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Ahmed A Almazroa,1– 3 Maria A Woodward,1,4 Paula Anne Newman-Casey,1,4 Manjool M Shah,1 Angela R Elam,1 Shivani S Kamat,1 Carrie A Karvonen-Gutierrez,5 Sarah D Wood,1 Navasuja Kumar,1 Sayoko E Moroi1,4 1Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA; 2Medical Imaging, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 3Medical Imaging, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 4Institute for Healthcare Policy & Innovation, University of Michigan, Ann Arbor, MI, USA; 5Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USACorrespondence: Ahmed A AlmazroaKing Abdullah International Medical Research Center, P.O. Box 3660, Riyadh 11481, Saudi ArabiaTel +966 (11)4294324Email almazroaah@ngha.med.saPurpose: 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.Keywords: telemedicine, tele-glaucoma, automated screening system, diabetic retinopathy screening, glaucoma screening

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for the one-degree of freedom tests of interaction and two-degree of freedom joint tests of the main and interaction effect. In the cross-population meta-analyses, the one-degree of freedom variant-sleep interaction test identified 10 loci (P int <5.0e-9) not previously observed for lipids. Of interest, the ASPH locus (TG, LTST) is a target for aspartic and succinic acid metabolism previously shown to improve sleep and cardiovascular risk. The two-degree of freedom analyses identified an additional 7 loci that showed evidence for variant-sleep interaction (P joint <5.0e-9 in combination with P int <6.6e-6). Of these, the SLC8A1 locus (TG, STST) has been considered a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the 17 (9 with STST; 8 with LTST) loci identified in this large-scale initiative provides evidence into the biomolecular mechanisms underpinning sleep-duration-associated changes in lipid levels. The identified druggable targets may contribute to the development of novel therapies for dyslipidemia in people with sleep disturbances.

