol-intake","ferritin"],"paperIds":["p-lim-dinges-2010","p-pmid-38233280","p-pmid-30670158","p-pmid-26612392"],"contributions":[{"paperId":"p-lim-dinges-2010","evidenceGrade":"abstract_only","designNote":"Identifying meta-analysis. Short-term deprivation on vigilance and working memory. Keep. Do not drop. abstract_only."},{"paperId":"p-pmid-38233280","evidenceGrade":"full_text","designNote":"RCT, randomized crossover. 65 healthy adults completed two 6-week conditions: habitual 7-9 h vs 1.5 h bedtime delay. NIH Toolbox WM and flanker. full_text. Abstract N=65; do not copy Archive n:null."},{"paperId":"p-pmid-30670158","evidenceGrade":"abstract_only","designNote":"Santisteban 2019. Double-blind RCT. 6 nights cutting 1 h from habitual vs placebo lamp. Working memory capacity rose in placebo, not restriction. Sustained attention, response inhibition, decision making did not move. Abstract N=93 (mean age 24.3); do not copy Archive n:null. abstract_only."},{"paperId":"p-pmid-26612392","evidenceGrade":"full_text","designNote":"Lo 2016 Need for Sleep. Parallel-group RCT. 56 adolescents 15-19y (SR 30, control 26). Boarding school: 3x9h baseline, 7 nights 5h vs 9h TIB, 3x9h recovery. PVT, n-back, MAT/SDMT 3x/day. PVT and KSS not back to baseline after 2 recovery nights. Archive n:null; N=56 from paper. full_text."}],"featured":true},{"id":"e-sleep-cortisol","sourceId":"sleep-hygiene","targetId":"cortisol","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Spiegel 1999 (N=11): 6 nights of 4 h bed raised evening cortisol. Voderholzer 2012 (N=88 adolescents): 4 nights of 5-9 h TIB did not move saliva cortisol."},"n":88,"summary":"Six 4-hour nights raised evening cortisol in eleven young men. Four nights of 5-to-9-hour beds in eighty-eight adolescents did not move evening or morning saliva cortisol.","mechanism":"Spiegel, Leproult, and Van Cauter restricted eleven young men to four hours in bed for six nights, then compared that week with six nights of twelve-hour recovery. Evening cortisol was higher after the short nights. Glucose tolerance also fell in that week; that is a different pair.\n\nVoderholzer and colleagues randomized eighty-eight healthy adolescents to four nights at 9, 8, 7, 6, or 5 hours in bed. They sampled saliva cortisol every half hour in the evening and the morning, before and after the last experimental night. Objective sleepiness rose as the nights got shorter. Evening and morning cortisol did not. The authors suggest sleep itself may have compensated.\n\nThe two trials are not the same exposure. Spiegel used a hard inpatient debt in young men against long recovery. Voderholzer used a graded four-night cut in adolescents and saliva at the edges of the night. Hours in bed can move cortisol. A milder adolescent week did not.","caveats":"Spiegel is eleven men and one inpatient week. The comparison is twelve-hour recovery nights, not habitual sleep. Evening cortisol is the named finding.\n\nVoderholzer is larger and still short: four nights, saliva at dusk and dawn, adolescents. Sleepiness rose; cortisol did not. That is a real result in a different population, not a copy of Spiegel. It does not erase the young-men trial. It also does not say that every short week raises cortisol in teenagers.\n\nDaytime sleepiness from Voderholzer is not this pair. The stamp is robust causal because Spiegel already ran a restriction trial. A second paper does not make that more certain.","confounders":[],"paperIds":["p-spiegel-1999","p-pmid-22198375"],"contributions":[{"paperId":"p-spiegel-1999","evidenceGrade":"abstract_only","designNote":"Identifying RCT. Lancet inpatient trial, 11 young men, 4 h in bed for 6 nights vs 12 h recovery for 6 nights. Evening cortisol raised. Keep. Do not drop. abstract_only."},{"paperId":"p-pmid-22198375","evidenceGrade":"abstract_only","designNote":"RCT. 88 healthy adolescents randomized to four nights at 9, 8, 7, 6, or 5 h TIB. Saliva cortisol half-hourly evening and morning: no significant change. Objective sleepiness rose. abstract_only. Do not copy Archive n:null onto the edge."}],"featured":true},{"id":"e-sleep-depression","sourceId":"sleep-hygiene","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Blom 2024 n=126: MADRS-S group by time p=0.11, between d=-0.16. Carney 2017 n=107: HAMD-17 groups ns. CBT-I plus placebo matched AD. Archive n empty."},"n":126,"summary":"In 126 adults with insomnia and major depression, adding internet CBT for insomnia to CBT for depression improved the insomnia score but not the depression score versus depression treatment plus a placebo sleep module.","mechanism":"Blom, Forsell, Hellberg and colleagues assigned 126 adults with physician-diagnosed insomnia and major depression to twelve weeks of therapist-guided internet CBT in Stockholm psychiatry (NCT01663844). One arm mixed CBT for insomnia with CBT for depression. The other mixed CBT for depression with a quasi-desensitization placebo for sleep. Sleep restriction and stimulus control were the insomnia pieces. Behavioral activation was the depression piece.\n\nThe combined arm beat control on the Insomnia Severity Index (group by time p=0.007). It did not beat control on the Montgomery-Åsberg self-rating (p=0.11). Observed means went from 24.1 to 18.6 versus 24.0 to 17.4. The between-group d at post was -0.16.\n\nCarney, Edinger, Kuchibhatla and colleagues assigned 107 adults with SCID major depression and insomnia to four biweekly sessions plus a daily pill: CBT-I plus escitalopram, CBT-I plus placebo, or escitalopram plus sleep-hygiene talk. Hamilton scores fell in every arm and the arms did not differ. The CBT-I plus placebo arm had no depression treatment and still fell, 25.52 to 14.67. Remission below 8 was 39, 39, and 41 percent.\n\nThe authors name time out of bed, less rumination in bed, morning light, and leftover REM as candidate paths. Those paths did not produce an extra depression drop once depression was already being treated.","caveats":"Blom's control already received a full CBT for depression. The test is the insomnia increment, not CBT-I versus nothing. Removing the sleep item from MADRS-S moved the interaction toward the control (p=0.054). Combined therapists spent more minutes, 154 versus 111. Stockholm, internet, 2013 to 2017. Inclusion allowed minor depression if MADRS-S was above 19. MADRS-S remission was 22 percent versus 34 percent at post, not a significant difference.\n\nCarney aimed for 201 and stopped at 107. The CBT-I plus placebo arm still took a pill. There is no no-treatment control. Four sessions, novice graduate therapists. Follow-up only for people who remitted, so durability is unknown. Hamilton includes sleep items; dropping them did not change the group test.\n\nThe papers name 126 and 107 people. This page is CBT-I for insomnia, not a one-week inpatient restriction protocol.\n\nThis is a journal entry, not medical advice and it is not a reason to start or skip a therapy.","confounders":["aerobic-exercise","outdoor-time"],"paperIds":["p-pmid-38286128","p-pmid-28199710"],"contributions":[{"paperId":"p-pmid-38286128","evidenceGrade":"full_text","designNote":"Blom 2024. Identifying RCT. ICBT 12 wk, n=126 (64/62), insomnia+MDD, NCT01663844. InsDep vs DepPlac (quasi-desensitization). ISI group by time p=0.007. MADRS-S p=0.11, between d=-0.16. Archive n null; N=126 from paper. full_text."},{"paperId":"p-pmid-28199710","evidenceGrade":"full_text","designNote":"Carney 2017. Identifying RCT. n=107 MDD+insomnia, 4 biweekly sessions. CBT-I+escitalopram vs CBT-I+placebo vs AD+sleep hygiene. HAMD-17 all improved, groups ns (p=1.0). Remission 39/39/41%. Archive n null; N=107 from paper. full_text."}],"featured":false},{"id":"e-sleep-insulin","sourceId":"sleep-hygiene","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Spiegel 1999 (N=11): sleep debt impaired IVGTT glucose tolerance. Later RCTs: clamp, HOMA-IR, adipocyte signaling. Restriction on a reducing diet did not worsen glucose (Nedeltcheva 2012)."},"n":38,"summary":"Experimental sleep restriction lowers insulin sensitivity. Spiegel, Leproult, and Van Cauter put eleven young men into sleep debt and watched glucose tolerance fall into a pre-diabetic range. Later randomized weeks, including clamp studies and a six-week trial in thirty-eight women, found the same direction.","mechanism":"Spiegel, Leproult, and Van Cauter restricted sleep in eleven young men. Intravenous glucose tolerance fell toward a pre-diabetic band. That is the identifying trial.\n\nNedeltcheva and colleagues kept eleven adults on 5.5-hour nights for two weeks of sitting and free eating. Two-hour oral glucose rose and insulin sensitivity fell, with the same weight gain as on 8.5-hour weeks. Buxton and colleagues kept twenty men on 5-hour nights for a week. Insulin sensitivity fell about 20 percent on an intravenous glucose test and about 11 percent on a clamp. Modafinil, which they randomized, did not prevent the drop.\n\nBroussard and colleagues biopsied fat cells after four 4.5-hour nights in seven adults. Insulin had a harder time turning on Akt, and whole-body insulin sensitivity fell. Rao and colleagues used a clamp after five 4-hour nights in fourteen people. Peripheral insulin sensitivity fell about 29 percent. Liver glucose production did not.\n\nZuraikat and colleagues cut sleep by about 90 minutes for six weeks in thirty-eight women. Fasting insulin and HOMA-IR rose, not through fat mass. The rise was larger after menopause. Singh and colleagues ran four short nights in postmenopausal women, then a clamp. Nine of fourteen were analyzed. The glucose infusion rate fell.\n\nDiet changes the picture. On a reducing diet, Nedeltcheva 2012 saw no loss of oral glucose control in ten overweight adults; 24-hour insulin went down. Cros and colleagues overfed ten people for six days. The overfeed raised liver fat and endogenous glucose production. Adding 4-hour nights did not move those numbers further.\n\nBuxton 2012 mixed three weeks of 5.6-hour sleep with 28-hour days in twenty-one adults. After a meal, glucose ran higher because the pancreas put out too little insulin. Nine recovery days put both back. Ness and colleagues found two 10-hour nights after five short nights in fifteen men restored the fat-release pattern, not the insulin-sensitivity drop.","caveats":"The early trials are small and inpatient. Spiegel is eleven men. Broussard is seven. Singh analyzed nine. Zuraikat is the largest randomized sample here, thirty-eight women, and it is still six weeks of restriction, not a decade of short sleep.\n\nA calorie deficit can hide the glucose hit. Nedeltcheva 2012 saw no loss of glucose control when the same restriction sat on a reducing diet. Cros 2019 saw no extra glucose hit when restriction sat on a six-day overfeed. Those are context, not a failed replication of restriction alone.\n\nTwo weekend nights did not restore insulin sensitivity in Ness 2020. Nine days of recovery plus a stable clock did in Buxton 2012, but that protocol also shifted the day length. Shift work is a mixed exposure. Ness and Buxton 2012 used sequential laboratory schedules, not a coin-flip between sleep lengths.\n\nThe stamp stays robust causal because Spiegel's design already set it. Eleven papers do not make the stamp more certain.","confounders":["alcohol-intake","ultraprocessed-food"],"paperIds":["p-spiegel-1999","p-pmid-19567526","p-pmid-20585000","p-pmid-22513492","p-pmid-23070488","p-pmid-25658017","p-pmid-30615104","p-pmid-36998155","p-pmid-37955852","p-pmid-22496545","p-pmid-30892916"],"contributions":[{"paperId":"p-spiegel-1999","evidenceGrade":"abstract_only","designNote":"Identifying RCT. Lancet inpatient trial, 11 young men, sleep debt vs recovery. IVGTT glucose tolerance fell toward a pre-diabetic range. Keep. Do not drop. abstract_only."},{"paperId":"p-pmid-19567526","evidenceGrade":"full_text","designNote":"Randomized crossover, 11 adults (5 women, 6 men), two 14-day periods, 5.5 vs 8.5 h bedtimes, sedentary plus ad libitum food. OGTT 2-h glucose and insulin sensitivity worsened. RCT, full_text. Do not copy Archive n:null."},{"paperId":"p-pmid-20585000","evidenceGrade":"full_text","designNote":"Inpatient, 20 healthy men. 10 h nights then 5 h for 7 nights. IVGTT insulin sensitivity down 20 percent; clamp down 11 percent. Randomized factor is modafinil, not sleep vs sleep. RCT, full_text. Do not copy Archive n:null."},{"paperId":"p-pmid-22513492","evidenceGrade":"full_text","designNote":"Two 14-day hypocaloric treatments, 5.5 vs 8.5 h, in random order. 10 overweight adults. Restriction did not worsen oral glucose tolerance; 24-h insulin economy improved. Infer randomized crossover. Do not copy Archive observational / n:null onto the edge. full_text."},{"paperId":"p-pmid-23070488","evidenceGrade":"full_text","designNote":"Randomized crossover, 7 healthy adults (1 woman, 6 men), 4 days of 4.5 vs 8.5 h. Adipocyte pAkt insulin signaling impaired; whole-body IVGTT insulin sensitivity fell. RCT, full_text. Do not copy Archive n:null."},{"paperId":"p-pmid-25658017","evidenceGrade":"full_text","designNote":"Randomized crossover, 14 subjects, 5 nights of 4 vs 8 h. Clamp: whole-body insulin sensitivity down 25 percent, peripheral down 29 percent; hepatic endogenous glucose production unchanged. RCT, full_text. Do not copy Archive n:null."},{"paperId":"p-pmid-30615104","evidenceGrade":"abstract_only","designNote":"Randomized crossover, 10 healthy subjects. 6-day overfeed (130 percent energy) with 8 h vs 4 h sleep opportunity. Overfeeding raised liver fat and endogenous glucose production; adding restriction did not change those glucose outcomes further. RCT, abstract_only. Do not copy Archive n:null."},{"paperId":"p-pmid-36998155","evidenceGrade":"full_text","designNote":"Randomized crossover. 14 postmenopausal women enrolled, 9 analyzed. Four nights habitual vs 60 percent of habitual sleep. Clamp glucose infusion rate down 20 percent (low-dose insulin) and 12 percent (high-dose). RCT, full_text. Do not copy Archive n:null."},{"paperId":"p-pmid-37955852","evidenceGrade":"full_text","designNote":"Randomized crossover, 38 women (11 postmenopausal), two 6-week phases: adequate sleep vs 1.5 h/night restriction. Fasting insulin and HOMA-IR rose; adiposity did not mediate. RCT, full_text. Do not copy Archive n:null."},{"paperId":"p-pmid-22496545","evidenceGrade":"full_text","designNote":"Sequential lab protocol, not a sleep-randomized RCT. 21 healthy adults, more than 5 weeks: baseline, 3 weeks of 5.6 h/24 h plus 28-h days, then 9 days recovery. Post-meal glucose rose from inadequate insulin secretion; recovered after 9 days. Archive observational / n:null. Do not copy those onto the edge. full_text."},{"paperId":"p-pmid-30892916","evidenceGrade":"full_text","designNote":"Inpatient sequential: 3 baseline 10-h nights, 5 nights of 5 h, 2 recovery 10-h nights. 15 healthy men. IVGTT insulin sensitivity and disposition index fell; 2 recovery nights restored NEFA dynamics, not the insulin-sensitivity drop. Archive observational. Do not copy that onto the edge. full_text."}],"featured":false},{"id":"e-sleep-mortality","sourceId":"sleep-hygiene","targetId":"mortality","relation":"spurious","direction":"forward","polarity":"non_linear","methodology":"meta_analysis","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Yin 2018: U-shape, nadir ~7h; <7h RR 1.06/h (1.04-1.07), >7h RR 1.13/h (1.11-1.15). Liu 2018: 40 cohorts, 2,200,425, J-shape. Both arms raise death. Design does not identify."},"n":2200425,"summary":"Yin 2018's dose-response meta of prospective cohorts found a U-shaped link between hours of sleep and all-cause death: each hour under 7 tracked a 6 percent higher risk, and each hour over 7 tracked 13 percent. Nobody randomized time in bed.","mechanism":"Hours asleep and how regular those hours are. Death from any cause. The duration metas are U-shaped or J-shaped. Both short and long sleep track more death.\n\nYin, Jin, Shan and colleagues (2018) pooled prospective cohorts to December 2016 in generally healthy people. Lowest all-cause death sat near 7 hours a day. Below 7 hours the pooled RR was 1.06 (1.04 to 1.07) per hour cut. Above 7 it was 1.13 (1.11 to 1.15) per hour added.\n\nLiu, Xu, Rota and colleagues (2018) fit a restricted cubic spline on 40 cohorts, 2,200,425 adults, 271,507 deaths. Versus 7 hours, 4 hours RR 1.05, 6 hours 1.04, 9 hours 1.13, 10 hours 1.25, 11 hours 1.38. Nonlinear P less than 0.01.\n\nCappuccio, D'Elia, Strazzullo, and Miller (2010) pooled 16 studies, 27 samples, 1,382,999 people, 112,566 deaths. Short sleep RR 1.12 (1.06 to 1.18). Long sleep RR 1.30 (1.22 to 1.38). Questionnaire sleep. Certificate death.\n\nWindred, Burns, Lane and colleagues (2024) scored sleep regularity from more than 10 million accelerometer hours in 60,977 UK Biobank adults. 1,859 deaths, mean 6.3 years. The top four regularity fifths tracked 20 to 48 percent lower all-cause death than the least regular fifth. Regularity beat duration in nested models. the record here is The paper names N=60,977.\n\nLiang, Ai, Xue and colleagues (2023) followed 90,398 of that accelerometer wave. Short sleep HR 1.27 (1.11 to 1.45). Long sleep HR 1.16 (1.06 to 1.28). Long sleep plus lower efficiency HR 2.11 (1.44 to 3.09).\n\nLiu, Niu, Duan and colleagues (2023) followed 5,772 older Chinese adults (median age 82). A 3-year drop of more than 3 hours HR 1.26. Short to long 1.28. Long to short 1.52.\n\nLiang, Feng, Chen and colleagues (2023) followed 92,221 of the same UK Biobank wave. Without recommended activity, short sleep HR 1.88 and long sleep HR 1.69 versus recommended activity and normal sleep.\n\nAuthors name metabolism, immune load, and illness that changes sleep. The files do not isolate one path.","caveats":"The stamp is smoke because nobody randomized hours in bed. These are cohorts and metas of cohorts. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim. A larger meta is still observation.\n\nReverse causation sits on the backdoor. Illness can shorten sleep, lengthen it, or wreck the clock, and also raise later death. Healthy-user habits travel with a regular 7-hour night: income, movement, less drinking. Residual confounding remains.\n\nYin's cardiovascular and stroke curves are not this page. This page is all-cause death. Sleep apnea is a different question.\n\nCappuccio's sleep was a questionnaire. Later UK Biobank files use a wrist accelerometer. Windred, Liang 90,398, and Liang 92,221 share that wave. They are not three independent samples.\n\nThis is a journal entry, not medical advice and it is not a reason to pick a number of hours.","confounders":["depression","alcohol-intake","insulin-resistance","disposable-income","aerobic-exercise"],"paperIds":["p-pmid-28889101","p-pmid-27067616","p-pmid-20469800","p-pmid-37738616","p-pmid-37186145","p-pmid-36940517","p-pmid-36990109"],"contributions":[{"paperId":"p-pmid-28889101","evidenceGrade":"full_text","designNote":"Yin 2018 JAHA. Dose-response meta of prospective cohorts to Dec 2016, generally healthy. Identifying. U-shape, nadir ~7h. All-cause <7h RR 1.06 (1.04-1.07)/h; >7h RR 1.13 (1.11-1.15)/h. Both arms. Archive n null. full_text."},{"paperId":"p-pmid-27067616","evidenceGrade":"abstract_only","designNote":"Liu 2018 Sleep Med Rev. Flexible RCS meta-regression, 40 cohorts, 2,200,425 adults, 271,507 deaths. J-shape vs 7h; 4h RR 1.05; 9h 1.13; 10h 1.25; 11h 1.38; P<0.01 nonlinear. Archive n null; N from abstract. abstract_only."},{"paperId":"p-pmid-20469800","evidenceGrade":"full_text","designNote":"Cappuccio 2010 Sleep. Meta of 16 prospective studies, 27 samples, 1,382,999 people, 112,566 deaths, 4-25 y. Short RR 1.12 (1.06-1.18); long RR 1.30 (1.22-1.38). Questionnaire sleep, certificate death. Both arms heterogeneous. Archive n null; N from paper. full_text."},{"paperId":"p-pmid-37738616","evidenceGrade":"full_text","designNote":"Windred 2024 Sleep. UK Biobank accelerometer, 60,977 adults, SRI from >10M hours, 1,859 deaths, mean 6.3 y. Top 4 SRI quintiles 20-48% lower all-cause vs least regular. Regularity > duration in nested models. Archive n null; N from paper. full_text."},{"paperId":"p-pmid-37186145","evidenceGrade":"abstract_only","designNote":"Liang 2023 J Gerontol A. UK Biobank accelerometer, 90,398, 2,685 deaths, median 6.4 y. Short HR 1.27 (1.11-1.45); long 1.16 (1.06-1.28); long+low efficiency 2.11 (1.44-3.09); Pinteraction=.001. Archive n null; N from abstract. abstract_only."},{"paperId":"p-pmid-36940517","evidenceGrade":"abstract_only","designNote":"Liu 2023 Sleep Med. Chinese older cohort, 5,772, median age 82, 1,762 deaths, median 4.08 y. 3-year change: <-3 h/d HR 1.26 (1.05-1.52); short-to-long 1.28; long-to-short 1.52. Archive n null; N from abstract. abstract_only."},{"paperId":"p-pmid-36990109","evidenceGrade":"abstract_only","designNote":"Liang 2023 Eur J Prev Cardiol. UK Biobank accelerometer, 92,221, 3,080 deaths, median 7.0 y. No recommended MVPA + short HR 1.88 (1.61-2.20); + long 1.69 (1.49-1.90) vs MVPA + normal sleep. Archive n null; N from abstract. abstract_only."}],"featured":false},{"id":"e-sleep-testosterone","sourceId":"sleep-hygiene","targetId":"testosterone","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"percent_change","value":-12,"note":"Leproult 2011: about 10 to 15% lower daytime T after 5-hour nights (N=10 men). Liu 2021: overnight wake lowered 24-h T (N=35 men). Alvarenga 2023: total T fell after total, not REM, deprivation."},"n":35,"summary":"In men, experimental sleep loss lowers testosterone. A week of 5-hour nights cut daytime T about 10 to 15 percent. One night of total wake cut 24-hour T. All-night deprivation cut total T; REM-only did not. In 37 healthy adults, T also fell during long wake; caffeine lessened that drop.","mechanism":"Leproult and Van Cauter kept ten young men on 5-hour nights for a week. Daytime testosterone fell. Cortisol did not fall with it in that protocol. Liu, Takahashi, Yang, Iranmanesh, and Veldhuis then kept 35 men awake all night or let them sleep from 10 pm to 6 am, in random order. Mean, basal, and pulsatile 24-hour testosterone fell, and pulse frequency fell, without a matching drop in luteinizing hormone across the day. The change was clearer in the men aged 60 to 80. The authors read this as a time-of-day uncoupling of testicular control, not a simple LH drop. Faraut, Andrillon, Drogou, Gauriau and colleagues also saw morning salivary testosterone fall after two 3-hour nights, but only when each man was compared with his own habitual sleep. The factor they randomized was blue light after the short nights. Alvarenga, Fernandes, Bittencourt, Tufik, and Andersen compared men who already had obstructive sleep apnea with healthy volunteers, then randomized the healthy men to total or REM deprivation. The apnea contrast is who already had the syndrome. After total sleep deprivation, total testosterone fell. After REM-only deprivation, it did not. Sperm counts did not move after either deprivation. The abstract does not say how many men were studied. Drogou, Sauvet, Erblang and colleagues kept 37 healthy people awake and randomized caffeine against placebo. Testosterone and cortisol both fell during that wakefulness. Caffeine lessened the testosterone drop. What they randomized was the caffeine, not sleep versus sleep. The testosterone change is the drop during wake, the same kind of contrast as Faraut's restriction-versus-baseline. Drogou's headline was IGF-1 and a gene variant. Testosterone was a measured hormone during the same wake.","caveats":"The protocols are still short. The longest lasted a week. Liu compared one night of total wake with 8 hours in bed. Alvarenga's abstract does not report N. A clinical-trial listing is not the paper. The apnea arm is not a randomized sleep contrast. In Faraut and in Drogou, testosterone fell during short sleep or long wake against each person's own baseline. What they randomized was blue light or caffeine. Drogou also saw cortisol fall; that is not this arrow. Most of the samples are men. Five papers do not make the stamp more certain.","confounders":[],"paperIds":["p-leproult-2011","p-pmid-31993665","p-pmid-31998056","p-pmid-35670262","p-pmid-37279709"],"contributions":[{"paperId":"p-leproult-2011","evidenceGrade":"abstract_only"},{"paperId":"p-pmid-31993665","evidenceGrade":"full_text","designNote":"Prospectively randomized crossover: total overnight wake vs 10pm-6am sleep. N=35 men (17 aged 18-30, 18 aged 60-80). Do not copy Archive observational / n=null. Treat as RCT/experimental crossover. Full text PMC7355405."},{"paperId":"p-pmid-31998056","evidenceGrade":"full_text","designNote":"Crossover randomized, 17 young men. Both arms: two 3-hour nights. Randomized factor is blue light, not sleep vs sleep. Sleep to T is restriction vs baseline. Full text PMC6961531."},{"paperId":"p-pmid-35670262","evidenceGrade":"abstract_only","designNote":"Multi-arm: OSA vs healthy (observational); healthy men randomized to total or REM deprivation. Total T fell after total deprivation, not REM-only. Spermograms unchanged. Archive observational / n null. Treat as experimental/RCT. N is missing from the abstract; do not invent 60 from a registry."},{"paperId":"p-pmid-37279709","evidenceGrade":"abstract_only","designNote":"Randomized crossover, caffeine vs placebo during total sleep deprivation. N=37 healthy. T and cortisol fell during wakefulness; caffeine lessened the T drop. Randomized factor is caffeine, not sleep vs sleep. T drop is wakefulness-vs-baseline, like Faraut. Archive observational / n null. Do not copy those. Stored abstract is the aims paragraph."}],"featured":true},{"id":"e-smoking-insulin","sourceId":"smoking","targetId":"insulin-resistance","relation":"spurious","direction":"forward","polarity":"positive","methodology":"observational","confidence":"low","effect":{"metric":"odds_ratio","value":1.74,"note":"Cho 2022 men continuous vs non-smoker high TyG: OR 1.74 (1.27-2.38). Women 2.01 (1.33-3.03). Eliasson 1997 clamp improved after quit; no M-value in abstract. Archive n null."},"n":4043,"summary":"In Cho 2022, 4,043 Korean adults without diabetes who met both urine NNAL and cotinine smoker cutoffs had higher triglyceride-glucose odds than people who met neither (men 1.74, women 2.01 after age, BMI, drink, walk, income, and pack-years); Eliasson 1997's 17 quitters, against 23 who kept smoking, improved clamp insulin sensitivity in eight weeks despite modest weight gain.","mechanism":"Cho treats smoking as a recent chemical exposure, read from urine. Cotinine marks the last day. NNAL marks the last month or so. People over both cutoffs had smoked through that window. People over NNAL only had smoked in the last weeks but not the last hours. The outcome is a triglyceride-glucose index, a fasting blood proxy for insulin resistance, not a HOMA-IR number and not a clamp.\n\nThe authors think nicotine and smoke push belly fat, raise cortisol, catecholamines, and growth hormone, free fatty acids, and lower adiponectin. Those are the pathways they name. They do not isolate one of them.\n\nEliasson asked healthy middle-aged men who already smoked to quit. Seventeen did. Twenty-three did not. Eight weeks later a euglycaemic clamp, the lab drip that measures how well insulin moves glucose, read better in the quitters even though they gained a little weight. That is less smoking and less resistance. It is the same directed pair as Cho, not a drug trial run backwards.\n\nCho, Jeong, Shin, Park and Jang (2022) used KNHANES 2016 to 2018. They kept 4,043 adults after dropping people under 19, people with diabetes, people menstruating or pregnant, and people missing NNAL or cotinine. High TyG sat at 8.3878 in men and 8.60248 in women. Continuous smokers versus non-smokers: odds 1.74 (1.27 to 2.38) in men and 2.01 (1.33 to 3.03) in women after age, marriage, school, income, region, job, BMI, drink, walk, energy, chronic disease, secondhand smoke, pack-years, and survey year. Past smokers (NNAL high, cotinine low): 1.47 (1.03 to 2.09) and 1.37 (1.00 to 1.87). The cotinine-only cell was 12 men and 22 women and did not show an association.\n\nEliasson, Attvall, Taskinen and Smith (1997) ran an open parallel follow-up, not a random assignment. Forty non-obese healthy men. Seventeen quit. Twenty-three kept smoking. The abstract reports better sensitivity and a better lipoprotein profile after eight weeks. It does not report the clamp M-value.","caveats":"Nobody assigned smoking in Cho. The seventeen who quit in Eliasson chose to quit. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim.\n\nCho is one survey wave. A high TyG and a high NNAL can share a backdoor: body fat, drink, school, income, walking. The models adjust those. They cannot close reverse flow or leftover confounding. The outcome is TyG, not HOMA-IR. People with diabetes were dropped, which the authors say may have shrunk the association. The cotinine-only group is too small to read as proof that a day of smoke is harmless.\n\nEliasson is forty men, eight weeks, and is available here only as an abstract. Weight rose a little and sensitivity still improved. That is a useful sign, not a trial.\n\nThis page is smoking to insulin resistance. It does not cover smoking to death, smoking to cognition, or an education-mediated smoking Mendelian randomization. Those are other pages.\n\nThis is a journal entry, not medical advice.","confounders":["alcohol-intake","education","disposable-income","employment-status"],"paperIds":["p-pmid-35241770","p-pmid-9179554"],"contributions":[{"paperId":"p-pmid-35241770","evidenceGrade":"full_text","designNote":"Cho 2022 Sci Rep. KNHANES VII 2016-18. n=4043 (2067 men, 1976 women). Urine NNAL and cotinine groups. High TyG (8.3878 men, 8.60248 women). Continuous vs non: men OR 1.74 (1.27-2.38), women 2.01 (1.33-3.03). Cross-sectional. full_text. Archive n null; N from paper."},{"paperId":"p-pmid-9179554","evidenceGrade":"abstract_only","designNote":"Eliasson 1997 Eur J Clin Invest. Open parallel. 40 non-obese healthy men; 17 quit, 23 continued. Euglycaemic clamp, 8 weeks. Sensitivity and lipids improved despite modest weight gain. Observational. abstract_only. Archive n null; N from abstract."}],"featured":false},{"id":"e-soi-not-hypergamy","sourceId":"sociosexuality","targetId":"hypergamy-preference","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"SOI-R measures orientation to uncommitted sex. Hypergamy measures resource weights. They are not substitutes."},"n":null,"summary":"Unrestricted sociosexuality is not a stealth measure of 'women want richer men'.","mechanism":"Penke and Asendorpf (2008) gave the field a stable SOI-R. Pop-evo threads collapse that instrument into resource hypergamy or into Buss's youth-preference item. Different constructs, different questions, often opposite short-term vs insurance logics.","caveats":"Correlations between SOI and mate-preference items exist in some samples and are sex-differentiated. They do not identify a causal path from sociosexuality to hypergamy. The stamp is smoke so the collapse has a place to die.","confounders":["education","disposable-income","youth-fertility-preference"],"paperIds":["p-penke-2008","p-buss-1989"],"contributions":[{"paperId":"p-penke-2008","evidenceGrade":"abstract_only"},{"paperId":"p-buss-1989","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-supplements-employment","sourceId":"vitamin-supplementation","targetId":"employment-status","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Healthy-adherer smoke. Simpson: placebo adherers die less (OR 0.56, 21 studies). Shrank names the same selection for preventive pills. Simpson measured death, not jobs."},"n":null,"summary":"People who buy vitamins look more employed because they already differ in ways that keep jobs, not because the pill caused the job. Shrank (2011) named that healthy-user bias. Simpson (2006) measured the same selection as death, not employment: in 21 studies and 46,847 people, good adherence, including to placebo, had an odds ratio of 0.56 for mortality.","mechanism":"Shrank, Patrick, and Brookhart (2011) named the healthy-user and healthy-adherer biases. People who take one preventive therapy also take others. They exercise more, show up for screening, and fill other bottles. An observational study that treats the pill as the cause will credit the pill for those other traits. That is the healthy-user effect. The related bias is healthy adherer: people who keep taking a preventive pill look healthier than people who stop. Shrank's striking example is placebo. Patients who take their sugar pills die less than patients who do not. Shrank also notes that observational vitamin stories, including beta carotene and vitamin E, later failed in trials.\n\nSimpson, Eurich, Majumdar, and colleagues (2006) are that placebo example. They pooled 21 studies and 46,847 people. Eight studies had placebo arms (19,633 people). Good adherence versus poor adherence had an odds ratio of 0.56 for death (95% CI 0.50 to 0.63). Good adherence to placebo had the same odds ratio, 0.56 (0.43 to 0.74). Good adherence to a useful drug was 0.55 (0.49 to 0.62). Good adherence to a harmful drug raised death (odds ratio 2.90). The pill can still work. The selection is who takes it. Simpson measured mortality after heart attacks, in HIV care, in primary prevention, and in diabetes. He did not measure jobs.\n\nThe folk story on this pair is that vitamins make careers. That is the same selection, pointed at employment. Multivitamin buyers are selected on cash, education, and the habit of taking the bottle. Those traits keep people employed. Simpson is here as the mechanism of the smoke: adherers look healthier even when the pill is a placebo. He is not here as an employment finding.","caveats":"Simpson's outcome is death, not a job title and not a vitamin. The 21 studies cover post-infarct drugs, HIV regimens, primary-prevention aspirin and pravastatin, diabetes, statins, digoxin, and transplant immunosuppression. He is on this pair as the mechanism of the smoke: the same selection that makes adherers look healthy on placebo will make vitamin buyers look employed. He did not measure employment.\n\nThe meta-analysis is observational. Simpson could not adjust for diet, exercise, clinic follow-up, or depression with individual data. Placebo-arm results had more scatter than the useful-drug results. Most adherence measures were indirect. Pill counts and refills assume the bottle that left the pharmacy was swallowed.\n\nShrank is a primer, not a labor-market regression. Correcting a documented B12, iron, or D deficiency can restore function in deficient people. That is a medical effect on fatigue or cognition, not a career effect. This page does not speak to fish oil and jobs, to cash buying bottles, or to genetic vitamin D and employment. Those are other edges.","confounders":["disposable-income","education","social-capital"],"paperIds":["p-shrank-2011","p-pmid-16790458"],"contributions":[{"paperId":"p-shrank-2011","evidenceGrade":"abstract_only","designNote":"Primer on healthy-user and healthy-adherer bias in observational prevention studies. Names placebo-adherence mortality (Simpson) and vitamin observational claims later contradicted by trials. Review; abstract_only."},{"paperId":"p-pmid-16790458","evidenceGrade":"full_text","designNote":"Simpson 2006. Meta-analysis of 21 observational adherence studies, N=46847; 8 placebo arms N=19633. Outcome mortality, not employment. Good vs poor adherence OR 0.56 (0.50-0.63); placebo OR 0.56 (0.43-0.74); beneficial OR 0.55; harmful OR 2.90. full_text."}],"featured":true},{"id":"e-t-cv","sourceId":"testosterone","targetId":"cardiovascular","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.96,"note":"Lincoff 2023 TRAVERSE: HR 0.96 (0.78-1.17), 182 vs 190 events, N=5198. Noninferiority margin 1.5. Secondary +revasc HR 1.02 (0.86-1.21)."},"n":5198,"summary":"Lincoff 2023 found that daily testosterone gel was noninferior to placebo for a first major cardiac event among 5198 men aged 45 to 80 with hypogonadism and preexisting or high-risk cardiovascular disease (hazard ratio 0.96, 95% CI 0.78 to 1.17).","mechanism":"Lincoff, Bhasin, Flevaris and colleagues assigned 5246 men aged 45 to 80 with two fasting testosterone readings under 300 ng per deciliter, hypogonadal symptoms, and either established cardiovascular disease or three or more cardiac risk factors to daily 1.62 percent testosterone gel or matching placebo (TRAVERSE, NCT03518034). Dose was titrated to keep testosterone between 350 and 750 ng per deciliter. The primary safety end point was the first of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.\n\nThe safety population was 5198 men who received at least one dose. Mean treatment lasted 21.7 months. Mean follow-up lasted 33.0 months. A primary event occurred in 182 men on testosterone (7.0 percent) and 190 on placebo (7.3 percent). The hazard ratio was 0.96 (0.78 to 1.17). The trial called this noninferior if the upper 95 percent confidence limit sat below 1.5. That test passed (P<0.001). The secondary composite, which added coronary revascularization, was 269 (10.4 percent) versus 264 (10.1 percent), hazard ratio 1.02 (0.86 to 1.21). Each piece of the primary looked similar.\n\nThis page is a safety contrast, not a claim that raising testosterone prevents heart attacks. The authors set out to test whether replacement raised major events in men already at risk. It did not, within that bound. Atrial fibrillation, acute kidney injury, and pulmonary embolism were more common on gel. Those are not the primary count.\n\nN=5198 is from the paper. Evidence grade is","caveats":"TRAVERSE enrolled US men 45 to 80 with low morning testosterone twice and a high cardiac load. About 55 percent already had cardiovascular disease. Mean body-mass index was about 35. About 70 percent had diabetes. About 80 percent were White. This is not young men, not eugonadal men, and not a shot or a pellet. It is a daily gel.\n\nThe noninferiority margin of 1.5 is wide. A true 40 percent rise in events could still have passed. About 61 percent of both groups stopped the assigned gel. Mean time on treatment was under two years. Industry funded the trial. The paper is available here only as an abstract.\n\nAtrial fibrillation (3.5 percent versus 2.4 percent), acute kidney injury (2.3 percent versus 1.5 percent), and pulmonary embolism (0.9 percent versus 0.5 percent) were higher on testosterone. Those signals are not the MACE composite and do not flip this page to a claim that testosterone causes heart attacks.\n\nThis is a journal entry, not medical advice and not a reason to start or stop a gel.","confounders":["sleep-apnea","insulin-resistance","alcohol-intake","sedentary-time"],"paperIds":["p-pmid-37326322"],"contributions":[{"paperId":"p-pmid-37326322","evidenceGrade":"abstract_only","designNote":"Lincoff 2023 NEJM, TRAVERSE. Identifying RCT. 1.62% T gel vs placebo, 5198 men 45-80, T<300 twice, hypogonadal symptoms, CVD or high CV risk. Mean treat 21.7mo, follow-up 33.0mo. Primary MACE 182 (7.0%) vs 190 (7.3%), HR 0.96 (0.78-1.17), P<0.001 NI. Margin 1.5. AF/AKI/PE higher on T, not the sign. Archive n null; 5198 from paper. abstract_only."}],"featured":false},{"id":"e-t-risk","sourceId":"testosterone","targetId":"risk-tolerance","relation":"causal_direct","direction":"forward","polarity":"unknown","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Dreber N=1000: null on lottery risk and loss aversion. Zethraeus N=200 women: null on certainty equivalents. Smaller RCTs mixed or null. Stanton 2011: U-shaped endogenous T. Huang: positive personal-gamble slope."},"n":1000,"summary":"Large randomized trials do not show that a testosterone dose moves lottery risk. A preregistered study of 1,000 men found no effect of a single nasal dose. Four weeks of testosterone in 200 postmenopausal women also left risk attitudes unchanged.","mechanism":"The folk story is that testosterone raises status-seeking and reward drive, so people should take more financial risk. Dreber, Johannesson, Nave, Apicella and colleagues gave 1,000 men either 11 mg of nasal testosterone or placebo and, after 30 minutes, an adaptive 40-choice task of a lottery versus a certain payoff. They found no treatment effect on risk aversion or loss aversion, and no reliable link from basal saliva testosterone to those same measures. Zethraeus, Kocoska-Maras, Ellingsen and colleagues gave 200 postmenopausal women four weeks of testosterone, estrogen, or placebo, then asked for the certainty equivalent of a 50/50 gamble to win 400 kronor. Nothing moved. Stanton, Welker, Bonin, Goldfarb, and Carré ran two testosterone trials and one correlational study of economic risk and loss aversion and saw no consistent pattern. Nadler, Wibral, Dohmen and colleagues found the same null on economic risk-taking after a single dose in two experiments (91 and 242 men). Vartanian and colleagues restored testosterone during a 28-day energy deficit; risky choices about cash and lives did not change. The observational file is different. Stanton, Mullette-Gillman, McLaurin and colleagues saw a U-shape in 298 men and women: low or high endogenous testosterone went with risk-neutral certain-versus-gamble choices, mid-range testosterone with risk aversion. Huang, Zhang, and Zhuang saw higher basal testosterone track more play on a personal probabilistic gambling wheel in 69 men. The same slope appeared when winnings went to charity. Cortisol did not moderate that slope.","caveats":"Dreber studied only men aged 18 to 45, one dose, and one timing. A longer course, a different dose, or women could still differ. Zethraeus studied postmenopausal women; the 4-week oral course is not a nasal pulse. Huang is saliva and a wheel gamble, not Holt–Laury, and N is 69. Charitable risk is not this page; the personal arm is. Vartanian's sample is 50 men under severe energy deficit; the hormone was restorative. Lieberman's balloon task from the same trial had no money at stake and is not on this page. A methods paper on testosterone and ultimatum bargaining is not this page. Failed replications lower confidence. They do not change the design stamp. Seven papers do not make the stamp more certain.","confounders":["cortisol","disposable-income"],"paperIds":["p-pmid-40986339","p-pmid-19366676","p-pmid-34214918","p-pmid-39531812","p-pmid-36481265","p-pmid-21393575","p-pmid-42073930"],"contributions":[{"paperId":"p-pmid-40986339","evidenceGrade":"full_text","designNote":"Preregistered double-blind RCT, 1000 men (500/500), 11 mg intranasal T vs placebo. Adaptive 40-choice lottery vs certain payoff. Null on risk aversion and loss aversion (n=954 on that task). Do not copy Archive n:null. Full text PMC12501127."},{"paperId":"p-pmid-19366676","evidenceGrade":"full_text","designNote":"Double-blind RCT, 200 postmenopausal women aged 50-65, 4 weeks testosterone undecanoate 40 mg/day vs estradiol 2 mg vs placebo. Certainty equivalent of a 50/50 SEK 400 gamble plus two hypothetical risk items. Null on all. Do not copy Archive n:null. Full text PMC2666090."},{"paperId":"p-pmid-34214918","evidenceGrade":"abstract_only","designNote":"Three studies: within-subjects RCT N=26 and between-subjects RCT N=117 on loss aversion and risk-taking; correlational N=213. Abstract reports no consistent T-finance link. Abstract_only. Infer RCT for studies 1-2; do not copy Archive n:null."},{"paperId":"p-pmid-39531812","evidenceGrade":"abstract_only","designNote":"Two independent double-blind RCTs of a single T dose on men's compete, confidence, and risk-taking in economic tasks (N=91 and N=242). Weak effects indistinguishable from zero. Abstract_only. Infer RCT; do not copy Archive n:null."},{"paperId":"p-pmid-36481265","evidenceGrade":"abstract_only","designNote":"Double-blind RCT, 50 men, 200 mg T enanthate weekly during 28-day energy deficit. fMRI risky choice for cash and lives, gains vs losses. T did not change choice; increased sensitivity to negative feedback after risky choices. Abstract_only. Infer RCT."},{"paperId":"p-pmid-21393575","evidenceGrade":"full_text","designNote":"Observational. N=298 (142 men, 156 women). Incentive-compatible certain-vs-gamble risk and ambiguity, plus loss aversion. U-shaped endogenous T with risk and ambiguity; no loss-aversion link. Full text. Do not copy Archive n:null."},{"paperId":"p-pmid-42073930","evidenceGrade":"full_text","designNote":"Observational leftover. 74 men recruited, 69 valid, ages 17-29. Adapted probabilistic gambling wheel, personal and charity beneficiaries. Hang the personal arm. Positive T slope on personal risk; cortisol suppressed charity risk; dual-hormone interaction not supported. Full text PMC13113937. Do not copy Archive n:null."}],"featured":true},{"id":"e-t-status-dual","sourceId":"testosterone","targetId":"status-seeking","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"observational","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Interaction: T tracks status-seeking mainly when cortisol is low; opponent status and gain/loss cues split the effect."},"n":null,"summary":"In observational samples, testosterone tracks status-seeking mainly when cortisol is low; the interaction is small, heterogeneous, and still contested.","mechanism":"Mehta and Josephs (2010) found that basal testosterone related to dominant leadership and to re-entering a contest only when cortisol was low. High cortisol flattened or reversed the slope. They proposed HPG-HPA crosstalk: glucocorticoids dampen androgen signaling and tilt the animal toward withdrawal under threat. Elahi and Knight (2026) separated opponent status from potential gains and losses in a status contest. Their abstract says testosterone raised sensitivity to opponent status and lowered sensitivity to gains and losses. Cortisol moderated that status-sensitivity effect and separately raised reward sensitivity. The model they test says testosterone raises status-seeking when cortisol is low, and status-loss avoidance when cortisol is high. They also report nonlinear testosterone effects using machine learning. We have the PubMed abstract only; sample size is not listed there. The Geniole meta still finds a small, mixed, publication-bias-sensitive effect.","caveats":"Not an RCT of testosterone. Elahi and Knight (2026) is abstract-only, and PubMed does not report N. The Geniole meta finds a small, heterogeneous effect with publication-bias risk. A lab contest is not organizational power. Labeling this causal_direct is generous: it is the best causal story in the file, not a settled identification. Another observational dual-hormone paper does not settle the interaction.","confounders":["cortisol","contest-outcome","formal-power"],"paperIds":["p-mehta-josephs-2010","p-mehta-prasad-2015","p-geniole-2020","p-pmid-42259165"],"contributions":[{"paperId":"p-mehta-josephs-2010","evidenceGrade":"abstract_only"},{"paperId":"p-mehta-prasad-2015","evidenceGrade":"abstract_only"},{"paperId":"p-geniole-2020","evidenceGrade":"abstract_only"},{"paperId":"p-pmid-42259165","evidenceGrade":"abstract_only","designNote":"Observational status-competition test. Abstract only; N not in PubMed."}],"featured":true},{"id":"e-t-status-feedback","sourceId":"testosterone","targetId":"contest-outcome","relation":"feedback","direction":"forward","polarity":"positive","methodology":"longitudinal","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Basal T weakly predicts contest entry; the sharper arrow is T change after the result."},"n":null,"summary":"The other half of the loop: higher T states make another challenge more likely. Evidence is thinner than the win→T half.","mechanism":"If T is a status-seeking hormone, people in a high-T state should pick fights they can win. Human evidence for this direction is mixed and context-bound. Do not draw it as thick as the winner effect.","caveats":"Selection: people who enter contests already differ. Identification of this direction needs panel designs or exogenous T, not a single saliva kit.","confounders":["status-seeking","formal-power"],"paperIds":["p-mazur-booth-1998","p-carre-olmstead-2015"],"contributions":[{"paperId":"p-mazur-booth-1998","evidenceGrade":"abstract_only"},{"paperId":"p-carre-olmstead-2015","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-t-ultimatum-rct","sourceId":"testosterone","targetId":"ultimatum-rejection","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"percent_change","value":null,"note":"Eisenegger: T increased fair offers in women. Zak: T decreased male generosity. Cueva: null on male rejections."},"n":121,"summary":"Exogenous T changes bargaining — but not in the folk direction, and not in every lab.","mechanism":"The brief's 'Camerer et al.' pointer is a misattribution. The Nature RCT is Eisenegger, Naef, Snozzi, Heinrichs, and Fehr (2010): T made women's proposals *fairer*. Belief that one got T made them *less* fair. Zak (2009) found less male generosity. Cueva et al. (2017) found no rejection-rate effect in men. The identified claim is 'T is not the aggression potion'; the signed effect on rejection is not settled.","caveats":"Different sexes, doses, timings, and roles (proposer vs responder). A 2020s reader should present the disagreement, not pick a camp. Camerer is a reproducibility author, not the T-ultimatum experimenter.","confounders":[],"paperIds":["p-eisenegger-2010","p-zak-2009","p-cueva-2017"],"contributions":[{"paperId":"p-eisenegger-2010","evidenceGrade":"abstract_only"},{"paperId":"p-zak-2009","evidenceGrade":"abstract_only"},{"paperId":"p-cueva-2017","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-tart-cherry-sleep","sourceId":"tart-cherry","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Losso 2018: 240 mL BID, 2 wk, N=8, PSG TST +84 min. Howatson 2013: N=20, 7 d, TST/efficiency up. Pigeon 2010: N=15, WASO only vs placebo. Hillman: N=44, 30 d, sleep null."},"n":8,"summary":"Losso 2018 found that 240 mL of Montmorency tart cherry juice twice a day for two weeks added 84 minutes of laboratory sleep time versus placebo in eight adults over 50 with insomnia. Howatson 2013 saw a similar direction in twenty healthy adults; Hillman found no sleep difference in forty-four healthy adults over thirty days.","mechanism":"Authors treat tart cherry juice as a source of melatonin and of procyanidins that spare tryptophan. They do not isolate one molecule.\n\nLosso, Finley, Karki and colleagues crossed eight completers older than 50 with insomnia through two weeks of juice (240 mL twice a day) and two weeks of placebo, with a two-week washout. Eleven were randomized; three with apnea were referred out. Laboratory sleep time rose 84 minutes (P=0.0182). Pittsburgh sleep efficiency improved (P=0.03). Other questionnaires did not.\n\nHowatson, Bell, Tallent and colleagues crossed twenty healthy adults through seven days of concentrate and placebo. Urinary melatonin rose. Time in bed, total sleep time, and sleep efficiency rose (P<0.05). The abstract does not publish the minute counts.\n\nPigeon, Carr, Gorman and Perlis crossed fifteen older adults with chronic insomnia through two weeks of a proprietary blend and placebo. Versus placebo, wake after sleep onset and insomnia severity fell. Latency, total sleep time, and efficiency did not beat placebo.\n\nHillman, Trickett, Brodsky and Chrismas assigned forty-four healthy adults to juice or powder or placebo for thirty days. Sleep time and quality did not differ.","caveats":"Researchers assigned people to a juice or a control, so this is a trial stamp. The files are small. More papers of the same design do not settle the claim.\n\nLosso is eight completers and two weeks. Pigeon is fifteen people and a branded blend; most diary contrasts missed versus placebo. Howatson is seven days in healthy adults without a published minute increment. Hillman is the largest file here and is null in healthy people.\n\nThis is a journal entry, not medical advice and not a reason to drink cherry juice for insomnia.","confounders":["caffeine","alcohol-intake","light-exposure"],"paperIds":["p-pmid-28901958","p-pmid-22038497","p-pmid-20438325","p-pmid-35790450"],"contributions":[{"paperId":"p-pmid-28901958","evidenceGrade":"full_text","designNote":"Losso 2018 Am J Ther. Crossover RCT. Juice 240 mL BID vs placebo, 2 wk, washout 2 wk. 11 randomized, 3 apnea excluded, N=8 completers >50 insomnia. PSG TST +84 min P=0.0182. PSQI efficiency P=0.03. Other questionnaires ns. full_text. Archive n null."},{"paperId":"p-pmid-22038497","evidenceGrade":"abstract_only","designNote":"Howatson 2013 Eur J Nutr. Crossover RCT. Concentrate vs placebo, 7 d, N=20 healthy. Urinary melatonin up. TIB, TST, efficiency P<0.05. No minute counts in abstract. abstract_only. Archive n null."},{"paperId":"p-pmid-20438325","evidenceGrade":"full_text","designNote":"Pigeon 2010 J Med Food. Crossover RCT. Proprietary blend vs placebo, 2 wk, N=15 older chronic insomnia. vs placebo: WASO and ISI down. Latency, TST, efficiency ns. Modest. full_text. Archive n null."},{"paperId":"p-pmid-35790450","evidenceGrade":"abstract_only","designNote":"Hillman Nutr Health. Parallel RCT. Juice or powder vs placebo, 30 d, N=44 healthy with sleep records. Sleep time and quality ns. Archive year 2026 is the record; DOI is 2022. abstract_only. Archive n null."}],"featured":false},{"id":"e-theanine-cognition","sourceId":"l-theanine","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Kahathuduwa 2018: 200 mg alone, N=20, RVRT P=0.019. Dassanayake 2023: N=32, simple RT only. Dodd 2016: 50 mg alone null. Haskell 2008: 250 mg alone serial sevens down. Combo files move attention."},"n":32,"summary":"Kahathuduwa 2018 found that 200 mg of L-theanine alone sped recognition visual reaction time versus placebo in 20 healthy men. Dassanayake 2023 saw a similar simple-reaction win in 32 young adults and no win on harder attention tasks. Tea-dose theanine alone has often missed.","mechanism":"Authors treat L-theanine as a quiet attention amino acid. Many files also assign caffeine.\n\nKahathuduwa, Dassanayake, Amarakoon and Weerasinghe crossed 20 men through 200 mg theanine, 160 mg caffeine, both, tea, and water. Theanine alone improved recognition reaction time (P=0.019). The combination was larger.\n\nDassanayake, Kahathuduwa and Weerasinghe crossed 32 young adults through 100, 200, and 400 mg and water. After placebo adjustment, only simple reaction time moved at 100 and 200 mg. Sustained attention and stop-signal did not.\n\nDodd, Kennedy, Riby and Haskell-Ramsay crossed 24 people through 50 mg theanine, 75 mg caffeine, both, and placebo. Theanine alone did not change behavior. The combination erased caffeine's attention and mood effects.\n\nHaskell, Kennedy, Milne, Wesnes and Scholey found that 250 mg theanine alone raised headache ratings and lowered serial-seven accuracy. Caffeine and the combination helped other tasks.\n\nGiesbrecht 2011 (n=44) and Einother 2010 found that 97 mg theanine plus 40 mg caffeine improved switch-task accuracy versus placebo.","caveats":"Researchers assigned people to a dose or a control, so this is a trial stamp. Theanine alone and theanine-plus-caffeine are not the same drink. More papers of the same design do not settle the claim.\n\nHigh-dose theanine can move a simple reaction task. Tea-ratio theanine alone has often been null. Haskell's 250 mg arm moved serial sevens the wrong way.\n\nThis is a journal entry, not medical advice and not a reason to take theanine for focus.","confounders":["caffeine","sleep-hygiene","green-tea"],"paperIds":["p-pmid-26869148","p-pmid-36263942","p-pmid-25761837","p-pmid-18006208","p-pmid-21040626","p-pmid-20079786"],"contributions":[{"paperId":"p-pmid-26869148","evidenceGrade":"abstract_only","designNote":"Kahathuduwa 2018 Nutr Neurosci. 5-way crossover. 200 mg theanine, 160 mg caffeine, both, tea, water. N=20 men. Theanine alone RVRT P=0.019. Combo P=0.001. abstract_only. Archive n null."},{"paperId":"p-pmid-36263942","evidenceGrade":"abstract_only","designNote":"Dassanayake 2023 Nutr Neurosci. 4-way crossover. 100/200/400 mg vs water, N=32. Placebo-adjusted simple RT at 100 and 200 mg. RVP and SST ns. abstract_only. Archive n null."},{"paperId":"p-pmid-25761837","evidenceGrade":"full_text","designNote":"Dodd 2016 Psychopharmacology. 4-way crossover. 50 mg theanine, 75 mg caffeine, both, placebo. N=24. Theanine alone ns. Combo erased caffeine cognition/mood. full_text. Archive n null."},{"paperId":"p-pmid-18006208","evidenceGrade":"abstract_only","designNote":"Haskell 2008 Biol Psychol. Crossover. 250 mg theanine, 150 mg caffeine, both, placebo. Theanine alone: headache up, serial sevens down. Caffeine/combo helped other tasks. abstract_only. Archive n null."},{"paperId":"p-pmid-21040626","evidenceGrade":"abstract_only","designNote":"Giesbrecht 2011 Nutr Neurosci. 97 mg theanine + 40 mg caffeine vs placebo. N=44. Switch accuracy and alertness P<0.01. Visual search/CRT/rotation ns. Combo. abstract_only. Archive n null."},{"paperId":"p-pmid-20079786","evidenceGrade":"abstract_only","designNote":"Einother 2010 Appetite. Crossover. 97 mg theanine + 40 mg caffeine vs placebo. Switch attention vs placebo. Alertness and intersensory attention ns. Combo. abstract_only. Archive n null."}],"featured":false},{"id":"e-training-depression","sourceId":"resistance-training","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"cohens_d","value":1.01,"note":"O'Sullivan 2023: Hedges' d 1.01 [0.44-1.57] QIDS vs wait-list at week 8 (n=55). AMDD d=1.71; ITT d=0.88. Strength change uncorrelated (r=-0.12)."},"n":55,"summary":"Eight weeks of twice-weekly supervised resistance training lowered QIDS scores versus wait-list in 55 young adults. Depression was a secondary read of two anxiety-primary randomized trials.","mechanism":"The assigned work is WHO and ACSM muscle-strengthening: two sets of eight to twelve repetitions, eight lifts, twice a week, about twenty-five minutes, load set by the investigator. Sessions were one-on-one in a university gym. A three-week familiarization came first.\n\nO'Sullivan, Gordon, Lyons, Meyer, and Herring pooled two parallel wait-list trials (NCT04116944). The primary files measured analogue GAD. This paper reads the 16-item self-report Quick Inventory of Depressive Symptomatology at baseline, week one, week four, and week eight.\n\nQIDS fell from 8.7 to 2.8 under training and from 8.0 to 7.0 on the wait-list. The between-group Hedges' d at week eight was 1.01 (95 percent CI 0.44 to 1.57). The analogue-MDD slice (QIDS of 6 or more) was 1.71. Intention-to-treat was 0.88. Total strength rose about 23 percent. That change did not move with mood (r = -0.12).\n\nThe authors list monoamines, the stress response, inflammation, and IGF-1 as candidate pathways. They also say a wait-list cannot hold attention, social contact, mastery, or expectancy still. A first drop was already visible after familiarization.\n\nAmong people who started at or above the analogue-MDD cut, 18 of 19 on training were below it at week eight, against 4 of 18 on wait-list. That is a QIDS threshold, not a structured interview.","caveats":"The control is a wait-list. People on the list filled weekly surveys and were offered the program later. They did not get a matched hour of attention. The authors name social interaction, mastery, and expectation as leftover explanations. SMILE II's placebo pill is a different contrast, and it lives on the aerobic edge.\n\nThis is a secondary analysis. Participants were screened for analogue GAD, not recruited for depression. Ten people were already on depression treatment. Four finished, two in each arm. People missing more than one QIDS were dropped from the complete-case file; intention-to-treat kept the same direction.\n\nThe sample is 55 people, mean age 26, 36 women, a university gym. Baseline QIDS sat in the mild range for the full sample. Analogue MDD here means a QIDS of 6 or more. The depression node can carry a named scale. It is not SMILE's DSM-IV interview.\n\nThere was no follow-up after week eight. The outcome is self-report. Attendance was 83 percent. Compliance was 80 percent.\n\nOmitted: Blumenthal SMILE, Babyak, SMILE II, Brush 2022, and Yu 2023. Those assigned walking or jogging. They sit on aerobic exercise to depression.\n\nThis page is a journal entry. It is not medical advice and it is not a reason to start or stop a treatment.","confounders":["sleep-hygiene","disposable-income"],"paperIds":["p-pmid-37429171"],"contributions":[{"paperId":"p-pmid-37429171","evidenceGrade":"full_text","designNote":"O'Sullivan 2023. Secondary analysis of two parallel 8-week wait-list RCTs (NCT04116944; primary: analogue GAD). 55 young adults (26±5y; 36 female), 26 RET vs 29 wait-list. WHO/ACSM RET, 2×/wk, ~25 min, one-on-one, after 3-week familiarization. QIDS-16. Group×time d=1.01 [0.44-1.57]; AMDD d=1.71; ITT d=0.88. Strength Δ uncorrelated. full_text. Identifying for the pair."}],"featured":false},{"id":"e-training-insulin","sourceId":"resistance-training","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"negative","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Waters 2022: REX+diet Matsuda ISI +1.0 (39%), COMB +1.9 (86%), N=160, 6 months. Ho 2013: no significant drop in fasting glucose or insulin at 12 weeks."},"n":160,"summary":"Waters 2022 randomized 160 older adults with obesity and found that resistance training during matched diet-induced weight loss of about 9 to 10 percent raised the OGTT insulin sensitivity index 39 percent; combination training raised it 86 percent.","mechanism":"Waters, Aguirre, Gurney, and colleagues randomized 160 sedentary adults aged 65 and older with obesity and mild-to-moderate frailty in Albuquerque. Forty people each went to control, aerobic plus diet, resistance plus diet, or both plus diet. Twenty-six weeks. The three exercise arms sat in the same weekly counseling and a 500 to 750 kcal daily deficit, aiming for about 10 percent weight loss. They trained three times a week for 60 to 90 minutes. Control got neither the diet nor the exercise.\n\nInsulin sensitivity was the Matsuda index from a 75-gram oral glucose tolerance test, done at least 48 hours after the last session. It is not HOMA-IR. Resistance plus diet raised the index by 1.0, a 39 percent rise from a baseline of 2.6. Aerobic plus diet raised it by 1.2, about 50 percent. Combination raised it by 1.9, 86 percent. Combination beat resistance-only. Resistance and aerobic did not differ from each other. Fasting glucose, two-hour glucose, and the glucose and insulin areas under the curve improved versus control in every exercise arm and did not differ among those arms.\n\nThigh intermuscular fat and abdominal visceral fat fell more with combination than with resistance alone. Those drops tracked the rise in the sensitivity index. The authors treat less fat sitting in and around muscle as the path to better insulin action.\n\nHo, Dhaliwal, Hills, and Pal randomized 64 overweight or obese adults to 12 weeks of moderate-intensity aerobic, resistance, or combination work, 30 minutes, five days a week, or a placebo-supplement control. They measured fasting glucose, insulin, and HOMA2-IR. They did not find a significant reduction in fasting glucose or insulin. Combination lost 1.6 percent of weight versus control. That is a shorter, lighter program and a fasting assay, not Waters' OGTT.","caveats":"Waters is a secondary analysis of LITOE (NCT01065636). Mean age 70. Older adults with obesity and frailty, not a general gym sample. Control did not diet. There is no weight-loss-only arm. The authors skipped it because diet without exercise had already been shown to cost bone and muscle. All three exercise arms lost about 9 percent of body weight. Combination beat resistance-only on the sensitivity index. The node on this atlas is labeled HOMA-IR; Waters used the Matsuda index from an OGTT.\n\nHo is 12 weeks at moderate intensity. Sixteen people in the resistance arm. Fasting insulin and glucose did not move. Session attendance was 67 to 74 percent.\n\nThis page is not a training prescription.","confounders":["ultraprocessed-food","sleep-hygiene"],"paperIds":["p-pmid-33839788","p-pmid-23006411"],"contributions":[{"paperId":"p-pmid-33839788","evidenceGrade":"full_text","designNote":"Waters 2022 RCT. N=160 (40 per arm). AEX vs REX vs COMB vs no-diet control, 26 weeks, matched ~9-10% weight loss. Matsuda ISI from 75-g OGTT. REX ISI +1.0 (39%); COMB +1.9 (86%); COMB vs REX p=.004. Archive n:null; N=160 from abstract. full_text."},{"paperId":"p-pmid-23006411","evidenceGrade":"full_text","designNote":"Ho 2013 RCT. Control 16, aerobic 15, resistance 16, combination 17. 12 weeks, 30 min, 5 days/week. Fasting glucose, insulin, HOMA2-IR. No significant reduction in fasting glucose or insulin. Archive n:null; N=64 from abstract arm sizes. full_text."}],"featured":false},{"id":"e-training-testosterone","sourceId":"resistance-training","targetId":"testosterone","relation":"causal_direct","direction":"forward","polarity":"non_linear","methodology":"observational","confidence":"low","effect":{"metric":"qualitative","value":null,"note":"Ahtiainen 2016: a 5×10RM session can raise serum T by lowering clearance; twelve months of training left production and clearance unchanged (5 younger, 8 older men)."},"n":13,"summary":"Ahtiainen 2016: twelve months of resistance training left testosterone production and clearance unchanged in five men near 28 and eight men near 70; a 5×10RM session could raise serum T by slowing clearance.","mechanism":"Ahtiainen, Nyman, Huhtaniemi, and colleagues trained five men aged about 28 and eight men aged about 70 for twelve months. Before and after that year they put each man through a 5×10RM leg-press session and measured testosterone production and metabolic clearance with a stable-isotope dilution method, plus muscle androgen receptors and serum LH.\n\nA session could raise serum testosterone. The authors traced that rise to a drop in clearance, not a rise in production. After twelve months, production, clearance, receptors, and LH had not moved. Older men already made less testosterone under gonadotropin stimulation and excreted less androsterone and etiocholanolone in urine. The year of lifting did not close that gap. Testosterone metabolism stayed stable in both age groups.\n\nLeproult and Van Cauter restricted sleep for one week in ten young men and cut daytime testosterone by 10 to 15 percent. That paper is not a resistance-training trial. Sleep still sits behind observational plots that treat lifting as a testosterone protocol.","caveats":"Ahtiainen is five younger men and eight older men. Men only. A year of lifting left testosterone production and clearance where they were. A session-day rise from slower clearance is not a higher resting level.\n\nLeproult 2011 restricted sleep in ten young men for one week. It is not a resistance-training trial. Sleep, and who can keep a year of training, still sit behind observational plots that treat lifting as a testosterone protocol.","confounders":["sleep-hygiene","disposable-income"],"paperIds":["p-leproult-2011","p-pmid-26079649"],"contributions":[{"paperId":"p-leproult-2011","evidenceGrade":"abstract_only","designNote":"Sleep-restriction RCT, N=10 young men, JAMA 2011. One week of 5-hour nights cut daytime T 10–15%. Keep p-leproult-2011. Not a training RCT. Copy previous.methodology observational. Stamp stays causal_direct. abstract_only."},{"paperId":"p-pmid-26079649","evidenceGrade":"abstract_only","designNote":"Archive methodology rct. Younger n=5 (28±3 y), older n=8 (70±2 y). 5×10RM leg presses before and after 12-month RT. Stable-isotope T production and clearance; no chronic change in T metabolism. Acute serum T rise via decreased clearance. Archive n:null; N=13 from abstract. abstract_only."}],"featured":false},{"id":"e-tre-insulin","sourceId":"eating-window","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Sutton 2019: early 6-h vs 12-h, weight-stable; insulin AUC ratio -36% (p=0.005). Later RCTs mixed by clock time and calories."},"n":8,"summary":"In eight men with prediabetes, a supervised 6-hour early eating window improved insulin sensitivity without weight loss; later RCTs show the effect depends on clock time and calories.","mechanism":"Insulin sensitivity and beta-cell response run higher in the morning than in the evening. Sutton's group treated that as a reason to finish dinner before 3pm and stretch the overnight fast, then matched food and held weight so the window could not smuggle a calorie deficit. Mean insulin during a 3-hour OGTT fell 26 mU/l. The incremental AUC ratio, their insulin-resistance index, fell 36 percent. Morning glucose did not move.\n\nXie compared two 8-hour windows in people without obesity. Early (6am to 3pm) lowered HOMA-IR. Mid-day (11am to 8pm) did not, even though both arms cut calories. That is a clock effect, not a fasting-hours effect.\n\nWhen calories are the comparison, the window often adds nothing. Liu's year-long 8am-to-4pm TRE plus calorie restriction moved HOMA-IR about as much as calorie restriction alone. Maruthur's isocaloric 10-hour window, with most calories before 1pm, did not beat a usual eating pattern on HOMA-IR or OGTT glucose. Lowe's noon-to-8pm 16:8, a late window with no calorie target, left fasting insulin, HOMA-IR, and HbA1c unchanged against three structured meals.\n\nManoogian's TIMET trial in metabolic syndrome found a 0.10 percent HbA1c edge for an 8-to-10-hour personalized window on top of counseling. Fasting insulin and HOMA-IR estimates included the null. Isolated TRE in Haganes did not move OGTT glucose AUC. The HbA1c change sat on TRE plus interval training.","caveats":"Sutton enrolled eight men and did not match the pre-test fast (about 18 hours on eTRF versus 12 hours on control). An acute fast can worsen insulin sensitivity, so the improvement may be conservative. The sample is small and male. Sequence effects after washout were real for insulin.\n\nLowe's metabolic labs were an in-person subset of 50. Liu is available here only as an abstract. HOMA-IR at 12 months differed by -0.5 (CI -1.4 to 0.4) between TRE plus calorie restriction and calorie restriction alone. Maruthur is available here only as an abstract, 41 people, 93 percent women, 93 percent Black, 12 weeks. Wilkinson is a 19-person single-arm pilot. HOMA-IR p=0.107.\n\nThis edge is insulin resistance. Weight, blood pressure, and lipids are not this page. Eating dinner at 1pm is not a job and not a protocol.","confounders":["sleep-hygiene","ultraprocessed-food","resistance-training"],"paperIds":["p-pmid-29754952","p-pmid-35194047","p-pmid-32986097","p-pmid-35443107","p-pmid-38639542","p-pmid-39348690","p-pmid-36198292","p-pmid-31813824"],"contributions":[{"paperId":"p-pmid-29754952","evidenceGrade":"full_text","designNote":"Sutton 2019. Randomized crossover supervised feeding. 8 men with prediabetes. 5 weeks eTRF (6-h, dinner before 3pm) vs 12-h, meals and calories matched, weight stable. Incremental AUC ratio -36% (p=0.005); mean insulin -26 mU/l (p=0.01). Archive tagged observational; the trial randomized the window. full_text."},{"paperId":"p-pmid-35194047","evidenceGrade":"full_text","designNote":"Xie 2022. Parallel RCT, 90 healthy adults without obesity, 82 completers. 5 weeks eTRF (6am-3pm) vs mTRF (11am-8pm) vs control. Primary: insulin resistance. eTRF HOMA-IR -1.08 vs mTRF +0.39 vs control -0.05. Both TRE arms cut calories; only eTRF beat control. full_text."},{"paperId":"p-pmid-32986097","evidenceGrade":"full_text","designNote":"Lowe 2021, TREAT. RCT, 116 adults BMI 27-43, 12 weeks. TRE noon-8pm vs 3 structured meals. In-person subset n=50: no within- or between-group change in fasting insulin, glucose, HOMA-IR, or HbA1c. Late 16:8, no calorie target. full_text."},{"paperId":"p-pmid-35443107","evidenceGrade":"abstract_only","designNote":"Liu 2022. RCT, 139 adults with obesity, 12 months. 8am-4pm TRE plus calorie restriction vs calorie restriction alone. HOMA-IR 12-month between-group -0.5 (CI -1.4 to 0.4). TRE added nothing beyond CR on insulin resistance. abstract_only."},{"paperId":"p-pmid-38639542","evidenceGrade":"abstract_only","designNote":"Maruthur 2024. RCT, 41 adults with obesity and prediabetes or diet-controlled diabetes (93% women, 93% Black). 12 weeks isocaloric TRE (10-h, 80% of calories before 1pm) vs usual eating pattern. Weight and glycemic measures, including HOMA-IR and OGTT AUC, did not differ. abstract_only."},{"paperId":"p-pmid-39348690","evidenceGrade":"full_text","designNote":"Manoogian 2024, TIMET. RCT, 108 completers with metabolic syndrome. 3 months personalized 8-10h TRE plus counseling vs counseling. HbA1c -0.10% (CI -0.19 to -0.003). Fasting insulin and HOMA-IR favored TRE but included the null. Window ended about 7pm. full_text."},{"paperId":"p-pmid-36198292","evidenceGrade":"abstract_only","designNote":"Haganes 2022. Four-arm RCT, 131 women with overweight/obesity, 7 weeks. Isolated TRE (10h or less) did not move OGTT glucose AUC vs control (-26.3 mmol/L, CI -82.3 to 29.7). HbA1c improved on TRE plus HIIT, not attributable to the window alone. abstract_only."},{"paperId":"p-pmid-31813824","evidenceGrade":"full_text","designNote":"Wilkinson 2021. Single-arm, 19 adults with metabolic syndrome, 12 weeks self-selected 10-h TRE. Fasting insulin -3.6 mIU/mL (p=0.064); HOMA-IR -1.54 (p=0.107). Insulin and glucose were reported; they did not reach significance. Observational pilot. full_text."}],"featured":false},{"id":"e-upf-insulin","sourceId":"ultraprocessed-food","targetId":"insulin-resistance","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Hall 2019 (N=20) and Hamano 2024 (N=9): ad-lib UPF raised intake and weight vs matched menus. Chen 2023: observational UPF-T2D, not HOMA-IR."},"n":20,"summary":"In Hall's ward trial and Hamano's Tokyo crossover, ultra-processed menus matched for presented calories raised ad-lib intake and weight; Chen's US cohorts associate the same food class with later type 2 diabetes, not with measured HOMA-IR.","mechanism":"Hall and colleagues randomized twenty adults to ultra-processed versus unprocessed menus matched on presented calories and macros. People ate more on the ultra-processed diet and gained weight. Energy surplus and adiposity then move HOMA-IR. The identified object is intake, not a direct hormone spell.\n\nHamano, Sawada, Aihara and colleagues ran a one-week open-label crossover in nine overweight Japanese men at the University of Tokyo Hospital. Meals were matched for energy and macros. On the ultra-processed week the men gained 1.1 kg more and ate 813 more kilocalories a day. They chewed less per calorie. That is a second experimental handle on intake and weight. It does not measure HOMA-IR.\n\nChen, Khandpur, Desjardins and colleagues followed the Nurses' Health Study, Nurses' Health Study II, and the Health Professionals Follow-Up Study. Diet came from food-frequency questionnaires coded with NOVA. The outcome was incident type 2 diabetes. Comparing the highest and lowest quintiles of ultra-processed intake, the hazard ratio was 1.46. The same paper's meta-analysis of prospective cohorts found about 12 percent higher diabetes risk for each 10 percent more ultra-processed food by weight. Some subgroups went the other way, including whole-grain breads and yogurt desserts. Those papers do not measure HOMA-IR and they do not identify insulin resistance.","caveats":"Hall is twenty adults, two inpatient weeks. Hamano is nine men, one week per arm, open-label, and they excluded diabetes. Neither trial measured HOMA-IR. Do not export this to \"ultra-processed food causes unemployment.\" Income still sits on who can avoid these foods.\n\nChen is a food-frequency cohort picture of later diabetes. Residual confounding remains. Type 2 diabetes is not HOMA-IR. Some ultra-processed subgroups were associated with lower diabetes risk.","confounders":["disposable-income"],"paperIds":["p-hall-2019","p-pmid-39267249","p-pmid-36854188"],"contributions":[{"paperId":"p-hall-2019","evidenceGrade":"abstract_only","designNote":"Identifying inpatient RCT. Ad-lib UPF vs unprocessed, N=20. Intake and weight; HOMA-IR is the surplus path, not the measured object. Keep p-hall-2019. Do not mint a second Hall id. abstract_only."},{"paperId":"p-pmid-39267249","evidenceGrade":"abstract_only","designNote":"RCT, randomized open-label crossover. 9 overweight Japanese men completed 1 week UPF vs non-UPF, 2-week washout. Weight +1.1 kg (0.2 to 2.0); +813.5 kcal/day. Chews per calorie lower. abstract_only. Do not copy Archive n:null; N=9 is in the abstract. Not a HOMA-IR assay."},{"paperId":"p-pmid-36854188","evidenceGrade":"full_text","designNote":"Observational. NHS, NHS II, HPFS plus cohort meta. Outcome is incident T2D, not HOMA-IR. HR 1.46 extreme quintiles. full_text. Does not identify this node. Do not copy n:null. Do not raise stamp."}],"featured":false},{"id":"e-valerian-sleep","sourceId":"valerian","targetId":"sleep-hygiene","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Taavoni 2011: 530 mg BID, 4 wk, N=100, 30% vs 4% PSQI improved. Chandra Shekhar 2024: N=80/72, PSQI and actigraphy moved. Donath 2000: N=16, single dose null; 14-d SWS latency 13.5 vs 21.3."},"n":100,"summary":"Taavoni 2011 found that 530 mg of valerian extract twice a day for four weeks raised the share of postmenopausal women whose Pittsburgh Sleep Quality Index improved to 30 percent versus 4 percent on placebo (n=100). Chandra Shekhar 2024 found a similar PSQI and actigraphy direction in 72 completers. Donath 2000's sixteen-person polysomnography was thinner.","mechanism":"Authors treat a valerian root extract as a mild sleep aid. They do not isolate one receptor.\n\nTaavoni, Ekbatani, Kashaniyan and Haghani (2011) assigned 100 postmenopausal women aged 50 to 60 with insomnia to 530 mg of concentrated valerian or placebo twice a day for four weeks. Sleep quality changed versus placebo (P<0.001). Thirty percent versus 4 percent were classed as improved.\n\nChandra Shekhar, Joshua and Thomas (2024) assigned 80 adults with sleep complaints to a standardized V. officinalis extract or placebo for eight weeks. 72 finished. PSQI total fell versus placebo on days 14, 28, and 56. Wrist actigraphy improved sleep latency and actual sleep time on days 3, 14, 28, and 56, and efficiency from day 14. The abstract does not publish the minute counts.\n\nDonath, Quispe, Diefenbach, Maurer, Fietze and Roots (2000) crossed 16 people with psychophysiological insomnia through single-dose and 14-day valerian and placebo, with eight polysomnography nights. A single dose did nothing. After 14 days, sleep efficiency rose versus baseline on both arms. Slow-wave sleep latency was 13.5 versus 21.3 minutes (P<0.05).","caveats":"Researchers assigned people to a root extract or a control, so this is a trial stamp. The larger files are questionnaires. More papers of the same design do not settle the claim.\n\nTaavoni is menopause and a Pittsburgh score, not a lab night. Chandra Shekhar is a branded extract. Donath is sixteen people: efficiency rose on placebo too, and a single dose was null.\n\nThis is a journal entry, not medical advice and not a reason to take a root for insomnia.","confounders":["caffeine","alcohol-intake","light-exposure"],"paperIds":["p-pmid-21775910","p-pmid-37899385","p-pmid-10761819"],"contributions":[{"paperId":"p-pmid-21775910","evidenceGrade":"abstract_only","designNote":"Taavoni 2011 Menopause. RCT. Valerian 530 mg BID vs placebo, 4 wk, N=100 postmenopausal insomnia 50-60. PSQI improved vs placebo P<0.001. 30% vs 4% classed improved. abstract_only. Archive n null."},{"paperId":"p-pmid-37899385","evidenceGrade":"full_text","designNote":"Chandra Shekhar 2024 Adv Ther. RCT. Standardized VE vs placebo, 8 wk, N=80 (72 completers). PSQI vs placebo days 14/28/56 P<0.05. Actigraphy SOL/TST days 3-56, efficiency from day 14. No minute increments in abstract. full_text. Archive n null."},{"paperId":"p-pmid-10761819","evidenceGrade":"abstract_only","designNote":"Donath 2000 Pharmacopsychiatry. Crossover RCT. N=16 psychophysiological insomnia. Single dose null. 14-d: efficiency rose vs baseline on both arms. SWS latency 13.5 vs 21.3 min P<0.05. abstract_only. Archive n null."}],"featured":false},{"id":"e-vitamins-cognition","sourceId":"vitamin-supplementation","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Chen 2021: MoCA total interaction β 1.033 (0.105-1.961), P=0.029, N=120 AD. ADAS-Cog total not different. Cochrane 2003: two B12 RCTs in dementia with low B12, no effect. Wang 2022 MMSE MD 0.14 (0.04-0.23)."},"n":120,"summary":"Chen 2021 found that six months of folic acid plus vitamin B12 moved MoCA total by about one point versus placebo in 120 people with Alzheimer's in Tianjin, while a 2003 Cochrane review of B12 in dementia with low serum B12 found no cognitive effect.","mechanism":"B vitamins are cofactors in the one-carbon cycle. Folate and B12 help remethylate homocysteine to methionine. The folk story is that a high homocysteine number damages the brain, so a B-vitamin pill that lowers it should protect memory.\n\nChen, Liu, Ge, and colleagues (2021) tested that in 120 people with probable Alzheimer's in Tianjin. China does not fortify flour with folic acid. Everyone stayed on a cholinesterase inhibitor or memantine. Half took folic acid 1.2 mg plus B12 50 µg a day for six months. Half took matching starch tablets. Participants did not know which. The trial was single-blind. Mean MoCA at baseline was about 12. The interaction on MoCA total was 1.03 points (95% CI 0.11 to 1.96, P=0.029). Naming and orientation moved. The ADAS-Cog total, the usual Alzheimer's severity scale, did not (P=0.123), and only 39 people sat that battery.\n\nMalouf and Areosa Sastre (Cochrane, 2003) reviewed randomized double-blind trials of vitamin B12 versus placebo. They included two trials in people who already had dementia and low serum B12. That is the named-deficit test. There was no statistically significant treatment effect. The reviewers wrote that evidence of efficacy was insufficient.\n\nWang, Zhu, Xing, Jia, and Tang (2022) pooled 25 trials, 20 cohorts, and 50 cross-sectional studies. The trial MMSE difference was 0.14 points (95% CI 0.04 to 0.23) in 6,155 people. The difference appeared in trials longer than a year and in people without dementia. The dementia stratum crossed zero. Higher dietary folate and later dementia is an observational diet finding, not a pill trial. More papers of the same design do not settle the claim.","caveats":"Chen enrolled people with Alzheimer's, not people picked for low B12 or low folate. Baseline B12 was about 280 pmol/L. Baseline folate was about 15 nmol/L. Homocysteine was about 14 µmol/L. This is not a deficiency-correction trial. The trial was single-blind and six months. Nineteen people did not finish. ADAS-Cog was missing for most of the sample. Everyone was already on dementia medication.\n\nThe Cochrane file is two small trials in dementia with low B12. It is available here only as an abstract. The reviewers could not show a cognitive benefit from treating that deficit.\n\nWang mixes trial MMSE scores with observational diet and blood-level papers. The 0.14 MMSE point is not a named task leaving a named deficit. The dementia-stratum trials were null.\n\nSmith 2011 (VITACOG) is already on file here. That paper's primary result is whole-brain atrophy rate. The authors say the trial was not powered for cognition and that cognitive scores would be reported separately. A post-hoc line ties faster atrophy to a lower final MMSE. That is not a treatment contrast on a cognitive test. This page does not include it.\n\nSrinivasan 2017 gave B12 to pregnant women and scored infants at nine months on the Bayley. That is prenatal maternal supplementation and infant neurodevelopment, not adult pills and adult cognition.\n\nvan der Zwaluw 2017 measured brain volumes after B-PROOF. There is no cognitive test on that page.\n\nThis page is B vitamins and folate, not iron stores. Ferritin sits on another edge. This page does not speak to jobs. It is not medical advice and not a recommendation to take B vitamins, to skip them, or to treat a homocysteine number.","confounders":["disposable-income","education"],"paperIds":["p-pmid-34101780","p-pmid-12918012","p-pmid-34432056"],"contributions":[{"paperId":"p-pmid-34101780","evidenceGrade":"full_text","designNote":"Chen 2021 JPAD. Single-blind RCT, folic acid 1.2 mg/d + B12 50 µg/d vs placebo, 6 months. 120 probable AD (60/60), MoCA <22, Tianjin, no folate fortification. 101 completed (51/50). MoCA total interaction β 1.033 (0.105-1.961) P=0.029; naming P=0.013; orientation P=0.004. ADAS-Cog total not different (P=0.123) on 24/15. Archive n:null; N=120 from paper. full_text."},{"paperId":"p-pmid-12918012","evidenceGrade":"abstract_only","designNote":"Malouf 2003 Cochrane. Review of RCTs of B12 vs placebo for cognition. Two included trials (Seal 2002; Fourniere 1997) in dementia with low serum B12. No statistically significant treatment effect. Reviewers: evidence of efficacy insufficient. abstract_only. Archive n:null."},{"paperId":"p-pmid-34432056","evidenceGrade":"abstract_only","designNote":"Wang 2022 Nutr Rev. 95 studies, 46175 people (25 RCTs, 20 cohorts, 50 cross-sectional). RCT MMSE MD 0.14 (0.04-0.23), N=6155; >12 months MD 0.15; shorter stratum CI crosses zero; dementia stratum MD 0.20 (-0.35 to 0.75). Folate-intake dementia HR 0.61 is observational diet, not this stamp. Archive n:null. abstract_only."}],"featured":false},{"id":"e-vitd-cognition","sourceId":"vitamin-d","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Kang 2022 VITAL: pooled annual global MD 0.01 (95% CI -0.01, 0.02), N=4218. Corbett 2025 VitaMIND: TMT-B MD 5770 (CI -2189 to 13730), N=620. Pham 2023 D-Health: TICS MD 0.04 (CI -0.14 to 0.23)."},"n":4218,"summary":"Kang 2022 found that 2000 IU a day of vitamin D3 versus placebo did not slow cognitive decline among 4218 adults aged 60 and older in VITAL (pooled annual global-score difference 0.01, 95% CI -0.01 to 0.02). Corbett 2025 and Pham 2023 then also found no cognitive gain.","mechanism":"Observational papers have tied low 25(OH)D to cognitive decline. The vitamin D receptor is expressed in cortex and hippocampus. Reverse causation can produce the same correlation: people who are starting to slip go indoors, and the number falls.\n\nKang, Vyas, Okereke, and colleagues tested 2000 IU a day of cholecalciferol inside VITAL. VITAL-Cog assessed 3424 people aged 60 and older by phone on eight tests, then again 2.8 years later. CTSC-Cog assessed 794 people in person on nine tests, then again 2.0 years later. The primary was annual change in a global composite. The pooled difference versus placebo was 0.01 standard units per year (95% CI -0.01 to 0.02, p=0.39). Baseline 25(OH)D did not modify the result (p=0.84). A year of the same dose in the parent trial raised mean 25(OH)D from 29.8 to 41.8 ng/mL. The blood number moved. The tests did not.\n\nA pre-specified analysis found slower decline among Black participants (difference 0.04, 95% CI 0.01 to 0.08). The authors call that modest and ask for confirmation. It does not rewrite the primary.\n\nCorbett and colleagues (VitaMIND, 2025) tested 4000 IU a day against placebo for 24 months in 620 UK adults aged 50 and older, enrolled for predicted mild to moderate deficiency and early cognitive impairment. The primary was a computerized Trail Making B score. The between-group difference was 5770 (95% CI -2189 to 13,730). The abstract does not name the unit. Cohen d was 0.11 (P=0.16). Secondary cognition was also null.\n\nPham and colleagues analyzed cognition inside D-Health, a five-year Australian trial of monthly 60,000 IU versus placebo. A random sample aged 70 and older sat the Telephone Interview for Cognitive Status at year 2 (3887 people) and year 5 (3614). The mean difference was 0.04 (95% CI -0.14 to 0.23). Cognitive impairment (TICS 25 or below) had an odds ratio of 1.00 (95% CI 0.75 to 1.33). It is the D-Health cognition read, not a new assigned design.","caveats":"The VITAL sample was generally healthy and well educated. More than half had some postgraduate study. Few people were vitamin D deficient. Placebo-arm decline was modest. Two assessments over two to three years can miss a slow effect. The larger arm used telephone tests. Participants could take up to 800 IU a day of vitamin D outside the trial. The Black-participant finding was pre-specified but not the primary.\n\nVitaMIND is smaller than Kang. The abstract names 620 adults. Deficiency was a questionnaire prediction, not a blood number for most people. The published table uses 163 people on placebo and 174 on vitamin D for the 24-month Trail Making B contrast. The trial was remote, 75 percent women, 98 percent White, and already online. The authors say they did not enroll enough people with 25(OH)D below 25 nmol/L to answer severe deficiency. The confidence interval crosses zero. This page does not treat VitaMIND as a flip of Kang.\n\nD-Health used a monthly bolus, not a daily pill. There was no baseline TICS. The sample was largely replete Australians. That add-on paper does not change the trial stamp.\n\nThis is not a trial of treating rickets, institutionalized deficiency, or dementia. It does not speak to employment or income. This page is not an argument against treating a true deficiency.","confounders":["outdoor-time","education","disposable-income"],"paperIds":["p-pmid-34853363","p-pmid-40480279","p-pmid-36715270"],"contributions":[{"paperId":"p-pmid-34853363","evidenceGrade":"full_text","designNote":"Kang 2022. VITAL-Cog n=3424 phone 8 tests 2.8y; CTSC-Cog n=794 in-person 9 tests 2.0y. VITAL 2x2, 2000 IU/d D3 vs placebo. Primary annual global composite decline. Pooled MD 0.01 (95% CI -0.01, 0.02; p=0.39). No baseline 25(OH)D interaction p=0.84. Race interaction p=0.01, Black MD 0.04, unconfirmed. Archive n:null; N=4218 from paper. full_text."},{"paperId":"p-pmid-40480279","evidenceGrade":"abstract_only","designNote":"Corbett 2025 VitaMIND. Remote 24-mo RCT. 620 adults ≥50 (310/310), predicted mild/moderate D deficiency + AACD. Daily 4000 IU D3 vs placebo. Primary computerized TMT-B. Between-group MD 5770 (95% CI -2189 to 13730); abstract does not name the unit. Cohen d 0.11, P=0.16. Secondary cognition also null. Archive n:null; N=620 from abstract. abstract_only."},{"paperId":"p-pmid-36715270","evidenceGrade":"abstract_only","designNote":"Pham 2023. D-Health cognition analyses. Monthly 60,000 IU D3 vs placebo, 5y, Australians 60-84. TICS in random sample ≥70: 3887 at y2, 3614 at y5. TICS MD 0.04 (95% CI -0.14 to 0.23). Impairment OR 1.00 (95% CI 0.75 to 1.33). Archive methodology observational; hang as cognition read only. Do not raise edge off rct. abstract_only."}],"featured":false},{"id":"e-vitd-depression","sourceId":"vitamin-d","targetId":"depression","relation":"causal_direct","direction":"forward","polarity":"null_effect","methodology":"rct","confidence":"moderate","effect":{"metric":"odds_ratio","value":0.97,"note":"Okereke 2020 VITAL-DEP: HR 0.97 (95% CI 0.87-1.09), 609 vs 625 events, N=18353. PHQ-8 MD 0.01 (-0.04 to 0.05). Rahman 2023 D-Health: PHQ-9 MD 0.02 (-0.06, 0.11), N=20487."},"n":18353,"summary":"Okereke 2020 found that 2000 IU a day of vitamin D3 versus placebo did not change the risk of depression or clinically relevant depressive symptoms among 18353 adults aged 50 and older in VITAL-DEP (hazard ratio 0.97, 95% CI 0.87 to 1.09). Rahman 2023 then found the same null on PHQ-9 in D-Health.","mechanism":"Observational papers have tied low 25(OH)D to later depression. The vitamin D receptor is expressed in brain. Reverse causation can produce the same correlation: people who are sliding stay indoors, and the number falls.