Associations of serum persistent organic pollutant concentrations with incident diabetes in midlife women: The Study of Women's Health Across the Nation Multi-Pollutant Study.

BACKGROUND: Organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that can negatively impact metabolic health through pathways including endocrine disruption. Few studies have evaluated diabetes risk associated with PBDEs. Little is known about the joint effect of exposure to POP mixtures on diabetes risk. OBJECTIVES: We investigated the relationship between POPs, individually and as mixtures, and diabetes development over 18 years (1999-2016) in midlife women. METHODS: We measured lipid-standardized serum concentrations of 34 PCBs, 19 OCPs, and 14 PBDEs in 1040 midlife women aged 45-56 years from the Study of Women's Health Across the Nation. We tested the association between POPs measured in 1999/2000 and incident diabetes using Cox proportional hazards models. We evaluated diabetes risk associated with the overall POP mixture using Quantile-Based G-Computation (QBGC). RESULTS: For most mixture components, single pollutant and mixtures analyses indicated null associations with diabetes risk, however results were inconsistent. After adjustment, hazard ratios (HRs) of developing diabetes (95% CI) associated with upper exposure tertiles (T2/T3) compared with the first tertile (T1), were 1.7 (1.0, 2.8) at T2 and 1.5 (0.84, 2.7) at T3 for hexachlorobenzene and 1.9 (1.1, 3.3) at T2 and 1.6 (0.88, 2.9) at T3 for PCB 123. A doubling of PBDE 47 was associated with 1.11 (1.00, 1.24) times the risk of T2D. QBGC identified no association for the overall joint effect of the POP mixture on diabetes (HR = 1.04 [0.53, 2.07]). CONCLUSION: Exposure to a mixture of PCBs, OCPs, and PBDEs was not associated with incident diabetes in midlife U.S. women, although some individual POPs demonstrated significant yet inconsistent associations with diabetes. Non-linear and non-monotonic dose-response dynamics deserve further exploration. More research is needed on the diabetogenic effects of PBDEs.

Neighborhood physical environments and change in cardiometabolic risk factors over 14 years in the study of Women's health across the nation.

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.

Determinants of urinary dialkyl phosphate metabolites in midlife women: the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS).

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.

Changes in Adipose Tissue and Circulating Concentrations of Persistent Organic Pollutants in Midlife Women.

Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are persistent organic pollutants (POPs) that bioaccumulate in adipose tissue. We investigated the relationship between change in central adiposity and changes in circulating concentrations of POPs over a 12-year period during the midlife. Serum concentrations of 34 PCBs and 19 OCPs were measured at four time points (1999/2000, 2002/03, 2005/06, 2009/11) in a cohort of midlife women, the Study of Women's Health Across the Nation. Linear mixed models were used to test the association between a change in waist circumference and a change in serum POP concentrations. Sixty-five women contributed 181 PCB observations. Fifty-nine women contributed 151 OCP observations. After adjustment for covariates (study site, race and ethnicity, age at baseline, parity), a one-inch (2.54 cm) increase in the change in waist circumference between visits was associated with a 4.9% decrease in the change in serum concentration of PCB 194 (95% CI: -8.0%, -1.6%). No associations were observed for other PCB congeners or the presence of OCPs. An increase in the difference in waist circumference over time was not associated with a change in the difference in serum concentrations of PCBs and OCPs except for PCB 194, possibly due to the high lipophilicity.

Structural differences contributing to sex-specific associations between FN BMD and whole-bone strength for adult White women and men.

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 (R2 = 0.468, P < .001) and males (R2 = 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 (R2 = 0.433, P < .001) and males (R2 = 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.

The association of urinary incontinence and disability among a diverse sample of midlife Study of Women's Health Across the Nation women.

