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Electrochemical fluorination manufacture of perfluorooctane sulfonic acid (PFOS), one of the most studied per- and polyfluoroalkyl substances, produces mixtures of linear and branched isomers, but little is known about human exposure to linear or branched PFOS isomers. We examined determinants affecting isomer-specific patterns of PFOS in serum in two adult populations in the United States, the National Health and Nutrition Examination Survey (NHANES) and the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). After adjusting for demographic variables, fish consumption (in both populations), a glomerular filtration rate above 90 mL/min/1.73 m

Purpose Previous work has focused on the role of diabetes in peripheral neuropathy (PN), but PN often occurs before, and independently from, diabetes. This study measures the association of cardiometabolic and inflammatory factor with PN, independent of diabetes. Methods Study of Women's Health Across the Nation participants (n = 1910), ages 60 to 73 (mean 65.6) were assessed for PN by symptom questionnaire and monofilament testing at the 15th follow-up visit (V15). Anthropometric measures and biomarkers were measured at study baseline approximately 20 years prior, and C-reactive protein (CRP) and fibrinogen were measured longitudinally. Log-binomial regression was used to model the association between metabolic syndrome (MetS), obesity (≥35 body mass index), CRP, and fibrinogen with PN, adjusting for sociodemographic and health behavior measures. Results Baseline MetS [prevalence ratio (PR) 1.79, 95% CI (1.45, 2.20)], obesity [PR 2.08 (1.65, 2.61)], median CRP [PR 1.32 per log(mg/dL), (1.20, 1.45)], and mean fibrinogen (PR 1.28 per 100 mg/dL, (1.09, 1.50)] were associated with PN symptoms at V15. After excluding participants with baseline diabetes or obesity, MetS [PR 1.59 (1.17, 2.14)] and CRP [PR 1.19 per log(mg/dL), (1.06, 1.35)] remained statistically significantly associated with PN. There was a negative interaction between MetS and obesity, and the association between these conditions and PN was mediated by CRP. Conclusions Cardiometabolic factors and inflammation are significantly associated with PN, independent of diabetes and obesity. CRP mediates the relationship of both obesity and MetS with PN, suggesting an etiological role of inflammation in PN in this sample.

Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous synthetic chemicals that may disrupt blood pressure controls; however, human evidence to support this hypothesis is scant. We examined the association between serum concentrations of PFAS and risks of developing hypertension. Methods: This study included 1058 midlife women initially free of hypertension from the multiracial and multiethnic SWAN (Study of Women’s Health Across the Nation) with annual follow-up visits between 1999 and 2017. Hypertension was defined as blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic or receiving antihypertensive treatment. Cox proportional hazards models were utilized to calculate hazard ratios and 95% CIs. Quantile g-computation was implemented to evaluate the joint effect of PFAS mixtures. Results: During 11 722 person-years of follow-up, 470 participants developed incident hypertension (40.1 cases per 1000 person-years). Compared with the lowest tertile, women in the highest tertile of baseline serum concentrations had adjusted hazard ratios of 1.42 (95% CI, 1.19–1.68) for perfluorooctane sulfonate ( P trend=0.01), 1.47 (95% CI, 1.24–1.75) for linear perfluorooctanoate ( P trend=0.01), and 1.42 (95% CI, 1.19–1.70) for 2-(N-ethyl-perfluorooctane sulfonamido) acetate ( P trend=0.01). No significant associations were observed for perfluorononanoate and perfluorohexane sulfonate. In the mixture analysis, women in the highest tertile of overall PFAS concentrations had a hazard ratio of 1.71 (95% CI, 1.15–2.54; P trend=0.008), compared with those in the lowest tertile. Conclusions: Several PFAS showed positive associations with incident hypertension. These findings suggest that PFAS might be an underappreciated contributing factor to women’s cardiovascular disease risk.

Background Daily 24-h sleep–wake cycles have important implications for health, however researcher preferences in choice and location of wearable devices for behavior measurement can make 24-h cycles difficult to estimate. Further, missing data due to device malfunction, improper initialization, and/or the participant forgetting to wear one or both devices can complicate construction of daily behavioral compositions. The Method for Activity Sleep Harmonization (MASH) is a process that harmonizes data from two different devices using data from women who concurrently wore hip (waking) and wrist (sleep) devices for ≥ 4 days. Methods MASH was developed using data from 1285 older community-dwelling women (ages: 60–72 years) who concurrently wore a hip-worn ActiGraph GT3X + accelerometer (waking activity) and a wrist-worn Actiwatch 2 device (sleep) for ≥ 4 days (N = 10,123 days) at the same time. MASH is a two-tiered process using (1) scored sleep data (from Actiwatch) or (2) one-dimensional convolutional neural networks (1D CNN) to create predicted wake intervals, reconcile sleep and activity data disagreement, and create day-level night-day-night pairings. MASH chooses between two different 1D CNN models based on data availability (ActiGraph + Actiwatch or ActiGraph-only). MASH was evaluated using Receiver Operating Characteristic (ROC) and Precision-Recall curves and sleep–wake intervals are compared before (pre-harmonization) and after MASH application. Results MASH 1D CNNs had excellent performance (ActiGraph + Actiwatch ROC-AUC = 0.991 and ActiGraph-only ROC-AUC = 0.983). After exclusions (partial wear [n = 1285], missing sleep data proceeding activity data [n = 269], and Conclusions Implementing MASH to harmonize concurrently worn hip and wrist devices can minimizes data loss and correct for disagreement between devices, ultimately improving accuracy of 24-h compositions necessary for time-use epidemiology.

