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IMPORTANCE: Gestational diabetes has been associated with numerous chronic diseases. However, few studies have examined the association of gestational diabetes with long-term mortality risk. OBJECTIVE: To investigate the associations between gestational diabetes and long-term risks of total and cause-specific mortality. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed participants of the Nurses’ Health Study II who were followed for 30 years (1989-2019). Participants included US female nurses aged 25 to 42 years who reported at least 1 pregnancy (≥6 months) at 18 years or older across their reproductive life span. Data were analyzed from May 1, 2022, to May 25, 2023. EXPOSURE: Gestational diabetes across the reproductive life span. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs with 95% CIs) for total and cause-specific mortality were estimated by Cox proportional hazards regression models. RESULTS: A total of 91 426 parous participants were included, with a mean (SD) age of 34.9 (4.7) years and a body mass index of 24.1 (4.7) at baseline. During a follow-up period of 2 609 753 person-years, 3937 deaths were documented, including 255 deaths from cardiovascular disease and 1397 from cancer. Participants with a history of gestational diabetes had a higher crude mortality rate than those without a history of gestational diabetes (1.74 vs 1.49 per 1000 person-years; absolute difference = 0.25 per 1000 person-years). The corresponding HR for total mortality was 1.28 (95% CI, 1.13-1.44), which did not materially change after additional adjustment for potential confounders and lifestyle factors during the reproductive life span (HR, 1.25; 95% CI, 1.11-1.41). The association persisted regardless of the subsequent development of type 2 diabetes and was more robust among participants who adopted less healthy lifestyles; experienced gestational diabetes in 2 or more pregnancies (HR, 1.48; 95% CI, 0.99-2.19); had gestational diabetes both in the initial and subsequent pregnancies (HR, 1.71; 95% CI, 1.11-2.63); and concurrently reported hypertensive disorders in pregnancy (HR, 1.80; 95% CI, 1.21-2.67), preterm birth (HR, 2.46; 95% CI, 1.66-3.64), or low birth weight (HR, 2.11; 95% CI, 1.21-3.68). Cause-specific mortality analyses revealed that gestational diabetes was directly associated with the risk of mortality due to cardiovascular disease (HR, 1.59; 95% CI, 1.03-2.47). Additionally, gestational diabetes was inversely associated with cancer mortality (HR, 0.76; 95% CI, 0.59-0.98); however, it was only evident among participants who later developed type 2 diabetes. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that participants who reported a history of gestational diabetes exhibited a small but elevated risk of subsequent mortality over 30 years. The findings emphasize the importance of considering gestational diabetes as a critical factor in later-life mortality risk.

IMPORTANCE: The best approach to identify younger postmenopausal women for osteoporosis screening is uncertain. The Fracture Risk Assessment Tool (FRAX), which includes self-identified racial and ethnic information, and the Osteoporosis Self-assessment Tool (OST), which does not, are risk assessment tools recommended by US Preventive Services Task Force guidelines to identify candidates for bone mineral density (BMD) testing in this age group. OBJECTIVE: To compare the ability of FRAX vs OST to discriminate between younger postmenopausal women who do and do not experience incident fracture during a 10-year follow-up in the 4 racial and ethnic groups specified by FRAX. DESIGN, SETTING, AND PARTICIPANTS: This cohort study of Women’s Health Initiative participants included 67 169 women (baseline age range, 50-64 years) with 10 years of follow-up for major osteoporotic fracture (MOF; including hip, clinical spine, forearm, and shoulder fracture) at 40 US clinical centers. Data were collected from October 1993 to December 2008 and analyzed between May 11, 2022, and February 23, 2023. MAIN OUTCOMES AND MEASURES: Incident MOF and BMD (in a subset of 4607 women) were assessed. The area under the receiver operating characteristic curve (AUC) for FRAX (without BMD information) and OST was calculated