This study examined the associations between ambient air pollution exposure, including fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ), with serum levels of high molecular weight (HMW) adiponectin, leptin, and soluble leptin receptors (sOB-R) in midlife women. The analysis included 1551 participants from the Study of Women's Health Across the Nation (median age = 52.3 years) with adipokine data from 2002 to 2003. Annual air pollution exposures were assigned by linking residential addresses with high-resolution machine learning models at a 1-km 2 resolution. Multivariable linear regression and Bayesian kernel machine regression (BKMR) were used to evaluate the associations for individual pollutants and pollutant mixtures. After adjusting for confounders in linear regression models, an interquartile range increase in PM 2.5 (2.5 μg/m 3 ) was associated with a 4.6 % lower HMW adiponectin level (95 % CI: -8.8 %, -0.3 %). Exposure to air pollutant mixtures showed negative associations with HMW adiponectin and positive associations with leptin levels in BKMR models. These findings suggest that exposures to PM 2.5 , NO 2 , and O 3 are associated with adverse levels of adipokines, which may contribute to obesity-related outcomes. Further research is needed to confirm these findings and explore the underlying biological mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Biomonitoring data and determinants of urinary dialkylphosphate (DAP) metabolites, markers of organophosphate pesticides, in racially diverse, non-occupationally exposed populations are scarce., Objective: This study evaluated urinary concentrations and potential determinants of DAP metabolites of organophosphate pesticides in a multi-site, multi-racial/ethnic cohort of women aged 45-56 years, the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS)., Methods: We analyzed 963 urine samples collected in 1999-2000, the baseline of SWAN-MPS for longitudinal studies, and quantified DAP metabolites, including dimethyl alkylphosphates (DMAPs): dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP); and diethyl alkylphosphates (DEAPs): diethylphosphate (DEP), diethylthiophosphate (DETP), diethyldithiophosphate (DEDTP), using gas chromatography and triple quadrupole mass spectroscopy. Adjusted least squared geometric means (LSGMs) and 95% confidence intervals (CIs) were computed to compare DAP concentrations by socio-demographic, behavioral and dietary factors., Results: The geometric means (geometric standard deviations) of total DAPs, DMAPs, and DEAPs were 141 (2.63) nmol/L, 102 (2.99) nmol/L, and 26.8 (2.46) nmol/L, respectively. Body mass index (BMI) was inversely associated with DMAPs and DEAPs: LSGM (95% CI) = 68.8 (55.7-84.9) and 21.0 (17.7-25.0) nmol/L for women with obesity vs. 102 (84.7-123) and 30.1 (25.7-35.1) nmol/L for women with normal/underweight, respectively. Fruit consumption was positively (74.9 (62.1-90.2) for less than 5-6 servings/week vs. 105 (84.8-130) nmol/L for 1 serving/day and more) whereas meat consumption was inversely associated with DMAPs (110 (95.0-128) for seldom vs. 82.3 (59.5-114) nmol/L for often consumption). Fresh apple consumption appears to be attributed to the DMAP differences. Alcohol consumption was positively associated with DEAPs (27.5 (23.1-32.7) for 2 drinks/week and more vs. 23.0 (20.0-26.6) nmol/L for less than 1 drink/month). Black women had higher concentrations of DEAPs compared with White women (27.3 (21.2-35.2) vs. 23.2 (20.2-26.7) nmol/L)., Impact Statement: Organophosphate pesticides (OPs) are synthetic chemicals and currently the most widely used type of insecticides. We examined multi-site, multi-ethnic cohort of midlife women in the U.S. that offers a unique opportunity to evaluate major determinants of OP exposure. We improved OP metabolite detection rates and obtained accurate concentrations using an improved analytical technique. Our findings suggest that consumptions of fruit, meat and alcohol are important determinants of OP exposure for midlife women. Higher concentrations of diethyl OP metabolites in Black women compared to White women, even after accounting for dietary intake, suggests additional, but unknown racial-ethnic differences that affect exposure., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Neighborhood physical environments may influence cardiometabolic health, but prior studies have been inconsistent, and few included long follow-up periods., Methods: Changes in cardiometabolic risk factors were measured for up to 14 years in 2830 midlife women in the Study of Women's Health Across the Nation, a multi-ethnic/racial cohort of women from seven U.S. sites. Data on neighborhood food retail environments (modified Retail Food Environment Index) and walkability (National Walkability Index) were obtained for each woman's residence at each follow-up. Data on neighborhood access to green space, parks, and supermarkets were available for subsets (32-42%) of women. Models tested whether rates of change in cardiometabolic outcomes differed based on neighborhood characteristics, independent of sociodemographic and health-related covariates., Results: Living in more (vs. less) walkable neighborhoods was associated with favorable changes in blood pressure outcomes (SBP: -0.27 mmHg/year, p = 0.002; DBP: -0.22 mmHg/year, p < 0.0001; hypertension status: ratio of ORs = 0.79, p < 0.0001), and small declines in waist circumference (-0.09 cm/year, p = 0.03). Small-magnitude associations were also observed between low park access and greater increases in blood pressure outcomes (SBP: 0.37 mmHg/year, p = 0.003; DBP: 0.15 mmHg/year, p = 0.04; hypertension status: ratio of ORs = 1.16, p = .04), though associations involving DBP and hypertension were only present after adjustment for sociodemographic variables. Other associations were statistically unreliable or contrary to hypotheses., Conclusion: Neighborhood walkability may have a meaningful influence on trajectories of blood pressure outcomes in women from midlife to early older adulthood, suggesting the need to better understand how individuals interact with their neighborhood environments in pursuit of cardiometabolic health., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women., Methods: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid β (Aβ)42, the Aβ42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models., Results: After adjusting for confounders, lower Aβ42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test., Discussion: Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings., Highlights: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aβ42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Hip areal BMD (aBMD) is widely used to identify individuals with increased fracture risk. Low aBMD indicates low strength, but this association differs by sex with men showing greater strength for a given aBMD than women. To better understand the structural basis giving rise to this sex-specific discrepancy, cadaveric proximal femurs from White female and male donors were imaged using nano-CT and loaded in a sideways fall configuration to assess strength. FN pseudoDXA images were generated to identify associations among structure, aBMD, and strength that differ by sex. Strength correlated significantly with pseudoDXA aBMD for females ( R 2  = 0.468, P  < .001) and males ( R 2  = 0.393, P  < .001), but the elevations ( y -intercepts) of the linear regressions differed between sexes ( P  < .001). Male proximal femurs were 1045 N stronger than females for a given pseudoDXA aBMD. However, strength correlated with pseudoDXA BMC for females ( R 2  = 0.433, P  < .001) and males ( R 2  = 0.443, P  < .001) but without significant slope ( P  = .431) or elevation ( P  = .058) differences. Dividing pseudoDXA BMC by FN-width, total cross-sectional area, or FN-volume led to significantly different associations between strength and the size-adjusted BMC measures for women and men. Three structural differences were identified that differentially affected aBMD and strength for women and men: First, men had more bone mass per unit volume than women; second, different cross-sectional shapes resulted in larger proportions of bone mass orthogonal to the DXA image for men than women; and third, men and women had different proportions of cortical and trabecular bone relative to BMC. Thus, the proximal femurs of women were not smaller versions of men but were constructed in fundamentally different manners. Dividing BMC by a bone size measure was responsible for the sex-specific associations between hip aBMD and strength. Thus, a new approach for adjusting measures of bone mass for bone size and stature is warranted., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objective: Carotid artery intima media thickness (cIMT) and adventitial diameter (AD) are subclinical atherosclerosis indicators. Metabolic syndrome (MetS) and obesity are risk factors for atherosclerosis, but their combined impact on atherosclerosis risk is unknown. This study sought to examine the effect of the co-occurrence of MetS with obesity on cIMT and AD., Methods: The Study of Women's Health Across the Nation (SWAN) is a multi-center, multi-ethnic study. Carotid ultrasound assessments and concurrent physiologic measurements were undertaken between 2009 and 2013. This cross-sectional analysis included 1,433 women with body mass index ≥18.5 kg/m 2 and free of prevalent clinical cardiovascular disease. Multivariable linear regression models were used to relate maximum cIMT and AD (dependent variables) with obesity, MetS and their interaction., Results: The average age was 60.1 years (standard deviation [SD], 2.7 y). The prevalence of obesity and MetS was 44% and 35%, respectively. Women with obesity had a 0.051 mm larger mean cIMT and women with MetS had a 0.057 mm larger cIMT versus women without the respective conditions (both P < 0.001). There was a statistically significant interaction between obesity and MetS ( P = 0.011); women with both had a model-adjusted predicted mean cIMT of 0.955 mm (95% confidence interval [CI], 0.897-1.013), higher than those with MetS alone (0.946 mm; 95% CI, 0.887-1.005), obesity alone (0.930 mm; 95% CI, 0.873-0.988), or neither condition (0.878 mm; 95% CI, 0.821-0.935). AD results were similar., Conclusions: Early detection and treatment of atherosclerotic changes may prevent significant disease. This study suggests there is a minimal impact of obesity on carotid artery thickness beyond MetS alone. All individuals with metabolic dysfunction, regardless of obesity status, should be considered at increased risk for atherosclerotic changes., Competing Interests: Financial disclosure/conflicts of interest: E.A.J. receives ongoing institutional funding from the National Institute of Health, Agency for Healthcare Research and Quality, and the VA health system. E.A.J. is a member of the American Heart Association editorial board, a consultant for American College of Cardiology and Optum Health, an expert witness for DeBlase, Brown, and Eyerly LLP, and received past institutional funding from Amgen Research. C.A.K.-G. received payment from the University of Jyväskylä Finland for services as expert reviewer of a dissertation. The other authors have nothing to disclose., (Copyright © 2023 by The Menopause Society.)