Over 645 million people worldwide have been infected with SARS-CoV-2, the virus that causes COVID-19. Critical knowledge gaps regarding the characteristics, duration, and impact of symptoms due to “long COVID”. This study evaluated the persistence of symptoms at one year following hospitalization with COVID-19, comparing responses on standardized measurement tools to population norms. Adults hospitalized with COVID-19 March-October 2020 during the initial emergence period in Southeast Michigan were eligible. A detailed survey was conducted via telephone 9-15 months after hospital discharge. Questions assessed fatigue, dyspnea, and physical functioning related to their COVID-19 illness. The median World Health Organization Disability Assessment Schedule (WHODAS) polytomous score placed 50% (n=20/40) of participants in the 90 percentile of disability based on population norms. The mean SF-36 physical functioning score was almost nine points below population norms (mean=70.6, standard deviation=27.4). Additionally, 47.5% of individuals (n=19) were severely emotionally affected by their health condition. Over half of participants surveyed were still impacted a year after initial infection, experiencing limited functional ability, fatigue, and emotional difficulties. Given the impact of these symptoms on day-to-day quality of life, further studies are needed to develop strategies for treatment and management of post-COVID conditions.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic and systemic inflammation affecting multiple organ systems, including an increased risk of cardiovascular disease due to the SLE-associated hyperinflammatory state. SLE shows a strong female predominance, suggesting a potential role of sex hormones in the pathogenesis of the disease. Evidence suggests an earlier age of menopause among women with SLE, despite mixed findings regarding other markers of ovarian aging. In healthy populations, the menopausal transition is associated with important physiologic changes resulting in increased cardiometabolic risk and risk of osteoporosis. Thus, women with SLE who experience the inflammatory effects of the autoimmune condition combined with the (potentially earlier) menopausal transition may represent a particularly vulnerable group of individuals during a particular window of time. Little is known, however, about strategies for cardiovascular risk or bone loss mitigation in women with SLE during the menopausal transition. Further, despite lack of knowledge regarding the burden of menopausal symptoms in women with SLE, existing recommendations provide only cautionary guidance for the use of hormone replacement therapy to address menopausal symptoms in this population. Importantly, the data regarding both SLE and menopause-associated cardiovascular and osteoporotic risk demonstrate the critical need for additional research to identify the type and timing of treatments or interventions needed to best mitigate this increased risk.

ImportanceRacial disparities in cardiometabolic health are consistently observed in cohort studies. However, most studies neither evaluate differences in age at onset nor account for systematic exclusion stemming from “weathering” (accelerated health declines for minoritized groups due to structural social and economic marginalization).ObjectiveTo evaluate racial or ethnic disparities in age at onset of 4 cardiometabolic outcomes (hypertension, isolated systolic hypertension [ISH], insulin resistance [IR], and diabetes), accounting for multiple forms of potential selection bias.Design, Setting, and ParticipantsThis cohort study used data from the Study of Women’s Health Across the Nation longitudinal cohort (1995-2016) and a cross-sectional screening sample (1995-1997). Data were analyzed from July 2019 to October 2021. Participants were eligible for the cohort if they were aged 42 to 52 years, had not received hormone therapy in the past 3 months, were not pregnant, had an intact uterus and at least 1 ovary, and were premenopausal or early perimenopausal (most recent menses ≤3 months).ExposuresSelf-reported racial or ethnic group (Black, Chinese, Hispanic, Japanese, or White).Main Outcomes and MeasuresThe main outcomes were hypertension (systolic blood pressure [BP] ≥140 mm Hg and diastolic BP ≥90 mm Hg or use of antihypertensive medication), ISH (systolic BP ≥140 mm Hg and diastolic BP 5.9 or insulin use), and diabetes (fasting serum glucose level ≥126 mg/dL [to convert to mmol/L, multiply by 0.0555], use of insulin or oral antidiabetic medication, or physician diagnosis). Selection into the cohort was addressed via inverse probability weighting and interval-censored survival models and selection out via multiple imputation. Accelerated failure time models were used to examine racial or ethnic differences in age at disease onset and estimate the median age at onset.ResultsA total of 3302 women were included in the study, with a median age of 46.2 years (range, 42-52 years) at baseline. In the sample, 42.6% had a bachelor’s degree or higher and 36.3% self-rated their health as “very good” at baseline; 23.9% had hypertension, 43.7% had ISH, 13.5% had IR, and 4.6% had diabetes at baseline. Hypertension occurred a median of 5.0 years (95% CI, 5.4-5.5 years) earlier and metabolic outcomes (diabetes and IR) a median of 11.3 years (95% CI, 9.7-12.9 years) earlier for Black and Hispanic women vs White women; ISH occurred a median of 7.7 years (95% CI, 7.3-8.1 years) earlier for Black women vs White women. Adjustment for selection was associated with a mean 20-year decrease in estimated median age at onset, with greater decreases among Black and Hispanic women.Conclusions and RelevanceIn this multiracial cohort of midlife women, failure to account for selection biases, especially at study onset, was associated with falsely high estimates of age at cardiometabolic onset, with greater misestimation among Black and Hispanic women. The results suggest that hypertension and metabolic interventions, particularly for Black and Hispanic women, should be targeted to women aged as young as 30 years for hypertension and 40 years for metabolic interventions. Considering the timing of disease and fully addressing inherent selection biases in research are critical to understanding aging and disease risk, especially for racial and ethnic minoritized populations.

Objectives To determine whether physical function (PF) before menopause is related to cardiovascular disease (CVD) risk. Methods Participants were N = 2950 pre-/early peri-menopausal women (median age 46, (25th–75th percentile: 43–48 years). Physical function was assessed at baseline using the Physical Function subscale of the SF-36 and scores were trichotomized (no, some, or substantial limitations). Clinical CVD events were ascertained at annual/biennial clinical assessments through the 15th follow-up visit. Risk of CVD was determined with Cox proportional hazards models. Results: Women were followed for a median of 19.1 years, during which 220 women had a CVD event. In fully adjusted models, women with substantial limitations at baseline had higher CVD risk compared to women with no limitations (hazards ratio [HR] = 1.55, 95% confidence interval [CI]: 1.12–2.33). Discussion: Substantial PF limitations in pre- and early peri-menopausal women are associated with higher risk of clinical CVD events, consistent with literature in older adults.

