Importance:Higher coffee intake has been associated with lower risk of type 2 diabetes (T2D), but the underlying biological pathways remain incompletely understood. Objective:To examine associations of coffee intake with insulin sensitivity, adiposity, and T2D risk, and assess whether coffee intake modifies associations between pathway-specific genetic susceptibility and incident T2D. Design Setting and Participants:Cross-sectional analyses among 806 participants without T2D in the VITamin D and OmegA-3 TriaL (VITAL) clinical sub-cohort, who underwent repeated dietary assessment, clinical phenotyping, and dual-energy X-ray absorptiometry imaging at baseline and year-2. Prospective analyses among 333,053 UK Biobank participants without T2D at baseline who had dietary and genetic data and were followed for a median of 13.3 years. Exposures:Coffee intake assessed by food frequency questionnaires. In UK Biobank, 12 pathway-specific polygenic scores (pPS) representing distinct T2D pathophysiological mechanisms were evaluated. Main Outcomes and Measures:The primary outcomes, in VITAL, were HbA1c, oral glucose tolerance test-derived measures of glucose response and insulin sensitivity, β-cell function, and overall, truncal, and visceral adiposity; in UK Biobank, was incident T2D. Results:In VITAL, higher coffee intake was associated with higher insulin sensitivity (standardized β per cup/day, 0.046; P = .004) and lower visceral adipose tissue mass (β, -0.047; P = .006), after adjusting for demographic, lifestyle, and clinical factors, including body mass index. In UK Biobank, higher coffee intake was associated with lower T2D incidence (hazard ratio per cup/day, 0.96; 95% CI, 0.95-0.97), lower triglyceride-to-HDL cholesterol ratio (β,-0.01; P = 2.51 × 10^-19), and lower visceral adipose tissue mass (β, -0.01; P = 4.28 × 10^-9). Associations of 3 pPS related to insulin resistance and fat distribution with incident T2D were attenuated among participants consuming higher amount of coffee than among non-consumers (P for interaction < .0043). Conclusions and Relevance:Higher coffee intake was associated with greater insulin sensitivity, lower visceral adiposity, and lower risk of T2D. Together with the attenuation of associations between pathway-specific genetic susceptibility and T2D risk among higher coffee consumers, these findings suggest that insulin resistance and visceral adiposity-related pathways may contribute to the association between coffee intake and T2D risk. Key Points:Question: Is coffee intake associated with specific insulin sensitivity and adiposity markers, and type 2 diabetes risk, and does it modify associations between pathway-specific genetic susceptibility and type 2 diabetes?Findings: In analyses repeated dietary, clinical, and imaging phenotyping in 806 VITAL participants and prospective data from 333,053 UK Biobank participants, higher coffee intake was associated with greater insulin sensitivity, lower visceral adiposity, and lower type 2 diabetes risk. Higher coffee intake also attenuated associations of three pathway-specific polygenic scores related to insulin resistance and fat distribution with type 2 diabetes risk.Meaning: These findings suggest that pathways related to insulin sensitivity and visceral adiposity may contribute to the associations between coffee intake and lower type 2 diabetes risk.