within each racial and ethnic category. RESULTS: Among the 67 169 participants, mean (SD) age at baseline was 57.8 (4.1) years. A total of 1486 (2.2%) self-identified as Asian, 5927 (8.8%) as Black, 2545 (3.8%) as Hispanic, and 57 211 (85.2%) as White. During follow-up, 5594 women experienced MOF. For discrimination of MOF, AUC values for FRAX were 0.65 (95% CI, 0.58-0.71) for Asian, 0.55 (95% CI, 0.52-0.59) for Black, 0.61 (95% CI, 0.56-0.65) for Hispanic, and 0.59 (95% CI, 0.58-0.59) for White women. The AUC values for OST were 0.62 (95% CI, 0.56-0.69) for Asian, 0.53 (95% CI, 0.50-0.57) for Black, 0.58 (95% CI, 0.54-0.62) for Hispanic, and 0.55 (95% CI, 0.54-0.56) for White women. For discrimination of femoral neck osteoporosis, AUC values were excellent for OST (range, 0.79 [95% CI, 0.65-0.93] to 0.85 [95% CI, 0.74-0.96]), higher for OST than FRAX (range, 0.72 [95% CI, 0.68-0.75] to 0.74 [95% CI, 0.60-0.88]), and similar in each of the 4 racial and ethnic groups. CONCLUSIONS AND RELEVANCE: These findings suggest that within each racial and ethnic category, the US FRAX and OST have suboptimal performance in discrimination of MOF in younger postmenopausal women. In contrast, for identifying osteoporosis, OST was excellent. The US version of FRAX should not be routinely used to make screening decisions in younger postmenopausal women. Future investigations should improve existing tools or create new approaches to osteoporosis risk assessment for this age group.

IMPORTANCE: The average life expectancy has increased substantially in the past few decades in most industrialized countries; however, not all of the increased life expectancy is being spent in optimal health, especially among individuals with low socioeconomic status. OBJECTIVE: To quantify the associations between levels of cardiovascular health (CVH), estimated by the American Heart Association’s Life’s Essential 8 (LE8) metrics, with life expectancy free of major chronic disease, including cardiovascular disease (CVD), diabetes, cancer, and dementia, in UK adults. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 135 199 adults in the UK Biobank study who were initially free of major chronic disease and had complete data on LE8 metrics. Data analyses were performed in August 2022. EXPOSURES: Cardiovascular health levels, as estimated by LE8 score. The LE8 score, which consists of 8 components: (1) diet, (2) physical activity, (3) tobacco/nicotine exposure, (4) sleep, (5) body mass index, (6) non–high-density lipoprotein cholesterol, (7) blood glucose, and (8) blood pressure. The CVH level was evaluated at baseline and categorized into low (LE8 score <50), moderate (LE8 score ≥50 but <80), and high (LE8 score ≥80) levels. MAIN OUTCOMES AND MEASURES: The primary outcome was the life expectancy free of 4 major chronic diseases (CVD, diabetes, cancer, and dementia). RESULTS: Of the 135 199 adults (44.7% men; mean [SD] age, 55.4 [7.9] years) included in the study, a total of 4712, 48 955, and 6748 men had low, moderate, and high CVH levels, respectively, and the corresponding numbers for women were 3661, 52 192, and 18 931. At age 50 years, the estimated disease-free years were 21.5 (95% CI, 21.0-22.0), 25.5 (95% CI, 25.4-25.6), and 28.4 (95% CI, 27.8-29.0) for men with low, moderate, and high CVH levels, respectively; the corresponding estimated disease-free years at age 50 years for women were 24.2 (95% CI, 23.5-24.8), 30.5 (95% CI, 30.4-30.6), and 33.6 (95% CI, 33.1-34.0). Equivalently, men with moderate or high CVH levels lived on average 4.0 (95% CI, 3.4-4.5) or 6.9 (95% CI, 6.1-7.7) longer years free of chronic disease, respectively, at age 50 years, compared with men with low CVH levels. The corresponding longer years lived free of disease for women were 6.3 (95% CI, 5.6-7.0) or 9.4 (95% CI, 8.5-10.2). For participants with high CVH level, there was not a statistically significant difference in disease-free life expectancy between participants with low and other socioeconomic status. CONCLUSIONS AND RELEVANCE: In this cohort study, a high level of CVH, evaluated using the LE8 metrics, was associated with longer life expectancy free of major chronic diseases and may contribute to narrowing socioeconomic health inequalities in both men and women.