\n\nOkereke, Reynolds, Mischoulon, Vyas, and colleagues tested 2000 IU a day of cholecalciferol inside VITAL. VITAL-DEP followed 18353 US adults aged 50 and older (mean 67.5) who were free of clinically relevant depressive symptoms at baseline. Median treatment was 5.3 years. The primary was depression or clinically relevant depressive symptoms, incident plus recurrent: a clinician diagnosis, new treatment, or a PHQ-8 of 10 or more. There were 609 events on vitamin D3 (12.9 per 1000 person-years) and 625 on placebo (13.3). The hazard ratio was 0.97 (95% CI 0.87 to 1.09, P=.62). Incident and recurrent splits were also null. PHQ-8 change differed by 0.01 points (-0.04 to 0.05). The authors had set 0.5 as the smallest change that would matter. Mean baseline 25(OH)D was 30.8 ng/mL. Subgroups, including baseline 25(OH)D, did not move the result.\n\nRahman and colleagues read depression inside D-Health, a five-year Australian trial of monthly 60,000 IU versus placebo. PHQ-9 in 20487 people differed by 0.02 (-0.06 to 0.11). Clinically relevant depression (PHQ-9 of 10 or more) had an odds ratio of 0.99 (0.90 to 1.08). New antidepressant use in 16670 people had a hazard ratio of 1.04 (0.96 to 1.12). People already on antidepressants sat 0.25 PHQ-9 points lower. That is not the primary.\n\nAlavi and colleagues assigned 50,000 IU a week versus placebo for eight weeks in 78 clinic patients aged 60 and older who already had moderate to severe depression. GDS-15 fell from 9.25 to 7.48 on vitamin D. The placebo arm did not fall. That is a treatment trial in people already under care, not the prevention contrast.","caveats":"VITAL-DEP is prevention in people without current depression or treatment. It is not a trial of treating major depression. Participants could take up to 800 IU a day outside the study. Mean baseline 25(OH)D was already adequate. Few people were deficient. Events came from annual questionnaires: a diagnosis, new treatment, or a PHQ-8 of 10 or more. A subset sat an in-person interview.\n\nD-Health used a monthly bolus, not a daily pill. The sample was older Australians. Depression was a PHQ-9 and a prescribing record, not a structured interview. Subgroup signals in people already on antidepressants, or with predicted 25(OH)D under 50 nmol/L, do not rewrite the primary.\n\nAlavi is 78 people, eight weeks, three psychiatric clinics, already in treatment, and abstract only. The published contrast leans on a within-group GDS drop. It does not flip the identifying files.\n\nThis page is not employment, income, or cognition. It is not an argument against treating a true deficiency. This is not medical advice and not a recommendation to take or skip a pill.","confounders":["outdoor-time","education","disposable-income"],"paperIds":["p-pmid-32749491","p-pmid-36462182","p-pmid-30316534"],"contributions":[{"paperId":"p-pmid-32749491","evidenceGrade":"full_text","designNote":"Okereke 2020 JAMA, VITAL-DEP ancillary. RCT, 2000 IU/d D3 vs placebo, 2x2 with fish oil. 18353 adults ≥50 without current depression (9181/9172). Median 5.3y. Primary: depression or PHQ-8≥10. 609 vs 625 events, HR 0.97 (0.87-1.09), P=.62. PHQ-8 MD 0.01 (-0.04 to 0.05). identifying. Archive n null; 18353 from paper. full_text."},{"paperId":"p-pmid-36462182","evidenceGrade":"full_text","designNote":"Rahman 2023 Int J Geriatr Psychiatry, D-Health depression read. Monthly 60,000 IU D3 vs placebo, Australians 60-84. PHQ-9 n=20487 MD 0.02 (-0.06, 0.11). PHQ-9≥10 OR 0.99 (0.90, 1.08). Incident antidepressant n=16670 HR 1.04 (0.96, 1.12). Subgroups not primary. Archive n null; 20487 from abstract. full_text."},{"paperId":"p-pmid-30316534","evidenceGrade":"abstract_only","designNote":"Alavi 2020 Clin Nutr. 8-week RCT, 50,000 U D3 weekly vs placebo, 78 clinic patients ≥60 with moderate-severe depression already in treatment (39/39). GDS-15 9.25 to 7.48 on D (p=0.0001); placebo ns rise. Treatment estimand, not prevention. Does not flip polarity. Archive n null; 78 from abstract. abstract_only."}],"featured":false},{"id":"e-vitd-employment-mr","sourceId":"vitamin-d","targetId":"employment-status","relation":"causal_genetic","direction":"forward","polarity":"null_effect","methodology":"mendelian_randomization","confidence":"high","effect":{"metric":"odds_ratio","value":1,"note":"MR-PheWAS and large MR catalogs do not support a causal 25(OH)D effect on general socioeconomic success."},"n":339256,"summary":"Genetic instruments for 25(OH)D do not buy you a job. The observational D–success link was a marker.","mechanism":"If lifelong higher 25(OH)D caused employment, SNPs that raise 25(OH)D should show up on socioeconomic and disease-wide scans. Meng et al. (2019) and Jiang et al. (2021) find no such general effect. Multiple sclerosis is the interesting exception in the medical catalog — not income.","caveats":"MR assumes no pleiotropy and a linear lifelong effect. It can miss threshold effects in the truly deficient. It is still the right tool for the 'D makes you successful' claim, and the claim fails.","confounders":["outdoor-time","disposable-income","education"],"paperIds":["p-meng-2019","p-jiang-2021"],"contributions":[{"paperId":"p-meng-2019","evidenceGrade":"abstract_only"},{"paperId":"p-jiang-2021","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-vitd-income-spurious","sourceId":"vitamin-d","targetId":"disposable-income","relation":"spurious","direction":"bidirectional","polarity":"null_effect","methodology":"observational","confidence":"high","effect":{"metric":"qualitative","value":null,"note":"Classic marker: outdoor leisure, latitude, adiposity, and wealth all move both variables."},"n":null,"summary":"People with money and outdoor lives have higher 25(OH)D. That is not D causing the money.","mechanism":"Autier et al. (2014): observational D–disease links do not survive RCTs. The same structure applies to D–income. Outdoor time, BMI, and health-seeking sit on the backdoor. VITAL then showed D3 does not even deliver the promised disease endpoints in a general population.","caveats":"Deficiency correction in institutionalized or deeply deficient groups is a different estimand. Do not use this edge to argue against treating rickets.","confounders":["outdoor-time","education","vitamin-supplementation"],"paperIds":["p-autier-2014","p-manson-2019"],"contributions":[{"paperId":"p-autier-2014","evidenceGrade":"abstract_only"},{"paperId":"p-manson-2019","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-vitd-mortality","sourceId":"vitamin-d","targetId":"mortality","relation":"causal_genetic","direction":"forward","polarity":"non_linear","methodology":"mendelian_randomization","confidence":"contested","effect":{"metric":"odds_ratio","value":1.25,"note":"Sutherland 2022 nonlinear MR: all-cause OR 1.25 (1.16-1.35) at 25 vs 50 nmol/L. L-shaped, P nonlinearity <0.001. Trummer 2013 and Ong 2019 linear MR were null."},"n":307601,"summary":"Sutherland 2022 found an L-shaped Mendelian randomization link between genetically predicted 25(OH)D and all-cause death in 307,601 white-European UK Biobank adults, with risk falling until about 50 nmol/L, while Trummer 2013 and Ong 2019 found no linear genetic effect.","mechanism":"People with low 25(OH)D die sooner in observational catalogs. Time outdoors, body fat, illness, and money sit on that backdoor. Illness can also pull D down.\n\nResearchers use a genetic shortcut called Mendelian randomization. It is good at ruling out diet, income, and who still goes outside. It can still be fooled when one gene affects two traits. A linear instrument can miss a threshold.\n\nTrummer, Pilz, März, and colleagues (2013) typed three 25(OH)D SNPs (GC, DHCR7, CYP2R1) in 3,316 people sent for coronary angiography. The genotypes predicted measured D (r-squared 0.175). Over a median 9.9 years, 955 people died, 619 from heart disease. The genotypes did not predict all-cause, cardiovascular, or other death.\n\nOng, Gharahkhani, Neale, and MacGregor (2019) used five 25(OH)D markers in 438,870 white-British UK Biobank adults. They counted 6,998 cancer deaths. A 20 nmol/L genetically predicted rise did not move cancer death or overall cancer risk.\n\nSutherland, Zhou, and Hyppönen (2022) stayed in UK Biobank but allowed a curve. They used 35 variants in 307,601 unrelated white-European adults and counted 18,700 deaths through June 2020. Genetically predicted 25(OH)D against all-cause death was L-shaped (P for nonlinearity under 0.001). Risk fell steeply until 50 nmol/L. At a measured 25 nmol/L versus 50, the genetic analysis put the odds of death at 1.25 (1.16 to 1.35). Cancer, heart, and lung death showed the same shape (P of 0.033 or lower).\n\nThe main paper is a deficiency threshold, not a linear lifelong bonus. The earlier linear papers stay on the page because they said the opposite.","caveats":"This page is circulating 25(OH)D and later death. It is not a job, not a cognitive score, and not a heart attack someone survived.\n\nSutherland and Ong are white-European or white-British UK Biobank. A volunteer cohort is healthier than the country. Trummer's sample was already in the cath lab.\n\nMendelian randomization assumes no pleiotropy. Nonlinear Mendelian randomization still uses measured D to place people on the curve. The authors say the size of the association is approximate. A linear instrument can miss a threshold if most of the sample sits above it.\n\nEach paper is Mendelian randomization, a genetic shortcut.\n\nTrummer 2016 (biochemical recurrence, metastases, and overall survival in 702 prostate cancer patients) is a prognosis file, not this page.\n\nThis is not medical advice and not a recommendation to take vitamin D, to skip it, or to treat a number.","confounders":["outdoor-time","disposable-income","education"],"paperIds":["p-pmid-36279545","p-pmid-23319826","p-pmid-30508204"],"contributions":[{"paperId":"p-pmid-36279545","evidenceGrade":"abstract_only","designNote":"Sutherland 2022 Ann Intern Med. Nonlinear MR, 307601 White European UKB, 37-73y. 35 25(OH)D variants. 18700 deaths to Jun 2020. L-shaped all-cause (P nonlinearity <0.001) until 50 nmol/L. OR 1.25 (1.16-1.35) at 25 vs 50 nmol/L. Cancer/CVD/respiratory P<=0.033. Archive observational; paper is MR. N from paper (Archive n null). abstract_only."},{"paperId":"p-pmid-23319826","evidenceGrade":"abstract_only","designNote":"Trummer 2013 Clin Chem. MR, 3316 angiography patients, mean 62.6y. 3 SNPs (GC rs2282679, DHCR7 rs12785878, CYP2R1 rs10741657). r-squared 0.175 for 25(OH)D. 955 deaths (30%), 619 CV, median 9.9y. Genotypes not associated with all-cause, CV, or non-CV death. Archive observational; paper is MR. N from paper. abstract_only."},{"paperId":"p-pmid-30508204","evidenceGrade":"abstract_only","designNote":"Ong 2019 Hum Mol Genet. MR, 438870 white British UKB, 37-73y. Five 25(OH)D markers. 46155 cancer cases, 6998 cancer deaths (keratinocyte/benign excluded). Per 20 nmol/L genetically predicted 25(OH)D: null for cancer risk and cancer mortality. Not all-cause death. Archive observational; paper is MR. abstract_only."}],"featured":false},{"id":"e-wealth-hypergamy","sourceId":"net-worth","targetId":"hypergamy-preference","relation":"spurious","direction":"forward","polarity":"null_effect","methodology":"observational","confidence":"moderate","effect":{"metric":"qualitative","value":null,"note":"Wealth is the stock version of the income story. Same backdoors, slower clock."},"n":400,"summary":"Assets change the feasible set in a mating market. That is not a new instinct.","mechanism":"Same identification problem as income→hypergamy. Neighborhood, education, and meeting technology sit on the backdoor. Fisman used neighborhood affluence, which is closer to wealth than to last month's paycheck.","caveats":"No RCT of endowments on preference weights.","confounders":["education","disposable-income"],"paperIds":["p-fisman-2006","p-buss-1989"],"contributions":[{"paperId":"p-fisman-2006","evidenceGrade":"abstract_only"},{"paperId":"p-buss-1989","evidenceGrade":"abstract_only"}],"featured":false},{"id":"e-widowhood-mortality","sourceId":"widowhood","targetId":"mortality","relation":"spurious","direction":"forward","polarity":"positive","methodology":"observational","confidence":"low","effect":{"metric":"odds_ratio","value":1.18,"note":"Elwert 2008: 373,189 couples. Men HR 1.18 (1.16-1.19) after wife's death; women HR 1.16 (1.14-1.17) after husband's. Observational. Design does not identify."},"n":373189,"summary":"In 373,189 elderly US couples followed from 1993 to 2002, a wife's death sat with 18 percent higher all-cause death hazard in the husband (HR 1.18, 1.16 to 1.19) and a husband's death sat with 16 percent in the wife (HR 1.16, 1.14 to 1.17). Nobody assigned widowhood.","mechanism":"Widowhood is the death of a spouse. Authors name the loss of care and of a person who noticed illness. They also name who married whom and a shared house: the same smoke, the same street, the same money.\n\nElwert and Christakis (2008) followed 373,189 elderly married couples in Medicare from 1993 to 2002 (746,378 people, 317,300 deaths). After age, race, poverty, both spouses' baseline Charlson scores and hospital days, and zip and county context, a wife's death sat with all-cause hazard 1.18 in men (1.16 to 1.19). A husband's death sat with 1.16 in women (1.14 to 1.17). The increment held after almost every cause of the first death. The exception was Alzheimer's or Parkinson's. Cause-specific hazards in the survivor rose for most cancers, infections, and vascular deaths. Causes came from two years of Medicare diagnoses, not the certificate.\n\nStahl, Arnold, Chen, Anderson and Schulz (2017) matched 593 people widowed in the Cardiovascular Health Study between 1989 and 1999 to 593 still-married people of the same age and sex. Over three years, 199 of 1,186 died. Bereavement overall sat at hazard 0.98 (0.74 to 1.30). Men sat at 1.77 (1.14 to 2.75). Women sat at 0.67 (0.46 to 0.97). The rise in men showed without cardiovascular disease. The fall in women showed with it. A CES-D of 8 or more sat with death (1.74, 1.13 to 2.68) and pulled down the men-without-CVD increment.","caveats":"The stamp is smoke because nobody randomized a death. These are cohorts. Observation alone cannot close the backdoor, so the stamp stays smoke. More papers of the same design do not settle the claim. Elwert and Christakis treat the increment as close to causal. The design still does not identify.\n\nCouples share a house. Residual smoking, accidents that hit both, and who married whom remain open. Elwert inferred causes from claims, not certificates. Same-day deaths were treated as not widowed. Alzheimer's or Parkinson's in the first spouse did not raise the survivor's all-cause hazard.\n\nStahl is 1,186 people and three years. The overall hazard crosses 1. The sex split is the opposite of Elwert's two increments above 1. Depression scores were missing for 276 people, often because they died before the next visit.\n\nOmitted Abell and Steptoe 2021: living alone, with divorce and bereavement lumped in one transition. The exposure is the household, not widowhood.\n\nOmitted heat and clozapine files: they do not identify this page.\n\nThis is a journal entry, not medical advice and not a reason to treat a number.","confounders":["disposable-income","education","social-capital","loneliness","depression","cardiovascular","smoking"],"paperIds":["p-pmid-18511733","p-pmid-26894326"],"contributions":[{"paperId":"p-pmid-18511733","evidenceGrade":"full_text","designNote":"Elwert 2008 AJPH. Medicare couples n=373189 (746378 people), 1993-2002, 317300 deaths. Observational Cox. Men HR 1.18 (1.16-1.19); women 1.16 (1.14-1.17). Exception: spouse Alzheimer's/Parkinson's. Causes from 2y claims. identifying. full_text. Archive n null; N from paper."},{"paperId":"p-pmid-26894326","evidenceGrade":"full_text","designNote":"Stahl 2017 Psychosom Med. CHS matched 593 bereaved + 593 married, 3y all-cause. Observational. Overall HR 0.98 (0.74-1.30). Men 1.77 (1.14-2.75); women 0.67 (0.46-0.97). CVD and CES-D modifiers. identifying. full_text. Archive n null; N=1186 from paper."}],"featured":false},{"id":"e-win-testosterone","sourceId":"contest-outcome","targetId":"testosterone","relation":"feedback","direction":"forward","polarity":"positive","methodology":"longitudinal","confidence":"moderate","effect":{"metric":"cohens_d","value":0.2,"note":"Winner–loser T difference is small; clearer in field than lab (updated metas)."},"n":null,"summary":"Winning a meaningful contest raises T relative to losing. That T change then colors the next contest. A loop, not an arrow.","mechanism":"Mazur and Booth's biosocial model: T rises in anticipation of a challenge and diverges after the result — up for winners, down for losers — which then biases willingness to re-enter. Booth et al. (1989) saw it in tennis; later metas shrink but do not erase the field effect.","caveats":"Tiny early N. Laboratory effects are often near zero. Mood about the win, home advantage, and cortisol all moderate the delta. Women are under-studied in the classic papers.","confounders":["cortisol","status-seeking"],"paperIds":["p-mazur-booth-1998","p-booth-1989","p-carre-olmstead-2015"],"contributions":[{"paperId":"p-mazur-booth-1998","evidenceGrade":"abstract_only"},{"paperId":"p-booth-1989","evidenceGrade":"abstract_only"},{"paperId":"p-carre-olmstead-2015","evidenceGrade":"abstract_only"}],"featured":true},{"id":"e-zinc-cognition","sourceId":"zinc","targetId":"cognitive-performance","relation":"causal_direct","direction":"forward","polarity":"context_dependent","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Maylor 2006 ZENITH: 15 or 30 mg, 6 mo, N=387 age 55-87. Spatial WM up at 3 mo; 15 mg attention down. de Vargas 2023: 30 mg, 12 wk, 32/42 overweight women, MMSE/Stroop vs placebo."},"n":387,"summary":"Maylor 2006 found that 15 or 30 mg of zinc a day for six months had a mixed effect on Cambridge tasks in 387 healthy adults aged 55 to 87: one spatial working-memory score moved at three months, and 15 mg worsened one attention score. de Vargas 2023 saw higher Mini-Mental and Stroop scores on 30 mg in 32 overweight women.","mechanism":"Authors treat zinc as a trace metal that might help attention or memory. They do not isolate one enzyme.\n\nMaylor, Simpson, Secker and colleagues assigned 387 healthy adults aged 55 to 87 to 0, 15, or 30 mg a day for six months (ZENITH). Younger adults beat older adults on every task. Two of eight outcomes showed a time-by-dose interaction: spatial working memory favored both zinc doses at three months only, and 15 mg hurt one attention score.\n\nde Vargas, Jantsch, Fontoura and colleagues assigned 42 overweight or obese women aged 40 to 60 to 30 mg a day or placebo for twelve weeks. 32 were analyzed. Mini-Mental and Stroop scores were higher on zinc. Anxiety and depression scales did not differ. Weight did not change.","caveats":"Researchers assigned people to a salt or a control, so this is a trial stamp. Task and dose split. More papers of the same design do not settle the claim.\n\nZENITH is healthy older adults and mostly practice plus two mixed interactions. de Vargas is 32 completers and no weight change.\n\nThis is a journal entry, not medical advice and not a reason to take zinc for memory.","confounders":["sleep-hygiene","alcohol-intake","ferritin"],"paperIds":["p-pmid-17010236","p-pmid-37892471"],"contributions":[{"paperId":"p-pmid-17010236","evidenceGrade":"abstract_only","designNote":"Maylor 2006 Br J Nutr. ZENITH RCT. 0/15/30 mg, 6 mo, N=387 age 55-87. Spatial WM vs placebo at 3 mo. 15 mg attention down. 6/8 tasks ns. abstract_only. Archive n null."},{"paperId":"p-pmid-37892471","evidenceGrade":"full_text","designNote":"de Vargas 2023 Nutrients. RCT. 30 mg vs placebo, 12 wk, 32/42 overweight women 40-60. MMSE and Stroop vs placebo. BDI/BAI ns. full_text. Archive n null."}],"featured":false},{"id":"e-zinc-t","sourceId":"zinc","targetId":"testosterone","relation":"causal_direct","direction":"forward","polarity":"positive","methodology":"rct","confidence":"contested","effect":{"metric":"qualitative","value":null,"note":"Mahajan 1982: zinc acetate 50 mg, 6 mo, N=20 HD. T 2.8 to 5.2 ng/mL. Prasad 1997: restriction N=4, T 39.9 to 10.6 nmol/L; elderly gluconate N=9, T 8.3 to 16.0."},"n":20,"summary":"Mahajan 1982 found that 50 mg of elemental zinc as acetate a day for six months raised serum testosterone from 2.8 to 5.2 ng per milliliter versus no change on placebo in 20 men on hemodialysis. Prasad 1997 then saw testosterone fall under zinc restriction in four young men and rise after zinc gluconate in nine older men.","mechanism":"Authors treat zinc deficiency as a reversible cause of low testosterone. They do not isolate one enzyme.\n\nMahajan, Abbasi, Prasad and colleagues assigned 20 stable hemodialysis patients to 50 mg of elemental zinc as acetate or placebo for six months. Plasma zinc rose from 75 to 100 micrograms per deciliter. Serum testosterone rose from 2.8 to 5.2 ng per milliliter. Sperm count rose. LH and FSH fell. The placebo arm did not move. ; the abstract is a double-blind trial.\n\nPrasad, Mantzoros, Beck, Hess and Brewer (1997) restricted dietary zinc in four young men. Serum testosterone fell from 39.9 to 10.6 nmol per liter after twenty weeks. In nine marginally zinc-deficient older men, 459 micromoles a day of zinc as gluconate for three to six months raised testosterone from 8.3 to 16.0 nmol per liter. A cross-section of forty men tied lymphocyte zinc to testosterone.","caveats":"Researchers assigned people to a salt or a control, so this is a trial stamp. Mahajan is twenty men on dialysis in 1982. Prasad's main slices are four and nine men, and the older-man arm is before-after, not placebo. More papers of the same design do not settle the claim.\n\nThis is a journal entry, not medical advice and not a reason to take zinc to raise testosterone.","confounders":["sleep-hygiene","alcohol-intake","resistance-training"],"paperIds":["p-pmid-7051913","p-pmid-8875519"],"contributions":[{"paperId":"p-pmid-7051913","evidenceGrade":"abstract_only","designNote":"Mahajan 1982 Ann Intern Med. Double-blind (Archive observational). Zinc acetate 50 mg vs placebo, 6 mo, N=20 hemodialysis. T 2.8 to 5.2. LH/FSH down. Dialysis. abstract_only. Archive n null."},{"paperId":"p-pmid-8875519","evidenceGrade":"abstract_only","designNote":"Prasad 1997 Nutrition. Restriction N=4 young men, T 39.9 to 10.6 nmol/L at 20 wk. Elderly gluconate 459 µmol/d, N=9, T 8.3 to 16.0. Cross-section N=40. Archive observational. abstract_only. Archive n null."}],"featured":false}],"papers":[{"id":"p-pmid-19010347","title":"The effect of a 12 week walking intervention on markers of insulin resistance and systemic inflammation.","authors":["SR Gray","G Baker","A Wright","CF Fitzsimons","N Mutrie","MA Nimmo"],"year":2009,"venue":"Preventive medicine","doi":"10.1016/j.ypmed.2008.10.013","pmid":"19010347","url":"https://pubmed.ncbi.nlm.nih.gov/19010347/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVES: The purpose of the present study was to determine whether a community-based walking intervention, using pedometers, is effective in reducing systemic inflammatory markers. METHODS: Participants (age=49(8.9)) were recruited in Glasgow, United Kingdom, from August to December 2006 and were randomly assigned to a control (n=24; 6 males, no change in walking) and intervention group (n=24; 5 males gradually increasing walking by 3000 steps/day on 5 days of the week). Blood samples were collected at baseline, and after 12 weeks, and analysed for glucose, insulin, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumour necrosis factor-alpha (TNF-alpha) and soluble TNF receptors I and II (sTNFR1 and sTNFRII). RESULTS: In the control group baseline step counts were 6356 (2953) steps/day and did not change (P&gt;0.05) after 12 weeks, 6709 (2918) steps/day. The intervention group increased (P&lt;0.001) step count from 6682 (3761) steps/day at baseline to 10182 (4081) steps/day at 12 weeks. Over the 12 week period there was no change in any other variables measured, in either control or intervention group. CONCLUSION: We conclude that the current community-based intervention did not affect systemic markers of inflammation or insulin sensitivity.","evidenceGrade":"abstract_only"},{"id":"p-pmid-24553426","title":"Alcohol consumption and cognitive impairment in older men: a mendelian randomization study.","authors":["OP Almeida","GJ Hankey","BB Yeap","J Golledge","L Flicker"],"year":2014,"venue":"Neurology","doi":"10.1212/WNL.0000000000000255","pmid":"24553426","url":"https://pubmed.ncbi.nlm.nih.gov/24553426/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: To determine whether alcohol consumption is causally associated with cognitive impairment in older men as predicted by mendelian randomization. METHODS: Retrospective analysis of a cohort study of 3,542 community-dwelling men aged 65 to 83 years followed for 6 years. Cognitive impairment was established by a Mini-Mental State Examination score of 23 or less. Participants provided detailed information about their use of alcohol during the preceding year and were classified as abstainers, occasional drinkers, and regular drinkers: mild (&lt;15 drinks/wk), moderate (15-27 drinks/wk), heavy (28-34 drinks/wk), and abusers (&#x2265;35 drinks/wk). We genotyped the rs1229984 G&#x2192;A variant of the alcohol dehydrogenase 1B (ADH1B) gene, which is associated with lower prevalence of alcohol abuse and dependence. Other measures included age, education, marital status, smoking and physical activity, body mass index, diabetes, hypertension, and cardiovascular diseases. RESULTS: At study entry, rs1229984 G&#x2192;A polymorphism was associated with lower prevalence of regular use of alcohol and decreased consumption among regular users. Six years later, 502 men (14.2%) showed evidence of cognitive impairment. Abstainers and irregular drinkers had higher odds of cognitive impairment than regular drinkers (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.00-1.51, after adjustment for other measured factors). The rs1229984 G&#x2192;A polymorphism did not decrease the odds of cognitive impairment (AA/GG OR = 1.35, 95% CI = 0.29-6.27; GA/GG OR = 1.05, 95% CI = 0.71-1.55). CONCLUSIONS: Alcohol consumption, including heavy regular drinking and abuse, is not a direct cause of cognitive impairment in later life. Our results are consistent with the possibility, but do not prove, that regular moderate drinking decreases the risk of cognitive impairment in older men.","evidenceGrade":"full_text"},{"id":"p-pmid-36079852","title":"Alcohol Consumption and Mild Cognitive Impairment: A Mendelian Randomization Study from Rural China.","authors":["Y Cui","W Si","C Zhu","Q Zhao"],"year":2022,"venue":"Nutrients","doi":"10.3390/nu14173596","pmid":"36079852","url":"https://pubmed.ncbi.nlm.nih.gov/36079852/","methodology":"observational","n":null,"openAccess":true,"abstract":"Alcohol consumption has been associated with the risk of mild cognitive impairment (MCI) in observational studies. The result is inconsistent and whether the association is causal remains unknown. To examine the causal effect of alcohol consumption on MCI in rural China, this study used a cross-sectional dataset that included 1966 observations collected in rural China, of which 235 observations' genotyping were collected. All participants accepted the MCI evaluation using Mini-Cog and were asked about the participants' alcohol consumption behavior. The causal effect of alcohol consumption on MCI was investigated by Mendelian randomization (MR) of genetic variation in the aldehyde dehydrogenase 2 (ALDH2 rs671) gene. The risk of MCI in Chinese rural areas was 43%. Alcohol consumption was causally associated with a higher risk of MCI under MR design. Parameter estimates of drinking or not (b = 0.271, p = 0.007, 95% CI = 0.073 to 0.469), drinking frequency during the past 30 days (b = 0.016, p = 0.003, 95% CI = 0.005 to 0.027), and the weekly ethanol consumption (b = 0.132, p = 0.004, 95% CI = 0.042 to 0.223) were all positive and statistically significant at the 5% level. In conclusion, there was a high risk of MCI in rural China, and alcohol consumption was causally associated with a higher risk of MCI.","evidenceGrade":"full_text"},{"id":"p-pmid-38196582","title":"Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States.","authors":["KA Campbell","M Fu","E MacDonald","M Zawistowski","KM Bakulski","EB Ware"],"year":2024,"venue":"medRxiv : the preprint server for health sciences","doi":"10.1101/2023.12.22.23300298","pmid":"38196582","url":"https://pubmed.ncbi.nlm.nih.gov/38196582/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: In observational studies, the association between alcohol consumption and dementia is mixed. METHODS: We performed two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies of weekly alcohol consumption and late-onset Alzheimer's disease and one-sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two-stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non-dementia relative to cognitively normal. RESULTS: Alcohol consumption was not associated with late-onset Alzheimer's disease using two-sample MR (OR=1.15, 95% confidence interval (CI):[0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n=1,322, OR=1.00, 95% CI [0.45, 2.25]; European ancestries, n=7,160, OR=1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non-dementia (African ancestries, n=1,322, OR=1.17, 95% CI [0.69, 1.98]; European ancestries, n=7,160, OR=0.75, 95% CI [0.47, 1.22]). CONCLUSION: Alcohol consumption was not associated with cognitively impaired, non-dementia or dementia status.","evidenceGrade":"full_text"},{"id":"p-pmid-25011450","title":"Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.","authors":["MV Holmes","CE Dale","L Zuccolo","RJ Silverwood","Y Guo","Z Ye","D Prieto-Merino","A Dehghan"],"year":2014,"venue":"BMJ (Clinical research ed.)","doi":"10.1136/bmj.g4164","pmid":"25011450","url":"https://pubmed.ncbi.nlm.nih.gov/25011450/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.","evidenceGrade":"full_text"},{"id":"p-pmid-30955975","title":"Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500&#x2008;000 men and women in China.","authors":["IY Millwood","RG Walters","XW Mei","Y Guo","L Yang","Z Bian","DA Bennett","Y Chen"],"year":2019,"venue":"Lancet (London, England)","doi":"10.1016/S0140-6736(18)31772-0","pmid":"30955975","url":"https://pubmed.ncbi.nlm.nih.gov/30955975/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink). METHODS: The prospective China Kadoorie Biobank enrolled 512&#x2008;715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161&#x2008;498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake. FINDINGS: 33% (69&#x2008;897/210&#x2008;205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302&#x2008;510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14&#x2008;930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all","evidenceGrade":"full_text"},{"id":"p-pmid-32367730","title":"Alcohol Consumption and Cardiovascular Disease: A Mendelian Randomization Study.","authors":["SC Larsson","S Burgess","AM Mason","K Micha&#xeb;lsson"],"year":2021,"venue":"Circulation. Genomic and precision medicine","doi":"10.1161/CIRCGEN.119.002814","pmid":"32367730","url":"https://pubmed.ncbi.nlm.nih.gov/32367730/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: The causal role of alcohol consumption for cardiovascular disease remains unclear. We used Mendelian randomization (MR) to predict the effect of alcohol consumption on 8 cardiovascular diseases. METHODS: Up to 94 single-nucleotide polymorphisms were used as instrumental variables for alcohol consumption. Genetic association estimates for cardiovascular diseases were obtained from large-scale consortia and UK Biobank. Analyses were conducted using the inverse variance-weighted, weighted median, MR-PRESSO, MR-Egger, and multivariable MR methods. RESULTS: Genetically predicted alcohol consumption was consistently associated with stroke and peripheral artery disease across the different analyses. The odds ratios (ORs) per 1-SD increase of log-transformed alcoholic drinks per week were 1.27 ([95% CI, 1.12-1.45] P=2.87&#xd7;10-4) for stroke and 3.05 ([95% CI, 1.92-4.85] P=2.30&#xd7;10-6) for peripheral artery disease in the inverse variance-weighted analysis. There was some evidence for positive associations of genetically predicted alcohol consumption with coronary artery disease (OR, 1.16 [95% CI, 1.00-1.36]; P=0.052), atrial fibrillation (OR, 1.17 [95% CI, 1.00-1.37]; P=0.050), and abdominal aortic aneurysm (OR, 2.60 [95% CI, 1.15-5.89]; P=0.022) in the inverse variance-weighted analysis. These associations were somewhat attenuated in multivariable MR analysis adjusted for smoking initiation. There was no evidence of associations of genetically predicted alcohol consumption with heart failure (OR, 1.00 [95% CI, 0.68-1.47]; P=0.996), venous thromboembolism (OR, 1.04 [95% CI, 0.77-1.39]; P=0.810), and aortic valve stenosis (OR, 1.03 [95% CI, 0.56-1.90]; P=0.926). CONCLUSIONS: This study provides evidence of a causal relationship between higher alcohol consumption and increased risk of stroke and peripheral artery disease. The causal role of alcohol consumption for other cardiovascular diseases requires further research.","evidenceGrade":"full_text"},{"id":"p-pmid-33275596","title":"Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: A multivariable Mendelian randomization study.","authors":["DB Rosoff","G Davey Smith","N Mehta","TK Clarke","FW Lohoff"],"year":2021,"venue":"PLoS medicine","doi":"10.1371/journal.pmed.1003410","pmid":"33275596","url":"https://pubmed.ncbi.nlm.nih.gov/33275596/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events. METHODS AND FINDINGS: Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04-0.47, P value = 1.72 &#xd7; 10-28), triglycerides (TRG) (beta -0.23, 95% CI, -0.30, -0.15, P value = 4.69 &#xd7; 10-10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03-0.18, P value = 4.72 &#xd7; 10-3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03-0.16, P value = 5.24 &#xd7; 10-3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014-0.027, P value = 6.59 &#xd7; 10-12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03-1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01-1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01-1.03, P","evidenceGrade":"full_text"},{"id":"p-pmid-34379647","title":"Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study.","authors":["J Lankester","D Zanetti","E Ingelsson","TL Assimes"],"year":2021,"venue":"PloS one","doi":"10.1371/journal.pone.0255801","pmid":"34379647","url":"https://pubmed.ncbi.nlm.nih.gov/34379647/","methodology":"observational","n":null,"openAccess":true,"abstract":"Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy","evidenceGrade":"full_text"},{"id":"p-pmid-25433705","title":"Increased alcohol consumption as a cause of alcoholism, without similar evidence for depression: a Mendelian randomization study.","authors":["MK Wium-Andersen","DD &#xd8;rsted","JS Tolstrup","BG Nordestgaard"],"year":2016,"venue":"International journal of epidemiology","doi":"10.1093/ije/dyu220","pmid":"25433705","url":"https://pubmed.ncbi.nlm.nih.gov/25433705/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Increased alcohol consumption has been associated with depression and alcoholism, but whether these associations are causal remains unclear. We tested whether alcohol consumption is causally associated with depression and alcoholism. METHODS: We included 78,154 men and women aged 20-100 years randomly selected in 1991-2010 from the general population of Copenhagen, Denmark, and genotyped 68,486 participants for two genetic variants in two alcohol dehydrogenase (ADH) genes, ADH-1B (rs1229984) and ADH-1C (rs698). We performed observational and causal analyses using a Mendelian randomization design with antidepressant medication use and hospitalization/death, with depression and alcoholism as outcomes. RESULTS: In prospective analyses, the multifactorially adjusted hazard ratio for participants reporting &gt;6 drinks/day vs participants reporting 0.1-1 drinks/day was 1.28 (95% confidence interval, 1.00-1.65) for prescription antidepressant use, with a corresponding hazard ratio of 0.80 (0.45-1.45) for hospitalization/death with depression and of 11.7 (8.77-15.6) for hospitalization/death with alcoholism. For hospitalization/death with alcoholism, instrumental variable analysis yielded a causal odds ratio of 28.6 (95 % confidence interval 6.47-126) for an increase of 1 drink/day estimated from the combined genotype combination, whereas the corresponding multifactorially adjusted observational odds ratio was 1.28 (1.25-1.31). Corresponding odds ratios were 1.11 (0.67-1.83) causal and 1.04 (1.03-1.06) observational for prescription antidepressant use, and 4.52 (0.99-20.5) causal and 0.98 (0.94-1.03) observational for hospitalization/death with depression. CONCLUSIONS: These data indicate that the association between increased alcohol consumption and alcoholism is causal, without similar strong evidence for depression.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33193720","title":"Alcohol Use and Depression: A Mendelian Randomization Study From China.","authors":["C Zhu","Q Chen","W Si","Y Li","G Chen","Q Zhao"],"year":2020,"venue":"Frontiers in genetics","doi":"10.3389/fgene.2020.585351","pmid":"33193720","url":"https://pubmed.ncbi.nlm.nih.gov/33193720/","methodology":"observational","n":null,"openAccess":true,"abstract":"Background: Alcohol use has been linked to a number of physical conditions, but the relationship between alcohol drinking and depression, one of the most common mental disorders that is a significant contributor to the global burden of disease, is still under debate. We aim to help fill the literature gap on the causal effect of alcohol use on depression by using genetic instruments of ALDH2 rs671 and ADH1B rs1229984 in the Mendelian randomization (MR) framework. Materials and Methods: We collected a sample of 476 middle-aged and older adults from mainland China. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to measure the status of depression. The frequency and intensity of alcohol consumption were measured by (1) a binary indicator of drinking or not, (2) the total number of drinking occasions during the past 30 days, and (3) the weekly ethanol consumption in grams. Results: MR estimates indicated that alcohol use was causally associated with a lower risk of depression. Parameter estimates of drinking or not (b = -0.127, p = 0.048), number of drinking occasions (b = -0.012, p = 0.040), and weekly ethanol consumption (b = -0.001, p = 0.039) were all negative and statistically significant. The results were robust after adjustments for potential confounders (e.g., income, smoking, and parental drinking behaviors), and the exclusion of heavy or former drinkers. Conclusions: This is one of the first study to investigate the causal relationship between alcohol use and mental health using an MR design in East Asian populations. Further studies are needed to clarify the mechanisms of this causal link.","evidenceGrade":"full_text"},{"id":"p-pmid-39562730","title":"Associations between dairy and alcohol consumption and major depressive disorder in a mendelian randomization study.","authors":["D Qiu","R Song","X Cao","Y Tian","X Cheng","D Sun","S Cai","Z Wang"],"year":2024,"venue":"Scientific reports","doi":"10.1038/s41598-024-80330-4","pmid":"39562730","url":"https://pubmed.ncbi.nlm.nih.gov/39562730/","methodology":"observational","n":null,"openAccess":true,"abstract":"This study explored the link between diet and major depressive disorder (MDD) to provide fresh insights for MDD prevention. Single nucleotide polymorphisms (SNPs) associated with common foods, such as meat, bread, cheese, fruits, cereals, vegetables, and four alcohol intake categories, were leveraged as instrumental variables. Accordingly, this study employed the inverse variance weighting (IVW) method to evaluate the genetically predicted associations of different food phenotypes with MDD risk. The sensitivity analysis involved MR&#x2012;Egger regression and Mendelian random polymorphism residuals, along with outlier tests, to assess instrumental variable pleiotropy. Additional analysis methods, such as MR&#x2012;Egger, the weighted median method, and the weighted model, were used to validate the robustness and reliability of the findings. The results of the univariable Mendelian randomization(UVMR) analysis using IVW indicated that genetically predicted consumption of cheese [OR&#x2009;=&#x2009;0.841, 95% CI: 0.737-0.959, P&#x2009;=&#x2009;0.0099], dried fruit [OR&#x2009;=&#x2009;0.7922, 95% CI: 0.644-0.973, P&#x2009;=&#x2009;0.0264], beer [OR&#x2009;=&#x2009;1.284, 95% CI: 1.026-1.608, P&#x2009;=&#x2009;0.0291], and spirits [OR&#x2009;=&#x2009;3.837, 95% CI: 1.993-7.387, P&#x2009;=&#x2009;0.0001] were significantly associated with the risk of developing major depressive disorder. Specifically, cheese and dried fruit intake exhibited a inverse correlation with MDD risk, whereas beer and spirits intake showed a positive correlation, with spirits showing a stronger positive correlation. Fourteen other foods, including meat, vegetables, fruits, red wine, and white wine, displayed no significant association with the occurrence of major depression through either type of alcohol intake. In the multivariable Mendelian randomization(MVMR) analysis, considering potential confounding factors such as insomnia, smoking, and the use of contraceptive pills, cheese was identifie","evidenceGrade":"full_text"},{"id":"p-pmid-38508868","title":"Alcohol consumption and the risk of all-cause and cause-specific mortality-a linear and nonlinear Mendelian randomization study.","authors":["NA Kassaw","A Zhou","A Mulugeta","SH Lee","S Burgess","E Hypp&#xf6;nen"],"year":2024,"venue":"International journal of epidemiology","doi":"10.1093/ije/dyae046","pmid":"38508868","url":"https://pubmed.ncbi.nlm.nih.gov/38508868/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Many observational studies support light-to-moderate alcohol intake as potentially protective against premature death. We used a genetic approach to evaluate the linear and nonlinear relationships between alcohol consumption and mortality from different underlying causes. METHODS: We used data from 278&#x200a;093 white-British UK Biobank participants, aged 37-73&#x2009;years at recruitment and with data on alcohol intake, genetic variants, and mortality. Habitual alcohol consumption was instrumented by 94 variants. Linear Mendelian randomization (MR) analyses were conducted using five complementary approaches, and nonlinear MR analyses by the doubly-ranked method. RESULTS: There were 20&#x200a;834 deaths during the follow-up (median 12.6&#x2009;years). In conventional analysis, the association between alcohol consumption and mortality outcomes was 'J-shaped'. In contrast, MR analyses supported a positive linear association with premature mortality, with no evidence for curvature (Pnonlinearity &#x2265; 0.21 for all outcomes). The odds ratio [OR] for each standard unit increase in alcohol intake was 1.27 (95% confidence interval [CI] 1.16-1.39) for all-cause mortality, 1.30 (95% CI 1.10-1.53) for cardiovascular disease, 1.20 (95% CI 1.08-1.33) for cancer, and 2.06 (95% CI 1.36-3.12) for digestive disease mortality. These results were consistent across pleiotropy-robust methods. There was no clear evidence for an association between alcohol consumption and mortality from respiratory diseases or COVID-19 (1.32, 95% CI 0.96-1.83 and 1.46, 95% CI 0.99-2.16, respectively; Pnonlinearity &#x2265; 0.21). CONCLUSION: Higher levels of genetically predicted alcohol consumption had a strong linear association with an increased risk of premature mortality with no evidence for any protective benefit at modest intake levels.","evidenceGrade":"full_text"},{"id":"p-emanuele-2001","title":"Alcohol and the male reproductive system","authors":["M. A. Emanuele","N. Emanuele"],"year":2001,"venue":"Alcohol Research & Health","doi":null,"pmid":"11810959","url":"https://pubmed.ncbi.nlm.nih.gov/11810959/","methodology":"review","n":null,"openAccess":true,"abstract":"Chronic heavy alcohol use suppresses the HPG axis in men: lower T, testicular atrophy, disrupted GnRH. Dose and chronicity matter. A drink at dinner is not this paper.","evidenceGrade":"abstract_only"},{"id":"p-spiegel-1999","title":"Impact of sleep debt on metabolic and endocrine function","authors":["K. Spiegel","R. Leproult","E. Van Cauter"],"year":1999,"venue":"The Lancet","doi":"10.1016/S0140-6736(99)01376-8","pmid":"10560671","url":"https://pubmed.ncbi.nlm.nih.gov/10560671/","methodology":"rct","n":11,"openAccess":false,"abstract":"Sleep debt in young men raised evening cortisol and reduced glucose tolerance to a pre-diabetic range. Foundational endocrine-sleep trial.","evidenceGrade":"abstract_only"},{"id":"p-pmid-35953878","title":"Effects of alcohol on sleep and nocturnal heart rate: Relationships to intoxication and morning-after effects.","authors":["E Pabon","IM Greenlund","JR Carter","H de Wit"],"year":2022,"venue":"Alcoholism, clinical and experimental research","doi":"10.1111/acer.14921","pmid":"35953878","url":"https://pubmed.ncbi.nlm.nih.gov/35953878/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Alcohol consumption produces feelings of well-being and stimulation, but also impairs psychomotor performance, disturbs cardiovascular function and sleep, and can disrupt next-day mood and behavior. A deeper understanding of how the acute effects of alcohol relate to its sleep and morning-after effects is needed to minimize harm resulting from its use. This study examined relationships between the effects of a high dose of alcohol on subjective and psychomotor measures, nocturnal heart rate, sleep quality, and morning-after mood and behavior. We hypothesized that alcohol would produce disturbances in cardiovascular and sleep regulation during the night, which would predict morning-after mood and behavioral performance. METHODS: Thirty-one men and women participated in two overnight laboratory visits during which they consumed either alcohol (1.0&#xa0;g/kg for men, 0.85&#x2009;g/kg for women) or placebo (randomized, crossover design). They consumed the beverage from 8 to 9&#xa0;pm, and remained in the laboratory overnight for polysomnographic sleep recording. Subjective and behavioral measures were obtained during consumption and at 7-8&#xa0;am the morning after. RESULTS: Alcohol increased both negative and positive arousal, urge to drink and sedation, and it impaired performance on behavioral tasks. During sleep, alcohol produced expected tachycardia and detriments in sleep quality including decreased total sleep time, sleep efficiency, and altered sleep architecture. Only modest effects on mood or performance were detected the following morning. The acute sedative-like effects of alcohol were related to increases in N2 sleep, but not to other disruptions in sleep or nocturnal heart rate, and neither sleep impairments nor nocturnal heart rate were related to mood or task performance the morning after. CONCLUSIONS: The effects of alcohol on sleep and nocturnal heart rate were not strongly related to either its acute or morning-after effects. These finding","evidenceGrade":"full_text"},{"id":"p-pmid-12711931","title":"Testosterone increases in men after a low dose of alcohol.","authors":["T Sarkola","CJ Eriksson"],"year":2003,"venue":"Alcoholism, clinical and experimental research","doi":null,"pmid":"12711931","url":"https://pubmed.ncbi.nlm.nih.gov/12711931/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Heavy acute alcohol drinking decreases blood testosterone in men due to an effect on the testicular level. An acute increase in blood testosterone levels after a low alcohol dose has, however, recently been reported in women. The objective of this investigation was to study the effect of a low alcohol dose on testosterone in men and further elucidate the mechanism behind the effect by using 4-methylpyrazole, an inhibitor of alcohol metabolism. METHODS: A double-blind placebo-controlled interventional crossover trial in random order (n = 13). RESULTS: After intake of alcohol (0.5 g/kg, 10% w/v), an acute increase in plasma testosterone (from 13.5 +/- 1.2 nmol/liter to 16.0 +/- 1.6 nmol/liter, mean +/- SEM; p &lt; 0.05), a decrease in androstenedione (from 5.1 +/- 0.4 nmol/liter to 4.0 +/- 0.3 nmol/liter; p &lt; 0.05), and an increase in the testosterone:androstenedione ratio (from 2.8 +/- 0.3 to 4.2 +/- 0.4; p &lt; 0.01) were observed. The effects were not observed during pretreatment with 4-methylpyrazole (10-15 mg/kg orally), which inhibited the ethanol elimination rate by 37 +/- 3%. CONCLUSIONS: Alcohol intake affects the androgen balance in men through an effect mediated by the alcohol-induced change in the redox state in the liver.","evidenceGrade":"abstract_only"},{"id":"p-pmid-15166654","title":"Effect of moderate alcohol consumption on plasma dehydroepiandrosterone sulfate, testosterone, and estradiol levels in middle-aged men and postmenopausal women: a diet-controlled intervention study.","authors":["A Sierksma","T Sarkola","CJ Eriksson","MS van der Gaag","DE Grobbee","HF Hendriks"],"year":2004,"venue":"Alcoholism, clinical and experimental research","doi":null,"pmid":"15166654","url":"https://pubmed.ncbi.nlm.nih.gov/15166654/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Moderate alcohol consumption is inversely associated with cardiovascular diseases. Changes in hormone levels might in part help explain the positive health effect. This study was performed to examine the effect of moderate alcohol consumption on plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and estradiol levels. METHODS: In a randomized, diet-controlled, crossover study, 10 middle-aged men and 9 postmenopausal women, all apparently healthy, nonsmoking, and moderate alcohol drinkers, consumed beer or no-alcohol beer with dinner during two successive periods of 3 weeks. During the beer period, alcohol intake equaled 40 and 30 g per day for men and women, respectively. The total diet was supplied and had essentially the same composition during these 6 weeks. Before each treatment there was a 1 week washout period, in which the subjects were not allowed to drink alcoholic beverages. At the end of each of the two experimental periods, fasting blood samples were collected in the morning. RESULTS: Moderate alcohol consumption increased plasma DHEAS level by 16.5% (95% confidence interval, 8.0-24.9), with similar changes for men and women. Plasma testosterone level decreased in men by 6.8% (95% confidence interval, -1.0- -12.5), but no effect was found in women. Plasma estradiol level was not affected. Serum high-density lipoprotein cholesterol level increased by 11.7% (95% confidence interval, 7.3-16.0), with similar changes for men and women. The overall alcohol-induced relative changes in DHEAS, testosterone, and estradiol correlated positively with the relative increase in high-density lipoprotein cholesterol (adjusted for the relative change in body weight); however, findings were only borderline significant for DHEAS and estradiol (r = 0.44, p = 0.08; r = 0.32, p = 0.21; and r = 0.46, p = 0.06, respectively). CONCLUSIONS: A protective effect of moderate alcohol consumption for cardiovascular disease risk may in part be explained by increased","evidenceGrade":"abstract_only"},{"id":"p-pmid-11566440","title":"Alcohol intake, androgen and glucocorticoid steroids in premenopausal women using oral contraceptives: an interventional study.","authors":["T Sarkola","H Adlercreutz","S Heinonen","CJ Eriksson"],"year":2001,"venue":"The Journal of steroid biochemistry and molecular biology","doi":null,"pmid":"11566440","url":"https://pubmed.ncbi.nlm.nih.gov/11566440/","methodology":"rct","n":null,"openAccess":false,"abstract":"Long-term heavy alcohol intake is associated with endocrinological abnormalities the mechanisms of which are still unclear. The objective of the present study was to investigate the effect of alcohol intake on plasma and urine glucocorticoid and androgen steroid levels in healthy premenopausal women using oral contraceptives. In a placebo-controlled interventional study with a cross-over design including nine premenopausal women using oral contraceptives no effect of tolerance was observed with regard to the magnitude of the acute transient alcohol-induced testosterone elevation after a 1-week alcohol drinking period (0.8 g/kg per day). At non-intoxicated time points elevated plasma testosterone and androstenedione levels were found in the afternoon but not in the morning during the alcohol drinking period compared with placebo. An increase in plasma cortisol levels was observed after the discontinuation of alcohol drinking. No effects were observed in total glucocorticoid conjugates in morning urine spot samples. An increase during the alcohol period relative to placebo was, however, observed in the urine etiocholanolone/androsterone, tetrahydrocortisol/allotetrahydrocortisol as well as the 20-hydroxy-/20-ketosteroid ratios. No consistent effect was observed in the urine (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortisone ratio. It is suggested that the alcohol-induced alterations in plasma glucocorticoid and androgen levels during non-intoxicated conditions are due to a change in the hypothalamic-pituitary-adrenal function. The effects observed in the conjugated urine glucocorticoid and androgen ratios are likely to be mediated by a change in the metabolism of these steroids in the liver. The present results may be of relevance in the development of disturbances in the glucocorticoid as well as sex steroid balance among heavy female drinkers.","evidenceGrade":"abstract_only"},{"id":"p-pmid-27055824","title":"Body Weight Management in Adults Under Chronic Stress Through Treatment With Ashwagandha Root Extract: A Double-Blind, Randomized, Placebo-Controlled Trial.","authors":["D Choudhary","S Bhattacharyya","K Joshi"],"year":2017,"venue":"Journal of evidence-based complementary &amp; alternative medicine","doi":null,"pmid":"27055824","url":"https://pubmed.ncbi.nlm.nih.gov/27055824/","methodology":"rct","n":null,"openAccess":true,"abstract":"Chronic stress has been associated with a number of illnesses, including obesity. Ashwagandha is a well-known adaptogen and known for reducing stress and anxiety in humans. The objective of this study was to evaluate the safety and efficacy of a standardized root extract of Ashwagandha through a double-blind, randomized, placebo-controlled trial. A total of 52 subjects under chronic stress received either Ashwagandha (300 mg) or placebo twice daily. Primary efficacy measures were Perceived Stress Scale and Food Cravings Questionnaire. Secondary efficacy measures were Oxford Happiness Questionnaire, Three-Factor Eating Questionnaire, serum cortisol, body weight, and body mass index. Each subject was assessed at the start and at 4 and 8 weeks. The treatment with Ashwagandha resulted in significant improvements in primary and secondary measures. Also, the extract was found to be safe and tolerable. The outcome of this study suggests that Ashwagandha root extract can be used for body weight management in adults under chronic stress.","evidenceGrade":"full_text"},{"id":"p-pmid-32540634","title":"A randomized, double blind, placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults.","authors":["A Deshpande","N Irani","R Balkrishnan","IR Benny"],"year":2021,"venue":"Sleep medicine","doi":"10.1016/j.sleep.2020.03.012","pmid":"32540634","url":"https://pubmed.ncbi.nlm.nih.gov/32540634/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: Non-restorative sleep (NRS) affects 10% people worldwide, leading to poor sleep quality, as well as physical and cognitive fatigue. This is the first human study in which an extract of ashwagandha (Withania somnifera Dunal L.) was evaluated for effects in improving overall sleep quality in subjects with NRS. METHODS: In this randomized, double-blind, placebo-controlled trial, 150 healthy subjects scoring high on non-restorative sleep measures were given 120&#xa0;mg of standardized ashwagandha extract (Shoden&#xae;) once daily for six weeks. Subjects were evaluated using the Restorative Sleep Questionnaire-weekly version and World Health Organization Quality of Life-Bref (WHOQOL) scale. Sleep actigraphy was used to measure the onset of sleep latency, sleep efficiency, total sleep time and wake after sleep onset. Safety of the treatment was determined by testing of vitals, hematology, biochemistry and urinalysis. RESULTS: A total of 144 subjects completed the study, with no dropouts due to adverse events. A 72% increase in self-reported sleep quality was found for the treatment group, compared with 29% in the placebo group (p&#xa0;&lt;&#xa0;0.001). Based on activity monitoring data, the treatment group showed significant improvement in sleep efficiency (SE) (p&#xa0;&lt;&#xa0;0.01), total sleep time (p&#xa0;&lt;&#xa0;0.001) and sleep latency (p&#xa0;&lt;&#xa0;0.01) and wake after sleep onset (WASO) (p&#xa0;&lt;&#xa0;0.05) versus placebo after six weeks. In the ashwagandha group quality of life (QOL) scores showed significant improvement in physical (p&#xa0;&lt;&#xa0;0.001), psychological (p&#xa0;&lt;&#xa0;0.001), and environment domains (p&#xa0;&lt;&#xa0;0.01). CONCLUSIONS: Supplementation with the standardized ashwagandha extract for six weeks improved the overall quality of sleep by significantly improving the NRS condition in healthy subjects. No treatment related adverse events were reported in the study. TRIAL REGISTRATION: Clinical Trials Registry-Indi","evidenceGrade":"abstract_only"},{"id":"p-pmid-32818573","title":"Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: A double-blind, randomized, parallel-group, placebo-controlled study.","authors":["D Langade","V Thakare","S Kanchi","S Kelgane"],"year":2021,"venue":"Journal of ethnopharmacology","doi":"10.1016/j.jep.2020.113276","pmid":"32818573","url":"https://pubmed.ncbi.nlm.nih.gov/32818573/","methodology":"rct","n":null,"openAccess":false,"abstract":"ETHNOPHARMACOLOGICAL RELEVANCE: Ashwagandha (Withania somnifera (L.) Dunal.) is long known for its sleep-inducing effects. Ashwagandha can be proposed as an alternative to the recommended present treatments for insomnia. This study aimed to evaluate the pharmacological effect of Ashwagandha root extract on sleep in healthy subjects and also in the subjects having insomnia. MATERIAL AND METHODS: We performed a randomized, parallel-group, stratified design, placebo-controlled study. A total of 80 eligible participants, 40 in Arm-A (healthy) and 40 in Arm-B (insomnia) were assigned to two groups, either Ashwagandha or placebo and studied for 8-weeks. The assessment was done based on the sleep parameters (Sleep Onset Latency, Total Sleep Time, Wake After Sleep Onset, Total time in bed, and Sleep Efficiency), Pittsburgh Sleep Quality Index and Hamilton Anxiety scale-A questionnaire, mental alertness on rising assessment, and sleep quality questionnaire. Safety and adverse events along with the concomitant medication were also assessed. RESULTS: In both healthy and insomnia subjects, there was a significant improvement in the sleep parameters in the Ashwagandha root extract supplemented group. The improvement was found more significant in insomnia subjects than healthy subjects. Repeat measure Analysis of variance (ANOVA) confirmed the significant improvement in SOL (p 0.013), HAM-A outcomes (p&#xa0;&lt;&#xa0;0.05), mental alertness (p 0.01), and sleep quality (p&#xa0;&lt;&#xa0;0.05) of the insomnia patients. A two-way ANOVA was used to confirm the outcomes that denoted sleep onset latency (p&#xa0;&lt;&#xa0;0.0001) and sleep efficiency (p&#xa0;&lt;&#xa0;0.0001) as the most improved parameters, followed by TST (p&#xa0;&lt;&#xa0;0.002) and WASO(p&#xa0;&lt;&#xa0;0.040). All these parameters (SOL, TST, WASO, TIB, SE, PSQI, HAM-A, Mental Alertness, and Sleep quality) were also statistically assessed for the significant improvement within the group both for the treatment, and t","evidenceGrade":"abstract_only"},{"id":"p-pmid-37740662","title":"Exploring the efficacy and safety of a novel standardized ashwagandha (Withania somnifera) root extract (Witholytin&#xae;) in adults experiencing high stress and fatigue in a randomized, double-blind, placebo-controlled trial.","authors":["SJ Smith","AL Lopresti","TJ Fairchild"],"year":2023,"venue":"Journal of psychopharmacology (Oxford, England)","doi":"10.1177/02698811231200023","pmid":"37740662","url":"https://pubmed.ncbi.nlm.nih.gov/37740662/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Stress is a state of homeostasis in the body being challenged, resulting in a systemic response. It has become more prevalent in recent years and affects mental and physical health. AIMS: Evaluate the effects of ashwagandha on stress, fatigue, and sex hormones in overweight or mildly obese men and women with self-reported stress and fatigue. METHODS: Two-arm, parallel-group, 12-week, randomized, double-blind, placebo-controlled trial on overweight or mildly obese men and women aged 40-75&#x2009;years, supplementing with 200&#x2009;mg of an ashwagandha root extract (Witholytin&#xae;) twice daily. RESULTS/OUTCOMES: Supplementation with ashwagandha was associated with a significant reduction in stress levels based on the Perceived Stress Scale (primary outcome); however, the improvements were not significantly different to the placebo group (p&#x2009;=&#x2009;0.867). Based on the Chalder Fatigue Scale, there was a statistically significant reduction in fatigue symptoms in the ashwagandha group compared to the placebo group (p&#x2009;=&#x2009;0.016), and participants taking ashwagandha also experienced a significant increase in heart rate variability (p&#x2009;=&#x2009;0.003). However, there were no significant between-group differences in other self-report outcome measures. In the men taking ashwagandha, there was a significant increase in the blood concentrations of free testosterone (p&#x2009;=&#x2009;0.048) and luteinizing hormone (p&#x2009;=&#x2009;0.002) compared to the placebo group. CONCLUSIONS/INTERPRETATION: The results of this study suggest that in overweight middle-to-older age adults experiencing high stress and fatigue, compared to the placebo, ashwagandha did not have a significantly greater impact on perceived stress levels. However, based on secondary outcome measures, it may have anti-fatigue effects. This may be via its impact on the autonomic nervous system. However, further research is required to expand on these current findings.","evidenceGrade":"full_text"},{"id":"p-pmid-18611150","title":"Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: a randomized, double-blind, placebo-controlled trial.","authors":["C Calabrese","WL Gregory","M Leo","D Kraemer","K Bone","B Oken"],"year":2009,"venue":"Journal of alternative and complementary medicine (New York, N.Y.)","doi":"10.1089/acm.2008.0018","pmid":"18611150","url":"https://pubmed.ncbi.nlm.nih.gov/18611150/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: Study aims were to evaluate effects of Bacopa monnieri whole plant standardized dry extract on cognitive function and affect and its safety and tolerability in healthy elderly study participants. DESIGN: The study was a randomized, double-blind, placebo-controlled clinical trial with a placebo run-in of 6 weeks and a treatment period of 12 weeks. SETTING/LOCATION: Volunteers were recruited from the community to a clinic in Portland, Oregon by public notification. SUBJECTS: Fifty-four (54) participants, 65 or older (mean 73.5 years), without clinical signs of dementia, were recruited and randomized to Bacopa or placebo. Forty-eight (48) completed the study with 24 in each group. INTERVENTIONS: Standardized B. monnieri extract 300 mg/day or a similar placebo tablet orally for 12 weeks. OUTCOME MEASURES: The primary outcome variable was the delayed recall score from the Rey Auditory Verbal Learning Test (AVLT). Other cognitive measures were the Stroop Task assessing the ability to ignore irrelevant information, the Divided Attention Task (DAT), and the Wechsler Adult Intelligence Scale (WAIS) letter-digit test of immediate working memory. Affective measures were the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression scale (CESD)-10 depression scale, and the Profile of Mood States. Vital signs were also monitored. RESULTS: Controlling for baseline cognitive deficit using the Blessed Orientation-Memory-Concentration test, Bacopa participants had enhanced AVLT delayed word recall memory scores relative to placebo. Stroop results were similarly significant, with the Bacopa group improving and the placebo group unchanged. CESD-10 depression scores, combined state plus trait anxiety scores, and heart rate decreased over time for the Bacopa group but increased for the placebo group. No effects were found on the DAT, WAIS digit task, mood, or blood pressure. The dose was well tolerated with few adverse events (Bacopa n = 9, placebo n = 10), ","evidenceGrade":"full_text"},{"id":"p-pmid-38538390","title":"Evaluating the effects of Bacopa monnieri on cognitive performance and sleep quality of patients with mild cognitive impairment: A triple-blinded, randomized, placebo-controlled trial.","authors":["M Delfan","P Kordestani-Moghaddam","M Gholami","K Kazemi","R Mohammadi"],"year":2024,"venue":"Explore (New York, N.Y.)","doi":"10.1016/j.explore.2024.02.008","pmid":"38538390","url":"https://pubmed.ncbi.nlm.nih.gov/38538390/","methodology":"rct","n":null,"openAccess":false,"abstract":"INTRODUCTION: Mild cognitive impairment is the middle level of natural cognitive impairment during primary steps of dementia. There are a few studies about improving the cognitive performance and sleep quality in patients with a limited dementia. So, this study was conducted to evaluate the effects of Bacopa monnieri on cognitive performance and sleep quality of patients with mild cognitive impairment. MATERIALS AND METHODS: In this study, 62 patients with mild cognitive impairment were categorized into two groups of control and intervention. The intervention group received one pill of 160 mg Bacopa monnieri extract in 2 months, and the control group received a pill containing starch powder. The cognitive impairment and sleep quality was assessed using a questionnaire containing demographic information, Montreal Cognitive Assessment, and the Pittsburg Sleep Quality Index in three time-points of before the study, one months after the intervention and 2 months after the intervention (the end of study). RESULTS: The results showed no statistically significant difference between two groups in all three time-points in overall cognitive performance score and its 6 parameters (P &gt; 0.05). While in the field of attention at the end of the first month (P = 0.033) and the end of the second month (P = 0.004), it was significant difference between the study groups. Also, in the field of verbal fluency at the end of the second month, this difference was significant (P = 0.003). The cognitive performance overall score showed no significant difference between two groups in first (P = 0.939) and second time-points (P = 0.661), although it was significant at third time-point (P = 0.029). There was no statistically significant difference between two groups in all time-points for sleep quality overall score (P &gt; 0.05). CONCLUSION: The results showed that Bacopa monnieri can improve the cognitive performance overall score and some of its parameters, but it had no effect on sleep q","evidenceGrade":"abstract_only"},{"id":"p-pmid-41091332","title":"The Effects of a Bacopa monnieri Extract (Bacumen&#xae;) on Cognition, Stress, and Fatigue in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.","authors":["AL Lopresti","SJ Smith"],"year":2025,"venue":"Clinical drug investigation","doi":"10.1007/s40261-025-01492-1","pmid":"41091332","url":"https://pubmed.ncbi.nlm.nih.gov/41091332/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND AND OBJECTIVES: Bacopa monnieri is a plant used in Ayurvedic medicine with traditional uses for memory and cognitive function. The objective of this study was to examine the effects of supplementation with a Bacopa monnieri extract (Bacumen&#xae;) on cognitive function, stress, and fatigue in adults with self-reported memory and attention problems. STUDY DESIGN: Two-arm, 12-week, parallel-group, randomized, double-blind, placebo-controlled trial. METHODS: Overall, 101 volunteers aged 40-70 years with self-reported memory and attention problems were supplemented with 300 mg daily of a Bacopa monnieri extract (Bacumen&#xae;) (n = 50) or a placebo (n = 51). Outcome measures included several computer and researcher-administered cognitive tasks assessing verbal learning, attention and working memory (primary outcome measures) and self-report measures assessing memory, mood, and fatigue (secondary outcome measures). Changes in blood concentrations of brain-derived neurotrophic factor, malondialdehyde, and acetylcholine esterase activity were also examined. Cognitive assessments, blood collections and self-reported questionnaires were completed in person on day 0 and week 12. Moreover, self-report questionnaires were completed online at weeks 4 and 8. Participants, researchers and the statistician were blinded until all data was collected and a blind review was completed. RESULTS: Of the 101 participants randomized, 87 participants completed the study, 47 in the placebo group and 40 in the Bacopa monnieri group. On the basis of complete data collected from 87 participants, there were no between-group differences in changes in the primary outcome measures comprising verbal learning (p = 0.391), attention (p = 0.713), and working memory (p = 0.610). However, in the Bacopa-supplemented participants, there were greater reductions in overall self-reported stress reactivity (p = 0.03); and fatigue and stress levels after exposure to a cognitive-demanding computer task","evidenceGrade":"abstract_only"},{"id":"p-pmid-23808999","title":"Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion.","authors":["KG P&#xe9;rez-Rubio","M Gonz&#xe1;lez-Ortiz","E Mart&#xed;nez-Abundis","JA Robles-Cervantes","MC Espinel-Berm&#xfa;dez"],"year":2014,"venue":"Metabolic syndrome and related disorders","doi":"10.1089/met.2012.0183","pmid":"23808999","url":"https://pubmed.ncbi.nlm.nih.gov/23808999/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: The aim of this study was to evaluate the effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. METHODS: A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with a diagnosis of metabolic syndrome. Glucose and insulin levels after a dextrose load were measured. Triglycerides and high-density lipoprotein cholesterol concentrations at baseline were also measured. Twelve patients received berberine hydrochloride (500&#x2009;mg) three times daily before meals for 3 months. The remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were assessed. RESULTS: After berberine administration, patients had a remission of 36% (P=0.037) in the presence of metabolic syndrome and a significant decrease in waist circumference in females (106&#xb1;4 vs. 103&#xb1;3&#x2009;cm, P&lt;0.05), systolic blood pressure (SBP) (123&#xb1;7 vs. 115&#xb1;9&#x2009;mmHg, P&lt;0.01), triglycerides (2.4&#xb1;0.7 vs. 1.4&#xb1;0.5&#x2009;mmol/L, P&lt;0.01), area under the curve (AUC) of glucose (1182.1&#xb1;253.6 vs. 1069.5&#xb1;172.4&#x2009;mmol/l, P&lt;0.05), AUC of insulin (92,056&#xb1;72,148 vs. 67,407&#xb1;46,441&#x2009;pmol/L, P&lt;0.01), and insulinogenic index (0.78&#xb1;0.69 vs. 0.62&#xb1;0.46, P&lt;0.05), as well as an increase in the Matsuda index (2.1&#xb1;1.0 vs. 3.1&#xb1;1.6, P&lt;0.01). CONCLUSIONS: Administration of berberine leads to remission of metabolic syndrome and decreases in waist circumference, SBP, triglycerides, and total insulin secretion, with an increase in insulin sensitivity.","evidenceGrade":"abstract_only"},{"id":"p-pmid-18397984","title":"Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine.","authors":["Y Zhang","X Li","D Zou","W Liu","J Yang","N Zhu","L Huo","M Wang"],"year":2008,"venue":"The Journal of clinical endocrinology and metabolism","doi":"10.1210/jc.2007-2404","pmid":"18397984","url":"https://pubmed.ncbi.nlm.nih.gov/18397984/","methodology":"rct","n":null,"openAccess":false,"abstract":"CONTEXT: Berberine, a natural plant alkaloid, is usually used as an antibiotic drug. The potential glucose-lowering effect of berberine was noted when it was used for diarrhea in diabetic patients. In vitro and in vivo studies have then showed its effects on hyperglycemia and dyslipidemia. OBJECTIVE: The objective of the study was to evaluate the efficacy and safety of berberine in the treatment of type 2 diabetic patients with dyslipidemia. DESIGN: One hundred sixteen patients with type 2 diabetes and dyslipidemia were randomly allocated to receive berberine (1.0 g daily) and the placebo for 3 months. The primary outcomes were changes in plasma glucose and serum lipid concentrations. Glucose disposal rate (GDR) was measured using a hyperinsulinemic euglycemic clamp to assess insulin sensitivity. RESULTS: In the berberine group, fasting and postload plasma glucose decreased from 7.0 +/- 0.8 to 5.6 +/- 0.9 and from 12.0 +/- 2.7 to 8.9 +/- 2.8 mm/liter, HbA1c from 7.5 +/- 1.0% to 6.6 +/- 0.7%, triglyceride from 2.51 +/- 2.04 to 1.61 +/- 1.10 mm/liter, total cholesterol from 5.31 +/- 0.98 to 4.35 +/- 0.96 mm/liter, and low-density lipoprotein-cholesterol from 3.23 +/- 0.81 to 2.55 +/- 0.77 mm/liter, with all parameters differing from placebo significantly (P &lt; 0.0001, P &lt; 0.0001, P &lt; 0.0001, P = 0.001, P &lt; 0.0001, and P &lt;0.0001, respectively). The glucose disposal rate was increased after berberine treatment (P = 0.037), although no significant change was found between berberine and placebo groups (P = 0.063). Mild to moderate constipation was observed in five participants in the berberine group. CONCLUSIONS: Berberine is effective and safe in the treatment of type 2 diabetes and dyslipidemia.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37611246","title":"Pilot study on the efficacy and safety of berberine in people with metabolic syndrome and human immunodeficiency virus infection.","authors":["VV Ruiz-Herrera","SA Navarro-Lara","JF Andrade-Villanueva","M Alvarez-Zavala","K S&#xe1;nchez-Reyes","M Toscano-Pi&#xf1;a","AS M&#xe9;ndez-Clemente","P Mart&#xed;nez-Ayala"],"year":2023,"venue":"International journal of STD &amp; AIDS","doi":"10.1177/09564624231196600","pmid":"37611246","url":"https://pubmed.ncbi.nlm.nih.gov/37611246/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Antiretroviral therapy has increased the life expectancy of people living with HIV. However, this increase is not free of comorbidities, and metabolic syndrome is one of the most prevalent. Berberine is an alkaloid nutraceutical that has been shown to ameliorate metabolic disorders such as prediabetes, polycystic ovary syndrome, and non-alcoholic fatty liver disease. However, it has not been tested in HIV infection. Therefore, we conducted a randomized controlled trial to evaluate the efficacy of berberine in improving metabolic syndrome. METHODS AND RESULTS: In this double-blind, placebo-controlled trial, adults living with HIV under virological suppression and metabolic syndrome received either berberine 500&#xa0;mg TID or placebo for 20&#xa0;weeks. The primary outcomes were a composite of weight reduction, insulin resistance decrease, and lipid profile improvement. A total of 43 participants were randomized (22 in the berberine group and 21 in the placebo group); 36 participants completed the follow-up and were analyzed. The berberine group showed a reduction in weight and body mass index, lower insulin resistance, and a reduction in TNF-alpha. The control group had higher total cholesterol, c-LDL, and IL-6 concentration. CONCLUSION: In people living with HIV under virological suppression, berberine was safe and improves clinical and biochemical components of metabolic syndrome. However, further studies with more participants and longer intervention periods need to be explored.","evidenceGrade":"abstract_only"},{"id":"p-pmid-25700532","title":"Breastfeeding duration and non-verbal IQ in children.","authors":["A Sajjad","A Tharner","JC Kiefte-de Jong","VV Jaddoe","A Hofman","FC Verhulst","OH Franco","H Tiemeier"],"year":2016,"venue":"Journal of epidemiology and community health","doi":"10.1136/jech-2014-204486","pmid":"25700532","url":"https://pubmed.ncbi.nlm.nih.gov/25700532/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Breastfeeding has been related to better cognitive development in children. However, due to methodological challenges, such as confounding, recall bias or insufficient power, the mechanism and nature of the relation remains subject to debate. METHODS: We included 3761 participants of a population-based cohort study from fetal life onwards and examined the association of breastfeeding duration with non-verbal intelligence in children of age 6&#x2005;years. Maternal and paternal lifestyle, sociodemographic factors, child factors and maternal IQ were tested for their confounding effects on the association. RESULTS: We observed an initial association between breastfeeding duration and child IQ conferring an advantage of 0.32 (0.20 to 0.44) points for each additional month of breastfeeding. This association strongly attenuated to 0.09 (-0.03 to 0.21) points after adjustment for child factors, sociodemographic factors, parental lifestyle factors and maternal IQ. Similarly, the associations with breastfeeding duration as a categorical variable largely disappeared after confounding factors were added to the models. CONCLUSIONS: The association between breastfeeding and child IQ can be largely explained by sociodemographic factors, parental lifestyle and maternal IQ. Our results cannot confirm beneficial effects of breastfeeding on child intelligence.","evidenceGrade":"abstract_only"},{"id":"p-pmid-24116864","title":"A cohort study on full breastfeeding and child neuropsychological development: the role of maternal social, psychological, and nutritional factors.","authors":["J Julvez","M Guxens","AE Carsin","J Forns","M Mendez","MC Turner","J Sunyer"],"year":2014,"venue":"Developmental medicine and child neurology","doi":"10.1111/dmcn.12282","pmid":"24116864","url":"https://pubmed.ncbi.nlm.nih.gov/24116864/","methodology":"observational","n":null,"openAccess":false,"abstract":"AIM: This study investigated whether duration of full breastfeeding is associated with child neuropsychological development and whether this association is explained by social, psychological, and nutritional factors within families. METHOD: Participants in this study were a population-based birth cohort in the city of Sabadell (Catalonia, Spain). Females were recruited during the first trimester of pregnancy between July 2004 and July 2006. Information about parental characteristics and breastfeeding was obtained through questionnaires. Full breastfeeding was categorized as never, short term (&#x2264;4mo), long term (4-6mo), or very long term (&gt;6mo). A trained psychologist assessed the neuropsychological development of children at 4 years of age (n=434) using the McCarthy Scales of Children's Abilities (MSCA). RESULTS: Full breastfeeding showed an independent association with child general MSCA scores after adjusting for a range of social, psychological, and nutritional factors (&gt;6mo, coefficient=7.4 [95% confidence interval=2.8-12.0], p=0.011). Maternal social class, education level, and IQ were also associated with child neuropsychological scores, but did not explain breastfeeding associations. Omega-3 (n3) fatty acid levels were not associated with child neuropsychological scores. INTERPRETATION: Very long-term full breastfeeding was independently associated with neuropsychological functions of children at 4 years of age. Maternal indicators of intelligence, psychopathology, and colostrum n3 fatty acids did not explain this association.","evidenceGrade":"abstract_only"},{"id":"p-pmid-28081886","title":"Breastfeeding, Polyunsaturated Fatty Acid Levels in Colostrum and Child Intelligence Quotient at Age 5-6 Years.","authors":["JY Bernard","M Armand","H Peyre","C Garcia","A Forhan","M De Agostini","MA Charles","B Heude"],"year":2017,"venue":"The Journal of pediatrics","doi":"10.1016/j.jpeds.2016.12.039","pmid":"28081886","url":"https://pubmed.ncbi.nlm.nih.gov/28081886/","methodology":"observational","n":null,"openAccess":false,"abstract":"OBJECTIVE: To examine the relationship of polyunsaturated fatty acid (PUFA) in breast milk with children's IQ. STUDY DESIGN: In the French Etude des D&#xe9;terminants pr&#xe9;- et postnatals pr&#xe9;coces du d&#xe9;veloppement et de la sant&#xe9; de l'Enfant (EDEN) mother-child cohort, colostrum samples were collected at the maternity unit. Colostrum omega-6 and omega-3 PUFA were analyzed by gas chromatography. At age 5-6 years, the IQs of 1080 children were assessed using the Wechsler Preschool and Primary Scale of Intelligence-III. The relationships of breastfeeding duration and PUFA levels with children's IQs were examined by linear regression. RESULTS: Full scale IQ of ever breastfed children was 4.5 (95% CI: 2.7, 6.2) higher than never breastfed children in the unadjusted model, but this was not statistically significant in the adjusted model (1.3 points higher [-0.4, 3.0]). Any breastfeeding duration was associated with full scale (0.20 [0.00, 0.41] points/month) and verbal (0.31 [0.09, 0.52]) IQ. Colostrum linoleic acid (LA) levels were negatively associated with Verbal IQ (-0.6 [-1.1, 0.0] points per 1% level increase). Children exposed to colostrum high in LA and low in docosahexaenoic acid (DHA) had lower IQs than those exposed to colostrum high in DHA (3.0 [0.5, 5.5] points) and those exposed to colostrum low in LA and DHA (4.4 [1.6, 7.3] points). Finally, the association between breastfeeding duration and child IQ was stronger when LA levels were high. CONCLUSIONS: Duration of breastfeeding and colostrum PUFA levels were associated with children's IQs in the EDEN cohort. These data support breastfeeding and add evidence for the role of early PUFA exposure on childhood cognition.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30786114","title":"Caffeinated and decaffeinated coffee consumption and risk of all-cause mortality: a dose-response meta-analysis of cohort studies.","authors":["Q Li","Y Liu","X Sun","Z Yin","H Li","C Cheng","L Liu","R Zhang"],"year":2020,"venue":"Journal of human nutrition and dietetics : the official journal of the British Dietetic Association","doi":"10.1111/jhn.12633","pmid":"30786114","url":"https://pubmed.ncbi.nlm.nih.gov/30786114/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: Previous meta-analysis showed an inverse association between coffee consumption and all-cause mortality. However, the relationship between caffeinated and decaffeinated coffee consumption and all-cause mortality is inconsistent. We aimed to identify and review the published evidence updating the association between coffee consumption and all-cause mortality and, furthermore, to investigate the association of caffeinated and decaffeinated coffee consumption and all-cause mortality. METHODS: We systematically searched PubMed and Web of Science for studies published up to 9 November 2017. Cohort studies in which authors reported relative risks (RRs) of all-cause mortality for at least three levels of coffee consumption were eligible. Random-effects models were used to estimate the pooled RR of all-cause mortality with coffee consumption. Restricted cubic splines were used to model the dose-response association. RESULTS: We included 21 cohort study articles (10&#xa0;103&#xa0;115 study participants and 240&#xa0;303 deaths). We found a nonlinear association between coffee consumption and all-cause mortality (Pnonlinearity &#xa0;&lt;&#xa0;0.001). Compared with no or rare coffee consumption, with a consumption of 3 cups&#xa0;day-1 , the risk of all-cause mortality might reduce 13% (RR&#xa0;=&#xa0;0.87; 95% confidence interval&#xa0;=&#xa0;0.84-0.89). CONCLUSIONS: The findings of the present study provide quantitative data suggesting that coffee consumption plays a role in reducing the risk of all-cause mortality. Similar inverse associations are found for caffeinated coffee and decaffeinated coffee.","evidenceGrade":"abstract_only"},{"id":"p-pmid-18559841","title":"The relationship of coffee consumption with mortality.","authors":["E Lopez-Garcia","RM van Dam","TY Li","F Rodriguez-Artalejo","FB Hu"],"year":2008,"venue":"Annals of internal medicine","doi":null,"pmid":"18559841","url":"https://pubmed.ncbi.nlm.nih.gov/18559841/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Coffee consumption has been linked to various beneficial and detrimental health effects, but data on its relation with mortality are sparse. OBJECTIVE: To assess the association between coffee consumption and mortality from cardiovascular disease (CVD), cancer, and all causes during 18 years of follow-up in men and 24 years of follow-up in women. DESIGN: Sex-specific Cox proportional hazard models were used to investigate the association between coffee consumption and incidence of all-cause and disease-specific mortality in a prospective cohort study. SETTING: Health Professionals Follow-up Study and Nurses' Health Study. PARTICIPANTS: 41,736 men and 86,214 women with no history of CVD or cancer at baseline. MEASUREMENTS: Coffee consumption was assessed first in 1986 for men and in 1980 for women and then every 2 to 4 years through 2004. Investigators documented 6888 deaths (2049 due to CVD and 2491 due to cancer) among men and 11,095 deaths (2368 due to CVD and 5011 due to cancer) among women. RESULTS: After adjustment for age, smoking, and other CVD and cancer risk factors, the relative risks for all-cause mortality in men across categories of coffee consumption (&lt;1 cup per month, 1 cup per month to 4 cups per week, 5 to 7 cups per week, 2 to 3 cups per day, 4 to 5 cups per day, and &gt;or=6 cups per day) were 1.0, 1.07 (95% CI, 0.99 to 1.16), 1.02 (CI, 0.95 to 1.11), 0.97 (CI, 0.89 to 1.05), 0.93 (CI, 0.81 to 1.07), and 0.80 (CI, 0.62 to 1.04), respectively (P for trend = 0.008). For women, the relative risks were 1.0, 0.98 (CI, 0.91 to 1.05), 0.93 (CI, 0.87 to 0.98), 0.82 (CI, 0.77 to 0.87), 0.74 (CI, 0.68 to 0.81), and 0.83 (CI, 0.73 to 0.95), respectively (P for trend &lt; 0.001). This inverse association was mainly due to a moderately reduced risk for CVD mortality and was independent of caffeine intake. By contrast, coffee consumption was not statistically significantly associated with risk for cancer death after adjustment for potential confo","evidenceGrade":"full_text"},{"id":"p-pmid-40368300","title":"Coffee Consumption and Mortality among United States Adults: A Prospective Cohort Study.","authors":["B Zhou","M Ruan","Y Pan","L Wang","FF Zhang"],"year":2025,"venue":"The Journal of nutrition","doi":"10.1016/j.tjnut.2025.05.004","pmid":"40368300","url":"https://pubmed.ncbi.nlm.nih.gov/40368300/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Although coffee consumption has been associated with a variety of health benefits, it remains unclear whether the addition of sugar and saturated fat modifies these effects. OBJECTIVES: This study aimed to examine the relationship between coffee intake, including the amount of added sugar and saturated fat, and mortality among United States adults. METHODS: We conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey from 1999 to 2018, linked to National Death Index Mortality Data. The study included 46,222 adults aged 20 y and older who completed valid first-day 24-h dietary recalls. Coffee consumption was categorized by type (caffeinated or decaffeinated) and by sugar (&lt;2.5 g per 8-oz), and saturated fat content (&lt;1 g per 8-oz). Mortality outcomes included all-cause, cancer, and cardiovascular disease (CVD) mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risk based on type, intake levels (nondrinkers, &lt;1 cup/d, 1 to &lt;2 cups/d, 2 to &lt;3 cups/d, and &#x2265;3 cups/d) and the amount of added sugar and saturated fat. RESULTS: Over a median follow-up of 9.3-11.3 y, a total of 7074 deaths occurred, including 1176 cancer-specific and 1089 CVD-specific deaths. Higher coffee consumption was associated with lower all-cause mortality [HR (95% CI): 0.89 (0.78, 1.02) for &lt; 1 cup/d; 0.84 (0.77, 0.92) for 1 to &lt;2 cups/d; 0.83 (0.75, 0.93) for 2 to &lt;3 cups/d; and 0.85 (0.77, 0.95) for &#x2265;3 cups/d; P-trend = 0.004]. However, the mortality benefits were restricted to black coffee [HR (95% CI): 0.86 (0.77, 0.97)] and coffee with low added sugar and saturated fat content [HR (95% CI): 0.86 (0.75, 0.99)]. CONCLUSIONS: The health benefits of coffee consumption may be diminished when sugar and saturated fat are added.","evidenceGrade":"full_text"},{"id":"p-pmid-28697850","title":"Association Between Caffeine Intake and All-Cause and Cause-Specific Mortality: A&#xa0;Population-Based Prospective Cohort Study.","authors":["T Tsujimoto","H Kajio","T Sugiyama"],"year":2017,"venue":"Mayo Clinic proceedings","doi":"10.1016/j.mayocp.2017.03.010","pmid":"28697850","url":"https://pubmed.ncbi.nlm.nih.gov/28697850/","methodology":"observational","n":null,"openAccess":false,"abstract":"OBJECTIVE: To assess whether caffeine intake is associated with all-cause and cause-specific mortality. PATIENTS AND METHODS: We conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey 1999-2010. Cox proportional hazards models were used to compare the multivariate-adjusted hazard ratios (HRs) of participants with a caffeine intake of 10 to 99, 100 to 199, and 200 mg/d or more with those of participants with a caffeine intake of less than 10 mg/d. RESULTS: In total, 17,594 participants were included, and the mean &#xb1; SD and median (interquartile range) follow-up was 6.5&#xb1;2.8 years and 6.4 (3.6-9.5) years, respectively; 17,568 participants (99.8%) completed the follow-up, and 1310 died. Compared with those who had a caffeine intake of less than 10 mg/d, HRs and 95% CIs for all-cause mortality were significantly lower in participants with a caffeine intake of 10 to 99 mg/d (HR, 0.81; 95% CI, 0.66-1.00; P=.05), 100 to 199 mg/d (HR, 0.63; 95% CI, 0.51-0.78; P&lt;.001), and 200 or more mg/d (HR, 0.69; 95% CI, 0.58-0.83; P&lt;.001). A similar association was observed in participants who consumed less than 1 cup of coffee per week, and the HR was lowest in those with a caffeine intake of 100&#xa0;to 199 mg/d (HR, 0.46; 95% CI, 0.22-0.93). There was no association between caffeine intake and cardiovascular mortality, whereas the HRs for noncardiovascular mortality were significantly lower in those with a caffeine intake of 10 to 99 mg/d (HR, 0.74; 95% CI, 0.57-0.95; P=.01), 100 to&#xa0;199 mg/d (HR, 0.60; 95% CI, 0.46-0.77; P&lt;.001), and 200 or more mg/d (HR, 0.65; 95% CI, 0.53-0.80; P&lt;.001). CONCLUSION: Moderate caffeine intake was associated with a decreased risk of all-cause mortality, regardless of the presence or absence of coffee consumption.