Context Phthalates are hypothesized to contribute to diabetes, but longitudinal evidence in humans is limited. Objective We examined whether phthalate exposure was associated with a higher incidence of diabetes in a racially/ethnically diverse cohort of midlife women. Methods In the Study of Women's Health Across the Nation Multipollutant Study, we followed 1308 women without diabetes in 1999-2000 for 6 years. Eleven phthalate metabolites were measured in spot urine samples in 1999-2000 and 2002-2003. Incident diabetes was ascertained between 1999-2000 and 2005-2006. Cox proportional hazards models with time-varying exposure were used to estimate the hazard ratio (HR) of diabetes associated with each phthalate metabolite, adjusting for demographic, lifestyle, and health-related factors. Effect modification by race/ethnicity was examined with interaction terms. Results Sixty-one women developed diabetes over 6 years (cumulative incidence = 4.7%). Among all women, several high-molecular-weight phthalate metabolites were associated with a higher incidence of diabetes, but none were statistically significant. There was effect modification by race/ethnicity. Among White women, each doubling of the concentrations of mono-isobutyl phthalate (MiBP), monobenzyl phthalate, mono-carboxyoctyl phthalate, mono-carboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate was associated with a 30% to 63% higher incidence of diabetes (HR = 1.30, 95% CI, 1.03-1.65 for MCNP; HR = 1.63, 95% CI, 1.18-2.25 for MiBP). In contrast, phthalates were not associated with diabetes incidence in Black or Asian women. Conclusions Some phthalate metabolites were associated with a higher incidence of diabetes over 6 years, but the associations were inconsistent across racial/ethnic groups. Whether phthalates cause diabetes requires further investigation.

OBJECTIVE We examined longitudinal associations of air pollution exposure, including fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), with weight, BMI, waist circumference, fat mass, lean mass, and proportion fat mass in midlife women. RESEARCH DESIGN AND METHODS The study population included 1,654 White, Black, Chinese, and Japanese women from the Study of Women’s Health Across the Nation, with the baseline median age of 49.6 years, followed from 2000 to 2008. Annual air pollution exposures were assigned by linking residential addresses with hybrid estimates of air pollutant concentrations at 1-km2 resolution. Body size was measured, and body composition was measured using DXA at approximately annual visits. Linear mixed effects models were used to examine the associations between air pollution and body size and composition measures and whether these associations differed by physical activity. RESULTS After adjusting for potential confounders, an interquartile range increase in PM2.5 concentration (4.5 μg/m3) was associated with 4.53% (95% CI 3.85%, 5.22%) higher fat mass, 1.10% (95% CI 0.95%, 1.25%) higher proportion fat mass, and 0.39% (95% CI −0.77%, −0.01%) lower lean mass. Similar associations were also observed for NO2 and O3. Weaker associations of PM2.5 and NO2 with body composition were observed in participants who engaged in more physical activity. CONCLUSIONS Our analyses provide evidence that exposure to PM2.5, NO2, and O3, is adversely associated with body composition, including higher fat mass, higher proportional fat mass, and lower lean mass, highlighting their potential contribution to obesity.

Environmental exposure to heavy metals may contribute to increased blood pressure; however, evidence from midlife women who are at greater risk of cardio-metabolic disease is limited. We evaluated the associations of urinary concentrations of arsenic, cadmium, mercury, and lead with longitudinal changes in blood pressure in the Study of Women’s Health Across the Nation Multi-Pollutant Study. The sample included 1317 White, Black, Chinese, and Japanese women, aged 45 to 56 years at baseline (1999–2000), whose systolic blood pressure (SBP) and diastolic blood pressure were measured annually or biannually through 2017. Urinary metal concentrations were determined at baseline. Longitudinal changes in SBP and diastolic blood pressure were modeled using linear mixed-effects models by tertiles of metal concentrations. After multivariable adjustment, estimated annualized increases (95% CI) in SBP in the highest and lowest tertiles were 0.93 (0.85–1.01) mm Hg and 0.74 (0.66–0.82) mm Hg for arsenic, 0.82 (0.75–0.90) mm Hg and 0.72 (0.65–0.80) mm Hg for mercury, and 0.86 (0.78–0.93) mm Hg and 0.72 (0.64–0.79) mm Hg for lead, respectively. Similar results were observed for associations of arsenic, mercury, lead with diastolic blood pressure. Urinary cadmium was associated with a greater rate of increase in SBP only among never smokers. Women with higher concentrations of all four metals had greater annualized increases in SBP and diastolic blood pressure than those with lower concentrations. Our findings suggest that exposure to heavy metals may accelerate the increase in blood pressure in midlife women, supporting the need for continued efforts to reduce these environmental exposures.

Background Little is known about how adverse, midlife metabolic profiles affect future physical functioning. We hypothesized that a higher number of midlife metabolic syndrome (MetS) components are associated with poorer physical performance in early old age for multiethnic women. Methods MetS status from 1996 to 2011 (8 visits) and objective physical performance in 2015/2016 (Short Physical Performance Battery [SPPB; 0–12], 40-foot walk [meter/second], 4-meter gait speed [meter/second], chair stands [seconds], stair climb [seconds]) were assessed in the Study of Women’s Health Across the Nation (SWAN; n = 1722; age 65.4 ± 2.7 years; 26.9% African American, 10.1% Chinese, 9.8% Japanese, 5.5% Hispanic). Poisson latent class growth modeling identified MetS component trajectory groups: none (23.9%), 1 = low-MetS (28.7%), 2 = mid-MetS (30.9%), and ≥3 = high-MetS (16.5%). Adjusted linear regression related MetS groups to physical performance outcomes. Results High-MetS versus none had higher body mass index, pain, financial strain, and lower physical activity and self-reported health (p < .0001). Compared with White, African American and Hispanic women were more likely to be in the high-MetS groups and had worse physical functioning along with Chinese women (SPPB, chair stand, stair climb, and gait speed—not Hispanic). After adjustments, high-MetS versus none demonstrated significantly worse 40-ft walk (β: −0.08; 95% CI: −0.13, −0.03), gait speed (β: −0.09; 95% CI: −0.15, −0.02), SPPB (β: −0.79; 95% CI: −1.15, −0.44), and chair stands (β: 0.69; 95% CI: 0.09, 1.28), but no difference in stair climb. Conclusions Midlife MetS groups were related to poor physical performance in early old age multiethnic women. Midlife management of metabolic function may improve physical performance later in life.