Background: Shorter average lifespans for minoritized populations are hypothesized to stem from 'weathering' or accelerated health declines among minoritized individuals due to systemic marginalization. However, evidence is mixed on whether racial/ethnic differences exist in reproductive ageing, potentially due to selection biases in cohort studies that may systematically exclude 'weathered' participants. This study examines racial/ethnic disparities in the age of menopause after accounting for differential selection 'into' (left truncation) and 'out of' (right censoring) a cohort of midlife women., Methods: Using data from the Study of Women's Health Across the Nation (SWAN) cross-sectional screener (N = 15 695) and accompanying ∼20-year longitudinal cohort (N = 3302) (1995-2016), we adjusted for potential selection bias using inverse probability weighting (left truncation) to account for socio-demographic/health differences between the screening and cohort study, and multiple imputation (right censoring) to estimate racial/ethnic differences in age at menopause (natural and surgical)., Results: Unadjusted for selection, no Black/White differences in menopausal timing [hazard ratio (HR)=0.98 (0.86, 1.11)] were observed. After adjustment, Black women had an earlier natural [HR = 1.13 (1.00, 1.26)] and surgical [HR= 3.21 (2.80, 3.62)] menopause than White women with natural menopause-corresponding to a 1.2-year Black/White difference in menopause timing overall., Conclusions: Failure to account for multiple forms of selection bias masked racial/ethnic disparities in the timing of menopause in SWAN. Results suggest that there may be racial differences in age at menopause and that selection particularly affected the estimated menopausal age for women who experienced earlier menopause. Cohorts should consider incorporating methods to account for all selection biases, including left truncation, as they impact our understanding of health in 'weathered' populations., (© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Per- and polyfluoroalkyl substances (PFAS) are associated with less favorable blood lipid profiles in epidemiological studies. However, little is known about the potential role of PFAS in longitudinal changes in lipids among midlife women even though women become more susceptible to metabolic alterations during the menopausal transition., Objectives: To examine associations of serum PFAS concentrations with longitudinal trajectories of blood total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in midlife women undergoing menopausal transition., Methods: The sample included 1,130 women from the Study of Women's Health Across the Nation 45-56 y of age at baseline (1999-2000). We measured serum PFAS concentrations including linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), linear and branched perfluorooctanesulfonic acid (n-PFOS and Sm-PFOS, respectively), and perfluorohexanesulfonic acid (PFHxS) at baseline. We used k -means clustering to identify subgroups with different patterns of PFAS mixture. Blood lipids were measured annually or biannually through 2016 with an average follow-up of 14.8 y. We identified longitudinal trajectories of each lipid using latent class growth models. We used multinomial log-linear models adjusted for covariates to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of lipid trajectory classes by PFAS and their mixtures., Results: Three distinct trajectories (low, middle, high) of total, LDL, and HDL cholesterol and two distinct trajectories (low and high) of triglycerides were identified. n-PFOS, Sm-PFOS, and PFHxS were positively associated with total and LDL cholesterol trajectories. n-PFOS was inversely associated with triglycerides trajectories. PFAS mixtures (high vs. low) showed positive associations with total and LDL cholesterol trajectories (high vs. low), showing ORs (95% CIs) of 1.69 (95% CI: 1.36, 2.12) and 1.79 (95% CI: 1.44, 2.22), respectively., Discussion: Concentrations of serum PFAS were positively associated with trajectories of total and LDL cholesterol, providing a line of evidence supporting adverse effects of PFAS on lipid homeostasis. https://doi.org/10.1289/EHP12351.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acute kidney injury (AKI) is a frequent yet understudied postoperative total joint arthroplasty complication. This study aimed to describe cardiometabolic disease co-occurrence using latent class analysis, and associated postoperative AKI risk., Methods: This retrospective analysis examined patients ≥18 years old undergoing primary total knee or hip arthroplasties within the US Multicenter Perioperative Outcomes Group of hospitals from 2008 to 2019. AKI was defined using modified Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Latent classes were constructed from eight cardiometabolic diseases including hypertension, diabetes, and coronary artery disease, excluding obesity. A mixed-effects logistic regression model was constructed for the outcome of any AKI and the exposure of interaction between latent class and obesity status adjusting for preoperative and intraoperative covariates., Results: Of 81 639 cases, 4007 (4.9%) developed AKI. Patients with AKI were more commonly older and non-Hispanic Black, with more significant comorbidity. A latent class model selected three groups of cardiometabolic patterning, labelled 'hypertension only' (n=37 223), 'metabolic syndrome (MetS)' (n=36 503), and 'MetS+cardiovascular disease (CVD)' (n=7913). After adjustment, latent class/obesity interaction groups had differential risk of AKI compared with those in 'hypertension only'/non-obese. Those 'hypertension only'/obese had 1.7-fold increased odds of AKI (95% confidence interval [CI]: 1.5-2.0). Compared with 'hypertension only'/non-obese, those 'MetS+CVD'/obese had the highest odds of AKI (odds ratio 3.1, 95% CI: 2.6-3.7), whereas 'MetS+CVD'/non-obese had 2.2 times the odds of AKI (95% CI: 1.8-2.7; model area under the curve 0.76)., Conclusions: The risk of postoperative AKI varies widely between patients. The current study suggests that the co-occurrence of metabolic conditions (diabetes mellitus, hypertension), with or without obesity, is a more important risk factor for acute kidney injury than individual comorbid diseases., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Racial/ethnic disparities in hypertension are a pressing public health problem. The contribution of environmental pollutants including PFAS have not been explored, even though certain PFAS are higher in Black population and have been associated with hypertension., Objectives: We examined the extent to which racial/ethnic disparities in incident hypertension are explained by racial/ethnic differences in serum PFAS concentrations., Methods: We included 1058 hypertension-free midlife women with serum PFAS concentrations in 1999-2000 from the multi-racial/ethnic Study of Women's Health Across the Nation with approximately annual follow-up visits through 2017. Causal mediation analysis was conducted using accelerated failure time models. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures., Results: During 11,722 person-years of follow-up, 470 participants developed incident hypertension (40.1 cases per 1000 person-years). Black participants had higher risks of developing hypertension (relative survival: 0.58, 95% CI: 0.45-0.76) compared with White participants, which suggests racial/ethnic disparities in the timing of hypertension onset. The percent of this difference in timing that was mediated by PFAS was 8.2% (95% CI: 0.7-15.3) for PFOS, 6.9% (95% CI: 0.2-13.8) for EtFOSAA, 12.7% (95% CI: 1.4-22.6) for MeFOSAA, and 19.1% (95% CI: 4.2, 29.0) for PFAS mixtures. The percentage of the disparities in hypertension between Black versus White women that could have been eliminated if everyone's PFAS concentrations were dropped to the 10th percentiles observed in this population was 10.2% (95% CI: 0.9-18.6) for PFOS, 7.5% (95% CI: 0.2-14.9) for EtFOSAA, and 17.5% (95% CI: 2.1-29.8) for MeFOSAA., Conclusions: These findings suggest differences in PFAS exposure may be an unrecognized modifiable risk factor that partially accounts for racial/ethnic disparities in timing of hypertension onset among midlife women. The study calls for public policies aimed at reducing PFAS exposures that could contribute to reductions in racial/ethnic disparities in hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