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

Importance:There is limited research on the long-term associations of plasma phosphorylated tau 217 (p-tau217) with mild cognitive impairment (MCI) and dementia. No study has evaluated whether such associations vary by race or hormone therapy (HT) use. Objective:To examine associations of baseline plasma p-tau217 with incident MCI and dementia and determine whether associations vary by age, race, APOE ε4 carrier status, or HT use. Design, Setting, and Participants:This cohort study examined women recruited from 39 US clinical sites between 1996 and 1999 into the Women's Health Initiative Memory Study who were randomized to either estrogen alone vs placebo or estrogen plus progestin vs placebo. Women were assessed for up to 25 years through 2021. Baseline plasma p-tau217 was measured in 2024 and analyzed between February and August 2025. Women aged 65 to 79 years who were cognitively unimpaired at baseline were included for this analysis. Exposure:Plasma p-tau217, quantified using the ALZpath Simoa assay. Main Outcomes and Measures:The primary outcome was the combined end point of incident MCI or probable dementia. Secondary outcomes included MCI and dementia examined separately. Cause-specific hazard ratios (HRs) and 95% CIs for the association of p-tau217 with MCI or dementia were estimated using Cox proportional hazards regression models. Results:Among 2766 participants (mean [SD] age, 69.9 [3.8] years; 486 [17.9%] Black, 196 [7.1%] Hispanic, and 2007 [73.9%] White), 1311 developed the combined end point of MCI or dementia (849 participants with MCI and 752 participants with dementia). Every 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR, 2.43; 95% CI, 2.18-2.71) and each individual outcome (MCI: HR, 1.94; 95% CI, 1.72-2.20; dementia: HR, 3.17; 95% CI, 2.79-3.61). Associations of p-tau217 with dementia were larger in magnitude for women randomized to estrogen plus progestin (HR, 4.18; 95% CI, 3.41-5.13) vs placebo (HR, 3.07; 95% CI, 2.41-3.91) (P for interaction = .04) but did not significantly vary by estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared with Black women (P for interaction < .001). However, the combination of p-tau217 and age performed similarly in White women (area under the curve = 72.0%; 95% CI, 70.3%-73.6%) and Black women (area under the curve = 70.4%; 95% CI, 64.0%-78.0%). P-tau217 was not associated with incident MCI in Black women. Conclusions and Relevance:In this cohort study of cognitively unimpaired older women, p-tau217 was associated with incident MCI or dementia up to 25 years later. These findings suggest that age, race, APOE ε4, and HT use should be considered when examining associations of p-tau217 with cognitive outcomes.

CONTEXT:Endothelial dysfunction and altered psychological measures have been identified in women with functional hypothalamic amenorrhea (FHA). Estradiol (E2) replacement, a known vasodilator, may potentially reverse vascular dysfunction and improve psychological health. OBJECTIVE:To evaluate 12 weeks of physiologic E2 replacement on vascular, hormonal, and psychological outcomes in women with FHA. METHODS:A randomized, double-blind, placebo-controlled trial was conducted in 29 women with FHA with 0.1 mg/day transdermal E2 (n = 14) or placebo patch (n = 15) twice weekly for 12 weeks. FHA was defined as amenorrhea ≥3 consecutive months, E2 < 50 pg/mL, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) <10 mIU/L, LH:FSH <1, excluding other etiologies. Endothelial dysfunction (reactive hyperemic index ≤ 1.67) was assessed, as were hormonal and psychological measures. RESULTS:Women with FHA had a mean age of 26.2 ± 6.3 years, body mass index of 21.5 ± 3.3 kg/m2, with 63% being non-Hispanic White. Baseline characteristics did not differ between groups. After 12 weeks, E2 levels were significantly higher in the E2 group (112.0 vs 36.5 pg/mL, P = .0002). However, there were no significant differences in vascular, hormonal, or psychological outcomes between E2 and placebo groups at week 12. Cortisol levels showed a near-significant decrease in the E2 group compared to an increase with placebo (-.4 vs 3.1 µg/dL, P = .05). CONCLUSION:In women with FHA, 12 weeks of transdermal E2 increased serum E2 levels but did not improve vascular or psychological health measures. Further studies with larger sample sizes and longer follow-up are needed to explore the long-term effects of E2 therapy on cardiovascular and mental health outcomes in this population.