Background In older adults, vision impairment (VI) is associated with worse cognitive function. However, the relationship between midlife vision and future cognitive function remains unknown. Methods The Study of Women’s Health Across the Nation, Michigan site, is a longitudinal cohort of midlife women aged 42–52 years at baseline. Presenting Titmus visual acuity (VA) in the better-seeing eye was assessed at baseline and categorized as no or mild VI (VA ≥20/60), or moderate or worse VI (VA Results About 394 women aged 42–52 at baseline with a maximum follow-up of 20 years were included in this analysis. After covariate adjustment, moderate or worse VI was associated with lower EMBTi (β = −0.56, p = .012), EBMTd (β = −0.60, p = .009), and DSB (β = −0.84, p = .04). While we detected significant associations between VI and levels of cognitive function scores, rates of cognitive decline as individuals aged did not vary by VI status. Conclusion Moderate or worse VI, assessed during midlife, was associated with lower scores on measures of cognitive function over a 15-year period during which women transitioned from midlife to older adulthood.

Purpose. Women's cardio-metabolic risk increases in midlife. Previous work relating menopause symptoms to diabetes/Metabolic Syndrome (MetS) does not consider the adverse impact of multiple concurrent physical and psychological symptoms in midlife. Methods. Data are from 3097 participants in the Study of Women's Health Across the Nation, a cohort of midlife women followed for over 20 years. Baseline latent symptom classes (LSC) were derived from 58 questions assessing physical, psychological and menopausal symptoms. Six identified LSCs ranged from 1 (most symptoms present at high severity) to 6 (few symptoms present at low severity). Accelerated failure time models estimated time to onset of type 2 diabetes and MetS for each LSC. Results. Women with multiple high/moderate severity symptoms had an earlier onset of diabetes (13.2%, 14.1% and 20.8% earlier onset in LSCs 1, 2, 3, respectively) and MetS (15.5%, 13.0% and 19.7% earlier onset in LSCs 1, 2, 3, respectively) than women with few/low severity symptoms. Conclusions. Having multiple concurrent moderate to high intensity physical and psychological symptoms in midlife are associated with early onset of diabetes and MetS. Monitoring and subsequent intervention on a broad range of symptoms in midlife may significantly mitigate cardio-metabolic risk during this critical life stage.

Aims The epidemiologic Study of Women's Health Across the Nation (SWAN) includes urinary incontinence (UI) questionnaire items. We introduced an independently self-administered paper towel test (PTT-ISA; invention disclosure #2021-347) to objectively demonstrate UI. Aims were to determine: (1) PTT-ISA compliance and (2) relationship to questionnaire results. Methods 276 community women were invited to complete both SWAN questionnaire and PTT-ISA. For PTT-ISA, a woman holds a trifold brown paper towel against her perineum while coughing hard three times. She checks the towel for wetness and compares it with pictorial showing wetted area gradations (dry towel through >6 ml/saturated). She then selects the best photo match for her towel. A newly conceptualized variable constructed as PTT-ISA plus questionnaire results was formed. Results Of 276 women, noncompliance with PTT-ISA was 2.2% (6 women). Four others (1.5%) were missing questionnaires. For the remaining 266 women, conceptual cohesiveness between questionnaire-only and PTT-ISA + questionnaire was demonstrated in 165 (62.0%). Lack of cohesiveness occurred in 101 (38.9%), including 41 women who said "no" to the questionnaire item indicative of stress UI and had leakage on PTT-ISA; leakage degree varied across the full pictorial spectrum from drops to saturated. Conclusion PTT-ISA demonstrates high compliance, with rate comparable to survey compliance. It is a novel measure for objective sign of urine loss when independently self-administered by community women outside of a clinic environment. Further research comparing PTT-ISA with clinician-observed cough test is warranted. As independently self-administered, PTT-ISA is simple, noninvasive, inexpensive, and an acceptable test that adds value to otherwise survey-dependent research.

Background Physical activity (PA) has the potential to attenuate cardiovascular disease risk in midlife women through multiple pathways, including improving lipid profiles. Longitudinal patterns of PA and blood lipid levels have not been studied in midlife women. Our study identified trajectories of PA and blood lipids across midlife and characterized the associations between these trajectories. Methods We evaluated 2,789 participants from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study with follow-up over the menopause transition. Women reported PA using the Kaiser Physical Activity Survey at seven study visits across 17 years of follow-up. Serum high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were measured at eight study visits across the same 17-year follow-up period. We used group-based trajectory models to characterize trajectories of PA and blood lipids over midlife and dual trajectory models to determine the association between PA and blood lipid trajectories adjusted for race/ethnicity, body mass index category, smoking, and lipid-lowering medication use. Results Women were 46 years old, on average, at study entry. Forty-nine percent were non-Hispanic white; 32 % were Black; 10 % were Japanese; and 9 % were Chinese. We identified four PA trajectories, three HDL cholesterol trajectories, four LDL cholesterol trajectories, and two triglyceride trajectories. The most frequently occurring trajectories were the consistently low PA trajectory (69 % of women), the low HDL cholesterol trajectory (43 % of women), the consistently moderate LDL cholesterol trajectory (45 % of women), and the consistently low triglycerides trajectory (90 % of women). In dual trajectory analyses, no clear associations were observed between PA trajectories and HDL cholesterol, LDL cholesterol, or triglycerides trajectories. Conclusions The most frequently observed trajectories across midlife were characterized by low physical activity, low HDL cholesterol, moderate LDL cholesterol, and low triglycerides. Despite the absence of an association between long-term trajectories of PA and blood lipids in this study, a large body of evidence has established the importance of clinical and public health messaging and interventions targeted at midlife women to promote regular and sustained PA during midlife to achieve other cardiovascular and metabolic benefits.