IMPORTANCE: The current Dietary Guidelines for Americans recommend multiple healthy eating patterns. However, few studies have examined the associations of adherence to different dietary patterns with long-term risk of total and cause-specific mortality. OBJECTIVE: To examine the associations of dietary scores for 4 healthy eating patterns with risk of total and cause-specific mortality. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included initially healthy women from the Nurses’ Health Study (NHS; 1984-2020) and men from the Health Professionals Follow-up Study (HPFS; 1986-2020). EXPOSURES: Healthy Eating Index 2015 (HEI-2015), Alternate Mediterranean Diet (AMED) score, Healthful Plant-based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI). MAIN OUTCOMES AND MEASURES: The main outcomes were total and cause-specific mortality overall and stratified by race and ethnicity and other potential risk factors. RESULTS: The final study sample included 75 230 women from the NHS (mean [SD] baseline age, 50.2 [7.2] years) and 44 085 men from the HPFS (mean [SD] baseline age, 53.3 [9.6] years). During a total of 3 559 056 person-years of follow-up, 31 263 women and 22 900 men died. When comparing the highest with the lowest quintiles, the pooled multivariable-adjusted HRs of total mortality were 0.81 (95% CI, 0.79-0.84) for HEI-2015, 0.82 (95% CI, 0.79-0.84) for AMED score, 0.86 (95% CI, 0.83-0.89) for HPDI, and 0.80 (95% CI, 0.77-0.82) for AHEI (P < .001 for trend for all). All dietary scores were significantly inversely associated with death from cardiovascular disease, cancer, and respiratory disease. The AMED score and AHEI were inversely associated with mortality from neurodegenerative disease. The inverse associations between these scores and risk of mortality were consistent in different racial and ethnic groups, including Hispanic, non-Hispanic Black, and non-Hispanic White individuals. CONCLUSIONS AND RELEVANCE: In this cohort study of 2 large prospective cohorts with up to 36 years of follow-up, greater adherence to various healthy eating patterns was consistently associated with lower risk of total and cause-specific mortality. These findings support the recommendations of Dietary Guidelines for Americans that multiple healthy eating patterns can be adapted to individual food traditions and preferences.

IMPORTANCE: The 2015-2020 Dietary Guidelines for Americans recommend multiple healthy eating patterns. However, few studies have examined the associations of adherence to different dietary patterns with long-term risk of cardiovascular disease (CVD). OBJECTIVE: To examine the associations of dietary scores for 4 healthy eating patterns with risk of incident CVD. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of initially healthy women from the Nurses’ Health Study (NHS) (1984-2016) and the NHS II (1991-2017) and men from the Health Professionals Follow-up Study (HPFS) (1986-2012). The dates of analysis were July 25 to December 4, 2019. EXPOSURES: Healthy Eating Index–2015 (HEI-2015), Alternate Mediterranean Diet Score (AMED), Healthful Plant-Based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI). MAIN OUTCOMES AND MEASURES: Cardiovascular disease events, including fatal and nonfatal coronary heart disease (CHD) and stroke. RESULTS: The final study sample included 74 930 women in the NHS (mean [SD] baseline age, 50.2 [7.2] years), 90 864 women in the NHS II (mean [SD] baseline age, 36.1 [4.7] years), and 43 339 