Importance: Whether prediabetes is associated with fracture is uncertain., Objective: To evaluate whether prediabetes before the menopause transition (MT) is associated with incident fracture during and after the MT., Design, Setting, and Participants: This 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., Exposure: Proportion 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 Measures: Time 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., Results: This 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 Relevance: This cohort study of midlife women suggests that prediabetes was associated with risk of fracture. Future research should determine whether treating prediabetes reduces fracture risk.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients are admitted to the hospital for respiratory illness at different stages of their disease course. It is important to appropriately analyse this heterogeneity in surveillance data to accurately measure disease severity among those hospitalized. The purpose of this study was to determine if unique baseline clusters of influenza patients exist and to examine the association between cluster membership and in-hospital outcomes., Methods: Patients hospitalized with influenza at two hospitals in Southeast Michigan during the 2017/2018 (n = 242) and 2018/2019 (n = 115) influenza seasons were included. Physiologic and laboratory variables were collected for the first 24 h of the hospital stay. K-medoids clustering was used to determine groups of individuals based on these values. Multivariable linear regression or Firth's logistic regression were used to examine the association between cluster membership and clinical outcomes., Results: Three clusters were selected for 2017/2018, mainly differentiated by blood glucose level. After adjustment, those in C 17 1 had 5.6 times the odds of mechanical ventilator use than those in C 17 2 (95% CI: 1.49, 21.1) and a significantly longer mean hospital length of stay than those in both C 17 2 (mean 1.5 days longer, 95% CI: 0.2, 2.7) and C 17 3 (mean 1.4 days longer, 95% CI: 0.3, 2.5). Similar results were seen between the two clusters selected for 2018/2019., Conclusion: In this study of hospitalized influenza patients, we show that distinct clusters with higher disease acuity can be identified and could be targeted for evaluations of vaccine and influenza antiviral effectiveness against disease attenuation. The association of higher disease acuity with glucose level merits evaluation., Competing Interests: ASL reports receiving research funding from the Centers for Disease Control and Prevention, National Institutes for Health, Burroughs Wellcome Fund, and FluLab, and receiving consulting fees from Sanofi (oseltamivir) and Roche (baloxavir) outside of submitted work. LEL reports receiving funding from the Centers for Disease Control and Prevention. AM reports receiving research funding from the Centers for Disease Control and Prevention. ETM reports receiving research funding from the Centers for Disease Control and Prevention and grant funding from Merck., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Bone mineral density (BMD) is heavily relied upon to reflect structural changes affecting hip strength and fracture risk. Strong correlations between BMD and strength are needed to provide confidence that structural changes are reflected in BMD and, in turn, strength. This study investigated how variation in bone structure gives rise to variation in BMD and strength and tested whether these associations differ with external bone size. Cadaveric proximal femurs ( n  = 30, White women, 36-89+ years) were imaged using nanocomputed tomography (nano-CT) and loaded in a sideways fall configuration to assess bone strength and brittleness. Bone voxels within the nano-CT images were projected onto a plane to create pseudo dual-energy X-ray absorptiometry (pseudo-DXA) images consistent with a clinical DXA scan. A validation study using 19 samples confirmed pseudo-DXA measures correlated significantly with those measured from a commercially available DXA system, including bone mineral content (BMC) ( R 2  = 0.95), area ( R 2  = 0.58), and BMD ( R 2  = 0.92). BMD-strength associations were conducted using multivariate linear regression analyses with the samples divided into narrow and wide groups by pseudo-DXA area. Nearly 80% of the variation in strength was explained by age, body weight, and pseudo-DXA BMD for the narrow subgroup. Including additional structural or density distribution information in regression models only modestly improved the correlations. In contrast, age, body weight, and pseudo-DXA BMD explained only half of the variation in strength for the wide subgroup. Including bone density distribution or structural details did not improve the correlations, but including post-yield deflection (PYD), a measure of bone material brittleness, did increase the coefficient of determination to more than 70% for the wide subgroup. This outcome suggested material level effects play an important role in the strength of wide femoral necks. Thus, the associations among structure, BMD, and strength differed with external bone size, providing evidence that structure-function relationships may be improved by judiciously sorting study cohorts into subgroups. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: All authors state they have no conflicts of interest., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