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend reducing saturated fat intake to lower LDL-C. However, the response to saturated fat in the diet is highly heterogeneous. Genetic factors may contribute to individual differences in response to saturated fat. Objectives: We aimed to examine whether genetic propensity for higher LDL-C modifies the association of saturated fat intake with LDL-C and incident ASCVD. Methods: We studied 20,940 genotyped postmenopausal women from the Women's Health Initiative. Exposures included saturated fat intake (percentage of total calories) derived from food frequency questionnaires and a genome-wide polygenic score for LDL-C (PGS-LDL). The primary outcome was LDL-C. The secondary outcome was incident ASCVD. Associations were assessed using multivariable linear and Cox regressions. Effect modification was evaluated using interaction terms and restricted cubic spline analyses. Models were adjusted for demographic, anthropometric, lifestyle, clinical, genetic, and technical covariates. Results: The median LDL-C at baseline for participants with PGS-LDL below and above the median was 135 mg/dL [Q1: 114, Q3: 160] and 162 mg/dL [137, 188], respectively. Saturated fat intake was positively associated with LDL-C in the high PGS-LDL group, but the association attenuated in the low PGS-LDL group (P-interaction for LDL-C = 0.01). Spline analysis revealed a non-linear interaction between PGS-LDL and saturated fat, with modifying effects emerging at higher PGS-LDL. Compared to individuals with low PGS-LDL and low saturated fat intake, only those with both high PGS-LDL and high saturated fat intake had increased risk for ASCVD in an adjusted analysis (HR 1.45, 95% CI 1.20-1.75). This association remained significant after further adjustment for baseline untreated LDL-C (HR 1.29, 95% CI 1.06-1.56), and evidence of an additive interaction was observed (relative excess risk due to interaction 0.37, 95% CI 0.06-0.67]). Conclusions: These findings suggest that the association between saturated fat intake and LDL-C and subsequent ASCVD risk may be stronger for individuals with a genetic propensity towards high LDL-C.

Importance:Weight gain is common during menopause, and healthy dietary patterns are key to its management. However, effectiveness of different diets for weight management during this period remains unclear. Objective:To examine and compare associations of multiple dietary patterns with weight gain and obesity risk in the years surrounding menopause. Design, Setting, and Participants:This prospective, population-based cohort study included women observed over a 12-year period surrounding menopause in the Nurses' Health Study II (1989-2019). Data analysis was performed between November 2024 and May 2025. Exposures:Diet was assessed every 4 years using validated food frequency questionnaires. Dietary scores included the plant-based diet index (PDI), healthy PDI, unhealthy PDI, Mediterranean diet, Dietary Approaches to Stop Hypertension, Planetary Health Diet Index (PHDI), low-carbohydrate diet (LCD), healthy LCD, unhealthy LCD, empirical dietary inflammatory pattern, empirical dietary index for hyperinsulinemia (EDIH), and ultraprocessed food intake. Main Outcomes and Measures:The outcomes were annual changes in self-reported body weight (kilograms per year) and incident obesity. Generalized estimating equations were used to estimate annual weight change across dietary patterns. Cox proportional hazards models were used to estimate risk of obesity across dietary patterns. Results:Among 38 283 women (mean [SD] age, 45.6 [3.0] years), the mean (SD) weight gain was 0.80 (1.00) kg per year. During 340 122 person-years of follow-up, 5214 women developed obesity. After adjusting for age, race and ethnicity, marital status, income, postmenopausal hormone therapy use, parity, smoking, alcohol, energy intake, physical activity, and baseline body mass index, the reverse EDIH (quintile 5 vs 1) was associated with the largest reduction in weight gain (mean, -0.28 kg/y; 95% CI, -0.30 to -0.26 kg/y). For incident obesity, the lowest risk was observed for the PHDI (hazard ratio, 0.46; 95% CI, 0.42 to 0.51) and reverse EDIH (hazard ratio, 0.51; 95% CI, 0.46 to 0.56). EDIH showed the largest positive correlations with red or processed meats, sodium, and French fries. PHDI showed the largest positive correlations with nuts, unsaturated fats, whole grain carbohydrates, and vegetable protein. Conclusions and Relevance:In this prospective cohort study of women during menopause, adopting low-insulinemic and planetary health diets, low in red and processed meats, sodium, potatoes, and French fries and rich in nuts, legumes, fruits, vegetables, and whole grains, was associated with optimized weight management.