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33633278","title":"The impact of daily caffeine intake on nighttime sleep in young adult men.","authors":["J Weibel","YS Lin","HP Landolt","J Kistler","S Rehm","KM Rentsch","H Slawik","S Borgwardt"],"year":2021,"venue":"Scientific reports","doi":"10.1038/s41598-021-84088-x","pmid":"33633278","url":"https://pubmed.ncbi.nlm.nih.gov/33633278/","methodology":"rct","n":null,"openAccess":true,"abstract":"Acute caffeine intake can delay sleep initiation and reduce sleep intensity, particularly when consumed in the evening. However, it is not clear whether these sleep disturbances disappear when caffeine is continuously consumed during daytime, which is common for most coffee drinkers. To address this question, we investigated the sleep of twenty male young habitual caffeine consumers during a double-blind, randomized, crossover study including three 10-day conditions: caffeine (3&#x2009;&#xd7;&#x2009;150&#xa0;mg caffeine daily), withdrawal (3&#x2009;&#xd7;&#x2009;150&#xa0;mg caffeine for 8&#xa0;days, then switch to placebo), and placebo (3&#x2009;&#xd7;&#x2009;placebo daily). After 9&#xa0;days of continuous treatment, electroencephalographically (EEG)-derived sleep structure and intensity were recorded during a scheduled 8-h nighttime sleep episode starting 8 (caffeine condition) and 15&#xa0;h (withdrawal condition) after the last caffeine intake. Upon scheduled wake-up time, subjective sleep quality and caffeine withdrawal symptoms were assessed. Unexpectedly, neither polysomnography-derived total sleep time, sleep latency, sleep architecture nor subjective sleep quality differed among placebo, caffeine, and withdrawal conditions. Nevertheless, EEG power density in the sigma frequencies (12-16&#xa0;Hz) during non-rapid eye movement sleep was reduced in both caffeine and withdrawal conditions when compared to placebo. These results indicate that daily caffeine intake in the morning and afternoon hours does not strongly impair nighttime sleep structure nor subjective sleep quality in healthy good sleepers who regularly consume caffeine. The reduced EEG power density in the sigma range might represent early signs of overnight withdrawal from the continuous presence of the stimulant during the day.","evidenceGrade":"full_text"},{"id":"p-pmid-34024173","title":"Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men.","authors":["J Weibel","YS Lin","HP Landolt","C Berthomier","M Brandewinder","J Kistler","S Rehm","KM Rentsch"],"year":2021,"venue":"Journal of biological rhythms","doi":"10.1177/07487304211013995","pmid":"34024173","url":"https://pubmed.ncbi.nlm.nih.gov/34024173/","methodology":"rct","n":null,"openAccess":true,"abstract":"Acute caffeine intake can attenuate homeostatic sleep pressure and worsen sleep quality. Caffeine intake-particularly in high doses and close to bedtime-may also affect circadian-regulated rapid eye movement (REM) sleep promotion, an important determinant of subjective sleep quality. However, it is not known whether such changes persist under chronic caffeine consumption during daytime. Twenty male caffeine consumers (26.4 &#xb1; 4 years old, habitual caffeine intake 478.1 &#xb1; 102.8 mg/day) participated in a double-blind crossover study. Each volunteer completed a caffeine (3 &#xd7; 150 mg caffeine daily for 10 days), a withdrawal (3 &#xd7; 150 mg caffeine for 8 days then placebo), and a placebo condition. After 10 days of controlled intake and a fixed sleep-wake cycle, we recorded electroencephalography for 8 h starting 5 h after habitual bedtime (i.e., start on average at 04:22 h which is around the peak of circadian REM sleep promotion). A 60-min evening nap preceded each sleep episode and reduced high sleep pressure levels. While total sleep time and sleep architecture did not significantly differ between the three conditions, REM sleep latency was longer after daily caffeine intake compared with both placebo and withdrawal. Moreover, the accumulation of REM sleep proportion was delayed, and volunteers reported more difficulties with awakening after sleep and feeling more tired upon wake-up in the caffeine condition compared with placebo. Our data indicate that besides acute intake, also regular daytime caffeine intake affects REM sleep regulation in men, such that it delays circadian REM sleep promotion when compared with placebo. Moreover, the observed caffeine-induced deterioration in the quality of awakening may suggest a potential motive to reinstate caffeine intake after sleep.","evidenceGrade":"full_text"},{"id":"p-pmid-26483209","title":"Effects of an intervention with drinking chamomile tea on sleep quality and depression in sleep disturbed postnatal women: a randomized controlled trial.","authors":["SM Chang","CH Chen"],"year":2016,"venue":"Journal of advanced nursing","doi":"10.1111/jan.12836","pmid":"26483209","url":"https://pubmed.ncbi.nlm.nih.gov/26483209/","methodology":"rct","n":null,"openAccess":false,"abstract":"AIM: The purpose of this study was to evaluate the effects of chamomile tea on sleep quality, fatigue and depression in postpartum women. BACKGROUND: Sleep quality is a significant issue for postnatal women. Chamomile is widely used as a folk remedy for its presumed sedative-hypnotic effects. DESIGN: A pretest-post-test randomized controlled trial was used. METHODS: A total of 80 Taiwanese postnatal women with poor sleep quality (Postpartum Sleep Quality Scale; PSQS score &#x2267;16) were recruited from November 2012-August 2013. They were systematically assigned, with a random start, to either the experimental group (n&#xa0;=&#xa0;40) or the control group (n&#xa0;=&#xa0;40). The participants in the experimental group were instructed to drink chamomile tea for a period of 2 weeks. The participants in the control group received regular postpartum care only. The PSQS, Edinburgh Postnatal Depression Scale, and Postpartum Fatigue Scale were used to assess outcomes. Two-sample t-tests were used to examine the mean differences in outcome variables between the two groups. RESULTS: Compared with the control group, the experimental group demonstrated significantly lower scores of physical-symptoms-related sleep inefficiency (t&#xa0;=&#xa0;-2&#xb7;482, P&#xa0;=&#xa0;0&#xb7;015) and the symptoms of depression (t&#xa0;=&#xa0;-2&#xb7;372, P&#xa0;=&#xa0;0&#xb7;020). However, the scores for all three instruments were similar for both groups at 4-week post-test, suggesting that the positive effects of chamomile tea were limited to the immediate term. CONCLUSION: Chamomile tea may be recommended to postpartum women as a supplementary approach to alleviating depression and sleep quality problems.","evidenceGrade":"abstract_only"},{"id":"p-pmid-26279073","title":"Chromium Supplementation and the Effects on Metabolic Status in Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.","authors":["M Jamilian","Z Asemi"],"year":2016,"venue":"Annals of nutrition &amp; metabolism","doi":null,"pmid":"26279073","url":"https://pubmed.ncbi.nlm.nih.gov/26279073/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: The aim of the present study was to evaluate the beneficial effects of chromium intake on markers of insulin metabolism and lipid profiles in women with polycystic ovary syndrome (PCOS). METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, 64 women with PCOS were randomized to receive 200 &#xb5;g chromium picolinate supplements (n = 32) or placebo (n = 32) for 8 weeks. Fasting blood samples were obtained at baseline and 8 weeks after the intervention to quantify markers of insulin metabolism and lipid concentrations. RESULTS: Chromium supplementation in women with PCOS resulted in significant decreases in serum insulin levels (-3.6 &#xb1; 7.4 vs. +3.6 &#xb1; 6.2 &#xb5;IU/ml, p &lt; 0.001), homeostasis model of assessment-insulin resistance (HOMA-IR; -0.8 &#xb1; 1.6 vs. +0.9 &#xb1; 1.5, p &lt; 0.001), homeostatic model assessment-beta cell function (HOMA-B; -15.5 &#xb1; 32.3 vs. +13.6 &#xb1; 23.1, p &lt; 0.001), and a significant increase in quantitative insulin sensitivity check index (QUICKI) score (+0.02 &#xb1; 0.03 vs. -0.008 &#xb1; 0.02, p = 0.001) compared with the placebo. In addition, a trend toward a significant effect of chromium supplementation on decreasing serum triglycerides (-12.4 &#xb1; 74.4 vs. +15.2 &#xb1; 32.4 mg/dl, p = 0.05), very low-density lipoprotein-cholesterol (-2.5 &#xb1; 14.9 vs. +3.0 &#xb1; 6.5 mg/dl, p = 0.05), and cholesterol concentrations (-8.6 &#xb1; 21.9 vs. +0.7 &#xb1; 22.4 mg/dl, p = 0.09) was seen. CONCLUSIONS: Eight weeks of chromium supplementation among PCOS women had favorable effects on markers of insulin metabolism.","evidenceGrade":"abstract_only"},{"id":"p-pmid-21216583","title":"Effects of short-term chromium supplementation on insulin sensitivity and body composition in overweight children: randomized, double-blind, placebo-controlled study.","authors":["CW Kim","BT Kim","KH Park","KM Kim","DJ Lee","SW Yang","NS Joo"],"year":2012,"venue":"The Journal of nutritional biochemistry","doi":"10.1016/j.jnutbio.2010.10.001","pmid":"21216583","url":"https://pubmed.ncbi.nlm.nih.gov/21216583/","methodology":"rct","n":null,"openAccess":false,"abstract":"Excessive body weight is inversely associated with insulin sensitivity in children and adults. Chromium supplementation produces modest improvement in insulin sensitivity in adults. The aim of this study was to examine the beneficial effects of chromium supplementation on insulin sensitivity and body composition in overweight children simultaneously modifying lifestyle. Twenty-five overweight children aged 9-12 years were randomized to receive either 400 &#x3bc;g of chromium chloride or placebo in double-blind fashion, during a 6-week lifestyle modification regimen that included nutritional education and 3&#xd7;90 min of aerobic physical activity weekly. Insulin sensitivity was demonstrated using homeostasis model assessment-insulin resistance and quantitative insulin sensitivity check index (QUICKI). Changes in body mass index (BMI; kg/m(2)), BMI Z-score, waist circumference, body composition and fasting plasma glucose were measured. Although no significant benefit of chromium supplementation over placebo was evident for BMI, BMI Z-score and fasting insulin level, children who received chromium chloride demonstrated more positive changes versus the placebo group in HOMA (-1.84&#xb1;1.07 vs. 0.05&#xb1;0.42, P=.05), QUICKI (0.02&#xb1;0.01 vs. -0.002&#xb1;0.01, P=.05), lean body mass (2.43&#xb1;0.68 kg vs. 1.36&#xb1;1.61 kg, P=.02) and percentage body fat (-3.32&#xb1;1.29% vs. 0.65&#xb1;1.05%, P=.04). The desirable effects of chromium supplementation on insulin sensitivity and body composition were more apparent in pre-pubertal children. These results suggest that short-term chromium supplementation can improve insulin sensitivity and body composition in overweight children.","evidenceGrade":"abstract_only"},{"id":"p-pmid-22674882","title":"Effect of chromium dinicocysteinate supplementation on circulating levels of insulin, TNF-&#x3b1;, oxidative stress, and insulin resistance in type 2 diabetic subjects: randomized, double-blind, placebo-controlled study.","authors":["SK Jain","G Kahlon","L Morehead","R Dhawan","B Lieblong","T Stapleton","G Caldito","R Hoeldtke"],"year":2013,"venue":"Molecular nutrition &amp; food research","doi":"10.1002/mnfr.201100719","pmid":"22674882","url":"https://pubmed.ncbi.nlm.nih.gov/22674882/","methodology":"rct","n":null,"openAccess":true,"abstract":"SCOPE: Chromium and cysteine supplementation have been shown to improve glucose metabolism in animal studies. This study examined the hypothesis that chromium dinicocysteinate (CDNC), a complex of chromium and l-cysteine, is beneficial in lowering oxidative stress, vascular inflammation, and glycemia in type 2 diabetic subjects. METHODS AND RESULTS: Type 2 diabetic subjects enrolled in this study were given placebo for 1 month for stabilization and then randomized into one of three groups: placebo (P), chromium picolinate (CP), or CDNC, after which they received daily oral supplementation for 3 months. Of the 100 patients enrolled in the study, 74 patients completed it. There were 25 patients in the P supplemented group, 25 in the CP supplemented and 24 in the CDNC supplemented group who completed the study. Blood markers of glycemia, vascular inflammation, HOMA insulin resistance, and oxidative stress were determined at randomization and after 3 months of supplementation with P, CP, or CDNC. There was a significant decrease at 3 months in insulin resistance (p = 0.02) and in the levels of protein oxidation (p = 0.02) and TNF-&#x3b1; (p = 0.01) in the CDNC supplemented cohort compared to baseline. However, there was no statistically significant change in these markers in the CP supplemented group compared to baseline. Insulin levels significantly decreased (p = 0.01) for subjects receiving CDNC but not CP. There was no significant impact of supplementation on HbA(1c) or glucose levels in either of the groups. CONCLUSION: CDNC supplementation lowers insulin resistance by reducing blood levels of TNF-&#x3b1;, insulin, and oxidative stress in type 2 diabetic subjects. Therefore, CDNC supplementation has potential as an adjunct therapy for individuals with type 2 diabetes.","evidenceGrade":"full_text"},{"id":"p-pmid-20163347","title":"In patients with HIV-infection, chromium supplementation improves insulin resistance and other metabolic abnormalities: a randomized, double-blind, placebo controlled trial.","authors":["E Aghdassi","BM Arendt","IE Salit","SS Mohammed","P Jalali","H Bondar","JP Allard"],"year":2010,"venue":"Current HIV research","doi":null,"pmid":"20163347","url":"https://pubmed.ncbi.nlm.nih.gov/20163347/","methodology":"rct","n":null,"openAccess":false,"abstract":"Chromium is an essential micronutrient; chromium deficiency has been reported to cause insulin resistance, hyperglycemia and hyperlipidemia. The aim was to investigate the effect of chromium supplementation on insulin-resistance, other metabolic abnormalities, and body composition in people living with HIV. This was a randomized, double-blind, placebo-controlled trial. Fifty-two HIV-positive subjects with elevated glucose, lipids, or evidence of body fat redistribution, and who had insulin-resistance based on the calculation of homeostasis model of assessment (HOMA-IR &gt; or = 2.5) were assessed. Subjects who were on insulin or hypoglycemic medications were excluded. Subjects were randomized to receive either 400 microg/day chromium-nicotinate or placebo for 16 weeks. Forty-six subjects, 23 in each group, completed the study. Fasting blood insulin, glucose, lipid profile and body composition were measured before and after intervention. Chromium was tolerated without side effects and resulted in a significant decrease in HOMA-IR (median (IQR) (pre:4.09 (3.02-8.79); post: 3.66 (2.40-5.46), p=0.004), insulin (pre: 102 (85-226); post: 99 (59-131) pmol/L, p=0.003), triglycerides, total body fat mass (mean+/-SEM) (pre: 17.3+/-1.7; post: 16.3+/-1.7 kg; p=0.002) and trunk fat mass (pre: 23.8+/-1.9; post: 22.7+/-2.0 %; p=0.008). Blood glucose, C-peptide, total, HDL and LDL cholesterol, and hemoglobin A1c remained unchanged. Biochemical parameters did not change in the placebo group except for LDL cholesterol which increased significantly. Body weight and medication profile remained stable throughout the study for both groups. In summary, chromium improved insulin resistance, metabolic abnormalities, and body composition in HIV+ patients. This suggests that chromium supplements alleviate some of the antiretroviral-associated metabolic abnormalities.","evidenceGrade":"abstract_only"},{"id":"p-pmid-16359984","title":"Effect of chromium supplementation on insulin resistance and ovarian and menstrual cyclicity in women with polycystic ovary syndrome.","authors":["RS Lucidi","AC Thyer","CA Easton","AE Holden","RS Schenken","RG Brzyski"],"year":2006,"venue":"Fertility and sterility","doi":null,"pmid":"16359984","url":"https://pubmed.ncbi.nlm.nih.gov/16359984/","methodology":"rct","n":null,"openAccess":false,"abstract":"In women with polycystic ovary syndrome, chromium picolinate (200 microg/d) improves glucose tolerance compared with placebo but does not improve ovulatory frequency or hormonal parameters. This pilot study indicates that future studies in the polycystic ovary syndrome population should examine higher dosages or longer durations of treatment.","evidenceGrade":"abstract_only"},{"id":"p-mehta-josephs-2010","title":"Testosterone and cortisol jointly regulate dominance: Evidence for a dual-hormone hypothesis","authors":["P. H. Mehta","R. A. Josephs"],"year":2010,"venue":"Hormones and Behavior","doi":"10.1016/j.yhbeh.2010.08.020","pmid":"20816841","url":"https://pubmed.ncbi.nlm.nih.gov/20816841/","methodology":"observational","n":null,"openAccess":false,"abstract":"In leadership and competition tasks, basal testosterone related to dominance only among people with low cortisol. High cortisol blocked or reversed the association. First empirical statement of the dual-hormone hypothesis.","evidenceGrade":"abstract_only"},{"id":"p-carre-olmstead-2015","title":"Social neuroendocrinology of human aggression: Examining the role of competition-induced testosterone dynamics","authors":["J. M. Carré","N. A. Olmstead"],"year":2015,"venue":"Neuroscience","doi":"10.1016/j.neuroscience.2014.05.033","pmid":"24881815","url":"https://pubmed.ncbi.nlm.nih.gov/24881815/","methodology":"review","n":null,"openAccess":false,"abstract":"Reviews how acute T change after contests, not just basal T, relates to subsequent aggressive and competitive behavior. The dual-hormone picture is a moderator, not a slogan.","evidenceGrade":"abstract_only"},{"id":"p-pmid-17828627","title":"Creatine supplementation and cognitive performance in elderly individuals.","authors":["T McMorris","G Mielcarz","RC Harris","JP Swain","A Howard"],"year":2008,"venue":"Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition","doi":null,"pmid":"17828627","url":"https://pubmed.ncbi.nlm.nih.gov/17828627/","methodology":"rct","n":null,"openAccess":false,"abstract":"The purpose of this study was to examine the effect of creatine supplementation on the cognitive performance of elderly people. Participants were divided into two groups, which were tested on random number generation, forward and backward number and spatial recall, and long-term memory tasks to establish a baseline level. Group 1 (n = 15) were given 5 g four times a day of placebo for 1 week, followed by the same dosage of creatine for the second week. Group 2 (n = 17) were given placebo both weeks. Participants were retested at the end of each week. Results showed a significant effect of creatine supplementation on all tasks except backward number recall. It was concluded that creatine supplementation aids cognition in the elderly.","evidenceGrade":"abstract_only"},{"id":"p-pmid-27890303","title":"Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial.","authors":["RA Toniolo","FBF Fernandes","M Silva","RDS Dias","B Lafer"],"year":2018,"venue":"Journal of affective disorders","doi":"10.1016/j.jad.2016.11.029","pmid":"27890303","url":"https://pubmed.ncbi.nlm.nih.gov/27890303/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Depressive episodes and cognitive impairment are major causes of morbidity and dysfunction in individuals suffering from bipolar disorder (BD). Novel treatment approaches that target clinical and cognitive aspects of bipolar depression are needed, and research on pathophysiology suggests that mitochondrial modulators such as the nutraceutical creatine monohydrate might have a therapeutic role for this condition. METHODS: Eighteen (N=18) patients with bipolar depression according to DSM-IV criteria who were enrollled in a 6-week, randomized, double-blind, placebo-controlled trial of creatine monohydrate 6g daily as adjunctive therapy were submitted to neuropsychological assessments (Wisconsin Card Sorting Test, Digit Span subtest of the Wechsler Adult Intelligence Scale-Third Edition, Stroop Color-Word Test, Rey-Osterrieth complex figure test, FAS Verbal Fluency Test) at baseline and week 6. RESULTS: There was a statistically significant difference between the treatment groups of the change on the total scores after 6 weeks in the verbal fluency test, with improvement in the group receiving adjunctive treatment with creatine. We did not find significant differences between the groups of the changes on other neuropsychological tests. LIMITATIONS: Small sample and lack of a control group of healthy subjects. CONCLUSIONS: Our trial, which was the first to investigate the cognitive effects of creatine monohydrate on bipolar depression, indicates that supplementation with this nutraceutical for 6 weeks is associated with improvement in verbal fluency tests in patients with this condition.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29177955","title":"A randomized, double-blind, placebo-controlled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression.","authors":["RA Toniolo","M Silva","FBF Fernandes","JAMS Amaral","RDS Dias","B Lafer"],"year":2019,"venue":"Journal of neural transmission (Vienna, Austria : 1996)","doi":"10.1007/s00702-017-1817-5","pmid":"29177955","url":"https://pubmed.ncbi.nlm.nih.gov/29177955/","methodology":"rct","n":null,"openAccess":true,"abstract":"Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6&#xa0;weeks: creatine monohydrate 6&#xa0;g daily (N&#xa0;=&#xa0;17) or placebo (N&#xa0;=&#xa0;18). Primary efficacy was assessed by the change in the Montgomery-&#xc5;sberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6&#xa0;weeks in an intention-to-treat (ITT) analysis (p&#xa0;=&#xa0;0.560; Cohen's d&#xa0;=&#xa0;0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score&#xa0;&#x2264;&#xa0;12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p&#xa0;=&#xa0;0.012; OR&#xa0;=&#xa0;9.0 and p&#xa0;=&#xa0;0.036; OR&#xa0;=&#xa0;9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjuncti","evidenceGrade":"full_text"},{"id":"p-pmid-37206869","title":"The role of resistance training and creatine supplementation on oxidative stress, antioxidant defense, muscle strength, and quality of life in older adults.","authors":["E Amiri","D Sheikholeslami-Vatani"],"year":2023,"venue":"Frontiers in public health","doi":"10.3389/fpubh.2023.1062832","pmid":"37206869","url":"https://pubmed.ncbi.nlm.nih.gov/37206869/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: The aim of this study was to evaluate the effect of resistance training (RT) with creatine monohydrate supplementation (CS) on serum levels of 8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA), glutathione peroxidase (GPX), and total antioxidant capacity (TAC) in older adults. OBJECTIVES: This study evaluated the effect of resistance training with creatine monohydrate supplementation on oxidative stress and antioxidant defense, muscle strength and quality of life in older adults. METHODS: We examined 45 non-athlete volunteer older men and women (mean, 68.1&#x2009;&#xb1;&#x2009;7.2&#x2009; years old), were randomly selected and divided into three groups of 15: RT with creatine supplementation (RT&#x2009;+&#x2009;CS), RT with placebo (RT&#x2009;+&#x2009;P) and control group. RT protocol was performed for 10 &#x2009;weeks, three sessions per week. Creatine supplement was taken daily at a dose of 0.1&#x2009;g/kg of body weight, while the placebo group consumed the same amount of starch. Fasting blood samples were taken before the start of program and at the end of the RT period. RESULTS: In the training groups, after 10&#x2009; weeks of RT, a significant decrease in MDA and 8 - OHDG as well as a significant increase in serum levels of GPX and TAC were observed (in all cases, p =&#x2009; 0.001). In addition, creatinine levels were enhanced in the RT&#x2009;+&#x2009;CS (p = &#x2009;0.014). Training intervention also improved quality of life and muscle strength in the experimental groups (p =&#x2009; 0.001), although muscle strength changes were more visible in the RT&#x2009;+&#x2009;CS group than in the RT&#x2009;+&#x2009;P group (p &lt; &#x2009;0/05). CONCLUSION: Regular resistance training can be recommended as a very suitable non-pharmacological approach to strengthen the body's antioxidant system, muscle strength and quality of life in older adults. There are no definite findings on the role of creatine on the antioxidant system and quality of life i","evidenceGrade":"full_text"},{"id":"p-pmid-10694109","title":"Acute creatine loading increases fat-free mass, but does not affect blood pressure, plasma creatinine, or CK activity in men and women.","authors":["S Mihic","JR MacDonald","S McKenzie","MA Tarnopolsky"],"year":2000,"venue":"Medicine and science in sports and exercise","doi":null,"pmid":"10694109","url":"https://pubmed.ncbi.nlm.nih.gov/10694109/","methodology":"rct","n":null,"openAccess":false,"abstract":"UNLABELLED: Creatine monohydrate (CrM) administration may enhance high intensity exercise performance and increase body mass, yet few studies have examined for potential adverse effects, and no studies have directly considered potential gender differences. PURPOSE: The purpose of this study was to examine the effect of acute creatine supplementation upon total and lean mass and to determine potential side effects in both men and women. METHODS: The effect of acute CrM (20 g x d(-1) x 5 d) administration upon systolic, diastolic, and mean BP, plasma creatinine, plasma CK activity, and body composition was examined in 15 men and 15 women in a randomized, double-blind experiment. Additionally, ischemic isometric handgrip strength was measured before and after CrM or placebo (PL). RESULTS: CrM did not affect blood pressure, plasma creatinine, estimated creatinine clearance, plasma CK activity, or handgrip strength (P &gt; 0.05). In contrast, CrM significantly increased fat-free mass (FFM) and total body mass (P &lt; 0.05) as compared with PL, with no changes in body fat. The observed mass changes were greater for men versus women. CONCLUSIONS: These findings suggest that acute CrM administration does not affect blood pressure, renal function, or plasma CK activity, but increases FFM. The effect of CrM upon FFM may be greater in men as compared with that in women.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37144634","title":"A 2-yr Randomized Controlled Trial on Creatine Supplementation during Exercise for Postmenopausal Bone Health.","authors":["PD Chilibeck","DG Candow","JJ Gordon","WRD Duff","R Mason","K Shaw","R Taylor-Gjevre","B Nair"],"year":2023,"venue":"Medicine and science in sports and exercise","doi":"10.1249/MSS.0000000000003202","pmid":"37144634","url":"https://pubmed.ncbi.nlm.nih.gov/37144634/","methodology":"rct","n":null,"openAccess":true,"abstract":"PURPOSE: Our purpose was to examine the effects of 2 yr of creatine monohydrate supplementation and exercise on bone health in postmenopausal women. METHODS: Two hundred and thirty-seven postmenopausal women (mean age, 59 yr) were randomized to receive creatine (0.14 g&#xb7;kg -1 &#xb7;d -1 ) or placebo during a resistance training (3 d&#xb7;wk -1 ) and walking (6 d&#xb7;wk -1 ) program for 2 yr. Our primary outcome was the femoral neck bone mineral density (BMD), with lumbar spine BMD and proximal femur geometric properties as the secondary outcomes. RESULTS: Compared with placebo, creatine supplementation had no effect on BMD of the femoral neck (creatine: 0.725 &#xb1; 0.110 to 0.712 &#xb1; 0.100 g&#xb7;cm -2 ; placebo: 0.721 &#xb1; 0.102 to 0.706 &#xb1; 0.097 g&#xb7;cm -2 ), total hip (creatine: 0.879 &#xb1; 0.118 to 0.872 &#xb1; 0.114 g&#xb7;cm -2 ; placebo: 0.881 &#xb1; 0.111 to 0.873 &#xb1; 0.109 g&#xb7;cm -2 ), or lumbar spine (creatine: 0.932 &#xb1; 0.133 to 0.925 &#xb1; 0.131 g&#xb7;cm -2 ; placebo: 0.923 &#xb1; 0.145 to 0.915 &#xb1; 0.143 g&#xb7;cm -2 ). Creatine significantly maintained section modulus (1.35 &#xb1; 0.29 to 1.34 &#xb1; 0.26 vs 1.34 &#xb1; 0.25 to 1.28 &#xb1; 0.23 cm 3 (placebo), P = 0.0011), predictive of bone bending strength, and buckling ratio (10.8 &#xb1; 2.6 to 11.1 &#xb1; 2.2 vs 11.0 &#xb1; 2.6 to 11.6 &#xb1; 2.7 (placebo), P = 0.011), predictive of reduced cortical bending under compressive loads, at the narrow part of the femoral neck. Creatine reduced walking time over 80 m (48.6 &#xb1; 5.6 to 47.1 &#xb1; 5.4 vs 48.3 &#xb1; 4.5 to 48.2 &#xb1; 4.9 s (placebo), P = 0.0008) but had no effect on muscular strength (i.e., one-repetition maximum) during bench press (32.1 &#xb1; 12.7 to 42.6 &#xb1; 14.1 vs 30.6 &#xb1; 10.9 to 41.4 &#xb1; 14 kg (placebo)) and hack squat (57.6 &#xb1; 21.6 to 84.4 &#xb1; 28.1 vs 56.6 &#xb1; 24.0 to 82.7 &#xb1; 25.0 kg (placebo)). In the subanalysis of valid completers, creatine increased lean tissue mass com","evidenceGrade":"full_text"},{"id":"p-pmid-38474743","title":"Effect of Creatine Supplementation on Body Composition and Malnutrition-Inflammation Score in Hemodialysis Patients: An Exploratory 1-Year, Balanced, Double-Blind Design.","authors":["ACB Marini","RM Schincaglia","DG Candow","GD Pimentel"],"year":2024,"venue":"Nutrients","doi":"10.3390/nu16050615","pmid":"38474743","url":"https://pubmed.ncbi.nlm.nih.gov/38474743/","methodology":"rct","n":null,"openAccess":true,"abstract":"Hemodialysis has a detrimental effect on fat-free mass (FFM) and muscle strength over time. Thus, we aimed to evaluate the effect of creatine supplementation on the body composition and Malnutrition-Inflammation Score (MIS) in patients with chronic kidney disease (CKD) undergoing hemodialysis. An exploratory 1-year balanced, placebo-controlled, and double-blind design was conducted with hemodialysis patients (&#x2265;18 years). The creatine group (CG) received 5 g of creatine monohydrate and 5 g of maltodextrin per day and the placebo group (PG) received 10 g of maltodextrin per day. MIS and body composition were analyzed at three time points: pre, intermediate (after 6 months), and post (after 12 months). After 6 months, 60% of patients on creatine experienced an increase in FFM compared to a 36.8% increase for those on placebo. Moreover, 65% of patients on creatine increased their skeletal muscle mass index (SMMI) compared to only 15.8% for those on placebo. Creatine increased intracellular water (ICW) in 60% of patients. MIS did not change after the intervention. In the CG, there was an increase in body weight (p = 0.018), FFM (p = 0.010), SMMI (p = 0.022). CG also increased total body water (pre 35.4 L, post 36.1 L; p = 0.008), mainly due to ICW (pre 20.2 L, intermediate 20.7 L, post 21.0 L; p = 0.016). Long-term creatine supplementation in hemodialysis patients did not attenuate the MIS, but enhanced FFM and SMMI, which was likely triggered by an increase in ICW.","evidenceGrade":"full_text"},{"id":"p-pmid-25046624","title":"Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study.","authors":["AL Lopresti","M Maes","GL Maker","SD Hood","PD Drummond"],"year":2015,"venue":"Journal of affective disorders","doi":"10.1016/j.jad.2014.06.001","pmid":"25046624","url":"https://pubmed.ncbi.nlm.nih.gov/25046624/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Curcumin, the principal curcuminoid derived from the spice turmeric, influences several biological mechanisms associated with major depression, namely those associated with monoaminergic activity, immune-inflammatory and oxidative and nitrosative stress pathways, hypothalamus-pituitary-adrenal (HPA) axis activity and neuroprogression. We hypothesised that curcumin would be effective for the treatment of depressive symptoms in individuals with major depressive disorder. METHODS: In a randomised, double-blind, placebo-controlled study, 56 individuals with major depressive disorder were treated with curcumin (500 mg twice daily) or placebo for 8 weeks. The primary measure was the Inventory of Depressive Symptomatology self-rated version (IDS-SR30). Secondary outcomes included IDS-SR30 factor scores and the Spielberger State-Trait Anxiety Inventory (STAI). RESULTS: From baseline to week 4, both curcumin and placebo were associated with improvements in IDS-SR30 total score and most secondary outcome measures. From weeks 4 to 8, curcumin was significantly more effective than placebo in improving several mood-related symptoms, demonstrated by a significant group x time interaction for IDS-SR30 total score (F1, 53=4.22, p=.045) and IDS-SR30 mood score (F1, 53=6.51, p=.014), and a non-significant trend for STAI trait score (F1, 48=2.86, p=.097). Greater efficacy from curcumin treatment was identified in a subgroup of individuals with atypical depression. CONCLUSIONS: Partial support is provided for the antidepressant effects of curcumin in people with major depressive disorder, evidenced by benefits occurring 4 to 8 weeks after treatment. LIMITATIONS: Investigations with larger sample sizes, over extended treatment periods, and with varying curcumin dosages are required.","evidenceGrade":"abstract_only"},{"id":"p-pmid-18482290","title":"Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial.","authors":["D Kritz-Silverstein","D von M&#xfc;hlen","GA Laughlin","R Bettencourt"],"year":2008,"venue":"Journal of the American Geriatrics Society","doi":"10.1111/j.1532-5415.2008.01768.x","pmid":"18482290","url":"https://pubmed.ncbi.nlm.nih.gov/18482290/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: To examine the effects of dehydroepiandrosterone (DHEA) supplementation on cognitive function and quality of life in healthy older adults. DESIGN: Double-blind, randomized, controlled clinical trial. SETTING: Clinical research facility. PARTICIPANTS: One hundred ten men and 115 women aged 55 to 85 (mean +/- standard deviation 68 +/- 8). INTERVENTION: Fifty milligrams daily oral DHEA versus placebo for 1 year. MEASUREMENTS: Six cognitive function tests at baseline and 12 months, the Beck Depression Inventory (BDI), the Medical Outcomes Study 36-item Short Form Survey (SF-36), the Life Satisfaction Index-Z, the Satisfaction with Life Scale, the Female Sexual Function Index (in women), and the 15-item International Index of Erectile Function (in men) at baseline and 3, 6, and 12 months. RESULTS: There were no differences between the DHEA and placebo groups in change over time in cognitive function (P&gt;.10). Over time, BDI scores decreased for men (P=.006) and women (P=.02), and Satisfaction with Life Scale scores increased for women (P=.004), but there were no differences between the DHEA and placebo groups over time on these measures or the SF-36, Life Satisfaction Index-Z scale, or sexual function scales (P&gt;.10). CONCLUSION: DHEA supplementation has no benefit on cognitive performance or well-being in healthy older adults, and it should not be recommended for that purpose in the general population.","evidenceGrade":"full_text"},{"id":"p-pmid-16393880","title":"Dhea supplementation and cognition in postmenopausal women.","authors":["TD Parsons","KM Kratz","E Thompson","FZ Stanczyk","JG Buckwalter"],"year":2006,"venue":"The International journal of neuroscience","doi":null,"pmid":"16393880","url":"https://pubmed.ncbi.nlm.nih.gov/16393880/","methodology":"rct","n":null,"openAccess":false,"abstract":"Previous work has suggested that DHEA supplementation may have adverse cognitive effects in elderly women. This article analyzed 24-h measurements of DHEA, DHEAS, and cortisol to determine if cognitive decrease with treatment is mediated by DHEA's impact on endogenous cortisol. It was found that DHEA administration increased cortisol at several hours during the day. In the treatment group, cortisol was positively associated with cognition at study completion. An increase in negative associations between DHEA(S) levels and cognition was found at completion. Increased cortisol does not explain the cognitive deficits associated with DHEA, suggesting a direct negative effect of exogenous DHEA on cognition.","evidenceGrade":"abstract_only"},{"id":"p-pmid-17054283","title":"Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people.","authors":["J Grimley Evans","R Malouf","F Huppert","JK van Niekerk"],"year":2007,"venue":"The Cochrane database of systematic reviews","doi":null,"pmid":"17054283","url":"https://pubmed.ncbi.nlm.nih.gov/17054283/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"BACKGROUND: In view of the theoretical possibility of beneficial effects of DHEA or DHEAS in retarding age-associated deterioration in cognitive function, we have reviewed studies in this area. OBJECTIVES: To establish whether administration of DHEA, or its sulphate, DHEAS, improves cognitive function or reduces the rate of decline of cognitive function in normal older adults. SEARCH STRATEGY: Trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 October 2005 using the terms dhea*, prasterone, dehydroepiandrosterone*. In addition MEDLINE, EMBASE, PsycINFO and CINAHL were searched to find trials with volunteers who had no or minor memory complaints. Relevant journals, personal communications and conference abstracts were searched for randomized controlled trials investigating the effects of DHEA/S on cognition in older adults. SELECTION CRITERIA: All randomized placebo-controlled trials enrolling people aged over 50 without dementia and to whom DHEA/S in any dosage was administered for more than one day were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Data for the specified outcomes were independently extracted by two reviewers (JGE and RM) and cross-checked. Any discrepancies were discussed and resolved. No data pooling was undertaken owing to the lack of availability of the relevant statistics. MAIN RESULTS: Only three studies provided results from adequate parallel-group data. Barnhart 1999 enrolled perimenopausal women with complaints of decreased well-being and, using three cognitive measures, found no significant effect of DHEA compared with placebo at 3 months. Wolf 1998b enrolled 75 healthy volunteers (37 women and 38 men aged 59-81) in a study of the effect of DHEA supplements on cognitive impairment induced by stress; after two weeks of treatment, placebo group performance deteriorated significantly on a test of selective attention following a ps","evidenceGrade":"full_text"},{"id":"p-pmid-11403980","title":"Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation.","authors":["JK van Niekerk","FA Huppert","J Herbert"],"year":2001,"venue":"Psychoneuroendocrinology","doi":null,"pmid":"11403980","url":"https://pubmed.ncbi.nlm.nih.gov/11403980/","methodology":"rct","n":null,"openAccess":false,"abstract":"Dehydroepiandrosterone (DHEA) is a steroid that shows a marked age-related decline in humans. Previous research suggests potential for DHEA replacement in old age to enhance cognition and well-being. We conducted a clinical trial to test these hypotheses in a non-clinical sample of 46 men aged 62-76. Participants received either 50 mg DHEA daily for 13 weeks, followed by placebo for 13 weeks, or the reverse, in a randomised double-blind cross-over trial design. Levels of salivary cortisol and DHEA were measured at 0800 h and 2000 h prior to each assessment session. Cognition was assessed with tests of speed, attention and episodic memory. Well-being was measured with questionnaires of mood and perceived health. Mood questionnaires were completed at the assessment session as well as concurrently with saliva sampling.A correlational analysis of baseline behavioural data with hormonal data, controlling for age, revealed that higher morning DHEA was associated with lower confusion (r=-0.33; P=0.04), while higher evening DHEA was associated with lower anxiety (r=-0.35; P=0.03) and lower current negative mood in the morning (r=-0.37; P=0.03). Conversely, higher morning cortisol and a morning cortisol/DHEA ratio were associated with higher anxiety (r=0.35; P=0.03), (r=0.46; P=0.004), general mood disturbance (r=0.32; P=0.046), (r=0.32; P=0.04) and higher current negative mood in the evening (r=0.37; P=0.03), (r=0.38; P=0.03). A higher morning cortisol/DHEA ratio was also associated with higher confusion (r=0.39; P=0.01) and lower visuo-spatial memory performance (r=-0.39; P=0.01). Unexpectedly, higher evening cortisol was associated with faster choice reaction time (r=-0.33; P=0.04). These findings are consistent with an impairing effect of high cortisol on episodic memory and mood in older men, which may be attenuated by DHEA. When treatment effects were analysed, no significant effects of DHEA were observed on any of the trial outcomes, providing no support for benefits ","evidenceGrade":"abstract_only"},{"id":"p-baulieu-2000","title":"Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue","authors":["E. E. Baulieu","G. Thomas","S. Legrain","N. Lahlou","M. Roger","B. Debuire"],"year":2000,"venue":"Proceedings of the National Academy of Sciences","doi":"10.1073/pnas.97.8.4279","pmid":"10760294","url":"https://pubmed.ncbi.nlm.nih.gov/10760294/","methodology":"rct","n":280,"openAccess":true,"abstract":"A year of DHEA replacement in older adults moved some hormone markers and skin/libido items. It did not produce a status, cognition, or income story. The optimization-panel favorite remains a biomarker looking for a job.","evidenceGrade":"abstract_only"},{"id":"p-henrich-2001","title":"The evolution of prestige: Freely conferred deference as a mechanism for enhancing the benefits of cultural transmission","authors":["J. Henrich","F. J. Gil-White"],"year":2001,"venue":"Evolution and Human Behavior","doi":"10.1016/S1090-5138(00)00071-4","pmid":null,"url":"https://doi.org/10.1016/S1090-5138(00)00071-4","methodology":"theory","n":null,"openAccess":false,"abstract":"Splits status into dominance (force) and prestige (freely conferred deference to those worth copying). Without this split, every T paper gets over-interpreted as an aggression paper.","evidenceGrade":"abstract_only"},{"id":"p-fisman-2006","title":"Gender differences in mate selection: Evidence from a speed dating experiment","authors":["R. Fisman","S. S. Iyengar","E. Kamenica","I. Simonson"],"year":2006,"venue":"Quarterly Journal of Economics","doi":"10.1162/qjec.2006.121.2.673","pmid":null,"url":"https://doi.org/10.1162/qjec.2006.121.2.673","methodology":"observational","n":400,"openAccess":false,"abstract":"Columbia speed-dating: men weighted attractiveness more; women weighted intelligence and race more; women preferred men from affluent neighborhoods; men did not value women's intelligence or ambition past their own. Revealed preference, not a survey slogan.","evidenceGrade":"abstract_only"},{"id":"p-gildersleeve-2014","title":"Do women's mate preferences change across the ovulatory cycle? A meta-analytic review","authors":["K. Gildersleeve","M. G. Haselton","M. R. Fales"],"year":2014,"venue":"Psychological Bulletin","doi":"10.1037/a0035438","pmid":"24564172","url":"https://pubmed.ncbi.nlm.nih.gov/24564172/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"A meta-analysis reported cycle shifts toward masculine/dominant cues at high fertility. The finding is the citation for the pop-evo cycle story — and the start of the replication fight, not the end of it.","evidenceGrade":"abstract_only"},{"id":"p-wood-2014","title":"Meta-analysis of menstrual cycle effects on women's mate preferences","authors":["W. Wood","L. Kressel","P. D. Joshi","B. Louie"],"year":2014,"venue":"Emotion Review","doi":"10.1177/1754073914523073","pmid":null,"url":"https://doi.org/10.1177/1754073914523073","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"A competing meta-analysis found little support for cycle-shifted mate preferences once methods were scrutinized. Keep it on the same edge as Gildersleeve. The honest stamp is contested, not 'debunked' and not 'settled biology'.","evidenceGrade":"abstract_only"},{"id":"p-pmid-10547175","title":"Effects of exercise training on older patients with major depression.","authors":["JA Blumenthal","MA Babyak","KA Moore","WE Craighead","S Herman","P Khatri","R Waugh","MA Napolitano"],"year":1999,"venue":"Archives of internal medicine","doi":null,"pmid":"10547175","url":"https://pubmed.ncbi.nlm.nih.gov/10547175/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Previous observational and interventional studies have suggested that regular physical exercise may be associated with reduced symptoms of depression. However, the extent to which exercise training may reduce depressive symptoms in older patients with major depressive disorder (MDD) has not been systematically evaluated. OBJECTIVE: To assess the effectiveness of an aerobic exercise program compared with standard medication (ie, antidepressants) for treatment of MDD in older patients, we conducted a 16-week randomized controlled trial. METHODS: One hundred fifty-six men and women with MDD (age, &gt; or = 50 years) were assigned randomly to a program of aerobic exercise, antidepressants (sertraline hydrochloride), or combined exercise and medication. Subjects underwent comprehensive evaluations of depression, including the presence and severity of MDD using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) scores before and after treatment. Secondary outcome measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. RESULTS: After 16 weeks of treatment, the groups did not differ statistically on HAM-D or BDI scores (P = .67); adjustment for baseline levels of depression yielded an essentially identical result. Growth curve models revealed that all groups exhibited statistically and clinically significant reductions on HAM-D and BDI scores. However, patients receiving medication alone exhibited the fastest initial response; among patients receiving combination therapy, those with less severe depressive symptoms initially showed a more rapid response than those with initially more severe depressive symptoms. CONCLUSIONS: An exercise training program may be considered an alternative to antidepressants for treatment of depression in older persons. Although antidepressants may facilitate a more rapid i","evidenceGrade":"abstract_only"},{"id":"p-pmid-11020092","title":"Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months.","authors":["M Babyak","JA Blumenthal","S Herman","P Khatri","M Doraiswamy","K Moore","WE Craighead","TT Baldewicz"],"year":2001,"venue":"Psychosomatic medicine","doi":null,"pmid":"11020092","url":"https://pubmed.ncbi.nlm.nih.gov/11020092/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: The purpose of this study was to assess the status of 156 adult volunteers with major depressive disorder (MDD) 6 months after completion of a study in which they were randomly assigned to a 4-month course of aerobic exercise, sertraline therapy, or a combination of exercise and sertraline. METHODS: The presence and severity of depression were assessed by clinical interview using the Diagnostic Interview Schedule and the Hamilton Rating Scale for Depression (HRSD) and by self-report using the Beck Depression Inventory. Assessments were performed at baseline, after 4 months of treatment, and 6 months after treatment was concluded (ie, after 10 months). RESULTS: After 4 months patients in all three groups exhibited significant improvement; the proportion of remitted participants (ie, those who no longer met diagnostic criteria for MDD and had an HRSD score &lt;8) was comparable across the three treatment conditions. After 10 months, however, remitted subjects in the exercise group had significantly lower relapse rates (p = .01) than subjects in the medication group. Exercising on one's own during the follow-up period was associated with a reduced probability of depression diagnosis at the end of that period (odds ratio = 0.49, p = .0009). CONCLUSIONS: Among individuals with MDD, exercise therapy is feasible and is associated with significant therapeutic benefit, especially if exercise is continued over time.","evidenceGrade":"abstract_only"},{"id":"p-pmid-17846259","title":"Exercise and pharmacotherapy in the treatment of major depressive disorder.","authors":["JA Blumenthal","MA Babyak","PM Doraiswamy","L Watkins","BM Hoffman","KA Barbour","S Herman","WE Craighead"],"year":2007,"venue":"Psychosomatic medicine","doi":null,"pmid":"17846259","url":"https://pubmed.ncbi.nlm.nih.gov/17846259/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: To assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls. METHODS: Between October 2000 and November 2005, we performed a prospective, randomized controlled trial (SMILE study) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital. A total of 202 adults (153 women; 49 men) diagnosed with major depression were assigned randomly to one of four conditions: supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50-200 mg daily); or placebo pill for 16 weeks. Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D). RESULTS: After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of &lt;8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31% (p = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (p = .23). CONCLUSIONS: The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors.","evidenceGrade":"full_text"},{"id":"p-pmid-32838817","title":"A randomized trial of aerobic exercise for major depression: examining neural indicators of reward and cognitive control as predictors and treatment targets.","authors":["CJ Brush","G Hajcak","AJ Bocchine","AA Ude","KM Muniz","D Foti","BL Alderman"],"year":2022,"venue":"Psychological medicine","doi":"10.1017/S0033291720002573","pmid":"32838817","url":"https://pubmed.ncbi.nlm.nih.gov/32838817/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Aerobic exercise has demonstrated antidepressant efficacy among adults with major depression. There is a poor understanding of the neural mechanisms associated with these effects. Deficits in reward processing and cognitive control may be two candidate targets and predictors of treatment outcome to exercise in depression. METHODS: Sixty-six young adults aged 20.23 years (s.d. = 2.39) with major depression were randomized to 8 weeks of moderate-intensity aerobic exercise (n = 35) or light stretching (n = 31). Depressive symptoms were assessed across the intervention to track symptom reduction. Reward processing [reward positivity (RewP)] and cognitive control [error-related negativity (ERN)] were assessed before and after the intervention using event-related brain potentials. RESULTS: Compared to stretching, aerobic exercise resulted in greater symptom reduction (gs = 0.66). Aerobic exercise had no impact on the RewP (gav = 0.08) or ERN (gav = 0.21). In the aerobic exercise group, individuals with a larger pre-treatment RewP [odds ratio (OR) = 1.45] and increased baseline depressive symptom severity (OR = 1.18) were more likely to respond to an aerobic exercise program. Pre-treatment ERN did not predict response (OR = 0.74). CONCLUSIONS: Aerobic exercise is effective in alleviating depressive symptoms in adults with major depression, particularly for those with increased depressive symptom severity and a larger RewP at baseline. Although aerobic exercise did not modify the RewP or ERN, there is preliminary support for the utility of the RewP in predicting who is most likely to respond to exercise as a treatment for depression.","evidenceGrade":"abstract_only"},{"id":"p-pmid-35579606","title":"Comparison of moderate and vigorous walking exercise on reducing depression in middle-aged and older adults: A pilot randomized controlled trial.","authors":["DJ Yu","AP Yu","CK Leung","EC Chin","DY Fong","CP Cheng","SY Yau","PM Siu"],"year":2023,"venue":"European journal of sport science","doi":"10.1080/17461391.2022.2079424","pmid":"35579606","url":"https://pubmed.ncbi.nlm.nih.gov/35579606/","methodology":"rct","n":null,"openAccess":false,"abstract":"The optimal intensity of physical activity for alleviating depression in middle-aged and older adults remains unclear. The World Health Organization (WHO) physical activity guidelines recommend adults and older adults to accumulate at least 150-300 minutes of moderate or 75-150 minutes of vigorous aerobic-type physical activity weekly or an equivalent combination of both for health benefits including reduced risk of depression. This parallel, assessor-blinded, pilot randomized controlled trial preliminarily compared the effectiveness of the minimal volume of aerobic-type physical activity at different intensities as recommended by WHO (150 minutes of moderate walking exercise and 75 minutes of vigorous walking exercise weekly) on alleviating depression in middle-aged and older adults. Thirty-five participants were randomized to the control group (CON), moderate walking exercise group (MOD), or vigorous walking exercise group (VIG). The exercise frequency was three times a week and the intervention duration was 12 weeks. The primary outcome was the severity of depression assessed by Beck Depression Inventory. Secondary outcomes included severity of anxiety, sleep quality, quality of life, and cardiorespiratory fitness. Thirty participants completed the study (CON: n&#x2009;=&#x2009;10, MOD: n&#x2009;=&#x2009;10, VIG: n&#x2009;=&#x2009;10). Participants in both MOD and VIG had significantly decreased depression severity after the intervention compared to CON (both p&#x2009;&lt;&#x2009;0.001). There was no significant difference between MOD and VIG (p&#x2009;=&#x2009;0.92). Both MOD and VIG interventions also mitigated anxiety severity, improved quality of life and cardiorespiratory fitness. The minimum volume of walking exercise at either moderate or vigorous intensity was found to alleviate depression in middle-aged and older adults.Trial registration: ClinicalTrials.gov identifier: NCT04403373.HighlightsThe 12-week 150-minute moderate walking exercise and 75-minute ","evidenceGrade":"abstract_only"},{"id":"p-pmid-21148807","title":"Exercise and pharmacotherapy in patients with major depression: one-year follow-up of the SMILE study.","authors":["BM Hoffman","MA Babyak","WE Craighead","A Sherwood","PM Doraiswamy","MJ Coons","JA Blumenthal"],"year":2011,"venue":"Psychosomatic medicine","doi":"10.1097/PSY.0b013e31820433a5","pmid":"21148807","url":"https://pubmed.ncbi.nlm.nih.gov/21148807/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: To examine a 1-year follow-up of a 4-month, controlled clinical trial of exercise and antidepressant medication in patients with major depressive disorder (MDD). METHODS: In the original study, 202 sedentary adults with MDD were randomized to: a) supervised exercise; b) home-based exercise; c) sertraline; or d) placebo pill. We examined two outcomes measured at 1-year follow-up (i.e., 16 months post randomization): 1) continuous Hamilton Depression Rating Scale score; and 2) MDD status (depressed; partial remission; full remission) in 172 available participants (85% of the original cohort). Regression analyses were performed to examine the effects of treatment group assignment, as well as follow-up antidepressant medication use and self-reported exercise (Godin Leisure-Time Exercise Questionnaire), on the two outcomes. RESULTS: In the original study, patients receiving exercise achieved similar benefits compared with those receiving sertraline. At the time of the 1-year follow-up, rates of MDD remission increased from 46% at post treatment to 66% for participants available for follow-up. Neither initial treatment group assignment nor antidepressant medication use during the follow-up period were significant predictors of MDD remission at 1 year. However, regular exercise during the follow-up period predicted both Hamilton Depression Rating Scale scores and MDD diagnosis at 1 year. This relationship was curvilinear, with the association concentrated between 0 minute and 180 minutes of weekly exercise. CONCLUSION: The effects of aerobic exercise on MDD remission seem to be similar to sertraline after 4 months of treatment; exercise during the follow-up period seems to extend the short-term benefits of exercise and may augment the benefits of antidepressant use. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00331305.","evidenceGrade":"full_text"},{"id":"p-pmid-32790020","title":"The role of comorbid anxiety in exercise and depression trials: Secondary analysis of the SMILE-II randomized clinical trial.","authors":["JA Blumenthal","MA Babyak","WE Craighead","J Davidson","A Hinderliter","B Hoffman","PM Doraiswamy","A Sherwood"],"year":2021,"venue":"Depression and anxiety","doi":"10.1002/da.23088","pmid":"32790020","url":"https://pubmed.ncbi.nlm.nih.gov/32790020/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: To explore the anxiolytic effects of a 4-month randomized, placebo-controlled trial of exercise and antidepressant medication in patients with major depressive disorder (MDD), and to examine the potential modifying effects of anxiety in treating depressive symptoms. MATERIALS AND METHODS: In this secondary analysis of the SMILE-II trial, 148 sedentary adults with MDD were randomized to: (a) supervised exercise, (b) home-based exercise, (c) sertraline, or (d) placebo control. Symptoms of state anxiety measured by the Spielberger Anxiety Inventory were examined before and after 4 months of treatment. Depressive symptoms were assessed by the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory-II (BDI-II). Analyses were carried out using general linear models. RESULTS: Compared to placebo controls, the exercise and sertraline groups had lower state anxiety scores (standardized difference&#x2009;=&#x2009;0.3 [95% CI&#x2009;=&#x2009;-0.6, -0.04]; p&#x2009;=&#x2009;0.02) after treatment. Higher pretreatment state anxiety was associated with poorer depression outcomes in the active treatments compared to placebo controls for both the HAMD (p&#x2009;=&#x2009;.004) and BDI-II (p&#x2009;=&#x2009;.02). CONCLUSION: Aerobic exercise as well as sertraline reduced symptoms of state anxiety in patients with MDD. Higher levels of pretreatment anxiety attenuated the effects of the interventions on depressive symptoms, however, especially among exercisers. Patients with MDD with higher comorbid state anxiety appear to be less likely to benefit from exercise interventions in reducing depression and thus may require supplemental treatment with special attention to anxiety.","evidenceGrade":"full_text"},{"id":"p-pmid-39570587","title":"Physical Activity and All-Cause Mortality by Age in 4 Multinational Megacohorts.","authors":["D Martinez-Gomez","M Luo","Y Huang","F Rodr&#xed;guez-Artalejo","U Ekelund","M Sotos-Prieto","D Ding","XQ Lao"],"year":2024,"venue":"JAMA network open","doi":"10.1001/jamanetworkopen.2024.46802","pmid":"39570587","url":"https://pubmed.ncbi.nlm.nih.gov/39570587/","methodology":"observational","n":null,"openAccess":true,"abstract":"IMPORTANCE: Physical activity (PA) guidelines recommend the same amount of PA through adulthood to live longer. OBJECTIVE: To explore whether there is an age-dependent association between PA and all-cause mortality and to investigate the age-dependent associations between other modifiable health factors (high educational level, not smoking, not regularly consuming alcohol, healthy body weight, and living without hypertension and diabetes) and mortality. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used a pooled analysis of 4 population-based prospective cohorts (National Health Interview Survey, 1997-2018; UK Biobank, 2006-2010; China Kadoorie Biobank, 2004-2008; and Mei Jau, 1997-2016). Data were analyzed from June 2022 to September 2024. EXPOSURES: Self-reported leisure-time PA. MAIN OUTCOMES AND MEASURES: The primary outcome was deaths identified through follow-up linkage to national death registries. Analyses were performed for the total sample and by age groups (20-29, 30-39, 40-49, 50-59, 60-69, 70-79, and &#x2265;80 years). Cox proportional hazards regression models with stratification by study were used to calculate mortality hazard ratios and their 95% CIs for the pooled dataset and by age group. RESULTS: A heterogeneous sample of 2&#x202f;011&#x202f;186 individuals (mean [SD] age, 49.1 [14.3] years; age range, 20-97 years; 1&#x202f;105&#x202f;581 women [55.0%]) were included. After a median (IQR) follow-up of 11.5 (9.3-13.5) years, 177&#x202f;436 deaths occurred. The association between PA and mortality in the total sample showed a nonlinear dose-response pattern, but age modified this association (P for interaction &lt;.001); PA was consistently associated with a lower risk of mortality across all age groups, but the reduction in risk was greater in older vs younger age groups, especially at high levels of PA. The hazard ratio for mortality associated with meeting the recommended PA in the total sample was 0.78 (95% CI, 0.77-0.79). This inverse as","evidenceGrade":"full_text"},{"id":"p-pmid-27475271","title":"Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women.","authors":["U Ekelund","J Steene-Johannessen","WJ Brown","MW Fagerland","N Owen","KE Powell","A Bauman","IM Lee"],"year":2016,"venue":"Lancet (London, England)","doi":"10.1016/S0140-6736(16)30370-1","pmid":"27475271","url":"https://pubmed.ncbi.nlm.nih.gov/27475271/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality. METHODS: We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time. FINDINGS: Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1&#x2008;005&#x2008;791 individuals who were followed up for 2-18&#xb7;1 years, during which 84&#x2008;609 (8&#xb7;4%) died. Compared with the referent group (ie, those sitting &lt;4 h/day and in the most active quartile [&gt;35&#xb7;5 MET-h per week]), mortality rates during follow-up were 12-59% higher in","evidenceGrade":"abstract_only"},{"id":"p-pmid-32611588","title":"Recommended physical activity and all cause and cause specific mortality in US adults: prospective cohort study.","authors":["M Zhao","SP Veeranki","CG Magnussen","B Xi"],"year":2020,"venue":"BMJ (Clinical research ed.)","doi":"10.1136/bmj.m2031","pmid":"32611588","url":"https://pubmed.ncbi.nlm.nih.gov/32611588/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVE: To determine the association between recommended physical activity according to the 2018 physical activity guidelines for Americans and all cause and cause specific mortality using a nationally representative sample of US adults. DESIGN: Population based cohort study. SETTING: National Health Interview Survey (1997-2014) with linkage to the National Death Index records to 31 December 2015. PARTICIPANTS: 479&#x2009;856 adults aged 18 years or older. EXPOSURES: Participant self-reports of the amount of leisure time spent in aerobic physical activity and muscle strengthening activity each week were combined and categorised into four groups: insufficient activity, aerobic activity only, muscle strengthening only, and both aerobic and muscle strengthening activities according to the physical activity guidelines. MAIN OUTCOME MEASURES: All cause mortality and cause specific mortality (cardiovascular disease, cancer, chronic lower respiratory tract diseases, accidents and injuries, Alzheimer's disease, diabetes mellitus, influenza and pneumonia, and nephritis, nephrotic syndrome, or nephrosis) obtained from the National Death Index records. RESULTS: During a median follow-up of 8.75 years, 59&#x2009;819 adults died from all causes, 13&#x2009;509 from cardiovascular disease, 14&#x2009;375 from cancer, 3188 from chronic lower respiratory tract diseases, 2477 from accidents and injuries, 1470 from Alzheimer's disease, 1803 from diabetes mellitus, 1135 from influenza and pneumonia, and 1129 from nephritis, nephrotic syndrome, or nephrosis. Compared with those who did not meet the physical activity guidelines (n=268&#x2009;193), those who engaged in recommended muscle strengthening activity (n=21&#x2009;428; hazard ratio 0.89, 95% confidence interval 0.85 to 0.94) or aerobic activity (n=113&#x2009;851; 0.71, 0.69 to 0.72) were found to be at reduced risk of all cause mortality; and even larger survival benefits were found in those engaged in both activities (n=76&#x2","evidenceGrade":"full_text"},{"id":"p-pmid-35876019","title":"Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults.","authors":["DH Lee","LFM Rezende","HK Joh","N Keum","G Ferrari","JP Rey-Lopez","EB Rimm","FK Tabung"],"year":2022,"venue":"Circulation","doi":"10.1161/CIRCULATIONAHA.121.058162","pmid":"35876019","url":"https://pubmed.ncbi.nlm.nih.gov/35876019/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: The 2018 physical activity guidelines for Americans recommend a minimum of 150 to 300 min/wk of moderate physical activity (MPA), 75 to 150 min/wk of vigorous physical activity (VPA), or an equivalent combination of both. However, it remains unclear whether higher levels of long-term VPA and MPA are, independently and jointly, associated with lower mortality. METHODS: A total of 116&#x2009;221 adults from 2 large prospective US cohorts (Nurses' Health Study and Health Professionals Follow-up Study, 1988-2018) were analyzed. Detailed self-reported leisure-time physical activity was assessed with a validated questionnaire, repeated up to 15 times during the follow-up. Cox regression was used to estimate the hazard ratio and 95% CI of the association between long-term leisure-time physical activity intensity and all-cause and cause-specific mortality. RESULTS: During 30 years of follow-up, we identified 47&#x2009;596 deaths. In analyses mutually adjusted for MPA and VPA, hazard ratios comparing individuals meeting the long-term leisure-time VPA guideline (75-149 min/wk) versus no VPA were 0.81 (95% CI, 0.76-0.87) for all-cause mortality, 0.69 (95% CI, 0.60-0.78) for cardiovascular disease (CVD) mortality, and 0.85 (95% CI, 0.79-0.92) for non-CVD mortality. Meeting the long-term leisure-time MPA guideline (150-299 min/wk) was similarly associated with lower mortality: 19% to 25% lower risk of all-cause, CVD, and non-CVD mortality. Compared with those meeting the long-term leisure-time physical activity guidelines, participants who reported 2 to 4 times above the recommended minimum of long-term leisure-time VPA (150-299 min/wk) or MPA (300-599 min/wk) showed 2% to 4% and 3% to 13% lower mortality, respectively. Higher levels of either long-term leisure-time VPA (&#x2265;300 min/wk) or MPA (&#x2265;600 min/wk) did not clearly show further lower all-cause, CVD, and non-CVD mortality or harm. In joint analyses, for individuals who reported &lt;300 min/wk of lon","evidenceGrade":"full_text"},{"id":"p-pmid-39267013","title":"Replacement of sedentary behavior with various physical activities and the risk of all-cause and cause-specific mortality.","authors":["Q Chang","Y Zhu","Z Liu","J Cheng","H Liang","F Lin","D Li","J Peng"],"year":2024,"venue":"BMC medicine","doi":"10.1186/s12916-024-03599-2","pmid":"39267013","url":"https://pubmed.ncbi.nlm.nih.gov/39267013/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Sedentary behavior (SB) has emerged as a significant health concern that deserves attention. This study aimed to examine the associations between prolonged sedentary behavior and the risk of all-cause and cause-specific mortality as well as to explore desirable alternatives to sitting in terms of physical activity (PA). METHODS: Two prospective cohort investigations were conducted using the UK Biobank and NHANES datasets, with a total of 490,659 and 33,534 participants, respectively. Cox proportional hazards regression models were used to estimate the associations between SB and the risk of all-cause and cause-specific mortality due to cancer, cardiovascular disease (CVD), respiratory diseases, and digestive diseases. In addition, we employed isotemporal substitution models to examine the protective effect of replacing sitting with various forms of PA. RESULTS: During the average follow-up times of 13.5 and 6.7&#xa0;years, 36,109 and 3057 deaths were documented in the UK Biobank and NHANES, respectively. Both cohorts demonstrated that, compared with individuals sitting less than 5&#xa0;h per day, individuals with longer periods of sitting had higher risks of all-cause and cause-specific mortality due to cancer, CVD, and respiratory diseases but not digestive diseases. Moreover, replacing SB per day with PA, even substituting 30&#xa0;min of walking for pleasure, reduced the risk of all-cause mortality by 3.5% (hazard ratio [HR] 0.965, 95% confidence interval [CI] 0.954-0.977), whereas cause-specific mortality from cancer, CVD, and respiratory diseases was reduced by 1.6% (HR 0.984, 95% CI 0.968-1.000), 4.4% (HR 0.956, 95% CI 0.930-0.982), and 15.5% (HR 0.845, 95% CI 0.795-0.899), respectively. Furthermore, the protective effects of substitution became more pronounced as the intensity of exercise increased or the alternative duration was extended to 1&#xa0;h. CONCLUSIONS: SB was significantly correlated with substantially increased risks of all-cause morta","evidenceGrade":"full_text"},{"id":"p-pmid-36805455","title":"Associations of timing of physical activity with all-cause and cause-specific mortality in a prospective cohort study.","authors":["H Feng","L Yang","YY Liang","S Ai","Y Liu","Y Liu","X Jin","B Lei"],"year":2023,"venue":"Nature communications","doi":"10.1038/s41467-023-36546-5","pmid":"36805455","url":"https://pubmed.ncbi.nlm.nih.gov/36805455/","methodology":"observational","n":null,"openAccess":true,"abstract":"There is a growing interest in the role of timing of daily behaviors in improving health. However, little is known about the optimal timing of physical activity to maximize health benefits. We perform a cohort study of 92,139 UK Biobank participants with valid accelerometer data and all-cause and cause-specific mortality outcomes, comprising over 7 years of median follow-up (638,825 person-years). Moderate-to-vigorous intensity physical activity (MVPA) at any time of day is associated with lower risks for all-cause, cardiovascular disease, and cancer mortality. In addition, compared with morning group (&gt;50% of daily MVPA during 05:00-11:00), midday-afternoon (11:00-17:00) and mixed MVPA timing groups, but not evening group (17:00-24:00), have lower risks of all-cause and cardiovascular disease mortality. These protective associations are more pronounced among the elderly, males, less physically active participants, or those with preexisting cardiovascular diseases. Here, we show that MVPA timing may have the potential to improve public health.","evidenceGrade":"full_text"},{"id":"p-pmid-31023430","title":"Sitting Time, Physical Activity, and Risk of Mortality in&#xa0;Adults.","authors":["E Stamatakis","J Gale","A Bauman","U Ekelund","M Hamer","D Ding"],"year":2020,"venue":"Journal of the American College of Cardiology","doi":"10.1016/j.jacc.2019.02.031","pmid":"31023430","url":"https://pubmed.ncbi.nlm.nih.gov/31023430/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: It is unclear what level of moderate to vigorous intensity physical activity (MVPA) offsets the health risks of sitting. OBJECTIVES: The purpose of this study was to examine the joint and stratified associations of sitting and MVPA with all-cause and cardiovascular disease (CVD) mortality, and to estimate the theoretical effect of replacing sitting time with physical activity, standing, and sleep. METHODS: A longitudinal analysis of the 45 and Up Study calculated the multivariable-adjusted hazard ratios (HRs) of sitting for each sitting-MVPA combination group and within MVPA strata. Isotemporal substitution modeling estimated the per-hour HR effects of replacing sitting. RESULTS: A total of 8,689 deaths (1,644 due to CVD) occurred among 149,077 participants over an 8.9-year (median) follow-up. There was a statistically significant interaction between sitting and MVPA only for all-cause mortality. Sitting time was associated with both mortality outcomes in a nearly dose-response manner in the least active groups reporting&#xa0;&lt;150 MVPA min/week. For example, among those reporting no MVPA, the all-cause mortality HR comparing the most sedentary (&gt;8&#xa0;h/day) to the least sedentary (&lt;4 h/day) groups was 1.52 (95% confidence interval: 1.13 to 2.03). There was inconsistent and weak evidence for elevated CVD and all-cause mortality risks with more sitting among those meeting the lower (150&#xa0;to&#xa0;299 MVPA min/week) or upper (&#x2265;300 MVPA min/week) limits of the MVPA recommendation. Replacing sitting with walking and MVPA showed stronger associations among high sitters (&gt;6 sitting h/day) where, for example, the per-hour CVD mortality HR for sitting replaced with vigorous activity was 0.36 (95% confidence interval: 0.17 to 0.74). CONCLUSIONS: Sitting is associated with all-cause and CVD mortality risk among the least physically active adults; moderate-to-vigorous physical activity doses equivalent to meeting the current recommendations a","evidenceGrade":"abstract_only"},{"id":"p-pmid-16470406","title":"Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine.","authors":["SR de Rooij","RC Painter","TJ Roseboom","DI Phillips","C Osmond","DJ Barker","MW Tanck","RP Michels"],"year":2006,"venue":"Diabetologia","doi":null,"pmid":"16470406","url":"https://pubmed.ncbi.nlm.nih.gov/16470406/","methodology":"observational","n":null,"openAccess":false,"abstract":"AIMS/HYPOTHESIS: People who were small at birth have an increased risk of type 2 diabetes in later life. People who were in utero during the Dutch famine had decreased glucose tolerance and raised insulin concentrations at age 50. We aimed to evaluate whether prenatal famine exposure leads to more rapid progression of impaired glucose/insulin homeostasis with increasing age. METHODS: We performed an OGTT in 702 men and women at age 50 and in 699 men and women at age 58, all born as term singletons immediately before, during or after the 1944-1945 Dutch famine. RESULTS: People who had been exposed to famine in utero had significantly higher 120-min glucose concentrations at age 58 compared with people who had not been exposed to famine (difference=0.4 mmol/l, 95% CI 0.1 to 0.7, adjusted for sex and BMI). Glucose tolerance deteriorated between the age of 50 and 58. The unadjusted 120-min glucose concentrations rose by 0.2 mmol/l (95% CI 0.0 to 0.4), while 120-min insulin concentrations had increased by 64 pmol/l (95% CI 48 to 82). There were no differences in the rates of glucose and insulin level increase between the famine-exposed group and the unexposed group (p=0.28 for the difference in increase in glucose concentrations and p=0.09 for insulin concentrations). CONCLUSIONS/INTERPRETATION: Although we confirmed that undernutrition during gestation is linked to decreased glucose tolerance, the effect does not seem to become more pronounced at age 58 as compared with age 50.","evidenceGrade":"abstract_only"},{"id":"p-pmid-16873799","title":"Impaired insulin secretion after prenatal exposure to the Dutch famine.","authors":["SR de Rooij","RC Painter","DI Phillips","C Osmond","RP Michels","IF Godsland","PM Bossuyt","OP Bleker"],"year":2006,"venue":"Diabetes care","doi":null,"pmid":"16873799","url":"https://pubmed.ncbi.nlm.nih.gov/16873799/","methodology":"observational","n":null,"openAccess":false,"abstract":"OBJECTIVE: We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944-1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both. RESEARCH DESIGN AND METHODS: We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the beta-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI. RESULTS: Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test K(g) value -21% [95% CI -41 to -4]). People exposed to famine during midgestation had a significantly lower disposition index (-53% [-126 to -3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance. CONCLUSIONS: Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect.","evidenceGrade":"abstract_only"},{"id":"p-pmid-26791805","title":"Testofen, a specialised Trigonella foenum-graecum seed extract reduces age-related symptoms of androgen decrease, increases testosterone levels and improves sexual function in healthy aging males in a double-blind randomised clinical study.","authors":["A Rao","E Steels","WJ Inder","S Abraham","L Vitetta"],"year":2017,"venue":"The aging male : the official journal of the International Society for the Study of the Aging Male","doi":"10.3109/13685538.2015.1135323","pmid":"26791805","url":"https://pubmed.ncbi.nlm.nih.gov/26791805/","methodology":"rct","n":null,"openAccess":false,"abstract":"This study examined the effect of Testofen, a specialised Trigonella foenum-graecum seed extract on the symptoms of possible androgen deficiency, sexual function and serum androgen concentrations in healthy aging males. This was a double-blind, randomised, placebo-controlled trial involving 120 healthy men aged between 43 and 70 years of age. The active treatment was standardised Trigonella foenum-graecum seed extract at a dose of 600&#x2009;mg/day for 12 weeks. The primary outcome measure was the change in the Aging Male Symptom questionnaire (AMS), a measure of possible androgen deficiency symptoms; secondary outcome measures were sexual function and serum testosterone. There was a significant decrease in AMS score over time and between the active and placebo groups. Sexual function improved, including number of morning erections and frequency of sexual activity. Both total serum testosterone and free testosterone increased compared to placebo after 12 weeks of active treatment. Trigonella foenum-graecum seed extract is a safe and effective treatment for reducing symptoms of possible androgen deficiency, improves sexual function and increases serum testosterone in healthy middle-aged and older men.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39288153","title":"Effect of a plant extract of fenugreek (Trigonella foenum-graecum) on testosterone in blood plasma and saliva in a double blind randomized controlled intervention study.","authors":["S Lee-&#xd8;deg&#xe5;rd","TE Gundersen","CA Drevon"],"year":2024,"venue":"PloS one","doi":"10.1371/journal.pone.0310170","pmid":"39288153","url":"https://pubmed.ncbi.nlm.nih.gov/39288153/","methodology":"rct","n":null,"openAccess":true,"abstract":"Many aging men experience reduced energy and libido related to non-optimal testosterone levels. We conducted a randomized double-blind trial with TrigozimR fenugreek extract to assess impact on plasma and saliva testosterone, and some subjective effects. 95 men (40-80y) completed a 12-week intervention, taking 3 tablets daily with 0 mg (placebo; n = 22), 600 mg (n = 21), 1200 mg (n = 25) and1800 mg (n = 27) fenugreek extract and essential nutrients. Samples were collected at weeks 0, 2, 6, and 12. Participants answered a pre- and post-intervention questionnaire on lifestyle and libido. We measured total testosterone (HPLC-MS/MS) and sex hormone binding globulin (ELISA), calculated free testosterone index (FTI), and measured saliva testosterone. Plasma total testosterone and FTI increased after any dose of TrigozimR vs. baseline (13.0%, p = 1.0x10-4 and 16.3%, p = 6.2x10-6), but not vs. placebo (9.0%, p = 0.122 and 11.3% p = 0.059). 1800 mg TrigozimR resulted in 12.2% increased FTI (p = 0.025). Saliva testosterone concentration increased after any dose of TrigozimR vs. baseline (31.1%, p = 2.3x10-4) and vs. placebo (37.2%, p = 0.042). 1800 mg TrigozimR for 12 weeks resulted in 19.6% (p = 0.006) increased saliva testosterone. Compliance was confirmed by enhanced plasma concentration of 25-hydroxy vitamin D3. We observed no subjective effects or side-effects of TrigozimR. TrigozimR increased saliva and plasma testosterone concentration during intervention but only for saliva vs. placebo. Saliva may be preferred for measuring free testosterone due to no protein-bound testosterone.","evidenceGrade":"full_text"},{"id":"p-pmid-31828857","title":"The effect of Trigonella foenum-graecum extract on prostate-specific antigen, and prostate function in otherwise healthy men with benign prostate hyperplasia.","authors":["A Rao","R Grant"],"year":2020,"venue":"Phytotherapy research : PTR","doi":"10.1002/ptr.6554","pmid":"31828857","url":"https://pubmed.ncbi.nlm.nih.gov/31828857/","methodology":"rct","n":null,"openAccess":false,"abstract":"The aim of this trial was to evaluate the effect of a standardised Trigonella foenum-graecum (Fenugreek) extract on the symptoms of benign prostate hyperplasia (BPH) using a double-blind randomised placebo controlled design. The study recruited 100 healthy males aged between 45 and 80 years with symptoms of BPH who recorded a minimum score of eight on the International Prostate Symptom Score. Participants were randomised to an oral dose of either 600mg Trigonella foenum-graceum per day or placebo for 12 weeks. The primary outcome measure was the International Prostate Symptom Score total and subdomain scores. The secondary outcomes were serum levels of the hormones (testosterone, free testosterone, and sex hormone binding globulin) prostate-specific antigen, and safety markers. The results indicated that Trigonella foenum-graceum did not have an effect on improving the symptoms of BPH. Hormone levels, safety markers, and prostate-specific antigen remained unchanged and within normal limits after 12 weeks, which adds to the safety profile of this specialised extract.","evidenceGrade":"abstract_only"},{"id":"p-murray-kolb-2007","title":"Iron treatment normalizes cognitive functioning in young women","authors":["L. E. Murray-Kolb","J. L. Beard"],"year":2007,"venue":"American Journal of Clinical Nutrition","doi":"10.1093/ajcn/85.3.778","pmid":"17344500","url":"https://pubmed.ncbi.nlm.nih.gov/17344500/","methodology":"rct","n":null,"openAccess":false,"abstract":"Treating iron deficiency in young women improved attention and memory on named tasks. This is a deficit-correction trial. It is not evidence that high ferritin is an executive stack.","evidenceGrade":"abstract_only"},{"id":"p-pmid-24379009","title":"Improvements in iron status and cognitive function in young women consuming beef or non-beef lunches.","authors":["C Blanton"],"year":2014,"venue":"Nutrients","doi":"10.3390/nu6010090","pmid":"24379009","url":"https://pubmed.ncbi.nlm.nih.gov/24379009/","methodology":"rct","n":null,"openAccess":true,"abstract":"Iron status is associated with cognitive performance and intervention trials show that iron supplementation improves mental function in iron-deficient adults. However, no studies have tested the efficacy of naturally iron-rich food in this context. This investigation measured the hematologic and cognitive responses to moderate beef consumption in young women. Participants (n=43; age 21.1&#xb1;0.4 years) were randomly assigned to a beef or non-beef protein lunch group [3-oz (85 g), 3 times weekly] for 16 weeks. Blood was sampled at baseline, and weeks 8 and 16, and cognitive performance was measured at baseline and week 16. Body iron increased in both lunch groups (p&lt;0.0001), with greater improvement demonstrated in women with lower baseline body iron (p&lt;0.0001). Body iron had significant beneficial effects on spatial working memory and planning speed (p&lt;0.05), and ferritin responders (n=17) vs. non-responders (n=26) showed significantly greater improvements in planning speed, spatial working memory strategy, and attention (p&lt;0.05). Lunch group had neither significant interactions with iron status nor consistent main effects on test performance. These findings support a relationship between iron status and cognition, but do not show a particular benefit of beef over non-beef protein consumption on either measure in young women.","evidenceGrade":"full_text"},{"id":"p-pmid-24959952","title":"A study of the effects of latent iron deficiency on measures of cognition: a pilot randomised controlled trial of iron supplementation in young women.","authors":["AJ Leonard","KA Chalmers","CE Collins","AJ Patterson"],"year":2015,"venue":"Nutrients","doi":"10.3390/nu6062419","pmid":"24959952","url":"https://pubmed.ncbi.nlm.nih.gov/24959952/","methodology":"rct","n":null,"openAccess":true,"abstract":"Rates of iron deficiency are high amongst healthy young women. Cognitive impairment occurs secondary to iron deficiency in infants and children, but evaluation of the impact on cognition among young women is inconsistent. The aim was to determine the suitability of the IntegNeuro test battery for assessing cognitive function in iron-deficient and iron-sufficient young women. A pilot double-blinded, placebo-controlled intervention trial was conducted in iron-deficient (serum ferritin &#x2264; 20 &#x3bc;g/L and haemoglobin &gt; 120 g/L) and iron-sufficient young women (18-35 years). Cognitive function and haematological markers of iron status were measured at baseline and follow-up. Iron-deficient participants (n = 24) were randomised to receive placebo, 60 mg or 80 mg elemental iron daily supplements for 16 weeks. A control group of iron-sufficient participants (n = 8) was allocated to placebo. Change scores for Impulsivity and Attention were significantly greater in plasma ferritin improvers than in non-improvers (p = 0.004, p = 0.026). IntegNeuro was easy to administer and acceptable to young women. Based on the differences in Memory and Attention scores between iron-deficient participants on iron treatment and those on placebo, it was decided that between 26 and 84 participants would be required in each iron treatment group for an adequately powered extension of this pilot RCT.","evidenceGrade":"full_text"},{"id":"p-pmid-28953856","title":"Effects of iron supplementation of low-birth-weight infants on cognition and behavior at 7 years: a randomized controlled trial.","authors":["SK Berglund","A Chmielewska","J Starnberg","B Westrup","B H&#xe4;ggl&#xf6;f","M Norman","M Domell&#xf6;f"],"year":2019,"venue":"Pediatric research","doi":"10.1038/pr.2017.235","pmid":"28953856","url":"https://pubmed.ncbi.nlm.nih.gov/28953856/","methodology":"rct","n":null,"openAccess":false,"abstract":"BackgroundLow-birth-weight infants (LBW) are at an increased risk of iron deficiency that has been associated with impaired neurodevelopment. We hypothesized that iron supplementation of LBW infants improves cognitive scores and reduces behavioral problems until school age.MethodsWe randomized 285 marginally LBW (2,000-2,500&#x2009;g) infants to receive 0, 1, or 2&#x2009;mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 7 years of age, 205 participants were assessed regarding cognition using Wechsler Intelligence Scale for Children (WISC-IV) and behavior using the parental questionnaires Child Behavior Checklist (CBCL) and Five to Fifteen (FTF).ResultsThere were no significant differences between the intervention groups in WISC-IV or FTF. However, the CBCL scores for externalizing problems were significantly different, in favor of supplemented children (P=0.045). When combining the supplemented groups, they had significantly lower scores for externalizing behavior compared with placebo (median (interquartile range): 44 [34;51] vs. 48.5 [41;56] P=0.013), and their risk ratio (95% confidence interval) for a total behavioral score above the cutoff for clinical problems was 0.31 (0.09-1.0), P=0.054.ConclusionLower scores of externalizing behavior in supplemented children support our previous findings at 3 years, and suggest that iron supplementation may have long-lasting effects on behavioral functions.","evidenceGrade":"abstract_only"},{"id":"p-pmid-42070571","title":"Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial.","authors":["MK Klausen","SK Justesen","JN Pedersen","L Rasmussen","A Jensen","ME Jensen","UB Knorr","ML Bergmann"],"year":2026,"venue":"Lancet (London, England)","doi":"10.1016/S0140-6736(26)00305-3","pmid":"42070571","url":"https://pubmed.ncbi.nlm.nih.gov/42070571/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Alcohol use disorder accounts for 5% of deaths worldwide annually, and there is an urgent need for new therapeutic interventions. Preclinical and initial human studies indicate that the GLP-1 receptor agonist semaglutide might reduce alcohol drinking. This study evaluated the efficacy of semaglutide once-weekly in treatment-seeking patients with alcohol use disorder and comorbid obesity. METHODS: In a 26-week, single-centre, randomised, double-blinded, placebo-controlled trial, treatment-seeking participants with moderate to severe alcohol use disorder and comorbid obesity were assigned (1:1) to receive once-weekly semaglutide (2&#xb7;4 mg subcutaneously) or placebo (saline subcutaneously), in addition to standard cognitive behavioural therapy. The primary endpoint was a reduction in the number of heavy drinking days assessed after 26 weeks of intervention, analysed with an ANCOVA model. Analysis adhered to the intention-to-treat principle, and missing outcome data were addressed using multiple imputations. Safety was assessed in all treated patients. The trial is registered at ClinicalTrials.govNCT05895643, and is complete. FINDINGS: From June 10, 2023, to Feb 4, 2025, 108 participants (53 women and 55 men) were enrolled, with 54 participants in each of the semaglutide and placebo treatment groups, and all were included in the data analysis. Overall, 88 participants (81%) completed the full intervention. Semaglutide was associated with a reduction in heavy drinking days (-41&#xb7;1 percentage points from baseline, 95% CI -48&#xb7;7 to -33&#xb7;5) compared with placebo (-26&#xb7;4, -34&#xb7;1 to -18&#xb7;6; estimated treatment difference -13&#xb7;7 percentage points, -22&#xb7;0 to -5&#xb7;4; p=0&#xb7;0015), and had substantial effects on multiple secondary alcohol-related and somatic outcomes. Adverse events were transient, generally mild to moderate gastrointestinal effects, and occurred more frequently in the semaglutide group. INTERPRETATION: Semaglut","evidenceGrade":"abstract_only"},{"id":"p-pmid-39937469","title":"Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial.","authors":["CS Hendershot","MP Bremmer","MB Paladino","G Kostantinis","TA Gilmore","NR Sullivan","AC Tow","SS Dermody"],"year":2025,"venue":"JAMA psychiatry","doi":"10.1001/jamapsychiatry.2024.4789","pmid":"39937469","url":"https://pubmed.ncbi.nlm.nih.gov/39937469/","methodology":"rct","n":null,"openAccess":true,"abstract":"IMPORTANCE: Preclinical, observational, and pharmacoepidemiology evidence indicates that glucagon-like peptide 1 receptor agonists (GLP-1RAs) may reduce alcohol intake. Randomized trials are needed to determine the clinical significance of these findings. OBJECTIVE: To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD). DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non-treatment-seeking participants with AUD were randomized. INTERVENTION: Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits. MAIN OUTCOMES AND MEASURES: The primary outcome was laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week). Secondary and exploratory outcomes, including prospective changes in alcohol consumption and craving, were assessed at outpatient visits. RESULTS: Forty-eight participants (34 [71%] female; mean [SD] age, 39.9 [10.6] years) were randomized. Low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration task, with evidence of medium to large effect sizes for grams of alcohol consumed (&#x3b2;, -0.48; 95% CI, -0.85 to -0.11; P&#x2009;=&#x2009;.01) and peak breath alcohol concentration (&#x3b2;, -0.46; 95% CI, -0.87 to -0.06; P&#x2009;=&#x2009;.03). Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day (&#x3b2;, -0.41; 95% CI, -0.73 to -0.09; P&#x2009;=&#x2009;.04) and weekly alcohol craving (&#x3b2;, -0.39; 95% CI, -0.73 to -0.06; P&#x2009;=&#x2009;.01), also predicting greater reduct","evidenceGrade":"full_text"},{"id":"p-pmid-36066977","title":"Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial.","authors":["MK Klausen","ME Jensen","M M&#xf8;ller","N Le Dous","A&#xd8; Jensen","VA Zeeman","CF Johannsen","A Lee"],"year":2022,"venue":"JCI insight","doi":"10.1172/jci.insight.159863","pmid":"36066977","url":"https://pubmed.ncbi.nlm.nih.gov/36066977/","methodology":"rct","n":null,"openAccess":true,"abstract":"BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI &gt; 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foght","evidenceGrade":"full_text"},{"id":"p-pmid-42522065","title":"Oral Semaglutide for Alcohol Use Disorder: A Randomized Clinical Trial.","authors":["JP Schacht","JT Sakai","K Raymond","R Shelton"],"year":2026,"venue":"The American journal of psychiatry","doi":"10.1176/appi.ajp.20260003","pmid":"42522065","url":"https://pubmed.ncbi.nlm.nih.gov/42522065/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: Accumulating preclinical and observational evidence suggests that glucagon-like peptide-1 receptor agonists, including semaglutide, reduce alcohol consumption. This phase 2 double-blind, randomized, parallel-arm trial evaluated the effects of oral semaglutide on alcohol craving and consumption among treatment-seeking adults with alcohol use disorder (AUD). METHODS: Fifty individuals with moderate to severe AUD were randomized to receive semaglutide (3 mg/day for 4 weeks, then 7 mg/day for 4 weeks) or placebo for 8 weeks. The primary outcome was laboratory-based alcohol cue-elicited craving at week 6. Key preregistered secondary outcomes were heavy drinking days and drinks per day during the last 4 weeks of treatment. Effects on other alcohol consumption measures, naturalistic alcohol craving, alcohol-related negative consequences, World Health Organization risk drinking level, and cannabis use were also explored. RESULTS: Semaglutide did not significantly reduce laboratory-assessed craving or drinks per day compared with placebo, but significantly reduced heavy drinking days (b=-0.580, 95% CI=-1.012, -0.148). Semaglutide also significantly reduced drinks per drinking day (b=-1.177, 95% CI=-2.307, -0.047), naturalistic alcohol craving (b=-2.195, 95% CI=-4.174, -0.216), and cannabis use days (b=-1.434, 95% CI=-2.568, -0.301). Semaglutide reduced alcohol-related consequences at a significantly greater rate than placebo (b=-4.618, 95% CI=-8.651, -0.585). Significantly more participants in the semaglutide group than the placebo group reduced their risk drinking level by one or more levels (Wald &#x3c7;2=4.01). CONCLUSIONS: These findings confirm previous results among non-treatment seekers with less severe AUD and suggest that continued development of semaglutide for AUD is warranted.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37991022","title":"Effects of dulaglutide on alcohol consumption during smoking cessation.","authors":["L Probst","S Monnerat","DR Vogt","S Lengsfeld","T Burkard","A Meienberg","C Bathelt","M Christ-Crain"],"year":2023,"venue":"JCI insight","doi":"10.1172/jci.insight.170419","pmid":"37991022","url":"https://pubmed.ncbi.nlm.nih.gov/37991022/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUNDAlcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODSThis is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTSIn the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33-53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52-0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSIONThese results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov NCT03204396.FUNDINGSwiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.","evidenceGrade":"full_text"},{"id":"p-pmid-37952131","title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.","authors":["AM Lincoff","K Brown-Frandsen","HM Colhoun","J Deanfield","SS Emerson","S Esbjerg","S Hardt-Lindberg","GK Hovingh"],"year":2023,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa2307563","pmid":"37952131","url":"https://pubmed.ncbi.nlm.nih.gov/37952131/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (&#xb1;SD) duration of exposure to semaglutide or placebo was 34.2&#xb1;13.7 months, and the mean duration of follow-up was 39.8&#xb1;9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P&lt;0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P&lt;0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 mont","evidenceGrade":"abstract_only"},{"id":"p-pmid-27295427","title":"Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.","authors":["SP Marso","GH Daniels","K Brown-Frandsen","P Kristensen","JF Mann","MA Nauck","SE Nissen","S Pocock"],"year":2016,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa1603827","pmid":"27295427","url":"https://pubmed.ncbi.nlm.nih.gov/27295427/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P&lt;0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS: In the time-to-event analysis, the rate of the fi","evidenceGrade":"full_text"},{"id":"p-pmid-31185157","title":"Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.","authors":["M Husain","AL Birkenfeld","M Donsmark","K Dungan","FG Eliaschewitz","DR Franco","OK Jeppesen","I Lingvay"],"year":2019,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa1901118","pmid":"31185157","url":"https://pubmed.ncbi.nlm.nih.gov/31185157/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of &#x2265;50 years with established cardiovascular or chronic kidney disease, or age of &#x2265;60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P&lt;0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), r","evidenceGrade":"abstract_only"},{"id":"p-pmid-39226070","title":"Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials.","authors":["TA Wadden","GK Brown","C Egebjerg","O Frenkel","B Goldman","RF Kushner","B McGowan","M Overvad"],"year":2024,"venue":"JAMA internal medicine","doi":"10.1001/jamainternmed.2024.4346","pmid":"39226070","url":"https://pubmed.ncbi.nlm.nih.gov/39226070/","methodology":"rct","n":null,"openAccess":true,"abstract":"IMPORTANCE: Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications. OBJECTIVE: To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously. INTERVENTIONS: Semaglutide, 2.4 mg, vs placebo. MAIN OUTCOMES AND MEASURES: Depressive symptoms and suicidal ideation/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated. RESULTS: This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was -0.56 (-0.81 to -0.32) (P&#x2009;&lt;&#x2009;.001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; P&#x2009;&lt;&#x2009;.001). Based on the Columbia-Suicide Severity Rating Scale, 1% or fewer of participants reported suicid","evidenceGrade":"full_text"},{"id":"p-pmid-41218611","title":"Semaglutide for the treatment of cognitive dysfunction in major depressive disorder: A randomized clinical trial.","authors":["S Badulescu","H Gill","H Shah","R Brudner","L Phan","JD Di Vincenzo","A Tabassum","M Armanyous"],"year":2026,"venue":"Med (New York, N.Y.)","doi":"10.1016/j.medj.2025.100916","pmid":"41218611","url":"https://pubmed.ncbi.nlm.nih.gov/41218611/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Evidence suggests that glucagon-like peptide 1 receptor agonists (GLP-1RAs) might have pro-cognitive effects. No prior study has evaluated the efficacy and safety of a GLP-1RA for the treatment of cognitive dysfunction in adults with major depressive disorder (MDD) in a randomized clinical trial. METHODS: This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345). Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese. Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide. The primary outcome was an executive function composite score comprising the digit symbol substitution test, the Stroop test, and the n-back test. Secondary outcomes included a global cognition composite score, measures of functioning, depressive symptom severity, suicidality, and body weight. FINDINGS: 72 participants were randomized to oral semaglutide (n = 35) or placebo (n = 37). Semaglutide did not improve executive function (adjusted Z score difference [semaglutide - placebo]: 0.32, 95% confidence interval [CI]: -0.92 to 1.58, p = 0.60). Preplanned secondary analysis showed treatment effects for global cognition (2.39, 95% CI: 0.19 to 4.60, p = 0.03) and body weight (kg) (adjusted mean difference -6.03, 95% CI: -8.76 to -3.29, p &lt; 0.001). Treatment did not affect depressive symptom severity or the frequency of suicidal ideation. Gastrointestinal side effects were common in the semaglutide group, with no serious adverse events. CONCLUSION: Semaglutide did not improve executive function; results from secondary analyses suggested effects on specific domains of cognition. Semaglutide was safe for patients with MDD. FUNDING: This work was supported by the Physicians' Services Incorporated Foundation.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29703793","title":"Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study.","authors":["V Salamun","M Jensterle","A Janez","E Vrtacnik Bokal"],"year":2018,"venue":"European journal of endocrinology","doi":"10.1530/EJE-18-0175","pmid":"29703793","url":"https://pubmed.ncbi.nlm.nih.gov/29703793/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has been investigated in regulation of reproductive system in animal models. The potential impact of short-term preconception intervention with liraglutide on fertility potential in polycystic ovary syndrome (PCOS) has not been evaluated yet. DESIGN: A prospective randomized open-label study was conducted in 28 infertile obese PCOS patients (age: 31.07&#x2009;&#xb1;&#x2009;4.75, BMI: 36.7&#x2009;&#xb1;&#x2009;3.5&#x2009;kg/m2, mean&#x2009;&#xb1;&#x2009;s.d.). They were assigned to metformin (MET) 1000&#x2009;mg BID or to MET 1000&#x2009;mg BID combined with low-dose liraglutide 1.2&#x2009;mg QD s.c. (COMBI) for 12 weeks. Ovarian stimulation protocol was started after a 4-week medication-free period. METHODS: The in vitro fertilization pregnancy rate (PR) was defined as the number of clinical pregnancies confirmed by ultrasound visualization of the fetal cardiac activity, divided by the total number of cycles performed or embryo transfers (ET). The spontaneous PR was followed for 12 months. RESULTS: Patients in the MET group on average lost 7.0&#x2009;&#xb1;&#x2009;6.0&#x2009;kg (P&#x2009;=&#x2009;0.001) compared with 7.5&#x2009;&#xb1;&#x2009;3.9&#x2009;kg in the COMBI group (P&#x2009;&lt;&#x2009;0.001) with no significant between-treatment difference (P&#x2009;=&#x2009;0.246). The PR per ET was significantly higher in the COMBI (85.7%) compared with the MET (28.6%) group (P&#x2009;=&#x2009;0.03). The cumulative PR in the time frame of 12 months was 69.2% in the COMBI group compared to 35.7% in the MET group. CONCLUSIONS: Preconception intervention with low-dose liraglutide added to metformin is superior to metformin alone in increasing PRs per ET and cumulative PRs in infertile obese women with PCOS, despite comparable weight reduction in both groups. A potential impact of liraglutide on the reproductive system needs further exploration, in particular the GLP-1 impact on endometrial quality and receptivity.","evidenceGrade":"abstract_only"},{"id":"p-pmid-28479118","title":"Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial.","authors":["M Nylander","S Fr&#xf8;ssing","HV Clausen","C Kistorp","J Faber","SO Skouby"],"year":2018,"venue":"Reproductive biomedicine online","doi":"10.1016/j.rbmo.2017.03.023","pmid":"28479118","url":"https://pubmed.ncbi.nlm.nih.gov/28479118/","methodology":"rct","n":null,"openAccess":false,"abstract":"Polycystic ovary syndrome (PCOS) encompasses an ovarian and a metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) analogues facilitate weight loss and ameliorate metabolic dysfunction in overweight women with PCOS, but their effect on ovarian dysfunction is scarcely reported. In a double-blind, randomized trial, 72 women with PCOS were allocated to intervention with the GLP-1 analogue liraglutide or placebo (1.8&#x2009;mg/day), in a 2:1 ratio. At baseline and 26-week follow-up, bleeding pattern, levels of AMH, sex hormones and gonadotrophins were assessed and ovarian morphology evaluated. Liraglutide caused 5.2&#x2009;kg (95% CI 3.0 to 7.5, P &lt; 0.0001) weight loss compared with placebo. Bleeding ratio improved with liraglutide: 0.28 (95% CI 0.20 to 0.36, P &lt; 0.001); placebo: 0.14 (95% CI 0.02 to 0.26, P &lt; 0.05); between-group difference: 0.14 (95% CI 0.03 to 0.24, P &lt; 0.05). In the liraglutide group, SHBG increased by 7.4&#x2009;nmol/L (95% CI 4.1 to 10.7) and free testosterone decreased by 0.005&#x2009;nmol/L (95% CI -0.009 to -0.001). Ovarian volume decreased by -1.6&#x2009;ml (95% CI -3.3 to 0.1) with liraglutide versus placebo. Nausea and constipation were more prevalent in the liraglutide group. Liraglutide improved markers of ovarian function in overweight women with PCOS, and might be a possible intervention.","evidenceGrade":"abstract_only"},{"id":"p-pmid-40713699","title":"Effects of combined metformin and semaglutide therapy on body weight, metabolic parameters, and reproductive outcomes in overweight/obese women with polycystic ovary syndrome: a prospective, randomized, controlled, open-label clinical trial.","authors":["H Chen","X Lei","Z Yang","Y Xu","D Liu","C Wang","H Du"],"year":2025,"venue":"Reproductive biology and endocrinology : RB&amp;E","doi":"10.1186/s12958-025-01447-3","pmid":"40713699","url":"https://pubmed.ncbi.nlm.nih.gov/40713699/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: This study aimed to assess the effects of metformin (MET) monotherapy versus a combination of semaglutide and MET on weight, metabolism, reproductive function, and inflammatory markers in women with polycystic ovary syndrome (PCOS). METHODS: A total of 100 overweight or obese women with PCOS diagnosed according to the Rotterdam criteria were randomly assigned to two groups: MET (1000&#xa0;mg twice daily [BID] for 16 weeks) and combination therapy (COM) (1000 &#x200a;mg MET BID plus 1-&#x200a;mg semaglutide once weekly [QW] for 16 weeks). Primary outcomes, assessed at Week 0 and Week 16, included changes in anthropometric measures related to obesity, while the secondary outcomes included alterations in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein (CRP) levels, Between Weeks 16 and 40, all participants received metformin monotherapy (1000&#xa0;mg BID) to evaluate pregnancy outcomes. RESULT: A total of 80 participants (80%) completed the study. After 16 weeks of intervention, the COM group exhibited significantly greater reductions in body weight, BMI, and waist-to-hip ratio (WHR) compared to the MET group (all P&#x2009;&lt;&#x2009;0.01). The COM group experienced an average weight loss of 6.09&#x2009;&#xb1;&#x2009;3.34&#xa0;kg, while the MET group lost only 2.25&#x2009;&#xb1;&#x2009;4.27&#xa0;kg. The COM group also demonstrated greater improvements in testosterone (TEST), Chinese visceral adiposity index (CVAI), and CRP levels compared to the MET group. Additionally, the COM group showed higher rates of menstrual cycle recovery than the MET group. From weeks 16 to 40, the COM group demonstrated a significantly higher natural pregnancy rate than the MET group (35% vs. 15%, P&#x2009;&lt;&#x2009;0.05). CONCLUSION: Compared to MET monotherapy, combination therapy with semaglutide and MET significantly reduced body weight, improved insulin resistance, decreased inflammatory markers, alleviated and menstrual irregularities and","evidenceGrade":"full_text"},{"id":"p-pmid-39511836","title":"Semaglutide improved sperm morphology in obese men with type 2 diabetes mellitus and functional hypogonadism.","authors":["N Gregori&#x10d;","J &#x160;ikonja","A Jane&#x17e;","M Jensterle"],"year":2025,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.16042","pmid":"39511836","url":"https://pubmed.ncbi.nlm.nih.gov/39511836/","methodology":"rct","n":null,"openAccess":true,"abstract":"AIMS: To compare the effects of semaglutide and testosterone replacement therapy (TRT) on semen quality and parameters of functional hypogonadism (FH) in men with type 2 diabetes mellitus and obesity. MATERIALS AND METHODS: We designed a randomised open-label trial in 25 men with type 2 diabetes (aged 50 [46-60] years, BMI 35.9 [32.8-38.7]&#x2009;kg/m2) and FH randomised to semaglutide (SEMA) 1&#x2009;mg/week or intramuscular testosterone undecanoate (TRT) 1000&#x2009;mg/10-12&#x2009;weeks for 24&#x2009;weeks. Semen analysis and parameters of FH were measured at baseline and after 24&#x2009;weeks of treatment. Participants completed questionnaires of the International Index of Erectile Function-15 (IIEF-15) and the Aging Symptoms in Men (AMS). RESULTS: The quality of baseline sperm parameters of our study cohort was poor, below the 5th percentile of reference values. In the SEMA group, there was a significant increase in morphologically normal sperm from baseline to the end of the study (2% [2; 3.5] vs. 4% [2; 5.5]; p&#x2009;=&#x2009;0.012), whereas sperm concentration and total number decreased significantly in the TRT group. Compared to TRT, the SEMA group had a significantly higher number of morphologically normal sperm, sperm concentration and total number. Both groups experienced an increase in total testosterone and improvement in the AMS score, whereas the IIEF-15 score significantly improved only in the TRT group. CONCLUSION: Semaglutide markedly improved sperm morphology, total testosterone levels and symptoms of hypogonadism. These findings highlight semaglutide's potential as a therapeutic approach for men with obesity-related FH who desire fertility. CLINICAL TRIAL REGISTRATION NUMBER: NCT06489457, www. CLINICALTRIALS: gov.","evidenceGrade":"full_text"},{"id":"p-pmid-35468322","title":"Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial.","authors":["T Heise","A Mari","JH DeVries","S Urva","J Li","EJ Pratt","T Coskun","MK Thomas"],"year":2022,"venue":"The lancet. Diabetes &amp; endocrinology","doi":"10.1016/S2213-8587(22)00085-7","pmid":"35468322","url":"https://pubmed.ncbi.nlm.nih.gov/35468322/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes. METHODS: This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete. FINDING","evidenceGrade":"abstract_only"},{"id":"p-pmid-38795393","title":"Effects of Tirzepatide vs Semaglutide on &#x3b2;-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.","authors":["KJ Mather","A Mari","T Heise","JH DeVries","M Hua","S Urva","T Coskun","A Haupt"],"year":2024,"venue":"The Journal of clinical endocrinology and metabolism","doi":"10.1210/clinem/dgae319","pmid":"38795393","url":"https://pubmed.ncbi.nlm.nih.gov/38795393/","methodology":"rct","n":null,"openAccess":false,"abstract":"CONTEXT: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE: This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. METHODS: A 28-week double-blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15&#x2005;mg, semaglutide 1&#x2005;mg, and placebo. Main outcome measures included glycemic control, model-derived &#x3b2;-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), &#x3b2;-cell glucose sensitivity (&#x3b2;-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P &lt; .01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P &lt; .01), in the context of greater improvement in insulin sensitivity with tirzepatide (P &lt; .01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P &lt; .05), showing improved &#x3b2;-CGS. MMTT-derived &#x3b2;-CGS was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P &lt; .01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSION: These results suggest that the greater glycemic control observed ","evidenceGrade":"abstract_only"},{"id":"p-pmid-38252888","title":"Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2).","authors":["JP Frias","C De Block","K Brown","H Wang","MK Thomas","M Zeytinoglu","JM Maldonado"],"year":2024,"venue":"The Journal of clinical endocrinology and metabolism","doi":"10.1210/clinem/dgae038","pmid":"38252888","url":"https://pubmed.ncbi.nlm.nih.gov/38252888/","methodology":"rct","n":null,"openAccess":true,"abstract":"CONTEXT: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and &#x3b2;-cell function to a greater extent than comparators. OBJECTIVE: Explore changes in biomarkers of &#x3b2;-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. DESIGN: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). SETTING: Post hoc analysis of 128 sites in 8 countries. PARTICIPANTS: A total of 1879 participants with type 2 diabetes. INTERVENTIONS: Once-weekly tirzepatide (5, 10, 15&#x2005;mg) or semaglutide 1&#x2005;mg. MAIN OUTCOMES MEASURES: Change in homeostatic model assessment indices for pancreatic &#x3b2;-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin. RESULTS: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15&#x2005;mg) doses (96.9-120.4%) than with semaglutide 1&#x2005;mg (84.0%) (P &lt; .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1&#x2005;mg (5.1%) (P &lt; .05). Tirzepatide 10 and 15&#x2005;mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1&#x2005;mg (P &lt; .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. CONCLUSION: In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline &#x3b2;-cell function and insulin resistance, compared with semaglutide.","evidenceGrade":"full_text"},{"id":"p-pmid-36200477","title":"Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses.","authors":["MN Kosiborod","M Bhatta","M Davies","JE Deanfield","WT Garvey","U Khalid","R Kushner","DM Rubino"],"year":2023,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.14890","pmid":"36200477","url":"https://pubmed.ncbi.nlm.nih.gov/36200477/","methodology":"observational","n":null,"openAccess":true,"abstract":"AIMS: Evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on cardiometabolic risk factors in people with overweight/obesity without diabetes in the STEP 1 and 4 trials. MATERIALS AND METHODS: STEP 1 and 4 were phase III, 68-week, placebo-controlled trials of once-weekly semaglutide 2.4&#xa0;mg combined with lifestyle intervention; STEP 4 had a 20-week semaglutide run-in and 48-week randomized withdrawal period. Participants had a body mass index &#x2265;30&#x2009;kg/m2 or &#x2265;27&#x2009;kg/m2 with one or more weight-related comorbidity, without diabetes. Pre-specified endpoints were changes in waist circumference, systolic/diastolic blood pressure (SBP/DBP), lipids, fasting plasma glucose (FPG), fasting serum insulin and antihypertensive/lipid-lowering medication use. Post-hoc assessments included non-high-density lipoprotein (HDL) cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR; STEP 1 only), atherosclerotic cardiovascular disease (ASCVD) risk (American College of Cardiology/American Heart Association algorithm; STEP 1 only) and cardiometabolic risk factors by weight loss achieved (&lt;5%, 5% to &lt;10%, 10% to &lt;15%, or &#x2265;15%) (STEP 1 only). RESULTS: Of the 1961 participants in STEP 1 and 803 in STEP 4, most had one or more complication/comorbidity at baseline, with dyslipidaemia and hypertension most prevalent. In STEP 1, reductions in waist circumference, SBP, DBP, FPG, fasting serum insulin, lipids and HOMA-IR were greater with semaglutide versus placebo (p&#x2009;&#x2264;&#x2009;.001). Reductions in SBP, non-HDL cholesterol, low-density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight-loss categories. Non-significant ASCVD risk reductions were observed with semaglutide versus placebo (p&#x2009;&gt;&#x2009;.05). In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run-in (week 0-20) were maintained ov","evidenceGrade":"full_text"},{"id":"p-pmid-38785209","title":"Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.","authors":["V Perkovic","KR Tuttle","P Rossing","KW Mahaffey","JFE Mann","G Bakris","FMM Baeres","T Idorn"],"year":2024,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa2403347","pmid":"38785209","url":"https://pubmed.ncbi.nlm.nih.gov/38785209/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. METHODS: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of &gt;300 and &lt;5000 or an eGFR of 25 to &lt;50 ml per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of &gt;100 and &lt;5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of &lt;15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. RESULTS: Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P&#x2009;=&#x2009;0.0003). Results were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P&lt;0.00","evidenceGrade":"abstract_only"},{"id":"p-pmid-28854085","title":"Liraglutide and Renal Outcomes in Type 2 Diabetes.","authors":["JFE Mann","DD &#xd8;rsted","K Brown-Frandsen","SP Marso","NR Poulter","S Rasmussen","K Torn&#xf8;e","B Zinman"],"year":2017,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa1616011","pmid":"28854085","url":"https://pubmed.ncbi.nlm.nih.gov/28854085/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown. METHODS: We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. RESULTS: A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively). CONCLUSIONS: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in low","evidenceGrade":"abstract_only"},{"id":"p-pmid-34903039","title":"Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: Pooled Analysis of SUSTAIN 6 and LEADER.","authors":["AM Shaman","SC Bain","GL Bakris","JB Buse","T Idorn","KW Mahaffey","JFE Mann","MA Nauck"],"year":2022,"venue":"Circulation","doi":"10.1161/CIRCULATIONAHA.121.055459","pmid":"34903039","url":"https://pubmed.ncbi.nlm.nih.gov/34903039/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes. METHODS: Pooled (n=12&#x2009;637) and by-trial data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n=3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline. RESULTS: The median follow-up durations were 2.1 years for SUSTAIN 6 and 3.8 years for LEADER. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years after randomization by 24% versus placebo (95% CI, 20%-27%; P&lt;0.001). Significant reductions were also observed in by-trial data analyses (P&lt;0.001 for all), the largest being with semaglutide 1.0 mg (33% [95% CI, 24%-40%]; P&lt;0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m2/y (P&lt;0.0001 and P&lt;0.001), respectively, versus placebo. Effects appeared larger in patients with baseline eGFR &lt;60 versus &#x2265;60 mL/min/1.73 m2 (Pinteraction=0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR], 0.86 [95% CI, 0.75-0.99]; P=0.039 and HR, 0.80 [95% CI, 0.66-0.97]; P=0.023, respectively). Similar, nonsignificant, directional results were observed for 30% and 57% eGFR reductions (HR, 0.92 [95% CI, 0.84-1.02]; P=0.10 and HR, 0.89 [95% CI, 0.69-1.13]; P=0.34). In patients with baseline eGFR 30 to &lt;60 mL/min/1.73 m2, the likelihood of persistent reduction for all thresholds was increased, ranging from HR 0.71 for 30% reduction (95% CI, 0.59-0.85; P=0.000","evidenceGrade":"full_text"},{"id":"p-pmid-38912654","title":"Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.","authors":["A Malhotra","RR Grunstein","I Fietze","TE Weaver","S Redline","A Azarbarzin","SA Sands","RJ Schwab"],"year":2024,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa2404881","pmid":"38912654","url":"https://pubmed.ncbi.nlm.nih.gov/38912654/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P&lt;0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P&lt;0.001). Significant improv","evidenceGrade":"full_text"},{"id":"p-pmid-41135142","title":"Tirzepatide for sleep-disordered breathing in SURMOUNT-OSA: Time course and association with body weight.","authors":["A Malhotra","RR Grunstein","A Azarbarzin","SA Sands","X Dang","S Chakladar","JP Dunn","B Falcon"],"year":2025,"venue":"Sleep medicine","doi":"10.1016/j.sleep.2025.106853","pmid":"41135142","url":"https://pubmed.ncbi.nlm.nih.gov/41135142/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder with major cardiometabolic and neurocognitive sequelae. It affects up to 1 billion people globally and is frequently attributable to excess weight [1]. Tirzepatide is a once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is FDA-approved for the treatment of moderate-to-severe OSA in adults with obesity. METHODS: The SURMOUNT-OSA program included two 52-week, randomized, double-blind, placebo-controlled, Phase 3 studies (Study 1 and Study 2). The objective of these analyses was to assess time to treatment effects for improvements in apnea-hypopnea index (AHI) and sleep apnea-specific hypoxic burden (SASHB), and how these changes correspond with body weight reduction. We also aimed to investigate weight-dependent and weight-independent effects of tirzepatide treatment for OSA using linear regression analysis. RESULTS: The results of peripheral AHI (pAHI) and SASHB measurements from WatchPAT 300 in Study 1 were consistent with the polysomnographic (PSG) findings. The tirzepatide-associated improvements in pAHI were significant vs baseline as early as Week 4. However, the estimated treatment difference compared to placebo was not significant until Week 20 for both pAHI and WatchPAT-based SASHB. The magnitude of changes in AHI and SASHB were associated with achieved weight reduction in both studies. CONCLUSIONS: The results from these post hoc analyses provide details regarding the time course of resolution and insights regarding the impact of weight reduction on OSA improvements. Additional research is needed to determine the impact of body weight reduction versus other effects of tirzepatide on the improvements in OSA measures. SURMOUNT-OSA ClinicalTrials.gov number NCT05412004.","evidenceGrade":"full_text"},{"id":"p-pmid-42675225","title":"Association of tirzepatide with changes in OSA-related measures based on baseline characteristics - post hoc analyses of SURMOUNT-OSA.","authors":["B Falcon","CC Xie","S Redline","R Grunstein","CD Turnbull","DM Rapoport","H Wang","S Chakladar"],"year":2026,"venue":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine","doi":"10.1007/s44470-026-00162-z","pmid":"42675225","url":"https://pubmed.ncbi.nlm.nih.gov/42675225/","methodology":"rct","n":null,"openAccess":false,"abstract":"PURPOSE: Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive collapse of the upper airway during sleep. Given that excess adiposity is a known risk factor for OSA, we aimed to descriptively assess the association of tirzepatide, a GIP/GLP-1 receptor agonist, with changes in AHI, hypoxic burden, body weight, and blood pressure in different patient populations based on baseline characteristics such as age, sex, BMI, AHI, and neck circumference. METHODS: These post hoc analyses examined data from two Phase 3 randomized, double-blind studies evaluating maximum tolerated dose (MTD) tirzepatide (10&#xa0;mg or 15&#xa0;mg) compared with placebo in adults with moderate-to-severe OSA (AHI&#x2009;&#x2265;&#x2009;15 events/h) and obesity (BMI&#x2009;&#x2265;&#x2009;30&#xa0;kg/m2) over a 52-week period. Baseline subgroup analyses were conducted in participants with non-missing relevant baseline measurements. RESULTS: Generally, participants treated with tirzepatide showed greater improvements in OSA outcomes compared with placebo, regardless of baseline subgroup. Participants treated with tirzepatide experienced reductions in AHI across subgroups, regardless of baseline age (-27.7 to -34.1 events/h), sex (-19.8 to -32.6 events/h), AHI severity (-12.1 to -52.2 events/h), BMI (-25.2 to -34.4 events/h), and neck circumference (-23.9 to -30.8 events/h). Additionally, improvements were observed in body weight, systolic blood pressure, and sleep apnea-specific hypoxic burden across baseline subgroups. Overall, most participants experienced an improvement in AHI severity category with tirzepatide treatment (68% to 79%), while the majority in the placebo group saw no clinically relevant change (64% to 70%). CONCLUSIONS: In these descriptive, hypothesis-generating, post hoc analyses, tirzepatide treatment was associated with improvements in multiple measures in participants with moderate-to-severe OSA and obesity. These improvements were observed across both st","evidenceGrade":"abstract_only"},{"id":"p-pmid-39996356","title":"Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight.","authors":["M Look","JP Dunn","RF Kushner","D Cao","C Harris","TH Gibble","A Stefanski","R Griffin"],"year":2025,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.16275","pmid":"39996356","url":"https://pubmed.ncbi.nlm.nih.gov/39996356/","methodology":"rct","n":null,"openAccess":true,"abstract":"AIMS: We assessed changes in body composition following tirzepatide treatment in a substudy of participants with obesity or overweight from the SURMOUNT-1 trial, overall and post hoc in clinically relevant subgroups. MATERIALS AND METHODS: Substudy participants (n&#x2009;=&#x2009;160 of the 2539 in SURMOUNT-1) underwent dual-energy X-ray absorptiometry (DXA) at baseline and Week 72. Body composition parameters were evaluated by analysis of covariance, logistic regression or Fisher's exact test. Post hoc subgroup analyses were conducted by sex (female or male), age (&lt;50, 50 to &lt;65, or &#x2265;65&#x2009;years) and total body weight reduction tertiles (&#x2264;15.3&#x2009;kg, &gt;15.3 to &#x2264;25.9&#x2009;kg, or &gt;25.9&#x2009;kg). RESULTS: The 160 participants (pooled tirzepatide doses n&#x2009;=&#x2009;124, placebo n&#x2009;=&#x2009;36) with baseline and end of study DXA data were 73% female and had a mean weight of 102.5&#x2009;kg and body mass index of 38.0&#x2009;kg/m2. The change in body weight, fat mass and lean mass from baseline to Week 72 was -21.3%, -33.9% and -10.9% with tirzepatide and -5.3%, -8.2% and -2.6% with placebo, respectively (p&#x2009;&lt;&#x2009;0.001 for all comparisons). Of the body weight lost, approximately 75% was fat mass and 25% was lean mass for both tirzepatide and placebo. These proportions remained consistent across most subgroup analyses. CONCLUSIONS: In participants with obesity or overweight from the SURMOUNT-1 trial, tirzepatide treatment significantly reduced body weight, fat mass and lean mass compared with placebo, while in post hoc analyses, the proportion of body weight lost as fat or lean mass was relatively consistent including in clinically relevant subgroups.","evidenceGrade":"full_text"},{"id":"p-pmid-31897524","title":"Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial.","authors":["RJ McCrimmon","AM Catarig","JP Frias","NL Lausvig","CW le Roux","D Thielke","I Lingvay"],"year":2021,"venue":"Diabetologia","doi":"10.1007/s00125-019-05065-8","pmid":"31897524","url":"https://pubmed.ncbi.nlm.nih.gov/31897524/","methodology":"rct","n":null,"openAccess":true,"abstract":"AIMS/HYPOTHESIS: Intra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0&#xa0;mg and canagliflozin 300&#xa0;mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning. METHODS: Adults (age&#x2009;&#x2265;18&#xa0;years) with type 2 diabetes, HbA1c 53-91&#xa0;mmol/mol (7.0-10.5%), on a stable daily dose of metformin (&#x2265;1500&#xa0;mg or maximum tolerated dose) and with an eGFR &#x2265;60&#xa0;ml&#xa0;min-1 [1.73&#xa0;m]-2 were randomised 1:1 to semaglutide 1.0&#xa0;mg once weekly and canagliflozin placebo once daily, or canagliflozin 300&#xa0;mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint. RESULTS: A subset of 178 participants (semaglutide, n&#x2009;=&#x2009;88; canagliflozin, n&#x2009;=&#x2009;90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n&#x2009;=&#x2009;53; canagliflozin, n&#x2009;=&#x2009;61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52&#xa0;weeks with both treatments. Total fat mass (baseline 33.2&#xa0;kg) was reduced by 3.4&#xa0;kg and 2.6&#xa0;kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.79 [95% CI -2.10, 0.51]). Although total lean mass (baseline 51.3&#xa0;kg) was also reduced by 2.3&#xa0;kg and 1.5&#xa0;kg ","evidenceGrade":"full_text"},{"id":"p-pmid-38698650","title":"Effect of semaglutide 2.4&#x2009;mg on physical functioning and weight- and health-related quality of life in adults with overweight or obesity: Patient-reported outcomes from the STEP 1-4 trials.","authors":["D Rubino","JB Bjorner","N Rathor","AM Sharma","L von Huth Smith","S Wharton","T Wadden","N Zeuthen"],"year":2024,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.15620","pmid":"38698650","url":"https://pubmed.ncbi.nlm.nih.gov/38698650/","methodology":"rct","n":null,"openAccess":false,"abstract":"AIMS: To summarize the effects of semaglutide 2.4&#x2009;mg on weight-related quality of life (WRQOL) and health-related quality of life (HRQOL), focusing on the confirmatory secondary endpoint of physical functioning. MATERIALS AND METHODS: The STEP 1-4 Phase 3a, 68-week, double-blind, randomized controlled trials assessed the efficacy and safety of semaglutide 2.4&#x2009;mg versus placebo in individuals with overweight/obesity. WRQOL and HRQOL were assessed by change from baseline to Week 68 in two different but complementary measures, the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT; STEP 1 and 2) and the SF-36v2 Health Survey Acute (SF-36v2; STEP 1-4). RESULTS: Superiority for semaglutide 2.4&#x2009;mg over placebo based on IWQOL-Lite-CT and SF-36v2 physical functioning scores was confirmed in STEP 1 and 2 and in STEP 1, 2 and 4, respectively. At Week 68, a greater proportion of participants treated with semaglutide 2.4&#x2009;mg than with placebo reached meaningful within-person change (MWPC) thresholds for IWQOL-Lite-CT Physical Function scores in STEP 1 (51.8% vs. 28.3%; p&#x2009;&lt;&#x2009;0.0001) and STEP 2 (39.6% vs. 29.5%; p&#x2009;=&#x2009;0.0083) and the MWPC threshold for SF-36v2 Physical Functioning in STEP 1 (39.8% vs. 24.1%; p&#x2009;&lt;&#x2009;0.0001), STEP 2 (41.0% vs. 27.3%; p&#x2009;=&#x2009;0.0005) and STEP 4 (18.0% vs. 6.6%; p&#x2009;&lt;&#x2009;0.0001). All other IWQOL-Lite-CT and SF-36v2 scale scores in STEP 1-4 were numerically improved with semaglutide 2.4&#x2009;mg versus placebo, except for SF-36v2 Role Emotional in STEP 2. CONCLUSIONS: Semaglutide 2.4&#x2009;mg significantly improved physical functioning, with greater proportions of participants achieving MWPC compared with placebo, and showed beneficial effects on WRQOL and HRQOL beyond physical functioning.","evidenceGrade":"abstract_only"},{"id":"p-pmid-40934115","title":"Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity.","authors":["S Wharton","I Lingvay","P Bogdanski","R Duque do Vale","S Jacob","T Karlsson","C Shaji","D Rubino"],"year":2025,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa2500969","pmid":"40934115","url":"https://pubmed.ncbi.nlm.nih.gov/40934115/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Oral semaglutide at a dose of 25 mg may provide an alternative treatment option to injectable semaglutide (2.4 mg) and higher-dose oral semaglutide (50 mg) for persons with overweight or obesity. METHODS: In a 71-week, double-blind, randomized, placebo-controlled trial conducted at 22 sites in four countries, we enrolled persons without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. The participants were randomly assigned in a 2:1 ratio to receive oral semaglutide (25 mg) or placebo once daily, plus lifestyle interventions. The coprimary end points at week 64 were the percent change in body weight and a reduction of 5% or more in body weight; confirmatory secondary end points included reductions in body weight of 10% or more, 15% or more, and 20% or more and the change in the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score. RESULTS: A total of 205 participants were randomly assigned to receive oral semaglutide, and 102 to receive placebo. The estimated mean change in body weight from baseline to week 64 was -13.6% in the oral semaglutide group and -2.2% in the placebo group (estimated difference, -11.4 percentage points; 95% confidence interval, -13.9 to -9.0; P&lt;0.001). Participants in the oral semaglutide group were significantly more likely than those in the placebo group to have body-weight reductions of 5% or more, 10% or more, 15% or more, and 20% or more (P&lt;0.001 for all comparisons) and to have an improved IWQOL-Lite-CT Physical Function score (P&lt;0.001). Gastrointestinal adverse events were more common with oral semaglutide than with placebo (74.0% vs. 42.2%). CONCLUSIONS: Oral semaglutide at a dose of 25 mg once daily resulted in a greater mean reduction in body weight than placebo in participants with overweight or obesity. (Fund","evidenceGrade":"abstract_only"},{"id":"p-pmid-22389082","title":"Epigallocatechin gallate, cerebral blood flow parameters, cognitive performance and mood in healthy humans: a double-blind, placebo-controlled, crossover investigation.","authors":["EL Wightman","CF Haskell","JS Forster","RC Veasey","DO Kennedy"],"year":2012,"venue":"Human psychopharmacology","doi":"10.1002/hup.1263","pmid":"22389082","url":"https://pubmed.ncbi.nlm.nih.gov/22389082/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: The aim of the study was to assess the effects of oral ingestion of the 'green tea' polyphenol epigallocatechin gallate (EGCG) on cognitive performance, mood and localised cerebral blood flow (CBF) parameters in healthy human adults. METHOD: In this double-blind, placebo-controlled, crossover study, 27 healthy adults received placebo and two doses (135 and 270 mg) of EGCG in counterbalanced order on separate days. Following a 45-min resting absorption period, participants performed a selection of computerised cognitive tasks that activate the frontal cortex for a further 42 min. CBF and haemodynamics, as indexed by concentration changes in oxygenated and deoxygenated haemoglobin, were assessed in the frontal cortex throughout the post-treatment period using Near-infrared spectroscopy (NIRS). RESULTS: During the post-dose task performance period, the administration of 135 mg EGCG resulted in reduced CBF in the frontal cortex, as indexed by significantly lower concentrations of both oxygenated and total haemoglobin, in comparison with placebo. Heart rate was significantly reduced from pre dose to post dose across all treatments. No significant differences were observed for the level of deoxygenated haemoglobin or on any of the cognitive performance/mood measures. CONCLUSIONS: These results demonstrate that a single dose of orally administered EGCG can modulate CBF parameters in healthy humans but that this is not associated with changes in cognitive performance or mood.","evidenceGrade":"abstract_only"},{"id":"p-pmid-28784536","title":"An intervention study on the effect of matcha tea, in drink and snack bar formats, on mood and cognitive performance.","authors":["C Dietz","M Dekker","B Piqueras-Fiszman"],"year":2019,"venue":"Food research international (Ottawa, Ont.)","doi":"10.1016/j.foodres.2017.05.002","pmid":"28784536","url":"https://pubmed.ncbi.nlm.nih.gov/28784536/","methodology":"rct","n":null,"openAccess":false,"abstract":"Matcha tea is gaining popularity throughout the world in recent years and is frequently referred to as a mood-and-brain food. Previous research has demonstrated that three constituents present in matcha tea, l-theanine, epigallocatechin gallate (EGCG), and caffeine, affect mood and cognitive performance. However, to date there are no studies assessing the effect of matcha tea itself. The present study investigates these effects by means of a human intervention study administering matcha tea and a matcha containing product. Using a randomized, placebo-controlled, single-blind study, 23 consumers participated in four test sessions. In each session, participants consumed one of the four test products: matcha tea, matcha tea bar (each containing 4g matcha tea powder), placebo tea, or placebo bar. The assessment was performed at baseline and 60min post-treatment. The participants performed a set of cognitive tests assessing attention, information processing, working memory, and episodic memory. The mood state was measured by means of a Profile of Mood States (POMS). After consuming the matcha products compared to placebo versions, there were mainly significant improvements in tasks measuring basic attention abilities and psychomotor speed in response to stimuli over a defined period of time. In contrast to expectations, the effect was barely present in the other cognitive tasks. The POMS results revealed no significant changes in mood. The influence of the food matrix was demonstrated by the fact that on most cognitive performance measures the drink format outperformed the bar format, particularly in tasks measuring speed of spatial working memory and delayed picture recognition. This study suggests that matcha tea consumed in a realistic dose can induce slight effects on speed of attention and episodic secondary memory to a low degree. Further studies are required to elucidate the influences of the food matrix.","evidenceGrade":"abstract_only"},{"id":"p-pmid-18710606","title":"Effects of dietary supplementation with the green tea polyphenol epigallocatechin-3-gallate on insulin resistance and associated metabolic risk factors: randomized controlled trial.","authors":["AL Brown","J Lane","J Coverly","J Stocks","S Jackson","A Stephen","L Bluck","A Coward"],"year":2009,"venue":"The British journal of nutrition","doi":"10.1017/S0007114508047727","pmid":"18710606","url":"https://pubmed.ncbi.nlm.nih.gov/18710606/","methodology":"rct","n":null,"openAccess":true,"abstract":"Animal evidence indicates that green tea may modulate insulin sensitivity, with epigallocatechin-3-gallate (EGCG) proposed as a likely health-promoting component. The purpose of this study was to investigate the effect of dietary supplementation with EGCG on insulin resistance and associated metabolic risk factors in man. Overweight or obese male subjects, aged 40-65 years, were randomly assigned to take 400 mg capsules of EGCG (n 46) or the placebo lactose (n 42), twice daily for 8 weeks. Oral glucose tolerance testing and measurement of metabolic risk factors (BMI, waist circumference, percentage body fat, blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, TAG) was conducted pre- and post-intervention. Mood was evaluated weekly using the University of Wales Institute of Science and Technology mood adjective checklist. EGCG treatment had no effect on insulin sensitivity, insulin secretion or glucose tolerance but did reduce diastolic blood pressure (mean change: placebo - 0.058 (se 0.75) mmHg; EGCG - 2.68 (se 0.72) mmHg; P = 0.014). No significant change in the other metabolic risk factors was observed. The EGCG group also reported feeling in a more positive mood than the placebo group across the intervention period (mean score for hedonic tone: EGCG, 29.11 (se 0.44); placebo, 27.84 (se 0.46); P = 0.048). In conclusion, regular intake of EGCG had no effect on insulin resistance but did result in a modest reduction in diastolic blood pressure. This antihypertensive effect may contribute to some of the cardiovascular benefits associated with habitual green tea consumption. EGCG treatment also had a positive effect on mood. Further studies are needed to confirm the findings and investigate their mechanistic basis.","evidenceGrade":"full_text"},{"id":"p-pmid-21649457","title":"Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial.","authors":["CH Hsu","YL Liao","SC Lin","TH Tsai","CJ Huang","P Chou"],"year":2011,"venue":"Alternative medicine review : a journal of clinical therapeutic","doi":null,"pmid":"21649457","url":"https://pubmed.ncbi.nlm.nih.gov/21649457/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Green tea is one of the most popular beverages in the world. It is believed to have beneficial effects in the prevention and treatment of many diseases, one of which is type 2 diabetes. The aim of the study is to examine the effect of a decaffeinated green tea extract (GTE) providing a daily dose of 856 mg of epigallocatechin gallate (EGCG) on obese individuals with type 2 diabetes. MATERIALS AND METHODS: The clinical trial was a randomized, double-blind, placebo-controlled clinical trial conducted from December 2007 through November 2008. The subjects were randomly assigned to either receive 1,500 mg of a decaffeinated GTE or placebo daily for 16 weeks. Sixty-eight of 80 subjects, ages 20-65 years with BMI &gt; 25 kg/m2 and type 2 diabetes for more than one year, completed this study. Homeostasis model assessment for insulin resistance (HOMA-IR) was used as the major outcome measurement. At baseline and after 16 weeks of treatment, anthropometric measurements, fasting glucose, hemoglobin A1C percent (HbA1C), hormone peptides, and plasma lipoproteins were measured from both groups. RESULTS: No statistically significant differences were detected between the decaffeinated GTE and placebo groups in any measured variable. A statistically significant within-group 0.4-percent reduction in HbA1C (from 8.4 to 8.0%) was observed after GTE treatment compared to baseline. Within-group comparison also revealed that the GTE group had significant reductions in waist circumference (WC), HOMA-IR index, and insulin level, and a significant increase in the level of ghrelin. Within-group comparison of those in the placebo group showed a significant increase in the level of ghrelin. CONCLUSIONS: This study found no statistical difference in any measured variable between the decaffeinated GTE and placebo groups; however, there were some statistically significant within-group changes detected. More research is required to determine whether a decaffeinated GTE standardized for","evidenceGrade":"abstract_only"},{"id":"p-pmid-16392704","title":"Randomized controlled trial for an effect of green tea consumption on insulin resistance and inflammation markers.","authors":["Y Fukino","M Shimbo","N Aoki","T Okubo","H Iso"],"year":2006,"venue":"Journal of nutritional science and vitaminology","doi":null,"pmid":"16392704","url":"https://pubmed.ncbi.nlm.nih.gov/16392704/","methodology":"rct","n":null,"openAccess":false,"abstract":"To study the effects of the intake of green tea and polyphenols, which are a component of green tea, on insulin resistance and systemic inflammation, a randomized controlled trial was conducted on 66 patients aged 32-73 y (53 males and 13 females) with borderline diabetes or diabetes. Subjects in the intervention group were asked to take a packet of green tea extracts/powder containing 544 mg polyphenols (456 mg catechins) daily, which was a dose that could be taken without difficulty, and were asked to divide the green tea extracts/powder in a packet into 3 or 4 fractions dissolved in hot water everyday and to take a fraction after every meal or snack for 2 mo, in addition to daily food intake. The subjects in the control group were simply followed. To calculate the level of green tea polyphenol intake that the subject usually drank at home, the subject was asked to taste 3 teas of different strengths (1, 2 and 3%) and the tea that was closest to the one that the subject drank at home, was selected by each subject. After 2 mo, the mean daily polyphenol intake in the intervention group was 747 mg, which was significantly higher than that of 469 mg in the control group. In the intervention group, the body weight, BMI, systolic and diastolic blood pressures, blood glucose level, Hb A1c level, insulin level and HOMA index after taking the supplementation for 2 mo, were lower than the respective value before intervention: however, these parameters in the intervention group at 2 mo did not significantly differ from those in the control group. Within the intervention group, changes in insulin level tended to be associated with changes in polyphenol intake. In addition, changes in BMI were associated with changes in blood glucose level and insulin level. In conclusion, the daily supplementary intake of 500 mg green tea polyphenols did not have clear effects on blood glucose level, Hb A1c level, insulin resistance or inflammation markers. The positive correlation between th","evidenceGrade":"abstract_only"},{"id":"p-pmid-37478886","title":"Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.","authors":["FR Lin","JR Pike","MS Albert","M Arnold","S Burgard","T Chisolm","D Couper","JA Deal"],"year":2023,"venue":"Lancet (London, England)","doi":"10.1016/S0140-6736(23)01406-X","pmid":"37478886","url":"https://pubmed.ncbi.nlm.nih.gov/37478886/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Hearing loss is associated with increased cognitive decline and incident dementia in older adults. We aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. METHODS: The ACHIEVE study is a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70-84 years with untreated hearing loss and without substantial cognitive impairment that took place at four community study sites across the USA. Participants were recruited from two study populations at each site: (1) older adults participating in a long-standing observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and (2) healthy de novo community volunteers. Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed up every 6 months. The primary endpoint was 3-year change in a global cognition standardised factor score from a comprehensive neurocognitive battery. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, NCT03243422. FINDINGS: From Nov 9, 2017, to Oct 25, 2019, we screened 3004 participants for eligibility and randomly assigned 977 (32&#xb7;5%; 238 [24%] from ARIC and 739 [76%] de novo). We randomly assigned 490 (50%) to the hearing intervention and 487 (50%) to the health education control. The cohort had a mean age of 76&#xb7;8 years (SD 4&#xb7;0), 523 (54%) were female, 454 (46%) were male, and most were White (n=858 [88%]). Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than those in the de novo cohort. In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly diff","evidenceGrade":"full_text"},{"id":"p-pmid-38788800","title":"Adult-onset hearing loss and incident cognitive impairment and dementia - A systematic review and meta-analysis of cohort studies.","authors":["RC Yu","D Proctor","J Soni","L Pikett","G Livingston","G Lewis","A Schilder","D Bamiou"],"year":2024,"venue":"Ageing research reviews","doi":"10.1016/j.arr.2024.102346","pmid":"38788800","url":"https://pubmed.ncbi.nlm.nih.gov/38788800/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: We comprehensively summarized the cohort evidence to date on adult-onset hearing loss as risk factor for incident cognitive impairment and dementia, and examined the evidence for dose-response, risk for various dementia subtypes, and other moderators. Previous meta-analyses were less comprehensive. METHODS: We included cohort studies with participants without dementia and with hearing assessments at baseline, minimum 2 years follow-up and incident cognitive outcomes. We used random-effect models and subgroup and meta-regression on moderator analyses. RESULTS: We identified fifty studies (N=1,548,754). Hearing loss (yes/no) was associated with incident dementia risk (HR=1.35 [95% CI = 1.26 - 1.45), mild cognitive impairment (MCI HR=1.29 [95% CI = 1.11 - 1.50]), cognitive decline not specified as MCI or dementia (HR=1.29 [95% CI = 1.17 - 1.42]), and Alzheimer's disease dementia (ADD, HR=1.56 [95% CI = 1.30 - 1.87]), but not with vascular dementia (HR, 1.30 [95% CI = 0.83 - 2.05]). Each 10-decibel worsening of hearing was associated with a 16% increase in dementia risk (95% CI = 1.07 - 1.27). The effect of hearing loss did not vary across potential moderators. CONCLUSIONS: Cohort studies consistently support that adult-onset hearing loss increases the risk of incident cognitive decline, dementia, MCI, and ADD.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39352700","title":"Hearing Loss, Hearing Aids, and Cognition.","authors":["B Grenier","C Berr","M Goldberg","X Jouven","M Zins","JP Empana","Q Lisan"],"year":2024,"venue":"JAMA network open","doi":"10.1001/jamanetworkopen.2024.36723","pmid":"39352700","url":"https://pubmed.ncbi.nlm.nih.gov/39352700/","methodology":"observational","n":null,"openAccess":true,"abstract":"IMPORTANCE: Most observational studies examining the association between hearing loss (HL) and cognitive impairment used subjective measures of hearing and addressed only one dimension of cognition, and very few investigated the potential benefit of hearing aids (HAs). OBJECTIVE: To evaluate objectively measured HL and several dimensions of cognition and estimate the association with HA use. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional analysis of the CONSTANCES cohort study, which recruited participants from January 1, 2012, to December 31, 2020, was conducted. Participants were a representative sample of adults (age, 45-69 years) with audiometric data and cognitive evaluation from 21 preventive health centers in France. Data analysis was conducted from April 1 to September 15, 2023. EXPOSURE: The main exposure was HL, which was defined by a pure-tone average in the best ear higher than 20 dB hearing level for mild loss and 35 dB hearing level for disabling loss. Secondary exposure was self-reported HA use. MAIN OUTCOMES AND MEASURES: Cognition was evaluated at study inclusion by a standardized battery of 5 cognitive tests conducted by trained neuropsychologists. A global cognitive score was computed from principal component analysis and global cognitive impairment was defined as having a score less than or equal to the 25th percentile of the distribution. RESULTS: The study population included 62&#x202f;072 participants with audiometric data (mean [SD] age, 57.4 [7] years; 52% women). Overall, 38% (n&#x2009;=&#x2009;23&#x202f;768) had mild HL, 10% (n&#x2009;=&#x2009;6012) had disabling HL, and 3% (n&#x2009;=&#x2009;1668) were HA users. In multivariable analyses, mild HL (odds ratio [OR], 1.10; 95% CI, 1.05-1.15) and disabling HL (OR, 1.24; 95% CI, 1.16-1.33) were associated with greater global cognitive impairment. The odds of cognitive impairment did not differ significantly between all participants with HA use and participants with disabling HL without H","evidenceGrade":"full_text"},{"id":"p-shrank-2011","title":"Healthy user and related biases in observational studies of preventive interventions: a primer for physicians","authors":["W. H. Shrank","A. R. Patrick","M. A. Brookhart"],"year":2011,"venue":"Journal of General Internal Medicine","doi":"10.1007/s11606-010-1609-1","pmid":"21203857","url":"https://pubmed.ncbi.nlm.nih.gov/21203857/","methodology":"review","n":null,"openAccess":true,"abstract":"The primer on Healthy User Bias: people who take preventive pills are different in a hundred ways that look like treatment effects. The right citation for 'supplement users have better jobs'.","evidenceGrade":"abstract_only"},{"id":"p-buss-1989","title":"Sex differences in human mate preferences: Evolutionary hypotheses tested in 37 cultures","authors":["D. M. Buss"],"year":1989,"venue":"Behavioral and Brain Sciences","doi":"10.1017/S0140525X00023992","pmid":null,"url":"https://doi.org/10.1017/S0140525X00023992","methodology":"observational","n":10047,"openAccess":false,"abstract":"Stated preferences across 37 cultures: women placed more value on earning capacity; men placed more value on youth and physical attractiveness. Foundational, survey-based, and the starting point later field experiments had to discipline.","evidenceGrade":"abstract_only"},{"id":"p-holt-laury-2002","title":"Risk aversion and incentive effects","authors":["C. A. Holt","S. K. Laury"],"year":2002,"venue":"American Economic Review","doi":"10.1257/000282802762024700","pmid":null,"url":"https://doi.org/10.1257/000282802762024700","methodology":"rct","n":212,"openAccess":false,"abstract":"The multiple-price-list that became the field's default risk-preference measure. Incentive level changes estimated risk aversion. This is how 'risk' should be operationalized in this atlas.","evidenceGrade":"abstract_only"},{"id":"p-pmid-20811299","title":"Effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome: a perspective, randomized, placebo-controlled study.","authors":["D Giordano","F Corrado","A Santamaria","S Quattrone","B Pintaudi","A Di Benedetto","R D'Anna"],"year":2011,"venue":"Menopause (New York, N.Y.)","doi":"10.1097/gme.0b013e3181e8e1b1","pmid":"20811299","url":"https://pubmed.ncbi.nlm.nih.gov/20811299/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: The aim of this study was to evaluate whether myo-inositol, an insulin-sensitizing substance, may improve some features of metabolic syndrome in postmenopausal women. METHODS: Eighty postmenopausal women affected by the metabolic syndrome were enrolled prospectively in the study and treated with diet plus supplementation of myo-inositol (2 g BID plus diet: intervention group) or with diet plus placebo (control group) for 6 months. They were evaluated at baseline and after 6 months for insulin resistance (homeostasis model assessment ratio [HOMA] insulin resistance), lipid profile, and blood pressure. RESULTS: Myo-inositol plus diet improved systolic and diastolic blood pressure, HOMA index, cholesterol, and triglyceride serum levels with highly significant differences, compared with the groups treated only with diet and placebo. In the group treated with myo-inositol, a decrease in diastolic blood pressure (-11%), HOMA index (-75%), and serum triglycerides (-20%) and an improvement in high-density lipoprotein cholesterol (22%) were shown. CONCLUSIONS: Supplementation with myo-inositol may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women.","evidenceGrade":"abstract_only"},{"id":"p-pmid-26241420","title":"Myo-inositol Supplementation for Prevention of Gestational Diabetes in Obese Pregnant Women: A Randomized Controlled Trial.","authors":["R D'Anna","A Di Benedetto","A Scilipoti","A Santamaria","ML Interdonato","E Petrella","I Neri","B Pintaudi"],"year":2015,"venue":"Obstetrics and gynecology","doi":"10.1097/AOG.0000000000000958","pmid":"26241420","url":"https://pubmed.ncbi.nlm.nih.gov/26241420/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: To evaluate whether myo-inositol supplementation, an insulin sensitizer, reduces the rate of gestational diabetes mellitus (GDM) and lowers insulin resistance in obese pregnant women. METHODS: In an open-label, randomized trial, myo-inositol (2 g plus 200 micrograms folic acid twice a day) or placebo (200 micrograms folic acid twice a day) was administered from the first trimester to delivery in pregnant obese women (prepregnancy body mass index 30 or greater. We calculated that 101 women in each arm would be required to demonstrate a 65% GDM reduction in the myo-inositol group with a statistical power of 80% (&#x3b1;=0.05). The primary outcomes were the incidence of GDM and the change in insulin resistance from enrollment until the diagnostic oral glucose tolerance test. RESULTS: From January 2011 to April 2014, 220 pregnant women at 12-13 weeks of gestation were randomized at two Italian university hospitals, 110 to myo-inositol and 110 to placebo. Most characteristics were similar between groups. The GDM rate was significantly reduced in the myo-inositol group compared with the control group, 14.0% compared with 33.6%, respectively (P=.001; odds ratio 0.34, 95% confidence interval 0.17-0.68). Furthermore, women treated with myo-inositol showed a significantly greater reduction in the homeostasis model assessment of insulin resistance compared with the control group, -1.0&#xb1;3.1 compared with 0.1&#xb1;1.8 (P=.048). CONCLUSION: Myo-inositol supplementation, started in the first trimester, in obese pregnant women seems to reduce the incidence in GDM through a reduction of insulin resistance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01047982.","evidenceGrade":"abstract_only"},{"id":"p-pmid-25670222","title":"Myo-inositol vs. D-chiro inositol in PCOS treatment.","authors":["C Formuso","M Stracquadanio","L Ciotta"],"year":2016,"venue":"Minerva ginecologica","doi":null,"pmid":"25670222","url":"https://pubmed.ncbi.nlm.nih.gov/25670222/","methodology":"rct","n":null,"openAccess":false,"abstract":"AIM: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in fertile age. It is an endocrine and metabolic disorder characterized by oligo-anovulation, hyperandrogenism and insulin-resistance. Various therapeutic approaches have been attempted in PCOS, including diet and the use of pharmacological agents such as oral contraceptives (OCs) or anti-androgens. Recently, the introduction of inositol in the treatment plan has proved to be as reasonable as useful in countering the endocrine-metabolic disorders of this syndrome. METHODS: The aim of our study was to compare the clinical, endocrine and metabolic response after 6 months of therapy in 137 PCOS women characterized by oligomenorrhea and/or acne and/or mild hirsutism and insulin-resistance. The patients were treated with myo-inositol or with D-chiro-inositol or with placebo. RESULTS: Our study showed that both myo-inositol (MI-PG) and D-chiro inositol (DCI-PG) treatments are able to significantly improve the regularity of the menstrual cycle, the Acne Score, the endocrine and metabolic parameters and the insulin-resistence in young, overweight, PCOS patients. CONCLUSION: Definitely, we assumed that both treatments with myo-inositol and with D-chiro inositol could be proposed as a potential valid therapeutic approach for the treatment of patients with PCOS. Additionally, further examination and for a longer period of treatment are needed.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29331802","title":"Hair cortisol and work stress: Importance of workload and stress model (JDCS or ERI).","authors":["L van der Meij","N Gubbels","J Schaveling","M Almela","M van Vugt"],"year":2018,"venue":"Psychoneuroendocrinology","doi":"10.1016/j.psyneuen.2017.12.020","pmid":"29331802","url":"https://pubmed.ncbi.nlm.nih.gov/29331802/","methodology":"observational","n":null,"openAccess":false,"abstract":"Hair cortisol concentrations (HCCs) are a potential physiological indicator of work related stress. However, studies that tested the relationship between HCC and self-reported stress in a work setting show mixed findings. This may be because few studies used worker samples that experience prolonged stress. Therefore, we compared a high workload sample (n&#x202f;=&#x202f;81) and a normal workload sample (n&#x202f;=&#x202f;91) and studied whether HCC was related to: (i) high job demands, low control, and low social support (JDCS model), and (ii) high effort, low reward, and high overcommitment (ERI model). Results showed that self-reported stress related to HCC only in the high workload sample and only for the variables of the ERI model. We found that HCC was higher when effort was high, reward low, and overcommitment high. An implication of this study is that a certain stress threshold may need to be reached to detect a relationship between self-reported stress and physiological measures such as HCC.","evidenceGrade":"abstract_only"},{"id":"p-pmid-10772410","title":"Job strain and anger expression predict early morning elevations in salivary cortisol.","authors":["A Steptoe","M Cropley","J Griffith","C Kirschbaum"],"year":2000,"venue":"Psychosomatic medicine","doi":null,"pmid":"10772410","url":"https://pubmed.ncbi.nlm.nih.gov/10772410/","methodology":"observational","n":null,"openAccess":false,"abstract":"OBJECTIVE: The objectives of this study were to test the hypothesis that high job demands and low job control (job strain) are associated with elevated free cortisol levels early in the working day and with reduced variability across the day and to evaluate the contribution of anger expression to this pattern. METHODS: One hundred five school teachers (41 men and 64 women) classified 12 months earlier as high (N = 48) or low (N = 57) in job strain according to the demand/control model sampled saliva at 2-hour intervals from 8:00 to 8:30 hours to 22:00 to 22:30 hours on a working day. Anger expression was assessed with the Speilberger State-Trait Anger Expression Inventory, and negative affect was also measured. RESULTS: Free cortisol was significantly elevated at 8:00 to 8:30 hours in the high job strain group but not at later times of the day or evening. After adjustment for age and negative affect, cortisol was an average of 21.7% higher early in the working day in the high job strain group. This effect was significantly greater in high job strain teachers, who also reported high anger-out. The cortisol decline from morning to evening was greater in the high than low job strain individuals. Independently of job strain, women had a higher cortisol concentration at 8:00 to 8:30 hours than men, whereas cortisol concentration was greater in men than women in the middle of the working day between 12:00 and 16:30 hours. CONCLUSIONS: Job strain is associated with elevated free cortisol concentrations early in the working day but not with reduced cortisol variability. The interaction with outward anger expression suggests that individual characteristics modulate the impact of chronic work stress on the hypothalamic-pituitary-adrenocortical system.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29414027","title":"Associations of work stress with hair cortisol concentrations - initial findings from a prospective study.","authors":["RM Herr","C Almer","A Loerbroks","A Barrech","I Elfantel","J Siegrist","H G&#xfc;ndel","P Angerer"],"year":2018,"venue":"Psychoneuroendocrinology","doi":"10.1016/j.psyneuen.2018.01.011","pmid":"29414027","url":"https://pubmed.ncbi.nlm.nih.gov/29414027/","methodology":"observational","n":null,"openAccess":false,"abstract":"There is ample evidence supporting the link between stress at the workplace and physical and mental health. One of the pathways potentially mediating those associations may involve the hypothalamic-pituitary-adrenal (HPA) axis, with cortisol as an end product. While theoretically plausible, findings on the association of self-reported work stress with hair cortisol concentrations (HCC) are inconclusive, being potentially biased by omitted pertinent factors. This issue can be addressed, among others, by eliminating time-invariant factors through consideration of variation within persons over time. To this end, the present study examined the association between variation in HCC and perceived work stress - as assessed by the Effort-Reward-Imbalance (ERI) model - between two points in time (t1 and t2) over one year in a sample of 40 male factory workers. Neither a cross-sectional association, nor a link between change in ERI and HCC levels at t2 was observed. There was however a robust association of the change in ERI with the change of HCC. This effect was independent of baseline HCC and other confounders (Beta&#x202f;=&#x202f;0.414, S.E.&#x202f;=&#x202f;0.155, p&#x202f;=&#x202f;0.012). Accordingly, this is the first study revealing prospective evidence for the associations of work stress with HCC, while excluding potentially time-stable confounding factors, like genetic factors or phenotypic hair color.","evidenceGrade":"abstract_only"},{"id":"p-pmid-26905339","title":"Job Strain and the Cortisol Diurnal Cycle in MESA: Accounting for Between- and Within-Day Variability.","authors":["KE Rudolph","BN S&#xe1;nchez","EA Stuart","B Greenberg","K Fujishiro","GS Wand","S Shrager","T Seeman"],"year":2016,"venue":"American journal of epidemiology","doi":"10.1093/aje/kwv280","pmid":"26905339","url":"https://pubmed.ncbi.nlm.nih.gov/26905339/","methodology":"observational","n":null,"openAccess":true,"abstract":"Evidence of the link between job strain and cortisol levels has been inconsistent. This could be due to failure to account for cortisol variability leading to underestimated standard errors. Our objective was to model the relationship between job strain and the whole cortisol curve, accounting for sources of cortisol variability. Our functional mixed-model approach incorporated all available data-18 samples over 3 days-and uncertainty in estimated relationships. We used employed participants from the Multi-Ethnic Study of Atherosclerosis Stress I Study and data collected between 2002 and 2006. We used propensity score matching on an extensive set of variables to control for sources of confounding. We found that job strain was associated with lower salivary cortisol levels and lower total area under the curve. We found no relationship between job strain and the cortisol awakening response. Our findings differed from those of several previous studies. It is plausible that our results were unique to middle- to older-aged racially, ethnically, and occupationally diverse adults and were therefore not inconsistent with previous research among younger, mostly white samples. However, it is also plausible that previous findings were influenced by residual confounding and failure to propagate uncertainty (i.e., account for the multiple sources of variability) in estimating cortisol features.","evidenceGrade":"full_text"},{"id":"p-pmid-28122650","title":"Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data.","authors":["IEH Madsen","ST Nyberg","LL Magnusson Hanson","JE Ferrie","K Ahola","L Alfredsson","GD Batty","JB Bjorner"],"year":2018,"venue":"Psychological medicine","doi":"10.1017/S003329171600355X","pmid":"28122650","url":"https://pubmed.ncbi.nlm.nih.gov/28122650/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"BACKGROUND: Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. METHOD: We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol. RESULTS: We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published [relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13] and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32). CONCLUSIONS: Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.","evidenceGrade":"full_text"},{"id":"p-pmid-34444078","title":"The Demand-Control Model as a Predictor of Depressive Symptoms-Interaction and Differential Subscale Effects: Prospective Analyses of 2212 German Employees.","authors":["H Burr","G M&#xfc;ller","U Rose","M Formazin","T Clausen","A Schulz","H Berthelsen","G Potter"],"year":2021,"venue":"International journal of environmental research and public health","doi":"10.3390/ijerph18168328","pmid":"34444078","url":"https://pubmed.ncbi.nlm.nih.gov/34444078/","methodology":"observational","n":null,"openAccess":true,"abstract":"Testing assumptions of the widely used demand-control (DC) model in occupational psychosocial epidemiology, we investigated (a) interaction, i.e., whether the combined effect of low job control and high psychological demands on depressive symptoms was stronger than the sum of their single effects (i.e., superadditivity) and (b) whether subscales of psychological demands and job control had similar associations with depressive symptoms. Logistic longitudinal regression analyses of the 5-year cohort of the German Study of Mental Health at Work (S-MGA) 2011/12-2017 of 2212 employees were conducted. The observed combined effect of low job control and high psychological demands on depressive symptoms did not indicate interaction (RERI = -0.26, 95% CI = -0.91; 0.40). When dichotomizing subscales at the median, differential effects of subscales were not found. When dividing subscales into categories based on value ranges, differential effects for job control subscales (namely, decision authority and skill discretion) were found (p = 0.04). This study does not support all assumptions of the DC model: (1) it corroborates previous studies not finding an interaction of psychological demands and job control; and (2) signs of differential subscale effects were found regarding job control. Too few prospective studies have been carried out regarding differential subscale effects.","evidenceGrade":"full_text"},{"id":"p-pmid-31797050","title":"Gender and age differences in the association between work stress and incident depressive symptoms among Korean employees: a cohort study.","authors":["SY Kim","YC Shin","KS Oh","DW Shin","WJ Lim","SJ Cho","SW Jeon"],"year":2021,"venue":"International archives of occupational and environmental health","doi":"10.1007/s00420-019-01487-4","pmid":"31797050","url":"https://pubmed.ncbi.nlm.nih.gov/31797050/","methodology":"observational","n":null,"openAccess":false,"abstract":"PURPOSE: The aim of this study was to identify gender- and age-specific occupational stress associated with depressive symptoms among Korean employees. METHODS: Data of 73,014 employees aged 18 and above who had undergone comprehensive health examinations at Kangbuk Samsung Hospital Health Screening Center, South Korea, in January 2012 and who were followed up until December 2017 were collected, and 63,959 (participation rate: 87.59%, men: 50,413, women: 13,546) were finally analyzed. A Cox proportional hazards model was used to estimate the hazard ratios and 95% confidence intervals of the relationship between occupational stress and depressive symptoms. In light of gender and age differences in the association between occupational stress and depressive symptoms, interaction and stratification by gender and age groups were tested. RESULTS: During 238,630 person-years of follow-up, case-level depressive symptoms developed in 4227 participants (an incident rate of 1.8%). There were gender differences in the relationship between job stress and incident depressive symptoms. For men, high job demand, job insecurity, lack of reward, and discomfort in their organizational climate were associated with incident depressive symptoms in all age groups. Insufficient job control was associated with the development of depressive symptoms only in midlife and organizational injustice only in early adulthood. For women, the results for high job demand, organizational injustice, and discomfort in an organizational climate were associated with the onset of depressive symptoms from early adulthood to the midlife decade. CONCLUSION: The results suggest gender and age differences in the relationship between occupational stress and incident depressive symptoms.","evidenceGrade":"abstract_only"},{"id":"p-pmid-22390450","title":"The impact of changes in job strain and its components on the risk of depression.","authors":["PM Smith","A Bielecky"],"year":2012,"venue":"American journal of public health","doi":"10.2105/AJPH.2011.300376","pmid":"22390450","url":"https://pubmed.ncbi.nlm.nih.gov/22390450/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVES: We assessed the impact of changes in dimensions of the psychosocial work environment on risk of depression in a longitudinal cohort of Canadian workers who were free of depression when work conditions were initially reported. METHODS: Using a sample (n = 3735) from the Canadian National Population Health Survey, we examined the effects of changes in job control, psychological demands, and social support over a 2-year period on subsequent depression. We adjusted models for a number of covariates, including personal history of depression. RESULTS: Respondents with increased psychological demands were more likely to have depression over the following 2 years (odds ratio = 2.36; 95% confidence interval = 1.14, 4.88). This risk remained statistically significant after adjustment for age, gender, marital status, presence of children, level of education, chronic health conditions, subclinical depression when work conditions were initially assessed, family history of depression, and personal history of depression. CONCLUSIONS: These results demonstrate that changes in psychological demands have a stronger influence than changes in job control on the onset of depression, highlighting the importance of not assuming an interaction between these 2 components of job strain when assessing health outcomes.","evidenceGrade":"full_text"},{"id":"p-pmid-12700371","title":"Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter.","authors":["RL Canfield","CR Henderson","DA Cory-Slechta","C Cox","TA Jusko","BP Lanphear"],"year":2003,"venue":"The New England journal of medicine","doi":null,"pmid":"12700371","url":"https://pubmed.ncbi.nlm.nih.gov/12700371/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Despite dramatic declines in children's blood lead concentrations and a lowering of the Centers for Disease Control and Prevention's level of concern to 10 microg per deciliter (0.483 micromol per liter), little is known about children's neurobehavioral functioning at lead concentrations below this level. METHODS: We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders. RESULTS: The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 microg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 microg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 microg per deciliter. CONCLUSIONS: Blood lead concentrations, even those below 10 microg per deciliter, are inversely associated with children's IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.","evidenceGrade":"full_text"},{"id":"p-pmid-16002379","title":"Low-level environmental lead exposure and children's intellectual function: an international pooled analysis.","authors":["BP Lanphear","R Hornung","J Khoury","K Yolton","P Baghurst","DC Bellinger","RL Canfield","KN Dietrich"],"year":2005,"venue":"Environmental health perspectives","doi":null,"pmid":"16002379","url":"https://pubmed.ncbi.nlm.nih.gov/16002379/","methodology":"observational","n":null,"openAccess":true,"abstract":"Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels &lt; 10 microg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels &lt; 10 microg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5-10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 microg/dL and declined to 9.4 microg/dL by 5-7 years of age; 244 (18%) children had a maximal blood lead concentration &lt; 10 microg/dL, and 103 (8%) had a maximal blood lead concentration &lt; 7.5 microg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2-9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 microg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 microg/dL, 10 to 20 microg/dL, and 20 to 30 microg/dL were 3.9 (95% CI, 2.4-5.3), 1.9 (95% CI, 1.2-2.6), and 1.1 (95% CI, 0.7-1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level &lt; 7.5 microg/dL was significantly greater than that observed for those with a maximal blood lead level &gt; or = 7.5 microg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels &lt; 7.5 microg/dL is associated with intellectual deficits.","evidenceGrade":"full_text"},{"id":"p-pmid-18288325","title":"Blood lead concentrations &lt; 10 microg/dL and child intelligence at 6 years of age.","authors":["TA Jusko","CR Henderson","BP Lanphear","DA Cory-Slechta","PJ Parsons","RL Canfield"],"year":2008,"venue":"Environmental health perspectives","doi":"10.1289/ehp.10424","pmid":"18288325","url":"https://pubmed.ncbi.nlm.nih.gov/18288325/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Few studies provide data directly relevant to the question of whether blood lead concentrations &lt; 10 microg/dL adversely affect children's cognitive function. OBJECTIVE: We examined the association between blood lead concentrations assessed throughout early childhood and children's IQ at 6 years of age. METHODS: Children were followed from 6 months to 6 years of age, with determination of blood lead concentrations at 6, 12, 18, and 24 months, and 3, 4, 5, and 6 years of age. At 6 years of age, intelligence was assessed in 194 children using the Wechsler Preschool and Primary Scale of Intelligence-Revised. We used general linear and semiparametic models to estimate and test the association between blood lead concentration and IQ. RESULTS: After adjustment for maternal IQ, HOME scale scores, and other potential confounding factors, lifetime average blood lead concentration (mean = 7.2 microg/dL; median = 6.2 microg/dL) was inversely associated with Full-Scale IQ (p = 0.006) and Performance IQ scores (p = 0.002). Compared with children who had lifetime average blood lead concentrations &lt; 5 microg/dL, children with lifetime average concentrations between 5 and 9.9 microg/dL scored 4.9 points lower on Full-Scale IQ (91.3 vs. 86.4, p = 0.03). Nonlinear modeling of the peak blood lead concentration revealed an inverse association (p = 0.003) between peak blood lead levels and Full-Scale IQ down to 2.1 microg/dL, the lowest observed peak blood lead concentration in our study. CONCLUSIONS: Evidence from this cohort indicates that children's intellectual functioning at 6 years of age is impaired by blood lead concentrations well below 10 microg/dL, the Centers for Disease Control and Prevention definition of an elevated blood lead level.","evidenceGrade":"full_text"},{"id":"p-pmid-33201203","title":"Association of Childhood Lead Exposure With MRI Measurements of Structural Brain Integrity in Midlife.","authors":["A Reuben","ML Elliott","WC Abraham","J Broadbent","RM Houts","D Ireland","AR Knodt","R Poulton"],"year":2021,"venue":"JAMA","doi":"10.1001/jama.2020.19998","pmid":"33201203","url":"https://pubmed.ncbi.nlm.nih.gov/33201203/","methodology":"observational","n":null,"openAccess":true,"abstract":"IMPORTANCE: Childhood lead exposure has been linked to disrupted brain development, but long-term consequences for structural brain integrity are unknown. OBJECTIVE: To test the hypothesis that childhood lead exposure is associated with magnetic resonance imaging (MRI) measurements of lower structural integrity of the brain in midlife. DESIGN, SETTING, AND PARTICIPANTS: The Dunedin Study followed a population-representative 1972-1973 birth cohort in New Zealand (N&#x2009;=&#x2009;564 analytic sample) to age 45 years (until April 2019). EXPOSURES: Childhood blood lead levels measured at age 11 years. MAIN OUTCOMES AND MEASURES: Structural brain integrity at age 45 years assessed via MRI (primary outcomes): gray matter (cortical thickness, surface area, hippocampal volume), white matter (white matter hyperintensities, fractional anisotropy [theoretical range, 0 {diffusion is perfectly isotropic} to 100 {diffusion is perfectly anisotropic}]), and the Brain Age Gap Estimation (BrainAGE), a composite index of the gap between chronological age and a machine learning algorithm-estimated brain age (0 indicates a brain age equivalent to chronological age; positive and negative values represent an older and younger brain age, respectively). Cognitive function at age 45 years was assessed objectively via the Wechsler Adult Intelligence Scale IV (IQ range, 40-160, standardized to a mean of 100 [SD, 15]) and subjectively via informant and self-reports (z-score units; scale mean, 0 [SD, 1]). RESULTS: Of 1037 original participants, 997 were alive at age 45 years, of whom 564 (57%) had received lead testing at age 11 years (302 [54%] male) (median follow-up, 34 [interquartile range, 33.7-34.7] years). Mean blood lead level at age 11 years was 10.99 (SD, 4.63) &#x3bc;g/dL. After adjusting for covariates, each 5-&#x3bc;g/dL higher childhood blood lead level was significantly associated with 1.19-cm2 smaller cortical surface area (95% CI, -2.35 to -0.02 cm2; P&#x2009;=&#x2009;.05), 0.","evidenceGrade":"full_text"},{"id":"p-pmid-28350927","title":"Association of Childhood Blood Lead Levels With Cognitive Function and Socioeconomic Status at Age 38 Years and With IQ Change and Socioeconomic Mobility Between Childhood and Adulthood.","authors":["A Reuben","A Caspi","DW Belsky","J Broadbent","H Harrington","K Sugden","RM Houts","S Ramrakha"],"year":2017,"venue":"JAMA","doi":"10.1001/jama.2017.1712","pmid":"28350927","url":"https://pubmed.ncbi.nlm.nih.gov/28350927/","methodology":"observational","n":null,"openAccess":true,"abstract":"IMPORTANCE: Many children in the United States and around the world are exposed to lead, a developmental neurotoxin. The long-term cognitive and socioeconomic consequences of lead exposure are uncertain. OBJECTIVE: To test the hypothesis that childhood lead exposure is associated with cognitive function and socioeconomic status in adulthood and with changes in IQ and socioeconomic mobility between childhood and midlife. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study based on a population-representative 1972-1973 birth cohort from New Zealand; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38 years (until December 2012). EXPOSURES: Childhood lead exposure ascertained as blood lead levels measured at age 11 years. High blood lead levels were observed among children from all socioeconomic status levels in this cohort. MAIN OUTCOMES AND MEASURES: The IQ (primary outcome) and indexes of Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed (secondary outcomes) were assessed at age 38 years using the Wechsler Adult Intelligence Scale-IV (WAIS-IV; IQ range, 40-160). Socioeconomic status (primary outcome) was assessed at age 38 years using the New Zealand Socioeconomic Index-2006 (NZSEI-06; range, 10 [lowest]-90 [highest]). RESULTS: Of 1037 original participants, 1007 were alive at age 38 years, of whom 565 (56%) had been lead tested at age 11 years (54% male; 93% white). Mean (SD) blood lead level at age 11 years was 10.99 (4.63) &#xb5;g/dL. Among blood-tested participants included at age 38 years, mean WAIS-IV score was 101.16 (14.82) and mean NZSEI-06 score was 49.75 (17.12). After adjusting for maternal IQ, childhood IQ, and childhood socioeconomic status, each 5-&#xb5;g/dL higher level of blood lead in childhood was associated with a 1.61-point lower score (95% CI, -2.48 to -0.74) in adult IQ, a 2.07-point lower score (95% CI, -3.14 to -1.01) in perceptual reasoning, and a 1.26-point low","evidenceGrade":"full_text"},{"id":"p-pmid-28687448","title":"Effects of low-level prenatal lead exposure on child IQ at 4 and 8 years in a UK birth cohort study.","authors":["CM Taylor","K Kordas","J Golding","AM Emond"],"year":2018,"venue":"Neurotoxicology","doi":"10.1016/j.neuro.2017.07.003","pmid":"28687448","url":"https://pubmed.ncbi.nlm.nih.gov/28687448/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: The association between childhood exposure to lead (Pb) and deficits in cognitive function is well established. The association with prenatal exposure, however, is not well understood, even though the potential adverse effects are equally important. OBJECTIVES: To evaluate the association between low prenatal exposure to lead and IQ in children, to determine whether there were sex differences in the associations, and to evaluate the moderation effect of prenatal Pb exposure on child IQ. METHODS: Whole blood samples from pregnant women enrolled in ALSPAC (n=4285) and from offspring at age 30 months (n=235) were analysed for Pb. Associations between prenatal blood lead concentrations (B-Pb) and child IQ at age 4 and 8 years (WPPSI and WISC-III, respectively) were examined in adjusted regression models. RESULTS: There was no association of prenatal lead exposure with child IQ at 4 or 8 years old in adjusted regression models, and no moderation of the association between child B-Pb and IQ. However, there was a positive association for IQ at age 8 years in girls with a predicted increase in IQ (points) per 1&#x3bc;g/dl of: verbal 0.71, performance 0.57, total 0.73. In boys, the coefficients tended to be negative (-0.15, -0.42 and -0.29 points, respectively). CONCLUSION: Prenatal lead exposure was not associated with adverse effects on child IQ at age 4 or 8 years in this study. There was, however, some evidence to suggest that boys are more susceptible than girls to prenatal exposure to lead. Further investigation in other cohorts is required.","evidenceGrade":"full_text"},{"id":"p-pmid-25535358","title":"Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness.","authors":["AM Chang","D Aeschbach","JF Duffy","CA Czeisler"],"year":2015,"venue":"Proceedings of the National Academy of Sciences of the United States of America","doi":"10.1073/pnas.1418490112","pmid":"25535358","url":"https://pubmed.ncbi.nlm.nih.gov/25535358/","methodology":"observational","n":null,"openAccess":true,"abstract":"In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength-enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.","evidenceGrade":"full_text"},{"id":"p-pmid-30506899","title":"Strategies to decrease social jetlag: Reducing evening blue light advances sleep and melatonin.","authors":["G Zerbini","T Kantermann","M Merrow"],"year":2021,"venue":"The European journal of neuroscience","doi":"10.1111/ejn.14293","pmid":"30506899","url":"https://pubmed.ncbi.nlm.nih.gov/30506899/","methodology":"observational","n":null,"openAccess":false,"abstract":"The timing of sleep is under the control of the circadian clock, which uses light to entrain to the external light-dark cycle. A combination of genetic, physiological and environmental factors produces individual differences in chronotype (entrained phase as manifest in sleep timing). A mismatch between circadian and societal (e.g., work) clocks leads to a condition called social jetlag, which is characterized by changing sleep times over work and free days and accumulation of sleep debt. Social jetlag, which is prevalent in late chronotypes, has been related to several health issues. One way to reduce social jetlag would be to advance the circadian clock via modifications of the light environment. We thus performed two intervention field studies to describe methods for decreasing social jetlag. One study decreased evening light exposure (via blue-light-blocking glasses) and the other used increased morning light (via the use of curtains). We measured behaviour as well as melatonin; the latter in order to validate that behaviour was consistent with this neuroendocrinological phase marker of the circadian clock. We found that a decrease in evening blue light exposure led to an advance in melatonin and sleep onset on workdays. Increased morning light exposure advanced neither melatonin secretion nor sleep timing. Neither protocol led to a significant change in social jetlag. Despite this, our findings show that controlling light exposure at home can be effective in advancing melatonin secretion and sleep, thereby helping late chronotypes to better cope with early social schedules.","evidenceGrade":"abstract_only"},{"id":"p-pmid-23509952","title":"Acute exposure to evening blue-enriched light impacts on human sleep.","authors":["SL Chellappa","R Steiner","P Oelhafen","D Lang","T G&#xf6;tz","J Krebs","C Cajochen"],"year":2014,"venue":"Journal of sleep research","doi":"10.1111/jsr.12050","pmid":"23509952","url":"https://pubmed.ncbi.nlm.nih.gov/23509952/","methodology":"observational","n":null,"openAccess":false,"abstract":"Light in the short wavelength range (blue light: 446-483&#xa0;nm) elicits direct effects on human melatonin secretion, alertness and cognitive performance via non-image-forming photoreceptors. However, the impact of blue-enriched polychromatic light on human sleep architecture and sleep electroencephalographic activity remains fairly unknown. In this study we investigated sleep structure and sleep electroencephalographic characteristics of 30 healthy young participants (16 men, 14 women; age range 20-31&#xa0;years) following 2&#xa0;h of evening light exposure to polychromatic light at 6500&#xa0;K, 2500&#xa0;K and 3000&#xa0;K. Sleep structure across the first three non-rapid eye movement non-rapid eye movement - rapid eye movement sleep cycles did not differ significantly with respect to the light conditions. All-night non-rapid eye movement sleep electroencephalographic power density indicated that exposure to light at 6500&#xa0;K resulted in a tendency for less frontal non-rapid eye movement electroencephalographic power density, compared to light at 2500&#xa0;K and 3000&#xa0;K. The dynamics of non-rapid eye movement electroencephalographic slow wave activity (2.0-4.0&#xa0;Hz), a functional index of homeostatic sleep pressure, were such that slow wave activity was reduced significantly during the first sleep cycle after light at 6500&#xa0;K compared to light at 2500&#xa0;K and 3000&#xa0;K, particularly in the frontal derivation. Our data suggest that exposure to blue-enriched polychromatic light at relatively low room light levels impacts upon homeostatic sleep regulation, as indexed by reduction in frontal slow wave activity during the first non-rapid eye movement episode.","evidenceGrade":"abstract_only"},{"id":"p-pmid-22017511","title":"The spectral composition of evening light and individual differences in the suppression of melatonin and delay of sleep in humans.","authors":["N Santhi","HC Thorne","DR van der Veen","S Johnsen","SL Mills","V Hommes","LJ Schlangen","SN Archer"],"year":2012,"venue":"Journal of pineal research","doi":"10.1111/j.1600-079X.2011.00970.x","pmid":"22017511","url":"https://pubmed.ncbi.nlm.nih.gov/22017511/","methodology":"observational","n":null,"openAccess":false,"abstract":"The effect of light on circadian rhythms and sleep is mediated by a multi-component photoreceptive system of rods, cones and melanopsin-expressing intrinsically photosensitive retinal ganglion cells. The intensity and spectral sensitivity characteristics of this system are to be fully determined. Whether the intensity and spectral composition of light exposure at home in the evening is such that it delays circadian rhythms and sleep also remains to be established. We monitored light exposure at home during 6-8wk and assessed light effects on sleep and circadian rhythms in the laboratory. Twenty-two women and men (23.1&#xb1;4.7yr) participated in a six-way, cross-over design using polychromatic light conditions relevant to the light exposure at home, but with reduced, intermediate or enhanced efficacy with respect to the photopic and melanopsin systems. The evening rise of melatonin, sleepiness and EEG-assessed sleep onset varied significantly (P&lt;0.01) across the light conditions, and these effects appeared to be largely mediated by the melanopsin, rather than the photopic system. Moreover, there were individual differences in the sensitivity to the disruptive effect of light on melatonin, which were robust against experimental manipulations (intra-class correlation=0.44). The data show that light at home in the evening affects circadian physiology and imply that the spectral composition of artificial light can be modified to minimize this disruptive effect on sleep and circadian rhythms. These findings have implications for our understanding of the contribution of artificial light exposure to sleep and circadian rhythm disorders such as delayed sleep phase disorder.","evidenceGrade":"abstract_only"},{"id":"p-pmid-28548897","title":"Evening light exposure to computer screens disrupts human sleep, biological rhythms, and attention abilities.","authors":["A Green","M Cohen-Zion","A Haim","Y Dagan"],"year":2018,"venue":"Chronobiology international","doi":"10.1080/07420528.2017.1324878","pmid":"28548897","url":"https://pubmed.ncbi.nlm.nih.gov/28548897/","methodology":"observational","n":null,"openAccess":false,"abstract":"The use of electronic devices with light-emitting screens has increased exponentially in the last decade. As a result, humans are almost continuously exposed to unintentional artificial light. We explored the independent and combined effects of two aspects of screen illumination, light wavelength, and intensity, on sleep, its biological regulation, and related functional outcomes. The 2 &#xd7; 2 repeated-measure design included two independent variables: screen light intensity (low ([LI] versus high [HI]) and wavelength (short [SWL] versus long [LWL]). Nineteen participants (11F, 8M; mean age 24.3 [&#xb1;2.8] years) underwent four light conditions, LI/SWL, HI/SWL, LI/LWL, and HI/LWL, in counterbalanced order. Each light exposure lasted for two hours (21:00-23:00), following which participants underwent an overnight polysomnography. On each experimental night, oral temperature and urine samples (for melatonin analysis) were collected at multiple time points. Each morning, participants filled out questionnaires and conducted a computerized attention task. Irrespective of light intensity, SWL illumination significantly disrupted sleep continuity and architecture and led to greater self-reported daytime sleepiness. SWL light also altered biological rhythms, subduing the normal nocturnal decline in body temperature and dampening nocturnal melatonin secretion. Light intensity seemed to independently affect sleep as well, but to a lesser degree. Both light intensity and wavelength negatively affected morning attention. In sum, light wavelength seems to have a greater influence than light intensity on sleep and a wide-range of biological and behavioral functions. Given the widespread use of electronic devices today, our findings suggest that screen light exposure at evening may have detrimental effects on human health and performance.","evidenceGrade":"abstract_only"},{"id":"p-pmid-34997782","title":"High sensitivity of melatonin suppression response to evening light in preschool-aged children.","authors":["LE Hartstein","CD Behn","LD Akacem","N Stack","KP Wright","MK LeBourgeois"],"year":2022,"venue":"Journal of pineal research","doi":"10.1111/jpi.12780","pmid":"34997782","url":"https://pubmed.ncbi.nlm.nih.gov/34997782/","methodology":"observational","n":null,"openAccess":true,"abstract":"Light at night in adults suppresses melatonin in a nonlinear intensity-dependent manner. In children, bright light of a single intensity before bedtime has a robust melatonin suppressing effect. To our knowledge, whether evening light of different intensities is related to melatonin suppression in young children is unknown. Healthy, good-sleeping children (n&#xa0;=&#xa0;36; 3.0-4.9&#xa0;years; 39% male) maintained a stable sleep schedule for 7&#xa0;days followed by a 29.5-h in-home dim-light circadian assessment (~1.5&#xa0;lux). On the final night of the protocol, children received a 1-h light exposure (randomized to one of 15&#xa0;light levels, ranging 5-5000&#xa0;lux, with &#x2265;2 participants assigned to each light level) in the hour before habitual bedtime. Salivary melatonin was measured to calculate the magnitude of melatonin suppression during light exposure compared with baseline levels from the previous evening, as well as the degree of melatonin recovery 50&#xa0;min after the end of light exposure. Melatonin levels were suppressed between 69.4% and 98.7% (M&#xa0;=&#xa0;85.4&#xa0;&#xb1;&#xa0;7.2%) during light exposure across the full range of intensities examined. Overall, we did not observe a light intensity-dependent melatonin suppression response; however, children exposed to the lowest quartile of light intensities (5-40&#xa0;lux) had an average melatonin suppression (77.5&#xa0;&#xb1;&#xa0;7.0%) which was significantly lower than that observed at each of the three higher quartiles of light intensities (86.4&#xa0;&#xb1;&#xa0;5.6%, 89.2&#xa0;&#xb1;&#xa0;6.3%, and 87.1&#xa0;&#xb1;&#xa0;5.0%, respectively). We further found that melatonin levels remained below 50% baseline for at least 50&#xa0;min after the end of light exposure for the majority (62%) of participants, and recovery was not influenced by light intensity. These findings indicate that preschool-aged children are highly sensitive to light exposure in the hour before bedtime and suggest the li","evidenceGrade":"full_text"},{"id":"p-pmid-10476002","title":"Effects of light exposure and sleep displacement on dim light melatonin onset.","authors":["MC Gordijn","DG Beersma","HJ Korte","RH van den Hoofdakker"],"year":1999,"venue":"Journal of sleep research","doi":null,"pmid":"10476002","url":"https://pubmed.ncbi.nlm.nih.gov/10476002/","methodology":"observational","n":null,"openAccess":false,"abstract":"The purpose of the study was to induce in two different ways, a phase-angle difference between the circadian pacemaker and the imposed sleep-wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep-wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light-dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3-h delayed sleep-phase when compared with 3 days of sleep at a normal or 3-h advanced sleep-phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking-up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking-up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30311830","title":"Systematic review of light exposure impact on human circadian rhythm.","authors":["L T&#xe4;hk&#xe4;m&#xf6;","T Partonen","AK Pesonen"],"year":2020,"venue":"Chronobiology international","doi":"10.1080/07420528.2018.1527773","pmid":"30311830","url":"https://pubmed.ncbi.nlm.nih.gov/30311830/","methodology":"review","n":null,"openAccess":false,"abstract":"Light is necessary for life, and artificial light improves visual performance and safety, but there is an increasing concern of the potential health and environmental impacts of light. Findings from a number of studies suggest that mistimed light exposure disrupts the circadian rhythm in humans, potentially causing further health impacts. However, a variety of methods has been applied in individual experimental studies of light-induced circadian impacts, including definition of light exposure and outcomes. Thus, a systematic review is needed to synthesize the results. In addition, a review of the scientific evidence on the impacts of light on circadian rhythm is needed for developing an evaluation method of light pollution, i.e., the negative impacts of artificial light, in life cycle assessment (LCA). The current LCA practice does not have a method to evaluate the light pollution, neither in terms of human health nor the ecological impacts. The systematic literature survey was conducted by searching for two concepts: light and circadian rhythm. The circadian rhythm was searched with additional terms of melatonin and rapid-eye-movement (REM) sleep. The literature search resulted to 128 articles which were subjected to a data collection and analysis. Melatonin secretion was studied in 122 articles and REM sleep in 13 articles. The reports on melatonin secretion were divided into studies with specific light exposure (101 reports), usually in a controlled laboratory environment, and studies of prevailing light conditions typical at home or work environments (21 studies). Studies were generally conducted on adults in their twenties or thirties, but only very few studies experimented on children and elderly adults. Surprisingly many studies were conducted with a small sample size: 39 out of 128 studies were conducted with 10 or less subjects. The quality criteria of studies for more profound synthesis were a minimum sample size of 20 subjects and providing details of the","evidenceGrade":"abstract_only"},{"id":"p-pmid-18844328","title":"Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial.","authors":["K Mori","S Inatomi","K Ouchi","Y Azumi","T Tuchida"],"year":2009,"venue":"Phytotherapy research : PTR","doi":"10.1002/ptr.2634","pmid":"18844328","url":"https://pubmed.ncbi.nlm.nih.gov/18844328/","methodology":"rct","n":null,"openAccess":false,"abstract":"A double-blind, parallel-group, placebo-controlled trial was performed on 50- to 80-year-old Japanese men and women diagnosed with mild cognitive impairment in order to examine the efficacy of oral administration of Yamabushitake (Hericium erinaceus), an edible mushroom, for improving cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R). After 2 weeks of preliminary examination, 30 subjects were randomized into two 15-person groups, one of which was given Yamabushitake and the other given a placebo. The subjects of the Yamabushitake group took four 250 mg tablets containing 96% of Yamabushitake dry powder three times a day for 16 weeks. After termination of the intake, the subjects were observed for the next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group showed significantly increased scores on the cognitive function scale compared with the placebo group. The Yamabushitake group's scores increased with the duration of intake, but at week 4 after the termination of the 16 weeks intake, the scores decreased significantly. Laboratory tests showed no adverse effect of Yamabushitake. The results obtained in this study suggest that Yamabushitake is effective in improving mild cognitive impairment.","evidenceGrade":"abstract_only"},{"id":"p-pmid-38004235","title":"The Acute and Chronic Effects of Lion's Mane Mushroom Supplementation on Cognitive Function, Stress and Mood in Young Adults: A Double-Blind, Parallel Groups, Pilot Study.","authors":["S Docherty","FL Doughty","EF Smith"],"year":2023,"venue":"Nutrients","doi":"10.3390/nu15224842","pmid":"38004235","url":"https://pubmed.ncbi.nlm.nih.gov/38004235/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Given the bioactive properties and limited work to date, Hericium erinaceus (Lion's mane) shows promise in improving cognitive function and mood. However, much of the human research has concentrated on chronic supplementation in cognitively compromised cohorts. OBJECTIVE: The current pilot study investigated the acute and chronic (28-day) cognitive and mood-enhancing effects of Hericium erinaceus in a healthy, young adult cohort. DESIGN: This randomized, double-blind, placebo-controlled, parallel-groups design investigated the acute (60 min post dose) and chronic (28-day intervention) effects of 1.8 g Hericium erinaceus in 41 healthy adults aged 18-45 years. RESULTS: Analysis revealed that following a single dose of Hericium erinaceus, participants performed quicker on the Stroop task (p = 0.005) at 60 min post dose. A trend towards reduced subjective stress was observed following 28-day supplementation (p = 0.051). CONCLUSIONS: The findings tentatively suggest that Hericium erinaceus may improve speed of performance and reduce subjective stress in healthy, young adults. However, null and limited negative findings were also observed. Given the small sample size, these findings should be interpreted with caution. Further investigation in larger sample sizes is crucial, however the findings of this trial offer a promising avenue of interest.","evidenceGrade":"full_text"},{"id":"p-pmid-40276537","title":"Acute effects of a standardised extract of Hericium erinaceus (Lion's Mane mushroom) on cognition and mood in healthy younger adults: a double-blind randomised placebo-controlled study.","authors":["G Surendran","J Saye","S Binti Mohd Jalil","J Spreadborough","K Duong","IM Shatwan","D Lilley","M Heinrich"],"year":2025,"venue":"Frontiers in nutrition","doi":"10.3389/fnut.2025.1405796","pmid":"40276537","url":"https://pubmed.ncbi.nlm.nih.gov/40276537/","methodology":"observational","n":null,"openAccess":true,"abstract":"INTRODUCTION: Animal studies have suggested that Lion's Mane mushroom [Hericium erinaceus (Bull.) Pers.] can enhance cognitive function and mood due to its bioactive metabolites, including erinacines and hericenones. However, despite being an ingredient used both culinarily and therapeutically in the East, and more and more commonly in the West, limited research has focused on the immediate effects of H. erinaceus on the cognitive function and mood of healthy young adults. METHODS: In an acute randomized, placebo-controlled, double-blinded, cross-over intervention study, we investigated the potential benefits of an acute dose of H. erinaceus fruiting body extract (3g of 10:1 extract) on cognitive performance and mood compared to a placebo. Eighteen healthy participants aged 18 to 35 years took part in the study. At baseline and 90 minutes post-consumption of the interventions, cognitive and mood assessments were administered to measure various cognitive abilities such as executive function, working memory, psychomotor skills, attention and information processing speed as well as positive and negative affect. RESULTS AND DISCUSSION: The results showed no significant effect of the H. erinaceus fruiting body extract for composite measures of global cognitive function and mood. However, when analysing individual tests, participants exhibited improved performance on the pegboard test at 90 minutes following a single dose of H. erinaceus. CONCLUSION: In conclusion, acute consumption of H. erinaceus fruiting body did not demonstrate a significant overall improvement in cognitive performance and mood compared to the placebo and any benefits may be task or domain specific. Further investigations should investigate the effects of chronic supplementation of H. erinaceus fruiting body on cognition and mood in healthy younger adults, as well as establish optimal dosage and the time to peak concentration of H. erinaceus bioactives in the human brain. Additionally, future research","evidenceGrade":"full_text"},{"id":"p-pmid-40962949","title":"From loneliness to depression: A longitudinal diagnostic study among Norwegian university students.","authors":["M Hysing","KJ Petrie","AG Harvey","B Sivertsen"],"year":2026,"venue":"Social psychiatry and psychiatric epidemiology","doi":"10.1007/s00127-025-02989-y","pmid":"40962949","url":"https://pubmed.ncbi.nlm.nih.gov/40962949/","methodology":"observational","n":null,"openAccess":true,"abstract":"PURPOSE: Loneliness is an increasing public health concern among young adults. There is insufficient prior research on the association between loneliness and depressive disorder among students in higher education. METHODS: This prospective population-based cohort study from Norway invited all full-time students aged 18-35 to participate in the 2022 Students' Health and Wellbeing Study (SHoT). Of the 53,362 respondents, a subgroup of 16,418 students was randomly selected for diagnostic follow-up, with valid data from 10,460 participants. Loneliness was assessed in 2022 using the Three-Item Loneliness Scale (T-ILS) and Major Depressive Episodes (MDE) were assessed in 2023 using a self-administered electronic version of the Composite International Diagnostic Interview, version 5.0 (CIDI 5.0). RESULTS: A clear dose-response relationship was observed: students in the highest loneliness quintile had a substantially increased risk of MDE one year later. After adjusting for age and baseline anxiety and depression symptoms, the relative risk (RR) for MDE in the highest versus lowest T-ILS quintile was 2.02 (95% CI: 1.58-2.63) for females and 2.64 (95% CI: 1.63-4.49) for males-representing a&#x2009;~&#x2009;70-75% reduction from unadjusted estimates. The overall prevalence of MDE was 21.1% in females and 11.2% in males. Formal interaction analyses indicated a statistically significant multiplicative interaction by sex, but no evidence of additive interaction. CONCLUSIONS: Loneliness is a strong and independent predictor of MDE in young adults, even after accounting for baseline mental health. Targeting loneliness may be important for preventing depression in university populations.","evidenceGrade":"full_text"},{"id":"p-pmid-37337095","title":"A systematic review and meta-analysis of 90 cohort studies of social isolation, loneliness and mortality.","authors":["F Wang","Y Gao","Z Han","Y Yu","Z Long","X Jiang","Y Wu","B Pei"],"year":2023,"venue":"Nature human behaviour","doi":"10.1038/s41562-023-01617-6","pmid":"37337095","url":"https://pubmed.ncbi.nlm.nih.gov/37337095/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"The associations between social isolation, loneliness and the risk of mortality from all causes, cardiovascular disease (CVD) and cancer are controversial. We systematically reviewed prospective studies on the association between social isolation, loneliness and mortality outcomes in adults aged 18 years or older, as well as studies on these relationships in individuals with CVD or cancer, and conducted a meta-analysis. The study protocol was registered with PROSPERO (reg. no. CRD42022299959). A total of 90 prospective cohort studies including 2,205,199 individuals were included. Here we show that, in the general population, both social isolation and loneliness were significantly associated with an increased risk of all-cause mortality (pooled effect size for social isolation, 1.32; 95% confidence interval (CI), 1.26 to 1.39; P&#x2009;&lt;&#x2009;0.001; pooled effect size for loneliness, 1.14; 95% CI, 1.08 to 1.20; P&#x2009;&lt;&#x2009;0.001) and cancer mortality (pooled effect size for social isolation, 1.24; 95% CI, 1.19 to 1.28; P&#x2009;&lt;&#x2009;0.001; pooled effect size for loneliness, 1.09; 95% CI, 1.01 to 1.17; P&#x2009;=&#x2009;0.030). Social isolation also increased the risk of CVD mortality (1.34; 95% CI, 1.25 to 1.44; P&#x2009;&lt;&#x2009;0.001). There was an increased risk of all-cause mortality in socially isolated individuals with CVD (1.28; 95% CI, 1.10 to 1.48; P&#x2009;=&#x2009;0.001) or breast cancer (1.51; 95% CI, 1.34 to 1.70; P&#x2009;&lt;&#x2009;0.001), and individuals with breast cancer had a higher cancer-specific mortality owing to social isolation (1.33; 95% CI, 1.02 to 1.75; P&#x2009;=&#x2009;0.038). Greater focus on social isolation and loneliness may help improve people's well-being and mortality risk.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39836319","title":"Loneliness, social isolation, and living alone: a comprehensive systematic review, meta-analysis, and meta-regression of mortality risks in older adults.","authors":["A Nakou","E Dragioti","NS Bastas","N Zagorianakou","V Kakaidi","D Tsartsalis","S Mantzoukas","F Tatsis"],"year":2025,"venue":"Aging clinical and experimental research","doi":"10.1007/s40520-024-02925-1","pmid":"39836319","url":"https://pubmed.ncbi.nlm.nih.gov/39836319/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"Loneliness, social isolation, and living alone are significant risk factors for mortality, particularly in older adults. This systematic review and meta-analysis aimed to quantify their associations with all-cause and cause-specific mortality in older adults, broadening previous research by including more social factors. Comprehensive searches were conducted in PubMed, APA PsycINFO, and CINAHL until December 31, 2023, following PRISMA 2020 and MOOSE guidelines. Studies included were prospective cohort or longitudinal studies examining the relationship between loneliness, social isolation, living alone, and mortality. Quality was assessed using the Newcastle-Ottawa Scale. Meta-analyses used random-effects models with the Restricted Maximum Likelihood method. Subgroup and meta-regression analyses explored the relationships further. Of 11,964 identified studies, 86 met the inclusion criteria. Loneliness was associated with increased all-cause mortality (HR 1.14, 95% CI 1.10-1.18), with substantial heterogeneity (I&#xb2; = 84.0%). Similar associations were found for social isolation (HR 1.35, 95% CI 1.27-1.43) and living alone (HR 1.21, 95% CI 1.13-1.30). Subgroup analyses revealed variations based on factors like sex, age, region, chronic diseases, and study quality. Meta-regression identified longer follow-up, female sex, validated social network indices, adjustments for cognitive function, and study quality as significant predictors of mortality risks. These findings highlight the need for public health interventions to address these social factors and improve health outcomes in older adults. However, further research is needed due to variability and heterogeneity across studies. Also studying the cumulative effect of these factors on mortality risks will be of considerable interest.","evidenceGrade":"full_text"},{"id":"p-pmid-35229887","title":"Social isolation, loneliness, and all-cause mortality: A cohort study of 35,254 Chinese older adults.","authors":["B Yu","A Steptoe","Y Chen"],"year":2022,"venue":"Journal of the American Geriatrics Society","doi":"10.1111/jgs.17708","pmid":"35229887","url":"https://pubmed.ncbi.nlm.nih.gov/35229887/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Few studies of social isolation, loneliness and associations with all-cause mortality in older adults have been conducted in non-Western countries. The aim of this study was to conduct such an analysis in a nationally representative sample of Chinese older adults. METHODS: This study used eight waves of data from the Chinese Longitudinal Healthy Longevity Survey from 1998 to 2018 and focused on participants aged &#x2265;60&#x2009;years. A total of 21,570 people died (61.2%) over a median follow-up of 4.8&#x2009;years. Social isolation, loneliness, demographic, health and lifestyle factors were measured at baseline. The primary outcome was all-cause mortality. Cox proportional hazard regression models were used to examine the associations of isolation and loneliness with all-cause mortality. RESULTS: This study included 35,254 participants with mean age of 86.63&#x2009;&#xb1;&#x2009;11.39&#x2009;years. Social isolation was significantly associated with an increased mortality (adjusted HR 1.22; 95% CI 1.18-1.25; p&#x2009;&lt;&#x2009;0.01). The association of loneliness with mortality was nonsignificant after adjustment for health indicators and low psychological well-being (HR 1.01; 95% CI 0.98-1.04; p&#xa0;=&#xa0;0.69). However, when stratified by age, there was a significant association of loneliness with mortality among participants aged &lt;80&#x2009;years (HR 1.15; 95% CI 1.05-1.26; p&#x2009;&lt;&#x2009;0.01). CONCLUSIONS: Social isolation was associated with an increased all-cause mortality among the older Chinese adults. However, loneliness was associated with an increased mortality only among younger participants. Public health interventions aimed at increasing social connectedness may potentially reduce excess mortality among older adults.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33939562","title":"The effects of loneliness and social isolation on all-cause, injury, cancer, and CVD mortality in a cohort of middle-aged Finnish men. A prospective study.","authors":["SL Kraav","O Awoyemi","N Junttila","R Vornanen","J Kauhanen","T Toikko","SM Lehto","S Hantunen"],"year":2021,"venue":"Aging &amp; mental health","doi":"10.1080/13607863.2020.1830945","pmid":"33939562","url":"https://pubmed.ncbi.nlm.nih.gov/33939562/","methodology":"observational","n":null,"openAccess":false,"abstract":"OBJECTIVES: Loneliness and social isolation both increase mortality and are likely to affect health via several pathways. However, information on the potential pathways remains scarce. We investigated the associations between loneliness, social isolation, and mortality, and possible mechanisms underlying these connections. METHODS: The analyzed data comprised a prospective population-based cohort of Finnish men (42-61&#x2009;years at baseline, n&#x2009;=&#x2009;2588) who were followed up for an average of 23.2&#x2009;years. Mortality data were obtained from the national population register in 2012. Cox proportional hazards analysis with adjustments for possible confounding factors was used to examine the associations between loneliness and social isolation at baseline and all-cause, injury, cancer, and cardiovascular disease (CVD) mortality. Mediation analysis was conducted to investigate the mechanisms underlying the associations of loneliness and social isolation with mortality. RESULTS: Loneliness predicted all-cause mortality, even after adjustments for all covariates. Loneliness predicted cancer mortality, except after adjustments for lifestyle variables or Human Population Laboratory (HPL) depression scores, and also predicted CVD mortality, except after adjustments for HPL depression scores. Social isolation predicted all-cause mortality and injury mortality. The effect of social isolation on all-cause mortality was mediated by loneliness and HPL depression scores. CONCLUSIONS: Our findings suggest that both loneliness and social isolation increase the risk of all-cause mortality, while they have differing effects on different causes of death. Loneliness and depressive symptoms may mediate the effect of social isolation on increased mortality.","evidenceGrade":"abstract_only"},{"id":"p-pmid-28654669","title":"Role of magnesium supplementation in the treatment of depression: A randomized clinical trial.","authors":["EK Tarleton","B Littenberg","CD MacLean","AG Kennedy","C Daley"],"year":2017,"venue":"PloS one","doi":"10.1371/journal.pone.0180067","pmid":"28654669","url":"https://pubmed.ncbi.nlm.nih.gov/28654669/","methodology":"rct","n":null,"openAccess":true,"abstract":"Current treatment options for depression are limited by efficacy, cost, availability, side effects, and acceptability to patients. Several studies have looked at the association between magnesium and depression, yet its role in symptom management is unclear. The objective of this trial was to test whether supplementation with over-the-counter magnesium chloride improves symptoms of depression. An open-label, blocked, randomized, cross-over trial was carried out in outpatient primary care clinics on 126 adults (mean age 52; 38% male) diagnosed with and currently experiencing mild-to-moderate symptoms with Patient Health Questionnaire-9 (PHQ-9) scores of 5-19. The intervention was 6 weeks of active treatment (248 mg of elemental magnesium per day) compared to 6 weeks of control (no treatment). Assessments of depression symptoms were completed at bi-weekly phone calls. The primary outcome was the net difference in the change in depression symptoms from baseline to the end of each treatment period. Secondary outcomes included changes in anxiety symptoms as well as adherence to the supplement regimen, appearance of adverse effects, and intention to use magnesium supplements in the future. Between June 2015 and May 2016, 112 participants provided analyzable data. Consumption of magnesium chloride for 6 weeks resulted in a clinically significant net improvement in PHQ-9 scores of -6.0 points (CI -7.9, -4.2; P&lt;0.001) and net improvement in Generalized Anxiety Disorders-7 scores of -4.5 points (CI -6.6, -2.4; P&lt;0.001). Average adherence was 83% by pill count. The supplements were well tolerated and 61% of participants reported they would use magnesium in the future. Similar effects were observed regardless of age, gender, baseline severity of depression, baseline magnesium level, or use of antidepressant treatments. Effects were observed within two weeks. Magnesium is effective for mild-to-moderate depression in adults. It works quickly and is well tolerated without th","evidenceGrade":"full_text"},{"id":"p-pmid-19271419","title":"Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial.","authors":["L Barrag&#xe1;n-Rodr&#xed;guez","M Rodr&#xed;guez-Mor&#xe1;n","F Guerrero-Romero"],"year":2009,"venue":"Magnesium research","doi":null,"pmid":"19271419","url":"https://pubmed.ncbi.nlm.nih.gov/19271419/","methodology":"rct","n":null,"openAccess":false,"abstract":"To evaluate the efficacy and safety of oral magnesium supplementation, with magnesium chloride (MgCl2), in the treatment of newly diagnosed depression in the elderly with type 2 diabetes and hypomagnesemia. Twenty-three elderly patients with type 2 diabetes and hypomagnesemia were enrolled and randomly allocated to receive either 50 mL of MgCl2 5% solution equivalent to 450 mg of elemental magnesium or Imipramine 50 mg daily during 12 weeks. Widowhood or divorce in the last six months, alcoholism, degenerative illnesses of the nervous central system, recent diagnosis of diabetes, previous or current treatment with antidepressants, chronic diarrhea, use of diuretics, and reduced renal function were exclusion criteria. Hypomagnesemia was defined by serum magnesium levels &lt; 1.8 mg/dL and depression by Yasavage and Brink score &gt; or = 11 points. The primary trial end point was the improvement of depression symptoms. At baseline, there were no differences by age (69 +/- 5.9 and 66.4 +/- 6.1 years, p = 0.39), duration of diabetes (11.8 +/- 7.9 and 8.6 +/- 5.7 years, p = 0.33), serum magnesium levels (1.3 +/- 0.04 and 1.4 +/- 0.04 mg/dL, p = 0.09), and Yasavage and Brink Score (17.9 +/- 3.9 and 16.1 +/- 4.5 point, p = 0.34) in the groups with MgCl2 and imipramine, respectively. At end of follow-up, there were no significant differences in the Yasavage and Brink score (11.4 +/- 3.8 and 10.9 +/- 4.3, p = 0.27) between the groups in study; whereas serum magnesium levels were significantly higher in the group with MgCl2 (2.1 +/- 0.08 mg/dL) than in the subjects with imipramine (1.5 +/- 0.07 mg/dL), p &lt; 0.0005. In conclusion, MgCl2 is as effective in the treatment of depressed elderly type 2 diabetics with hypomagnesemia as imipramine 50 mg daily.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37922013","title":"Oral magnesium supplementation does not affect insulin sensitivity in people with insulin-treated type 2 diabetes and a low serum magnesium: a randomised controlled trial.","authors":["LCA Drenthen","JHF de Baaij","L Rodwell","AE van Herwaarden","CJ Tack","BE de Galan"],"year":2024,"venue":"Diabetologia","doi":"10.1007/s00125-023-06029-9","pmid":"37922013","url":"https://pubmed.ncbi.nlm.nih.gov/37922013/","methodology":"rct","n":null,"openAccess":true,"abstract":"AIMS/HYPOTHESIS: Hypomagnesaemia has been associated with insulin resistance and an increased risk of type 2 diabetes. Whether magnesium supplementation improves insulin sensitivity in people with type 2 diabetes and a low serum magnesium level is unknown. METHODS: Using a randomised, double-blind (both participants and investigators were blinded to the participants' treatment sequences), placebo-controlled, crossover study design, we compared the effect of oral magnesium supplementation (15 mmol/day) for 6 weeks with that of matched placebo in individuals with insulin-treated type 2 diabetes (age &#x2265;18 years, BMI 18-40 kg/m2, HbA1c &lt;100 mmol/mol [11.3%], serum magnesium &#x2264;0.79 mmol/l). Participants were recruited from the outpatient clinic and through advertisements. Randomisation to a treatment sequence order was done using a randomisation list. We used block randomisation and the two possible treatment sequences were evenly distributed among the trial population. The primary outcome was the mean glucose infusion rate during the final 30 min of a hyperinsulinaemic-euglycaemic clamp (i.e. M value). Secondary outcomes included variables of glucose control, insulin need, BP, lipid profile and hypomagnesaemia-related symptoms during follow-up. RESULTS: We recruited 14 participants (50% women, 100% White, mean &#xb1; SD age 67&#xb1;6 years, BMI 31&#xb1;5 kg/m2, HbA1c 58&#xb1;9 mmol/mol [7.4&#xb1;0.9%]) with insulin-treated type 2 diabetes. Magnesium supplementation increased both mean &#xb1; SEM serum magnesium level (0.75&#xb1;0.02 vs 0.70&#xb1;0.02 mmol/l, p=0.016) and urinary magnesium excretion (magnesium/creatinine ratio, 0.23&#xb1;0.02 vs 0.15&#xb1;0.02, p=0.005), as compared with placebo. The M value of the glucose clamp did not differ between the magnesium and placebo study arms (4.6&#xb1;0.5 vs 4.4&#xb1;0.6 mg kg-1 min-1, p=0.108). During the 6 weeks of treatment, continuous glucose monitoring outcomes, HbA1c, insulin dose, lipid profile and BP a","evidenceGrade":"full_text"},{"id":"p-pmid-37393389","title":"The Effect of Magnesium Supplementation on Insulin Resistance and Metabolic Profiles in Women with Polycystic Ovary Syndrome: a Randomized Clinical Trial.","authors":["S Shahmoradi","H Chiti","M Tavakolizadeh","R Hatami","N Motamed","M Ghaemi"],"year":2024,"venue":"Biological trace element research","doi":"10.1007/s12011-023-03744-7","pmid":"37393389","url":"https://pubmed.ncbi.nlm.nih.gov/37393389/","methodology":"rct","n":null,"openAccess":false,"abstract":"Due to the definitive known effect of magnesium on insulin resistance and the fact that insulin resistance is a main etiology in polycystic ovary syndrome (PCOS), it is assumed the use of magnesium supplements can improve insulin resistance, lipid profiles, and glucose and thus may also play a role in improving the clinical condition of patients with PCOS. We aimed to assess the effects of magnesium supplements on anthropometric, clinical, and metabolic parameters in women suffering from PCOS. This triple-blind randomized clinical trial study was conducted on women aged 15-35 years with PCOS. The patients were randomly assigned to receive a magnesium oxide supplement (250 mg/day for 2 months) or a placebo. The study parameters were evaluated and compared between two groups before as well as 2 months and 5 months after the initial assessment. In total, 40 cases (20 in each group) were recruited in the study. A significant reduction in the serum insulin level (P-value = 0.036) and insulin resistance (p-value = 0.032) was observed in the case group. Prescribing magnesium supplements could also lead to lowering total cholesterol, low-density lipoprotein, and fasting blood sugar along with increasing the level of high-density lipoprotein. We could not find any significant difference in anthropometric parameters as well as the mean systolic and diastolic blood pressures before and after intervention between the two groups. Although the rate of oligomenorrhea significantly decreased in the two study groups, it was no different across the two groups before and also after the intervention. The use of magnesium supplements in patients with PCO, regardless of the etiology or progression of the disease, can greatly improve the metabolic status of these patients by improving insulin resistance and modulating the level of lipid profile.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30835085","title":"Oral Magnesium Supplementation Improved Lipid Profile but Increased Insulin Resistance in Patients with Diabetic Nephropathy: a Double-Blind Randomized Controlled Clinical Trial.","authors":["M Sadeghian","L Azadbakht","N Khalili","M Mortazavi","A Esmaillzadeh"],"year":2020,"venue":"Biological trace element research","doi":"10.1007/s12011-019-01687-6","pmid":"30835085","url":"https://pubmed.ncbi.nlm.nih.gov/30835085/","methodology":"rct","n":null,"openAccess":false,"abstract":"Low serum magnesium concentrations were associated with development of renal failure. We aimed to determine whether magnesium supplementation improves renal function, insulin resistance, and metabolic profiles in patients with diabetic nephropathy. A total of 80 hypomagnesemic patients diagnosed with type 2 diabetes and early-stage nephropathy were recruited. Subjects received either daily magnesium oxide or placebo for 12&#xa0;weeks. Biochemical and anthropometric variables were measured. Physical activity and dietary intakes were also recorded. This study was approved by the ethics committee of Isfahan University of Medical Sciences and was registered on the Iranian Registry of Clinical Trials website (IRCT registration no. IRCT201404271485N12). Serum magnesium levels were not changed significantly. Although the supplementation did not influence glycemic indices, patients in the magnesium group had greater insulin resistance compared with the placebo group after intervention (0.3&#x2009;&#xb1;&#x2009;2.3&#xa0;&#x3bc;IU/mL vs. -&#x2009;0.04&#x2009;&#xb1;&#x2009;2.05, P&#x2009;=&#x2009;0.04). No significant changes were observed in serum total cholesterol, triglycerides, HDL, LDL, and total cholesterol/HDL cholesterol ratio. Furthermore, magnesium did not affect inflammation, serum levels of creatinine, and blood urine nitrogen. However, a marginal decrease in microalbuminuria (-&#x2009;3.1&#x2009;&#xb1;&#x2009;2.2&#xa0;mg/L vs. -&#x2009;14&#x2009;&#xb1;&#x2009;9.9, P&#x2009;=&#x2009;0.09) was observed. Oral magnesium supplementation slightly improved microalbuminuria but resulted in increased insulin resistance in patients with diabetic nephropathy.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29793665","title":"Oral Magnesium Supplementation and Metabolic Syndrome: A Randomized Double-Blind Placebo-Controlled Clinical Trial.","authors":["M Rodr&#xed;guez-Mor&#xe1;n","LE Simental-Mend&#xed;a","CI Gamboa-G&#xf3;mez","F Guerrero-Romero"],"year":2019,"venue":"Advances in chronic kidney disease","doi":"10.1053/j.ackd.2018.02.011","pmid":"29793665","url":"https://pubmed.ncbi.nlm.nih.gov/29793665/","methodology":"rct","n":null,"openAccess":false,"abstract":"The objective of the study was to evaluate the efficacy of oral magnesium supplementation in the improvement of metabolic syndrome (MetS) and its components. This is a randomized double-blind, placebo-controlled clinical trial that enrolled 198 individuals with MetS and hypomagnesemia who were randomly allocated to receive either 30&#xa0;mL of magnesium chloride 5% solution, equivalent to 382&#xa0;mg of elemental magnesium (n&#xa0;=&#xa0;100), or placebo solution (n&#xa0;=&#xa0;98), daily for 16 weeks. Serum magnesium levels &lt;1.8&#xa0;mg/dL defined hypomagnesemia. At final conditions, a total of 48 (48%) and 76 (77.5%) individuals had MetS in the magnesium and placebo groups (P&#xa0;=&#xa0;0.01), respectively. At baseline, percent of individuals with 3, 4, and 5 criteria of MetS in the magnesium group were 60.0%, 37.0%, and 3.0%, respectively, and in the control group 55.1%, 35.7%, and 9.2%, respectively. Between basal and final conditions, changes in the components of MetS were significantly higher in the magnesium than placebo groups: -3.6&#xa0;&#xb1;&#xa0;3.3&#xa0;mmHg, P&#xa0;=&#xa0;0.001 for systolic blood pressure; -5.5&#xa0;&#xb1;&#xa0;1.7&#xa0;mmHg, P&#xa0;=&#xa0;0.005 for diastolic blood pressure; -12.4&#xa0;&#xb1;&#xa0;3.6&#xa0;mg/dL, P&#xa0;&lt;&#xa0;0.005 for fasting glucose; -61.2&#xa0;&#xb1;&#xa0;24&#xa0;mg/dL, P&#xa0;=&#xa0;0.003 for triglycerides; and 0.9&#xa0;&#xb1;&#xa0;0.4&#xa0;mg/dL, P&#xa0;=&#xa0;0.06 for high-density lipoprotein cholesterol. Magnesium supplementation improves MetS by reducing blood pressure, hyperglycemia, and hypertriglyceridemia.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29788815","title":"Effect of Magnesium Loading Dose on Insulin Resistance in Patients With Stress-Induced Hyperglycemia: A Randomized Clinical Trial.","authors":["Z Heidary","H Khalili","M Mohammadi","MT Beigmohammadi","A Abdollahi"],"year":2021,"venue":"Journal of intensive care medicine","doi":"10.1177/0885066618777431","pmid":"29788815","url":"https://pubmed.ncbi.nlm.nih.gov/29788815/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVES: There is currently no evidence that whether magnesium supplementation would improve stress-induced hyperglycemia (SIH) in critically ill patients. In this study, effects of magnesium loading dose on insulin resistance (IR) indices were evaluated in critically ill patients without diabetes having SIH. METHODS: Seventy critically ill patients with SIH were assigned to receive a loading dose of magnesium (7.5 g of magnesium sulfate in 500 mL normal saline as intravenous infusion over an 8-hour period) or placebo. Changes in baseline of serum and intracellular magnesium and serum adiponectin (AD) levels, homeostasis model assessment of IR (HOMA-IR), and HOMA-AD ratio were assessed in this study. RESULTS: Serum and intracellular magnesium levels increased significantly in patients in the magnesium group (P &lt; .001). At day 3, there were significant differences between the magnesium group and the placebo group in the mean changes from baseline in the HOMA (between-group difference: -0.11; 95% confidence interval [CI]: -0.19 to -0.01; P = .02), the AD (between-group difference: 0.94; 95% CI: 0.41-1.48; P = .04), and the HOMA-AD ratio (between-group difference: -0.03; 95% CI: -0.04 to -0.01; P &lt; .001). CONCLUSION: In the present study, a single-loading dose of intravenous magnesium improved IR indices in critically ill patients with SIH.","evidenceGrade":"abstract_only"},{"id":"p-pmid-40918053","title":"Magnesium Bisglycinate Supplementation in Healthy Adults Reporting Poor Sleep: A Randomized, Placebo-Controlled Trial.","authors":["J Schuster","I Cycelskij","A Lopresti","A Hahn"],"year":2025,"venue":"Nature and science of sleep","doi":"10.2147/NSS.S524348","pmid":"40918053","url":"https://pubmed.ncbi.nlm.nih.gov/40918053/","methodology":"observational","n":null,"openAccess":true,"abstract":"PURPOSE: To assess the effects of magnesium bisglycinate supplementation on insomnia symptoms in healthy adults reporting poor sleep quality. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial enrolled 155 adults aged 18-65 years with self-reported poor sleep quality. Participants were randomly assigned to either magnesium bisglycinate supplementation (250 mg elemental magnesium, daily) or placebo capsules. Sleep quality was assessed using the Insomnia Severity Index (ISI) and additional psychological questionnaires at baseline and multiple time points throughout the study. Generalized linear mixed models (GLMM) adjusted for baseline ISI scores, age, sex, body mass index, and occupation were applied. RESULTS: The magnesium bisglycinate group showed a significantly greater reduction in ISI scores compared to the placebo group from baseline to Week 4 (-3.9 [95% CI: -5.8 to -2.0] vs -2.3 [95% CI: -4.1 to -0.4], respectively; p = 0.049). The effect size was small (Cohen's d = 0.2), indicating a modest benefit. Exploratory analyses suggested notably greater improvements among participants reporting lower baseline dietary magnesium intake, potentially indicating a subgroup of high responders. No significant differences were observed in other psychological outcomes. CONCLUSION: Magnesium bisglycinate supplementation modestly improved insomnia severity in adults reporting poor sleep quality. Future research should include objective sleep assessments, longer intervention periods, and better characterization of potential high responders by systematically assessing baseline dietary magnesium intake and status. CLINICAL TRIAL REGISTRATION NAME: Effect of magnesium bisglycinate supplementation on sleep and fatigue parameters in healthy adults reporting poor sleep quality; https://drks.de/search/en/trial/DRKS00031494 DRKS-ID: DRKS00031494.","evidenceGrade":"full_text"},{"id":"p-pmid-39252819","title":"Magnesium-L-threonate improves sleep quality and daytime functioning in adults with self-reported sleep problems: A randomized controlled trial.","authors":["HA Hausenblas","T Lynch","S Hooper","A Shrestha","D Rosendale","J Gu"],"year":2025,"venue":"Sleep medicine: X","doi":"10.1016/j.sleepx.2024.100121","pmid":"39252819","url":"https://pubmed.ncbi.nlm.nih.gov/39252819/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVE/BACKGROUND: Sleep problems challenge overall wellbeing. Magnesium has been implicated to benefit sleep, although the clinical evidences varied based on the magnesium source used. Magnesium L-threonate (MgT) is a promising intervention due to its brain bioavailability and effects on cognition, memory and mood. We investigated MgT supplementation on sleep quality and daily function. PATIENTS/METHODS: Eighty 35-55-year-olds with self-assessed sleep problems participated in a randomized, double-blind, placebo-controlled, parallel-arm study, taking 1&#xa0;g/day of MgT or placebo for 21 days. Sleep and daily behaviors were measured subjectively using standardized questionnaires including the Insomnia Severity Index, Leeds Sleep Evaluation Questionnaire, and Restorative Sleep Questionnaire, and objectively using an Oura ring. The Profile of Mood States questionnaire and a daily diary were used to evaluate mood, energy and productivity, and record any safety concerns. RESULTS: The MgT group maintained good sleep quality and daytime functioning, while placebo declined. From objective Oura ring measurements, MgT significantly (p&#xa0;&lt;&#xa0;0.05) improved vs placebo deep sleep score, REM sleep score, light sleep time, and activity and readiness parameters activity score, activity daily movement score, readiness score, readiness activity balance, and readiness sleep balance. From subjective questionnaires, MgT significantly (p&#xa0;&lt;&#xa0;0.05) improved vs placebo behavior upon awakening, energy and daytime productivity, grouchiness, mood and mental alertness. MgT was safe and well tolerated. CONCLUSIONS: This showed MgT improved sleep quality, especially deep/REM sleep stages, improved mood, energy, alertness, and daily activity and productivity. These are consistent with how MgT works in neuron cells and animal models, suggesting broader positive impacts on overall brain health.","evidenceGrade":"full_text"},{"id":"p-pmid-20929998","title":"Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial.","authors":["J Salas-Salvad&#xf3;","M Bull&#xf3;","N Babio","M&#xc1; Mart&#xed;nez-Gonz&#xe1;lez","N Ibarrola-Jurado","J Basora","R Estruch","MI Covas"],"year":2011,"venue":"Diabetes care","doi":"10.2337/dc10-1288","pmid":"20929998","url":"https://pubmed.ncbi.nlm.nih.gov/20929998/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: To test the effects of two Mediterranean diet (MedDiet) interventions versus a low-fat diet on incidence of diabetes. RESEARCH DESIGN AND METHODS: This was a three-arm randomized trial in 418 nondiabetic subjects aged 55-80 years recruited in one center (PREDIMED-Reus, northeastern Spain) of the Prevenci&#xf3;n con Dieta Mediterr&#xe1;nea [PREDIMED] study, a large nutrition intervention trial for primary cardiovascular prevention in individuals at high cardiovascular risk. Participants were randomly assigned to education on a low-fat diet (control group) or to one of two MedDiets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day). Diets were ad libitum, and no advice on physical activity was given. The main outcome was diabetes incidence diagnosed by the 2009 American Diabetes Association criteria. RESULTS: After a median follow-up of 4.0 years, diabetes incidence was 10.1% (95% CI 5.1-15.1), 11.0% (5.9-16.1), and 17.9% (11.4-24.4) in the MedDiet with olive oil group, the MedDiet with nuts group, and the control group, respectively. Multivariable adjusted hazard ratios of diabetes were 0.49 (0.25-0.97) and 0.48 (0.24-0.96) in the MedDiet supplemented with olive oil and nuts groups, respectively, compared with the control group. When the two MedDiet groups were pooled and compared with the control group, diabetes incidence was reduced by 52% (27-86). In all study arms, increased adherence to the MedDiet was inversely associated with diabetes incidence. Diabetes risk reduction occurred in the absence of significant changes in body weight or physical activity. CONCLUSIONS: MedDiets without calorie restriction seem to be effective in the prevention of diabetes in subjects at high cardiovascular risk.","evidenceGrade":"full_text"},{"id":"p-pmid-37775736","title":"Yearly attained adherence to Mediterranean diet and incidence of diabetes in a large randomized trial.","authors":["MA Mart&#xed;nez-Gonz&#xe1;lez","P Montero","M Ruiz-Canela","E Toledo","R Estruch","E G&#xf3;mez-Gracia","J Li","E Ros"],"year":2023,"venue":"Cardiovascular diabetology","doi":"10.1186/s12933-023-01994-2","pmid":"37775736","url":"https://pubmed.ncbi.nlm.nih.gov/37775736/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet. METHODS: PREDIMED (''PREvenci&#xf3;n con DIeta MEDiterr&#xe1;nea'') was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n&#x2009;=&#x2009;1147, control group), Mediterranean diet supplemented with extra virgin olive (n&#x2009;=&#x2009;1154) or Mediterranean diet supplemented with mixed nuts (n&#x2009;=&#x2009;1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups:&#x2009;&lt;&#x2009;8, 8-&lt;&#x2009;10, 10-&#x2009;&lt;&#x2009;12, and 12-14 points. The outcome was new-onset type 2 diabetes. RESULTS: Multivariable-adjusted hazard ratios from time-varying Cox models were 0.80 (95% confidence interval, 0.70-0.92) per&#x2009;+&#x2009;2 points in Mediterranean Diet Adherence Screener (linear trend p&#x2009;=&#x2009;.001), and 0.46 (0.25-0.83) for the highest (12-14 points) versus the lowest (&lt;&#x2009;8) adherence. This inverse association was maintained after additionally adjusting for the randomized ","evidenceGrade":"full_text"},{"id":"p-pmid-19584739","title":"The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia.","authors":["R Luthringer","M Muzet","N Zisapel","L Staner"],"year":2009,"venue":"International clinical psychopharmacology","doi":"10.1097/YIC.0b013e32832e9b08","pmid":"19584739","url":"https://pubmed.ncbi.nlm.nih.gov/19584739/","methodology":"rct","n":null,"openAccess":false,"abstract":"Objectives of this study were to investigate the effects of prolonged-release melatonin 2 mg (PRM) on sleep and subsequent daytime psychomotor performance in patients aged &gt; or =55 years with primary insomnia, as defined by fourth revision of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. Patients (N = 40) were treated nightly single-blind with placebo (2 weeks), randomized double-blind to PRM or placebo (3 weeks) followed by withdrawal period (3 weeks). Sleep was assessed by polysomnography, all-night sleep electroencephalography spectral analysis and questionnaires. Psychomotor performance was assessed by the Leeds Psychomotor Test battery. By the end of the double-blind treatment, the PRM group had significantly shorter sleep onset latency (9 min; P = 0.02) compared with the placebo group and scored significantly better in the Critical Flicker Fusion Test (P = 0.008) without negatively affecting sleep structure and architecture. Half of the patients reported substantial improvement in sleep quality at home with PRM compared with 15% with placebo (P = 0.018). No rebound effects were observed during withdrawal. In conclusion, nightly treatment with PRM effectively induced sleep and improved perceived quality of sleep in patients with primary insomnia aged &gt; or =55 years. Daytime psychomotor performance was not impaired and was consistently better with PRM compared with placebo. PRM was well tolerated with no evidence of rebound effects.","evidenceGrade":"abstract_only"},{"id":"p-pmid-27107670","title":"Objective and subjective sleep quality: Melatonin versus placebo add-on treatment in patients with schizophrenia or bipolar disorder withdrawing from long-term benzodiazepine use.","authors":["L Baandrup","BY Glenth&#xf8;j","PJ Jennum"],"year":2017,"venue":"Psychiatry research","doi":"10.1016/j.psychres.2016.04.031","pmid":"27107670","url":"https://pubmed.ncbi.nlm.nih.gov/27107670/","methodology":"rct","n":null,"openAccess":false,"abstract":"Benzodiazepines are frequently long-term prescribed for the treatment of patients with severe mental illness. This prescribing practice is problematic because of well-described side effects including risk of dependence. We examined the efficacy of prolonged-release melatonin on objective and subjective sleep quality during benzodiazepine discontinuation and whether sleep variables were associated with benzodiazepine withdrawal. Eligible patients included adults with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder and long-term use of benzodiazepines in combination with antipsychotics. All participants gradually tapered the use of benzodiazepines after randomization to add-on treatment with melatonin versus placebo. Here we report a subsample of 23 patients undergoing sleep recordings (one-night polysomnography) and 55 patients participating in subjective sleep quality ratings. Melatonin had no effect on objective sleep efficiency, but significantly improved self-reported sleep quality. Reduced benzodiazepine dosage at the 24-week follow-up was associated with a significantly decreased proportion of stage 2 sleep. These results indicate that prolonged-release melatonin has some efficacy for self-reported sleep quality after gradual benzodiazepine dose reduction, and that benzodiazepine discontinuation is not associated with rebound insomnia in medicated patients with severe mental illness. However, these findings were limited by a small sample size and a low retention rate.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30088834","title":"Mindfulness-based cognitive therapy for patients with chronic, treatment-resistant depression: A pragmatic randomized controlled trial.","authors":["MB Cladder-Micus","AEM Speckens","JN Vrijsen","AR T Donders","ES Becker","J Spijker"],"year":2019,"venue":"Depression and anxiety","doi":"10.1002/da.22788","pmid":"30088834","url":"https://pubmed.ncbi.nlm.nih.gov/30088834/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Chronic and treatment-resistant depressions pose serious problems in mental health care. Mindfulness-based cognitive therapy (MBCT) is an effective treatment for remitted and currently depressed patients. It is, however, unknown whether MBCT is effective for chronic, treatment-resistant depressed patients. METHOD: A pragmatic, multicenter, randomized-controlled trial was conducted comparing treatment-as-usual (TAU) with MBCT + TAU in 106 chronically depressed outpatients who previously received pharmacotherapy (&#x2265;4&#xa0;weeks) and psychological treatment (&#x2265;10 sessions). RESULTS: Based on the intention-to-treat (ITT) analysis, participants in the MBCT + TAU condition did not have significantly fewer depressive symptoms than those in the TAU condition (-3.23 [-6.99 to 0.54], d&#xa0;=&#xa0;0.35, P&#xa0;=&#xa0;0.09) at posttreatment. However, compared to TAU, the MBCT + TAU group reported significantly higher remission rates (&#x3c7;2 (2)&#xa0;=&#xa0;4.25, &#x3c6;&#xa0;=&#xa0;0.22, P&#xa0;=&#xa0;0.04), lower levels of rumination (-3.85 [-7.55 to -0.15], d&#xa0;=&#xa0;0.39, P&#xa0;=&#xa0;0.04), a higher quality of life (4.42 [0.03-8.81], d&#xa0;=&#xa0;0.42, P&#xa0;=&#xa0;0.048), more mindfulness skills (11.25 [6.09-16.40], d&#xa0;=&#xa0;0.73, P&#xa0;&lt;&#xa0;0.001), and more self-compassion (2.91 [1.17-4.65], d&#xa0;=&#xa0;0.64, P&#xa0;=&#xa0;0.001). The percentage of non-completers in the MBCT + TAU condition was relatively high (n&#xa0;=&#xa0;12, 24.5%). Per-protocol analyses revealed that those who completed MBCT + TAU had significantly fewer depressive symptoms at posttreatment compared to participants receiving TAU (-4.24 [-8.38 to -0.11], d&#xa0;=&#xa0;0.45, P&#xa0;=&#xa0;0.04). CONCLUSION: Although the ITT analysis did not reveal a significant reduction in depressive symptoms of MBCT + TAU over TAU, MBCT + TAU seems to have beneficial effects for chronic, treatment-resistant depressed patients in terms of remission rates, rumination, qual","evidenceGrade":"full_text"},{"id":"p-pmid-33688840","title":"Online Mindfulness-Based Cognitive Behavioral Therapy Intervention for Youth With Major Depressive Disorders: Randomized Controlled Trial.","authors":["P Ritvo","Y Knyahnytska","M Pirbaglou","W Wang","G Tomlinson","H Zhao","R Linklater","S Bai"],"year":2021,"venue":"Journal of medical Internet research","doi":"10.2196/24380","pmid":"33688840","url":"https://pubmed.ncbi.nlm.nih.gov/33688840/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Approximately 70% of mental health disorders appear prior to 25 years of age and can become chronic when ineffectively treated. Individuals between 18 and 25 years old are significantly more likely to experience mental health disorders, substance dependencies, and suicidality. Treatment progress, capitalizing on the tendencies of youth to communicate online, can strategically address depressive disorders. OBJECTIVE: We performed a randomized controlled trial (RCT) that compared online mindfulness-based cognitive behavioral therapy (CBT-M) combined with standard psychiatric care to standard psychiatric care alone in youth (18-30 years old) diagnosed with major depressive disorder. METHODS: Forty-five participants were randomly assigned to CBT-M and standard care (n=22) or to standard psychiatric care alone (n=23). All participants were provided standard psychiatric care (ie, 1 session per month), while participants in the experimental group received an additional intervention consisting of the CBT-M online software program. Interaction with online workbooks was combined with navigation coaching delivered by phone and secure text messaging. RESULTS: In a two-level linear mixed-effects model intention-to-treat analysis, significant between-group differences were found for the Beck Depression Inventory-II score (difference -8.54, P=.01), Quick Inventory of Depressive Symptoms score (difference -4.94, P=.001), Beck Anxiety Inventory score (difference -11.29, P&lt;.001), and Brief Pain Inventory score (difference -1.99, P=.03), while marginal differences were found for the Five Facet Mindfulness Questionnaire-Nonjudging subscale (difference -2.68, P=.05). CONCLUSIONS: These results confirm that youth depression can be effectively treated with online CBT-M that can be delivered with less geographic restriction. TRIAL REGISTRATION: Clinical Trials.gov NCT03406052; https://www.clinicaltrials.gov/ct2/show/NCT03406052.","evidenceGrade":"full_text"},{"id":"p-granovetter-1973","title":"The strength of weak ties","authors":["M. S. Granovetter"],"year":1973,"venue":"American Journal of Sociology","doi":"10.1086/225469","pmid":null,"url":"https://doi.org/10.1086/225469","methodology":"observational","n":null,"openAccess":false,"abstract":"Job information travels over weak ties. Network position is a labor-market technology. The paper this atlas uses whenever 'social capital gets you hired' is the claim.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36107999","title":"A causal test of the strength of weak ties.","authors":["K Rajkumar","G Saint-Jacques","I Bojinov","E Brynjolfsson","S Aral"],"year":2022,"venue":"Science (New York, N.Y.)","doi":"10.1126/science.abl4476","pmid":"36107999","url":"https://pubmed.ncbi.nlm.nih.gov/36107999/","methodology":"observational","n":null,"openAccess":false,"abstract":"The authors analyzed data from multiple large-scale randomized experiments on LinkedIn's People You May Know algorithm, which recommends new connections to LinkedIn members, to test the extent to which weak ties increased job mobility in the world's largest professional social network. The experiments randomly varied the prevalence of weak ties in the networks of over 20 million people over a 5-year period, during which 2 billion new ties and 600,000 new jobs were created. The results provided experimental causal evidence supporting the strength of weak ties and suggested three revisions to the theory. First, the strength of weak ties was nonlinear. Statistical analysis found an inverted U-shaped relationship between tie strength and job transmission such that weaker ties increased job transmission but only to a point, after which there were diminishing marginal returns to tie weakness. Second, weak ties measured by interaction intensity and the number of mutual connections displayed varying effects. Moderately weak ties (measured by mutual connections) and the weakest ties (measured by interaction intensity) created the most job mobility. Third, the strength of weak ties varied by industry. Whereas weak ties increased job mobility in more digital industries, strong ties increased job mobility in less digital industries.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37580544","title":"Long-Term Exposure to Traffic Noise and Risk of Incident Cardiovascular Diseases: a Systematic Review and Dose-Response Meta-Analysis.","authors":["X Fu","L Wang","L Yuan","H Hu","T Li","J Zhang","Y Ke","M Wang"],"year":2023,"venue":"Journal of urban health : bulletin of the New York Academy of Medicine","doi":"10.1007/s11524-023-00769-0","pmid":"37580544","url":"https://pubmed.ncbi.nlm.nih.gov/37580544/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"While noise pollution from transportation has become an important public health problem, the relationships between different sources of traffic noise and cardiovascular diseases (CVDs) remain inconclusive. A comprehensive meta-analysis was therefore conducted to quantitatively assess the effects of long-term exposure to road traffic, railway, and aircraft noise on CVDs and relevant subtypes. We systematically retrieved PubMed, Embase, and Web of Science for articles published before April 4, 2022. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated by the fixed- or random-effects models. In total, 23 articles were included in our meta-analysis. The risk of CVDs increased by 2% (RR 1.020, 95% CI 1.006-1.035) and 1.6% (RR 1.016, 95% CI 1.000-1.032) for every 10 dB increment of road traffic and aircraft noise. For CVD subtypes, the risk increased by 3.4% (1.034, 1.026-1.043) for stroke and 5% (1.050, 1.006-1.096) for heart failure with each 10 dB increment of road traffic noise; the risk of atrial fibrillation increased by 1.1% (1.011, 1.002-1.021) with each 10 dB increment of railway noise; and the risk increased by 1% (1.010, 1.003-1.017) for myocardial infarction, 2.7% (1.027, 1.004-1.050) for atrial fibrillation, and 2.3% (1.023, 1.016-1.030) for heart failure with each 10 dB increment in aircraft noise. Further, effects from road traffic, railway, and aircraft noise all followed positive linear trends with CVDs. Long-term exposure to traffic noise is positively related to the incidence risk of cardiovascular events, especially road traffic noise which significantly increases the risk of CVDs, stroke, and heart failure.","evidenceGrade":"full_text"},{"id":"p-pmid-35358546","title":"Associations of road traffic noise with cardiovascular diseases and mortality: Longitudinal results from UK Biobank and meta-analysis.","authors":["G Hao","L Zuo","X Weng","Q Fei","Z Zhang","L Chen","Z Wang","C Jing"],"year":2022,"venue":"Environmental research","doi":"10.1016/j.envres.2022.113129","pmid":"35358546","url":"https://pubmed.ncbi.nlm.nih.gov/35358546/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: Epidemiological evidence suggests potential associations of road traffic noise exposure with cardiovascular disease (CVD) and mortality, but uncertainty remains. OBJECTIVES: We examined the association of road traffic noise with the risk of CVD and mortality in a large longitudinal cohort study and meta-analysis. METHODS: We analyzed 342, 566 participants from the UK Biobank who were free of CVD at baseline and had complete covariate data. We also performed a meta-analysis of road traffic noise effects on CVD and mortality by including qualified cohort studies published before April 2021. RESULTS: After adjustment for potential confounders, the odds for the risk of stroke, CVD, and all-cause mortality increased by 1.07 (95%CI: 1.01-1.13, P&#xa0;=&#xa0;0.019), 1.13 (95%CI: 1.04-1.22, P&#xa0;=&#xa0;0.003) and 1.08 (95%CI: 1.04-1.12, P&#xa0;&lt;&#xa0;0.001) times per 10&#xa0;dB increases in road traffic noise, respectively. Among men, high road traffic noise exposure was significantly associated with an increased risk in stroke (HR&#xa0;=&#xa0;1.08 per 10&#xa0;dB increase, 95%CI: 1.00-1.16, P&#xa0;=&#xa0;0.043), CVD (HR&#xa0;=&#xa0;1.12 per 10&#xa0;dB increase, 95%CI: 1.02-1.23, P&#xa0;=&#xa0;0.020) and all-cause mortality (HR&#xa0;=&#xa0;1.12 per 10&#xa0;dB increase, 95%CI: 1.07-1.17&#xa0;P&#xa0;&lt;&#xa0;0.001), whereas we did not find a significant association in women. The meta-analysis showed that road traffic noise exposure was significantly associated with a high risk of stroke (risk ratio [RR]: 1.06, 95% CI: 1.02-1.11), CVD mortality (RR: 1.03, 95% CI: 1.00-1.05), all-cause mortality (RR: 1.05, 95% CI: 1.02-1.07). CONCLUSIONS: This study provides more evidence of increased risk of stroke, CVD, and all-cause mortality in association with exposure to road traffic noise pollution, especially in men.","evidenceGrade":"abstract_only"},{"id":"p-pmid-18270405","title":"Road traffic noise and cardiovascular risk.","authors":["W Babisch"],"year":2008,"venue":"Noise &amp; health","doi":null,"pmid":"18270405","url":"https://pubmed.ncbi.nlm.nih.gov/18270405/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"Studies on the association between community noise and cardiovascular risk were subjected to a meta-analysis for deriving a common dose-effect curve. Peer-reviewed articles, objective assessment of exposure and outcome as well as control for confounding and multiple exposure categories were all necessary inclusion criteria. A distinction was made between descriptive (cross-sectional) and analytical (case-control, cohort) studies. Meta-analyses were carried out for two descriptive and five analytical studies for calculating a pooled dose-effect curve for the association between road traffic noise levels and the risk of myocardial infarction. No increase in risk was found below 60 dB(A) for the average A-weighted sound pressure levels during the day. An increase in risk was found with increasing noise levels above 60 dB(A) thus showing a dose-response relationship. A risk curve was estimated for the association using a polynomial fit of the data that can be used for risk assessment and the environmental burden of disease calculations.","evidenceGrade":"abstract_only"},{"id":"p-pmid-35857401","title":"Environmental Noise and Effects on Sleep: An Update to the WHO Systematic Review and Meta-Analysis.","authors":["MG Smith","M Cordoza","M Basner"],"year":2022,"venue":"Environmental health perspectives","doi":"10.1289/EHP10197","pmid":"35857401","url":"https://pubmed.ncbi.nlm.nih.gov/35857401/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"BACKGROUND: Nighttime noise carries a significant disease burden. The World Health Organization (WHO) recently published guidelines for the regulation of environmental noise based on a review of evidence published up to the year 2015 on the effects of environmental noise on sleep. OBJECTIVES: This systematic review and meta-analysis will update the WHO evidence review on the effects of environmental noise on sleep disturbance to include more recent studies. METHODS: Investigations of self-reported sleep among residents exposed to environmental traffic noise at home were identified using Scopus, PubMed, Embase, and PsycINFO. Awakenings, falling asleep, and sleep disturbance were the three outcomes included. Extracted data were used to derive exposure-response relationships for the probability of being highly sleep disturbed by nighttime noise [average outdoor A-weighted noise level (Lnight) 2300-0700 hours] for aircraft, road, and rail traffic noise, individually. The overall quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. RESULTS: Eleven studies (n=109,070 responses) were included in addition to 25 studies (n=64,090 responses) from the original WHO analysis. When sleep disturbance questions specifically mentioned noise as the source of disturbance, there was moderate quality of evidence for the probability of being highly sleep disturbed per 10-dB increase in Lnight for aircraft [odds ratio&#x2009;(OR)=2.18; 95% confidence interval (CI): 2.01, 2.36], road (OR=2.52; 95% CI: 2.28, 2.79), and railway (OR=2.97; 95% CI: 2.57, 3.43) noise. When noise was not mentioned, there was low to very low quality of evidence for being sleep disturbed per 10-dB increase in Lnight for aircraft (OR=1.52; 95% CI: 1.20, 1.93), road (OR=1.14; 95% CI: 1.08, 1.21), and railway (OR=1.17; 95% CI: 0.91, 1.49) noise. Compared with the original WHO review, the exposure-response relationships closely agreed at low (40 d","evidenceGrade":"full_text"},{"id":"p-pmid-36981810","title":"Traffic-Related High Sleep Disturbance in the LIFE-Adult Cohort Study: A Comparison to the WHO Exposure-Response-Curves.","authors":["M Schubert","K Romero Starke","J Gerlach","M Reusche","P Kaboth","W Schmidt","D Friedemann","J Hegewald"],"year":2023,"venue":"International journal of environmental research and public health","doi":"10.3390/ijerph20064903","pmid":"36981810","url":"https://pubmed.ncbi.nlm.nih.gov/36981810/","methodology":"observational","n":null,"openAccess":true,"abstract":"Sleep is negatively affected by environmental noise. In the present study, we investigated self-reported high sleep disturbances (being \"highly sleep disturbed\"-HSD) from road traffic (primary and secondary road networks), rail (train and tram) and air traffic noise in the LIFE-Adult cohort study in Leipzig, Germany. For this, we used exposure data from 2012 and outcome data of Wave 2 (collected during 2018-2021). HSD was determined and defined according to internationally standardized norms. The highest risk for transportation noise-related HSD was found for aircraft noise: the odds ratio (OR) was 19.66, 95% CI 11.47-33.71 per 10 dB increase in Lnight. For road and rail traffic, similar risk estimates were observed (road: OR = 2.86, 95% CI 1.92-4.28; rail: OR = 2.67, 95% CI 2.03-3.50 per 10 dB Lnight increase). Further, we compared our exposure-risk curves with the curves of the WHO environmental noise guidelines for the European region. The proportion of individuals with HSD for a given noise level was lower for rail traffic but higher for aircraft noise in the LIFE study than in the WHO curves. For road traffic, curves are not directly comparable because we also included the secondary road network. The results of our study add to the body of evidence for increased health risks by traffic noise. Moreover, the results indicate that aircraft noise is particularly harmful to health. We recommend reconsidering threshold values for nightly aircraft exposure.","evidenceGrade":"full_text"},{"id":"p-pmid-27529260","title":"Sleep Disturbance from Road Traffic, Railways, Airplanes and from Total Environmental Noise Levels in Montreal.","authors":["S Perron","C Plante","MS Ragettli","DJ Kaiser","S Goudreau","A Smargiassi"],"year":2017,"venue":"International journal of environmental research and public health","doi":"10.3390/ijerph13080809","pmid":"27529260","url":"https://pubmed.ncbi.nlm.nih.gov/27529260/","methodology":"observational","n":null,"openAccess":true,"abstract":"The objective of our study was to measure the impact of transportation-related noise and total environmental noise on sleep disturbance for the residents of Montreal, Canada. A telephone-based survey on noise-related sleep disturbance among 4336 persons aged 18 years and over was conducted. LNight for each study participant was estimated using a land use regression (LUR) model. Distance of the respondent's residence to the nearest transportation noise source was also used as an indicator of noise exposure. The proportion of the population whose sleep was disturbed by outdoor environmental noise in the past 4 weeks was 12.4%. The proportion of those affected by road traffic, airplane and railway noise was 4.2%, 1.5% and 1.1%, respectively. We observed an increased prevalence in sleep disturbance for those exposed to both rail and road noise when compared for those exposed to road only. We did not observe an increased prevalence in sleep disturbance for those that were both exposed to road and planes when compared to those exposed to road or planes only. We developed regression models to assess the marginal proportion of sleep disturbance as a function of estimated LNight and distance to transportation noise sources. In our models, sleep disturbance increased with proximity to transportation noise sources (railway, airplane and road traffic) and with increasing LNight values. Our study provides a quantitative estimate of the association between total environmental noise levels estimated using an LUR model and sleep disturbance from transportation noise.","evidenceGrade":"full_text"},{"id":"p-pmid-22517305","title":"Review of the effect of aircraft noise on sleep disturbance in adults.","authors":["S Perron","LF T&#xe9;treault","N King","C Plante","A Smargiassi"],"year":2012,"venue":"Noise &amp; health","doi":"10.4103/1463-1741.95133","pmid":"22517305","url":"https://pubmed.ncbi.nlm.nih.gov/22517305/","methodology":"review","n":null,"openAccess":false,"abstract":"Noise exposure generated by air traffic has been linked with sleep disturbances. The purpose of this systematic review is to clarify whether there is a causal link between aircraft noise exposure and sleep disturbances. Only complete, peer-reviewed articles published in scientific journals were examined. Papers published until December 2010 were considered. To be included, articles had to focus on subjects aged 18 or over and include an objective evaluation of noise levels. Studies were classified according to quality. Given the paucity of studies with comparable outcome measures, we performed a narrative synthesis using a best-evidence synthesis approach. The primary study findings were tabulated. Similarities and differences between studies were investigated. Of the 12 studies surveyed that dealt with sleep disturbances, four were considered to be of high quality, five were considered to be of moderate quality and three were considered to be of low quality. All moderate- to high-quality studies showed a link between aircraft noise events and sleep disturbances such as awakenings, decreased slow wave sleep time or the use of sleep medication. This review suggests that there is a causal relation between exposure to aircraft noise and sleep disturbances. However, the evidence comes mostly from experimental studies focusing on healthy adults. Further studies are necessary to determine the impact of aircraft noise on sleep disturbance for individuals more than 65 years old and for those with chronic diseases.","evidenceGrade":"abstract_only"},{"id":"p-pmid-20406712","title":"Nocturnal road traffic noise: A review on its assessment and consequences on sleep and health.","authors":["S Pirrera","E De Valck","R Cluydts"],"year":2010,"venue":"Environment international","doi":"10.1016/j.envint.2010.03.007","pmid":"20406712","url":"https://pubmed.ncbi.nlm.nih.gov/20406712/","methodology":"review","n":null,"openAccess":false,"abstract":"Research on the impact of nocturnal road traffic noise on sleep and the consequences on daytime functioning demonstrates detrimental effects that cannot be ignored. The physiological reactions due to continuing noise processing during night time lead to primary sleep disturbances, which in turn impair daytime functioning. This review focuses on noise processing in general and in relation to sleep, as well as methodological aspects in the study of noise and sleep. More specifically, the choice of a research setting and noise assessment procedure is discussed and the concept of sleep quality is elaborated. In assessing sleep disturbances, we differentiate between objectively measured and subjectively reported complaints, which demonstrates the need for further understanding of the impact of noise on several sleep variables. Hereby, mediating factors such as noise sensitivity appear to play an important role. Research on long term effects of noise intrusion on sleep up till now has mainly focused on cardiovascular outcomes. The domain might benefit from additional longitudinal studies on deleterious effects of noise on mental health and general well-being.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30415628","title":"Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.","authors":["DL Bhatt","PG Steg","M Miller","EA Brinton","TA Jacobson","SB Ketchum","RT Doyle","RA Juliano"],"year":2019,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa1812792","pmid":"30415628","url":"https://pubmed.ncbi.nlm.nih.gov/30415628/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P&lt;0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P&lt;0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hos","evidenceGrade":"abstract_only"},{"id":"p-pmid-33190147","title":"Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.","authors":["SJ Nicholls","AM Lincoff","M Garcia","D Bash","CM Ballantyne","PJ Barter","MH Davidson","JJP Kastelein"],"year":2021,"venue":"JAMA","doi":"10.1001/jama.2020.22258","pmid":"33190147","url":"https://pubmed.ncbi.nlm.nih.gov/33190147/","methodology":"rct","n":null,"openAccess":true,"abstract":"IMPORTANCE: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. OBJECTIVE: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13&#x202f;078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. INTERVENTIONS: Participants were randomized to receive 4 g/d of omega-3 CA (n&#x2009;=&#x2009;6539) or corn oil, which was intended to serve as an inert comparator (n&#x2009;=&#x2009;6539), in addition to usual background therapies, including statins. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. RESULTS: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13&#x202f;078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive ","evidenceGrade":"full_text"},{"id":"p-pmid-20929341","title":"n-3 fatty acids and cardiovascular events after myocardial infarction.","authors":["D Kromhout","EJ Giltay","JM Geleijnse","D Kromhout","EG Schouten","JM Geleijnse","J de Goede","LM Oude Griep"],"year":2010,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa1003603","pmid":"20929341","url":"https://pubmed.ncbi.nlm.nih.gov/20929341/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases. We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. METHODS: In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. RESULTS: The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA-DHA alone, was associated with a reduction in the rate of major cardiovascular events that approache","evidenceGrade":"abstract_only"},{"id":"p-pmid-20584525","title":"The efficacy of omega-3 supplementation for major depression: a randomized controlled trial.","authors":["F Lesp&#xe9;rance","N Frasure-Smith","E St-Andr&#xe9;","G Turecki","P Lesp&#xe9;rance","SR Wisniewski"],"year":2011,"venue":"The Journal of clinical psychiatry","doi":"10.4088/JCP.10m05966blu","pmid":"20584525","url":"https://pubmed.ncbi.nlm.nih.gov/20584525/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: To document the short-term efficacy of omega-3 supplementation in reducing depressive symptoms in patients experiencing a major depressive episode (MDE). METHOD: Inclusive, double-blind, randomized, controlled, 8-week, parallel-group trial, conducted October 17, 2005 through January 30, 2009 in 8 Canadian academic and psychiatric clinics. Adult outpatients (N = 432) with MDE (Mini-International Neuropsychiatric Interview, version 5.0.0, criteria) lasting at least 4 weeks, including 40.3% taking antidepressants at baseline, were randomly assigned to 8 weeks of 1,050 mg/d of eicosapentaenoic acid (EPA) and 150 mg/d of docosahexaenoic acid (DHA) or matched sunflower oil placebo (2% fish oil). The primary outcome was the self-report Inventory of Depressive Symptomatology (IDS-SR(30)); the secondary outcome was the clinician-rated Montgomery-&#xc5;sberg Depression Rating Scale (MADRS). RESULTS: The adjusted mean difference between treatment and placebo was 1.32 points (95% CI, -0.20 to 2.84; P = .088) on the IDS-SR(30) and 0.97 points (95% CI, -0.012 to 1.95; P = .053) on the MADRS. Planned subgroup analyses revealed a significant interaction of comorbid anxiety disorders and study group (P = .035). For patients without comorbid anxiety disorders (n = 204), omega-3 supplementation was superior to placebo, with an adjusted mean difference of 3.17 points on the IDS-SR(30) (95% CI, 0.89 to 5.45; P = .007) and 1.93 points (95% CI, 0.50 to 3.36; P = .008) on the MADRS. CONCLUSIONS: In this heterogeneous sample of patients with MDE, there was only a trend toward superiority of omega-3 supplementation over placebo in reducing depressive symptoms. However, there was a clear benefit of omega-3 supplementation among patients with MDE without comorbid anxiety disorders. TRIAL REGISTRATION: controlled-trials.com Identifier: ISRCTN47431149.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39519521","title":"The Efficacy of Omega-3 Fatty Acids as the Monotherapy for Depression: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.","authors":["SK Wu","KJ Yang","WC Liu","IA Malau","H Zailani","CH Chang","SY Huang","JP Chang"],"year":2024,"venue":"Nutrients","doi":"10.3390/nu16213688","pmid":"39519521","url":"https://pubmed.ncbi.nlm.nih.gov/39519521/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have demonstrated protective effects in major depressive disorder (MDD) patients receiving antidepressant treatment. However, there have been a few double-blind randomized controlled trials focused on n-3 PUFAs as monotherapy in MDD, and the outcomes have been mixed. This study aimed to assess the clinical effects of n-3 PUFAs monotherapy in patients with MDD. METHODS: A total of 60 patients with MDD participated in this 12-week double-blind randomized controlled trial. They were randomized to either the n-3 PUFAs group (n = 30; 3.2 g of eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA per day) or the placebo group (n = 30; 3.2 g of soybean oil per day). The severity of depression was evaluated using the Hamilton Rating Scale for Depression (HRSD). RESULTS: The n-3 PUFAs group had a significantly lower HRSD score compared with the placebo group at week 4 (p = 0.004), week 6 (p = 0.006), week 8 (p = 0.004), and week 12 (p = 0.01). The n-3 PUFAs group showed slightly higher rates for both remission (26.7% vs. 10%, p = 0.095) and response (23.3% vs. 6.7%, p = 0.145) compared with the placebo group at week 12, but these differences did not reach statistical significance. CONCLUSIONS: These findings suggested that monotherapy of n-3 PUFAs could improve depression and potentially serve as an alternative option for MDD patients.","evidenceGrade":"full_text"},{"id":"p-pmid-36005883","title":"Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.","authors":["D Mischoulon","BW Dunlop","B Kinkead","PJ Schettler","S Lamon-Fava","JJ Rakofsky","AA Nierenberg","AJ Clain"],"year":2022,"venue":"The Journal of clinical psychiatry","doi":"10.4088/JCP.21m14074","pmid":"36005883","url":"https://pubmed.ncbi.nlm.nih.gov/36005883/","methodology":"rct","n":null,"openAccess":false,"abstract":"Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms. Methods: Sixty-one unmedicated adults (75% female; 45.5&#x2009;&#xb1;&#x2009;13.8 years) with DSM-5 major depressive disorder (MDD), body mass index &gt;&#x2009;25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP)&#x2009;&#x2265;&#x2009;3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a&#x2009;&#x2265;&#x2009;0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a&#x2009;&#x2265;&#x2009;50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo. Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a&#x2009;&#x2265;&#x2009;0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR]&#x2009;=&#x2009;2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P&#x2009;&gt;&#x2009;.05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman &#x3c1;&#x2009;=&#x2009;0.691, P&#x2009;=&#x2009;.019). Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response. Trial Registration: ClinicalTrials.gov identifier: NCT02553915.