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 2 (observed in NHANES; not tested in SWAN-MPS), premenopausal status (only observed in SWAN-MPS), and less consumption of processed food (observed in SWAN-MPS; not tested in NHANES) were associated with a higher proportion of linear PFOS. Non-Hispanic Black and Asian participants were likely to have a higher proportion of linear PFOS than non-Hispanic White participants in both populations. Our findings suggest that isomer-specific patterns of PFOS serum concentrations in humans vary depending on population characteristics that affect PFOS exposure and excretion. Consideration of specific PFOS isomers in future human biomonitoring and epidemiologic studies can provide useful insight to better understand PFOS exposure.

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 < 60 min sleep [n = 9]), 8560 days were used to show the utility of MASH. Of the 8560 days, 46.0% had ≥ 1-min disagreement between the devices or used the 1D CNN for sleep estimates. The MASH waking intervals were corrected (median minutes [IQR]: -27.0 [-115.0, 8.0]) relative to their pre-harmonization estimates. Most correction (-18.0 [-93.0, 2.0] minutes) was due to reducing sedentary behavior. The other waking behaviors were reduced a median (IQR) of -1.0 (-4.0, 1.0) minutes., 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.

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 2 (metabolite) interactions were examined, adjusting for demographic, lifestyle, and menopause-related factors. Analyses were conducted overall and stratified by baseline obesity status. As sensitivity analyses, all analyses were repeated using a second set of metabolites measured in 2002/2003. Higher levels of all metabolites except mono-carboxy-isononyl phthalate were associated with faster increases in BF%. Per doubling of metabolite concentrations, differences in five-year BF% change ranged from 0.03 percentage point (ppt) (95% confidence interval (CI): -0.03, 0.09) for mono-isobutyl phthalate to 0.09 ppt (95% CI: 0.02, 0.16) for mono(3-carboxypropyl) phthalate. Results were similar for FM change, but associations with BW change were mostly null. In stratified analyses by baseline obesity status, positive associations were strongest in women who were normal/underweight at baseline. When metabolites from 2002/2003 were used as exposures, most associations were attenuated and not statistically significant, but they remained positive for normal/underweight women. In conclusion, phthalate metabolites were associated with more rapid body fat gain in midlife women, but our results need confirmation given attenuation of estimates in the sensitivity analyses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022 by the American Diabetes Association.)

Importance: Racial 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)., Objective: To 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 Participants: This 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)., Exposures: Self-reported racial or ethnic group (Black, Chinese, Hispanic, Japanese, or White)., Main Outcomes and Measures: The 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 <90 mm Hg or use of antihypertensive medication), IR (homeostasis model assessment for IR value >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., Results: A 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 Relevance: In 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.

Purpose: This study examined whether employment status during mid-life and older adulthood is associated with physical function impairment., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To quantify the burden of vision impairment (VI) and ocular conditions among early late-life women., Methods: Women ( n = 254, mean age 66.0 years) participated in a comprehensive vision assessment. Visual acuity (VA) and ocular disorders (diabetic retinopathy, macular degeneration, hypertensive retinopathy, glaucoma and cataracts) were defined clinically. Race, economic strain and education were self-reported., Results: The prevalence of presenting VI (VA 20/40 or worse) was 11.0% and 75% of that was correctable (best-corrected VI 2.8%). Black women and those with greater economic strain or less education had a higher prevalence of presenting VI. These disparities were no longer present after considering best-corrected VI. Ocular disease prevalence ranged from 3.3% (age-related macular degeneration) to 30.2% (hypertensive retinopathy), but most participants were unaware of their ocular diagnosis., Conclusion: The discordance of presenting versus best-corrected VI and lack of knowledge of ocular conditions suggests a need for increased vision services. Access to optimal vision correction may attenuate differences across sociodemographic groups.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

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.