INTRODUCTION:Cognitive impairment among older adults is often due to multiple pathologies and heterogenous risk factors. We assessed whether Alzheimer's blood-based biomarkers (BBMs) were associated with incident mild cognitive impairment (MCI)/probable dementia, and whether associations were modified by age, apolipoprotein E (APOE), and hormone therapy (HT). METHODS:Analyses included 2467 Women's Health Initiative Memory Study women (≥65 years of age) randomized between 1995 and 1998 to 3-5-years of HT or placebo. Cox regression (mean 18-year follow-up) assessed associations between the z-scored BBMs and MCI/dementia. RESULTS:Lower baseline amyloid beta (Aβ)42/40 ratio and higher phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were associated with an increased risk of MCI and dementia; GFAP was most strongly associated. The p-tau181 and NfL associations were stronger among APOE ε4 carriers; BBMs varied non-linearly by age. The associations of BBMs with the cognitive outcomes also varied inconsistently between HT groups. DISCUSSION:BBMs for AD and related dementias (ADRD) are associated with incident MCI/dementia in older women. Interactions between the BBMs and HT were inconsistent and require further investigation.

BACKGROUND:Data from randomized controlled trials of vitamin D3 supplementation in modifying the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are sparse. OBJECTIVES:We evaluated the effect of vitamin D3 supplementation on healthcare utilization and other clinical outcomes among adults with coronavirus disease 2019 (COVID-19) and their close contacts. METHODS:We conducted a parallel 2-group randomized controlled double-blinded trial targeting free-living adults in the United States and Mongolia. Index participants with newly diagnosed COVID-19 were cluster-randomized with up to one of their cohabiting contacts either to an oral vitamin D3 loading dose of 9600 IU/d for 2 d followed by 3200 IU/d for 4 wk or to placebo. Participants completed weekly questionnaires on healthcare utilization, disease severity, and long COVID (index participants) or new SARS-CoV-2 infection (household contacts). The primary outcome was ≥1 healthcare visits (including hospitalization) or death within 4 wk among the index participants. RESULTS:Index participants (n = 1747) were a median of 38.0 y old (IQR: 31.1-47.0), 65.6% female/other sex, 4.2% Black non-Hispanic, 4.8% Hispanic/Latinx, 43.2% Asian, 44.3% non-Hispanic White, and 44.9% vitamin D deficient or insufficient (25-hydroxyvitamin D3 <20 ng/mL). Baseline characteristics for the household contacts (n = 277) were similar. The 4-wk cumulative incidence of healthcare utilization in index participants did not significantly differ between the vitamin D3 (n = 863) and placebo (n = 884) groups [cumulative incidences, 0.28 compared with 0.29; odds ratio (OR), 0.97; 95% confidence interval (CI): 0.75, 1.24]. Similar nonsignificant results were observed for the prespecified secondary treatment and prevention outcomes, though per-protocol analyses showed a nonsignificant trend toward benefit of vitamin D3 on the prevalence of long COVID at 8 wk (OR, 0.78; 95% CI: 0.59, 1.03). No safety concerns were identified. CONCLUSIONS:Among adults with newly diagnosed SARS-CoV-2 infections, vitamin D3 supplementation did not significantly change the 4-wk cumulative incidence of healthcare utilization or COVID-19-related outcomes compared with placebo. Promising results for long COVID warrant further study. This study was registered at clinicaltrials.gov as NCT04536298. First registered on 1 September, 2020.