Aging affects men and women differently; however, the impact of sex and gender on the aging process is not well understood. Moreover, these 2 concepts are often conflated, which further contributes to a lack of clarity on this important issue. In an effort to better understand the relevance of sex and gender in aging research, the Research Centers Collaborative Network sponsored a 1.5-day conference on sex and gender differences in aging that brought together key thought leaders from the 6 National Institute on Aging center programs. The meeting included sessions on comparing males and females, pathophysiological differences, sex/gender in clinical care, and gender and health in the social context. Presenters from a wide array of disciplines identified opportunities for multidisciplinary research to address current gaps in the field and highlighted the need for a more systematic approach to understanding the how and why of sex/gender differences, as well as the health implications of these differences and the sex/gender biases that affect clinical treatment and outcomes. This article summarizes the proceedings of the workshop and provides several recommendations to move the field forward, such as better data collection tools to assess the intersection of sex and gender in epidemiological research; a life course perspective with attention to fetal/developmental origins and key life stages; innovative animal models to distinguish contributions from sex hormones versus sex chromosomes; and integration of sex/gender into teaching and clinical practice. Ultimately, successful implementation of these recommendations will require thoughtful investigations across the translational spectrum and increased collaborations among those with expertise in sex and gender differences.

Obesity is a major threat to health, but the etiology of obesity is incompletely understood. Phthalates, synthetic chemicals ubiquitous in the environment, are suspected to have obesogenic effects, but the relationship of phthalates and obesity in humans remains uncertain. We examined whether phthalate exposure was associated with body fat gain in midlife women. We analyzed data from 1369 women in the Study of Women's Health Across the Nation Multi-Pollutant Study. Eleven phthalate metabolites measured in spot urine samples at baseline (1999/2000) were standardized with covariate-adjusted creatinine. Body weight (BW), fat mass (FM) from dual-energy X-ray absorptiometry (DXA), and body fat percentage (BF%) from DXA were measured near-annually until 2016/2017. For each metabolite, linear mixed effects models with time and log

Purpose The purpose of this study was to evaluate the ability to screen for glaucoma using a Food Drug Administration (FDA) Class II diagnostic digital fundus photography system used for diabetic retinopathy screening (DRS). Methods All research participants underwent a comprehensive eye examination as well as non-mydriatic 45°single photograph retinal imaging centered on the macula. Optic nerve images within the 45° non-mydriatic and non-stereo DRS image were evaluated by two methods: 1) grading by three glaucoma specialists, and 2) a computer-aided automated segmentation system to determine the vertical cup-to-disc ratio (VCDR). Using VCDR from clinical assessment as gold standard, VCDR results from two methods were compared to that from clinical assessment. Inter-grader agreement was assessed by computing intraclass correlation coefficient (ICC). In addition, sensitivity and specificity were calculated. Results Among 245 fundus photos, 166 images met quality specifications for analysis. Fifty images were not processed by the automated system due to the poor quality of the optic disc, and 29 images did not include the optic nerve head due to the patient movement during the photo acquisition. The ICC value for the VCDR between the gold standard clinical exam and the automated system was 0.41, indicating fair agreement. The ICC value between the three ophthalmologists and the gold standard was 0.51, 0.56, and 0.69, respectively, indicating fair to moderate agreement. Discussion Assessing the VCDR on non-mydriatic and non-stereo DRS fundus photographs by either the computer-aided automated segmentation system or by glaucoma specialists showed similar fair to moderate agreement. In summary, optic nerve assessment for glaucoma from these 45° non-mydriatic and non-stereo DRS images is not yet suitable for tele-glaucoma screening.

Purpose: To examine racial/ethnic differences in participant-reported and device-based estimates of sedentary and physical activity behaviors and correlations between measurement methods in midlife and young-old women. Methods: Data are from 1,257 Study of Women’s Health Across the Nation participants, aged 60–72 who agreed to participate in an accelerometer protocol and had valid wear time (46% White, 26% Black, 12% Chinese, 10% Japanese, 6% Hispanic). Measures from the Kaiser Physical Activity Scale (KPAS) and ActiGraph wGT3X-BT were summarized overall and by race/ethnic groups. Partial Spearman rank order correlation coefficients between the KPAS and accelerometer were computed overall and by race/ethnic groups. Fisher’s z transformation-derived confidence intervals were calculated to evaluate differences in observed correlations in the various race/ethnic groups, compared to White women. Results: Participants spent an average of 7.5 ± 2.1 h·d−1 in sedentary behaviors, 4.5 ± 1.1 h·d−1 and 2.3 ± 0.8 h·d−1 in low or high light intensity physical activity, respectively, and 56 ± 35 min·d−1 in moderate-to-vigorous intensity physical activity. Time spent in each category differed by race/ethnic group. Overall, correlation coefficients comparing the KPAS domain-specific and total physical activity scores with accelerometry were low to moderate (range: 0.062–0.462), and few statistically significant differences in correlations were noted for race/ethnic groups, compared to White women. Conclusions: Study findings complement prior studies describing sedentary and physical activity behaviors using multi-methods in a diverse population of older women, and provide additional evidence on the convergent validity of the KPAS by race/ethnic groups.

This study examined whether employment status during mid-life and older adulthood is associated with physical function impairment.Participants were 2700 women in the multiracial/multiethnic Study of Women's Health Across the Nation. Time-varying, lagged, and cumulative exposure analyses modeled associations between self-reported employment status and the likelihood of severe physical function impairment across 19 years of follow-up.Independent of demographic variables, women who were not working (OR = 1.58, 95% CI = 1.22, 2.04) or employed part-time (OR = 1.29, 95% CI = 1.04, 1.61) were more likely to report severe physical function impairments than women employed full-time. This same pattern was seen in lagged analyses predicting risk of physical function impairment from employment status at the prior assessment (not working vs. full-time: OR = 1.53, 95% CI = 1.08, 2.18; part-time vs. full-time: OR = 1.53, 95% CI = 1.17, 2.00). The likelihood of severe physical function impairment increased by 20% for every additional 10% of follow-up spent not working (OR = 1.02, 95% CI: 1.01, 1.03). Associations were robust to adjustment for health-related variables, body mass index, and physical activity.Women with lower levels of employment from mid-life to older adulthood were more likely to experience severe impairment in physical function. However, the underlying mechanisms, and the timescales over which associations unfold, require further study.

