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A study ancillary to a large trial showed that supplemental vitamin D 3 did not lower the risk of fractures among generally healthy midlife and older adults not selected for vitamin D deficiency, low bone mass, or osteoporosis.

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk ( P <5 × 10 −8 ), implicating genes involved in sex steroid hormone pathways ( FN1 , CCDC170 , ESR1 , SYNE1 and FSHB ). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts. Endometriosis is a major cause of infertility. Molecular mechanisms underlying the disease involve genetic and environmental risk factors. In a meta-analysis of eleven GWA studies, Sapkota and colleagues identify five novel risk loci, implicating steroid sex hormone pathways in the pathogenesis.

Dry eye disease affects women twice as often as men, but there is little information on whether dry eye treatments, treatment satisfaction, or the impact of dry eye disease on patients' lives and vision might differ by sex. Questionnaire survey of 4000 participants in the Women's Health Study and the Physicians' Health Studies I and II with a prior report of a diagnosis of DED. Among participants who re-confirmed a diagnosis of dry eye disease, we assessed symptoms, treatments, patient satisfaction and impact of dry eye disease, and analyzed differences between men and women using regression models. The final study population consisted of 1,518 women (mean age 70.7 years) and 581 men (mean age 76.7 years), with a mean reported duration of dry eye disease of 10.5 years and 10.1 years, respectively. The frequency and severity of dry eye disease symptoms were higher among women (each P<0.0001), and women reported a greater impact on everyday activities (P<0.0001). Women were more likely to use artificial tears (P<0.0001) use them more often (P<0.0001), and to use Restasis® (P<0.0001), omega-3 fatty acids (P=0.0006), and have punctal occlusion (P=0.005). Women spent more money per month on dry eye treatments (P<0.0001), but reported greater dissatisfaction with treatment side effects (P=0.001), and the amount of time before treatments started working (P=0.03). These data show that dry eye disease is generally experienced as being more severe among women, having a greater impact on their self-assessed well-being.

The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.

It is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass [non-HDL cholesterol (nonHDLc)] or particle concentration [apolipoprotein B (apo B) and LDL particle concentration (LDLp)] more accurately reflects risk of incident coronary heart disease (CHD). We evaluated CHD risk among women in whom these markers where discordant. Among 27533 initially healthy women in the Women's Health Study (NCT00000479), using residuals from linear regression models, we compared risk among women with higher or lower observed particle concentration relative to nonHDLc (highest and lowest residual quartiles, respectively) to individuals with agreement between markers (middle quartiles) using Cox proportional hazards models. Although all 3 biomarkers were correlated ( ≥ 0.77), discordance occurred in up to 20.2% of women. Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes (both < 0.001). Over a median follow-up of 20.4 years, 1246 CHD events occurred (514725 person-years). Women with high particle concentration relative to nonHDLc had increased CHD risk: age-adjusted hazard ratio (95% CI) = 1.77 (1.56-2.00) for apo B and 1.70 (1.50-1.92) for LDLp. After adjustment for clinical risk factors including MetS, these risks attenuated to 1.22 (1.07-1.39) for apo B and 1.13 (0.99-1.29) for LDLp. Discordant low apo B or LDLp relative to nonHDLc was not associated with lower risk. Discordance between atherogenic particle cholesterol mass and particle concentration occurs in a sizeable proportion of apparently healthy women and should be suspected clinically among women with cardiometabolic traits. In such women, direct measurement of lipoprotein particle concentration might better inform CHD risk assessment.

Background Alcohol intake is associated with a higher risk of estrogen receptor-positive (ER+) breast cancer (BC), presumably through its confirmed ability to increase sex hormone levels. Whether consuming alcohol within the recommended limit of one serving per day increases sex hormone levels among postmenopausal women taking aromatase inhibitors (AI) to inhibit estrogen production remains unknown. Therefore, we compared sex hormone levels following white wine to levels following white grape juice among ER + BC survivors taking AIs. Methods In this 10-week randomized controlled two-period crossover trial conducted from September 2022 to July 2023 among 20 postmenopausal women on AIs, we examined within-person changes in sex hormone levels following 3 weeks of 5 ounces of white wine daily versus 3 weeks of 6 ounces of white grape juice daily, with each drinking period preceded by two-week washouts and drinking period sequence allocated by randomization. Results All 20 participants completed the trial. Compared to daily grape juice, daily wine led to decreases in total estradiol (11.1%, 95%confidence interval[CI] -49.8%,57.2%), free estradiol index (0.7%, 95%CI -2%,0.7%), and free estradiol concentration (7.7%, 95%CI -48%, 63.9%) but increases in estrone (13.8%, 95%CI -9.5%,43.1%), dehydroepiandrosterone sulfate (DHEAS; 11.4%, 95%CI -3.3%,28.4%), and testosterone (12.6%, 95%CI -0.8%,27.7%) and decreased sex hormone-binding globulin (SHBG; -2.7%, 95%CI -21.9%,21.2%). Conclusions Five ounces of white wine daily did not lead to statistically significant increases in estradiol, but it led to changes in other sex hormones suggesting higher BC risk. Whether this level of alcohol intake diminishes AI effectiveness warrants further investigation. Trials Registration Clinicaltrials.gov NCT05423730 registered June 14, 2022.