men in the HPFS (mean [SD] baseline age, 53.2 [9.6] years). During a total of 5 257 190 person-years of follow-up, 23 366 incident CVD cases were documented (18 092 CHD and 5687 stroke) (some individuals were diagnosed as having both CHD and stroke). Comparing the highest with the lowest quintiles, the pooled multivariable-adjusted hazard ratios (HRs) of CVD were 0.83 (95% CI, 0.79-0.86) for the HEI-2015, 0.83 (95% CI, 0.79-0.86) for the AMED, 0.86 (95% CI, 0.82-0.89) for the HPDI, and 0.79 (95% CI, 0.75-0.82) for the AHEI (P for trend <.001 for all). In addition, a 25-percentile higher dietary score was associated with 10% to 20% lower risk of CVD (pooled HR, 0.80 [95% CI, 0.77-0.83] for the HEI-2015; 0.90 [95% CI, 0.87-0.92] for the AMED; 0.86 [95% CI, 0.82-0.89] for the HPDI; and 0.81 [95% CI, 0.78-0.84] for the AHEI). These dietary scores were statistically significantly associated with lower risk of both CHD and stroke. In analyses stratified by race/ethnicity and other potential risk factors for CVD, the inverse associations between these scores and risk of CVD were consistent in most subgroups. CONCLUSIONS AND RELEVANCE: In 3 large prospective cohorts with up to 32 years of follow-up, greater adherence to various healthy eating patterns was consistently associated with lower risk of CVD. These findings support the recommendations of the 2015-2020 Dietary Guidelines for Americans that multiple healthy eating patterns can be adapted to individual food traditions and preferences.

IMPORTANCE: Biological sex and sociocultural gender represent major sources of diversity among patients, and recent research has shown the association of sex and gender with health. A growing body of literature describes widespread associations of sex and gender with cells, organs, and the manner in which individual patients interact with health care systems. Sex- and gender-informed medicine is a young paradigm of clinical practice and medical research founded on this literature that considers the association of sex and gender with each element of the disease process from risk, to presentation, to response to therapy. OBSERVATIONS: Characteristics that underlie sex and gender involve both endogenous and exogenous factors that change throughout the life course. This review details clinical examples with broad applicability that highlight sex and gender differences in the key domains of genetics, epigenomic modifiers, hormonal milieu, immune function, neurocognitive aging process, vascular health, response to therapeutics, and interaction with health care systems. These domains interact with one another in multidimensional associations, contributing to the diversity of the sex and gender spectra. Novel research has identified differences of clinical relevance with the potential to improve care for all patients. CONCLUSIONS AND RELEVANCE: Clinicians should consider incorporating sex and gender in their decision-making to practice precision medicine that integrates fundamental components of patient individuality. Recognizing the biological and environmental factors that affect the disease course is imperative to optimizing care for each patient. Research highlights the myriad ways sex and gender play a role in health and disease. However, these clinically relevant insights have yet to be systematically incorporated into care. The framework described in this review serves as a guide to help clinicians consider sex and gender as they practice precision medicine.