ImportanceWhether prediabetes is associated with fracture is uncertain.ObjectiveTo evaluate whether prediabetes before the menopause transition (MT) is associated with incident fracture during and after the MT.Design, Setting, and ParticipantsThis cohort study used data collected between January 6, 1996, and February 28, 2018, in the Study of Women’s Health Across the Nation cohort study, an ongoing, US-based, multicenter, longitudinal study of the MT in diverse ambulatory women. The study included 1690 midlife women in premenopause or early perimenopause at study inception (who have since transitioned to postmenopause) who did not have type 2 diabetes before the MT and who did not take bone-beneficial medications before the MT. Start of the MT was defined as the first visit in late perimenopause (or first postmenopausal visit if participants transitioned directly from premenopause or early perimenopause to postmenopause). Mean (SD) follow-up was 12 (6) years. Statistical analysis was conducted from January to May 2022.ExposureProportion of visits before the MT that women had prediabetes (fasting glucose, 100-125 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), with values ranging from 0 (prediabetes at no visits) to 1 (prediabetes at all visits).Main Outcomes and MeasuresTime to first fracture after the start of the MT, with censoring at first diagnosis of type 2 diabetes, initiation of bone-beneficial medication, or last follow-up. Cox proportional hazards regression was used to examine the association (before and after adjustment for bone mineral density) of prediabetes before the MT with fracture during the MT and after menopause.ResultsThis analysis included 1690 women (mean [SD] age, 49.7 [3.1] years; 437 Black women [25.9%], 197 Chinese women [11.7%], 215 Japanese women [12.7%], and 841 White women [49.8%]; mean [SD] body mass index [BMI] at the start of the MT, 27.6 [6.6]). A total of 225 women (13.3%) had prediabetes at 1 or more study visits before the MT, and 1465 women (86.7%) did not have prediabetes before the MT. Of the 225 women with prediabetes, 25 (11.1%) sustained a fracture, while 111 of the 1465 women without prediabetes (7.6%) sustained a fracture. After adjustment for age, BMI, and cigarette use at the start of the MT; fracture before the MT; use of bone-detrimental medications; race and ethnicity; and study site, prediabetes before the MT was associated with more subsequent fractures (hazard ratio for fracture with prediabetes at all vs no pre-MT visits, 2.20 [95% CI, 1.11-4.37]; P = .02). This association was essentially unchanged after controlling for BMD at the start of the MT.Conclusions and RelevanceThis cohort study of midlife women suggests that prediabetes was associated with risk of fracture. Future research should determine whether treating prediabetes reduces fracture risk.

BACKGROUND: Body composition strongly influences physical function in older adults. Bioelectrical impedance analysis (BIA) differentiates fat mass from skeletal muscle mass, and may be more useful than body mass index (BMI) for classifying women on their likelihood of physical function impairment. AIMS: This study tested whether BIA-derived estimates of percentage body fat (%BF) and height-normalized skeletal muscle mass (skeletal muscle mass index; SMI) enhance classification of physical function impairment relative to BMI. METHOD: Black, White, Chinese, and Japanese midlife women (N=1,482) in the Study of Women’s Health Across the Nation (SWAN) completed performance-based measures of physical function. BMI (kg/m(2)) was calculated. %BF and SMI were derived through BIA. Receiver-operating characteristic (ROC) curve analysis, conducted in the overall sample and stratified by racial group, evaluated optimal cutpoints of BMI, %BF, and SMI for classifying women on moderate-severe physical function impairment. RESULTS: In the overall sample, a BMI cutpoint of ≥30.1 kg/m(2) correctly classified 71.1% of women on physical function impairment, and optimal cutpoints for %BF (>43.4%) and SMI (≥8.1 kg/m(2)) correctly classified 69% and 62% of women, respectively. SMI did not meaningfully enhanced classification relative to BMI (change in area under the ROC curve=.002; net reclassification improvement=.021; integrated discrimination improvement=−.003). Optimal cutpoints for BMI, %BF, and SMI varied substantially across race. Among Black women, a %BF cutpoint of 43.9% performed somewhat better than BMI (change in area under the ROC curve=.017; sensitivity=0.69, specificity=0.64). CONCLUSION: Some race-specific BMI and %BF cutpoints have moderate utility for identifying impaired physical function among midlife women.

PURPOSE: Peripheral neuropathy (PN) is highly prevalent condition with serious sequelae. However, many studies of the condition have been restricted to populations with diabetes, limiting evidence of potential contributing risk factors including salient psychosocial risk factors such as discrimination. METHODS: The longitudinal Study of Women’s Health Across the Nation was used to assess the relationship between perceived discrimination and prevalent peripheral neuropathy in 1,718 racially/ethnically diverse midlife women. We used multivariable logistic regression to determine the association between perceived discrimination (Detroit Area Study Everyday Discrimination Scale) and PN (symptom questionnaire and monofilament testing) and conducted a formal assessment of the mediating effects of body mass index (BMI). RESULTS: The overall prevalence of PN was 26.1% in the total sample and 40.9% among women with diabetes. Women who reported perceived discrimination had 29% higher odds of PN as compared to women who did not report perceived discrimination (95% confidence interval (CI): 1.01, 1.66). Approximately 30% of the total effect of discrimination on PN was mediated indirectly by BMI. CONCLUSIONS: More research is needed to determine the contributing factors to non-diabetic PN. Additionally findings re-affirm the impact of financial strain, BMI and diabetes as significant correlates of PN and highlight discrimination as an important risk factor.