Exposure to metals may contribute to the development of metabolic syndrome (MetS); however, evidence from midlife women who are at greater risk of cardiometabolic disease is limited. We assessed the associations of 15 urinary metal concentrations with incident MetS in a prospective cohort of midlife women in the United States. The study population included 947 White, Black, Chinese and Japanese women, aged 45-56 years, free of MetS at baseline (1999-2000), who participated in the Study of Women's Health Across the Nation Multi-Pollutant Study. Fifteen metals were detected in almost all participants urine samples using inductively coupled plasma mass spectrometry at the baseline. Incident MetS was identified annually through 2017 as having at least three of the following five components: high blood pressure, impaired fasting glucose, abdominal obesity, high triglycerides, and poor high-density lipoprotein cholesterol. We used the Cox proportional hazards models to investigate the associations between individual metals and MetS incidence. The adjusted hazard ratios (HR) (95% CI) for MetS in associations with each doubling of urinary metal concentration were 1.14 (1.08, 1.23) for arsenic, 1.14 (1.01, 1.29) for cobalt, and 1.20 (1.06, 1.37) for zinc. We further evaluated the associations between metal mixtures and MetS using the elastic net penalized Cox model and summarized the results into the environmental risk score (ERS). Arsenic, barium, cobalt, copper, nickel, antimony, thallium, and zinc had positive weights, and cadmium, cesium, mercury, molybdenum, lead, and tin had negative weights in the construction of the ERS. The adjusted HR of MetS comparing 75th vs. 25th percentiles of the ERS was 1.45 (1.13, 1.87). These findings support the view that arsenic, cobalt, zinc, as well as metal mixtures, might influence the risks of incident MetS in midlife women., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Diabetogenic effects of per- and polyfluoroalkyl substances (PFAS) have been suggested. However, evidence based on prospective cohort studies is limited. We examined the association between serum PFAS concentrations and incident diabetes in the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS)., Methods: We included 1237 diabetes-free women aged 45-56 years at baseline (1999-2000) who were followed up to 2017. At each follow-up visit, women with incident diabetes were identified by the presence of one or more of the following conditions: (1) use of a glucose-lowering medication at any visit; (2) fasting glucose ≥7 mmol/l on two consecutive visits while not on steroids; and (3) any two visits with self-reported diabetes and at least one visit with fasting blood glucose ≥7 mmol/l. Serum concentrations of 11 PFAS were quantified by online solid-phase extraction-HPLC-isotope dilution-tandem MS. Seven PFAS with high detection rates (>96%) (n-perfluorooctanoic acid [n-PFOA], perfluorononanoic acid [PFNA], perfluorohexane sulfonic acid [PFHxS], n-perfluorooctane sulfonic acid [n-PFOS], sum of perfluoromethylheptane sulfonic acid isomers [Sm-PFOS], 2-[N-methyl-perfluorooctane sulfonamido] acetic acid [MeFOSAA] and 2-[N-ethyl-perfluorooctane sulfonamido] acetic acid) were included in data analysis. Cox proportional hazards models were used to compute HRs and 95% CIs. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures., Results: After adjustment for race/ethnicity, site, education, smoking status, alcohol consumption, total energy intake, physical activity, menopausal status and BMI, the HR (95% CI) comparing the lowest with the highest tertile was 1.67 (1.21, 2.31) for n-PFOA (p trend  = 0.001), 1.58 (1.13, 2.21) for PFHxS (p trend  = 0.003), 1.36 (0.97, 1.90) for Sm-PFOS (p trend  = 0.05), 1.85 (1.28, 2.67) for MeFOSAA (p trend  = 0.0004) and 1.64 (1.17, 2.31) for the sum of four common PFAS (n-PFOA, PFNA, PFHxS and total PFOS) (p trend  = 0.002). Exposure to seven PFAS as mixtures was associated with an HR of 2.62 (95% CI 1.12, 6.20), comparing the top with the bottom tertiles for all seven PFAS., Conclusions/interpretation: This study suggests that PFAS may increase diabetes risk in midlife women. Reduced exposure to these 'forever and everywhere chemicals' may be an important preventative approach to lowering population-wide diabetes risk., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Morphological parameters measured for the second metacarpal from hand radiographs are used clinically for assessing bone health during growth and aging. Understanding how these morphological parameters relate to metacarpal strength and strength at other anatomical sites is critical for providing informed decision-making regarding treatment strategies and effectiveness. The goals of this study were to evaluate the extent to which 11 morphological parameters, nine of which were measured from hand radiographs, relate to experimentally measured whole-bone strength assessed at multiple anatomical sites and to test whether these associations differed between men and women. Bone morphology and strength were assessed for the second and third metacarpals, radial diaphysis, femoral diaphysis, and proximal femur for 28 white male donors (18-89 years old) and 35 white female donors (36-89+ years old). The only morphological parameter to show a significant correlation with strength without a sex-specific effect was cortical area. Dimensionless morphological parameters derived from hand radiographs correlated significantly with strength for females, but few did for males. Males and females showed a significant association between the circularity of the metacarpal cross-section and the outer width measured in the mediolateral direction. This cross-sectional shape variation contributed to systematic bias in estimating strength using cortical area and assuming a circular cross-section. This was confirmed by the observation that use of elliptical formulas reduced the systematic bias associated with using circular approximations for morphology. Thus, cortical area was the best predictor of strength without a sex-specific difference in the correlation but was not without limitations owing to out-of-plane shape variations. The dependence of cross-sectional shape on the outer bone width measured from a hand radiograph may provide a way to further improve bone health assessments and informed decision making for optimizing strength-building and fracture-prevention treatment strategies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Many questionnaires ascertain physical activity (PA) frequency, duration, and intensity to benchmark achievement of PA recommendations. However, most scoring algorithms utilize absolute intensity estimates when exertion may be influenced by age or health characteristics. This study quantified PA estimates with and without adjustments for perceived exertion and evaluated if differences were associated with individual-level characteristics. Women (n = 2,711) in the United States from the Study of Women's Health Across the Nation who completed ≥ 3 Kaiser Physical Activity Surveys (KPAS) across 8 biennial visits were included (baseline age: 46.4 ± 2.7 years). KPAS responses about activity mode and exertion were converted to metabolic equivalent of a task (METs) using the 2011 Compendium of Physical Activities to estimate absolute and perceived intensity-adjusted METs. Repeated measures (linear mixed effects) regression models were used to examine associations of sociodemographic and health-related characteristics with change in the difference between absolute MET estimates and perceived intensity-adjusted MET estimates. Older age (p < 0.001), Chinese (p < 0.001) and Japanese (p = 0.01) ethnicity, and current smoking (p = 0.001) were associated with positive differences between absolute and perceived intensity-adjusted MET estimates, which is suggestive of lower perceived-intensity physical activity. However, for most participants, absolute intensity-based estimates closely approximated perceived intensity-adjusted estimates over time. Traditional PA scoring techniques using absolute intensity estimates only may provide sufficient estimates of PA in longitudinal cohort studies of mid-life and older adult women., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Poor vision affects physical health but the relationship with depressive symptoms among midlife adults (40-65 y), who often present with early stage vision impairment (VI), is not well understood. The goal of this study was to assess the impact of vision on depressive symptoms during midlife., Methods: The Michigan site of the Study of Women's Health Across the Nation conducted assessments of distance visual acuity at six consecutive, near-annual follow-up visits. At each visit, depressive symptoms (Center for Epidemiological Studies-Depression Scale) were assessed. VI was defined as mild (20/30-20/60) or moderate-severe (20/70 or worse). Multivariable logistic regression models using generalized estimating equations were used to assess the association of VI and reporting of depressive symptoms at the subsequent visit., Results: At analytic baseline, the mean age of participants (N = 226) was 50.0 years (standard deviation = 2.6). More than half (53.5%) of women had mild VI and 8.0% had moderate-severe VI. Adjusting for age, preexisting depressive symptoms, race, education, economic strain, body mass index, and smoking, participants with mild and moderate-severe VI had 68% (95% C (0.97-2.90)) and 2.55-fold (95% CI 1.13-5.75) higher odds of reporting depressive symptoms at their subsequent study visit as compared with women without VI. Further adjustment for diabetes, hypertension, and osteoarthritis attenuated the estimates and the associations were no longer statistically significant., Conclusion: VI was associated with increased odds of future depressive symptoms among mid-life women. Timely detection and appropriate correction of VI may be important to consider in maintaining the mental health status of midlife women., Competing Interests: Financial disclosure/conflicts of interest: D.C.M. receives funding from Applied Genetic Technologies Corporation, ClinReg Consulting, ONL Therapeutics, Inc, and Editas Medicine, Inc. S.E.M. receives funding from the NIH for unrelated research, NSF for unrelated research; and has received industry support for glaucoma pharmacology trials while at University of Michigan (Allergan) and book royalties for Shields Textbook of Glaucoma, 6th ed. The other authors have nothing to disclose., (Copyright © 2021 by The North American Menopause Society.)