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39998447","title":"Effects of Continuous Positive Airway Pressure on Neuroimaging Biomarkers and Cognition in Adult Obstructive Sleep Apnea: A Randomized Controlled Trial.","authors":["H Xu","Y Liu","C Li","X Li","L Shen","H Wang","F Liu","J Zou"],"year":2025,"venue":"American journal of respiratory and critical care medicine","doi":"10.1164/rccm.202406-1170OC","pmid":"39998447","url":"https://pubmed.ncbi.nlm.nih.gov/39998447/","methodology":"rct","n":null,"openAccess":false,"abstract":"Rationale: Obstructive sleep apnea (OSA) is associated with cognitive impairment. The effects of continuous positive airway pressure (CPAP) on neuroimaging biomarkers and cognitive performance among middle-aged patients with OSA and normal cognition remain unclear. Objectives: To investigate the effects of CPAP therapy over 12 months on neuroimaging biomarkers and cognitive performance. Methods: In this multicenter, randomized clinical trial, we randomly assigned 148 participants with normal cognition and an apnea-hypopnea index &#x2a7e;15/h into two groups: patients receiving CPAP with best supportive care (BSC); and patients receiving BSC alone. The primary endpoint was Montreal Cognitive Assessment (MoCA) score at 6 months after enrollment. The secondary endpoints were intranetwork functional connectivity (FC) of default mode network (DMN) and cortical thickness assessed by functional and structural magnetic resonance imaging, other neuroimaging biomarkers, and neurobehavioral tests. Measurements and Main Results: Between 2017 and 2021, 148 patients were recruited from five hospitals. Linear mixed models showed that there was no significant difference in MoCA scores at 6 months between the CPAP and BSC groups (difference, -0.04; 95% confidence interval [CI], -0.72 to 0.65; P&#x2009;=&#x2009;0.91). However, there were significant differences in the FC of DMN (difference, -13.73; 95% CI, -23.40 to -4.06; P&#x2009;=&#x2009;0.01) and cortical thickness (difference, -0.06 mm; 95% CI, -0.10 to -0.01 mm; P&#x2009;=&#x2009;0.02) between CPAP and BSC groups at 6 months after treatment. No serious adverse events occurred. Conclusions: CPAP improved cortical thickness and FC of DMN, suggesting that patients with OSA may recover from brain atrophic processes after CPAP treatment. However, no improvement in MoCA was found. Clinical trial registered with www.clinicaltrials.gov (NCT02886156).","evidenceGrade":"abstract_only"},{"id":"p-pmid-32310179","title":"Cognitive Effects of Treating Obstructive Sleep Apnea: A Meta-Analysis of Randomized Controlled Trials.","authors":["ML Wang","C Wang","M Tuo","Y Yu","L Wang","JT Yu","L Tan","S Chi"],"year":2021,"venue":"Journal of Alzheimer's disease : JAD","doi":"10.3233/JAD-200088","pmid":"32310179","url":"https://pubmed.ncbi.nlm.nih.gov/32310179/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: Obstructive sleep apnea (OSA) is associated with cognitive impairment and increased risks of dementia. However, the effect of continuous positive airway pressure (CPAP) on cognitive function in patients with OSA is still controversial. OBJECTIVE: To evaluate the cognitive effects of CPAP treatment on OSA. METHODS: We systematically searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCT) in the corresponding fields. RESULTS: Totally 14 studies and 1,926 participants were included in our meta-analysis. Standardized mean difference (SMD) or weighted mean difference (WMD) were calculated for subjective sleepiness and cognitive domains including attention and speed of information processing, executive function, and memory. Individual cognitive scale and subgroup analyses according to OSA severity, length of trial, and RCT design type were further conducted. Significant treatment effect on attention and speed of information processing was only observed in severe OSA patients (SMD, 0.17; 95% CI, 0.02 to 0.31; p&#x200a;=&#x200a;0.025; I2&#x200a;=&#x200a;0%). CONCLUSIONS: Therefore, our meta-analysis indicates that CPAP treatment can partially improve cognitive impairment in the population of severe OSA.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39226674","title":"Impact of continuous positive airway pressure on cognitive functions in adult patients with obstructive sleep apnea: A systematic review and meta-analysis.","authors":["A Durtette","B Dargent","F Gierski","C Barbe","G Desl&#xe9;e","JM Perotin","A Henry","C Launois"],"year":2024,"venue":"Sleep medicine","doi":"10.1016/j.sleep.2024.08.019","pmid":"39226674","url":"https://pubmed.ncbi.nlm.nih.gov/39226674/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: Obstructive sleep apnea (OSA) is associated with the impairment of a range of cognitive functions. Whether treatment with continuous positive airway pressure (CPAP) improves these cognitive functions is still a matter of debate. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that included OSA patients (apnea hypopnea index, AHI &gt;10/h), naive to CPAP treatment, with a cognitive assessment before and after CPAP initiation. We compared CPAP versus sham-CPAP or placebo tablet or dietary rules or no treatment. This systematic review and meta-analysis were registered in PROSPERO (ID CRD42021275214). RESULTS: Eleven RCTs encompassing 923 OSA patients were included. For most of them, CPAP initiation was &#x2264;3 months. A significant post-treatment improvement was found for the Trail Making Test part B (TMT-B; SMD&#xa0;=&#xa0;-0.93, 95&#xa0;% CI&#xa0;=&#xa0;[-1.60, -0.25], Z&#xa0;=&#xa0;-2.70, p&#xa0;=&#xa0;0.007), but not for the other neuropsychological assessments. No global effects on other cognitive domains (information processing speed, executive functions, working memory) were found. CONCLUSION: The significant improvement in the TMT-B supports a short-term enhancement in cognitive flexibility with CPAP treatment. Further studies that take into account OSA comorbidities, cognitive profiles, a more diverse range of cognition assessments and include long-term evaluations are needed.","evidenceGrade":"abstract_only"},{"id":"p-pmid-27571048","title":"CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.","authors":["RD McEvoy","NA Antic","E Heeley","Y Luo","Q Ou","X Zhang","O Mediano","R Chen"],"year":2016,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa1606599","pmid":"27571048","url":"https://pubmed.ncbi.nlm.nih.gov/27571048/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS: After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS: Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS: Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health ","evidenceGrade":"abstract_only"},{"id":"p-pmid-26914592","title":"Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.","authors":["Y Peker","H Glantz","C Eulenburg","K Wegscheider","J Herlitz","E Thunstr&#xf6;m"],"year":2017,"venue":"American journal of respiratory and critical care medicine","doi":"10.1164/rccm.201601-0088OC","pmid":"26914592","url":"https://pubmed.ncbi.nlm.nih.gov/26914592/","methodology":"rct","n":null,"openAccess":false,"abstract":"RATIONALE: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain. OBJECTIVES: To determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA. METHODS: This single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index &#x2265;15/h) without daytime sleepiness (Epworth Sleepiness Scale score &lt;10) were randomized to auto-titrating CPAP (n&#x2009;=&#x2009;122) or no positive airway pressure (n&#x2009;=&#x2009;122). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P&#x2009;=&#x2009;0.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for &#x2265;4 versus &lt;4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P&#x2009;=&#x2009;0.026). CONCLUSIONS: Routine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).","evidenceGrade":"abstract_only"},{"id":"p-pmid-31839558","title":"Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.","authors":["M S&#xe1;nchez-de-la-Torre","A S&#xe1;nchez-de-la-Torre","S Bertran","J Abad","J Duran-Cantolla","V Cabriada","O Mediano","MJ Masdeu"],"year":2020,"venue":"The Lancet. Respiratory medicine","doi":"10.1016/S2213-2600(19)30271-1","pmid":"31839558","url":"https://pubmed.ncbi.nlm.nih.gov/31839558/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Despite the improvement in the prognosis of acute coronary syndrome (ACS), substantial morbidity and mortality remain. We aimed to evaluate the effect of obstructive sleep apnoea (OSA) and its treatment with continuous positive airway pressure (CPAP) on the clinical evolution of patients with ACS. METHODS: We designed a multicentre, open-label, parallel-group, randomised controlled trial of patients with ACS at 15 hospitals in Spain. Eligible non-sleepy patients were men and women aged 18 years and older, admitted to hospital for documented symptoms of ACS. All patients underwent respiratory polygraphy during the first 24-72 h after admission. OSA patients were randomly assigned (1:1) to CPAP treatment plus usual care (CPAP group) or usual care alone (UC group) by a computerised system available 24 h a day. A group of patients with ACS but without OSA was also included as a reference group. Because of the nature of the intervention, the trial intervention could not be masked to either investigators or patients. Patients were monitored and followed for a minimum of 1 year. Patients were examined at the time of inclusion; after 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months; and every 12 months thereafter, if applicable, during the follow-up period. The primary endpoint was the prevalence of a composite of cardiovascular events (cardiovascular death or non-fatal events [Acute myocardial infarction, non-fatal stroke, hospital admission for heart failure, and new hospitalisations for unstable angina or transient ischaemic attack]) in patients followed up for a minimum of 1 year. The primary analysis was done according to the intention-to-treat principle. This study is registered with Clinicaltrials.gov, NCT01335087 and is now closed. FINDINGS: Between April 25, 2011, and Feb 2, 2018, a total of 2834 patients with ACS had respiratory polygraphy, of whom 2551 (90&#xb7;01%) were recruited. 1264 (49&#xb7;55%) patients had ","evidenceGrade":"abstract_only"},{"id":"p-pmid-26350474","title":"A Randomized Controlled Trial of Continuous Positive Airway Pressure on Glucose Tolerance in Obese Patients with Obstructive Sleep Apnea.","authors":["N Salord","AM Fortuna","C Monasterio","M Gasa","A P&#xe9;rez","MR Bonsignore","N Vilarrasa","JM Montserrat"],"year":2016,"venue":"Sleep","doi":"10.5665/sleep.5312","pmid":"26350474","url":"https://pubmed.ncbi.nlm.nih.gov/26350474/","methodology":"rct","n":null,"openAccess":true,"abstract":"STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with an increased prevalence of metabolic syndrome (MetS), even in patients with morbid obesity. Our goal was to address whether continuous positive airway pressure (CPAP) treatment improved glucose metabolism in this population. METHODS: A prospective randomized controlled trial was performed in severe OSA patients with morbid obesity without diabetes in two university referral hospitals. Patients received conservative (CT) versus CPAP treatment for 12 weeks. MetS components, homeostasis model assessment of insulin resistance (HOMA-IR) and oral glucose tolerance were assessed at baseline and after treatment. RESULTS: A total of 80 patients completed the study (42 CPAP and 38 CT patients). After 12 w of CPAP treatment, weight loss was similar in both groups and physical activity, prevalence of MetS, and HOMA-IR did not change in either group. In the CPAP group impaired glucose tolerance (IGT) reversed in nine patients and IGT developed in none, whereas IGT reversed in five patients and IGT developed in five patients in the CT group (P = 0.039 in the Fisher test). Changes in 2-h plasma glucose after glucose load were greater in the CPAP group than in the CT group (CPAP: -0.5 &#xb1; 1.5 versus CT: 0.33 &#xb1; 1.9, P = 0.007). CONCLUSIONS: The improvement of glucose tolerance in morbidly obese patients with severe obstructive sleep apnea, without changes in homeostasis model assessment of insulin resistance, supports an improvement in peripheral insulin resistance after continuous positive airway pressure treatment. CLINICAL TRIALS REGISTRATION: NCT 01029561.","evidenceGrade":"full_text"},{"id":"p-pmid-17494789","title":"Fixed and autoadjusting continuous positive airway pressure treatments are not similar in reducing cardiovascular risk factors in patients with obstructive sleep apnea.","authors":["V Patruno","S Aiolfi","G Costantino","R Murgia","C Selmi","A Malliani","N Montano"],"year":2007,"venue":"Chest","doi":null,"pmid":"17494789","url":"https://pubmed.ncbi.nlm.nih.gov/17494789/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: A strong association between obstructive sleep apnea (OSA) and the risk for cardiovascular and cerebrovascular diseases has been reported. Continuous positive airway pressure (CPAP) is the first-line therapy for OSA, able not only to reduce daytime sleepiness but also to improve cardiovascular and metabolic outcomes. Autoadjusting CPAP (APAP), an alternative treatment to CPAP, can reduce OSA symptoms while increasing long-term CPAP compliance without the high costs of CPAP titration. However, no data are available on the effects of APAP on cardiovascular risk factors METHODS: We performed standard full polysomnography; obtained plasma levels of glucose, insulin, and C-reactive protein (CRP); and measured systolic BP (SBP) and diastolic BP (DBP) in 31 patients with newly diagnosed, severe OSA. After standard CPAP titration, all subjects were randomized to CPAP or APAP treatment. Measurements were obtained at baseline and after 3 months of treatment. RESULTS: The two groups were similar in terms of age, sex, body mass index (BMI), and severity of OSA. SBP, DBP, heart rate (HR), homeostasis model assessment index (HOMA-IR), and CRP were similar in the two groups. After 3 months of treatment, BMI, HR, and compliance to therapy were also comparable. OSA indexes were significantly reduced in both groups. Significant reductions in SBP, DBP, and HOMA-IR were observed in the CPAP group but not in the APAP group, while CRP plasma levels were similarly reduced. CONCLUSIONS: Our results suggest that CPAP and APAP, despite significant effects on OSA indexes and symptoms, do not improve cardiovascular risk factors in the same fashion.","evidenceGrade":"abstract_only"},{"id":"p-pmid-22492705","title":"The impact of effective continuous positive airway pressure on homeostasis model assessment insulin resistance in non-diabetic patients with moderate to severe obstructive sleep apnea.","authors":["D Yang","Z Liu","H Yang"],"year":2013,"venue":"Diabetes/metabolism research and reviews","doi":"10.1002/dmrr.2301","pmid":"22492705","url":"https://pubmed.ncbi.nlm.nih.gov/22492705/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"Previous studies on the effects of continuous positive airway pressure (CPAP) on homeostasis model assessment insulin resistance (HOMA-IR) in obstructive sleep apnea patients have yielded conflicting results. Therefore, we conducted this meta-analysis to evaluate the impact of effective CPAP on HOMA-IR in non-diabetic patients with moderate to severe obstructive sleep apnea. We searched PubMed, HighWire Press, Ovid Medline (R), Cochrane library and EMBASE before December 2011 on original English language studies. The data on HOMA-IR and body mass index (BMI) were extracted from these studies. As compared with baseline values, 8 to 24&#x2009;weeks of effective CPAP (&gt;4&#x2009;h/night) treatment significantly reduced HOMA-IR by an average of 0.75(95% CI, from -0.96 to -0.53; p&#x2009;&lt;&#x2009;0.001). However, in subjects with irregular CPAP (&lt;4&#x2009;h/night), this effect was not observed (-0.22; 95%CI, from -2.24 to 1.80; p&#x2009;=&#x2009;0.83). There were no intervention-related changes in BMI in both regular and irregular CPAP. Our analysis showed that 8 to 24&#x2009;weeks of effective CPAP could significantly improve HOMA-IR in non-diabetic patients with moderate to severe obstructive sleep apnea, while no significant changes in BMI were detected. Further large scale, randomized and controlled trials are needed to evaluate the longer treatment and its possible effects on weight control and cardiovascular disease.","evidenceGrade":"abstract_only"},{"id":"p-pmid-23607839","title":"Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes.","authors":["IH Iftikhar","MF Khan","A Das","UJ Magalang"],"year":2013,"venue":"Annals of the American Thoracic Society","doi":"10.1513/AnnalsATS.201209-081OC","pmid":"23607839","url":"https://pubmed.ncbi.nlm.nih.gov/23607839/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"RATIONALE: Obstructive sleep apnea (OSA) is an independent risk factor for the development of insulin resistance (IR). Treatment with continuous positive airway pressure (CPAP) for OSA has shown conflicting results on IR. OBJECTIVES: To conduct a meta-analysis of randomized controlled trials (RCTs) that have evaluated the effect of CPAP on a validated index of IR, the homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: PubMed and Embase were searched through August 10, 2012. Two independent reviewers screened citations to identify trials of the effect of CPAP on HOMA-IR. Data were extracted for postintervention HOMA-IR values. MEASUREMENTS AND MAIN RESULTS: A total of five studies that enrolled 244 subjects (83% male) met the inclusion criteria. None of the subjects in the included studies had diabetes. The pooled estimate of the difference in means in HOMA-IR between the CPAP and sham CPAP/control groups was -0.44 (95% confidence interval, -0.82 to -0.06; P = 0.02). The funnel plot does not suggest the presence of any publication bias. The I-squared index for the data on difference in means in HOMA-IR between the CPAP and sham CPAP/control groups was 0.00 (P = 0.61). CONCLUSIONS: The pooled estimate of RCTs shows a favorable effect of CPAP on insulin resistance as measured by HOMA-IR in patients with OSA without diabetes. The effect size on HOMA-IR is modest, but not insignificant, when compared with the effects of thiazolidinedione in nondiabetic patients with metabolic syndrome. Further research and RCTs are warranted involving a larger number of patients and longer treatment periods to determine the beneficial effects of CPAP on IR.","evidenceGrade":"full_text"},{"id":"p-pmid-25700870","title":"Meta-analyses of the Association of Sleep Apnea with Insulin Resistance, and the Effects of CPAP on HOMA-IR, Adiponectin, and Visceral Adipose Fat.","authors":["IH Iftikhar","CM Hoyos","CL Phillips","UJ Magalang"],"year":2016,"venue":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine","doi":"10.5664/jcsm.4610","pmid":"25700870","url":"https://pubmed.ncbi.nlm.nih.gov/25700870/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"OBJECTIVE: We sought to conduct an updated meta-analysis of randomized controlled trials (RCTs) on the effect of continuous positive airway pressure (CPAP) on insulin resistance, as measured by homeostasis model assessment of insulin resistance (HOMA-IR), visceral abdominal fat (VAF), and adiponectin. Additionally, we performed a separate meta-analysis and meta-regression of studies on the association of insulin resistance and obstructive sleep apnea (OSA). METHODS: All included studies were searched from PubMed (from conception to March 15, 2014). Data were pooled across all included RCTs as the mean difference in HOMA-IR and VAF, and as the standardized mean difference in the case of adiponectin analysis. From the included case-control studies, data on the difference of HOMA-IR between cases and controls were pooled across all studies, as the standardized mean difference (SMD). RESULTS: There was a significant difference in HOMA-IR (-0.43 [95% CIs: -0.75 to -0.11], p = 0.008) between CPAP treated and non CPAP treated participants. However, there was no significant difference in VAF or adiponectin; (-47.93 [95% CI: -112.58 to 16.72], p = 0.14) and (-0.06 [95% CI: -0.28 to 0.15], p = 0.56), respectively. Meta-analysis of 16 case-control studies showed a pooled SMD in HOMA-IR of 0.51 (95% CI: 0.28 to 0.75), p &#x2264; 0.001, between cases and controls. CONCLUSIONS: The results of our meta-analyses show that CPAP has a favorable effect on insulin resistance. This effect is not associated with any significant changes in total adiponectin levels or amount of VAF. Our findings also confirm a significant association between OSA and insulin resistance.","evidenceGrade":"full_text"},{"id":"p-pmid-31518943","title":"Efficacy of continuous positive airway pressure (CPAP) preventing type 2 diabetes mellitus in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and insulin resistance: a systematic review and meta-analysis.","authors":["R Abud","M Salgueiro","L Drake","T Reyes","J Jorquera","G Labarca"],"year":2020,"venue":"Sleep medicine","doi":"10.1016/j.sleep.2018.12.017","pmid":"31518943","url":"https://pubmed.ncbi.nlm.nih.gov/31518943/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a very common, yet undiagnosed, breathing disorder that has many more implications besides disrupted sleep. Its role as an independent risk factor for metabolic abnormalities such as insulin resistance (IR) and impaired glucose tolerance is becoming increasingly recognized. The main treatment for OSAHS is continuous positive airway pressure (CPAP), however the impact of CPAP on IR and glucose metabolism is still debated. OBJECTIVES: Compile all available evidence regarding the effect of CPAP on IR in non-diabetic OSA patients. METHODS: A literature search in Medline, Epistemonikos and the Cochrane Controlled Trial Register were searched through March 2018. We included Randomized Controlled Trials (RCTs) comparing CPAP treatment with sham CPAP, placebo or no treatment in non-diabetic adults with OSAHS. Risk of Bias was evaluated using Cochrane tool and a meta-analysis evaluating the efficacy of CPAP in both HOMA index and fasting glucose was done. Certain of evidence was rated using GRADE approach. RESULTS: Nine studies consisting of 443 participants were included. CPAP treatment significantly improved HOMA index (Mean difference&#xa0;=&#xa0;-0.39 Ui (CI,&#xa0;-0.69 to&#xa0;-0.08), p&#xa0;&lt;&#xa0;0.05. I2&#xa0;=&#xa0;57% (GRADE&#xa0;=&#xa0;LOW). However, CPAP showed no significant changes in fasting glucose (GRADE&#xa0;=&#xa0;LOW). CONCLUSION: This systematic review and meta-analysis shows evidence that metabolic disturbances could be halted and regressed with CPAP treatment in patients with insulin resistance and OSAHS. In conclusion, treatment with CPAP could improve HOMA IR index.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33146450","title":"Benefits of continuous positive airway pressure on glycaemic control and insulin resistance in patients with type 2 diabetes and obstructive sleep apnoea: A meta-analysis.","authors":["W Shang","Y Zhang","G Wang","D Han"],"year":2021,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.14247","pmid":"33146450","url":"https://pubmed.ncbi.nlm.nih.gov/33146450/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"AIM: To conduct a meta-analysis to determine the effects of continuous positive airway pressure (CPAP) treatment on glycaemic control and insulin resistance in patients with type 2 diabetes and obstructive sleep apnoea (OSA). METHODS: A systematic search was made of the MEDLINE, SCOPUS, ISI Web of Science, Cochrane databases, and clinicaltrials.gov, without language restrictions. Randomized controlled trials on treatment of type 2 diabetes and OSA with CPAP, compared with sham CPAP or no CPAP, were reviewed. Studies were pooled to obtain standardized mean differences (SMDs), with 95% confidence intervals (CIs). RESULTS: Seven trials (enrolling 691 participants) met the inclusion criteria. CPAP showed significant effects on glycated haemoglobin (HbA1c; SMD -0.32, 95% CI -0.60 to -0.03; P = 0.029), fasting glucose (SMD -0.39, 95% CI -0.76 to -0.02; P = 0.040), homeostatic model assessment of insulin resistance (HOMA-IR; SMD -1.05, 95% CI -1.91 to -0.19; P = 0.016), systolic blood pressure (SMD -1.18, 95% CI -2.29 to -0.07&#x2009;mm Hg; P = 0.037), and diastolic blood pressure (SMD -1.29, 95% CI -2.48 to -0.09; P = 0.035). CONCLUSIONS: Continuous positive airway pressure treatment significantly improved glycaemic control and insulin resistance, as shown by the decreased HbA1c levels, fasting glucose levels and HOMA-IR values in patients with type 2 diabetes and OSA.","evidenceGrade":"abstract_only"},{"id":"p-autier-2014","title":"Vitamin D status and ill health: a systematic review","authors":["P. Autier","M. Boniol","C. Pizot","P. Mullie"],"year":2014,"venue":"The Lancet Diabetes & Endocrinology","doi":"10.1016/S2213-8587(13)70165-7","pmid":"24622671","url":"https://pubmed.ncbi.nlm.nih.gov/24622671/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"Observational associations between low 25(OH)D and disease are abundant; supplementation RCTs do not reproduce them. The authors' reading: low D is a marker of ill health, not the cause of it.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33244559","title":"Sunlight Exposure and Vitamin D Levels in Older People- An Intervention Study in Swedish Nursing Homes.","authors":["M Samefors","A Tengblad","CJ &#xd6;stgren"],"year":2021,"venue":"The journal of nutrition, health &amp; aging","doi":"10.1007/s12603-020-1435-z","pmid":"33244559","url":"https://pubmed.ncbi.nlm.nih.gov/33244559/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: Older people are recommended to take oral vitamin D supplements, but the main source of vitamin D is sunlight. Our aim was to explore whether active encouragement to spend time outdoors could increase the levels of serum 25-hydroxyvitamin D (25(OH)D) and increase the mental well-being of nursing home residents. DESIGN: A cluster randomized intervention trial. SETTING: Nursing homes in southern Sweden. PARTICIPANTS: In total 40 people &gt;65 years. INTERVENTION: The intervention group was encouraged to go outside for 20-30 minutes between 11 a.m. and 3 p.m. every day for two months during the summer of 2018. MEASUREMENTS: We analyzed serum 25(OH)D before and after the summer. Data from SF-36 questionnaires measuring vitality and mental health were used for the analyses. RESULTS: In the intervention group, the baseline median (interquartile range (IQR)) of serum 25(OH)D was 42.5 (23.0) nmol/l and in the control group it was 52.0 (36.0) nmol/l. In the intervention group, the 25(OH)D levels increased significantly during the summer (p=0.011). In the control group, there was no significant change. The intervention group reported better self-perceived mental health after the summer compared to before the summer (p=0.015). In the control group, there was no difference in mental health. CONCLUSION: Active encouragement to spend time outdoors during summertime improved the levels of serum 25(OH)D and self-perceived mental health significantly in older people in nursing homes and could complement or replace oral vitamin D supplementation in the summer.","evidenceGrade":"full_text"},{"id":"p-kosfeld-2005","title":"Oxytocin increases trust in humans","authors":["M. Kosfeld","M. Heinrichs","P. J. Zak","U. Fischbacher","E. Fehr"],"year":2005,"venue":"Nature","doi":"10.1038/nature03701","pmid":"15931222","url":"https://pubmed.ncbi.nlm.nih.gov/15931222/","methodology":"rct","n":58,"openAccess":false,"abstract":"Intranasal oxytocin raised transfers in the trust game relative to placebo. The paper created the trust-hormone slogan. It is an RCT. It is not the last word.","evidenceGrade":"abstract_only"},{"id":"p-nave-2015","title":"Does Oxytocin Increase Trust in Humans? A Critical Review of Research","authors":["G. Nave","C. Camerer","M. McCullough"],"year":2015,"venue":"Perspectives on Psychological Science","doi":"10.1177/1745691615600138","pmid":"26581735","url":"https://pubmed.ncbi.nlm.nih.gov/26581735/","methodology":"review","n":null,"openAccess":false,"abstract":"A critical review of the oxytocin–trust literature: small samples, publication bias, and mixed conceptual replications. Camerer is on this paper. He is not on the ultimatum T RCT.","evidenceGrade":"abstract_only"},{"id":"p-declerck-2020","title":"A registered replication study on oxytocin and trust","authors":["C. H. Declerck","C. Boone","L. Pauwels","B. Vogt","E. Fehr"],"year":2020,"venue":"Nature Human Behaviour","doi":"10.1038/s41562-020-0878-x","pmid":"32514040","url":"https://pubmed.ncbi.nlm.nih.gov/32514040/","methodology":"rct","n":677,"openAccess":false,"abstract":"A registered, high-powered double-blind replication, including the original minimal-social-contact condition, found no effect of oxytocin on trusting behavior there. Fehr is a coauthor of both the 2005 paper and this one.","evidenceGrade":"abstract_only"},{"id":"p-pmid-38820421","title":"The impact of oxytocin on emotion recognition and trust: Does disordered eating moderate these relationships?","authors":["I Krug","S Fung","S Liu","J Treasure","C Huang","K Felmingham","M Fuller-Tyszkiewicz","O McConchie"],"year":2024,"venue":"PloS one","doi":"10.1371/journal.pone.0303824","pmid":"38820421","url":"https://pubmed.ncbi.nlm.nih.gov/38820421/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: The current study aimed to investigate the impact of oxytocin on emotion recognition, trust, body image, affect, and anxiety and whether eating disorder (ED) symptoms moderated any of these relationships. METHOD: Participants (n = 149) were female university students, who were randomly allocated to receive in a double-blind nature, a single dose of oxytocin intranasal spray (n = 76) or a placebo (saline) intranasal spray (n = 73). Participants were asked to complete an experimental measure of emotion recognition and an investor task aimed to assess trust. RESULTS: The oxytocin group exhibited better overall performance on the emotion recognition task (especially with recognising positive emotions), and a decline in state positive affect than the control group at post-intervention. However, these effects were not moderated by ED symptom severity, nor were effects found for state anxiety, negative affect, body image and recognising negative emotions in the emotion recognition task. CONCLUSION: The current findings contribute to the growing literature on oxytocin, emotion recognition and positive affect and suggest that ED pathology does not moderate these relationships. Future research would benefit from examining the efficacy of an oxytocin intervention using a within-subjects, cross-over design, in those with sub-clinical and clinical EDs, as well as healthy controls.","evidenceGrade":"full_text"},{"id":"p-pmid-41880977","title":"Absence of a meaningful effect of intranasal oxytocin on trusting behavior: a registered report with pooled equivalence testing.","authors":["CF Kroll","KRJ Schruers","W Viechtbauer","C Vingerhoets","L Seidel","A Riedl","D Hernaus"],"year":2026,"venue":"Cortex; a journal devoted to the study of the nervous system and behavior","doi":"10.1016/j.cortex.2026.03.006","pmid":"41880977","url":"https://pubmed.ncbi.nlm.nih.gov/41880977/","methodology":"observational","n":null,"openAccess":false,"abstract":"The neuropeptide oxytocin (OXT) is thought to modulate important aspects of prosocial behavior. In a seminal paper, Kosfeld et al. (2005) reported that intranasally administered OXT modulated trusting behavior in an economic trust game. Several attempts to conceptually replicate these findings yielded mixed results, which might be partly due to small sample sizes that can reduce the ability to detect, or reject, meaningful effects. We performed a large-scale replication (n = 211) of Kosfeld et al. (2005) with specific attention for small effects and subpopulations whose trusting behavior may be sensitive to OXT manipulations. Moreover, we conducted a pooled analysis of the two largest, recent, replications by merging our data with data from Declerck et al. (2020; n = 321). We found no evidence that intranasal OXT administration increases trusting behavior, neither in our data nor in the pooled dataset. While equivalence testing in our dataset was inconclusive, equivalence testing in the pooled dataset (n = 532) indicated that the effect of OXT administration on trusting behavior lies within a minimal range of effects, suggesting that the effect is too small to be of interest to (most) lab-based studies due to feasibility constraints of collecting data from larger samples required to reject smaller effect sizes. In addition, we found no evidence that OXT administration effects on trusting behavior are influenced by baseline trust, reward sensitivity, and punishment sensitivity. Our findings invite a critical evaluation of current methodology in OXT research and a reconsideration of OXT's involvement in social behaviors and beyond.","evidenceGrade":"abstract_only"},{"id":"p-pmid-25036432","title":"Air pollution during pregnancy and childhood cognitive and psychomotor development: six European birth cohorts.","authors":["M Guxens","R Garcia-Esteban","L Giorgis-Allemand","J Forns","C Badaloni","F Ballester","R Beelen","G Cesaroni"],"year":2015,"venue":"Epidemiology (Cambridge, Mass.)","doi":"10.1097/EDE.0000000000000133","pmid":"25036432","url":"https://pubmed.ncbi.nlm.nih.gov/25036432/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of &lt;2.5, &lt;10, and 2.5-10 &#x3bc;m (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 &#x3bc;g/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36913239","title":"Cognitive Development and Prenatal Air Pollution Exposure in the CHAMACOS Cohort.","authors":["SM Holm","JR Balmes","RB Gunier","K Kogut","KG Harley","B Eskenazi"],"year":2023,"venue":"Environmental health perspectives","doi":"10.1289/EHP10812","pmid":"36913239","url":"https://pubmed.ncbi.nlm.nih.gov/36913239/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Because fine particulate matter [PM, with aerodynamic diameter &#x2264;2.5&#x3bc;m (PM2.5)] is a ubiquitous environmental exposure, small changes in cognition associated with PM2.5 exposure could have great societal costs. Prior studies have demonstrated a relationship between in utero PM2.5 exposure and cognitive development in urban populations, but it is not known whether these effects are similar in rural populations and whether they persist into late childhood. OBJECTIVES: In this study, we tested for associations between prenatal PM2.5 exposure and both full-scale and subscale measures of IQ among a longitudinal cohort at age 10.5 y. METHODS: This analysis used data from 568 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort study in California's agricultural Salinas Valley. Exposures were estimated at residential addresses during pregnancy using state of the art, modeled PM2.5 surfaces. IQ testing was performed by bilingual psychometricians in the dominant language of the child. RESULTS: A 3-&#x3bc;g/m3 higher average PM2.5 over pregnancy was associated with -1.79 full-scale IQ points [95% confidence interval (CI): -2.98, -0.58], with decrements specifically in Working Memory IQ (WMIQ) and Processing Speed IQ (PSIQ) subscales [WMIQ -1.72 (95% CI: -2.98, -0.45) and PSIQ -1.19 (95% CI: -2.54, 0.16)]. Flexible modeling over the course of pregnancy illustrated mid-to-late pregnancy (months 5-7) as particularly susceptible times, with sex differences in the timing of susceptible windows and in which subscales were most affected [Verbal Comprehension IQ (VCIQ) and WMIQ in males; and PSIQ in females]. DISCUSSION: We found that small increases in outdoor PM2.5 exposure in utero were associated with slightly lower IQ in late childhood, robust to many sensitivity analyses. In this cohort there was a larger effect of PM2.5 on childhood IQ than has previously been observed, perhaps due to di","evidenceGrade":"full_text"},{"id":"p-pmid-37793592","title":"Long-term exposure to air pollution and mortality in Scotland: A register-based individual-level longitudinal study.","authors":["M Abed Al Ahad","U Dem&#x161;ar","F Sullivan","H Kulu"],"year":2023,"venue":"Environmental research","doi":"10.1016/j.envres.2023.117223","pmid":"37793592","url":"https://pubmed.ncbi.nlm.nih.gov/37793592/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Air pollution is associated with several adverse health outcomes. However, heterogeneity in the size of effect estimates between cohort studies for long-term exposures exist and pollutants like SO2 and mental/behavioural health outcomes are little studied. This study examines the association between long-term exposure to multiple ambient air pollutants and all-cause and cause-specific mortality from both physical and mental illnesses. METHODS: We used individual-level administrative data from the Scottish-Longitudinal-Study (SLS) on 202,237 individuals aged 17 and older, followed between 2002 and 2017. The SLS dataset was linked to annual concentrations of NO2, SO2, and particulate-matter (PM10, PM2.5) pollution at 1&#xa0;km2 spatial resolution using the individuals' residential postcode. We applied survival analysis to assess the association between air pollution and all-cause, cardiovascular, respiratory, cancer, mental/behavioural disorders/suicides, and other-causes mortality. RESULTS: Higher all-cause mortality was associated with increasing concentrations of PM2.5, PM10, NO2, and SO2 pollutants. NO2, PM10, and PM2.5 were also associated with cardiovascular, respiratory, cancer and other-causes mortality. For example, the mortality hazard from respiratory diseases was 1.062 (95%CI&#xa0;=&#xa0;1.028-1.096), 1.025 (95%CI&#xa0;=&#xa0;1.005-1.045), and 1.013 (95%CI&#xa0;=&#xa0;1.007-1.020) per 1&#xa0;&#x3bc;g/m3 increase in PM2.5, PM10 and NO2 pollutants, respectively. In contrast, mortality from mental and behavioural disorders was associated with 1&#xa0;&#x3bc;g/m3 higher exposure to SO2 pollutant (HR&#xa0;=&#xa0;1.042; 95%CI&#xa0;=&#xa0;1.015-1.069). CONCLUSION: This study revealed an association between long-term (16-years) exposure to ambient air pollution and all-cause and cause-specific mortality. The results suggest that policies and interventions to enhance air quality would reduce the mortality hazard from cardio-respiratory, cancer, and menta","evidenceGrade":"abstract_only"},{"id":"p-pmid-37074132","title":"National Cohort Study of Long-Term Exposure to PM2.5 Components and Mortality in Medicare American Older Adults.","authors":["H Hao","Y Wang","Q Zhu","H Zhang","A Rosenberg","J Schwartz","H Amini","A van Donkelaar"],"year":2023,"venue":"Environmental science &amp; technology","doi":"10.1021/acs.est.2c07064","pmid":"37074132","url":"https://pubmed.ncbi.nlm.nih.gov/37074132/","methodology":"observational","n":null,"openAccess":true,"abstract":"There is increasing evidence linking long-term fine particulate matter (PM2.5) exposure to negative health effects. However, the relative influence of each component of PM2.5 on health risk is poorly understood. In a cohort study in the contiguous United States between 2000 and 2017, we examined the effect of long-term exposure to PM2.5 main components and all-cause mortality in older adults who had to be at least 65 years old and enrolled in Medicare. We estimated the yearly mean concentrations of six key PM2.5 compounds, including black carbon (BC), organic matter (OM), soil dust (DUST), nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+), using two independently sourced well-validated prediction models. We applied Cox proportional hazard models to evaluate the hazard ratios for mortality and penalized splines for assessing potential nonlinear concentration-response associations. Results suggested that increased exposure to PM2.5 mass and its six main constituents were significantly linked to elevated all-cause mortality. All components showed linear concentration-response relationships in the low exposure concentration ranges. Our research indicates that long-term exposure to PM2.5 mass and its essential compounds are strongly connected to increased mortality risk. Reductions of fossil fuel burning may yield significant air quality and public health benefit.","evidenceGrade":"full_text"},{"id":"p-pmid-37505744","title":"Ambient Air Pollution and Risk of Enterotomy, Gastrointestinal Cancer, and All-Cause Mortality among 4,708 Individuals with Inflammatory Bowel Disease: A Prospective Cohort Study.","authors":["J Chen","L Dan","Y Sun","S Yuan","W Liu","X Chen","F Jiang","T Fu"],"year":2023,"venue":"Environmental health perspectives","doi":"10.1289/EHP12215","pmid":"37505744","url":"https://pubmed.ncbi.nlm.nih.gov/37505744/","methodology":"observational","n":null,"openAccess":true,"abstract":"BACKGROUND: Previous studies indicated that air pollution plausibly increases the risk of adverse outcomes in inflammatory bowel disease (IBD) via proinflammatory mechanisms. However, there is scant epidemiological data and insufficient prospective evidence assessing associations between ambient air pollution and clinical outcomes of IBD. OBJECTIVES: We aimed to investigate the associations between ambient air pollution and clinical outcomes among individuals with IBD. METHODS: Leveraging data from the UK Biobank, we included 4,708 individuals with IBD recruited in the period 2006-2010 in this study. A land use regression model was used to assess annual mean concentrations of ambient air pollutants nitrogen including oxides (NOx), nitrogen dioxide (NO2), and particulate matter (PM) with aerodynamic diameter &#x2264;10&#x3bc;m (PM10) and PM with aerodynamic diameter &#x2264;2.5&#x3bc;m (PM2.5). Individuals with IBD were followed up for incident clinical outcomes of enterotomy, gastrointestinal cancer, and all-cause mortality, ascertained via death registry, inpatient, primary care, and cancer registry data. Cox proportional hazard model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the magnitude of the associations. RESULTS: During a mean follow-up of 12.0 y, 265 enterotomy events, 124 incident gastrointestinal cancer, and 420 death events were documented among individuals with IBD. We found that each interquartile range (IQR) increase in exposure to PM2.5 was associated with increased risk of enterotomy (HR=1.16; 95% CI: 1.00, 1.34, p=0.043), whereas an IQR increase in exposure to NOx (HR=1.10; 95% CI: 1.01, 1.20, p=0.016), NO2 (HR=1.16; 95% CI: 1.03, 1.29, p=0.010), PM10 (HR=1.15; 95% CI: 1.03, 1.30, p=0.015), and PM2.5 (HR=1.14; 95% CI: 1.02, 1.28, p=0.019) was associated with increased risk of all-cause mortality among individuals with IBD. We did not observe any significant associations between air pollutants and gastrointestin","evidenceGrade":"full_text"},{"id":"p-carney-2010","title":"Power Posing: Brief Nonverbal Displays Affect Neuroendocrine Levels and Risk Tolerance","authors":["D. R. Carney","A. J. C. Cuddy","A. J. Yap"],"year":2010,"venue":"Psychological Science","doi":"10.1177/0956797610383437","pmid":"20855902","url":"https://pubmed.ncbi.nlm.nih.gov/20855902/","methodology":"rct","n":42,"openAccess":false,"abstract":"Two minutes of expansive versus contractive posture were reported to raise testosterone, lower cortisol, and increase risk-taking. N=42. This is the TED-talk paper. It is the start of the file, not the identification.","evidenceGrade":"abstract_only"},{"id":"p-ranehill-2015","title":"Assessing the Robustness of Power Posing: No Effect on Hormones and Risk Tolerance in a Large Sample of Men and Women","authors":["E. Ranehill","A. Dreber","M. Johannesson","S. Leiberg","S. Sul","R. A. Weber"],"year":2015,"venue":"Psychological Science","doi":"10.1177/0956797614553946","pmid":"25810452","url":"https://pubmed.ncbi.nlm.nih.gov/25810452/","methodology":"rct","n":200,"openAccess":true,"abstract":"A larger sample found no effect of expansive posture on testosterone, cortisol, or risk-taking. The hormone and risk claims from 2010 do not survive this test.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39633430","title":"The effects of power posing on neuroendocrine levels and risk-taking.","authors":["E Barel","S Shahrabani","L Mahagna","R Massalha","R Colodner","O Tzischinsky"],"year":2024,"venue":"BMC psychology","doi":"10.1186/s40359-024-02194-7","pmid":"39633430","url":"https://pubmed.ncbi.nlm.nih.gov/39633430/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: The current study attempted to replicate the original findings regarding the effects of power posing on testosterone and cortisol levels, risk-taking behavior, and perceived power. We further extended the investigation by testing the effect of power posing on estradiol and progesterone levels. METHODS: A sample of 92 young adults (30 males; 32 females taking oral contraceptives; and 30 females not taking oral contraceptives who were in their midluteal phase) were randomly assigned to high-power-pose or low-power-pose conditions and asked about their feelings of power. They completed a risk-taking task, and their neuroendocrine levels were measured both at baseline and following the power manipulation. RESULTS: Power posing was not found to replicate the original results regarding effects on testosterone levels or feelings of power; however, our findings partially supported the original results regarding effects on cortisol levels and risk-taking. Among high-power posers, a decrease in cortisol levels was associated with risk tolerance. Power posing was not found to influence progesterone levels. However, among females taking oral contraceptives, high-power posing increased estradiol levels. CONCLUSIONS: These preliminary findings suggest that estradiol is influenced by short-term exposure to social cues under specific hormonal profiles.","evidenceGrade":"full_text"},{"id":"p-simmons-2017","title":"Power Posing: P-Curving the Evidence","authors":["J. P. Simmons","U. Simonsohn"],"year":2017,"venue":"Psychological Science","doi":"10.1177/0956797616658563","pmid":"28485698","url":"https://pubmed.ncbi.nlm.nih.gov/28485698/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"A p-curve of the supportive postural-feedback set is indistinguishable from a null plus selective reporting. Weak evidence is not a reason to hunt for moderators or to prescribe a pose.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29731182","title":"Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial.","authors":["A Kazemi","AA Noorbala","K Azam","MH Eskandari","K Djafarian"],"year":2020,"venue":"Clinical nutrition (Edinburgh, Scotland)","doi":"10.1016/j.clnu.2018.04.010","pmid":"29731182","url":"https://pubmed.ncbi.nlm.nih.gov/29731182/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Disturbance in the equilibrium of the gut microbiota has been involved in the pathophysiology of depression. Probiotics have the potential to healthfully modulate the gut microbiome. Prebiotics could also be effective by stimulation of growth of some bacterial species in the gut microbiota. OBJECTIVE: The aim of this double blind clinical trial, was to compare the effect of supplementation with the probiotic and prebiotic on the Beck Depression Inventory (BDI) score as a primary outcome as well as the kynurenine/tryptophan ratio and tryptophan/branch chain amino acids (BCAAs) ratio as secondary outcomes in patients with major depressive disorder (MDD). DESIGN: One hundred and ten depressed patients were randomly assigned to receive the probiotic (Lactobacillus helveticus and Bifidobacterium longum), prebiotic (galactooligosaccharide) or placebo for 8 weeks. Serum tryptophan and BCAAs were measured by HPLC, and kynurenine by ELISA kit. Dietary intake and physical activity of the participants were recorded at baseline. RESULTS: A total of 81 subjects (aged 36.5&#xa0;&#xb1;&#xa0;8.03 y; mean (95% CI), 2.27 (1.76-2.93) y of depression duration) completed the trial (28 in the probiotic group, 27 in the prebiotic group, and 26 in the placebo group). From baseline to 8 weeks, probiotic supplementation resulted in a significant decrease in BDI score (17.39-9.1) compared to the placebo (18.18-15.55) and prebiotic (19.72-14.14) supplementation (p&#xa0;=&#xa0;0.042). Inter-group comparison indicated no significant differences among the groups in terms of serum kynurenine/tryptophan ratio and tryptophan/BCAAs ratio. However, the kynurenine/tryptophan ratio decreased significantly in the probiotic group compared to the placebo group after adjusting for serum isoleucine (p&#xa0;=&#xa0;0.048). In addition, the tryptophan/isoleucine ratio increased significantly in the probiotic group when compared to the placebo group (p&#xa0;=&#xa0;0.023). CONCLUSION: Overall, 8 weeks","evidenceGrade":"abstract_only"},{"id":"p-pmid-26706022","title":"Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial.","authors":["G Akkasheh","Z Kashani-Poor","M Tajabadi-Ebrahimi","P Jafari","H Akbari","M Taghizadeh","MR Memarzadeh","Z Asemi"],"year":2016,"venue":"Nutrition (Burbank, Los Angeles County, Calif.)","doi":"10.1016/j.nut.2015.09.003","pmid":"26706022","url":"https://pubmed.ncbi.nlm.nih.gov/26706022/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: We are aware of no study examining the effects of probiotic supplementation on symptoms of depression, metabolic profiles, serum high-sensitivity C-reactive protein (hs-CRP), and biomarkers of oxidative stress in patients with major depressive disorder (MDD). The present study was designed to determine the effects of probiotic intake on symptoms of depression and metabolic status in patients with MDD. METHODS: This randomized, double-blind, placebo-controlled clinical trial included 40 patients with a diagnosis of MDD based on DSM-IV criteria whose age ranged between 20 and 55 y. Patients were randomly allocated into two groups to receive either probiotic supplements (n = 20) or placebo (n = 20) for 8 wk. Probiotic capsule consisted of three viable and freeze-dried strains: Lactobacillus acidophilus (2 &#xd7; 10(9) CFU/g), Lactobacillus casei (2 &#xd7; 10(9) CFU/g), and Bifidobacterium bifidum (2 &#xd7; 10(9) CFU/g). Fasting blood samples were taken at the beginning and end of the trial to quantify the relevant variables. All participants provided three dietary records (two weekdays and one weekend) and three physical activity records during the intervention. RESULTS: Dietary intake of study participants was not significantly different between the two groups. After 8 wk of intervention, patients who received probiotic supplements had significantly decreased Beck Depression Inventory total scores (-5.7 &#xb1; 6.4 vs. -1.5 &#xb1; 4.8, P = 0.001) compared with the placebo. In addition, significant decreases in serum insulin levels (-2.3 &#xb1; 4.1 vs. 2.6 &#xb1; 9.3 &#x3bc;IU/mL, P = 0.03), homeostasis model assessment of insulin resistance (-0.6 &#xb1; 1.2 vs. 0.6 &#xb1; 2.1, P = 0.03), and serum hs-CRP concentrations (-1138.7 &#xb1; 2274.9 vs. 188.4 &#xb1; 1455.5 ng/mL, P = 0.03) were observed after the probiotic supplementation compared with the placebo. Additionally, taking probiotics resulted in a significant rise in plasma total glutathione levels (1.8","evidenceGrade":"abstract_only"},{"id":"p-pmid-39048549","title":"Examining immune-inflammatory mechanisms of probiotic supplementation in depression: secondary findings from a randomized clinical trial.","authors":["L Sempach","JPK Doll","V Limbach","F Marzetta","AC Schaub","E Schneider","C Kettelhack","L M&#xe4;hlmann"],"year":2024,"venue":"Translational psychiatry","doi":"10.1038/s41398-024-03030-7","pmid":"39048549","url":"https://pubmed.ncbi.nlm.nih.gov/39048549/","methodology":"rct","n":null,"openAccess":true,"abstract":"We recently indicated that four-week probiotic supplementation significantly reduced depression along with microbial and neural changes in people with depression. Here we further elucidated the biological modes of action underlying the beneficial clinical effects of probiotics by focusing on immune-inflammatory processes. The analysis included a total of N&#x2009;=&#x2009;43 participants with depression, from which N&#x2009;=&#x2009;19 received the probiotic supplement and N&#x2009;=&#x2009;24 received a placebo over four weeks, in addition to treatment as usual. Blood and saliva were collected at baseline, at post-intervention (week 4) and follow-up (week 8) to assess immune-inflammatory markers (IL-1&#x3b2;, IL-6, CRP, MIF), gut-related hormones (ghrelin, leptin), and a stress marker (cortisol). Furthermore, transcriptomic analyses were conducted to identify differentially expressed genes. Finally, we analyzed the associations between probiotic-induced clinical and immune-inflammatory changes. We observed a significant group x time interaction for the gut hormone ghrelin, indicative of an increase in the probiotics group. Additionally, the increase in ghrelin was correlated with the decrease in depressive symptoms in the probiotics group. Transcriptomic analyses identified 51 up- and 57 down-regulated genes, which were involved in functional pathways related to enhanced immune activity. We identified a probiotic-dependent upregulation of the genes ELANE, DEFA4 and OLFM4 associated to immune activation and ghrelin concentration. These results underscore the potential of probiotic supplementation to produce biological meaningful changes in immune activation in patients with depression. Further large-scale mechanistic trials are warranted to validate and extend our understanding of immune-inflammatory measures as potential biomarkers for stratification and treatment response in depression. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.","evidenceGrade":"full_text"},{"id":"p-pmid-25282031","title":"The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial.","authors":["SA Mortensen","F Rosenfeldt","A Kumar","P Dolliner","KJ Filipiak","D Pella","U Alehagen","G Steurer"],"year":2015,"venue":"JACC. Heart failure","doi":"10.1016/j.jchf.2014.06.008","pmid":"25282031","url":"https://pubmed.ncbi.nlm.nih.gov/25282031/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVES: This randomized controlled multicenter trial evaluated coenzyme Q10 (CoQ10) as adjunctive treatment in chronic heart failure (HF). BACKGROUND: CoQ10 is an essential cofactor for energy production and is also a powerful antioxidant. A low level of myocardial CoQ10 is related to the severity of HF. Previous randomized controlled trials of CoQ10 in HF were underpowered to address major clinical endpoints. METHODS: Patients with moderate to severe HF were randomly assigned in a 2-year prospective trial to either CoQ10 100 mg 3 times daily or placebo, in addition to standard therapy. The primary short-term endpoints at 16 weeks were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro-B type natriuretic peptide. The primary long-term endpoint at 2 years was composite major adverse cardiovascular events as determined by a time to first event analysis. RESULTS: A total of 420 patients were enrolled. There were no significant changes in short-term endpoints. The primary long-term endpoint was reached by 15% of the patients in the CoQ10 group versus 26% in the placebo group (hazard ratio: 0.50; 95% confidence interval: 0.32 to 0.80; p = 0.003) by intention-to-treat analysis. The following secondary endpoints were significantly lower in the CoQ10 group compared with the placebo group: cardiovascular mortality (9% vs. 16%, p = 0.026), all-cause mortality (10% vs. 18%, p = 0.018), and incidence of hospital stays for HF (p = 0.033). In addition, a significant improvement of NYHA class was found in the CoQ10 group after 2 years (p = 0.028). CONCLUSIONS: Long-term CoQ10 treatment of patients with chronic HF is safe, improves symptoms, and reduces major adverse cardiovascular events. (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/","evidenceGrade":"abstract_only"},{"id":"p-pmid-30835327","title":"Effect of coenzyme Q10 in Europeans with chronic heart failure: A sub-group analysis of the Q-SYMBIO randomized double-blind trial.","authors":["AL Mortensen","F Rosenfeldt","KJ Filipiak"],"year":2020,"venue":"Cardiology journal","doi":"10.5603/CJ.a2019.0022","pmid":"30835327","url":"https://pubmed.ncbi.nlm.nih.gov/30835327/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Geographical differences in patient characteristics, management and outcomes in heart failure (HF) trials are well recognized. The aim of this study was to assess the consistency of the treat- ment effect of coenzyme Q10 (CoQ10) in the European sub-population of Q-SYMBIO, a randomized double-blind multinational trial of treatment with CoQ10, in addition to standard therapy in chronic HF. METHODS: Patients with moderate to severe HF were randomized to CoQ10 300 mg daily or placebo in addition to standard therapy. At 3 months the primary short-term endpoints were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro-B type natriuretic peptide. At 2 years the primary long-term endpoint was major adverse cardiovascular events (MACE). RESULTS: There were no significant changes in short-term endpoints. The primary long-term endpoint of MACE was reached by significantly fewer patients in the CoQ10 group (n = 10, 9%) compared to the placebo group (n = 33, 27%, p = 0.001). The following secondary endpoints were significantly improved in the CoQ10 group compared with the placebo group: all-cause and cardiovascular mortality, NYHA classification and left ventricular ejection fraction (LVEF). In the European sub-population, when compared to the whole group, there was greater adherence to guideline directed therapy and similar results for short- and long-term endpoints. A new finding revealed a significant improvement in LVEF. CONCLUSIONS: The therapeutic efficacy of CoQ10 demonstrated in the Q-SYMBIO study was confirmed in the European sub-population in terms of safely reducing MACE, all-cause mortality, cardiovascular mortality, hospitalization and improvement of symptoms.","evidenceGrade":"full_text"},{"id":"p-pmid-8241697","title":"Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study.","authors":["C Morisco","B Trimarco","M Condorelli"],"year":1994,"venue":"The Clinical investigator","doi":null,"pmid":"8241697","url":"https://pubmed.ncbi.nlm.nih.gov/8241697/","methodology":"rct","n":null,"openAccess":false,"abstract":"The improved cardiac function in patients with congestive heart failure treated with coenzyme Q10 supports the hypothesis that this condition is characterized by mitochondrial dysfunction and energy starvation, so that it may be ameliorated by coenzyme Q10 supplementation. However, the main clinical problems in patients with congestive heart failure are the frequent need of hospitalization and the high incidence of life-threatening arrhythmias, pulmonary edema, and other serious complications. Thus, we studied the influence of coenzyme Q10 long-term treatment on these events in patients with chronic congestive heart failure (New York Heart Association functional class III and IV) receiving conventional treatment for heart failure. They were randomly assigned to receive either placebo (n = 322, mean age 67 years, range 30-88 years) or coenzyme Q10 (n = 319, mean age 67 years, range 26-89 years) at the dosage of 2 mg/kg per day in a 1-year double-blind trial. The number of patients who required hospitalization for worsening heart failure was smaller in the coenzyme Q10 treated group (n = 73) than in the control group (n = 118, P &lt; 0.001). Similarly, the episodes of pulmonary edema or cardiac asthma were reduced in the control group (20 versus 51 and 97 versus 198, respectively; both P &lt; 0.001) as compared to the placebo group. Our results demonstrate that the addition of coenzyme Q10 to conventional therapy significantly reduces hospitalization for worsening of heart failure and the incidence of serious complications in patients with chronic congestive heart failure.","evidenceGrade":"abstract_only"},{"id":"p-mehta-prasad-2015","title":"The dual-hormone hypothesis: a brief review and future research agenda","authors":["P. H. Mehta","S. Prasad"],"year":2015,"venue":"Current Opinion in Behavioral Sciences","doi":"10.1016/j.cobeha.2014.12.001","pmid":null,"url":"https://doi.org/10.1016/j.cobeha.2014.12.001","methodology":"review","n":null,"openAccess":false,"abstract":"Reviews evidence that testosterone predicts status-seeking when cortisol is low, and sets boundary conditions (context, sex, measurement) that later meta-analyses would stress.","evidenceGrade":"abstract_only"},{"id":"p-pmid-25837277","title":"Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial.","authors":["JJ Mao","SX Xie","J Zee","I Soeller","QS Li","K Rockwell","JD Amsterdam"],"year":2015,"venue":"Phytomedicine : international journal of phytotherapy and phytopharmacology","doi":"10.1016/j.phymed.2015.01.010","pmid":"25837277","url":"https://pubmed.ncbi.nlm.nih.gov/25837277/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder. HYPOTHESIS: We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events. STUDY DESIGN: Phase II randomized placebo controlled clinical trial. METHODS: 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models. RESULTS: Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p = 0.79, p = 0.28, and p = 0.17, respectively). The decline in HAM-D scores was greater for sertraline (-8.2, 95% confidence interval [CI], -12.7 to -3.6) versus R. rosea (-5.1, 95% CI: -8.8 to -1.3) and placebo (-4.6, 95% CI: -8.6 to -0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44-8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38-5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p = 0.012). CONCLUSIONS: Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression.","evidenceGrade":"full_text"},{"id":"p-pmid-17990195","title":"Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression.","authors":["V Darbinyan","G Aslanyan","E Amroyan","E Gabrielyan","C Malmstr&#xf6;m","A Panossian"],"year":2008,"venue":"Nordic journal of psychiatry","doi":null,"pmid":"17990195","url":"https://pubmed.ncbi.nlm.nih.gov/17990195/","methodology":"rct","n":null,"openAccess":false,"abstract":"The objective of this study was to assess the efficacy and safety of standardized extract SHR-5 of rhizomes of Rhodiola rosea L. in patients suffering from a current episode of mild/moderate depression. The phase III clinical trial was carried out as a randomized double-blind placebo-controlled study with parallel groups over 6 weeks. Participants, males and females aged 18-70 years, were selected according to DSM-IV diagnostic criteria for depression, the severity of which was determined by scores gained in Beck Depression Inventory and Hamilton Rating Scale for Depression (HAMD) questionnaires. Patients with initial HAMD scores between 21 and 31 were randomized into three groups, one of which (group A: 31 patients) received two tablets daily of SHR-5 (340 mg/day), a second (group B: 29 patients) received two tablets twice per day of SHR-5 (680 mg/day), and a third (group C: 29 patients) received two placebo tablets daily. The efficacy of SHR-5 extract with respect to depressive complaints was assessed on days 0 and 42 of the study period from total and specific subgroup HAMD scores. For individuals in groups A and B, overall depression, together with insomnia, emotional instability and somatization, but not self-esteem, improved significantly following medication, whilst the placebo group did not show such improvements. No serious side-effects were reported in any of the groups A-C. It is concluded that the standardized extract SHR-5 shows anti-depressive potency in patients with mild to moderate depression when administered in dosages of either 340 or 680 mg/day over a 6-week period.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33725639","title":"Screen time and working memory in adolescents: A longitudinal study.","authors":["PSM Soares","PD de Oliveira","FC Wehrmeister","AMB Menezes","H Gon&#xe7;alves"],"year":2021,"venue":"Journal of psychiatric research","doi":"10.1016/j.jpsychires.2021.02.066","pmid":"33725639","url":"https://pubmed.ncbi.nlm.nih.gov/33725639/","methodology":"observational","n":null,"openAccess":false,"abstract":"Little is known about the effects of excessive screen time on Working Memory (WM) in adolescents. The aim of this study was to investigate the association between measures of screen time in adolescence and Working Memory. Data from the 1993 Pelotas (Brazil) Birth Cohort Study were analyzed (N&#xa0;=&#xa0;3625). Self-reported screen time was collected at ages 11, 15 and 18. Working Memory performance (Digit Span backward score) was examined at age 22. Multiple linear regression was used to assess the associations between three screen time measures (television, video game and computer time) for each age and WM at age 22. We also evaluated the direct and indirect effect by mediation analysis, using the intelligence quotient (IQ) at 18 years as mediator. In men, television and video game time at 11 years and computer at ages 11 and 15 years had a positive effect on WM. Also, these effects were mediated through IQ. In women there was no significant association between screen time measures at ages 11, 15, and 18 and WM. This study provides new insights about the relationship between television, videogame, and computer time with WM in adolescents, by exploring the paths of these associations and considering the important mediating role of IQ.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36027980","title":"Adherence to Screen Time and Physical Activity Guidelines is Associated with Executive Function in US Toddlers Participating in the STRONG Kids 2 Birth Cohort Study.","authors":["AL McMath","S Iwinski","S Shen","KF Bost","SM Donovan","NA Khan"],"year":2022,"venue":"The Journal of pediatrics","doi":"10.1016/j.jpeds.2022.08.026","pmid":"36027980","url":"https://pubmed.ncbi.nlm.nih.gov/36027980/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVE: To test the hypothesis that healthy weight status and adherence to American Academy of Pediatrics (AAP) guidelines for diet and physical activity would extend to greater executive function (EF) at age 24&#xa0;months. STUDY DESIGN: Parents of 24-month-old children from the STRONG Kids 2 cohort study (n&#xa0;=&#xa0;352) completed the Behavioral Rating Inventory of Executive Function for Preschoolers (BRIEF-P) and reported physical activities, diet, and screen time. Toddlers met AAP guidelines if they consumed at least 5 servings of fruits and vegetables, were physically active, refrained from sugar-sweetened beverages, and limited daily screen time to &lt;60&#xa0;minutes. Relationships between EF, 24-month weight status, and meeting AAP guidelines were tested independent of child sex, ethnicity, socioeconomic status, weight status at birth, and maternal pregnancy weight status. RESULTS: Weight-for-length z-score had no effect on EF. Toddlers meeting the screen time guideline had greater EF (&#x3b2;, -0.125; 95% CI, 0.234 to -0.008), inhibitory self-control (&#x3b2;, -0.142; 95% CI, -0.248 to -0.029), and emergent metacognition (&#x3b2;, -0.111; 95% CI, -0.221 to 0.002), indicated by lower BRIEF-P scores. Those with more minutes of screen time had poorer overall EF (&#x3b2;, 0.257; 95% CI, 0.118-0.384), inhibitory self-control (&#x3b2;, 0.231; 95% CI, 0.099-0.354), cognitive flexibility (&#x3b2;, 0.217; 95% CI, 0.082-0.342), and emergent metacognition (&#x3b2;, 0.257; 95% CI, 0.120-0.381). Daily physical activity was associated with greater emergent metacognition (&#x3b2;, -0.116; 95% CI, -0.225 to -0.005). CONCLUSIONS: Meeting AAP guidelines for physical activity and screen time was related to greater EF in a demographically homogenous sample of toddlers. Future randomized control trials and more diverse samples are needed to confirm the directionality of this relationship. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03341858.","evidenceGrade":"full_text"},{"id":"p-pmid-29356345","title":"Four days of simulated shift work reduces insulin sensitivity in humans.","authors":["R Bescos","MJ Boden","ML Jackson","AJ Trewin","EC Marin","I Levinger","A Garnham","DS Hiam"],"year":2019,"venue":"Acta physiologica (Oxford, England)","doi":"10.1111/apha.13039","pmid":"29356345","url":"https://pubmed.ncbi.nlm.nih.gov/29356345/","methodology":"observational","n":null,"openAccess":false,"abstract":"AIM: The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with a simulated day shift schedule. METHODS: Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n&#xa0;=&#xa0;9; day shift work n&#xa0;=&#xa0;8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively. RESULTS: Fasting plasma glucose increased (4.4&#xa0;&#xb1;&#xa0;0.1 vs. 4.6&#xa0;&#xb1;&#xa0;0.1&#xa0;mmol&#xa0;L-1 ; P&#xa0;=&#xa0;.001) and insulin sensitivity decreased (25&#xa0;&#xb1;&#xa0;7%, P&#xa0;&lt;&#xa0;.05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1&#x3b1;, UCP3, TFAM and mitochondria Complex II-V) or insulin-stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2). CONCLUSION: Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.","evidenceGrade":"abstract_only"},{"id":"p-pmid-35527601","title":"Shift work and insulin resistance (HOMA-IR) among professional drivers.","authors":["K Sadeghniiat-Haghighi","F Abbaslou","S Akbar Sharifian","N Izadi"],"year":2022,"venue":"Work (Reading, Mass.)","doi":"10.3233/WOR-210056","pmid":"35527601","url":"https://pubmed.ncbi.nlm.nih.gov/35527601/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Shift work may be associated with insulin resistance. OBJECTIVE: This study aimed to investigate the potential association between shift work and the homeostatic model assessment of insulin resistance (HOMA-IR) index in professional drivers. METHOD: A total of four hundred fifty-three professional drivers were invited to participate in the study within a periodic medical examination in the occupational setting. One hundred seventy-seven daytime workers were compared with 175 night shifts and 101 early morning shift drivers. Demographic, occupational, and medical examination including blood pressure, anthropometric data was assessed. Measurement of serum insulin, fasting blood glucose and lipid profile were done for all drivers. RESULTS: Compared with day workers, night shift and early morning shift drivers displayed higher levels of HOMA-IR. Metabolic syndrome was found to be significantly increased in night workers. In linear regression analysis, insulin resistance was correlated with shift work independently of demographic and occupational characteristics. CONCLUSION: The study revealed that shift work could be a risk factor in developing the risk of metabolic syndrome and insulin resistance. Suggestively, health strategies such as structured lifestyle counseling in occupational health settings are warranted to improve and modify cardiometabolic risk factors.","evidenceGrade":"abstract_only"},{"id":"p-pmid-27208318","title":"Benefits for Type 2 Diabetes of Interrupting Prolonged Sitting With Brief Bouts of Light Walking or Simple Resistance Activities.","authors":["PC Dempsey","RN Larsen","P Sethi","JW Sacre","NE Straznicky","ND Cohen","E Cerin","GW Lambert"],"year":2017,"venue":"Diabetes care","doi":"10.2337/dc15-2336","pmid":"27208318","url":"https://pubmed.ncbi.nlm.nih.gov/27208318/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: To determine whether interrupting prolonged sitting with brief bouts of light-intensity walking (LW) or simple resistance activities (SRA) improves postprandial cardiometabolic risk markers in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men 62 &#xb1; 6 years old) underwent the following 8-h conditions on three separate days (with 6-14 days washout): uninterrupted sitting (control) (SIT), sitting plus 3-min bouts of LW (3.2 km &#xb7; h(-1)) every 30 min, and sitting plus 3-min bouts of SRA (half-squats, calf raises, gluteal contractions, and knee raises) every 30 min. Standardized meals were consumed during each condition. Incremental areas under the curve (iAUCs) for glucose, insulin, C-peptide, and triglycerides were compared between conditions. RESULTS: Compared with SIT, both activity-break conditions significantly attenuated iAUCs for glucose (SIT mean 24.2 mmol &#xb7; h &#xb7; L(-1) [95% CI 20.4-28.0] vs. LW 14.8 [11.0-18.6] and SRA 14.7 [10.9-18.5]), insulin (SIT 3,293 pmol &#xb7; h &#xb7; L(-1) [2,887-3,700] vs. LW 2,104 [1,696-2,511] and SRA 2,066 [1,660-2,473]), and C-peptide (SIT 15,641 pmol &#xb7; h &#xb7; L(-1) [14,353-16,929] vs. LW 11,504 [10,209-12,799] and SRA 11,012 [9,723-12,301]) (all P &lt; 0.001). The iAUC for triglycerides was significantly attenuated for SRA (P &lt; 0.001) but not for LW (SIT 4.8 mmol &#xb7; h &#xb7; L(-1) [3.6-6.0] vs. LW 4.0 [2.8-5.1] and SRA 2.9 [1.7-4.1]). CONCLUSIONS: Interrupting prolonged sitting with brief bouts of LW or SRA attenuates acute postprandial glucose, insulin, C-peptide, and triglyceride responses in adults with T2D. With poor adherence to structured exercise, this approach is potentially beneficial and practical.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30403772","title":"Metabolic Effects of Breaking Prolonged Sitting With Standing or Light Walking in Older South Asians and White Europeans: A Randomized Acute Study.","authors":["T Yates","CL Edwardson","C Celis-Morales","SJH Biddle","D Bodicoat","MJ Davies","D Esliger","J Henson"],"year":2020,"venue":"The journals of gerontology. Series A, Biological sciences and medical sciences","doi":"10.1093/gerona/gly252","pmid":"30403772","url":"https://pubmed.ncbi.nlm.nih.gov/30403772/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Prolonged sitting is common in older adults and is associated with insulin resistance and poor cardiometabolic health. We investigate whether breaking prolonged sitting with regular short bouts of standing or light walking improves postprandial metabolism in older white European and South Asian adults and whether effects are modified by ethnic group. METHODS: Thirty South Asian (15 women) and 30 white European (14 women) older adults (aged 65-79 years) undertook three experimental conditions in random order. (a) Prolonged sitting: continuous sitting during an observation period if 7.5 hours consuming two standardized mixed meals. (b) Standing breaks: sitting interrupted with 5 minutes of standing every 30 minutes (accumulating 60 minutes of standing over the observation period). (c) Walking breaks: sitting interrupted with 5 minutes of self-paced light walking every 30 minutes (accumulating 60 minutes of walking). Blood samples (glucose, insulin, triglycerides) and blood pressure were sampled regularly throughout each condition. RESULTS: Compared with prolonged sitting, walking breaks lowered postprandial insulin by 16.3 mU/L, (95% CI: 19.7, 22.0) with greater reductions (p = .029) seen in South Asians (22.4 mU/L; 12.4, 32.4) than white Europeans (10.3 mU/L; 5.9, 14.7). Glucose (0.3 mmol/L; 0.1, 0.5) and blood pressure (4 mm Hg; 2, 6), but not triglycerides, were lower with walking breaks, with no ethnic differences. Standing breaks did not improve any outcome. CONCLUSIONS: Breaking prolonged sitting with short bouts of light walking, but not standing, resulted in clinically meaningful improvements in markers of metabolic health in older adults, with South Asians gaining a greater reduction in postprandial insulin. TRIAL REGISTRATION: NCT02453204.","evidenceGrade":"full_text"},{"id":"p-pmid-29431272","title":"Prolonged uninterrupted sitting elevates postprandial hyperglycaemia proportional to degree of insulin resistance.","authors":["PC Dempsey","RN Larsen","EAH Winkler","N Owen","BA Kingwell","DW Dunstan"],"year":2018,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.13254","pmid":"29431272","url":"https://pubmed.ncbi.nlm.nih.gov/29431272/","methodology":"rct","n":null,"openAccess":false,"abstract":"Prolonged uninterrupted sitting is related adversely to cardiometabolic risk markers and postprandial hyperglycaemia, relative to sitting interrupted by regular brief activity breaks. However, whether the magnitude of hyperglycaemic responses to prolonged sitting is dependent upon the underlying degree of insulin resistance remains unclear. Data were pooled from 3 randomized cross-over laboratory-based trials (n&#x2009;=&#x2009;62) that examined the postprandial blood glucose- and insulin-lowering effects of prolonged sitting vs sitting interrupted by regular brief activity breaks in overweight/obese adults who had normal or impaired glucose metabolism (2 trials) or type 2 diabetes not treated by insulin (1 trial). Corrected for study effects, the magnitude of differences in postprandial glucose and insulin responses between the 2 conditions was significantly exacerbated with poorer baseline levels of fasting glucose, insulin and/or surrogate markers of &#x3b2;-cell function and insulin resistance. This suggests that those with higher underlying levels of insulin resistance may derive greater metabolic benefits from regularly interrupting prolonged sitting than their healthier counterparts. If these findings can be replicated, they may have implications for future targeting and optimization of physical activity/sedentary behaviour interventions in the prevention and management of type 2 diabetes.","evidenceGrade":"abstract_only"},{"id":"p-pmid-33308235","title":"Combined effects of continuous exercise and intermittent active interruptions to prolonged sitting on postprandial glucose, insulin, and triglycerides in adults with obesity: a randomized crossover trial.","authors":["MJ Wheeler","DJ Green","E Cerin","KA Ellis","I Heinonen","J Lewis","LH Naylor","N Cohen"],"year":2021,"venue":"The international journal of behavioral nutrition and physical activity","doi":"10.1186/s12966-020-01057-9","pmid":"33308235","url":"https://pubmed.ncbi.nlm.nih.gov/33308235/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Postprandial glucose, insulin, and triglyceride metabolism is impaired by prolonged sitting, but enhanced by exercise. The aim of this study was to assess the effects of a continuous exercise bout with and without intermittent active interruptions to prolonged sitting on postprandial glucose, insulin, and triglycerides. METHODS: Sedentary adults who were overweight to obese (n&#x2009;=&#x2009;67; mean age 67&#x2009;yr SD&#x2009;&#xb1;&#x2009;7; BMI 31.2&#x2009;kg&#x2219;m-&#x2009;2 SD&#x2009;&#xb1;&#x2009;4.1), completed three conditions: SIT: uninterrupted sitting (8-h, control); EX+SIT: sitting (1-h), moderate-intensity walking (30-min), uninterrupted sitting (6.5-h); EX+BR: sitting (1-h), moderate-intensity walking (30-&#x2009;min), sitting interrupted every 30-min with 3-min of light-intensity walking (6.5&#x2009;h). Participants consumed standardized breakfast and lunch meals and blood was sampled at 13 time-points. RESULTS: When compared to SIT, EX+SIT increased total area under the curve (tAUC) for glucose by 2% [0.1-4.1%] and EX+BR by 3% [0.6-4.7%] (all p&#x2009;&lt;&#x2009;0.05). Compared to SIT, EX+SIT reduced insulin and insulin:glucose ratio tAUC by 18% [11-22%] and 21% [8-33%], respectively; and EX+BR reduced values by 25% [19-31%] and 28% [15-38%], respectively (all p&#x2009;&lt;&#x2009;0.001 vs SIT, all p&#x2009;&lt;&#x2009;0.05 EX+SIT-vs-EX+BR). Compared to SIT, EX+BR reduced triglyceride tAUC by 6% [1-10%] (p&#x2009;=&#x2009;0.01 vs SIT), and compared to EX+SIT, EX+BR reduced this value by 5% [0.1-8.8%] (p&#x2009;=&#x2009;0.047 vs EX+SIT). The magnitude of reduction in insulin tAUC from SIT-to-EX+BR was greater in those with increased basal insulin resistance. No reduction in triglyceride tAUC from SIT-to-EX+BR was apparent in those with high fasting triglycerides. CONCLUSIONS: Additional reductions in postprandial insulin-glucose dynamics and triglycerides may be achieved by combining exercise with breaks in sitting. Relative to uninter","evidenceGrade":"full_text"},{"id":"p-pmid-31310990","title":"Effect of Breaks in Prolonged Sitting or Low-Volume High-Intensity Interval Exercise on Markers of Metabolic Syndrome in Adults With Excess Body Fat: A Crossover Trial.","authors":["YA Freire","GAD Mac&#xea;do","RAV Browne","LF Farias-Junior","&#xc1;DL Bezerra","APT Fayh","JC Farias J&#xfa;nior","KF Boreskie"],"year":2020,"venue":"Journal of physical activity &amp; health","doi":"10.1123/jpah.2018-0492","pmid":"31310990","url":"https://pubmed.ncbi.nlm.nih.gov/31310990/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: This study analyzed the effect of walking breaks or low-volume high-intensity interval exercise (LV-HIIE) on markers of metabolic syndrome relative to a day of prolonged sitting. METHODS: Twenty-five adults with excess body fat participated in this crossover trial: (1)&#xa0;10-hour sitting day (SIT), (2)&#xa0;LV-HIIE followed by a sitting day (EX+SIT), and (3)&#xa0;sitting day with 5-minute walking breaks for every 20 minutes (SIT+WB). Glucose and blood pressure (BP) were measured before and 1&#xa0;hour after 4 meals and 2 hours after lunch. Triglycerides were measured at baseline, 2, and 3.5 hours after lunch. Generalized mixed models were used to identify differences in the area under the curve (AUC) of BP and incremental AUC (iAUC) of glucose and triglycerides among the sessions. RESULTS: iAUC-glucose was lower in SIT+WB than SIT (&#x3b2; = -35.3&#xa0;mg/dL&#xb7;10&#xa0;h; 95% confidence interval, -52.5 to -8.2). AUC-diastolic BP was lower in SIT+WB than SIT (&#x3b2; = -14.1&#xa0;mm Hg&#xb7;10&#xa0;h; 95% confidence interval, -26.5 to -1.6) and EX+SIT (&#x3b2; = -14.5&#xa0;mm&#xa0;Hg&#xb7;10&#xa0;h; 95% confidence interval, -26.9 to -2.1). There were no differences in triglycerides and systolic BP levels among the sessions. CONCLUSION: Adults with excess body fat present lower glucose and diastolic BP during a day with breaks in sitting time compared with a prolonged sitting day with or without an LV-HIIE session.