Objectives Evaluate degree to which racial/ethnic differences in physical performance are mediated by sociodemographic, health, behavioral, and psychosocial factors. Methods Physical performance was evaluated using a decile score derived from grip strength, timed 4 m walk, and timed repeat chair stand in 1,855 African American, Caucasian, Chinese, Hispanic, and Japanese women, mean age = 61.8 (SD = 2.7) in the Study of Women’s Health Across the Nation. Mediators included education, financial strain, comorbidities, pain, body mass index (BMI), physical activity, and perceived stress. Structural equation models provided estimates of the total difference in physical performance between Caucasians and each race/ethnic groups and differences due to direct effects of race/ethnicity and indirect effects through mediators. Results The mean decile score for Caucasian women was 16.9 (SD = 5.6), 1.8, 2.6, and 2.1 points higher than the model-estimated scores in African Americans, Hispanics and Chinese, respectively, and 1.3 points lower than the Japanese. Differences between Caucasians and the Chinese and Japanese were direct effects of race/ethnicity whereas in African Americans and Hispanics 75% or more of that disparity was through mediators, particularly education, financial strain, BMI, physical activity, and pain. Discussion Addressing issues of poverty, racial inequality, pain, and obesity could reduce some racial/ethnic disparity in functional limitations as women age.

Highlights • Mobility disability in older adults is highly prevalent; particularly in women. • The role of light intensity activity and differences by race/ethnicity are unknown. • Findings support the importance of MVPA on physical functioning in older women., To determine the cross-sectional associations of accelerometer-measured time spent in physical activity intensity categories (sedentary, low and high light intensity, or moderate to vigorous intensity physical activity (MVPA) with physical performance outcomes [stair climb ascent, 40 foot walk test, and short physical performance battery (SPPB)] in older women and examine differences by race/ethnicity. Data were from 1,256 Study of Women’s Health Across the Nation (SWAN) participants [aged 64.9 (2.7) years at Visit 15 (2015–16); 54.1% non-White]. Three sets of adjusted multivariable linear or logistic regression models were built to test the study objectives using the backward elimination approach to identify relevant covariates. In the full analytic sample, a 10 min increment in MVPA was related to faster performance on the stair climb [β = −0.023 (95% CI: −0.04, −0.005) seconds] and 40 foot walk test [β = −0.066 (95% CI: −0.133, −0.038) seconds], and a 9% lower odds [OR: 0.91; 95% CI: 0.87, 0.96; p = 0.004] of limitations based on the SPPB. Statistically significant differences by race/ethnicity were found for the stair climb ascent time as MVPA was associated with better performance for White, Chinese, and Japanese participants while high light intensity physical activity, but not MVPA, was deemed beneficial in Black women. Findings from the isotemporal substitution models were consistent. Findings further support the importance of MVPA on physical performance outcomes in older women. Further research is needed to examine the complex associations between physical (in)activity and physical performance outcomes by race/ethnicity to provide more targeted recommendations.

This cohort study examines the association over time of physical activity levels and cognitive test results among women at midlife., Key Points Question Is physical activity during midlife associated with better performance in cognitive measures over time? Findings This cohort study of 1718 women at midlife found that, with adjustment for socioeconomic characteristics, menopause symptoms, hormone therapy use, and presence of diabetes and hypertension, self-reported physical activity was not associated with measured cognitive performance in the domains of processing speed, verbal memory, or working memory. Meaning These findings suggest that the cognitive protection effect of physical activity observed in later life may be an artifact of reverse causation., Importance The increasing prevalence of cognitive decline, impairment, and dementia spurs intense interest in cognitive preservation strategies. Objective To explore the longitudinal association between physical activity (PA) and cognitive performance among women at midlife. Design, Setting, and Participants This cohort study is an analysis from the Study of Women’s Health Across the Nation. Enrollment occurred from 1996 through 1997, and follow-up extended into 2017. Included individuals were those who had undergone cognitive measures during the first 3 cognitive test visits and had at least 1 additional cognitive measurement. Stroke prior to baseline was an exclusion, and observations were censored for subsequent stroke. Data were analyzed from June 2018 through August 2019. Exposures Engaging in sport or exercise PA (self-reported). Main Outcomes and Measures The Symbol Digit Modalities Test (SDMT) was used to assess cognitive processing speed. The East Boston Memory Test-Delayed (EBMT-D) was used to measure verbal episodic memory. The digit span backwards (DSB) test was used to evaluate working memory. Results Among 1718 women with a median (range) observation time of 11.9 (0.60-13.5) years, the mean (SD) baseline age was 45.7 (2.5) years. From baseline through age 61 years, mean change in SDMT score was −0.20 annually (95% CI, −0.26 to −0.15; P

Background The menopausal transition is characterized by increased cardiovascular risk, weight gain, and increased adiposity for many women. The adipose‐derived secretory proteins adiponectin and leptin are associated with insulin resistance, metabolic syndrome, and cardiovascular disease but their role in subclinical atherosclerotic disease is unclear. This cross‐sectional study evaluated the associations of adiponectin and leptin with carotid artery intima‐media thickness, adventitial diameter, presence of carotid plaques, and brachial‐ankle pulse wave velocity (baPWV) in women aged 54 to 65 years. Methods and Results Participants were 1399 women from SWAN (Study of Women's Health Across the Nation), a community‐based study of women transitioning through menopause. Carotid ultrasound and baPWV measures were obtained at SWAN follow‐up visits 12 or 13, when 97% of participants were post‐menopausal. Adipokines were assayed from serum specimens obtained concurrently at these visits. Linear and logistic regression models were used to evaluate adiponectin or leptin, both log‐transformed attributable to skewness, in relationship to carotid artery intima‐media thickness, adventitial diameter, baPWV, and presence of carotid plaque. Covariates included age, race, study site, smoking, alcohol use, obesity, cardiovascular disease risk factors, and menopausal status. Lower levels of adiponectin were related to greater carotid artery intima‐media thickness, wider adventitial diameter, and faster baPWV; associations were attenuated after adjusting for cardiovascular disease risk factors. Higher levels of leptin were associated with greater carotid artery intima‐media thickness and wider adventitial diameter in minimally and fully adjusted models, and contrary to expectation, with slower baPWV, particularly among women with diabetes mellitus or obesity. Conclusions Adiponectin and leptin are 2 important inflammatory pathways that may contribute to adverse subclinical cardiovascular disease risk profiles in women at midlife.