BACKGROUND:Type 2 diabetes (T2D) is associated with an increased risk of premature death. Diet may influence long-term health outcomes among individuals with T2D, but prospective evidence on dietary patterns and mortality remains limited. OBJECTIVES:To prospectively examine associations of eleven pre-defined or empirically-developed dietary patterns with all-cause and cause-specific mortality (e.g., cardiovascular disease [CVD] and cancer) among U.S. individuals with T2D. METHODS:We included 7,795 participants with incident T2D in the Nurses' Health Study (1984-2016) and Health Professionals Follow-Up Study (1986-2020), who were free of CVD and cancer at diagnosis. Diet was assessed using a validated food frequency questionnaire and updated every four years. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS:Over 24 years of follow-up, 3,509 deaths were confirmed, including 1,079 from CVD and 649 from cancer. Adherence to healthy dietary patterns after diagnosis (comparing the 90th with the 10th percentile of dietary pattern scores) was consistently associated with lower all-cause mortality, with multivariable-adjusted HRs ranging from 0.78 (95% CI: 0.71, 0.85) for the Planetary Health Diet to 0.92 (95% CI: 0.84, 1.01) for the Dietary Approaches to Stop Hypertension. Furthermore, greater improvements in dietary pattern adherence from pre- to post-diagnosis (comparing the 90th with the 10th percentile of change scores) were also associated with lower all-cause mortality, with HRs (95% CI) ranging from 0.63 (0.58, 0.70) to 0.92 (0.85, 1.01). A similar pattern of inverse associations with CVD mortality was also observed for these dietary scores. Additionally, the reversed Empirical Dietary Index for Hyperinsulinemia was specifically associated with lower cancer mortality. CONCLUSIONS:Adherence to healthy dietary patterns is universally associated with better survival in individuals with T2D. These findings suggest the importance of consuming high-quality diets in the prevention of premature deaths among individuals with T2D.

AIMS:Interleukin-6 (IL-6) levels have been related to increased risk of chronic disease and mortality. Whether genetic IL-6 receptor (IL6R) blockade is associated with lower chronic disease risk or greater longevity is unknown. METHODS AND RESULTS:The analytic cohort consisted of 38 807 Women's Health Initiative participants who had available genotyping information, of which 23 464 were eligible to survive to 90 years of age through February 192 023. Carrier status of the IL6R variant (rs8192284; p.Asp358Ala) was determined via genotyping. Chronic-disease outcome data were available through 19 February 2023 for coronary heart disease (CHD), heart failure (HF), stroke, and invasive cancer events. Prospective associations of IL6R carrier status with chronic-disease outcomes were assessed with the Cox proportional hazards models, and logistic regression was used to evaluate survival to 90 years of age during follow-up. During a median follow-up of 20 years, 12 181 of 23 464 women (52.0%) survived to age 90. No significant difference in the likelihood of surviving to age 90 was detected between women with 2 alleles of the IL6R gene variant compared to women without any allele (Odds Ratio, 1.00; 95% confidence interval, 0.91-1.09). The risks of CHD, HF, stroke, or cancer did not differ among IL6R variant carriers. High-sensitive C-reactive Protein (hsCRP) levels ≥2 mg/L compared to <2 mg/L were associated with a modest increase in all-cause mortality and CHD risk, independent of IL6R allele carrier status. CONCLUSION:Genetic IL6R blockade was not associated with incident chronic-disease risk, including invasive cancer and longevity, in a large, ethnically diverse cohort of postmenopausal women. No significant interaction with hsCRP levels was observed. While pharmacological blockade of IL6R has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease, these long-term data on genetic IL6R blockade do not indicate an altered likelihood for survival to very old age.