Observational and experimental evidence suggests that vitamin D plays a role in type 2 diabetes (T2D). However, prior randomized supplementation trials are limited to high-risk patients with prediabetes. Here we aim to evaluate whether vitamin D supplementation reduces risk of T2D in a general population of older US adults. The study design is an ancillary analysis (VITAL-T2D) of The Vitamin D and Omega-3 Trial (VITAL), a completed randomized, double-blind, placebo-controlled 2 × 2 trial of daily vitamin D 3 (cholecalciferol; 2000 IU/day) and omega-3 fatty acids (1 g/day) for the primary prevention of cancer and cardiovascular disease. We also conducted a systematic review and meta-analysis of vitamin D trial (≥1000 IU/d cholecalciferol) vs. placebo and T2D risk. We analyzed 22,220 adults with mean age 67.2 years (SD = 7.1) without T2D at enrollment (2011 to 2014), randomized to vitamin D 3 or placebo. Mean body mass index (BMI) was 27.5 kg/m 2 (SD = 5.3), with 51% female and 17% Black race/ethnicity. A subcohort ( n  = 911) attended in-person visits at baseline and 2 years for glycemic trait analyses. Our meta-analysis included 3 additional trials (5205 participants; 936 T2D cases). The primary outcome for the VITAL-T2D is intention-to-treat effect of vitamin D vs. placebo for incident T2D. T2D incidence (cases/1000py) at median follow-up of 5.3 y was 3.98 for vitamin D and 4.37 for placebo (hazard ratio [HR] = 0.91; 95% confidence interval [CI] = 0.76, 1.09). Results did not differ by age, sex, BMI, or baseline 25-hydroxyvitamin D, and vitamin D had no effect on glycemic traits at 2 years. Meta-analysis of 4 trials ( n  = 5205; 936 T2D cases) obtained HR = 0.89 (CI = 0.80, 0.99). In conclusion, Vitamin D supplementation did not reduce T2D in older US adults, but a modest reduction was observed when meta-analyzed with prior trials. Trial Registration : ClinicalTrials.gov #NCT01633177. Systematic Review Registration : PROSPERO #CRD42019147562. Observational and experimental evidence suggests that vitamin D plays a role in glycemic control. Here, the authors report that in an ancillary study of the placebo-controlled randomized VITAL trial there is no effect of 2000 IU/day of vitamin D supplementation over 5 years on the prevention of type 2 diabetes in 22,220 older US adults.