PURPOSE The Female Athlete Triad (Triad) is common in female athletes. The Triad is caused by low-energy availability (EA), which is often difficult to measure and has been postulated to be associated with low-iron status. Here, we explore whether markers of low-iron status may be associated with indicators of low EA including Triad risk factors. METHODS A total of 239 female National Collegiate Athletic Association Division I athletes completed preparticipation examinations that included Triad risk factors, medication/supplement use, diagnosis of anemia, and elected to complete dual-energy x-ray absorptiometry scan to measure bone mineral density. The association of markers of low iron (defined as self-report of iron supplementation and/or history of anemia) with each component of the Triad risk assessment score was assessed by stratifying low-iron status across different levels of Triad risk category. Differences across iron status groups were assessed using Fisher exact testing. RESULTS Every component of the Triad risk assessment score excluding delayed menarche was associated with low-iron status. The proportion of women who reported low iron was 11.5% in the low-risk EA group compared with 50% in the moderate-risk and 66.7% in the high-risk EA groups (P = 0.02); respectively. These numbers were 11.6%, 25.0%, and 66.7% (P = 0.02) for body mass index; 9.7%, 16.7%, and 25.0% (P < 0.05) for oligomenorrhea; 10.3%, 45.5%, and 50.0% (P < 0.01) for bone mineral density; and 10.4%, 20.8%, and 30.8% (P = 0.03) for history of stress reaction or fracture. Lean/endurance athletes were more likely to have low-iron status than other athletes (15.5% vs 3.4%, P = 0.02). CONCLUSIONS Markers for low-iron status were associated with Triad risk factors. Our study suggests that female athletes with a history of anemia or iron supplementation may require further screening for low EA.

This longitudinal cohort study's aim was to detect whether larger increases in C‐reactive protein (CRP) predict greater amounts of subsequent bone loss in women transitioning from premenopause to postmenopause. Participants were initially 42 to 52 years of age and premenopausal or early perimenopausal. The sample included 1431 women who were not using hormone therapy and whose CRP values were not consistent with acute inflammation. Individual fixed effects (IFE) models estimated the association of log2 CRP with subsequent bone mineral density (BMD) decline rate, adjusted for menopause transition (MT) stage (1: premenopausal or early perimenopausal; 2: late perimenopausal or early postmenopausal; or 3: late postmenopausal), body mass index, diabetes, smoking, alcohol, bone active medications, and anti‐inflammatory medications. BMD decline at both the lumbar spine (LS) and femoral neck (FN) was faster for observations made in MT stage 2 than that during other stages (all p

Study Objectives Examine the association between trajectories of self-reported insomnia symptoms and sleep duration over 13 years with objective physical function. Methods We utilized data from 1,627 Study of Women’s Health Across the Nation participants, aged 61.9 ± 2.7 years at the end of the 13-year follow-up. Latent class growth models identified trajectories of insomnia symptoms (trouble falling asleep, frequent night-time awakenings, and/or early morning awakening) and sleep duration over 13 years. Physical function tests were performed at the end of the 13-year period: 40-ft walk, 4-m walk, repeated chair stand, grip strength, and balance. Multivariable regression analyses examined each physical function measure according to the insomnia symptom or sleep duration trajectory group. Results Five insomnia symptom trajectories and two sleep duration trajectories were identified. Women with a consistently high likelihood of insomnia symptoms and women with a decreased likelihood of insomnia symptoms (i.e. improving) had slower gait speed (3.5% slower 40-ft walk [consistently high], 3.7% slower 4-m walk [improving]; each p ≤ .05) than those with a consistently low likelihood of insomnia symptoms. In contrast, women with a steep increase in the likelihood of insomnia symptoms over time and women with persistent insufficient sleep duration had lower odds of having a balance problem (odds ratio [OR] = 0.36 and OR = 0.61, respectively; each p < .02) compared to those with a consistently low likelihood of insomnia symptoms and those with persistent sufficient sleep duration, respectively. Conclusion These results suggest that women’s sleep during midlife has important implications for maintaining physical function during the transition into older adulthood.

Background Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure have been associated with obesity and related comorbidities, possibly through disrupting signaling pathways of adipokines. Both leptin and adiponectin can modulate metabolic processes. However, the effects of PFAS on adipokines are not well understood. Objective We determined if serum PFAS concentrations were associated with adipokine profiles in midlife women. Methods We examined 1245 women aged 45–56 years from the Study of Women's Health Across the Nation. Concentrations of 11 PFAS were quantified in baseline serum samples collected in 1999–2000. Linear and branched perfluorooctane sulfonic acid isomers (n-PFOS and Sm-PFOS) and their sum (PFOS), linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA) with detection frequencies >60% were included in the analysis. Adipokines including leptin, soluble leptin receptor (sOB-R), free leptin index (FLI, the ratio of leptin to sOB-R), total and high molecular weight (HMW) adiponectin were assessed in 2002–2003. We utilized multivariable linear regressions and Bayesian kernel machine regression (BKMR) to assess individual and overall joint effects of PFAS on adipokines with adjustment for age, race/ethnicity, study site, education, smoking status, physical activity, menopausal status, and waist circumference. Results A doubling of PFAS concentrations was associated with 7.8% (95% CI: 2.5%, 13.4%) higher FLI for PFOS, 9.4% (95% CI: 3.7%, 15.3%) for n-PFOA, 5.5% (95% CI: 2.2%, 9.0%) for EtFOSAA and 7.4% (95% CI: 2.8%, 12.2%) for MeFOSAA. Similar associations were found for leptin. Only EtFOSAA was associated with lower sOB-R concentrations (−1.4%, 95% CI: −2.7%, −0.1%). Results remained in women with overweight or obesity but not those with normal weight or underweight. No statistically significant associations were observed with total or HMW adiponectin, except for PFNA with total and HMW adiponectin observed in women with normal weight or underweight. In BKMR analysis, women with PFAS concentrations at the median and the 90th percentile had 30.9% (95% CI: 15.6%, 48.3%) and 52.1% (95% CI: 27.9%, 81.0%) higher FLI, respectively, compared with those with concentrations fixed at the 10th percentile. Conclusion Some PFAS may alter circulating levels of leptin. Understanding associations between PFAS and adipokines may help elucidate whether PFAS can influence obesity and metabolic disease.