IMPORTANCE: Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear. OBJECTIVE: We evaluated the predictive accuracy of the PCE in the Women’s Health Initiative (WHI), a multiethnic cohort of contemporary US postmenopausal women. We evaluated the effects of time-varying treatments such as aspirin and statins, and ascertainment of additional ASCVD events by linkage with the Centers for Medicare and Medicaid Services (CMS) claims. DESIGN, SETTING, AND PARTICIPANTS: The WHI recruited the largest number of US women (n = 161 808) with the racial/ethnic, geographic, and age diversity of the general population (1993-1998). For this study, we included women aged 50 to 79 (n = 19 995) participating in the WHI with data on the risk equation variables at baseline and who met the guideline inclusion and exclusion criteria. Median follow-up was 10 years. MAIN OUTCOMES AND MEASURES: For this study, ASCVD was defined as myocardial infarction, stroke, or cardiovascular death. RESULTS: Among the 19 995 women (mean [SD] age, 64 [7.3] years; 8305 [41.5%] white, 7688 [38.5%] black, 3491 [17.5%] Hispanic, 103 [0.5%] American Indian, 321 [1.6%] Asian/Pacific Islander, and 87 [0.4%] other/unknown), a total of 1236 ASCVD events occurred in 10 years and were adjudicated through medical record review by WHI investigators. The WHI-adjudicated observed risks were lower than predicted. The observed (predicted) risks for baseline 10-year risk categories less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more were 1.7 (2.8), 4.4 (6.2), 5.3 (8.7), and 12.4 (18.2), respectively. Small changes were noted after adjusting for time-dependent changes in statin and aspirin use. Among women 65 years or older enrolled in Medicare, WHI-adjudicated risks were also lower than predicted, but observed (predicted) risks became aligned after including events ascertained by linkage with CMS for additional surveillance for events: 3.8 (4.3), 7.1 (6.4), 8.3 (8.7), and 18.9 (18.7), respectively. Similar results were seen across ethnic/racial groups. Overall, the equations discriminated risk well (C statistic, 0.726; 95% CI, 0.714-0.738). CONCLUSIONS AND RELEVANCE: Without including surveillance for ASCVD events using CMS, observed risks in the WHI were lower than predicted by PCE as noted in several other US cohorts, but risks were better aligned after including CMS events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00000611

IMPORTANCE: Previous studies identify gestational diabetes (GD) as a risk factor for intermediate markers of cardiovascular disease (CVD) risk; however, few are prospective, evaluate hard CVD end points, or account for shared risk factors including body weight and lifestyle. OBJECTIVE: To prospectively evaluate history of GD in relation to incident CVD risk. DESIGN, SETTING, AND PARTICIPANTS: The Nurses’ Health Study II (NHS II) is an observational cohort study of US female nurses established in 1989, with ongoing follow-up. Biennial questionnaires updated behavioral characteristics, health outcomes, and lifestyle factors. Multivariable Cox models estimated the hazard ratio (HR) and 95% CI for CVD risk. We included 89 479 women who reported at least 1 pregnancy and were free of CVD and cancer at baseline. Follow-up through May 31, 2015, was complete for more than 90% of eligible participants. EXPOSURES: History of GD was self-reported at baseline (1989) via questionnaire and updated every 2 years. MAIN OUTCOMES AND MEASURES: We observed 1161 incident self-reported nonfatal or fatal myocardial infarction or stroke, confirmed via medical records. RESULTS: Participants had a mean (SD) age of 34.9 (4.7) years. Adjusting for age, prepregnancy body mass index, and other covariates, GD vs no GD was associated with subsequent CVD (HR, 1.43; 95% CI, 1.12-1.81). Additional adjustment for weight gain since pregnancy and updated lifestyle factors attenuated the association (HR, 1.29; 95% CI, 1.01-1.65). Classifying GD by progression to T2D in relation to CVD risk indicated a positive association for GD with progression to T2D vs no GD or T2D (HR, 4.02; 95% CI, 1.94-8.31), and an attenuated relationship for GD only (HR, 1.30; 95% CI, 0.99-1.71). CONCLUSIONS AND RELEVANCE: Gestational diabetes was positively associated with CVD later in life, although the absolute rate of CVD in this younger cohort of predominantly white women was low. This relationship is possibly mediated in part by subsequent weight gain and lack of healthy lifestyle.