OBJECTIVE: The aim of the study is to examine whether urinary incontinence (UI) type, frequency, and amount are associated with self-reported disability in a racially/ethnically diverse cohort of community-dwelling midlife women. METHODS: Data were from longitudinal analyses of questionnaires from the multicenter, prospective cohort Study of Women's Health Across the Nation (SWAN). We used multivariable ordinal logistic regression to examine whether urinary incontinence type, frequency, and amount at the 13th follow-up were associated with the World Health Organization Disability Assessment Schedule at the 15th follow-up controlling for other factors (menopause status, body mass index, lifestyle and psychosocial factors, and disability at follow-up 13). RESULTS: Urinary incontinence was associated with subsequent reports of disability in participants, particularly in the World Health Organization Disability Assessment Schedule domains of mobility ( P < 0.0001), communication ( P = 0.0057), and life activities ( P = 0.0407). Associations were strongest for mixed UI type compared with stress UI or urgency UI (odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.26-2.17, P < 0.001), daily frequency of UI compared with monthly or less than weekly frequency of UI (OR = 1.61, 95% CI = 1.04-2.47, P < 0.001), and larger amounts of urine leakage compared with drops of leakage (OR = 2.98, 95% CI = 1.58-5.62, P < 0.0001) for mobility/getting around domain. CONCLUSIONS: Urinary incontinence seems to have a strong association with multiple domains of disability, including mobility and interacting with others, after approximately 3.7 years. Thus, UI may be an important factor limiting social engagement among women. Screening for mixed UI and UI that occurs greater than weekly and in amounts requiring pads may yield better information regarding an individual's future disability risk and may preserve social interaction.

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

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 ß (Aß)42, the Aß42/40 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 Aß42/40 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 Aß42/40 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.

Carotid intima media thickness and cardiometabolic dysfunction: the Study of Women's Health Across the Nation.

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.

Method for Activity Sleep Harmonization (MASH): a novel method for harmonizing data from two wearable devices to estimate 24-h sleep-wake cycles.

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.

Derivation and external validation of a risk score for clinically important declines in health and function among two longitudinal cohorts of women in the mid-life.

OBJECTIVES: Women in mid-life often develop chronic conditions and experience declines in physical health and function. Identifying factors associated with declines provides opportunity for targeted interventions. We derived and externally validated a risk score for clinically important declines over 10 years among women ages 55-65 using the Physical Component Summary Score (PCS) of the SF-36. DESIGN: Derivation and validation of a risk score. SETTING: Two longitudinal cohorts from sites in the USA were used. PARTICIPANTS: Women from the Study of Women's Health Across the Nation (SWAN) and women from the Women's Health Initiative (WHI) Observational Study and/or clinical trials. OUTCOME MEASURES: A clinically important decline over 10 years among women ages 55-65 using the PCS of the SF-36 predictors was measured at the beginning of the 10 years of follow-up. RESULTS: Seven factors-lower educational attainment, smoking, higher body mass index, history of cardiovascular disease, history of osteoarthritis, depressive symptoms and baseline PCS level-were found to be significant predictors of PCS decline among women in SWAN with an area under the curve (AUC)=0.71 and a Brier Score=0.14. The same factors were associated with a decline in PCS in WHI with an AUC=0.64 and a Brier Score=0.18. Regression coefficients from the SWAN analysis were used to estimate risk scores for PCS decline in both cohorts. Using a threshold of a 30% probability of a significant decline, the risk score created a binary test with a specificity between 89%-93% and an accuracy of 73%-79%. CONCLUSIONS: Seven clinical variables were used to create a valid risk score for PCS declines that was replicated in an external cohort. The risk score provides a method for identifying women at high risk for a significant mid-life PCS decline.

Per- and Polyfluoroalkyl Substances (PFAS) and Lipid Trajectories in Women 45-56 Years of Age: The Study of Women's Health Across the Nation.

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.

Systematic exclusion at study commencement masks earlier menopause for Black women in the Study of Women's Health Across the Nation (SWAN).

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.

Physical and Behavioral Factors Associated With Improvement in Physical Health and Function Among US Women During Midlife.