OBJECTIVE:To determine associations between central adiposity, cognitive function, and randomized menopausal hormone therapy (MHT) in a reanalysis of the Kronos Early Estrogen Prevention Study-Cognitive and Affective (KEEPS-Cog) sub-study participants. METHODS:KEEPS randomized 727 women (ages 42-58) who were <36 months postnatural menopause to oral conjugated equine estrogens (o-CEE), transdermal 17-β-estradiol (t-E2), or placebo for 48 months. Participants with diabetes, body mass index >35 kg/m 2 , coronary artery calcium score >50 Agatston Units, and other cardiometabolic disease risk indicators were excluded from enrollment. In the ancillary KEEPS-Cog study, cognitive tests were completed at baseline, 18-, 36-, and 48-month post-randomization. In these analyses, cognitive variables were summarized as four cognitive domain-specific factor scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and speeded language and mental flexibility. Waist-hip-ratio (WHR), an indicator of central adiposity, was measured at screening (baseline) and modeled as a covariate in linear latent growth models assessing associations of MHT with cognitive functions at baseline and over time. RESULTS:Higher baseline WHR was associated with poorer performance on all domain-specific cognitive outcomes at baseline and with changes in visual attention and executive function across time. Models including interaction effects were not significant for either o-CEE x WHR or t-E2 x WHR. CONCLUSION:Central adiposity is a risk factor for domain-specific cognitive decline, and thus, cognitive health effects should be investigated in early postmenopausal women, even in women with low cardiovascular risk statuses.

Metabolomic indices summarizing diet-related metabolic responses are instrumental for examining and replicating diet–disease associations. Here we aim to identify metabolomic signatures characterizing the amounts and types of dietary carbohydrate and assess their associations with type 2 diabetes (T2D) risk. Nutritional metabolomics indices were developed using data from 1,196 healthy participants in the Lifestyle Validation Study with 7-day diet records (7DDRs). Elastic net regression within cross-validation was used to derive metabolomic indices of total carbohydrates and primary food sources. Replication was conducted using feeding menu data among 153 women from the Nutrition and Physical Activity Assessment Study. Associations with incident T2D were examined using multivariable Cox regression in 11,454 participants from the Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-up Study. Metabolites positively associated with total carbohydrates and added sugars mainly included glycerolipids (diacylglycerols and triglycerides), whereas glycerophospholipids (phosphatidylethanolamines and phosphatidylcholines) were inversely associated. Whole grains were linked to betaine, 3-indolepropionic acid (IPA) and hippuric acid; vegetables and legumes to IPA, N-acetylornithine and pipecolic acid; and fruits to proline-betaine and IPA. Identified metabolomic signatures showed significant correlations with a 7-day diet record-assessed diet in the Lifestyle Validation Study (Pearson r 0.33–0.65). In the Nutrition and Physical Activity Assessment Study, the metabolomic index of total carbohydrates was also significantly correlated with intake (r = 0.40). Signatures for total carbohydrates, added sugars, refined grains and potatoes were associated with higher T2D risk (HR per s.d. (95

BACKGROUND:Multivitamin-multimineral (MVM) supplements have been associated with lower blood pressure (BP) in several small trials. We investigated the effects of a MVM on incident hypertension and BP in a secondary analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). METHODS:COSMOS is a 2×2 factorial, double-blinded RCT testing effects of cocoa extract and MVM supplementation among women aged ≥65 years and men aged ≥60 years. Among 8905 COSMOS participants free from hypertension, effects of MVM supplementation on incident hypertension were investigated. Hypertension diagnosis was ascertained through self-reports. Additionally, in two substudies with BP measurements (N = 529 at clinic by research staff and 994 at home by technician), we evaluated the effects on 2-year BP changes. RESULTS:Incident hypertension was observed in N = 1034 (22.9%) in MVM arm and N = 1039 (23.6%) in placebo arm over a median of 3.4 years (IQR: 3.0, 3.9) of follow-up, with hazard ratio (HR) 0.98 [95% CI: 0.90, 1.06]. Effects differed according to baseline diet quality, with HRs of incident hypertension 0.81 [0.70, 0.95] and 1.14 [1.01, 1.28] among participants with lower and higher Alternate Mediterranean Diet score, respectively (P-interaction = .001). There was no effect of MVM on 2-year changes in systolic BP (4.4 mmHg in MVM; 4.5 mmHg in placebo), while pronounced effects were observed for baseline normal BP (P-interaction = .004). CONCLUSIONS:MVM supplementation versus placebo did not reduce hypertension incidence or lower BP overall. Exploratory analyses showed greater reduction in hypertension risk and BP changes among those with lower dietary quality and normal BP at baseline, respectively. CLINICAL TRIAL REGISTRATION:NCT02422745.