IMPORTANCE: Previous studies have shown distinct associations between specific dietary fat and cardiovascular disease. However, evidence on specific dietary fat and mortality remains limited and inconsistent. OBJECTIVE: To examine the associations of specific dietary fats with total and cause-specific mortality in 2 large ongoing cohort studies. DESIGN, SETTING, AND PARTICIPANTS: This cohort study investigated 83 349 women from the Nurses’ Health Study (July 1, 1980, to June 30, 2012) and 42 884 men from the Health Professionals Follow-up Study (February 1, 1986, to January 31, 2012) who were free of cardiovascular disease, cancer, and types 1 and 2 diabetes at baseline. Dietary fat intake was assessed at baseline and updated every 2 to 4 years. Information on mortality was obtained from systematic searches of the vital records of states and the National Death Index, supplemented by reports from family members or postal authorities. Data were analyzed from September 18, 2014, to March 27, 2016. MAIN OUTCOMES AND MEASURES: Total and cause-specific mortality. RESULTS: During 3 439 954 person-years of follow-up, 33 304 deaths were documented. After adjustment for known and suspected risk factors, dietary total fat compared with total carbohydrates was inversely associated with total mortality (hazard ratio [HR] comparing extreme quintiles, 0.84; 95% CI, 0.81-0.88; P < .001 for trend). The HRs of total mortality comparing extreme quintiles of specific dietary fats were 1.08 (95% CI, 1.03-1.14) for saturated fat, 0.81 (95% CI, 0.78-0.84) for polyunsaturated fatty acid (PUFA), 0.89 (95% CI, 0.84-0.94) for monounsaturated fatty acid (MUFA), and 1.13 (95% CI, 1.07-1.18) for trans-fat (P < .001 for trend for all). Replacing 5% of energy from saturated fats with equivalent energy from PUFA and MUFA was associated with estimated reductions in total mortality of 27% (HR, 0.73; 95% CI, 0.70-0.77) and 13% (HR, 0.87; 95% CI, 0.82-0.93), respectively. The HR for total mortality comparing extreme quintiles of ω-6 PUFA intake was 0.85 (95% CI, 0.81-0.89; P < .001 for trend). Intake of ω-6 PUFA, especially linoleic acid, was inversely associated with mortality owing to most major causes, whereas marine ω-3 PUFA intake was associated with a modestly lower total mortality (HR comparing extreme quintiles, 0.96; 95% CI, 0.93-1.00; P = .002 for trend). CONCLUSIONS AND RELEVANCE: Different types of dietary fats have divergent associations with total and cause-specific mortality. These findings support current dietary recommendations to replace saturated fat and trans-fat with unsaturated fats.

IMPORTANCE: Clinical decision making regarding the appropriate use of aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) events is complex, and requires an individualized benefit to risk assessment. OBJECTIVE: To review advances in the individualized assessment for ASCVD and bleeding risk, and to provide an update of the randomized clinical trial evidence that examined the use of aspirin for primary prevention (primarily for ASCVD, and secondarily for colorectal cancer). The recently released 2016 US Preventive Services Task Force recommendations are discussed, as well as the role of ASCVD risk, age, sex, and aspirin dose/formulation in clinical decision making. EVIDENCE REVIEW: We performed a detailed review of peer-reviewed publications that were identified through searches of MEDLINE and the Cochrane Database through 2016 using the literature search terms “aspirin,” “primary prevention,” “cardiovascular disease,” “mortality,” “cancer.” Bibliographies from these references as well as meta-analyses of these randomized clinical trials were also reviewed. FINDINGS: Evidence from a total of 11 trials involving more than 118 000 patients is available to guide clinical decision making for aspirin use in the primary prevention of ASCVD. Clinicians should balance the benefit to risk ratio and the individual’s preferences, calculating the 10-year ASCVD risk and evaluating risk factors for gastrointestinal bleeding, to facilitate a safer and more personalized approach to appropriate selection of candidates for low-dose aspirin (75 to 81 mg/d) for the primary prevention of ASCVD, with secondary considerations for reducing colorectal cancer risk when taken for longer periods (>10 years). Both the net ASCVD benefit and the bleeding risk of aspirin therapy increased as the absolute ASCVD risk increased, but the net benefits generally exceeded the risks at higher baseline ASCVD risk (≥10% ASCVD 10-year risk). The Aspirin-Guide is a clinical decision making support tool (app for mobile devices) with internal risk calculators to help clinicians with this dual assessment by calculating the ASCVD risk and the bleeding risk in the individual patient, and incorporating age- and sex-specific guidance based on randomized trial results. CONCLUSIONS AND RELEVANCE: Balancing the benefit of ASCVD reduction with the risk of bleeding from low-dose aspirin is difficult but essential for informed decision making and achieving a net clinical benefit from aspirin for primary prevention. This is facilitated by a free and readily available evidence-based clinical decision support tool.