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39506625","title":"Effect of Interrupting Prolonged Sitting with Frequent Activity Breaks on Postprandial Glycemia and Insulin Sensitivity in Adults with Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion Therapy: A Randomized Crossover Pilot Trial.","authors":["R Larsen","F Taylor","PC Dempsey","M McNarry","K Rickards","P Sethi","A Homer","N Cohen"],"year":2025,"venue":"Diabetes technology &amp; therapeutics","doi":"10.1089/dia.2024.0146","pmid":"39506625","url":"https://pubmed.ncbi.nlm.nih.gov/39506625/","methodology":"rct","n":null,"openAccess":false,"abstract":"Objective: This study examined acute effects of interrupting prolonged sitting with short activity breaks on postprandial glucose/insulin responses and estimations of insulin sensitivity in adults with type 1 diabetes (T1D). Method: In a randomized crossover trial, eight adults (age = 46 &#xb1; 14 years [mean &#xb1; SD], body mass index [BMI] = 27.2&#x2009;&#xb1;&#x2009;3.8 kg/m2) receiving continuous subcutaneous insulin infusion (CSII) therapy completed two 6-h conditions as follows: uninterrupted sitting (SIT) and sitting interrupted with 3-min bouts of simple resistance activities (SRAs) every 30 min. Basal and bolus insulin were standardized across conditions except in cases of hypoglycemia. Postprandial responses were assessed using incremental area-under-the-curve (iAUC) and total AUC (tAUC) from half-hourly venous sampling. Meal-based insulin sensitivity determined from glucose sensor and insulin pump (SiSP) was assessed from flash continuous glucose monitor and insulin pump data. Outcomes were analyzed using mixed models adjusted for sex, BMI, treatment order, and preprandial values. Results: Glucose iAUC did not differ by condition (SIT: 19.8&#x2009;&#xb1;&#x2009;3.0 [estimated marginal means &#xb1; standard error] vs. SRA: 14.4&#x2009;&#xb1;&#x2009;3.0 mmol.6 h.L-1; P = 0.086). Despite CSII being standardized between conditions, insulin iAUC was higher in SRA compared to SIT (137.1&#x2009;&#xb1;&#x2009;22.7 vs. 170.9&#x2009;&#xb1;&#x2009;22.7 mU.6 h.L-1; P &lt; 0.001). This resulted in a lower glucose response relative to the change in plasma insulin in SRA (tAUCglu/tAUCins: 0.32&#x2009;&#xb1;&#x2009;0.02 vs. 0.40&#x2009;&#xb1;&#x2009;0.02 mmol.mU-1; P = 0.03). SiSP was also higher at dinner following the SRA condition, with no between-condition differences at breakfast or lunch. Conclusion: Regularly interrupting prolonged sitting in T1D may increase plasma insulin and improve insulin sensitivity when meals and CSII are standardized. Future studies shoul","evidenceGrade":"abstract_only"},{"id":"p-pmid-11939866","title":"Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial.","authors":["JR Davidson","KM Gadde","JA Fairbank","KRR Krishnan","RM Califf","C Binanay","CB Parker","N Pugh"],"year":2002,"venue":"JAMA","doi":null,"pmid":"11939866","url":"https://pubmed.ncbi.nlm.nih.gov/11939866/","methodology":"rct","n":null,"openAccess":false,"abstract":"CONTEXT: Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. OBJECTIVE: To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. DESIGN AND SETTING: Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. PARTICIPANTS: Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. INTERVENTIONS: Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. MAIN OUTCOME MEASURES: Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. RESULTS: On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this ","evidenceGrade":"abstract_only"},{"id":"p-pmid-16612487","title":"Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression: a randomized double-blind trial in a Brazilian sample.","authors":["RA Moreno","CT Teng","KM Almeida","H Tavares Junior"],"year":2006,"venue":"Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)","doi":null,"pmid":"16612487","url":"https://pubmed.ncbi.nlm.nih.gov/16612487/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: Hypericum perforatum has demonstrated antidepressant efficacy when compared to placebo, but comparisons with other antidepressants remain controversial. We assessed the efficacy and safety of Hypericum perforatum in comparison with fluoxetine, in a 8-week double-blind trial in patients with mild to moderate depression. METHOD: Seventy-two outpatients were randomly assigned to receive Hypericum perforatum 900 mg/day, fluoxetine 20 mg/day or placebo. Efficacy measures included the HAM-D21 scale, the Montgomery-Asberg Rating Scale, and the Clinical Global Impression. Safety was assessed with the UKU Side Effect Rating Scale. RESULTS: Intention-to-treat analysis showed no differences between the mean scores of the three groups. In the analyses of observed cases, patients receiving Hypericum perforatum had the lowest remission rates (12%, p = 0.016) compared to fluoxetine (34.6%) and placebo (45%). CONCLUSIONS: Hypericum perforatum was less efficacious than both fluoxetine and placebo. Both drugs were safe and well-tolerated. Larger trials are needed for definite conclusions.","evidenceGrade":"abstract_only"},{"id":"p-lim-dinges-2010","title":"A meta-analysis of the impact of short-term sleep deprivation on cognitive variables","authors":["J. Lim","D. F. Dinges"],"year":2010,"venue":"Psychological Bulletin","doi":"10.1037/a0018883","pmid":"20804237","url":"https://pubmed.ncbi.nlm.nih.gov/20804237/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"Short-term sleep deprivation reliably degrades attention and working memory across named tasks. Hours of sleep are a cognitive intervention. A nootropic stack is not a substitute for this paper.","evidenceGrade":"abstract_only"},{"id":"p-pmid-38233280","title":"The effects of insufficient sleep and adequate sleep on cognitive function in healthy adults.","authors":["ME Zimmerman","G Benasi","C Hale","LK Yeung","J Cochran","AM Brickman","MP St-Onge"],"year":2024,"venue":"Sleep health","doi":"10.1016/j.sleh.2023.11.011","pmid":"38233280","url":"https://pubmed.ncbi.nlm.nih.gov/38233280/","methodology":"rct","n":null,"openAccess":true,"abstract":"STUDY OBJECTIVES: Although sleep affects a range of waking behaviors, the majority of studies have focused on sleep loss with relatively little attention on sustained periods of adequate sleep. The goal of this study was to use an experimental design to examine the effect of both of these sleep patterns on cognitive performance in healthy adults. METHODS: This study used a randomized crossover design. Participants who regularly slept 7-9&#xa0;hours/night completed two 6-week intervention conditions, adequate sleep (maintenance of habitual bed/wake times) and insufficient sleep (reduction in sleep of 1.5&#xa0;hours relative to adequate sleep), separated by a 2-6weeks (median=43days) washout period. Cognitive functioning was evaluated at baseline and endpoint of each intervention using the NIH Toolbox Cognition Battery. General linear models contrasted scores following each condition to the baseline of the first condition; the baseline of the second condition was included to evaluate practice effects. RESULTS: Sixty-five participants (age 35.9&#xa0;&#xb1;&#xa0;4.9years, 89% women, 52% non-White race/ethnicity) completed study procedures. There was improvement in performance on the List Sorting Working Memory task after the adequate sleep condition that exceeded practice effects. Cognitive performance after insufficient sleep did not reach the level expected with practice and did not differ from baseline. A similar pattern was found on the Flanker Inhibitory Control and Attention task. CONCLUSIONS: These findings contribute to our understanding of the complex interplay between sleep and cognition and demonstrate that consistent, stable sleep of at least 7&#xa0;hours/night improves working memory and response inhibition in healthy adults. CLINICAL TRIAL REGISTRATION: The manuscript reports on data from two clinical trials: Impact of Sleep Restriction on Performance in Adults (URL: https://clinicaltrials.gov/ct2/show/NCT02960776, ID Number: NCT02960776) and Impact of Sle","evidenceGrade":"full_text"},{"id":"p-pmid-30670158","title":"Cumulative mild partial sleep deprivation negatively impacts working memory capacity but not sustained attention, response inhibition, or decision making: a randomized controlled trial.","authors":["JA Santisteban","TG Brown","MC Ouimet","R Gruber"],"year":2019,"venue":"Sleep health","doi":"10.1016/j.sleh.2018.09.007","pmid":"30670158","url":"https://pubmed.ncbi.nlm.nih.gov/30670158/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Twenty-eight per cent (28%) of adults sleep at least 1&#x202f;hour less than they consider optimal, yet the effects of such cumulative mild partial sleep deprivation on cognitive functions are unknown. The objective of this study was to examine how cumulative mild partial sleep deprivation over 6 nights can impact working memory, sustained attention, response inhibition, and decision making. METHODS: A double-blind placebo-controlled randomized study was conducted to determine the impact of sleep restriction (elimination of 1&#x202f;hour of sleep relative to the baseline habitual sleep duration) vs placebo (exposure to a lamp with no known therapeutic effect) on cognitive performance. The primary outcomes were performance on tasks that measure working memory, sustained attention, response inhibition, and decision making. The participants consisted of 93 adults (mean age 24.3&#x202f;years, SD 4.7; 46 men, 47 women) with no reported sleep problem, behavioral issue, or medical issue. RESULTS: Performance on the working memory capacity task improved between the baseline and experimental sessions for the placebo group but not the sleep-restriction group. Performance on tasks measuring sustained attention, response inhibition, and decision making did not change under either experimental condition. CONCLUSION: Cumulative partial sleep deprivation negatively affects performance on a test of working memory capacity but does not affect performance on tests of sustained attention, response inhibition, or decision making.","evidenceGrade":"abstract_only"},{"id":"p-pmid-26612392","title":"Cognitive Performance, Sleepiness, and Mood in Partially Sleep Deprived Adolescents: The Need for Sleep Study.","authors":["JC Lo","JL Ong","RL Leong","JJ Gooley","MW Chee"],"year":2016,"venue":"Sleep","doi":"10.5665/sleep.5552","pmid":"26612392","url":"https://pubmed.ncbi.nlm.nih.gov/26612392/","methodology":"rct","n":null,"openAccess":true,"abstract":"STUDY OBJECTIVES: To investigate the effects of sleep restriction (7 nights of 5 h time in bed [TIB]) on cognitive performance, subjective sleepiness, and mood in adolescents. METHODS: A parallel-group design was adopted in the Need for Sleep Study. Fifty-six healthy adolescents (25 males, age = 15-19 y) who studied in top high schools and were not habitual short sleepers were randomly assigned to Sleep Restriction (SR) or Control groups. Participants underwent a 2-w protocol consisting of 3 baseline nights (TIB = 9 h), 7 nights of sleep opportunity manipulation (TIB = 5 h for the SR and 9 h for the control groups), and 3 nights of recovery sleep (TIB = 9 h) at a boarding school. A cognitive test battery was administered three times each day. RESULTS: During the manipulation period, the SR group demonstrated incremental deterioration in sustained attention, working memory and executive function, increase in subjective sleepiness, and decrease in positive mood. Subjective sleepiness and sustained attention did not return to baseline levels even after 2 recovery nights. In contrast, the control group maintained baseline levels of cognitive performance, subjective sleepiness, and mood throughout the study. Incremental improvement in speed of processing, as a result of repeated testing and learning, was observed in the control group but was attenuated in the sleep-restricted participants, who, despite two recovery sleep episodes, continued to perform worse than the control participants. CONCLUSIONS: A week of partial sleep deprivation impairs a wide range of cognitive functions, subjective alertness, and mood even in high-performing high school adolescents. Some measures do not recover fully even after 2 nights of recovery sleep. COMMENTARY: A commentary on this article appears in this issue on page 497.","evidenceGrade":"full_text"},{"id":"p-pmid-22198375","title":"The impact of increasing sleep restriction on cortisol and daytime sleepiness in adolescents.","authors":["U Voderholzer","H Piosczyk","J Holz","B Feige","B Loessl","M Kopasz","D Riemann","C Nissen"],"year":2012,"venue":"Neuroscience letters","doi":"10.1016/j.neulet.2011.12.014","pmid":"22198375","url":"https://pubmed.ncbi.nlm.nih.gov/22198375/","methodology":"rct","n":null,"openAccess":false,"abstract":"Sleep restriction is a widespread phenomenon, specifically in adolescents. This study investigated the impact of increasing sleep restriction in adolescents on cortisol levels and daytime sleepiness. Eighty-eight healthy adolescents were randomized to five sleep restriction protocols (four consecutive nights with 9, 8, 7, 6, or 5 h time in bed). Polysomnography (baseline and last experimental night) and multiple sleep latency test (day 6) data were obtained. Saliva cortisol levels were assessed half-hourly in the evening before and in the morning after the baseline and the last experimental night. Four nights of sleep restriction in healthy adolescents lead to a linear increase of objective sleepiness, but had no significant effect on evening or morning cortisol levels. The lack of detrimental effects of sleep restriction on cortisol levels might be due to compensation mechanisms during sleep.","evidenceGrade":"abstract_only"},{"id":"p-pmid-38286128","title":"Psychological Treatment of Comorbid Insomnia and Depression: A Double-Blind Randomized Placebo-Controlled Trial.","authors":["K Blom","E Forsell","M Hellberg","C Svanborg","S Jernel&#xf6;v","V Kaldo"],"year":2024,"venue":"Psychotherapy and psychosomatics","doi":"10.1159/000536063","pmid":"38286128","url":"https://pubmed.ncbi.nlm.nih.gov/38286128/","methodology":"rct","n":null,"openAccess":true,"abstract":"INTRODUCTION: Insomnia and depression are highly prevalent disorders and commonly occur together. Cognitive behavioral therapy for insomnia, CBT-I, has been shown to be effective in treating insomnia and also comorbid depression. However, it is unclear whether effects of CBT-I on depression are specific or nonspecific. Also, depressive symptoms often remain too high after CBT-I, indicating a need for improved treatments. The objective was to determine whether combining CBT-I with CBT for depression, without increasing treatment length, reduces both insomnia and depression more than CBT for depression with a placebo insomnia intervention. METHODS: A 12-week double-blind randomized controlled trial with a 6-month follow-up in a psychiatric setting using therapist-guided internet-delivered treatments was conducted. Patients (N = 126) were diagnosed with insomnia disorder and major depression by physicians. Primary outcome measures were as follows: self-rating scales Insomnia Severity Index (ISI) and Montgomery-&#xc5;sberg Depression Rating Scale (MADRS-S). RESULTS: The combined treatment showed specific effects on insomnia severity over the control treatment (p = 0.007) but was not more effective in reducing depression severity. Within-group effects (Cohen's d) at post and at 6 months were as follows: ISI 1.40 and 1.42 (combined treatment), 0.95 and 1.00 (control); MADRS-S 0.97 and 1.12 (combined), 0.88 and 0.89 (control). CONCLUSIONS: CBT-I shows large specific effects on insomnia severity and is superior to control in this regard. Both treatments had similar effects on depression severity, i.e., combining CBT-I with CBT for depression did not enhance outcomes on depression compared to control. We suggest CBT-I should always be offered to patients with insomnia and depression comorbidity, possibly as the first-hand choice. Combining it with a psychological treatment for depression could be too burdening and may not be beneficial.","evidenceGrade":"full_text"},{"id":"p-pmid-28199710","title":"Cognitive Behavioral Insomnia Therapy for Those With Insomnia and Depression: A Randomized Controlled Clinical Trial.","authors":["CE Carney","JD Edinger","M Kuchibhatla","AM Lachowski","O Bogouslavsky","AD Krystal","CM Shapiro"],"year":2017,"venue":"Sleep","doi":"10.1093/sleep/zsx019","pmid":"28199710","url":"https://pubmed.ncbi.nlm.nih.gov/28199710/","methodology":"rct","n":null,"openAccess":true,"abstract":"STUDY OBJECTIVE: To compare cognitive behavioral therapy for insomnia (CBT-I) + antidepressant medication (AD) against treatments that target solely depression or solely insomnia. DESIGN: A blinded, randomized split-plot experimental study. SETTING: Two urban academic clinical centers. PARTICIPANTS: 107 participants (68% female, mean age 42 &#xb1; 11) with major depressive disorder and insomnia. INTERVENTIONS: Randomization was to one of three groups: antidepressant (AD; escitalopram) + CBT-I (4 sessions), CBT-I + placebo pill, or AD + 4-session sleep hygiene control (SH). MEASUREMENTS AND RESULTS: Subjective sleep was assessed via 2 weeks of daily sleep diaries (use of medication was covaried in all analyses); although there were no statistically significant group differences detected, all groups improved from baseline to posttreatment on subjective sleep efficiency (SE) and total wake time (TWT) and the effect sizes were large. Objective sleep was assessed via overnight polysomnographic monitoring at baseline and posttreatment; analyses revealed both CBT groups improved on TWT (p = .03), but the AD + SH group worsened. There was no statistically significant effect for PSG SE (p = .07). There was a between groups medium effect observed for the AD + SH and CBT + placebo group differences on diary TWT and both PSG variables. All groups improved significantly from baseline to posttreatment on the Hamilton Rating Scale for Depression (HAMD-17); the groups did not differ. CONCLUSIONS: Although all groups self-reported sleeping better after treatment, only the CBT-I groups improved on objective sleep, and AD + SH's sleep worsened. This suggests that we should be treating sleep in those with depression with an effective insomnia treatment and relying on self-report obscures sleep worsening effects. All groups improved on depression, even a group with absolutely no depression-focused treatment component (CBT-I + placebo). The depression effect in CBT-I only group has been ","evidenceGrade":"full_text"},{"id":"p-pmid-19567526","title":"Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance.","authors":["AV Nedeltcheva","L Kessler","J Imperial","PD Penev"],"year":2009,"venue":"The Journal of clinical endocrinology and metabolism","doi":"10.1210/jc.2009-0483","pmid":"19567526","url":"https://pubmed.ncbi.nlm.nih.gov/19567526/","methodology":"rct","n":null,"openAccess":true,"abstract":"CONTEXT: Epidemiological data indicate that reduced sleep duration is associated with increased incidence of type-2 diabetes. OBJECTIVE: The aim of the study was to test the hypothesis that, when part of a Western-like lifestyle, recurrent bedtime restriction may result in decreased glucose tolerance and reduced insulin secretion and action. DESIGN AND SETTING: We conducted a randomized crossover study at a university clinical research center and sleep research laboratory. PARTICIPANTS: Eleven healthy volunteers (five females and six males) with a mean (+/-sd) age of 39 +/- 5 yr and body mass index of 26.5 +/- 1.5 kg/m(2) participated in the study. INTERVENTION: The study included two 14-d periods of controlled exposure to sedentary living with ad libitum food intake and 5.5- or 8.5-h bedtimes. MAIN OUTCOME MEASURES: Oral and iv glucose challenges were used to obtain measures of glucose tolerance, glucose effectiveness, insulin secretion, and insulin sensitivity at the end of each intervention. Secondary measures included circulating concentrations of the glucose counter-regulatory hormones, cortisol, GH, epinephrine, and norepinephrine. RESULTS: Bedtime restriction reduced daily sleep by 122 +/- 25 min. Both study periods were associated with comparable weight gain; however, recurrent sleep restriction resulted in reduced oral glucose tolerance (2-h glucose value, 144 +/- 25 vs. 132 +/- 36 mg/dl; P &lt; 0.01) and insulin sensitivity [3.3 +/- 1.1 vs. 4.0 +/- 1.6 (mU/liter)(-1) x min(-1); P &lt; 0.03], and increased glucose effectiveness (0.023 +/- 0.005 vs. 0.020 +/- 0.005 min(-1); P &lt; 0.04). Although 24-h cortisol and GH concentrations did not change, there was a modest increase in 24-h epinephrine and nighttime norepinephrine levels during the 5.5-h bedtime condition. CONCLUSIONS: Experimental bedtime restriction, designed to approximate the short sleep times experienced by many individuals in Westernized societies, may facilitate the development of insulin res","evidenceGrade":"full_text"},{"id":"p-pmid-20585000","title":"Sleep restriction for 1 week reduces insulin sensitivity in healthy men.","authors":["OM Buxton","M Pavlova","EW Reid","W Wang","DC Simonson","GK Adler"],"year":2010,"venue":"Diabetes","doi":"10.2337/db09-0699","pmid":"20585000","url":"https://pubmed.ncbi.nlm.nih.gov/20585000/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: Short sleep duration is associated with impaired glucose tolerance and an increased risk of diabetes. The effects of sleep restriction on insulin sensitivity have not been established. This study tests the hypothesis that decreasing nighttime sleep duration reduces insulin sensitivity and assesses the effects of a drug, modafinil, that increases alertness during wakefulness. RESEARCH DESIGN AND METHODS: This 12-day inpatient General Clinical Research Center study included 20 healthy men (age 20-35 years and BMI 20-30 kg/m(2)). Subjects spent 10 h/night in bed for &gt;or=8 nights including three inpatient nights (sleep-replete condition), followed by 5 h/night in bed for 7 nights (sleep-restricted condition). Subjects received 300 mg/day modafinil or placebo during sleep restriction. Diet and activity were controlled. On the last 2 days of each condition, we assessed glucose metabolism by intravenous glucose tolerance test (IVGTT) and euglycemic-hyperinsulinemic clamp. Salivary cortisol, 24-h urinary catecholamines, and neurobehavioral performance were measured. RESULTS: IVGTT-derived insulin sensitivity was reduced by (means +/- SD) 20 +/- 24% after sleep restriction (P = 0.001), without significant alterations in the insulin secretory response. Similarly, insulin sensitivity assessed by clamp was reduced by 11 +/- 5.5% (P &lt; 0.04) after sleep restriction. Glucose tolerance and the disposition index were reduced by sleep restriction. These outcomes were not affected by modafinil treatment. Changes in insulin sensitivity did not correlate with changes in salivary cortisol (increase of 51 +/- 8% with sleep restriction, P &lt; 0.02), urinary catecholamines, or slow wave sleep. CONCLUSIONS: Sleep restriction (5 h/night) for 1 week significantly reduces insulin sensitivity, raising concerns about effects of chronic insufficient sleep on disease processes associated with insulin resistance.","evidenceGrade":"full_text"},{"id":"p-pmid-22513492","title":"Effects of sleep restriction on glucose control and insulin secretion during diet-induced weight loss.","authors":["AV Nedeltcheva","JG Imperial","PD Penev"],"year":2012,"venue":"Obesity (Silver Spring, Md.)","doi":"10.1038/oby.2012.97","pmid":"22513492","url":"https://pubmed.ncbi.nlm.nih.gov/22513492/","methodology":"observational","n":null,"openAccess":true,"abstract":"Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-h blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean (s.d.) age 41 (5) years; BMI 27.4 (2.0) kg/m(2)) completed two 14-day treatments with hypocaloric diet and 8.5- or 5.5-h nighttime sleep opportunity in random order 7 (3) months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free fatty acids (FFA), 24-h blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 (0.3) BMI units) during each treatment. Bedtime restriction reduced sleep by 131 (30) min/day. Recurrent sleep curtailment decreased 24-h serum insulin concentrations (i.e., enhanced 24-h insulin economy) without changes in oral glucose tolerance and 24-h glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA, which suppressed normally following glucose ingestion, and lower total and low-density lipoprotein cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-h insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability.","evidenceGrade":"full_text"},{"id":"p-pmid-23070488","title":"Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study.","authors":["JL Broussard","DA Ehrmann","E Van Cauter","E Tasali","MJ Brady"],"year":2013,"venue":"Annals of internal medicine","doi":"10.7326/0003-4819-157-8-201210160-00005","pmid":"23070488","url":"https://pubmed.ncbi.nlm.nih.gov/23070488/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown. OBJECTIVE: To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance. DESIGN: Randomized, 2-period, 2-condition, crossover clinical study. SETTING: University of Chicago Clinical Resource Center. PARTICIPANTS: Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m(2) (SD, 1.6). INTERVENTION: Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity. MEASUREMENTS: Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt-tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test. RESULTS: The insulin concentration for the half-maximal pAkt-tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt-tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity","evidenceGrade":"full_text"},{"id":"p-pmid-25658017","title":"Subchronic sleep restriction causes tissue-specific insulin resistance.","authors":["MN Rao","TC Neylan","C Grunfeld","K Mulligan","M Schambelan","JM Schwarz"],"year":2015,"venue":"The Journal of clinical endocrinology and metabolism","doi":"10.1210/jc.2014-3911","pmid":"25658017","url":"https://pubmed.ncbi.nlm.nih.gov/25658017/","methodology":"rct","n":null,"openAccess":true,"abstract":"CONTEXT: Short sleep duration is associated with an increased risk of type 2 diabetes. Subchronic sleep restriction (SR) causes insulin resistance, but the mechanisms and roles of specific tissues are unclear. OBJECTIVE: The purpose of this article was to determine whether subchronic SR altered (1) hepatic insulin sensitivity, (2) peripheral insulin sensitivity, and (3) substrate utilization. DESIGN: This was a randomized crossover study in which 14 subjects underwent 2 admissions separated by a washout period. Each admission had 2 acclimatization nights followed by 5 nights of either SR (4 hours time in bed) or normal sleep (8 hours time in bed). MAIN OUTCOME MEASURE/METHODS: Insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp) and hepatic insulin sensitivity (measured by stable isotope techniques) were measured. In addition, we assayed stress hormone (24-hour urine free cortisol, metanephrine, and normetanephrine), nonesterified fatty acid (NEFA), and &#x3b2;-hydroxybutyrate (&#x3b2;-OH butyrate) levels. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured by indirect calorimetry. RESULTS: Compared to normal sleep, whole-body insulin sensitivity decreased by 25% (P = .008) with SR and peripheral insulin sensitivity decreased by 29% (P = .003). Whereas hepatic insulin sensitivity (endogenous glucose production) did not change significantly, percent gluconeogenesis increased (P = .03). Stress hormones increased modestly (cortisol by 21%, P = .04; metanephrine by 8%, P = .014; normetanephrine by 18%, P = .002). Fasting NEFA and &#x3b2;-OH butyrate levels increased substantially (62% and 55%, respectively). REE did not change (P = 0.98), but RQ decreased (0.81 &#xb1; .02 vs 0.75 &#xb1; 0.02, P = .045). CONCLUSION: Subchronic SR causes unique metabolic disturbances characterized by peripheral, but not hepatic, insulin resistance; this was associated with a robust increase in fasting NEFA levels (indicative of increased lipolysis),","evidenceGrade":"full_text"},{"id":"p-pmid-30615104","title":"Impact of sleep restriction on metabolic outcomes induced by overfeeding: a randomized controlled trial in healthy individuals.","authors":["J Cros","E Pianezzi","R Rosset","L Egli","P Schneiter","F Cornette","B Pouymayou","R Heinzer"],"year":2019,"venue":"The American journal of clinical nutrition","doi":"10.1093/ajcn/nqy215","pmid":"30615104","url":"https://pubmed.ncbi.nlm.nih.gov/30615104/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Overconsumption of energy-dense foods and sleep restriction are both associated with the development of metabolic and cardiovascular diseases, but their combined effects remain poorly evaluated. OBJECTIVE: The aim of this study was to assess whether sleep restriction potentiates the effects of a short-term overfeeding on intrahepatocellular lipid (IHCL) concentrations and on glucose homeostasis. DESIGN: Ten healthy subjects were exposed to a 6-d overfeeding period (130% daily energy needs, with 15% extra energy as sucrose and 15% as fat), with normal sleep (8 h sleep opportunity time) or sleep restriction (4 h sleep opportunity time), according to a randomized, crossover design. At baseline and after intervention, IHCL concentrations were measured by proton magnetic resonance spectroscopy, and a dual intravenous [6,6-2H2]-, oral 13C-labeled glucose tolerance test and a polysomnographic recording were&#xa0;performed. RESULTS: Overfeeding significantly increased IHCL concentrations (Poverfeeding&#xa0;&lt;&#xa0;0.001; overfeeding&#xa0;+&#xa0;normal sleep: +53%&#xa0;&#xb1;&#xa0;16%). During the oral glucose tolerance test, overfeeding significantly increased endogenous glucose production (Poverfeeding&#xa0;=&#xa0;0.034) and the oxidation of 13C-labeled glucose load (Poverfeeding&#xa0;=&#xa0;0.038). Sleep restriction significantly decreased total sleep time, and the duration of stages 1 and 2 and rapid eye movement sleep (all P&#xa0;&lt;&#xa0;0.001), whereas slow-wave sleep duration was preserved (Poverfeeding &#xd7; sleep&#xa0;=&#xa0;0.809). Compared with overfeeding, overfeeding&#xa0;+&#xa0;sleep restriction did not change IHCL concentrations (Poverfeeding &#xd7; sleep&#xa0;=&#xa0;0.541; +83%&#xa0;&#xb1;&#xa0;33%), endogenous glucose production (Poverfeeding &#xd7; sleep&#xa0;=&#xa0;0.567), or exogenous glucose oxidation (Poverfeeding &#xd7; sleep&#xa0;=&#xa0;0.118). Sleep restriction did not significantly alter blood pressure, heart rate, or plasma cortiso","evidenceGrade":"abstract_only"},{"id":"p-pmid-36998155","title":"Effect of sleep restriction on insulin sensitivity and energy metabolism in postmenopausal women: A randomized crossover trial.","authors":["P Singh","RA Beyl","JM Stephens","RC Noland","AJ Richard","A Boudreau","RC Hebert","E Ravussin"],"year":2023,"venue":"Obesity (Silver Spring, Md.)","doi":"10.1002/oby.23739","pmid":"36998155","url":"https://pubmed.ncbi.nlm.nih.gov/36998155/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: The aim of this study was to investigate the effect of sleep restriction (SR) on insulin sensitivity and energy metabolism in postmenopausal women. METHODS: In a randomized crossover trial, 14 women underwent four nights of habitual sleep (HS, 100% normal sleep) and SR (60% of HS) while following a eucaloric diet. Outcomes included the following: (1) insulin sensitivity by hyperinsulinemic-euglycemic clamp, defined as the glucose infusion rate (GIR); (2) resting metabolism and substrate oxidation by indirect calorimetry; and (3) glucose, insulin, and C-peptide concentrations following a standard meal test. RESULTS: Nine postmenopausal women (mean [SD], age 59&#x2009;[4]&#x2009;years, BMI 28.0&#x2009;&#x2009;[2.6]&#xa0;kg/m2 ) were analyzed. Accelerometer-determined total time in bed was 8.4&#xa0;&#xb1;&#x2009;0.6&#xa0;hours during HS versus 5.0&#x2009;&#xb1;&#x2009;0.4&#xa0;hours during SR (38% reduction, p&#x2009;&lt;&#x2009;0.0001). SR reduced low-dose insulin GIR by 20% (HS: 2.55&#x2009;&#xb1;&#x2009;0.22 vs. SR: 2.03&#x2009;&#xb1;&#x2009;0.20&#x2009;mg/kg/min; p&#xa0;=&#xa0;0.01) and high-dose insulin GIR by 12% (HS: 10.48&#x2009;&#xb1;&#x2009;0.72 vs. SR: 9.19&#x2009;&#xb1;&#x2009;0.72&#x2009;mg/kg/min; p&#x2009;&lt;&#x2009;0.001). SR reduced fat oxidation during high-dose insulin infusion (p&#x2009;&lt;&#x2009;0.01), and it did not alter resting energy metabolism. CONCLUSIONS: Four nights of SR reduced insulin sensitivity and fat oxidation in postmenopausal women. These findings underscore the role of insufficient sleep in metabolic dysfunction following menopause. Larger trials investigating how sleep disturbances cause metabolic dysfunction during menopause are needed across all stages of menopause.","evidenceGrade":"full_text"},{"id":"p-pmid-37955852","title":"Chronic Insufficient Sleep in Women Impairs Insulin Sensitivity Independent of Adiposity Changes: Results of a Randomized Trial.","authors":["FM Zuraikat","B Laferr&#xe8;re","B Cheng","SE Scaccia","Z Cui","B Aggarwal","S Jelic","MP St-Onge"],"year":2023,"venue":"Diabetes care","doi":"10.2337/dc23-1156","pmid":"37955852","url":"https://pubmed.ncbi.nlm.nih.gov/37955852/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVE: Insufficient sleep is associated with type 2 diabetes, yet the causal impact of chronic insufficient sleep on glucose metabolism in women is unknown. We investigated whether prolonged mild sleep restriction (SR), resembling real-world short sleep, impairs glucose metabolism in women. RESEARCH DESIGN AND METHODS: Women (aged 20-75 years) without cardiometabolic diseases and with actigraphy-confirmed habitual total sleep time (TST) of 7-9 h/night were recruited to participate in this randomized, crossover study with two 6-week phases: maintenance of adequate sleep (AS) and 1.5 h/night SR. Outcomes included plasma glucose and insulin levels, HOMA of insulin resistance (HOMA-IR) values based on fasting blood samples, as well as total area under the curve for glucose and insulin, the Matsuda index, and the disposition index from an oral glucose tolerance test. RESULTS: Our sample included 38 women (n = 11 postmenopausal women). Values are reported with &#xb1;SEM. Linear models adjusted for baseline outcome values demonstrated that TST was reduced by 1.34 &#xb1; 0.04 h/night with SR versus AS (P &lt; 0.0001). Fasting insulin (&#x3b2; = 6.8 &#xb1; 2.8 pmol/L; P = 0.016) and HOMA-IR (&#x3b2; = 0.30 &#xb1; 0.12; P = 0.016) values were increased with SR versus AS, with effects on HOMA-IR more pronounced in postmenopausal women compared with premenopausal women (&#x3b2; = 0.45 &#xb1; 0.25 vs. &#x3b2; = 0.27 &#xb1; 0.13, respectively; P for interaction = 0.042). Change in adiposity did not mediate the effects of SR on glucose metabolism or change results in the full sample when included as a covariate. CONCLUSIONS: Curtailing sleep duration to 6.2 h/night, reflecting the median sleep duration of U.S. adults with short sleep, for 6 weeks impairs insulin sensitivity, independent of adiposity. Findings highlight insufficient sleep as a modifiable risk factor for insulin resistance in women to be targeted in diabetes prevention efforts.","evidenceGrade":"full_text"},{"id":"p-pmid-22496545","title":"Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption.","authors":["OM Buxton","SW Cain","SP O'Connor","JH Porter","JF Duffy","W Wang","CA Czeisler","SA Shea"],"year":2012,"venue":"Science translational medicine","doi":"10.1126/scitranslmed.3003200","pmid":"22496545","url":"https://pubmed.ncbi.nlm.nih.gov/22496545/","methodology":"observational","n":null,"openAccess":true,"abstract":"Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent &gt;5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour \"days\"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.","evidenceGrade":"full_text"},{"id":"p-pmid-30892916","title":"Two nights of recovery sleep restores the dynamic lipemic response, but not the reduction of insulin sensitivity, induced by five nights of sleep restriction.","authors":["KM Ness","SM Strayer","NG Nahmod","AM Chang","OM Buxton","GC Shearer"],"year":2020,"venue":"American journal of physiology. Regulatory, integrative and comparative physiology","doi":"10.1152/ajpregu.00336.2018","pmid":"30892916","url":"https://pubmed.ncbi.nlm.nih.gov/30892916/","methodology":"observational","n":null,"openAccess":true,"abstract":"Chronic inadequate sleep is associated with increased risk of cardiometabolic diseases. The mechanisms involved are poorly understood but involve changes in insulin sensitivity, including within adipose tissue. The aim of this study was to assess the effects of sleep restriction on nonesterified fatty acid (NEFA) suppression profiles in response to an intravenous glucose tolerance test (IVGTT) and to assess whether 2 nights of recovery sleep (a \"weekend\") is sufficient to restore metabolic health. We hypothesized that sleep restriction impairs both glucose and lipid metabolism, specifically adipocyte insulin sensitivity, and the dynamic lipemic response of adipocyte NEFA release during an IVGTT. Fifteen healthy men completed an inpatient study of 3 baseline nights (10 h of time in bed/night), followed by 5 nights of 5 h of time in bed/night and 2 recovery nights (10 h of time in bed/night). IVGTTs were performed on the final day of each condition. Reductions in insulin sensitivity without a compensatory change in acute insulin response to glucose were consistent with prior studies (insulin sensitivity P = 0.002; acute insulin response to glucose P = 0.23). The disposition index was suppressed by sleep restriction and did not recover after recovery sleep (P &lt; 0.0001 and P = 0.01, respectively). Fasting NEFAs were not different from baseline in either the restriction or recovery conditions. NEFA rebound was significantly suppressed by sleep restriction (P = 0.01) but returned to baseline values after recovery sleep. Our study indicates that sleep restriction impacts NEFA metabolism and demonstrates that 2 nights of recovery sleep may not be adequate to restore glycemic health.","evidenceGrade":"full_text"},{"id":"p-pmid-28889101","title":"Relationship of Sleep Duration With All-Cause Mortality and Cardiovascular Events: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.","authors":["J Yin","X Jin","Z Shan","S Li","H Huang","P Li","X Peng","Z Peng"],"year":2018,"venue":"Journal of the American Heart Association","doi":"10.1161/JAHA.117.005947","pmid":"28889101","url":"https://pubmed.ncbi.nlm.nih.gov/28889101/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"BACKGROUND: Effects of extreme sleep duration on risk of mortality and cardiovascular outcomes remain controversial. We aimed to quantify the dose-response relationships of sleep duration with risk of all-cause mortality, total cardiovascular disease, coronary heart disease, and stroke. METHODS AND RESULTS: PubMed and Embase were systematically searched for prospective cohort studies published before December 1, 2016, that examined the associations between sleep duration and at least 1 of the 4 outcomes in generally healthy populations. U-shaped associations were indicated between sleep duration and risk of all outcomes, with the lowest risk observed for &#x2248;7-hour sleep duration per day, which was varied little by sex. For all-cause mortality, when sleep duration was &lt;7 hours per day, the pooled relative risk (RR) was 1.06 (95% CI, 1.04-1.07) per 1-hour reduction; when sleep duration was &gt;7 hours per day, the pooled RR was 1.13 (95% CI, 1.11-1.15) per 1-hour increment. For total cardiovascular disease, the pooled RR was 1.06 (95% CI, 1.03-1.08) per 1-hour reduction and 1.12 (95% CI, 1.08-1.16) per 1-hour increment of sleep duration. For coronary heart disease, the pooled RR was 1.07 (95% CI, 1.03-1.12) per 1-hour reduction and 1.05 (95% CI, 1.00-1.10) per 1-hour increment of sleep duration. For stroke, the pooled RR was 1.05 (95% CI, 1.01-1.09) per 1-hour reduction and 1.18 (95% CI, 1.14-1.21) per 1-hour increment of sleep duration. CONCLUSIONS: Our findings indicate that both short and long sleep duration is associated with an increased risk of all-cause mortality and cardiovascular events.","evidenceGrade":"full_text"},{"id":"p-pmid-27067616","title":"Sleep duration and risk of all-cause mortality: A flexible, non-linear, meta-regression of 40 prospective cohort studies.","authors":["TZ Liu","C Xu","M Rota","H Cai","C Zhang","MJ Shi","RX Yuan","H Weng"],"year":2018,"venue":"Sleep medicine reviews","doi":"10.1016/j.smrv.2016.02.005","pmid":"27067616","url":"https://pubmed.ncbi.nlm.nih.gov/27067616/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"Approximately 27-37% of the general population experience prolonged sleep duration and 12-16% report shortened sleep duration. However, prolonged or shortened sleep duration may be associated with serious health problems. A comprehensive, flexible, non-linear meta-regression with restricted cubic spline (RCS) was used to investigate the dose-response relationship between sleep duration and all-cause mortality in adults. Medline (Ovid), Embase, EBSCOhost-PsycINFO, and EBSCOhost-CINAHL Plus databases, reference lists of relevant review articles, and included studies were searched up to Nov. 29, 2015. Prospective cohort studies investigating the association between sleep duration and all-cause mortality in adults with at least three categories of sleep duration were eligible for inclusion. We eventually included in our study 40 cohort studies enrolling 2,200,425 participants with 271,507 deaths. A J-shaped association between sleep duration and all-cause mortality was present: compared with 7&#xa0;h of sleep (reference for 24-h sleep duration), both shortened and prolonged sleep durations were associated with increased risk of all-cause mortality (4&#xa0;h: relative risk [RR]&#xa0;=&#xa0;1.05; 95% confidence interval [CI]&#xa0;=&#xa0;1.02-1.07; 5&#xa0;h: RR&#xa0;=&#xa0;1.06; 95% CI&#xa0;=&#xa0;1.03-1.09; 6&#xa0;h: RR&#xa0;=&#xa0;1.04; 95% CI&#xa0;=&#xa0;1.03-1.06; 8&#xa0;h: RR&#xa0;=&#xa0;1.03; 95% CI&#xa0;=&#xa0;1.02-1.05; 9&#xa0;h: RR&#xa0;=&#xa0;1.13; 95% CI&#xa0;=&#xa0;1.10-1.16; 10&#xa0;h: RR&#xa0;=&#xa0;1.25; 95% CI&#xa0;=&#xa0;1.22-1.28; 11&#xa0;h: RR&#xa0;=&#xa0;1.38; 95% CI&#xa0;=&#xa0;1.33-1.44; n&#xa0;=&#xa0;29; P&#xa0;&lt;&#xa0;0.01 for non-linear test). With regard to the night-sleep duration, prolonged night-sleep duration was associated with increased all-cause mortality (8&#xa0;h: RR&#xa0;=&#xa0;1.01; 95% CI&#xa0;=&#xa0;0.99-1.02; 9&#xa0;h: RR&#xa0;=&#xa0;1.08; 95% CI&#xa0;=&#xa0;1.05-1.11; 10&#xa0;h: RR&#xa0;=&#xa0;1.24; 95% CI&#xa0;=&#xa0;1.21-1.28; n","evidenceGrade":"abstract_only"},{"id":"p-pmid-20469800","title":"Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies.","authors":["FP Cappuccio","L D'Elia","P Strazzullo","MA Miller"],"year":2010,"venue":"Sleep","doi":null,"pmid":"20469800","url":"https://pubmed.ncbi.nlm.nih.gov/20469800/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"BACKGROUND: Increasing evidence suggests an association between both short and long duration of habitual sleep with adverse health outcomes. OBJECTIVES: To assess whether the population longitudinal evidence supports the presence of a relationship between duration of sleep and all-cause mortality, to investigate both short and long sleep duration and to obtain an estimate of the risk. METHODS: We performed a systematic search of publications using MEDLINE (1966-2009), EMBASE (from 1980), the Cochrane Library, and manual searches without language restrictions. We included studies if they were prospective, had follow-up &gt;3 years, had duration of sleep at baseline, and all-cause mortality prospectively. We extracted relative risks (RR) and 95% confidence intervals (CI) and pooled them using a random effect model. We carried out sensitivity analyses and assessed heterogeneity and publication bias. RESULTS: Overall, the 16 studies analyzed provided 27 independent cohort samples. They included 1,382,999 male and female participants (followup range 4 to 25 years), and 112,566 deaths. Sleep duration was assessed by questionnaire and outcome through death certification. In the pooled analysis, short duration of sleep was associated with a greater risk of death (RR: 1.12; 95% CI 1.06 to 1.18; P &lt; 0.01) with no evidence of publication bias (P = 0.74) but heterogeneity between studies (P = 0.02). Long duration of sleep was also associated with a greater risk of death (1.30; [1.22 to 1.38]; P &lt; 0.0001) with no evidence of publication bias (P = 0.18) but significant heterogeneity between studies (P &lt; 0.0001). CONCLUSION: Both short and long duration of sleep are significant predictors of death in prospective population studies.","evidenceGrade":"full_text"},{"id":"p-pmid-37738616","title":"Sleep regularity is a stronger predictor of mortality risk than sleep duration: A prospective cohort study.","authors":["DP Windred","AC Burns","JM Lane","R Saxena","MK Rutter","SW Cain","AJK Phillips"],"year":2024,"venue":"Sleep","doi":"10.1093/sleep/zsad253","pmid":"37738616","url":"https://pubmed.ncbi.nlm.nih.gov/37738616/","methodology":"observational","n":null,"openAccess":true,"abstract":"Abnormally short and long sleep are associated with premature mortality, and achieving optimal sleep duration has been the focus of sleep health guidelines. Emerging research demonstrates that sleep regularity, the day-to-day consistency of sleep-wake timing, can be a stronger predictor for some health outcomes than sleep duration. The role of sleep regularity in mortality, however, has not been investigated in a large cohort with objective data. We therefore aimed to compare how sleep regularity and duration predicted risk for all-cause and cause-specific mortality. We calculated Sleep Regularity Index (SRI) scores from&#x2005;&gt;&#x2005;10 million hours of accelerometer data in 60 977 UK Biobank participants (62.8&#x2005;&#xb1;&#x2005;7.8 years, 55.0% female, median[IQR] SRI: 81.0[73.8-86.3]). Mortality was reported up to 7.8 years after accelerometer recording in 1859 participants (4.84 deaths per 1000 person-years, mean (&#xb1;SD) follow-up of 6.30&#x2005;&#xb1;&#x2005;0.83 years). Higher sleep regularity was associated with a 20%-48% lower risk of all-cause mortality (p&#x2005;&lt;&#x2005;.001 to p&#x2005;=&#x2005;0.004), a 16%-39% lower risk of cancer mortality (p&#x2005;&lt;&#x2005;0.001 to p&#x2005;=&#x2005;0.017), and a 22%-57% lower risk of cardiometabolic mortality (p&#x2005;&lt;&#x2005;0.001 to p&#x2005;=&#x2005;0.048), across the top four SRI quintiles compared to the least regular quintile. Results were adjusted for age, sex, ethnicity, and sociodemographic, lifestyle, and health factors. Sleep regularity was a stronger predictor of all-cause mortality than sleep duration, by comparing equivalent mortality models, and by comparing nested SRI-mortality models with and without sleep duration (p&#x2005;=&#x2005;0.14-0.20). These findings indicate that sleep regularity is an important predictor of mortality risk and is a stronger predictor than sleep duration. Sleep regularity may be a simple, effective target for improving general health and survival.","evidenceGrade":"full_text"},{"id":"p-pmid-37186145","title":"Joint Associations of Device-Measured Sleep Duration and Efficiency With All-Cause and Cause-Specific Mortality: A Prospective Cohort Study of 90 398 UK Biobank Participants.","authors":["YY Liang","S Ai","H Xue","Y Chen","J Zhou","X Shu","F Weng","M Zhou"],"year":2023,"venue":"The journals of gerontology. Series A, Biological sciences and medical sciences","doi":"10.1093/gerona/glad108","pmid":"37186145","url":"https://pubmed.ncbi.nlm.nih.gov/37186145/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Both sleep duration and efficiency are essential for health outcomes. However, few studies have considered the effects of both sleep duration and efficiency on predicting the risks of mortality. This study investigated the independent and joint associations of accelerometer-measured sleep duration and efficiency with all-cause and cause-specific mortality. METHODS: The UK Biobank is a cohort study of over 500 000 individuals recruited between 2006 and 2010. This study included participants wearing wrist accelerometers for 7 consecutive days between February 2013 and December 2015. Mortality was ascertained by the national death registries. RESULTS: Of the 90 398 participants (age, 62.4 [7.8] years, 43.5% male) who were included, 2 685 deaths were reported within a median follow-up duration of 6.4 years. Both accelerometer-measured short (adjusted hazard ratios, 1.27; 95% confidence interval [CI]: 1.11-1.45) and long sleep duration (adjusted hazard ratios, 1.16; 95% CI: 1.06-1.28) were positively associated with the risks of all-cause mortality. Lower sleep efficiency was associated with an increased risk of all-cause and cause-specific mortality. Significant interaction existed between accelerometer-measured sleep duration and efficiency for the risk of all-cause mortality (Pinteraction = .001), participants with long sleep duration and lower sleep efficiency had a double mortality risk compared with those with higher sleep efficiency and normal sleep duration (adjusted hazard ratios = 2.11; 95% CI: 1.44-3.09). CONCLUSIONS: Accelerometer-measured short/long sleep duration and lower sleep efficiency were associated with increased risks of mortality. Sleep efficiency modified the effects of long sleep duration on survival.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36940517","title":"Association of 3-year change in sleep duration with risk of all-cause mortality in Chinese older population: A national cohort study.","authors":["D Liu","Y Niu","Y Duan","J Wang","G Yan"],"year":2023,"venue":"Sleep medicine","doi":"10.1016/j.sleep.2023.03.005","pmid":"36940517","url":"https://pubmed.ncbi.nlm.nih.gov/36940517/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Existing evidence on the association of dynamic change in sleep duration with risk of all-cause mortality in Chinese older population is limited. We aimed to explore the association of 3-year change in sleep duration with risk of all-cause mortality in a Chinese older population. MATERIALS AND METHODS: A total of 5772 Chinese older participants (median age 82 years) were enrolled in the current study. Cox proportional-hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of 3-year change in sleep duration with risk of all-cause mortality. Subgroup analyses of the association between 3-year change in sleep duration and risk of all-cause mortality were conducted by age, sex and residence. RESULTS: During a median of 4.08 years of follow-up, death developed in 1762 participants. Compared with&#xa0;-1 to &lt;1&#xa0;h/day change in sleep duration, the adjusted risk of all-cause mortality with &lt;&#xa0;-3&#xa0;h/day change in sleep duration may increase 26% (HR&#xa0;=&#xa0;1.26, 95% CI: 1.05-1.52); the risk of all-cause mortality with 3-year change from short to long sleep duration, or long to short sleep duration versus stable normal sleep duration status was increased about 28% and 52%, respectively (HR&#xa0;=&#xa0;1.28, 95% CI: 1.00-1.64 and HR&#xa0;=&#xa0;1.52, 95% CI: 1.21-1.92). Subgroup analyses demonstrated that similar significant associations were observed among participants with 65 to &lt;85 years, men and living in city and town. CONCLUSIONS: Dynamic sleep duration change was significantly associated with risk of all-cause mortality. The current study suggests that sleep duration may be a non-invasive indicator for interventions aiming to reduction risk of all-cause mortality in Chinese older population.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36990109","title":"Joint association of physical activity and sleep duration with risk of all-cause and cause-specific mortality: a population-based cohort study using accelerometry.","authors":["YY Liang","H Feng","Y Chen","X Jin","H Xue","M Zhou","H Ma","S Ai"],"year":2023,"venue":"European journal of preventive cardiology","doi":"10.1093/eurjpc/zwad060","pmid":"36990109","url":"https://pubmed.ncbi.nlm.nih.gov/36990109/","methodology":"observational","n":null,"openAccess":false,"abstract":"AIMS: To investigate the joint association of accelerometer-measured physical activity (PA) and sleep duration with mortality risk. METHODS AND RESULTS: A 7-day accelerometer recording was performed on 92 221 participants (age 62.4 &#xb1; 7.8 years; 56.4% women) from the UK Biobank between February 2013 and December 2015. We divided sleep duration into three groups (short, normal, and long), total volume of PA into three levels according to tertiles (high, intermediate, low), and moderate-to-vigorous PA (MVPA) into two groups based on the World Health Organization guidelines. The mortality outcomes were prospectively collected through the death registry. Over a median follow-up of 7.0 years, 3080 adults died, of which 1074 died from cardiovascular disease (CVD) and 1871 from cancer. The associations of PA and sleep duration with mortality risk were all in a curvilinear dose-response pattern (Pnonlinearity &lt;0.001). PA and sleep duration had additive and multiplicative interactions on mortality risk (Pinteraction &lt;0.05). Compared with the participants with guideline-recommended MVPA and normal sleep duration, those without recommended MVPA but having short or long sleep duration were at a higher risk for all-cause mortality [short sleep: hazard ratio (HR) = 1.88; 95% confidence interval (CI), 1.61-2.20; long sleep: HR = 1.69; 95% CI, 1.49-1.90]. A higher volume of PA or recommended MVPA attenuated the detrimental effects of short or long sleep duration on all-cause and CVD mortality risks. CONCLUSION: MVPA meeting recommendations or a higher volume of PA at any intensity potentially diminished the adverse effects on all-cause and cause-specific mortality associated with short and long sleep duration. All-cause and cause-specific mortality risks associated with accelerometer-measured short or long sleep duration were attenuated by physical activity (PA).Both accelerometer-measured short and long sleep duration were associated with higher risk for all-cause and CV","evidenceGrade":"abstract_only"},{"id":"p-leproult-2011","title":"Effect of 1 week of sleep restriction on testosterone levels in young healthy men","authors":["R. Leproult","E. Van Cauter"],"year":2011,"venue":"JAMA","doi":"10.1001/jama.2011.710","pmid":"21632481","url":"https://pubmed.ncbi.nlm.nih.gov/21632481/","methodology":"rct","n":10,"openAccess":true,"abstract":"One week of 5-hour nights cut daytime T by 10–15% in young men. Small N, clean design, the right direction of effect. Sleep is not a wellness garnish.","evidenceGrade":"abstract_only"},{"id":"p-pmid-31993665","title":"Age and time-of-day differences in the hypothalamo-pituitary-testicular, and adrenal, response to total overnight sleep deprivation.","authors":["PY Liu","PY Takahashi","RJ Yang","A Iranmanesh","JD Veldhuis"],"year":2021,"venue":"Sleep","doi":"10.1093/sleep/zsaa008","pmid":"31993665","url":"https://pubmed.ncbi.nlm.nih.gov/31993665/","methodology":"rct","n":null,"openAccess":true,"abstract":"STUDY OBJECTIVES: In young men, sleep restriction decreases testosterone (Te) and increases afternoon cortisol (F), leading to anabolic-catabolic imbalance, insulin resistance, and other andrological health consequences. Age-related differences in the hypothalamo-pituitary-testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk. We aimed to evaluate and compare the 24-h and time-of-day effect of sleep restriction on F, luteinizing hormone (LH), and Te in young and older men. METHODS: Thirty-five healthy men, aged 18-30 (n = 17) and 60-80 (n =18) years, underwent overnight sleep deprivation (complete nighttime wakefulness) or nighttime sleep (10 pm to 6 am) with concurrent 10-min blood sampling in a prospectively randomized crossover study. F, LH, and Te secretion were calculated by deconvolution analysis. RESULTS: Sleep deprivation had multiple effects on 24-h Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each p &lt; 0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (p = 0.03) and Te pulse frequency (p = 0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning and afternoon, reduced LH in the morning in both age groups, and increased F in the afternoon in older men. CONCLUSIONS: These data suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis and of F secretion. Future studies will need to directly verify these regulatory possibilities specifically and separately in young and older men. CLINICAL TRIAL: Not applicable.","evidenceGrade":"full_text"},{"id":"p-pmid-31998056","title":"Daytime Exposure to Blue-Enriched Light Counters the Effects of Sleep Restriction on Cortisol, Testosterone, Alpha-Amylase and Executive Processes.","authors":["B Faraut","T Andrillon","C Drogou","C Gauriau","A Dubois","A Servonnet","P Van Beers","M Guillard"],"year":2020,"venue":"Frontiers in neuroscience","doi":"10.3389/fnins.2019.01366","pmid":"31998056","url":"https://pubmed.ncbi.nlm.nih.gov/31998056/","methodology":"observational","n":null,"openAccess":true,"abstract":"Sleep debt is becoming a better acknowledged cause of physiological stress and neurobehavioral deficits with major public-health concerns. We investigated whether exposure to blue light during daytime could be an efficient countermeasure to limit sleep restriction's impact on relevant behavioral (stress, sleepiness, sustained attention, and memory performance) and physiological (saliva cortisol, testosterone, and alpha-amylase) markers. Our semi-ecological, crossover, randomized design included 17 young men that underwent two sleep-restricted nights (3 h each) followed or not by blue light exposure (30-min-long sessions at 100 lux repeated four times throughout the day). Behavioral and physiological measurements were performed in the lab but outside these periods the participants kept following their usual routine. After sleep restriction, morning cortisol and testosterone, and afternoon alpha-amylase levels decreased. In parallel, subjective ratings of stress and sleepiness increased while performance on the sustained attention and memory tasks deteriorated. In contrast, after periods of blue light exposure, all these parameters were largely restored to baseline levels, despite an identical sleep restriction procedure, although this restorative effect was reduced for the memory task. Our findings suggest that even short exposure to blue light could trigger persistent beneficial effects throughout the day and could be potentially efficient in real-life settings.","evidenceGrade":"full_text"},{"id":"p-pmid-35670262","title":"The effects of sleep deprivation and obstructive sleep apnea syndrome on male reproductive function: a multi-arm randomised trial.","authors":["TA Alvarenga","GL Fernandes","LR Bittencourt","S Tufik","ML Andersen"],"year":2023,"venue":"Journal of sleep research","doi":"10.1111/jsr.13664","pmid":"35670262","url":"https://pubmed.ncbi.nlm.nih.gov/35670262/","methodology":"rct","n":null,"openAccess":false,"abstract":"Sleep is essential for the maintenance of health and systemic homeostasis. Decreased sleep time and sleep quality have been associated with a wide range of diseases. To evaluate the effects of obstructive sleep apnea (OSA) and total or selective rapid eye movement (REM) sleep deprivation on male reproductive function, we performed a three-arm parallel study with one pre-defined OSA group and a group of healthy volunteers who were then randomised into total or REM sleep deprivation groups. Questionnaires were completed and overnight polysomnography was undertaken, and blood and sperm samples were collected at the Sleep Institute, S&#xe3;o Paulo, Brazil. OSA was diagnosed using questionnaires and polysomnography. Male sexual function was assessed through the questionnaires, blood tests, and semen samples. Data showed an association between OSA and lower circulating levels of total and free testosterone and high-density lipoproteins, as well as a lower proportion of healthy sperm cells and decreased sperm concentration, in comparison to volunteers. Volunteers subjected to either total or REM sleep deprivation had increased circulating levels of thyroid-stimulating hormone, insulin, and higher homeostatic model assessment of insulin resistance (HOMA-IR) values. Both sleep-deprived groups also shown decreased cholesterol, and low-density lipoproteins when compared to their baseline levels, but had no alterations in their spermograms. We observed a reduction in total testosterone following total sleep deprivation, but no effect after REM sleep deprivation. OSA was associated with a hormonal imbalance, which is probably linked with impaired reproductive function and associated comorbidities, such as sleep fragmentation/loss and obesity.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37279709","title":"Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with COMT Polymorphism - A Randomized, Crossover Study.","authors":["C Drogou","F Sauvet","M Erblang","D Leger","C Thomas","M Chennaoui","D Gomez-Merino"],"year":2023,"venue":"Lifestyle genomics","doi":"10.1159/000529897","pmid":"37279709","url":"https://pubmed.ncbi.nlm.nih.gov/37279709/","methodology":"rct","n":null,"openAccess":false,"abstract":"INTRODUCTION: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. METHODS: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. RESULTS: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [&#xb1;SEM]: 118 &#xb1; 8, 121 &#xb1; 10, and 121 &#xb1; 10 vs. 105 &#xb1; 7 ng/mL for A/A, 127 &#xb1; 11, 128 &#xb1; 12, and 129 &#xb1; 13 vs. 120 &#xb1; 11 ng/mL for G/G, and 106 &#xb1; 9, 110 &#xb1; 10, and 106 &#xb1; 10 vs. 101 &#xb1; 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p &amp;lt; 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 &#xb1; 26, 107 &#xb1; 27, and 106 &#xb1; 26 vs. 100 &#xb1; 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p &amp;lt; 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 &#xb1; 5 vs. 113 &#xb1; 6 ng/mL) (p &amp;lt; 0.05, condition X SNP). Testosterone and cortisol concentrations decrease","evidenceGrade":"abstract_only"},{"id":"p-pmid-35241770","title":"Short-term smoking increases the risk of insulin resistance.","authors":["SH Cho","SH Jeong","J Shin","S Park","SI Jang"],"year":2022,"venue":"Scientific reports","doi":"10.1038/s41598-022-07626-1","pmid":"35241770","url":"https://pubmed.ncbi.nlm.nih.gov/35241770/","methodology":"observational","n":null,"openAccess":true,"abstract":"Insulin resistance can be affected directly or indirectly by smoking. This cross-sectional study aimed at examining the association between smoking patterns and insulin resistance using objective biomarkers. Data from 4043 participants sourced from the Korea National Health and Nutrition Examination Survey, conducted from 2016 to 2018, were examined. Short-term smoking patterns were used to classify participants according to urine levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and cotinine as continuous-smokers, past-smokers, current-smokers, and non-smokers. Insulin resistance was calculated using the triglyceride-glucose index from blood samples and was defined as either high or low. Multiple logistic regression analysis was performed to investigate the association between smoking behavior and insulin resistance. Men and women who were continuous-smokers (men: odds ratio [OR]&#x2009;=&#x2009;1.74, p&#x2009;=&#x2009;0.001; women: OR&#x2009;=&#x2009;2.01, p&#x2009;=&#x2009;0.001) and past-smokers (men: OR&#x2009;=&#x2009;1.47, p&#x2009;=&#x2009;0.033; women: OR&#x2009;=&#x2009;1.37, p&#x2009;=&#x2009;0.050) were more likely to have high insulin resistance than their non-smoking counterparts. Long-term smokers (&#x2265;&#x2009;40&#xa0;days) are at an increased risk of insulin resistance in short-term smoking patterns. Smoking cessation may protect against insulin resistance. Therefore, first-time smokers should be educated about the health benefits of quitting smoking.","evidenceGrade":"full_text"},{"id":"p-pmid-9179554","title":"Smoking cessation improves insulin sensitivity in healthy middle-aged men.","authors":["B Eliasson","S Attvall","MR Taskinen","U Smith"],"year":1997,"venue":"European journal of clinical investigation","doi":null,"pmid":"9179554","url":"https://pubmed.ncbi.nlm.nih.gov/9179554/","methodology":"observational","n":null,"openAccess":false,"abstract":"Cigarette smokers have recently been shown to exhibit insulin resistance, dyslipidaemia and markers of the insulin resistance syndrome (IRS). The aim of this study was to examine the effects of smoking cessation on insulin sensitivity and IRS. Forty male, non-obese healthy smokers participated in this open parallel study with 8 weeks of follow-up. Seventeen subjects were able to stop smoking, while 23 subjects continued to smoke and served as a controls group. Anthropometric and metabolic data were measured. Degree of insulin sensitivity was determined with the euglycaemic hyperinsulinaemic clamp technique. Smoking cessation increased insulin sensitivity and improved the lipoprotein profile in spite of a modest increase in body weight. Initial smoking habits correlated positively with the increase in BMI as well as the improvements in the metabolic variables after smoking cessation. These data support the view that smoking causes insulin resistance and IRS, and also demonstrate that the beneficial metabolic effects of smoking cessation override the effects of an accompanying modest increase in body weight.","evidenceGrade":"abstract_only"},{"id":"p-penke-2008","title":"Beyond global sociosexual orientations: A more differentiated look at sociosexuality and its effects on courtship and romantic relationships","authors":["L. Penke","J. B. Asendorpf"],"year":2008,"venue":"Journal of Personality and Social Psychology","doi":"10.1037/0022-3514.95.5.1113","pmid":"18954197","url":"https://pubmed.ncbi.nlm.nih.gov/18954197/","methodology":"observational","n":2724,"openAccess":false,"abstract":"Validates SOI-R: behavior, attitude, and desire are separable. The instrument this atlas uses whenever 'sociosexuality' is a node.","evidenceGrade":"abstract_only"},{"id":"p-pmid-16790458","title":"A meta-analysis of the association between adherence to drug therapy and mortality.","authors":["SH Simpson","DT Eurich","SR Majumdar","RS Padwal","RT Tsuyuki","J Varney","JA Johnson"],"year":2006,"venue":"BMJ (Clinical research ed.)","doi":null,"pmid":"16790458","url":"https://pubmed.ncbi.nlm.nih.gov/16790458/","methodology":"meta_analysis","n":null,"openAccess":true,"abstract":"OBJECTIVE: To evaluate the relation between adherence to drug therapy, including placebo, and mortality. DESIGN: Meta-analysis of observational studies. DATA SOURCES: Electronic databases, contact with investigators, and textbooks and reviews on adherence. Review methods Predefined criteria were used to select studies reporting mortality among participants with good and poor adherence to drug therapy. Data were extracted for disease, drug therapy groups, methods for measurement of adherence rate, definition for good adherence, and mortality. RESULTS: Data were available from 21 studies (46,847 participants), including eight studies with placebo arms (19,633 participants). Compared with poor adherence, good adherence was associated with lower mortality (odds ratio 0.56, 95% confidence interval 0.50 to 0.63). Good adherence to placebo was associated with lower mortality (0.56, 0.43 to 0.74), as was good adherence to beneficial drug therapy (0.55, 0.49 to 0.62). Good adherence to harmful drug therapy was associated with increased mortality (2.90, 1.04 to 8.11). CONCLUSION: Good adherence to drug therapy is associated with positive health outcomes. Moreover, the observed association between good adherence to placebo and mortality supports the existence of the \"healthy adherer\" effect, whereby adherence to drug therapy may be a surrogate marker for overall healthy behaviour.","evidenceGrade":"full_text"},{"id":"p-pmid-37326322","title":"Cardiovascular Safety of Testosterone-Replacement Therapy.","authors":["AM Lincoff","S Bhasin","P Flevaris","LM Mitchell","S Basaria","WE Boden","GR Cunningham","CB Granger"],"year":2023,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa2215025","pmid":"37326322","url":"https://pubmed.ncbi.nlm.nih.gov/37326322/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo. RESULTS: The mean (&#xb1;SD) duration of treatment was 21.7&#xb1;14.1 months, and the mean follow-up was 33.0&#xb1;12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P&lt;0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A highe","evidenceGrade":"abstract_only"},{"id":"p-pmid-40986339","title":"Investigating the effects of single-dose intranasal testosterone on economic preferences in a large randomized trial of men.","authors":["A Dreber","M Johannesson","G Nave","C L Apicella","SN Geniole","T Imai","E L Knight","D Manfredi"],"year":2025,"venue":"Proceedings of the National Academy of Sciences of the United States of America","doi":"10.1073/pnas.2508519122","pmid":"40986339","url":"https://pubmed.ncbi.nlm.nih.gov/40986339/","methodology":"rct","n":null,"openAccess":true,"abstract":"There is conflicting evidence on whether testosterone affects economic preferences such as risk taking, fairness, and altruism, with most evidence coming from correlational studies or small testosterone administration studies. To credibly test this hypothesis, we conducted a large-scale, preregistered, double-blind randomized controlled trial with 1,000 male participants-10 to 20 times larger than typical prior studies. Participants were randomly allocated to receive a single dose of either placebo or intranasal testosterone, and carried out a series of economic tasks capturing social preferences, competitiveness, and risk preferences. We find no evidence of a treatment effect for any of our nine primary outcome measures, and no strong evidence of an association between basal salivary testosterone and economic preferences within men. These results fail to conceptually replicate previous high-impact publications reporting positive findings in smaller samples, calling into question the idea that short-term testosterone fluctuations are important drivers of men's economic preferences. Our results do not rule out the possibility that different effects might emerge under alternative dosages, administration protocols, or task timings, or that behavioral effects differ between men and women. The potential for developmental or long-term effects of testosterone also remains an open question for future research, though such effects are ethically challenging to investigate experimentally in humans.","evidenceGrade":"full_text"},{"id":"p-pmid-19366676","title":"A randomized trial of the effect of estrogen and testosterone on economic behavior.","authors":["N Zethraeus","L Kocoska-Maras","T Ellingsen","B von Schoultz","AL Hirschberg","M Johannesson"],"year":2009,"venue":"Proceedings of the National Academy of Sciences of the United States of America","doi":"10.1073/pnas.0812757106","pmid":"19366676","url":"https://pubmed.ncbi.nlm.nih.gov/19366676/","methodology":"rct","n":null,"openAccess":true,"abstract":"Existing correlative evidence suggests that sex hormones may affect economic behavior such as risk taking and reciprocal fairness. To test this hypothesis we conducted a double-blind randomized study. Two-hundred healthy postmenopausal women aged 50-65 years were randomly allocated to 4 weeks of treatment with estrogen, testosterone, or placebo. At the end of the treatment period, the subjects participated in a series of economic experiments that measure altruism, reciprocal fairness, trust, trustworthiness, and risk attitudes. There was no significant effect of estrogen or testosterone on any of the studied behaviors.","evidenceGrade":"full_text"},{"id":"p-pmid-34214918","title":"The effect of testosterone on economic risk-taking: A multi-study, multi-method investigation.","authors":["SJ Stanton","KM Welker","PL Bonin","B Goldfarb","JM Carr&#xe9;"],"year":2021,"venue":"Hormones and behavior","doi":"10.1016/j.yhbeh.2021.105014","pmid":"34214918","url":"https://pubmed.ncbi.nlm.nih.gov/34214918/","methodology":"rct","n":null,"openAccess":false,"abstract":"Testosterone has been suggested to influence individuals' economic decision making, yet the effects of testosterone on economic behavior are not well-understood and existing research is equivocal. In response, in three studies, we examined the extent to which testosterone affected or was associated with several different facets of economic decision making. Study 1 was a double-blind, placebo-controlled, within-subjects study examining loss aversion and risk-taking (N&#xa0;=&#xa0;26), whereas Study 2 was a larger double-blind, placebo-controlled, between-subjects study examining loss aversion and risk-taking behavior (N&#xa0;=&#xa0;117). As a methodological compliment, Study 3 was a larger correlational design (N&#xa0;=&#xa0;213) with a highly accurate measure of endogenous testosterone examining a wider range of economic behaviors and trait-like preferences. Broadly, the results of all three studies suggest no consistent relationship between testosterone and financial behavior or preferences. Although there were significant effects in specific cases, these findings did not replicate in other studies or would not remain significant when controlling for family-wise error rate. We consider potential contextual moderators that may determine under what circumstances testosterone affects economic decision making.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39531812","title":"Does a single dose of testosterone increase willingness to compete, confidence, and risk-taking in men? Evidence from two randomised placebo-controlled experiments.","authors":["A Nadler","M Wibral","T Dohmen","A Falk","A Previtero","B Weber","C Camerer","A Dreber"],"year":2024,"venue":"Hormones and behavior","doi":"10.1016/j.yhbeh.2024.105659","pmid":"39531812","url":"https://pubmed.ncbi.nlm.nih.gov/39531812/","methodology":"rct","n":null,"openAccess":false,"abstract":"The sex steroid hormone testosterone regulates aggression and display of dominance in non-human animals. According to the Challenge Hypothesis, these effects arise from context-sensitive testosterone increases that facilitate inter-male competitions over resources, status, and mates. A growing body of literature documents similar testosterone effects on behaviors related to competition and risk-taking in humans, though the findings have been mixed. Here, we report two randomised double-blind placebo-controlled testosterone administration experiments (N1&#xa0;=&#xa0;91, N2&#xa0;=&#xa0;242) designed independently by researchers in Europe and the US. Both experiments investigated the effect of a single dose of testosterone (at 4&#xa0;h and 21-24&#xa0;h post administration) on men's willingness to compete, confidence, and risk-taking in economic tasks. We estimate weak treatment effects that are statistically indistinguishable from zero for all behavioral outcomes across the two experiments. Our findings cast doubt on the proposition that there is an overall effect of a single dose of testosterone administration on the dimensions of economic behavior studied. If such effects existed, detecting them experimentally via pharmacological studies would require very large samples. We discuss different explanations for our results, including the possibility that context and individual difference factors moderate the effects.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36481265","title":"Effect of exogenous testosterone in the context of energy deficit on risky choice: Behavioural and neural evidence from males.","authors":["O Vartanian","TK Lam","DR Mandel","S Ann Saint","G Navarrete","OT Carmichael","K Murray","SR Pillai"],"year":2023,"venue":"Biological psychology","doi":"10.1016/j.biopsycho.2022.108468","pmid":"36481265","url":"https://pubmed.ncbi.nlm.nih.gov/36481265/","methodology":"rct","n":null,"openAccess":false,"abstract":"Previous research has shown greater risk aversion when people make choices about lives than cash. We tested the hypothesis that compared to placebo, exogenous testosterone administration would lead to riskier choices about cash than lives, given testosterone's association with financial risk-taking and reward sensitivity. A double-blind, placebo-controlled, randomized trial was conducted to test this hypothesis (Clinical Trials Registry: NCT02734238, www.clinicaltrials.gov). We collected functional magnetic resonance imaging (fMRI) data from 50 non-obese males before and shortly after 28 days of severe exercise-and-diet-induced energy deficit, during which testosterone (200&#xa0;mg testosterone enanthate per week in sesame oil) or placebo (sesame seed oil only) was administered. Because we expected circulating testosterone levels to be reduced due to severe energy deficit, testosterone administration served a restorative function to mitigate the impact of energy deficit on testosterone levels. The fMRI task involved making choices under uncertainty for lives and cash. We also manipulated whether the outcomes were presented as gains or losses. Consistent with prospect theory, we observed the reflection effect such that participants were more risk averse when outcomes were presented as gains than losses. Brain activation in the thalamus covaried with individual differences in exhibiting the reflection effect. Testosterone did not impact choice, but it increased sensitivity to negative feedback following risky choices. These results suggest that exogenous testosterone administration in the context of energy deficit can impact some aspects of risky choice, and that individual differences in the reflection effect engage a brain structure involved in processing emotion, reward and risk.","evidenceGrade":"abstract_only"},{"id":"p-pmid-21393575","title":"Low- and high-testosterone individuals exhibit decreased aversion to economic risk.","authors":["SJ Stanton","OA Mullette-Gillman","RE McLaurin","CM Kuhn","KS LaBar","ML Platt","SA Huettel"],"year":2011,"venue":"Psychological science","doi":"10.1177/0956797611401752","pmid":"21393575","url":"https://pubmed.ncbi.nlm.nih.gov/21393575/","methodology":"observational","n":null,"openAccess":true,"abstract":"Testosterone is positively associated with risk-taking behavior in social domains (e.g., crime, physical aggression). However, the scant research linking testosterone to economic risk preferences presents inconsistent findings. We examined the relationship between endogenous testosterone and individuals' economic preferences (i.e., risk preference, ambiguity preference, and loss aversion) in a large sample (N = 298) of men and women. We found that endogenous testosterone levels have a significant U-shaped association with individuals' risk and ambiguity preferences, but not loss aversion. Specifically, individuals with low or high levels of testosterone (more than 1.5 SD from the mean for their gender) were risk and ambiguity neutral, whereas individuals with intermediate levels of testosterone were risk and ambiguity averse. This relationship was highly similar in men and women. In contrast to received wisdom regarding testosterone and risk, the present data provide the first robust evidence for a nonlinear association between economic preferences and levels of endogenous testosterone.","evidenceGrade":"full_text"},{"id":"p-pmid-42073930","title":"Opposing Roles of Testosterone and Cortisol in Prosocial Risk-Taking.","authors":["S Huang","D Zhang","J Zhuang"],"year":2026,"venue":"Behavioral sciences (Basel, Switzerland)","doi":"10.3390/bs16040568","pmid":"42073930","url":"https://pubmed.ncbi.nlm.nih.gov/42073930/","methodology":"observational","n":null,"openAccess":true,"abstract":"Prosocial risk-taking is defined as engagement in altruistic behaviors that may have personal costs. Emerging research indicates that testosterone-a gonadal steroid hormone-is linked to behaviors aimed at promoting one's social status. In line with these findings, we hypothesized that testosterone levels would be associated positively with prosocial risk-taking. Additionally, according to the dual-hormone hypothesis, this relationship may be moderated by cortisol. To examine these hypotheses, we administered an adapted version of the probabilistic gambling task, which included a prosocial condition. In the original task, participants were the beneficiaries of their choices; under the prosocial condition, the benefits were directed to charitable organizations. Our results revealed that, consistent with previous findings, the endogenous testosterone level was associated positively with risk-taking for personal gain. Notably, we also observed an association between the endogenous testosterone level and prosocial risk-taking. These relationships were not moderated by cortisol, meaning that the dual-hormone hypothesis was not supported. Instead, elevated cortisol independently suppressed prosocial risk-taking. Collectively, these results demonstrate that basal testosterone and cortisol levels play different roles in the modulation of prosocial risk-taking behavior.","evidenceGrade":"full_text"},{"id":"p-geniole-2020","title":"Evidence from meta-analyses of the facial width-to-height ratio versus the dual-hormone hypothesis as predictors of status-seeking","authors":["S. N. Geniole","T. L. F. McCormick"],"year":2020,"venue":"Adaptive Human Behavior and Physiology","doi":"10.1007/s40750-019-00120-5","pmid":null,"url":"https://doi.org/10.1007/s40750-019-00120-5","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"Later quantitative reviews of the dual-hormone literature find a small, heterogeneous, publication-bias-sensitive effect. The interaction is not a law of nature. It is a live, contested hypothesis.","evidenceGrade":"abstract_only"},{"id":"p-pmid-42259165","title":"Separable, nonlinear, and interactive effects of testosterone and cortisol during status competition in humans: Evidence for the context-dependent dual hormone hypothesis.","authors":["RI Elahi","EL Knight"],"year":2026,"venue":"Hormones and behavior","doi":"10.1016/j.yhbeh.2026.105962","pmid":"42259165","url":"https://pubmed.ncbi.nlm.nih.gov/42259165/","methodology":"observational","n":null,"openAccess":false,"abstract":"The Dual Hormone Hypothesis is a biosocial model that describes the interactive effects of testosterone and cortisol on status-relevant behavior. Under this model, testosterone increases status-seeking behavior when cortisol is low, and status-loss-avoidance when cortisol is high. This manifests as high-testosterone individuals preferentially competing against high-status opponents when cortisol is low, and low-status opponents when cortisol is high. However, opponent status indicates both potential status gain as well as opponent strength. The present study separates opponent status from potential gains and losses to understand how testosterone and cortisol interact with different status cues during competition. Results suggest that testosterone increases sensitivity to opponent status while decreasing sensitivity to gains and losses. Cortisol moderates testosterone's effects on status sensitivity while independently increasing reward sensitivity. Furthermore, the present work leverages machine learning to elucidate how testosterone influences behavior in a nonlinear fashion.","evidenceGrade":"abstract_only"},{"id":"p-mazur-booth-1998","title":"Testosterone and dominance in men","authors":["A. Mazur","A. Booth"],"year":1998,"venue":"Behavioral and Brain Sciences","doi":"10.1017/S0140525X98001228","pmid":"10097017","url":"https://pubmed.ncbi.nlm.nih.gov/10097017/","methodology":"review","n":null,"openAccess":false,"abstract":"States the biosocial model: T encourages dominance attempts; winning raises T and losing lowers it. Reciprocal, not one-way. The paper to cite for the winner–loser loop.","evidenceGrade":"abstract_only"},{"id":"p-eisenegger-2010","title":"Prejudice and truth about the effect of testosterone on human bargaining behaviour","authors":["C. Eisenegger","M. Naef","R. Snozzi","M. Heinrichs","E. Fehr"],"year":2010,"venue":"Nature","doi":"10.1038/nature08711","pmid":"19997098","url":"https://pubmed.ncbi.nlm.nih.gov/19997098/","methodology":"rct","n":121,"openAccess":false,"abstract":"Single-dose T in women increased fair ultimatum offers. Belief that one received T — regardless of actual drug — increased unfairness. The folk hypothesis moved behavior more than the molecule in the belief arm.","evidenceGrade":"abstract_only"},{"id":"p-zak-2009","title":"Testosterone administration decreases generosity in the ultimatum game","authors":["P. J. Zak","R. Kurzban","S. Ahmadi"],"year":2009,"venue":"PLoS ONE","doi":"10.1371/journal.pone.0008330","pmid":"20016825","url":"https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008330","methodology":"rct","n":25,"openAccess":true,"abstract":"Androgel in men reduced generosity in the ultimatum game. Small crossover sample. Later labs did not treat this as settled; several failed to move rejection rates.","evidenceGrade":"abstract_only"},{"id":"p-cueva-2017","title":"Testosterone administration does not affect men's rejections of low ultimatum game offers or aggressive mood","authors":["C. Cueva","R. E. Roberts","T. J. Spencer","P. N. Tobler","A. Rustichini"],"year":2017,"venue":"Hormones and Behavior","doi":"10.1016/j.yhbeh.2016.09.012","pmid":"27702573","url":"https://pubmed.ncbi.nlm.nih.gov/27702573/","methodology":"rct","n":40,"openAccess":false,"abstract":"48-hour T vs placebo in men: no effect on rejection of low ultimatum offers. A necessary counterweight to the 2009 generosity paper.","evidenceGrade":"abstract_only"},{"id":"p-pmid-28901958","title":"Pilot Study of the Tart Cherry Juice for the Treatment of Insomnia and Investigation of Mechanisms.","authors":["JN Losso","JW Finley","N Karki","AG Liu","A Prudente","R Tipton","Y Yu","FL Greenway"],"year":2018,"venue":"American journal of therapeutics","doi":"10.1097/MJT.0000000000000584","pmid":"28901958","url":"https://pubmed.ncbi.nlm.nih.gov/28901958/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Insomnia is common in the elderly and is associated with chronic disease, but use of hypnotics increases the incidence of falls. Montmorency tart cherry juice has improved insomnia by self-report questionnaire. STUDY QUESTION: Is insomnia confirmed by polysomnography and is tryptophan availability a potential mechanism for treating insomnia? STUDY DESIGN: A placebo-controlled balanced crossover study with subjects older than 50 years and insomnia were randomized to placebo (2 weeks) or cherry juice (2 weeks) (240 mL 2 times/d) separated by a 2-week washout. MEASURES AND OUTCOMES: Sleep was evaluated by polysomnography and 5 validated questionnaires. Serum indoleamine 2,3-dioxygenase (IDO), the kynurenine-to-tryptophan ratio, and prostaglandin E2 were measured. In vitro, Caco-2 cells were stimulated with interferon-gamma, and the ability of cherry juice procyanidin to inhibit IDO which degrades tryptophan and stimulates inflammation was measured. The content of procyanidin B-2 and other major anthocyanins in cherry juice were determined. RESULTS: Eleven subjects were randomized; 3 with sleep apnea were excluded and referred. The 8 completers with insomnia increased sleep time by 84 minutes on polysomnography (P = 0.0182) and sleep efficiency increased on the Pittsburgh Sleep Quality Index (P = 0.03). Other questionnaires showed no significant differences. The serum kynurenine-to-tryptophan ratio decreased, as did the level of prostaglandin E2 (both P &lt; 0.05). In vitro, cherry juice procyanidin B-2 dose-dependently inhibited IDO. CONCLUSIONS: Cherry juice increased sleep time and sleep efficiency. Cherry juice procyanidin B-2 inhibited IDO, increased tryptophan availability, reduced inflammation, and may be partially responsible for improvement in insomnia.","evidenceGrade":"full_text"},{"id":"p-pmid-22038497","title":"Effect of tart cherry juice (Prunus cerasus) on melatonin levels and enhanced sleep quality.","authors":["G Howatson","PG Bell","J Tallent","B Middleton","MP McHugh","J Ellis"],"year":2013,"venue":"European journal of nutrition","doi":"10.1007/s00394-011-0263-7","pmid":"22038497","url":"https://pubmed.ncbi.nlm.nih.gov/22038497/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Tart Montmorency cherries have been reported to contain high levels of phytochemicals including melatonin, a molecule critical in regulating the sleep-wake cycle in humans. PURPOSE: The aim of our investigation was to ascertain whether ingestion of a tart cherry juice concentrate would increase the urinary melatonin levels in healthy adults and improve sleep quality. METHODS: In a randomised, double-blind, placebo-controlled, crossover design, 20 volunteers consumed either a placebo or tart cherry juice concentrate for 7 days. Measures of sleep quality recorded by actigraphy and subjective sleep questionnaires were completed. Sequential urine samples over 48 h were collected and urinary 6-sulfatoxymelatonin (major metabolite of melatonin) determined; cosinor analysis was used to determine melatonin circadian rhythm (mesor, acrophase and amplitude). In addition, total urinary melatonin content was determined over the sampled period. Trial differences were determined using a repeated measures ANOVA. RESULTS: Total melatonin content was significantly elevated (P &lt; 0.05) in the cherry juice group, whilst no differences were shown between baseline and placebo trials. There were significant increases in time in bed, total sleep time and sleep efficiency total (P &lt; 0.05) with cherry juice supplementation. Although there was no difference in timing of the melatonin circardian rhythm, there was a trend to a higher mesor and amplitude. CONCLUSIONS: These data suggest that consumption of a tart cherry juice concentrate provides an increase in exogenous melatonin that is beneficial in improving sleep duration and quality in healthy men and women and might be of benefit in managing disturbed sleep.","evidenceGrade":"abstract_only"},{"id":"p-pmid-20438325","title":"Effects of a tart cherry juice beverage on the sleep of older adults with insomnia: a pilot study.","authors":["WR Pigeon","M Carr","C Gorman","ML Perlis"],"year":2010,"venue":"Journal of medicinal food","doi":"10.1089/jmf.2009.0096","pmid":"20438325","url":"https://pubmed.ncbi.nlm.nih.gov/20438325/","methodology":"rct","n":null,"openAccess":true,"abstract":"This study ascertained whether a proprietary tart cherry juice blend (CherryPharm, Inc., Geneva, NY, USA) associated with anecdotal reports of sleep enhancement improves subjective reports of insomnia compared to a placebo beverage. The pilot study used a randomized, double-blind, crossover design where each participant received both treatment and placebo for 2 weeks with an intervening 2-week washout period. Sleep continuity (sleep onset, wake after sleep onset, total sleep time, and sleep efficiency) was assessed by 2-week mean values from daily sleep diaries and disease severity by the Insomnia Severity Index in a cohort of 15 older adults with chronic insomnia who were otherwise healthy. The tart cherry juice beverage was associated with statistically significant pre- to post-treatment improvements on all sleep variables. When compared to placebo, the study beverage produced significant reductions in insomnia severity (minutes awake after sleep onset); no such improvements were observed for sleep latency, total sleep time, or sleep efficiency compared to placebo. Effect sizes were moderate and in some cases negligible. The results of this pilot study suggest that CherryPharm, a tart cherry juice blend, has modest beneficial effects on sleep in older adults with insomnia with effect sizes equal to or exceeding those observed in studies of valerian and in some, but not all, studies of melatonin, the two most studied natural products for insomnia. These effects, however, were considerably less than those for evidence-based treatments of insomnia: hypnotic agents and cognitive-behavioral therapies for insomnia.","evidenceGrade":"full_text"},{"id":"p-pmid-35790450","title":"Montmorency tart cherry supplementation does not impact sleep, body composition, cellular health, or blood pressure in healthy adults.","authors":["AR Hillman","O Trickett","C Brodsky","B Chrismas"],"year":2026,"venue":"Nutrition and health","doi":"10.1177/02601060221111230","pmid":"35790450","url":"https://pubmed.ncbi.nlm.nih.gov/35790450/","methodology":"rct","n":null,"openAccess":false,"abstract":"Background: Sleep disturbances are linked with cardiovascular and metabolic disease as well as poor body composition. Aim: To investigate the use of tart cherry supplements, which are high in antioxidants and may contain melatonin, on parameters of health such as sleep, body composition, cellular health, and blood pressure (BP). Methods: Forty-four participants had completed sleep record data and were included in this analysis. Participants consumed either two 240&#x2005;ml bottles per day of Montmorency tart cherry (MTC) juice or placebo or two capsules per day of powdered MTC or placebo for 30 days. Participants tracked their sleep daily via questionnaire and completed body composition and BP assessments at baseline, 14 days, and 30 days after supplementation. Results: There were no significant differences in sleep time or quality between groups, though both increased over 30 days. The capsule groups had significantly lower body mass (BM) 14 days versus baseline for placebo group (p&#x2009;=&#x2009;0.01, mean difference: 0.70&#x2005;kg) and at 30 days versus 14 days in MTC group (p&#x2009;=&#x2009;0.02, mean difference: 0.75&#x2005;kg). No other differences in body composition or cellular health were found. BP was unaffected by MTC supplementation over 30 days. Despite the potential benefits of antioxidants and melatonin, we did not find improvements in sleep time or quality, cellular health or BP in participants consuming MTC for 30 days, though BM decreased in capsule groups. Conclusion: These results conflict with previous data on MTC and sleep and BP, therefore further investigation is warranted.","evidenceGrade":"abstract_only"},{"id":"p-pmid-26869148","title":"Acute effects of theanine, caffeine and theanine-caffeine combination on attention.","authors":["CN Kahathuduwa","TL Dassanayake","AMT Amarakoon","VS Weerasinghe"],"year":2018,"venue":"Nutritional neuroscience","doi":"10.1080/1028415X.2016.1144845","pmid":"26869148","url":"https://pubmed.ncbi.nlm.nih.gov/26869148/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: l-theanine is a constituent of tea which is claimed to enhance cognitive functions. We aimed to determine whether theanine and theanine-caffeine combination have acute positive effects on cognitive and neurophysiological measures of attention, compared to caffeine (a positive control) and a placebo in healthy individuals. DESIGN: In a placebo-controlled, five-way crossover trial in 20 healthy male volunteers, we compared the effects of l-theanine (200&#x2005;mg), caffeine (160&#x2005;mg), their combination, black tea (one cup) and a placebo (distilled water) on cognitive (simple [SVRT] and recognition visual reaction time [RVRT]) and neurophysiological (event-related potentials [ERPs]) measures of attention. We also recorded visual (VEPs) and motor evoked potentials (MEPs) to examine any effects of treatments on peripheral visual and motor conduction, respectively. RESULTS: Mean RVRT was significantly improved by theanine (P&#x2009;=&#x2009;0.019), caffeine (P&#x2009;=&#x2009;0.043), and theanine-caffeine combination (P&#x2009;=&#x2009;0.001), but not by tea (P&#x2009;=&#x2009;0.429) or placebo (P&#x2009;=&#x2009;0.822). VEP or MEP latencies or SVRT did not show significant inter-treatment differences. Theanine (P&#x2009;=&#x2009;0.001) and caffeine (P&#x2009;=&#x2009;0.001) elicited significantly larger mean peak-to-peak N2-P300 ERP amplitudes than the placebo, whereas theanine-caffeine combination elicited a significantly larger mean N2-P300 amplitude than placebo (P&#x2009;&lt;&#x2009;0.001), theanine (P&#x2009;=&#x2009;0.029) or caffeine (P&#x2009;=&#x2009;0.005). No significant theanine&#x2009;&#xd7;&#x2009;caffeine interaction was observed for RVRT or N2-P300 amplitude. DISCUSSION: A dose of theanine equivalent of eight cups of back tea improves cognitive and neurophysiological measures of selective attention, to a degree that is comparable with that of caffeine. Theanine and caffeine seem to have additive effects on attention in high doses.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36263942","title":"Dose-response effect of L-theanine on psychomotor speed, sustained attention, and inhibitory control: a double-blind, placebo-controlled, crossover study.","authors":["TL Dassanayake","D Wijesundara","CN Kahathuduwa","VS Weerasinghe"],"year":2023,"venue":"Nutritional neuroscience","doi":"10.1080/1028415X.2022.2136884","pmid":"36263942","url":"https://pubmed.ncbi.nlm.nih.gov/36263942/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: L-theanine is a non-protein-forming amino acid found in tea. Previous research shows high doses (100-400&#x2005;mg) of L-theanine enhances attention, mainly by reducing mind wandering and distracter processing. We hypothesized that these indirect mechanisms could significantly improve the performance of low-level attentional tasks, whereas the relative contribution could be less in complex attentional tasks that require active, higher-order processing of target stimuli. METHODS: To test this hypothesis, we conducted a double-blind, placebo-controlled, counterbalanced, four-way crossover study in 32 healthy young adults, where we compared the effects of three doses of L-theanine (100, 200 and 400&#x2005;mg) with a placebo (distilled water), administered before and 50 min after dosing, on three attentional tasks from the Cambridge Neuropsychological Test Automated Battery [viz. Reaction Time (RTI)-visuomotor speed, Rapid Visual Information Processing (RVP)-sustained attention, and Stop Signal Task (SST)-inhibitory control]. Results were analyzed in dose&#x2009;&#xd7;&#x2009;time repeated measures ANOVA models, with subsequent pairwise comparisons. RESULTS: Active doses significantly improved reaction times in the RTI (100-200&#x2005;mg) and RVP (200-400&#x2005;mg) tasks from baseline (p&#x2009;&lt;&#x2009;0.05), but once controlled for the change-from-baseline caused by placebo, only the RTI simple reaction times showed significant improvements, following 100 mg (&#x394;&#x2009;=&#x2009;16.3&#x2005;ms, p&#x2009;=&#x2009;0.009) and 200&#x2005;mg (&#x394;&#x2009;=&#x2009;16.9&#x2005;ms, p&#x2009;=&#x2009;0.009) of L-theanine. CONCLUSIONS: Consistent with our hypothesis, these findings suggest that L-theanine significantly improves attention in simple visuomotor tasks, but not in more complex sustained attention tasks, or executive control tasks that require top-down inhibition of pre-active responses.","evidenceGrade":"abstract_only"},{"id":"p-pmid-25761837","title":"A double-blind, placebo-controlled study evaluating the effects of caffeine and L-theanine both alone and in combination on cerebral blood flow, cognition and mood.","authors":["FL Dodd","DO Kennedy","LM Riby","CF Haskell-Ramsay"],"year":2016,"venue":"Psychopharmacology","doi":"10.1007/s00213-015-3895-0","pmid":"25761837","url":"https://pubmed.ncbi.nlm.nih.gov/25761837/","methodology":"rct","n":null,"openAccess":true,"abstract":"RATIONALE: Evidence suggests interactive effects of the tea components caffeine and L-theanine on behaviour, yet no data exists exploring the impact of the two on cerebral blood flow (CBF). OBJECTIVES: The current placebo-controlled, double-blind, counterbalanced, crossover study examined the effects of caffeine and L-theanine on CBF and extended previous cognitive and mood findings by using lower doses than previous studies of a similar methodology, which more closely reflect the ratios present in tea. METHODS: Twelve habitual consumers and 12 non-habitual consumers of caffeine each received 75&#xa0;mg caffeine, 50&#xa0;mg&#xa0;L-theanine, 75&#xa0;mg caffeine plus 50&#xa0;mg&#xa0;L-theanine, and placebo in a counterbalanced order across four separate visits. CBF was measured via near-infrared spectroscopy with cognition and mood assessed at baseline and 30&#xa0;min post-dose. Salivary caffeine and peripheral haemodynamics were co-monitored. RESULTS: Caffeine reduced oxygenated haemoglobin (oxy-Hb), increased deoxygenated haemoglobin (deoxy-Hb), improved performance on attention tasks and increased overall mood ratings. Increases in deoxy-Hb following caffeine were more pronounced in non-consumers. Some evidence for increased deoxy-Hb remained when caffeine was combined with L-theanine, but this effect was attenuated and the effects of caffeine on oxy-Hb, cognition and mood were eradicated. CONCLUSIONS: Combining L-theanine with caffeine, at levels and ratios equivalent to one to two cups of tea, eliminated the vasoconstrictive effect and behavioural effects of caffeine. This supports previous findings of an interaction between these substances, despite a lack of effects of L-theanine in isolation. However, at the levels tested here, this did not lead to a positive impact on behaviour.","evidenceGrade":"full_text"},{"id":"p-pmid-18006208","title":"The effects of L-theanine, caffeine and their combination on cognition and mood.","authors":["CF Haskell","DO Kennedy","AL Milne","KA Wesnes","AB Scholey"],"year":2008,"venue":"Biological psychology","doi":null,"pmid":"18006208","url":"https://pubmed.ncbi.nlm.nih.gov/18006208/","methodology":"rct","n":null,"openAccess":false,"abstract":"L-Theanine is an amino acid found naturally in tea. Despite the common consumption of L-theanine, predominantly in combination with caffeine in the form of tea, only one study to date has examined the cognitive effects of this substance alone, and none have examined its effects when combined with caffeine. The present randomised, placebo-controlled, double-blind, balanced crossover study investigated the acute cognitive and mood effects of L-theanine (250 mg), and caffeine (150 mg), in isolation and in combination. Salivary caffeine levels were co-monitored. L-Theanine increased 'headache' ratings and decreased correct serial seven subtractions. Caffeine led to faster digit vigilance reaction time, improved Rapid Visual Information Processing (RVIP) accuracy and attenuated increases in self-reported 'mental fatigue'. In addition to improving RVIP accuracy and 'mental fatigue' ratings, the combination also led to faster simple reaction time, faster numeric working memory reaction time and improved sentence verification accuracy. 