SummaryBackgroundPrimary stroke prevention guidelines recommend routine screening of individuals for elevated LDL cholesterol from the age of 40 years, but recommendations are ambiguous for high-sensitivity C-reactive protein (hsCRP) and lipoprotein(a). We aimed to examine correlations between hsCRP, LDL cholesterol, and lipoprotein(a) and 30-year risk of stroke in healthy women. MethodsIn this prospective, longitudinal cohort study, participants who were enrolled in the Women's Health Study (a randomised controlled trial of aspirin and vitamin E for the prevention of cardiovascular disease and cancer in women in the USA that completed in 2004) were prospectively followed for up to 30 years via annual questionnaires. Healthy women (ie, without cardiovascular disease and cancer) aged 45 years and older were eligible for the original trial. Individuals with available baseline measurements for hsCRP, LDL cholesterol, or lipoprotein(a) were included in our analyses. We constructed cumulative incidence curves and calculated hazard ratios (HRs) for total, ischaemic, and haemorrhagic stroke across biomarker quintiles and for combined elevation of all biomarkers from age-adjusted and multivariable-adjusted cause-specific Cox models. FindingsBetween September, 1992 and May, 1995, 39 876 women were enrolled in the Women's Health Study, of whom 28 345 consented to participate in further follow-up and provided a baseline blood sample. Baseline concentrations of hsCRP and LDL cholesterol were available for 27 939 participants, with lipoprotein(a) measurements also reported for most participants. At enrolment, median age was 53 years (IQR 49–59), median BMI was 25 kg/m 2 (22–28), 3252 (12%) were current smokers, 7026 (25%) had hypertension, and 685 (2%) had a history of diabetes. 1345 stroke events accrued during a median of 27·7 years (IQR 23·1–29·0) of follow-up. Baseline hsCRP concentrations increasing from the lowest quintile (<0·7 mg/L) to the highest quintile (≥5·2 mg/L) were associated with an increasing cumulative incidence of total stroke. Only individuals in the highest LDL cholesterol (≥3·4 mmol/L) and lipoprotein(a) quintiles (≥44·1 mg/dL) had higher cumulative incidences of total stroke than those in the lowest quintiles (<2·5 mmol/L and <3·6 mg/dL, respectively). Multivariable-adjusted hazard ratios (HRs) for total and ischaemic stroke for quintile five versus quintile one were 1·32 (95% CI 1·07–1·61) and 1·56 (1·22–1·99), respectively, for hsCRP; 1·05 (0·88–1·25) and 1·17 (0·95–1·45), respectively, for LDL cholesterol; and 1·23 (1·04–1·45) and 1·27 (1·05–1·55), respectively, for lipoprotein(a). Women with three versus no biomarkers in the fifth quintile had HRs of 1·60 (1·10–2·34) for total stroke and 1·79 (1·23–2·61) for ischaemic stroke. None of the biomarkers correlated with risk of haemorrhagic stroke. InterpretationElevated plasma concentrations of hsCRP, LDL cholesterol, and lipoprotein(a), individually and in combination, are associated with 30-year risk of ischaemic stroke. Early screening for these risk factors might facilitate improved lifestyle interventions for the primary prevention of stroke. FundingThe US National Heart, Lung, and Blood and Cancer Institutes and the Independent Research Fund Denmark.

Objective To examine the effects of reduction in dietary sodium intake on cardiovascular events using data from two completed randomised trials, TOHP I and TOHP II.Design Long term follow-up assessed 10-15 years after the original trial.Setting 10 clinic sites in 1987-90 (TOHP I) and nine sites in 1990-5 (TOHP II). Central follow-up conducted by post and phone.Participants Adults aged 30-54 years with prehypertension.Intervention Dietary sodium reduction, including comprehensive education and counselling on reducing intake, for 18 months (TOHP I) or 36-48 months (TOHP II).Main outcome measure Cardiovascular disease (myocardial infarction, stroke, coronary revascularisation, or cardiovascular death).Results 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control. Net sodium reductions in the intervention groups were 44 mmol/24 h and 33 mmol/24 h, respectively. Vital status was obtained for all participants and follow-up information on morbidity was obtained from 2415 (77%), with 200 reporting a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex, and 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial. In secondary analyses, 67 participants died (0.80, 0.51 to 1.26, P=0.34).Conclusion Sodium reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events.

Short sleep duration is associated with increased cardiovascular disease (CVD) risk. However, it is uncertain whether sleep debt, a measure of sleep deficiency during the week compared to the weekend, confers increased cardiovascular risk. Because sleep disturbances increase with age particularly in women, we examined the relationship between sleep debt and ideal cardiovascular health (ICH) in older women. Sleep debt is defined as the difference between self-reported total weekday and weekend sleep hours of at least 2 hours among women without apparent CVD and cancer participating in the Women's Health Stress Study follow-up cohort of female health professionals (N = 22 082). The ICH consisted of seven health factors and behaviors as defined by the American Heart Association Strategic 2020 goals including body mass index, smoking, physical activity, diet, blood pressure, total cholesterol, and glucose. Mean age was 72.1 ± 6.0 years. Compared to women with no sleep debt, women with sleep debt were more likely to be obese and have hypertension (pall < .05). Linear regression models adjusted for age and race/ethnicity revealed that sleep debt was significantly associated with poorer ICH (B = -0.13 [95% CI = -0.18 to -0.08]). The relationship was attenuated but remained significant after adjustment for education, income, depression/anxiety, cumulative stress, and snoring. Sleep debt was associated with poorer ICH, despite taking into account socioeconomic status and psychosocial factors. These results suggest that weekly sleep duration variation, possibly leading to circadian misalignment, may be associated with cardiovascular risk in older women.