BACKGROUND:The impact of vitamin D on fall incidence remains controversial. We studied the effect of 5 years of vitamin D3 supplementation on the risk of falls in a double-blind, placebo-controlled randomized trial with generally healthy, community-dwelling men and women in Finland. METHODS:The study included 2495 participants, men aged ≥ 60 and women aged ≥ 65, who were randomized into three arms: 1600 IU/day or 3200 IU/day of vitamin D3 or placebo. A random subgroup of 551 participants underwent more detailed examinations. Falls and fall-related injuries were collected with questionnaires at months 0, 12, 24, 36, and 60. General linear mixed models and generalized linear models were used for analyses. RESULTS:Over the 5-year follow-up, a similar fall risk of 55% and fall-injury risk of 11% were observed in the placebo, 1600 IU/day, and 3200 IU/day arms, with the mean number of falls and fall-injuries per person-year of 1.26 (95% CI 1.14-1.38) and 0.07 (95% CI 0.06-0.08), respectively. Age, sex, or BMI did not modify the results. In the random subgroup, the mean baseline serum 25(OH)D concentration was 75 nmol/L (SD 18). After 12 months, the concentrations were 73, 100, and 120 nmol/L in the placebo, 1600 IU/day, and 3200 IU/day arms, respectively. CONCLUSIONS:Five-year vitamin D3 supplementation of 1600 IU/day or 3200 IU/day did not affect the overall risk of falls or fall injuries among generally healthy, largely vitamin D sufficient men and women. The findings do not support the use of high vitamin D doses for fall prevention in such populations. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01463813, https://clinicaltrials.gov/ct2/show/NCT01463813.

BACKGROUND:Weight changes after menopause contribute to cardiometabolic risk, yet hormonal determinants of long-term weight trajectories remain incompletely understood. Asprosin, a fasting-induced adipokine involved in hepatic gluconeogenesis and appetite regulation, has been associated with metabolic disease, although its prospective role in affecting weight change remains unknown. OBJECTIVES:This study aimed to examine whether plasma asprosin concentrations are directly and prospectively associated with changes in body weight and body composition among postmenopausal women. METHODS:In a case-control study of 4020 postmenopausal women (1987 newly developed/incident diabetes cases and 2033 matched controls) nested within the Women's Health Initiative, we prospectively evaluated participants' baseline plasma concentrations of asprosin in relation to 3-y changes in weight, measures of central obesity, and the risk of major weight gain or loss (≥7% of baseline weight). Associations were examined overall and stratified by baseline body mass index (BMI) or whether the participant developed diabetes during follow-up. Dual-energy X-ray absorptiometry-derived fat and lean mass were available for a subset of participants (n = 178). RESULTS:In the full cohort (n = 4020), baseline asprosin was not associated with 3-y weight change or changes in central adiposity. However, among matched controls with BMI <30 kg/m2, participants in the highest asprosin quartile gained 1.61 kg less than those in the lowest quartile [adjusted β: -1.61; 95% confidence interval (CI): -2.69, -0.52; P-trend < 0.01] and had lower odds of major weight gain (adjusted OR: 0.57; 95% CI: 0.37, 0.88; P-trend < 0.01) and higher odds of major weight loss (adjusted odds ratio: 1.83; 95% CI: 1.10, 3.05; P-trend = 0.02). CONCLUSIONS:In this prospective study of postmenopausal women followed for 3 y, baseline asprosin concentrations were associated with weight change in apparently healthy women without diabetes or obesity.