'Headache' and 'tired' ratings were reduced and 'alert' ratings increased. There was also a significant positive caffeine x L-theanine interaction on delayed word recognition reaction time. These results suggest that beverages containing L-theanine and caffeine may have a different pharmacological profile to those containing caffeine alone.","evidenceGrade":"abstract_only"},{"id":"p-pmid-21040626","title":"The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness.","authors":["T Giesbrecht","JA Rycroft","MJ Rowson","EA De Bruin"],"year":2011,"venue":"Nutritional neuroscience","doi":"10.1179/147683010X12611460764840","pmid":"21040626","url":"https://pubmed.ncbi.nlm.nih.gov/21040626/","methodology":"rct","n":null,"openAccess":false,"abstract":"The non-proteinic amino acid L-theanine and caffeine, a methylxanthine derivative, are naturally occurring ingredients in tea. The present study investigated the effect of a combination of 97 mg L-theanine and 40 mg caffeine as compared to placebo treatment on cognitive performance, alertness, blood pressure, and heart rate in a sample of young adults (n = 44). Cognitive performance, self-reported mood, blood pressure, and heart rate were measured before L-theanine and caffeine administration (i.e. at baseline) and 20 min and 70 min thereafter. The combination of moderate levels of L-theanine and caffeine significantly improved accuracy during task switching and self-reported alertness (both P &lt; 0.01) and reduced self-reported tiredness (P &lt; 0.05). There were no significant effects on other cognitive tasks, such as visual search, choice reaction times, or mental rotation. The present results suggest that 97 mg of L-theanine in combination with 40 mg of caffeine helps to focus attention during a demanding cognitive task.","evidenceGrade":"abstract_only"},{"id":"p-pmid-20079786","title":"L-theanine and caffeine improve task switching but not intersensory attention or subjective alertness.","authors":["SJ Ein&#xf6;ther","VE Martens","JA Rycroft","EA De Bruin"],"year":2010,"venue":"Appetite","doi":"10.1016/j.appet.2010.01.003","pmid":"20079786","url":"https://pubmed.ncbi.nlm.nih.gov/20079786/","methodology":"rct","n":null,"openAccess":false,"abstract":"Tea ingredients L-theanine and caffeine have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. The current randomized, placebo-controlled, double-blind, cross-over study compared a combination of L-theanine (97 mg) and caffeine (40 mg) to a placebo on two attention tasks and a self-report questionnaire before, and 10 and 60 min after consumption. The combination of L-theanine and caffeine significantly improved attention on a switch task as compared to the placebo, while subjective alertness and intersensory attention were not improved significantly. The results support previous evidence that L-theanine and caffeine in combination can improve attention.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37429171","title":"Effects of resistance exercise training on depressive symptoms among young adults: A randomized controlled trial.","authors":["D O'Sullivan","BR Gordon","M Lyons","JD Meyer","MP Herring"],"year":2023,"venue":"Psychiatry research","doi":"10.1016/j.psychres.2023.115322","pmid":"37429171","url":"https://pubmed.ncbi.nlm.nih.gov/37429171/","methodology":"rct","n":null,"openAccess":true,"abstract":"Evidence supports the antidepressant effects of resistance exercise training (RET); however, findings among young adults at-risk for elevated depressive symptoms are limited. This randomized controlled trial examined the effects of eight weeks of ecologically-valid, guidelines-based RET, compared to a wait-list control, on depressive symptoms among 55 young adults (26&#xb1;5y; 36 female) with and without subclinical, or analogue, Generalized Anxiety Disorder (AGAD; Psychiatric Diagnostic Screening Questionnaire GAD subscale &#x2265;6 and Penn State Worry Questionnaire &#x2265;45) and Major Depressive Disorder (AMDD). Following a three-week familiarization period, participants completed one-on-one, twice-weekly RET sessions. The 16-item, self-reported Quick Inventory of Depressive Symptomatology (QIDS) assessed depressive symptoms. RM-ANCOVAs examined between-group differences, and significant interactions were decomposed with simple effects analysis. Hedges' d effect sizes (95%CI) quantified the magnitude of differences in change between groups across time. Stratified analyses were conducted among subsamples with AMDD and AGAD. There were no baseline depressive symptom differences between groups. Attendance was 83%, and compliance was 80%. RET induced statistically significant, clinically-meaningful, large-magnitude reductions in depressive symptoms from baseline to week eight in the total (d&#xa0;=&#xa0;1.01; [95%CI: 0.44-1.57]), AMDD (d&#xa0;=&#xa0;1.71; [95%CI: 0.96-2.46]), and AGAD (d&#xa0;=&#xa0;1.39; [95%CI: 0.55-2.24]) samples. These findings support guidelines-based RET as a promising treatment for mild depression.","evidenceGrade":"full_text"},{"id":"p-pmid-33839788","title":"Effect of Aerobic or Resistance Exercise, or Both, on Intermuscular and Visceral Fat and Physical and Metabolic Function in Older Adults With Obesity While Dieting.","authors":["DL Waters","L Aguirre","B Gurney","DR Sinacore","K Fowler","G Gregori","R Armamento-Villareal","C Qualls"],"year":2022,"venue":"The journals of gerontology. Series A, Biological sciences and medical sciences","doi":"10.1093/gerona/glab111","pmid":"33839788","url":"https://pubmed.ncbi.nlm.nih.gov/33839788/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Obesity exacerbates age-related effects on body composition and physical and metabolic function. Which exercise mode is most effective in mitigating these deleterious changes in dieting older adults with obesity is unknown. METHODS: In a randomized controlled trial, we performed a head-to-head comparison of aerobic (AEX), resistance (REX), or combination (COMB) exercise during matched ~10% weight loss in 160 obese older adults. Prespecified analyses compared 6-month changes in intermuscular adipose tissue (IMAT) and visceral adipose tissue (VAT) assessed using MRI, insulin sensitivity index (ISI) by oral glucose tolerance test, physical function using Modified Physical Performance Test (PPT), VO2peak, gait speed, and knee strength by dynamometry. RESULTS: IMAT and VAT decreased more in COMB than AEX and REX groups (IMAT; -41% vs -28% and -23% and VAT: -36% vs -19% and -21%; p = .003 to .01); IMAT and VAT decreased in all groups more than control (between-group p &lt; .001). ISI increased more in COMB than AEX and REX groups (86% vs 50% and 39%; p = .005 to .03). PPT improved more in COMB than AEX and REX groups, while VO2peak improved more in COMB and AEX than REX group (all p &lt; .05). Knee strength improved more in COMB and REX than AEX group (all p &lt; .05). Changes in IMAT and VAT correlated with PPT (r = -0.28 and -0.39), VO2peak (r = -0.49 and -0.52), gait speed (r = -0.25 and -0.36), and ISI (r = -0.49 and -0.52; all p &lt; .05). CONCLUSIONS: Weight loss plus combination aerobic and resistance exercise was most effective in improving ectopic fat deposition and physical and metabolic function in older adults with obesity.","evidenceGrade":"full_text"},{"id":"p-pmid-23006411","title":"The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial.","authors":["SS Ho","SS Dhaliwal","AP Hills","S Pal"],"year":2013,"venue":"BMC public health","doi":"10.1186/1471-2458-12-704","pmid":"23006411","url":"https://pubmed.ncbi.nlm.nih.gov/23006411/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Evidence suggests that exercise training improves CVD risk factors. However, it is unclear whether health benefits are limited to aerobic training or if other exercise modalities such as resistance training or a combination are as effective or more effective in the overweight and obese. The aim of this study is to investigate whether 12 weeks of moderate-intensity aerobic, resistance, or combined exercise training would induce and sustain improvements in cardiovascular risk profile, weight and fat loss in overweight and obese adults compared to no exercise. METHODS: Twelve-week randomized parallel design examining the effects of different exercise regimes on fasting measures of lipids, glucose and insulin and changes in body weight, fat mass and dietary intake. Participants were randomized to either: Group 1 (Control, n = 16); Group 2 (Aerobic, n = 15); Group 3 (Resistance, n = 16); Group 4 (Combination, n = 17). Data was analysed using General Linear Model to assess the effects of the groups after adjusting for baseline values. Within-group data was analyzed with the paired t-test and between-group effects using post hoc comparisons. RESULTS: Significant improvements in body weight (-1.6%, p = 0.044) for the Combination group compared to Control and Resistance groups and total body fat compared to Control (-4.4%, p = 0.003) and Resistance (-3%, p = 0.041). Significant improvements in body fat percentage (-2.6%, p = 0.008), abdominal fat percentage (-2.8%, p = 0.034) and cardio-respiratory fitness (13.3%, p = 0.006) were seen in the Combination group compared to Control. Levels of ApoB48 were 32% lower in the Resistance group compared to Control (p = 0.04). CONCLUSION: A 12-week training program comprising of resistance or combination exercise, at moderate-intensity for 30 min, five days/week resulted in improvements in the cardiovascular risk profile in overweight and obese participants compared to no exercise. From our observations, combination exercis","evidenceGrade":"full_text"},{"id":"p-pmid-26079649","title":"Effects of resistance training on testosterone metabolism in younger and older men.","authors":["JP Ahtiainen","K Nyman","I Huhtaniemi","T Parviainen","M Helste","A Rannikko","WJ Kraemer","K H&#xe4;kkinen"],"year":2016,"venue":"Experimental gerontology","doi":"10.1016/j.exger.2015.06.010","pmid":"26079649","url":"https://pubmed.ncbi.nlm.nih.gov/26079649/","methodology":"rct","n":null,"openAccess":false,"abstract":"This study investigated the effects of resistance training (RT) on the metabolism of testosterone (T) in younger (n=5, 28&#xb1;3yrs.) and older (n=8, 70&#xb1;2yrs.) men. Experimental heavy resistance exercises (5&#xd7;10RM leg presses) were performed before and after a 12-month of RT. No age differences were found in the production or metabolic clearance rate of T (determined by stable isotope dilution method), skeletal muscle androgen receptor content or serum LH concentrations due to acute or chronic RT. The T production capacity response to gonadotropin stimulation and the concentrations of the urinary T metabolites (androsterone and etiocholanolone) were lower in the older compared to younger men (p&lt;0.05-0.01). This study further showed that RT may have acute effect on T production and clearance rates, while the exercise-induced increases in serum T appeared to be induced by decreased metabolic clearance rate of T. Attenuated T production capacity and urinary excretion of T metabolites in older men may reflect the known reduction in testicular steroidogenesis upon aging. No changes were observed in T metabolism due to RT indicating a homeostatic stability for this hormone in men of different ages.","evidenceGrade":"abstract_only"},{"id":"p-pmid-29754952","title":"Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes.","authors":["EF Sutton","R Beyl","KS Early","WT Cefalu","E Ravussin","CM Peterson"],"year":2019,"venue":"Cell metabolism","doi":"10.1016/j.cmet.2018.04.010","pmid":"29754952","url":"https://pubmed.ncbi.nlm.nih.gov/29754952/","methodology":"observational","n":null,"openAccess":true,"abstract":"Intermittent fasting (IF) improves cardiometabolic health; however, it is unknown whether these effects are due solely to weight loss. We conducted the first supervised controlled feeding trial to test whether IF has benefits independent of weight loss by feeding participants enough food to maintain their weight. Our proof-of-concept study also constitutes the first trial of early time-restricted feeding (eTRF), a form of IF that involves eating early in the day to be in alignment with circadian rhythms in metabolism. Men with prediabetes were randomized to eTRF (6-hr feeding period, with dinner before 3 p.m.) or a control schedule (12-hr feeding period) for 5&#xa0;weeks and later crossed over to the other schedule. eTRF improved insulin sensitivity, &#x3b2; cell responsiveness, blood pressure, oxidative stress, and appetite. We demonstrate for the first time in humans that eTRF improves some aspects of cardiometabolic health and that IF's effects are not solely due to weight loss.","evidenceGrade":"full_text"},{"id":"p-pmid-35194047","title":"Randomized controlled trial for time-restricted eating in healthy volunteers without obesity.","authors":["Z Xie","Y Sun","Y Ye","D Hu","H Zhang","Z He","H Zhao","H Yang"],"year":2022,"venue":"Nature communications","doi":"10.1038/s41467-022-28662-5","pmid":"35194047","url":"https://pubmed.ncbi.nlm.nih.gov/35194047/","methodology":"rct","n":null,"openAccess":true,"abstract":"Time-restricted feeding (TRF) improves metabolic health. Both early TRF (eTRF, food intake restricted to the early part of the day) and mid-day TRF (mTRF, food intake restricted to the middle of the day) have been shown to have metabolic benefits. However, the two regimens have yet to be thoroughly compared. We conducted a five-week randomized trial to compare the effects of the two TRF regimens in healthy individuals without obesity (ChiCTR2000029797). The trial has completed. Ninety participants were randomized to eTRF (n=30), mTRF (n=30), or control groups (n=30) using a computer-based random-number generator. Eighty-two participants completed the entire five-week trial and were analyzed (28 in eTRF, 26 in mTRF, 28 in control groups). The primary outcome was the change in insulin resistance. Researchers who assessed the outcomes were blinded to group assignment, but participants and care givers were not. Here we show that eTRF was more effective than mTRF at improving insulin sensitivity. Furthermore, eTRF, but not mTRF, improved fasting glucose, reduced total body mass and adiposity, ameliorated inflammation, and increased gut microbial diversity. No serious adverse events were reported during the trial. In conclusion, eTRF showed greater benefits for insulin resistance and related metabolic parameters compared with mTRF. Clinical Trial Registration URL: http://www.chictr.org.cn/showproj.aspx?proj=49406 .","evidenceGrade":"full_text"},{"id":"p-pmid-32986097","title":"Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity: The TREAT Randomized Clinical Trial.","authors":["DA Lowe","N Wu","L Rohdin-Bibby","AH Moore","N Kelly","YE Liu","E Philip","E Vittinghoff"],"year":2021,"venue":"JAMA internal medicine","doi":"10.1001/jamainternmed.2020.4153","pmid":"32986097","url":"https://pubmed.ncbi.nlm.nih.gov/32986097/","methodology":"rct","n":null,"openAccess":true,"abstract":"IMPORTANCE: The efficacy and safety of time-restricted eating have not been explored in large randomized clinical trials. OBJECTIVE: To determine the effect of 16:8-hour time-restricted eating on weight loss and metabolic risk markers. INTERVENTIONS: Participants were randomized such that the consistent meal timing (CMT) group was instructed to eat 3 structured meals per day, and the time-restricted eating (TRE) group was instructed to eat ad libitum from 12:00 pm until 8:00 pm and completely abstain from caloric intake from 8:00 pm until 12:00 pm the following day. DESIGN, SETTING, AND PARTICIPANTS: This 12-week randomized clinical trial including men and women aged 18 to 64 years with a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 27 to 43 was conducted on a custom mobile study application. Participants received a Bluetooth scale. Participants lived anywhere in the United States, with a subset of 50 participants living near San Francisco, California, who underwent in-person testing. MAIN OUTCOMES AND MEASURES: The primary outcome was weight loss. Secondary outcomes from the in-person cohort included changes in weight, fat mass, lean mass, fasting insulin, fasting glucose, hemoglobin A1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure. RESULTS: Overall, 116 participants (mean [SD] age, 46.5 [10.5] years; 70 [60.3%] men) were included in the study. There was a significant decrease in weight in the TRE (-0.94 kg; 95% CI, -1.68 to -0.20; P&#x2009;=&#x2009;.01), but no significant change in the CMT group (-0.68 kg; 95% CI, -1.41 to 0.05, P&#x2009;=&#x2009;.07) or between groups (-0.26 kg; 95% CI, -1.30 to 0.78; P&#x2009;=&#x2009;.63). In the in-person cohort (n&#x2009;=&#x2009;25 TRE, n&#x2009;=&#x2009;25 CMT), there was a significant within-group decrease in weight in the TRE group (-1.70 kg; 95% CI, -2.56 to -0.83; P&#x2009;&lt;&#x2009;.001). There was also a significant diff","evidenceGrade":"full_text"},{"id":"p-pmid-35443107","title":"Calorie Restriction with or without Time-Restricted Eating in Weight Loss.","authors":["D Liu","Y Huang","C Huang","S Yang","X Wei","P Zhang","D Guo","J Lin"],"year":2022,"venue":"The New England journal of medicine","doi":"10.1056/NEJMoa2114833","pmid":"35443107","url":"https://pubmed.ncbi.nlm.nih.gov/35443107/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: The long-term efficacy and safety of time-restricted eating for weight loss are not clear. METHODS: We randomly assigned 139 patients with obesity to time-restricted eating (eating only between 8:00 a.m. and 4:00 p.m.) with calorie restriction or daily calorie restriction alone. For 12 months, all the participants were instructed to follow a calorie-restricted diet that consisted of 1500 to 1800 kcal per day for men and 1200 to 1500 kcal per day for women. The primary outcome was the difference between the two groups in the change from baseline in body weight; secondary outcomes included changes in waist circumference, body-mass index (BMI), amount of body fat, and measures of metabolic risk factors. RESULTS: Of the total 139 participants who underwent randomization, 118 (84.9%) completed the 12-month follow-up visit. The mean weight loss from baseline at 12 months was -8.0 kg (95% confidence interval [CI], -9.6 to -6.4) in the time-restriction group and -6.3 kg (95% CI, -7.8 to -4.7) in the daily-calorie-restriction group. Changes in weight were not significantly different in the two groups at the 12-month assessment (net difference, -1.8 kg; 95% CI, -4.0 to 0.4; P&#x2009;=&#x2009;0.11). Results of analyses of waist circumferences, BMI, body fat, body lean mass, blood pressure, and metabolic risk factors were consistent with the results of the primary outcome. In addition, there were no substantial differences between the groups in the numbers of adverse events. CONCLUSIONS: Among patients with obesity, a regimen of time-restricted eating was not more beneficial with regard to reduction in body weight, body fat, or metabolic risk factors than daily calorie restriction. (Funded by the National Key Research and Development Project [No. 2018YFA0800404] and others; ClinicalTrials.gov number, NCT03745612.).","evidenceGrade":"abstract_only"},{"id":"p-pmid-38639542","title":"Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity : A Randomized Controlled Trial.","authors":["NM Maruthur","SJ Pilla","K White","B Wu","MTT Maw","D Duan","RA Turkson-Ocran","D Zhao"],"year":2024,"venue":"Annals of internal medicine","doi":"10.7326/M23-3132","pmid":"38639542","url":"https://pubmed.ncbi.nlm.nih.gov/38639542/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND: Time-restricted eating (TRE) lowers body weight in many studies. Whether TRE induces weight loss independent of reductions in calorie intake, as seen in rodent studies, is unknown. OBJECTIVE: To determine the effect of TRE versus a usual eating pattern (UEP) on body weight in the setting of stable caloric intake. DESIGN: Randomized, isocaloric feeding study. (ClinicalTrials.gov: NCT03527368). SETTING: Clinical research unit. PARTICIPANTS: Adults with obesity and prediabetes or diet-controlled diabetes. INTERVENTION: Participants were randomly assigned 1:1 to TRE (10-hour eating window, 80% of calories before 1 p.m.) or UEP (&#x2264;16-hour window, &#x2265;50% of calories after 5 p.m.) for 12 weeks. Both groups had the same nutrient content and were isocaloric with total calories determined at baseline. MEASUREMENTS: Primary outcome was change in body weight at 12 weeks. Secondary outcomes were fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), glucose area under the curve by oral glucose tolerance test, and glycated albumin. We used linear mixed models to evaluate the effect of interventions on outcomes. RESULTS: All 41 randomly assigned participants (mean age, 59 years; 93% women; 93% Black race; mean BMI, 36 kg/m2) completed the intervention. Baseline weight was 95.6 kg (95% CI, 89.6 to 101.6 kg) in the TRE group and 103.7 kg (CI, 95.3 to 112.0 kg) in the UEP group. At 12 weeks, weight decreased by 2.3 kg (CI, 1.0 to 3.5 kg) in the TRE group and by 2.6 kg (CI, 1.5 to 3.7 kg) in the UEP group (average difference TRE vs. UEP, 0.3 kg [CI, -1.2 to 1.9 kg]). Change in glycemic measures did not differ between groups. LIMITATION: Small, single-site study; baseline differences in weight by group. CONCLUSION: In the setting of isocaloric eating, TRE did not decrease weight or improve glucose homeostasis relative to a UEP, suggesting that any effects of TRE on weight in prior studies may be due to reductions in caloric intake. PRIMAR","evidenceGrade":"abstract_only"},{"id":"p-pmid-39348690","title":"Time-Restricted Eating in Adults With Metabolic Syndrome : A Randomized Controlled Trial.","authors":["ENC Manoogian","MJ Wilkinson","M O'Neal","K Laing","J Nguyen","D Van","A Rosander","A Pazargadi"],"year":2024,"venue":"Annals of internal medicine","doi":"10.7326/M24-0859","pmid":"39348690","url":"https://pubmed.ncbi.nlm.nih.gov/39348690/","methodology":"rct","n":null,"openAccess":true,"abstract":"BACKGROUND: Time-restricted eating (TRE), limiting daily dietary intake to a consistent 8 to 10 hours without mandating calorie reduction, may provide cardiometabolic benefits. OBJECTIVE: To determine the effects of TRE as a lifestyle intervention combined with current standard-of-care treatments on cardiometabolic health in adults with metabolic syndrome. DESIGN: Randomized controlled trial. (ClinicalTrials.gov: NCT04057339). SETTING: Clinical research institute. PARTICIPANTS: Adults with metabolic syndrome including elevated fasting glucose or hemoglobin A1c (HbA1c; pharmacotherapy allowed). INTERVENTION: Participants were randomly assigned to standard-of-care (SOC) nutritional counseling alone (SOC group) or combined with a personalized 8- to 10-hour TRE intervention (&#x2265;4-hour reduction in eating window) (TRE group) for 3 months. Timing of dietary intake was tracked in real time using the myCircadianClock smartphone application. MEASUREMENTS: Primary outcomes were HbA1c, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance, and glycemic assessments from continuous glucose monitors. RESULTS: 108 participants from the TIMET study completed the intervention (89% of those randomly assigned; 56 women, mean baseline age, 59 years; body mass index of 31.22 kg/m2; eating window of 14.19 hours). Compared with SOC, TRE improved HbA1c by -0.10% (95% CI, -0.19% to -0.003%). Statistical outcomes were adjusted for age. There were no major adverse events. LIMITATION: Short duration, self-reported diet, potential for multiple elements affecting outcomes. CONCLUSION: Personalized 8- to 10-hour TRE is an effective practical lifestyle intervention that modestly improves glycemic regulation and may have broader benefits for cardiometabolic health in adults with metabolic syndrome on top of SOC pharmacotherapy and nutritional counseling. PRIMARY FUNDING SOURCE: National Institutes of Health.","evidenceGrade":"full_text"},{"id":"p-pmid-36198292","title":"Time-restricted eating and exercise training improve HbA1c and body composition in women with overweight/obesity: A randomized controlled trial.","authors":["KL Haganes","CP Silva","SK Eyj&#xf3;lfsd&#xf3;ttir","S Steen","M Grindberg","S Lydersen","JA Hawley","T Moholdt"],"year":2022,"venue":"Cell metabolism","doi":"10.1016/j.cmet.2022.09.003","pmid":"36198292","url":"https://pubmed.ncbi.nlm.nih.gov/36198292/","methodology":"rct","n":null,"openAccess":false,"abstract":"Diet modification and exercise training are primary lifestyle strategies for obesity management, but poor adherence rates limit their effectiveness. Time-restricted eating (TRE) and high-intensity interval training (HIIT) improve cardiometabolic health in at-risk individuals, but whether these two interventions combined induce superior improvements in glycemic control than each individual intervention is not known. In this four-armed randomized controlled trial (ClinicalTrials.gov NCT04019860), we determined the isolated and combined effects of 7&#xa0;weeks of TRE (&#x2264;10-h daily eating window, with ad libitum energy intake) and HIIT (three exercise sessions per week), compared with a non-intervention control group, on glycemic control and secondary cardiometabolic outcomes in 131 women (36.2&#xa0;&#xb1; 6.2 years) with overweight/obesity. There were no statistically significant effects after isolated TRE, HIIT, or a combination (TREHIIT) on glucose area under the curve during an oral glucose tolerance test (the primary outcome) compared with the control group (TRE, -26.3&#xa0;mmol/L; 95% confidence interval [CI], -82.3 to 29.7, p&#xa0;= 0.36; HIIT, -53.8&#xa0;mmol/L; 95% CI, -109.2 to 1.6, p&#xa0;= 0.057; TREHIIT, -41.3&#xa0;mmol/L; 95% CI, -96.4 to 13.8, p&#xa0;= 0.14). However, TREHIIT improved HbA1c and induced superior reductions in total and visceral fat mass compared with TRE and HIIT alone. High participant adherence rates suggest that TRE, HIIT, and a combination thereof may be realistic diet-exercise strategies for improving markers of metabolic health in women at risk of cardiometabolic disease.","evidenceGrade":"abstract_only"},{"id":"p-pmid-31813824","title":"Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome.","authors":["MJ Wilkinson","ENC Manoogian","A Zadourian","H Lo","S Fakhouri","A Shoghi","X Wang","JG Fleischer"],"year":2021,"venue":"Cell metabolism","doi":"10.1016/j.cmet.2019.11.004","pmid":"31813824","url":"https://pubmed.ncbi.nlm.nih.gov/31813824/","methodology":"observational","n":null,"openAccess":true,"abstract":"In animal models, time-restricted feeding (TRF) can prevent and reverse aspects of metabolic diseases. Time-restricted eating (TRE) in human pilot studies reduces the risks of metabolic diseases in otherwise healthy individuals. However, patients with diagnosed metabolic syndrome often undergo pharmacotherapy, and it has never been tested whether TRE can act synergistically with pharmacotherapy in animal models or humans. In a single-arm, paired-sample trial, 19 participants with metabolic syndrome and a baseline mean daily eating window of &#x2265;14 h, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10&#xa0;h of TRE (all dietary intake within a consistent self-selected 10&#xa0;h window) for 12&#xa0;weeks. We found this TRE intervention improves cardiometabolic health for patients with metabolic syndrome receiving standard medical care including high rates of statin and anti-hypertensive use. TRE is a potentially powerful lifestyle intervention that can be added to standard medical practice to treat metabolic syndrome. VIDEO ABSTRACT.","evidenceGrade":"full_text"},{"id":"p-hall-2019","title":"Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake","authors":["K. D. Hall","A. Ayuketah","R. Brychta"],"year":2019,"venue":"Cell Metabolism","doi":"10.1016/j.cmet.2019.05.008","pmid":"31105044","url":"https://pubmed.ncbi.nlm.nih.gov/31105044/","methodology":"rct","n":20,"openAccess":true,"abstract":"Adults ate more and gained weight on an ultra-processed diet matched for presented calories and macros versus an unprocessed diet. A rare experimental handle on UPF, not a SES fairy tale.","evidenceGrade":"abstract_only"},{"id":"p-pmid-39267249","title":"Ultra-processed foods cause weight gain and increased energy intake associated with reduced chewing frequency: A randomized, open-label, crossover study.","authors":["S Hamano","M Sawada","M Aihara","Y Sakurai","R Sekine","S Usami","N Kubota","T Yamauchi"],"year":2024,"venue":"Diabetes, obesity &amp; metabolism","doi":"10.1111/dom.15922","pmid":"39267249","url":"https://pubmed.ncbi.nlm.nih.gov/39267249/","methodology":"rct","n":null,"openAccess":false,"abstract":"AIM: To elucidate the effects of ultra-processed foods (UPFs) on body weight and ad libitum energy intake compared with non-UPFs. MATERIALS AND METHODS: In this randomized, open-label crossover study conducted at the University of Tokyo Hospital, overweight/obese Japanese male participants were randomly assigned (1:1) to start the study with consumption of either UPFs or non-UPFs for 1 week, followed by a 2-week washout period, before crossing over to the alternate food diet for 1 week. Individuals with diabetes, hypertension or any other medical conditions who visited a hospital regularly were excluded. The meals were designed to be matched for the total energy and macronutrient levels. The primary outcome was the difference in the body weight change between the UPF and non-UPF periods. The differences in the average daily energy intake and chewing frequency were assessed as one of the prespecified secondary outcomes. RESULTS: Nine eligible participants were randomly assigned to start the study with either UPFs or non-UPFs. All participants completed the study. During the UPF period, participants gained 1.1&#x2009;kg more weight (95% confidence interval 0.2 to 2.0; P&#x2009;=&#x2009;.021) and consumed 813.5&#x2009;kcal more per day (342.4 to 1284.7; P&#x2009;=&#x2009;.0041) compared with during the non-UPF period. Regarding the chewing frequency, the number of chews per calorie was significantly lower during the UPF period (P&#x2009;=&#x2009;.016). CONCLUSIONS: Consumption of UPFs causes significant weight gain. Medical nutritional therapy focused on reducing the consumption of UPFs could be an effective strategy for preventing obesity.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36854188","title":"Ultra-Processed Food Consumption and Risk of Type 2 Diabetes: Three Large Prospective U.S. Cohort Studies.","authors":["Z Chen","N Khandpur","C Desjardins","L Wang","CA Monteiro","SL Rossato","TT Fung","JE Manson"],"year":2023,"venue":"Diabetes care","doi":"10.2337/dc22-1993","pmid":"36854188","url":"https://pubmed.ncbi.nlm.nih.gov/36854188/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVE: We examined the relationship between ultra-processed food (UPF) intake and type 2 diabetes (T2D) risk among 3 large U.S. cohorts, conducted a meta-analysis of prospective cohort studies, and assessed meta-evidence quality. RESEARCH DESIGN AND METHODS: We included 71,871 women from the Nurses' Health Study, 87,918 women from the Nurses' Health Study II, and 38,847 men from the Health Professional Follow-Up Study. Diet was assessed using food frequency questionnaires and UPF was categorized per the NOVA classification. Associations of total and subgroups of UPF with T2D were assessed using Cox proportional hazards models. We subsequently conducted a meta-analysis of prospective cohort studies on total UPF and T2D risk, and assessed meta-evidence quality using the NutriGrade scoring system. RESULTS: Among the U.S. cohorts (5,187,678 person-years; n = 19,503 T2D cases), the hazard ratio for T2D comparing extreme quintiles of total UPF intake (percentage of grams per day) was 1.46 (95% CI 1.39-1.54). Among subgroups, refined breads; sauces, spreads, and condiments; artificially and sugar-sweetened beverages; animal-based products; and ready-to-eat mixed dishes were associated with higher T2D risk. Cereals; dark and whole-grain breads; packaged sweet and savory snacks; fruit-based products; and yogurt and dairy-based desserts were associated with lower T2D risk. In the meta-analysis (n = 415,554 participants; n = 21,932 T2D cases), each 10% increment in total UPF was associated with a 12% (95% CI 10%-13%) higher risk. Per NutriGrade, high-quality evidence supports this relationship. CONCLUSIONS: High-quality meta-evidence shows that total UPF consumption is associated with higher T2D risk. However, some UPF subgroups were associated with lower risk in the U.S. cohorts.","evidenceGrade":"full_text"},{"id":"p-pmid-21775910","title":"Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial.","authors":["S Taavoni","N Ekbatani","M Kashaniyan","H Haghani"],"year":2011,"venue":"Menopause (New York, N.Y.)","doi":"10.1097/gme.0b013e31820e9acf","pmid":"21775910","url":"https://pubmed.ncbi.nlm.nih.gov/21775910/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVE: Sleep disturbances reduce the quality of life. About 50% of postmenopausal women experience sleep disturbances such as insomnia. Complementary and alternative medical therapies may be useful for the management of sleep disturbances among postmenopausal women. The aim of the present study was to evaluate the effects of valerian extract taken nightly on the improvement of sleep quality in postmenopausal women experiencing insomnia. METHODS: A randomized, triple-blind, controlled trial design was used for this study. Participants consisted of 100 postmenopausal women aged 50 to 60 years who were experiencing insomnia. A demographic data form and the Pittsburgh Sleep Quality Index were used to collect data. The women were randomly divided into two groups. Each group received either 530 mg of concentrated valerian extract or a placebo twice a day for 4 weeks. Descriptive and inferential statistics were used to analyze the data. RESULTS: A statistically significant change was reported in the quality of sleep of the intervention group in comparison with the placebo group (P &lt; 0.001). Also, 30% of the participants in the intervention group and 4% in the placebo group showed an improvement in the quality of sleep (P &lt; 0.001). CONCLUSIONS: Valerian improves the quality of sleep in women with menopause who are experiencing insomnia. Findings from this study add support to the reported effectiveness of valerian in the clinical management of insomnia.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37899385","title":"Standardized Extract of Valeriana officinalis Improves Overall Sleep Quality in Human Subjects with Sleep Complaints: A Randomized, Double-Blind, Placebo-Controlled, Clinical Study.","authors":["H Chandra Shekhar","L Joshua","JV Thomas"],"year":2024,"venue":"Advances in therapy","doi":"10.1007/s12325-023-02708-6","pmid":"37899385","url":"https://pubmed.ncbi.nlm.nih.gov/37899385/","methodology":"rct","n":null,"openAccess":true,"abstract":"INTRODUCTION: Sleep deficit or poor sleep leads to ill-health, whereas sleep deprivation for longer periods of time increases the risk of developing adverse conditions associated with poor quality of life, and high socioeconomic impact. The treatments for sleep disturbances include melatonin and over-the-counter medicines like diphenhydramine and doxylamine, all of which have negative side effects. Valerian (Valeriana officinalis L.) is a traditional herb and the most preferred alternate sleep solution to manage sleep complaints. METHODS: Eighty adult subjects with sleep complaints were randomized in 1:1 ratio to receive either V. officinalis extract (VE) or placebo for 8&#xa0;weeks in a double-blind, placebo-controlled, parallel, clinical study. Primary efficacy endpoints included the Pittsburgh Sleep Quality Index (PSQI) and sleep latency using wrist actigraphy (WA), as well as a number of secondary endpoints, including sleep parameters such as actual sleep time and sleep efficiency using WA, the Epworth Sleepiness Scale (ESS), the Beck Anxiety Inventory (BAI), the Visual Analogue Scale (VAS) for the feeling of waking up refreshed, and a tertiary endpoint of sleep parameters using polysomnography (PSG) in a subset of 20 subjects per group. Safety parameters included physical examination, vital sign measurements, hematology, and clinical chemistry tests. Adverse events and serious adverse events were monitored throughout the study period. RESULTS: Seventy-two&#xa0;subjects (35 and 37 subjects in the placebo and VE groups, respectively) completed the study and were included in the efficacy assessments. On Days 14, 28, and 56, the PSQI Total Score in the VE group decreased significantly (p&#xa0;&lt;&#xa0;0.05) compared to the placebo group. Further, the VE group showed significant improvements (p&#xa0;&lt;&#xa0;0.05) in sleep latency and actual sleep time on Days 3, 14, 28, and 56, and sleep efficiency on Days 14, 28, and 56, as evaluated by WA. There was a decrease ","evidenceGrade":"full_text"},{"id":"p-pmid-10761819","title":"Critical evaluation of the effect of valerian extract on sleep structure and sleep quality.","authors":["F Donath","S Quispe","K Diefenbach","A Maurer","I Fietze","I Roots"],"year":2000,"venue":"Pharmacopsychiatry","doi":null,"pmid":"10761819","url":"https://pubmed.ncbi.nlm.nih.gov/10761819/","methodology":"rct","n":null,"openAccess":false,"abstract":"A carefully designed study assessed the short-term (single dose) and long-term (14 days with multiple dosage) effects of a valerian extract on both objective and subjective sleep parameters. The investigation was performed as a randomised, double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12 female) with previously established psychophysiological insomnia (ICSD-code 1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the study. The main inclusion criteria were reported primary insomnia according to ICSD criteria, which was confirmed by polysomnographic recording, and the absence of acute diseases. During the study, the patients underwent 8 polysomnographic recordings: i.e., 2 recordings (baseline and study night) at each time point at which the short and long-term effects of placebo and valerian were tested. The target variable of the study was sleep efficiency. Other parameters describing objective sleep structure were the usual features of sleep-stage analysis, based on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective parameters such as sleep quality, morning feeling, daytime performance, subjectively perceived duration of sleep latency, and sleep period time were assessed by means of questionnaires. After a single dose of valerian, no effects on sleep structure and subjective sleep assessment were observed. After multiple-dose treatment, sleep efficiency showed a significant increase for both the placebo and the valerian condition in comparison with baseline polysomnography. We confirmed significant differences between valerian and placebo for parameters describing slow-wave sleep. In comparison with the placebo, slow-wave sleep latency was reduced after administration of valerian (21.3 vs. 13.5 min respectively, p&lt;0.05). The SWS percentage of time in bed (TIB) was increased after long-term valerian treatm","evidenceGrade":"abstract_only"},{"id":"p-pmid-34101780","title":"Effects of Folic Acid and Vitamin B12 Supplementation on Cognitive Impairment and Inflammation in Patients with Alzheimer's Disease: A Randomized, Single-Blinded, Placebo-Controlled Trial.","authors":["H Chen","S Liu","B Ge","D Zhou","M Li","W Li","F Ma","Z Liu"],"year":2021,"venue":"The journal of prevention of Alzheimer's disease","doi":"10.14283/jpad.2021.22","pmid":"34101780","url":"https://pubmed.ncbi.nlm.nih.gov/34101780/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: To evaluate the combined action of folic acid and vitamin B12 supplementation on cognitive performance and inflammation in patients with Alzheimer's disease (AD). DESIGN: This was a randomized, single-blind, placebo-controlled trial. PARTICIPANTS: Patients (n=120) diagnosed clinically as probable AD and in stable condition from Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases. MEASUREMENTS: Individuals were randomly divided into the intervention group (n=60, folic acid 1.2 mg/d + vitamin B12 50 &#x3bc;g/d) and the placebo group (n=60). Cognitive performance, blood folate, vitamin B12, one carbon cycle metabolite, and inflammatory cytokine levels were measured at baseline and after 6 months. The data were analyzed using linear mixed models for repeated measures. RESULTS: A total of 101 participants (51 in the intervention group and 50 in the placebo group) completed the trial. Folic acid plus vitamin B12 supplementation had a beneficial effect on the MoCA total scores (P=0.029), naming scores (P=0.013), orientation scores (P=0.004), and ADAS-Cog domain score of attention (P=0.008), as compared to those of the control subjects. Moreover, supplementation significantly increased plasma SAM (P&lt;0.001) and SAM/SAH (P&lt;0.001), and significantly decreased the levels of serum Hcy (P&lt;0.001), plasma SAH (P&lt;0.001), and serum TNF&#x3b1; (P&lt;0.001) compared to in the control subjects. CONCLUSIONS: Folic acid and vitamin B12 supplementation showed a positive therapeutic effect in AD patients who were not on a folic acid-fortified diet. The findings of this study help to delineate nutrient intervention as far as public health management for the prevention of dementia is concerned.","evidenceGrade":"full_text"},{"id":"p-pmid-12918012","title":"Vitamin B12 for cognition.","authors":["R Malouf","A Areosa Sastre"],"year":2003,"venue":"The Cochrane database of systematic reviews","doi":null,"pmid":"12918012","url":"https://pubmed.ncbi.nlm.nih.gov/12918012/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"BACKGROUND: An association between neuropsychiatric disorders and vitamin B12 deficiency has been recognized since 1849 when pernicious anaemia was first described. It has been suggested that deficiency of vitamin B12 might contribute to age-associated cognitive impairment. Low serum vitamin B12 concentrations are found in more than 10% of older people. A high prevalence of low serum vitamin B12 levels, and other indicators of vitamin B12 deficiency have been reported among people with Alzheimer's disease. A review is needed of trials assessing effects of vitamin B12 supplementation on cognitive function in later life. OBJECTIVES: To examine the effect of B12 supplementation on cognitive function of demented and elderly healthy people in terms of preventing the onset or progression of cognitive impairment or dementia. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 12 September 2002 using the terms listed in additional table 1. In addition MEDLINE 1966 to 2002/09 and EMBASE 1980-2002/08 were searched using the same terms and cognit* to pick up studies with healthy volunteers. SELECTION CRITERIA: All randomized double-blind trials in which vitamin B12 at any dose was compared with placebo. DATA COLLECTION AND ANALYSIS: Both reviewers applied the selection criteria to assess the quality of the studies. One reviewer collated and analysed the data. For each outcome measure data were sought on every patient randomized. MAIN RESULTS: From the two included studies (Seal 2002; Fourniere 1997) of people with dementia and low serum vitamin B12 levels, there was no statistically significant evidence of treatment effect, vitamin B12 supplementation compared with placebo, on cognitive function. REVIEWER'S CONCLUSIONS: Evidence of any efficacy of vitamin B12 in improving the cognitive function of people with dementia and low serum B12 levels is insufficient. The two trials of accepta","evidenceGrade":"abstract_only"},{"id":"p-pmid-34432056","title":"B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis.","authors":["Z Wang","W Zhu","Y Xing","J Jia","Y Tang"],"year":2022,"venue":"Nutrition reviews","doi":"10.1093/nutrit/nuab057","pmid":"34432056","url":"https://pubmed.ncbi.nlm.nih.gov/34432056/","methodology":"meta_analysis","n":null,"openAccess":false,"abstract":"CONTEXT: Elevation of homocysteine (Hcy) levels is well-established as a risk factor for dementia, yet controversy exists regarding whether B-vitamin-mediated reduction of homocysteine levels can benefit cognitive function. OBJECTIVE: To investigate whether B vitamin supplementation can reduce the risk of cognitive decline and incident dementia. DATA SOURCES: The PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for articles published from the inception dates to March 1, 2020. Randomized controlled trials (RCT) were included if B vitamins were supplied to investigate their effect on the rate of cognitive decline. Cohort studies investigating dietary intake of B vitamins and the risk of incident dementia were eligible. Cross-sectional studies comparing differences in levels of B vitamins and Hcy were included. DATA EXTRACTION: Two reviewers independently performed data extraction and assessed the study quality. DATA ANALYSIS: Random-effect or fixed-effect models, depending on the degree of heterogeneity, were performed to calculate mean differences (MDs), hazard ratios (HRs), and odds ratios (ORs). RESULTS: A total of 95 studies with 46175 participants (25 RCTs, 20 cohort studies, and 50 cross-sectional studies) were included in this meta-analysis. This meta-analysis supports that B vitamins can benefit cognitive function as measured by Mini-Mental State Examination score changes (6155 participants; MD, 0.14, 95%CI 0.04 to 0.23), and this result was also significant in studies where placebo groups developed cognitive decline (4211 participants; MD, 0.16, 95%CI 0.05 to 0.26), suggesting that B vitamins slow cognitive decline. For the&#x2009;&gt;&#x2009;12&#x2009;months interventional period stratum, B vitamin supplementation decreased cognitive decline (3814 participants; MD, 0.15, 95%CI 0.05 to 0.26) compared to placebo; no such outcome was detected for the shorter interventional stratum (806 participants; MD, 0.18, 95%CI -0.25 to 0.61","evidenceGrade":"abstract_only"},{"id":"p-pmid-34853363","title":"Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial.","authors":["JH Kang","CM Vyas","OI Okereke","S Ogata","M Albert","IM Lee","D D'Agostino","JE Buring"],"year":2022,"venue":"Scientific reports","doi":"10.1038/s41598-021-02485-8","pmid":"34853363","url":"https://pubmed.ncbi.nlm.nih.gov/34853363/","methodology":"rct","n":null,"openAccess":true,"abstract":"Low vitamin D levels have been associated with cognitive decline; however, few randomized trials have been conducted. In a trial, we evaluated vitamin D3 supplementation on cognitive decline. We included participants aged 60+ years (mean[SD]&#x2009;=&#x2009;70.9[5.8]&#xa0;years) free of cardiovascular disease and cancer in two substudies in the VITAL 2&#x2009;&#xd7;&#x2009;2 randomized trial of vitamin D3 (2000&#xa0;IU/day of cholecalciferol) and fish oil supplements: 3424 had cognitive assessments by phone (eight neuropsychologic tests; 2.8&#xa0;years follow-up) and 794 had in-person assessments (nine tests; 2.0&#xa0;years follow-up). The primary, pre-specified outcome was decline over two assessments in global composite score (average z-scores of all tests); substudy-specific results were meta-analyzed. The pooled mean difference in annual rate of decline (MD) for vitamin D3 versus placebo was 0.01 (95% CI -&#x2009;0.01, 0.02; p&#x2009;=&#x2009;0.39). We observed no interaction with baseline 25-hydroxyvitamin-D levels (p-interaction&#x2009;=&#x2009;0.84) and a significant interaction with self-reported race (p-interaction&#x2009;=&#x2009;0.01). Among Black participants (19%), those assigned vitamin D3 versus placebo had better cognitive maintenance (MD&#x2009;=&#x2009;0.04, 95% CI 0.01, 0.08, similar to that observed for Black participants 1.2&#xa0;years apart in age). Thus, vitamin D3 (2000&#xa0;IU/day cholecalciferol) supplementation was not associated with cognitive decline over 2-3&#xa0;years among community-dwelling older participants but may provide modest cognitive benefits in older Black adults, although these results need confirmation.Trial registration ClinicalTrials.gov; VITAL (NCT01169259), VITAL-DEP (NCT01696435) and VITAL-Cog (NCT01669915); the date the registration for the parent trial (NCT01169259) was submitted to the registry: 7/26/2010 and the date of first patient enrollment in either of the ancillary studies for cognitive function in a subset ","evidenceGrade":"full_text"},{"id":"p-pmid-40480279","title":"Impact of Vitamin D Supplementation on Cognition in Adults With Mild to Moderate Vitamin D Deficiency: Outcomes From the VitaMIND Randomized Controlled Trial.","authors":["A Corbett","R Taylor","D Llewellyn","JM Ranson","A Hampshire","E Pickering","A Palmer","D Aarsland"],"year":2025,"venue":"Journal of the American Medical Directors Association","doi":"10.1016/j.jamda.2025.105711","pmid":"40480279","url":"https://pubmed.ncbi.nlm.nih.gov/40480279/","methodology":"rct","n":null,"openAccess":false,"abstract":"OBJECTIVES: Preserved cognitive health with ageing is a public health imperative. Vitamin D deficiency is associated with poor cognition, but it is unclear whether supplementation would provide benefit, particularly in individuals with mild/moderate deficiencies which do not have other clinical risks. The objective of this study was to establish the impact of daily vitamin D supplementation on cognition in older adults with mild to moderate vitamin D deficiency. DESIGN: Two-arm, parallel, 24-month randomized controlled trial, with vitamin D supplementation compared with a placebo. SETTING AND PARTICIPANTS: This was a remote trial, completed from home involving 620 adults, aged &#x2265; 50 years, with mild to moderate vitamin D deficiency and early cognitive impairment. METHODS: The primary outcome was executive function measured through Trail Making Test Part B and other secondary measures of cognition, function, and well-being. RESULTS: Vitamin D supplementation conferred no significant benefit to executive function compared with placebo at follow-up on the primary outcome (between-group difference, 5770; 95% CI, -2189 to 13,730) or cognition, function, or well-being. Secondary analyses in defined subgroups and a per-protocol analysis also showed no significant impact on any outcome measures. CONCLUSIONS AND IMPLICATIONS: Vitamin D supplementation produced no measurable improvement in cognitive outcomes in older adults with mild to moderate vitamin D deficiency. The remote trial methodology provides an innovative approach to large-scale trials.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36715270","title":"Vitamin D supplementation and cognition-Results from analyses of the D-Health trial.","authors":["H Pham","M Waterhouse","S Rahman","C Baxter","BD Romero","DSA McLeod","BK Armstrong","PR Ebeling"],"year":2023,"venue":"Journal of the American Geriatrics Society","doi":"10.1111/jgs.18247","pmid":"36715270","url":"https://pubmed.ncbi.nlm.nih.gov/36715270/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Observational studies have consistently found a link between low serum 25-hydroxyvitamin D concentration and higher risk of cognitive impairment. Results from randomized controlled trials have been mixed, and few have been conducted in the general population. METHODS: We recruited 21,315 community-dwelling Australians aged between 60 and 84&#x2009;years to participate in the D-Health Trial, a randomized, double-blind, placebo-controlled trial. The intervention was monthly oral doses of 60,000 international units of vitamin D or placebo for 5&#x2009;years. We assessed cognitive function in a randomly sampled group of participants aged &#x2265;70&#x2009;years using the Telephone Interview for Cognitive Status (TICS) at 2 and 5&#x2009;years after randomization. The primary outcome for this analysis was TICS score; the secondary outcome was the proportion of people who had cognitive impairment (defined as TICS score &#x2264;25). We analyzed data using mixed models (linear and logistic). RESULTS: We interviewed 3887 participants at year 2 and 3614 participants at year 5. The mean TICS score at these time points was 32.3 and 32.2, respectively. Vitamin D supplementation did not affect cognitive function as measured by TICS score (mean difference between vitamin D and placebo groups 0.04; 95% CI -0.14 to 0.23), or alter risk of cognitive impairment (odds ratio 1.00; 95% CI 0.75 to 1.33). CONCLUSIONS: Monthly bolus doses of vitamin D supplementation neither enhanced nor hindered cognitive function among older adults. Population-wide vitamin D supplementation of older adults that are largely vitamin D replete is unlikely to substantially benefit cognition.","evidenceGrade":"abstract_only"},{"id":"p-pmid-32749491","title":"Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial.","authors":["OI Okereke","CF Reynolds","D Mischoulon","G Chang","CM Vyas","NR Cook","A Weinberg","V Bubes"],"year":2020,"venue":"JAMA","doi":"10.1001/jama.2020.10224","pmid":"32749491","url":"https://pubmed.ncbi.nlm.nih.gov/32749491/","methodology":"rct","n":null,"openAccess":true,"abstract":"IMPORTANCE: Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials. OBJECTIVE: To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores. DESIGN, SETTING, AND PARTICIPANTS: There were 18&#x202f;353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25&#x202f;871 adults in the US. There were 16&#x202f;657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up. INTERVENTION: Randomized assignment in a 2&#x2009;&#xd7;&#x2009;2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points). RESULTS: Among the 18&#x202f;353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant","evidenceGrade":"full_text"},{"id":"p-pmid-36462182","title":"Effect of vitamin D supplementation on depression in older Australian adults.","authors":["ST Rahman","M Waterhouse","BD Romero","C Baxter","DR English","OP Almeida","M Berk","PR Ebeling"],"year":2023,"venue":"International journal of geriatric psychiatry","doi":"10.1002/gps.5847","pmid":"36462182","url":"https://pubmed.ncbi.nlm.nih.gov/36462182/","methodology":"rct","n":null,"openAccess":true,"abstract":"OBJECTIVES: To investigate whether vitamin D supplementation reduces depressive symptoms and incidence of antidepressant use. METHODS: We used data from the D-Health Trial (N&#xa0;=&#xa0;21,315), a randomized double-blind placebo-controlled trial of monthly vitamin D3 for the prevention of all-cause mortality. Participants were Australians aged 60-84&#xa0;years. Participants completed the Patient Health Questionnaire (PHQ-9) at 1, 2 and 5&#xa0;years after randomization to measure depressive symptoms; national prescribing records were used to capture antidepressant use. We used mixed models and survival models. RESULTS: Analyses of PHQ-9 scores included 20,487 participants (mean age 69&#xb7;3&#xa0;years, 46% women); the mean difference (MD) in PHQ-9 score (vitamin D vs. placebo) was 0&#xb7;02 (95% CI -0&#xb7;06, 0&#xb7;11). There was negligible difference in the prevalence of clinically relevant depression (PHQ-9 score &#x2265;10) (odds ratio 0&#xb7;99; 95% CI 0&#xb7;90, 1&#xb7;08). We included 16,670 participants in the analyses of incident antidepressant use (mean age 69&#xb7;4&#xa0;years, 43% women). Incidence of antidepressant use was similar between the groups (hazard ratio [HR] 1&#xb7;04; 95% CI 0&#xb7;96, 1&#xb7;12). In subgroup analyses, vitamin D improved PHQ-9 scores in those taking antidepressants at baseline (MD -0&#xb7;25; 95% CI -0&#xb7;49, -0&#xb7;01; p-interaction&#xa0;=&#xa0;0&#xb7;02). It decreased risk of antidepressant use in participants with predicted 25(OH)D concentration &lt;50&#xa0;nmol/L (HR 0&#xb7;88; 95% CI 0&#xb7;75, 1&#xb7;02; p-interaction&#xa0;=&#xa0;0&#xb7;01) and increased risk in those with predicted 25(OH)D&#xa0;&#x2265;&#xa0;50&#xa0;nmol/L (HR 1&#xb7;10; 95% CI 1&#xb7;01, 1&#xb7;20). CONCLUSION: Monthly supplementation with high-dose vitamin D3 was not of benefit for measures of depression overall, but there was some evidence of benefit in subgroup analyses. CLINICAL TRIAL REGISTRATION: The trial is registered on the Australian Ne","evidenceGrade":"full_text"},{"id":"p-pmid-30316534","title":"Effect of vitamin D supplementation on depression in elderly patients: A randomized clinical trial.","authors":["NM Alavi","S Khademalhoseini","Z Vakili","F Assarian"],"year":2020,"venue":"Clinical nutrition (Edinburgh, Scotland)","doi":"10.1016/j.clnu.2018.09.011","pmid":"30316534","url":"https://pubmed.ncbi.nlm.nih.gov/30316534/","methodology":"rct","n":null,"openAccess":false,"abstract":"BACKGROUND &amp; AIMS: Treatment of depression in elderly population is a crucial issue. The effect of vitamin D supplementation on treatment of depression in older adults was investigated in this clinical trial. METHODS: It was an 8-week, randomized clinical trial of vitamin D supplementation and placebo in the treatment of depression in 3 psychiatric clinics. The study sample included 78 older adults aged over 60 years with moderate to severe depression. Subjects were randomly allocated to receive 50,000&#xa0;U vitamin D3 pearl weekly for 8 weeks or placebo (39 subjects in each group). Main outcome measures comprised Geriatric Depression Scale-15 (GDS-15) questionnaire and 25-hydroxyvitamin D3 [25(OH)D3]. The analysis utilized Mann Whitney U test, Wilcoxon signed ranks test, chi-square and multiple regression analysis. RESULTS: The mean baseline 25(OH)D3 concentration was 22.57&#xa0;&#xb1;&#xa0;6.2&#xa0;ng/ml in vitamin D group and 21.2&#xa0;&#xb1;&#xa0;5.8&#xa0;ng/ml in placebo group (p&#xa0;=&#xa0;0.16). The Vitamin D increased to 43.48&#xa0;&#xb1;&#xa0;9.5&#xa0;ng/ml in vitamin D and 25.9&#xa0;&#xb1;&#xa0;15.3&#xa0;ng/ml in placebo group. The depression score decreased from 9.25 to 7.48 in vitamin D group (p&#xa0;=&#xa0;0.0001), while there was a non-significant increase in depression score in placebo group. The multiple regression analysis showed that the vitamin D group and the score of depression before study were the variables that could explain 81.8% of depression score after intervention. CONCLUSION: The findings indicated that vitamin D supplementation can improve the depression score in persons aged 60 and over.","evidenceGrade":"abstract_only"},{"id":"p-meng-2019","title":"Phenome-wide Mendelian-randomization study of genetically determined vitamin D on multiple health outcomes using the UK Biobank study","authors":["X. Meng","X. Li","M. N. Timofeeva"],"year":2019,"venue":"International Journal of Epidemiology","doi":"10.1093/ije/dyz182","pmid":"31518429","url":"https://pubmed.ncbi.nlm.nih.gov/31518429/","methodology":"mendelian_randomization","n":339256,"openAccess":true,"abstract":"MR-PheWAS in 339,256 White British UK Biobank participants. Genetically predicted 25(OH)D was not associated with the pre-specified disease outcomes. A wide net, and it came up empty.","evidenceGrade":"abstract_only"},{"id":"p-jiang-2021","title":"The causal role of circulating vitamin D concentrations in human complex traits and diseases: a large-scale Mendelian randomization study","authors":["X. Jiang","P. F. O'Reilly","H. Aschard"],"year":2021,"venue":"Scientific Reports","doi":"10.1038/s41598-020-80655-w","pmid":"33420254","url":"https://www.nature.com/articles/s41598-020-80655-w","methodology":"mendelian_randomization","n":443734,"openAccess":true,"abstract":"138 25(OH)D instruments against 190 GWAS. Multiple sclerosis is the standout exception; anthropometrics and most other complex traits are not. Socioeconomic success is not in the 'caused by D' column.","evidenceGrade":"abstract_only"},{"id":"p-manson-2019","title":"Vitamin D supplements and prevention of cancer and cardiovascular disease","authors":["J. E. Manson","N. R. Cook","I. M. Lee"],"year":2019,"venue":"New England Journal of Medicine","doi":"10.1056/NEJMoa1809944","pmid":"30415629","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1809944","methodology":"rct","n":25871,"openAccess":true,"abstract":"VITAL: 25,871 adults, 2000 IU/day vitamin D3. No reduction in invasive cancer or major cardiovascular events in the primary analysis. The trial that should have ended 'D pills prevent decline' as a general claim.","evidenceGrade":"abstract_only"},{"id":"p-pmid-36279545","title":"Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study.","authors":["JP Sutherland","A Zhou","E Hypp&#xf6;nen"],"year":2022,"venue":"Annals of internal medicine","doi":"10.7326/M21-3324","pmid":"36279545","url":"https://pubmed.ncbi.nlm.nih.gov/36279545/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking. OBJECTIVE: To assess genetic evidence for the causal role of low vitamin D status in mortality. DESIGN: Nonlinear Mendelian randomization analyses. SETTING: UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010. PARTICIPANTS: 307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data. MEASUREMENTS: Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020. RESULTS: There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity &lt; 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P &#x2264; 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L. LIMITATIONS: Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate. CONCLUSION: Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated ","evidenceGrade":"abstract_only"},{"id":"p-pmid-23319826","title":"Vitamin D and mortality: a Mendelian randomization study.","authors":["O Trummer","S Pilz","MM Hoffmann","BR Winkelmann","BO Boehm","W M&#xe4;rz","TR Pieber","B Obermayer-Pietsch"],"year":2013,"venue":"Clinical chemistry","doi":"10.1373/clinchem.2012.193185","pmid":"23319826","url":"https://pubmed.ncbi.nlm.nih.gov/23319826/","methodology":"observational","n":null,"openAccess":false,"abstract":"BACKGROUND: Decreased circulating 25-hydroxy-vitamin D (25-OH-vitamin D) concentrations have been associated with mortality rates, but it is unclear whether this association is causal. We performed a Mendelian randomization study and analyzed whether 3 common single-nucleotide polymorphisms (SNPs) associated with 25-OH-vitamin D concentrations are causal for mortality rates. METHODS: Genotypes of SNPs in the group-specific component gene (GC, rs2282679), 7-dehydrocholesterol reductase gene (DHCR7, rs12785878), and cytochrome P450 IIR-1 gene (CYP2R1, rs10741657) were determined in a prospective cohort study of 3316 male and female participants [mean age 62.6 (10.6) years] scheduled for coronary angiography between 1997 and 2000. 25-OH-vitamin D concentrations were determined by RIA. The main outcome measures were all-cause deaths, cardiovascular deaths, and noncardiovascular deaths. RESULTS: In a linear regression model adjusting for month of blood sampling, age, and sex, vitamin D concentrations were predicted by GC genotype (P &lt; 0.001), CYP2R1 genotype (P = 0.068), and DHCR7 genotype (P &lt; 0.001), with a coefficient of determination (r(2)) of 0.175. During a median follow-up time of 9.9 years, 955 persons (30.0%) died, including 619 deaths from cardiovascular causes. In a multivariate Cox regression adjusted for classical risk factors, GC, CYP2R1, and DHCR7 genotypes were not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality. CONCLUSIONS: Genetic variants associated with 25-OH-vitamin D concentrations do not predict mortality. This suggests that low 25-OH-vitamin D concentrations are associated with, but unlikely to be causal for, higher mortality rates.","evidenceGrade":"abstract_only"},{"id":"p-pmid-30508204","title":"Vitamin D and overall cancer risk and cancer mortality: a Mendelian randomization study.","authors":["JS Ong","P Gharahkhani","J An","MH Law","DC Whiteman","RE Neale","S MacGregor"],"year":2019,"venue":"Human molecular genetics","doi":"10.1093/hmg/ddy307","pmid":"30508204","url":"https://pubmed.ncbi.nlm.nih.gov/30508204/","methodology":"observational","n":null,"openAccess":false,"abstract":"There is considerable debate regarding the role that 25-hydroxyvitamin D [25(OH)D] concentrations play in cancer risk or mortality, with earlier studies drawing mixed conclusions. Using data from the UK Biobank (UKB), we evaluate whether genetically predicted 25(OH)D concentrations are associated with overall cancer susceptibility and cancer mortality using five 25(OH)D genetic markers. Data comprised 438&#xa0;870 white British UKB participants aged 37-73, including 46&#xa0;155 cancer cases and 6998 cancer-specific deaths. Participants with keratinocyte cancers and/or benign tumors were excluded from the analysis. Odds ratios were calculated per 20&#xa0;nmol/L increase in genetically predicted 25(OH)D for cancer risk and cancer mortality. For individual cancer risks, estimates were meta-analyzed with publicly available data using a fixed-effect inverse-variance-weighted model. We demonstrated that genetically low plasma 25(OH)D concentrations were not associated with increased cancer risk nor cancer mortality. Stratification by sex or cancer types did not reveal any meaningful differences albeit wider confidence intervals. Fixed-effect meta-analysis of our individual cancer risk estimates with those derived from publicly available cancer consortia data and previous studies further reinforced our null Mendelian randomization findings on prostate, lung, colorectal and breast cancers with tight confidence intervals; for ovarian and pancreatic cancers, our estimates were less precise despite being not statistically significant. Taken altogether, our results provide no genetic evidence for an association between vitamin D and overall cancer outcomes, with tight confidence intervals to exclude all but very small effect sizes.","evidenceGrade":"abstract_only"},{"id":"p-pmid-18511733","title":"The effect of widowhood on mortality by the causes of death of both spouses.","authors":["F Elwert","NA Christakis"],"year":2008,"venue":"American journal of public health","doi":"10.2105/AJPH.2007.114348","pmid":"18511733","url":"https://pubmed.ncbi.nlm.nih.gov/18511733/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVES: We investigated the effect of spousal bereavement on mortality to document cause-specific bereavement effects by the causes of death of both the predecedent spouse and the bereaved partner. METHODS: We obtained data from a nationally representative cohort of 373 189 elderly married couples in the United States who were followed from 1993 to 2002. We used competing risk and Cox models in our analyses. RESULTS: For both men and women, the death of a predecedent spouse from almost all causes, including various cancers, infections, and cardiovascular diseases, increased the all-cause mortality of the bereaved partner to varying degrees. Moreover, the death of a predecedent spouse from any cause increased the survivor's cause-specific mortality for almost all causes, including cancers, infections, and cardiovascular diseases, to varying degrees. CONCLUSIONS: The effect of widowhood on mortality varies substantially by the causes of death of both spouses, suggesting that the widowhood effect is not restricted to one aspect of human biology. Future research should examine the specific mechanisms of the widowhood effect and identify opportunities for health interventions.","evidenceGrade":"full_text"},{"id":"p-pmid-26894326","title":"Mortality After Bereavement: The Role of Cardiovascular Disease and Depression.","authors":["ST Stahl","AM Arnold","JY Chen","S Anderson","R Schulz"],"year":2017,"venue":"Psychosomatic medicine","doi":"10.1097/PSY.0000000000000317","pmid":"26894326","url":"https://pubmed.ncbi.nlm.nih.gov/26894326/","methodology":"observational","n":null,"openAccess":true,"abstract":"OBJECTIVES: Late-life bereavement is associated with an increased risk of mortality. This study assesses the associations among bereavement, cardiovascular disease (CVD), and depressive symptoms on mortality in older men and women. METHODS: We examined data from the Cardiovascular Health Study, a prospective population-based cohort study of older adults. We compared mortality in those who became bereaved from 1989 to 1999 (n = 593) to an age- and sex-matched sample of individuals who remained married (n = 593). Cox regression was used to examine the association between bereavement and 3-year all-cause mortality and whether or not the association differed by sex, presence of CVD, or postbereavement depressive symptoms. RESULTS: One hundred ninety-nine (16.8%) individuals died. There was no association of bereavement with mortality (hazard ratio [HR] = 0.98 [0.74-1.30]). However, there were significant interaction effects of bereavement with participant sex (p &lt; .001) and CVD (p = .010). Bereavement decreased the risk of mortality in women (HR = 0.67 [0.46-0.97]) and increased the risk of mortality in men (HR = 1.77 [1.14-2.75]). Within sex, the association of bereavement with mortality differed according to CVD status. The reduced risk of mortality associated with bereavement in women was only observed in women with CVD, and the increased risk in men was only observed in men without CVD. High levels of depressive symptoms attenuated the relation between bereavement and mortality in men without CVD. CONCLUSIONS: The relation between bereavement and mortality was different in men and women and varied by CVD status. Bereavement decreased mortality in women with CVD and increased mortality in men without CVD.","evidenceGrade":"full_text"},{"id":"p-booth-1989","title":"Testosterone, and winning and losing in human competition","authors":["A. Booth","G. Shelley","A. Mazur","G. Tharp","R. Kittok"],"year":1989,"venue":"Hormones and Behavior","doi":"10.1016/0018-506X(89)90042-1","pmid":"2638686","url":"https://pubmed.ncbi.nlm.nih.gov/2638686/","methodology":"longitudinal","n":6,"openAccess":false,"abstract":"University tennis players across a season: T rose before matches and rose after wins relative to losses, especially when mood about the victory was high. Tiny N; historically important.","evidenceGrade":"abstract_only"},{"id":"p-pmid-17010236","title":"Effects of zinc supplementation on cognitive function in healthy middle-aged and older adults: the ZENITH study.","authors":["EA Maylor","EE Simpson","DL Secker","N Meunier","M Andriollo-Sanchez","A Polito","B Stewart-Knox","C McConville"],"year":2006,"venue":"The British journal of nutrition","doi":null,"pmid":"17010236","url":"https://pubmed.ncbi.nlm.nih.gov/17010236/","methodology":"rct","n":null,"openAccess":false,"abstract":"A randomised double-blind placebo-controlled design was employed to investigate the effects of Zn supplementation on cognitive function in 387 healthy adults aged 55-87 years. Several measures of visual memory, working memory, attention and reaction time were obtained using the Cambridge Automated Neuropsychological Test Battery at baseline and then after 3 and 6 months of 0 (placebo), 15 or 30 mg Zn/d. Younger adults (&lt; 70 years) performed significantly better on all tests than older adults (&gt; 70 years), and performance improved with practice on some measures. For two out of eight dependent variables, there were significant interactions indicating a beneficial effect (at 3 months only) of both 15 and 30 mg/d on one measure of spatial working memory and a detrimental effect of 15 mg/d on one measure of attention. Further work is required to establish whether these findings generalise to older adults in poorer mental and physical health and with less adequate Zn intake and status than the present sample.","evidenceGrade":"abstract_only"},{"id":"p-pmid-37892471","title":"Effects of Zinc Supplementation on Inflammatory and Cognitive Parameters in Middle-Aged Women with Overweight or Obesity.","authors":["LDS de Vargas","J Jantsch","JR Fontoura","GP Dorneles","A Peres","RP Guedes"],"year":2023,"venue":"Nutrients","doi":"10.3390/nu15204396","pmid":"37892471","url":"https://pubmed.ncbi.nlm.nih.gov/37892471/","methodology":"rct","n":null,"openAccess":true,"abstract":"Obesity has been linked to cognitive decline and adverse effects on brain health. Zinc (Zn) is a mineral with important metabolic functions that can modulate obesity-related neurological impairment. Thus, the present study aimed to evaluate the effects of 12 weeks of Zn supplementation on the inflammatory profile, cognitive function, and mood of overweight or obese women through a double-blind, placebo-controlled study. The study included 42 women aged between 40 and 60, randomly divided into two groups: Zn supplementation (30 mg/day) or placebo for 12 weeks. Data regarding sociodemographic, anthropometric, dietary, and physical activity were collected. Mini-mental state examination (MMSE), verbal fluency test, clock drawing test, and Stroop test were performed. Anxiety and depression symptoms were assessed using the Beck anxiety inventory and the BDI-II, respectively. Saliva samples were collected to evaluate IL-1&#x3b2;, IL-6, TNF-&#x3b1;, insulin, nitrite, and Zn levels. Of the 42 participants (mean age 49.58 &#xb1; 6.46 years), 32 were included in the study analyses. Changes in body weight and macronutrient consumption were not different between placebo and Zn supplementation groups. Cognitive scores on the MMSE and Stroop tests were higher in the Zn supplementation group than in the placebo group. Salivary levels of IL-1b and Zn increased in the Zn group compared to placebo. There was no significant change in the adjusted means of the BDI-II and BECK scores between the zinc vs. placebo groups. Twelve weeks of Zn supplementation was able to partially improve the cognitive scores assessed in overweight or obese women, regardless of weight loss. These findings suggest that Zn supplementation can be considered an adjunct strategy to enhance cognitive health in overweight or obese women.","evidenceGrade":"full_text"},{"id":"p-pmid-7051913","title":"Effect of oral zinc therapy on gonadal function in hemodialysis patients. A double-blind study.","authors":["SK Mahajan","AA Abbasi","AS Prasad","P Rabbani","WA Briggs","FD McDonald"],"year":1982,"venue":"Annals of internal medicine","doi":null,"pmid":"7051913","url":"https://pubmed.ncbi.nlm.nih.gov/7051913/","methodology":"observational","n":null,"openAccess":false,"abstract":"Zinc deficiency may account for the persistence of gonadal dysfunction in a majority of uremic men despite adequate dialysis. Twenty stable patients having hemodialysis three times a week completed a double-blind trial using either 50 mg of elemental zinc as zinc acetate (10 patients) or placebo (10 patients), orally. At the end of the 6-month study period, a significant increase in the mean (+/- SE) plasma zinc (75 +/- 2 micrograms/dL to 100 +/- 2 micrograms/dL, p less than 0.001), serum testosterone (2.8 +/- 0.3 ng/dL to 5.2 +/- 0.5 ng/mL, p less than 0.001), and sperm count (30 +/- 3 million/mL to 63 +/- 5 million/mL, p less than 0.001) occurred in the zinc-treated group, but not in those receiving the placebo. The zinc-treated group also had a significant fall in serum luteinizing hormone (92 +2- 10 mIU/mL to 49 +/- 26 mIU/mL, p less than 0.005) and follicle stimulating hormone (45 +/- 9 mIU/mL to 25 +/- 7 mIU/mL, p less than 0.05), not seen in the placebo group. Patients receiving zinc had an improvement in potency, libido, and frequency of intercourse not found in the placebo group. These results suggest that zinc deficiency is a reversible cause of gonadal dysfunction in patients having regular hemodialysis.","evidenceGrade":"abstract_only"},{"id":"p-pmid-8875519","title":"Zinc status and serum testosterone levels of healthy adults.","authors":["AS Prasad","CS Mantzoros","FW Beck","JW Hess","GJ Brewer"],"year":1997,"venue":"Nutrition (Burbank, Los Angeles County, Calif.)","doi":null,"pmid":"8875519","url":"https://pubmed.ncbi.nlm.nih.gov/8875519/","methodology":"observational","n":null,"openAccess":false,"abstract":"Zinc deficiency is prevalent throughout the world, including the USA. Severe and moderate deficiency of zinc is associated with hypogonadism in men. However, the effect of marginal zinc deficiency on serum testosterone concentration is not known. We studied the relationship between cellular zinc concentrations and serum testosterone cross-sectionally in 40 normal men, 20 to 80 y of age. In four normal young men (27.5 +/- 0.5 y), we measured serum testosterone before and during marginal zinc deficiency induced by restricting dietary zinc intake. We also measured serum testosterone in nine elderly men (64 +/- 9 y) who were marginally zinc deficient before and after 3 to 6 mo of supplementation with 459 mumol/ d oral zinc administered as zinc gluconate. Serum testosterone concentrations were significantly correlated with cellular zinc concentrations in the cross-sectional study (lymphocyte zinc versus serum testosterone, r = 0.43, p = 0.006; granulocyte zinc versus serum testosterone, r = 0.30, p = 0.03). Dietary zinc restriction in normal young men was associated with a significant decrease in serum testosterone concentrations after 20 weeks of zinc restriction (baseline versus post-zinc restriction mean +/- SD, 39.9 +/- 7.1 versus 10.6 +/- 3.6 nmol/L, respectively; p = 0.005). Zinc supplementation of marginally zinc-deficient normal elderly men for six months resulted in an increase in serum testosterone from 8.3 +/- 6.3 to 16.0 +/- 4.4 nmol/L (p = 0.02). We conclude that zinc may play an important role in modulating serum testosterone levels in normal men.","evidenceGrade":"abstract_only"}],"cases":[{"id":"cycle-shifts","slug":"cycle-shifts","title":"The ovulatory-shift fight","dek":"Two meta-analyses in the same year. The honest atlas keeps both and refuses the calendar hack.","folkClaim":"Women want dominant men at peak fertility. Time the ask to the luteal phase. Estradiol is the dial.","actualFinding":"Gildersleeve, Haselton, and Fales (2014) reported cycle shifts toward masculine and dominant cues. Wood, Kressel, Joshi, and Louie (2014) reported that those shifts mostly vanish under a different meta-analytic lens. Estradiol is the named mediator in the positive story. Neither paper licenses a negotiation calendar, and neither identifies dominance-strategy as this atlas uses the term.","takeaway":"When two competent metas collide, the stamp is contested. Cite both. Do not sell a cycle hack.","layerIds":["biology","psychology"],"edgeIds":["e-estradiol-cycle-pref"],"paperIds":["p-gildersleeve-2014","p-wood-2014"],"sections":[{"heading":"What the positive meta claimed","body":"Gildersleeve et al. aggregated cycle-shift studies and reported that preferences for purported good-gene cues rose near ovulation. That is the paper Instagram needed. It is also a paper about facial masculinity and scent, not about who becomes CFO."},{"heading":"What the other meta took away","body":"Wood et al. argued that researcher degrees of freedom and fertile-window coding were doing more work than hormones. A reader who only cites Gildersleeve is doing advocacy. A reader who only cites Wood is doing the mirror image."},{"heading":"What this atlas does with a split literature","body":"The edge stays on the atlas, stamped spurious-until-settled (contested confidence), with both DOIs. Inquire will not tell you to change a pitch meeting. If a preregistered, large, hormonal-assay study later identifies a narrow effect, we upgrade the stamp. We do not upgrade the folklore."}]},{"id":"dual-hormone","slug":"dual-hormone","title":"The dual-hormone hypothesis","dek":"High testosterone is not a leadership stack. It is a term in an interaction, and the other term is cortisol.","folkClaim":"High testosterone makes leaders. Optimize T and you optimize status.","actualFinding":"Mehta and Josephs (2010) found T related to dominant, leader-like behavior only when cortisol was low. When cortisol was high, the relationship vanished or reversed. Mehta and Prasad (2015) and Carré and Olmstead (2015) refined the claim around contest-induced T change. Later quantitative reviews find a small, messy effect. The folk line is a dropped interaction term.","takeaway":"If you insist on an endocrine story of rank, tell the two-hormone story, cite the small effect, and remember that lab leadership is not a P&L.","layerIds":["biology","psychology"],"edgeIds":["e-t-status-dual","e-cortisol-moderates-t","e-win-testosterone","e-t-ultimatum-rct"],"paperIds":["p-mehta-josephs-2010","p-mehta-prasad-2015","p-carre-olmstead-2015","p-eisenegger-2010","p-geniole-2020"],"sections":[{"heading":"The paper that should have killed the slogan","body":"Mehta and Josephs ran leadership and competition protocols and plotted T against behavior at high vs low cortisol. The simple slope that Instagram wanted existed on one side of the split only. On the other side it died. That is an interaction, and interactions are easy to hide in a thread."},{"heading":"What exogenous T actually did to bargaining","body":"The brief mentioned 'Camerer et al.' and the ultimatum game. The Nature experiment is Eisenegger et al. (2010): T made women more fair as proposers; the belief that one received T made them less fair. Zak (2009) found less male generosity. Cueva et al. (2017) found a null on male rejections. This atlas keeps all three on the same edge. A contested RCT is still more informative than a confident blog."},{"heading":"The loop people skip","body":"Mazur and Booth's winner–loser model is a feedback loop: the contest moves T, T colors the next contest. Treating T as a fixed 'level you optimize' misses the dynamics. Sleep restriction (Leproult 2011; Spiegel 1999) is a cleaner experimental handle on the same system than a supplement stack."}]},{"id":"income-mate-preferences","slug":"income-mate-preferences","title":"Income, power, and who we choose","dek":"Hypergamy is real as a historical average and incomplete as a law. Close the income gap and the market switches toward homogamy.","folkClaim":"High-earning men are biologically programmed to chase youth; high-earning women still chase richer men. The preference is an instinct, not a budget.","actualFinding":"Buss (1989) does show sex-typical stated weights: men on youth/attractiveness, women on earning capacity. Fisman, Iyengar, Kamenica, and Simonson (2006) show those weights in a real choice environment — and also show intelligence, race, neighborhood affluence, and own-ambition ceilings. The modern quantitative reading is an incentives story: as women's own income and education rise, strict economic hypergamy loosens and educational/cultural homogamy takes the slack.","takeaway":"Treat mate preference as a function of market position and insurance, then look for residual sex differences. Do not start from the residual and work backwards to a myth.","layerIds":["ses","psychology"],"edgeIds":["e-income-youth-pref","e-income-hypergamy","e-education-homogamy"],"paperIds":["p-fisman-2006","p-buss-1989"],"sections":[{"heading":"What the surveys actually asked","body":"Buss's 37-culture study is a stated-preference inventory, not a marriage registry. It is large, famous, and the correct citation for 'on average, men say they want younger partners and women say they want providers'. It is the wrong citation for 'therefore a raise will change your type'. Stated preference plus social-desirability is a soft instrument."},{"heading":"What the Columbia rooms revealed","body":"Fisman et al. randomly seated Columbia speed-daters and recorded yes/no decisions, not essays. Men put more weight on physical attractiveness. Women put more weight on intelligence and race, preferred men from affluent neighborhoods, and men's value for a woman's intelligence/ambition fell once it exceeded their own. That is a much sharper object than a magazine listicle."},{"heading":"The identification problem","body":"Nobody randomized wealth. Neighborhood affluence, education, and beauty are bundled. The backdoor from income to preference runs through the rooms you are allowed to enter. Close those rooms — or equalize female earnings — and the revealed weights move. That is why this atlas marks the income→preference edges spurious-until-identified, not 'debunked' and not 'proven instinct'."}]},{"id":"pose-and-spray","slug":"pose-and-spray","title":"Poses, sprays, and the replication wave","dek":"Two TED-ready hormones. Two failed replications. The atlas keeps the original RCTs and the papers that took them down.","folkClaim":"Stand like a CEO and your hormones will make you one. Spray oxytocin and strangers will trust you.","actualFinding":"Carney, Cuddy, and Yap (2010) reported that two minutes of expansive posture raised testosterone, cut cortisol, and increased risk-taking (N=42). Ranehill et al. (2015) ran 200 people and found no hormone or risk effect. Simmons and Simonsohn (2017) p-curved the supportive set and found it consistent with selective reporting. Kosfeld et al. (2005) reported that intranasal oxytocin raised trust-game transfers. Nave, Camerer, and McCullough (2015) reviewed the follow-ups as inconclusive. Declerck et al. (2020), including Fehr, registered a high-powered replication with the original social-contact condition and found no OT effect on trusting behavior there.","takeaway":"A viral RCT that dies in a larger registered study stays on the atlas as smoke, with both papers linked. Replication is a stamp, not a vibe.","layerIds":["biology","psychology","lifestyle"],"edgeIds":["e-pose-testosterone","e-pose-risk","e-oxytocin-trust"],"paperIds":["p-carney-2010","p-ranehill-2015","p-simmons-2017","p-kosfeld-2005","p-nave-2015","p-declerck-2020"],"sections":[{"heading":"What the 2010 pose paper claimed","body":"Carney, Cuddy, and Yap assigned 42 people to expansive or contractive poses for two minutes and reported a T rise, a cortisol drop, and more risk-taking. That is a real RCT. It is also N=42 on three correlated outcomes. The TED talk dropped the sample size and kept the endocrine story. The folk mechanism needs the hormone step. Without it, 'feeling powerful' is a mood item."},{"heading":"What the larger test and the p-curve took away","body":"Ranehill, Dreber, Johannesson, Leiberg, Sul, and Weber (2015) used the same pose logic in 200 men and women and found no effect on T, cortisol, or risk. Simmons and Simonsohn (2017) p-curved the supportive postural-feedback set Carney et al. had cited and found a distribution you would expect if the average effect were zero and significant results were selected. A later reply argued for self-report effects in a wider set. That is a different claim than 'the pose moves androgens.' This atlas stamps the hormone and risk arrows smoke."},{"heading":"The spray, and Camerer on the right paper","body":"Kosfeld, Heinrichs, Zak, Fischbacher, and Fehr (2005) is the Nature RCT behind 'oxytocin is the trust hormone.' Nave, Camerer, and McCullough (2015) is the review that should have ended the slogan — and the paper that actually has Camerer on it, unlike the ultimatum T trial the brief misattributed. Declerck, Boone, Pauwels, Vogt, and Fehr (2020) then registered a 677-person double-blind replication, including the original minimal-social-contact condition, and found no OT effect on trusting behavior there. Fehr signed both the discovery and the registered null. We keep both. We do not sell a spray."}]},{"id":"sleep-is-the-handle","slug":"sleep-is-the-handle","title":"Sleep is the handle","dek":"Restriction trials move T, cortisol, glucose, and attention. A mattress is not a promotion — and a spray is not a substitute.","folkClaim":"Optimize testosterone and focus with a stack. Sleep is hygiene. The causal inputs are pills, poses, and grit.","actualFinding":"Leproult and Van Cauter (2011) cut young men's nights to five hours for a week and lowered daytime T about 10–15% (N=10). Spiegel, Leproult, and Van Cauter (1999) raised evening cortisol and pushed glucose tolerance into a pre-diabetic band. Lim and Dinges (2010) meta-analyzed short-term deprivation and found reliable losses on vigilance and working memory. Alcohol sits on the backdoor: it fragments the night that those trials restricted. The identified object is hours, not a title.","takeaway":"If you want a lifestyle arrow onto the dual-hormone system, cite hours of sleep. Inquire will still name alcohol as an open backdoor. Do not smuggle a career claim.","layerIds":["lifestyle","biology","psychology"],"edgeIds":["e-sleep-testosterone","e-sleep-cortisol","e-sleep-insulin","e-sleep-cognition","e-alcohol-sleep"],"paperIds":["p-leproult-2011","p-spiegel-1999","p-lim-dinges-2010","p-emanuele-2001"],"sections":[{"heading":"The trial that actually moved T","body":"Leproult 2011 is small and male and one week long. It is also a restriction protocol with a named hormone outcome. That is more identification than a pose, a spray, or an optimization panel. This atlas stamps it MECHANISM and writes the N on the edge. A mattress brand that cites this paper for 'executive androgen' is smuggling."},{"heading":"Cortisol, glucose, and attention are the same handle","body":"Spiegel 1999 is the HPA and metabolic twin: sleep debt leaves evening cortisol high and wrecks glucose tolerance. Lim and Dinges 2010 take the same exposure onto vigilance and working memory. If you only cite the T paper you are doing advocacy for a supplement stack. The honest object is time asleep, with three named outcomes."},{"heading":"The backdoor Inquire will not let you skip","body":"Alcohol fragments the second half of the night. A sleep protocol that ignores drinks is theatre. Inquire from sleep to T stays blocked_by_backdoor for that reason — not because the restriction trial is fake. A real handle can still have an open door. That is the point of the engine."}]},{"id":"supplements-healthy-user","slug":"supplements-healthy-user","title":"Pills, paychecks, and the healthy user","dek":"People who buy omega-3 and vitamin D look employable. The bottles are not why.","folkClaim":"Supplement users have lower unemployment and better jobs. Therefore the pills cause the career.","actualFinding":"This is the textbook Healthy User Effect (Shrank, Patrick, Brookhart 2011). Mendelian randomization of 25(OH)D (Meng 2019; Jiang 2021) does not produce socioeconomic or general-disease effects. VITAL (Manson 2019) does not produce the promised cancer or cardiovascular benefit in a general population. Autier et al. (2014) already warned that observational D is a marker of ill health. Condition on income, education, and outdoor time and the career arrow disappears. What remains are clinical-deficiency corrections.","takeaway":"If a health input can be bought, income is on the backdoor. Genetic instruments and RCTs are how this atlas takes the backdoor away.","layerIds":["lifestyle","ses","biology"],"edgeIds":["e-supplements-employment","e-omega3-employment","e-vitd-employment-mr","e-vitd-income-spurious","e-income-buys-supplements","e-outdoors-vitd"],"paperIds":["p-shrank-2011","p-meng-2019","p-jiang-2021","p-manson-2019","p-autier-2014"],"sections":[{"heading":"Name the bias","body":"Healthy users floss, show up to work, fill preventive prescriptions, and buy fish oil. Their kids' schools and their parents' degrees came first. An observational regression of job quality on pill count without those covariates is a press release, not an estimate."},{"heading":"What genetics and trials take away","body":"MR asks: do people whose genomes push 25(OH)D higher have different lives? In UK Biobank-scale data, not in the ways wellness marketing needs. VITAL asks a related question with a pill and a randomization. The primary endpoints did not move. Together they identify the observational D–success link as smoke."},{"heading":"What remains after the demolition","body":"Treat deficiency. B12 in the deficient, iron in the anemic, D in the dark and institutionalized. Those are medical arrows onto fatigue and bone, maybe mood. They are not arrows onto title, comp, or mate value. This atlas will keep those clinical edges if and when a paper identifies them — and will refuse to let them smuggle a career claim."}]}]}