Importance: Women often experience physiological and functional changes in their health during midlife. Identifying women who have clinically important improvements in physical health and function and evaluating the factors associated with these improvements can identify intervention targets at midlife. Objective: To identify factors associated with improvements in physical health and function among women during midlife. Design, Setting, and Participants: Participants were part of the Study of Women's Health Across the Nation (SWAN), a diverse cohort of US women early in midlife, and followed up annually for up to 21 years between 1996 and 2017. Analyses were based on visit 8 (2004-2006) through visit 15 (2015-2017). Statistical analysis was conducted from October 2021 to March 2023. Exposures: Sociodemographic indicators, health status measures, and comorbidities measured at visit 8. Main Outcomes and Measures: The main outcome was a clinically important (≥5 points) improvement in the physical component score (PCS) of the 36-item Short-Form Health Survey between visit 8 and visit 15. Results: Of the 1807 women (at visit 8: mean [SD] age, 54.5 [2.7] years; 898 [50%] White participants) in SWAN who qualified for analysis, 265 (15%) experienced a clinically important improvement in PCS over a median of 11.1 years (IQR, 10.9-11.4 years). Factors associated with improvement in PCS included no financial strain (odds ratio [OR], 1.73; 95% CI, 1.18-2.52), no sleep disturbances (OR, 1.43; 95% CI, 1.05-1.96), no osteoarthritis (OR, 1.42; 95% CI, 1.01-1.99), and having a higher physical activity score (OR, 1.17; 95% CI, 1.00-1.37) as assessed at visit 8. Women who had a higher PCS at visit 8 (OR, 0.84; 95% CI, 0.83-0.86), who had a higher body mass index (OR, 0.95; 95% CI, 0.93-0.97), or who were taking more medications (OR, 0.93; 95% CI, 0.88-0.98) had lower odds of an improved PCS. Conclusions and Relevance: This cohort study of women in midlife suggests that approximately 15% of women experienced clinically important improvements in health and function over an 11-year period. Several potentially modifiable factors associated with improvements may inform women of variables to target for future interventions.

Prediabetes and Fracture Risk Among Midlife Women in the Study of Women's Health Across the Nation.

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.

Cardiometabolic disease and obesity patterns differentially predict acute kidney injury after total joint replacement: a retrospective analysis.

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.

The role of exposure to per- and polyfluoroalkyl substances in racial/ethnic disparities in hypertension: Results from the study of Women's health across the nation.

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.

Leisure time physical activity and bone mineral density preservation during the menopause transition and postmenopause: a longitudinal cohort analysis from the Study of Women's Health Across the Nation (SWAN).

Background: Whether greater leisure time physical activity (LTPA) is associated with less bone mineral density (BMD) loss during the menopause transition (MT) remains an open question. We hypothesized that: 1) larger increases in LTPA from pre-/early perimenopause (period 1) to late perimenopause/postmenopause (period 2) would be associated with a slower period 2 BMD loss rate; and 2) greater entire-study LTPA levels would be associated with better final absolute BMD (g/cm2). Methods: Data were from of the Study of Women's Health Across the Nation (1996-2017). Exclusions were: bone beneficial medications, inability to identify start of the MT, and extreme BMD change rates. LTPA measures were a validated ordinal scale and number of metabolic equivalents per hour per week (MET hr wk-1) from sport/exercise. Multiply adjusted, linear regression models estimated: 1) BMD decline rate (annualized %) as a function of LTPA change; and 2) final BMD as a function of entire-study LTPA. Findings: Median [p25, p75] MET hr wk-1 were 4.2 [0.9, 10.1] and 4.9 [1.4, 11.2] in periods 1 and 2, respectively; walking was the commonest activity. In adjusted models (N = 875), greater increases in LTPA ordinal score and MET hr wk-1 were statistically significantly associated with a slower decline in femoral neck (FN) BMD. Larger entire-study averages of each LTPA measure were statistically significantly related to better final FN and lumbar spine BMD levels. Interpretation: Findings suggest that LTPA, at modest levels, mitigate MT-related BMD decline and even small increases in intensity, duration or frequency of common activities may lessen bone loss at the population level. Funding: US-NIH.

K-medoids clustering of hospital admission characteristics to classify severity of influenza virus infection.

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 C171 had 5.6 times the odds of mechanical ventilator use than those in C172 (95% CI: 1.49, 21.1) and a significantly longer mean hospital length of stay than those in both C172 (mean 1.5 days longer, 95% CI: 0.2, 2.7) and C173 (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.

Associations Among Hip Structure, Bone Mineral Density, and Strength Vary With External Bone Size in White Women.

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.

Phthalates and Incident Diabetes in Midlife Women: The Study of Women's Health Across the Nation (SWAN).

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.