Background/objectives: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been suggested as obesogens but epidemiologic evidence is limited. We examined associations of serum PFAS concentrations with longitudinal trajectories of weight, waist circumference (WC), fat mass, and proportion fat in midlife women., Subjects/methods: This study included 1,381 midlife women, with a total of 15,000 repeated measures from the multi-racial/ethnic Study of Women's Health Across the Nation between 1999 and 2018. The average follow-up was 14.9 (range: 0-18.6) years. Body size (objectively measured weight and WC) and body composition from dual-energy X-ray absorptiometry were assessed at near-annual visits. Linear mixed models with piecewise linear splines were utilized to model non-linear trajectories of body size and composition., Results: After multivariable adjustment, PFAS concentrations were positively associated with weight, WC, fat mass, and proportion fat at baseline and during follow-up. Comparing the highest to the lowest tertiles of PFAS concentrations, adjusted geometric mean weight was 73.9 kg vs. 69.6 kg for PFOS (P < 0.0001), and 74.0 vs. 69.4 kg for linear PFOA (P < 0.0001) at baseline. Women with the highest tertile of PFOS had an annual increase rate of 0.33% (95% CI: 0.27%, 0.40%) in weight, compared to the lowest tertile with 0.10% (95% CI: 0.04%, 0.17%) (P < 0.0001). PFOS was also significantly related to higher increase rates in WC (difference = 0.12% per year, P = 0.002) and fat mass (difference = 0.25% per year, P = 0.0002). EtFOSAA and MeFOSAA showed similar effects to PFOS. Although PFHxS was not related to body size or fat at baseline, PFHxS was significantly associated with accelerated increases in weight (P < 0.0001), WC (P = 0.003), fat mass (P < 0.0001), and proportion fat (P = 0.0009). No significant results were found for PFNA., Conclusions: Certain PFAS were positively associated with greater body size and body fat, and higher rates of change over time. PFAS may be an underappreciated contributing factor to obesity risk., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (Copyright © 2021 by the American College of Sports Medicine.)