IMPORTANCE Postmenopausal hormone therapy with conjugated equine estrogens (CEEs) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women. OBJECTIVE To test whether prescribing CEE-based hormone therapy to postmenopausal women aged 50 to 55 years has longer-term effects on cognitive function. DESIGN Trained, masked staff assessed participants with an annual telephone-administered cognitive battery that included measures of global and domain-specific cognitive functions. Cognitive testing was conducted an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years, and repeated 1 year later. Enrollment occurred from 1996 through 1999. SETTING Forty academic research centers. PARTICIPANTS The study population comprised 1326 postmenopausal women, who had begun treatment in 2 randomized placebo-controlled clinical trials of hormone therapy when aged 50 to 55 years. INTERVENTION The clinical trials in which the women had participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years. MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function. Secondary outcomes were verbal memory, attention, executive function, verbal fluency, and working memory. RESULTS Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean (95% CI) intervention effect of 0.02 (−0.08 to 0.12) standard deviation units (P = .66). Similarly, no overall differences were found for any individual cognitive domain (all P > .15). Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 (−0.33 to −0.02) and −0.25 (−0.42 to −0.08), respectively; however, this may be a chance finding. CONCLUSIONS AND RELEVANCE CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years. We are not able to address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01124773

IMPORTANCE Red meat consumption has been consistently associated with an increased risk of type 2 diabetes mellitus (T2DM). However, whether changes in red meat intake are related to subsequent T2DM risk remains unknown. OBJECTIVE To evaluate the association between changes in red meat consumption during a 4-year period and subsequent 4-year risk of T2DM in US adults. DESIGN AND SETTING Three prospective cohort studies in US men and women. PARTICIPANTS We followed up 26 357 men in the Health Professionals Follow-up Study (1986-2006), 48 709 women in the Nurses’ Health Study (1986-2006), and 74 077 women in the Nurses’ Health Study II (1991-2007). Diet was assessed by validated food frequency questionnaires and updated every 4 years. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios with adjustment for age, family history, race, marital status, initial red meat consumption, smoking status, and initial and changes in other lifestyle factors (physical activity, alcohol intake, total energy intake, and diet quality). Results across cohorts were pooled by an inverse variance–weighted, fixed-effect meta-analysis. MAIN OUTCOMES AND MEASURES Incident T2DM cases validated by supplementary questionnaires. RESULTS During 1 965 824 person-years of follow-up, we documented 7540 incident T2DM cases. In the multivariate-adjusted models, increasing red meat intake during a 4-year interval was associated with an elevated risk of T2DM during the subsequent 4 years in each cohort (all P < .001 for trend). Compared with the reference group of no change in red meat intake, increasing red meat intake of more than 0.50 servings per day was associated with a 48% (pooled hazard ratio, 1.48; 95% CI, 1.37-1.59) elevated risk in the subsequent 4-year period, and the association was modestly attenuated after further adjustment for initial body mass index and concurrent weight gain (1.30; 95% CI, 1.21-1.41). Reducing red meat consumption by more than 0.50 servings per day from baseline to the first 4 years of follow-up was associated with a 14% (pooled hazard ratio, 0.86; 95% CI, 0.80-0.93) lower risk during the subsequent entire follow-up through 2006 or 2007. CONCLUSIONS AND RELEVANCE Increasing red meat consumption over time is associated with an elevated subsequent risk of T2DM, and the association is partly mediated by body weight. Our results add further evidence that limiting red meat consumption over time confers benefits for T2DM prevention.