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., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

[Figure: see text].

Objective: Physical activity (PA) may slow aging-related declines in physical functioning (PF), but the relationship of PA and falls is not well understood. This study examined the association of PA and PF with falls. Methods: The Study of Women's Health Across the Nation participants ( n = 1597; age: 65.1 years ± 2.7) reported PF and PA in 2012-2013 and falls in 2016-2017. Four phenotypes were identified: high PA-high PF, high PA-low PF, low PA-high PF, and low PA-low PF. Results: One-third (29.3%) reported ≥1 fall. Women with low PA-low PF (RR = 1.32; 95% CI: 1.06, 1.66) and with high PA-low PF (RR = 1.37; 95% CI: 1.07, 1.74) were more likely to fall than high PA-high PF. Over time, women with worsening PF had increased fall risk (RR = 1.43; 95% CI: 1.17, 1.74), but women who increased PA did not. Discussion: Poor PF increases the risk of falls, regardless of PA. However, increasing PA does not necessarily increase fall risk, reinforcing the importance of PA engagement.

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., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2021 Wiley Periodicals LLC.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Information on the associations between metal exposures and adipokines in human populations is limited and results are inconsistent. We evaluated the associations between metals and adipokines., Methods: Urinary concentrations of 15 metals (arsenic, barium, cadmium, cobalt, cesium, copper, mercury, manganese, molybdenum, nickel, lead, antimony, tin, thallium, and zinc) were measured in 1999-2000 among 1228 women of the Study of Women's Health Across the Nation Multi-Pollutant Study. Serum adipokines including high molecular weight (HMW)-adiponectin, leptin, and soluble leptin receptor (sOB-R) were measured at the follow-up visit (2002-2003). Linear regression models with adaptive elastic-net (AENET) were fit to identify metals associated with adipokines and to compute estimated percent changes in adipokines for one standard deviation increase in log-transformed urinary metal concentrations., Results: After adjustment for confounders, urinary molybdenum was associated with a 5.54% higher level (95% CI: 1.36%, 9.90%), whereas cadmium was associated with a 4.53% lower level (95% CI: -8.17%, -0.76%) of HMW-adiponectin. Urinary molybdenum was also associated with a 5.95% lower leptin level (95% CI: -10.15%, -1.56%) and a 2.98% (95% CI: 0.69%, 5.32%) higher sOB-R level. Urinary cesium and lead were associated with a 3.58% (95% CI: -6.06%, -1.03%) and a 2.53% (95% CI: -4.80%, -0.21%) lower level of sOB-R, respectively., Conclusions: Our findings suggest that molybdenum was associated with favorable profiles of HMW-adiponectin, leptin, and sOB-R. Exposures to cadmium, cesium, and lead were associated with adverse adipokine profiles., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Epidemiologic studies on associations between metals and insulin resistance and β-cell dysfunction have been cross-sectional and focused on individual metals., Objective: We assessed the association of exposure to metal mixtures, based on assessment of 15 urinary metals, with both baseline levels and longitudinal changes in homeostatic model assessments for insulin resistance (HOMA-IR) and β-cell function (HOMA-β)., Methods: We examined 1262 women, aged 45-56 years at baseline (1999-2000), who were followed through 2015-2016, from the Study of Women's Health Across the Nation. Urinary concentrations of 15 metals (arsenic, barium, cadmium, cobalt, cesium, copper, mercury, manganese, molybdenum, nickel, lead, antimony, tin, thallium, and zinc) were determined at baseline. HOMA-IR and HOMA-β were repeatedly measured over 16 years of follow-up. A two-stage modeling was used to account for correlations in dependent and independent variables: In stage-1, linear mixed effects models were used to estimate the participant-specific baseline HOMA levels from random intercepts and participant-specific rates of changes from random slopes. In stage-2, adaptive elastic-net (AENET) models were fit to identify components of metal mixtures associated with participant-specific baseline levels and rates of changes in HOMA-IR and HOMA-β, respectively. An environmental risk score (ERS) was used to integrate metal mixture effects from AENET results., Results: In multivariable adjusted AENET models, urinary zinc was associated with higher HOMA-IR at baseline, whereas molybdenum was associated with lower HOMA-IR at baseline. The estimated changes in baseline HOMA-IR for one standard deviation increase in log-transformed urinary metal concentrations were 5.76% (3.05%, 8.55%) for zinc and -3.25% (-5.45%, -1.00%) for molybdenum, respectively. Urinary zinc was also associated with lower HOMA- β at baseline. Arsenic was associated with a slightly faster rate of decline in HOMA-β in the AENET model evaluating associations between metals and rate of changes. Significant associations of ERS with both HOMA-IR and HOMA-β at baseline were observed. ERS for the rate of changes was not calculated and examined in relation to rates of changes in HOMA-IR and HOMA-β because only a single metal was selected by AENET., Conclusion: Exposure to metal mixtures may be exerting effects on insulin resistance and β-cell dysfunction, which might be mechanisms by which metal exposures lead to elevated diabetes risks., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)