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Purpose Studies examining biomarkers associated with fatigue in breast cancer survivors treated with radiation are limited. Therefore, we examined the longitudinal association between serum biomarkers and post-breast cancer fatigue in survivors treated with radiation: [oxidative stress] 8-hydroxyguanosine, myeloperoxidase; [inflammation] interleukin-6 (IL-6), c-reactive protein, growth differentiation factor-15 (GDF-15), placental growth factor, transforming growth factor-beta, [cardiac damage] cystatin-C, troponin-I. Methods In a secondary analysis, we included participants from the Women’s Health Initiative if they had: a previous breast cancer diagnosis (stages I-III), no prior cardiovascular diseases, pre-and post-breast cancer serum samples drawn approximately 3 years apart, and fatigue measured using the Short-Form 36 vitality subscale at both serum collections. Biomarkers were measured using ELISA or RT-qPCR and modeled as the log2 post-to pre-breast cancer ratio. Results Overall, 180 women with a mean (SD) age of 67.0 (5.5) years were included. The mean (SD) vitality scores were 66.2 (17.2) and 59.7 (19.7) pre- and post-breast cancer, respectively. Using multivariable weighted linear regression, higher biomarker ratios of cystatin-C, IL-6, and GDF-15 were associated with a lower vitality score (i.e., higher fatigue). For example, for each 2-fold difference in cystatin-C biomarker ratio, the vitality score was lower by 7.31 points (95% CI: −14.2, −0.45). Conclusion Inflammatory and cardiac damage biomarkers are associated with fatigue in breast cancer survivors treated with radiation; however, these findings should be replicated in a larger sample. Biomarkers could be measured in clinical practice or assessed in risk prediction models to help identify patients at high risk for fatigue.

Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n = 1528) of Women’s Health Initiative Memory Study (WHIMS) participants (mean [SD] baseline age, 71.3 [SD 3.8] years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimer’s disease (AD) pathology (Aβ42/40) and/or neurodegeneration (NfL), and related to an MRI-defined index of neurodegenerative brain atrophy in a separate cohort (BLSA). In addition to evaluating their biological relevance, assessing their potential role in AD, and characterizing their immune-tissue/cell-specific expression, we leveraged published RNA-seq results to examine how the in vitro regulation of genes encoding these candidate proteins might be altered in response to an immune challenge. Our findings indicate how dietary patterns with higher inflammatory potential relate to plasma levels of immunologically relevant proteins and highlight the molecular mediators which predict subsequent risk for age-related cognitive impairment.

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p

Background: Social support may be a modifiable risk factor for cognitive impairment. However, few long-term, large prospective studies have examined associations of various forms of social support with incident mild cognitive impairment (MCI) and dementia. Objective: To examine associations of perceived social support with incident MCI and dementia among community-dwelling older women. Methods: This prospective cohort study included 6,670 women from the Women’s Health Initiative Memory Study who were cognitively unimpaired at enrollment. We used Cox proportional hazards models to assess associations between perceived social support with incident MCI, dementia, or either MCI/dementia during an average 10.7 (SD = 6.1)-year follow-up. Modelling was repeated for emotional/information support, affection support, tangible support, and positive social interaction subscales of social support. Results: Among 6,670 women (average age = 70 years [SD = 3.8]; 97.0% non-Hispanic/Latina; 89.8% White), greater perceived social support was associated with lower risk of MCI/dementia after adjustment for age, ethnicity, race, hormone therapy, education, income, diabetes, hypertension, and body mass index (Tertile [T]3 versus T1: HR = 0.85, 95% CI 0.74–0.99; ptrend = 0.08). Associations were significant for emotional/information support (T3 versus T1: HR = 0.84, 95% CI 0.72–0.97; ptrend = 0.04) and positive social interaction (T3 versus T1: HR = 0.85, 95% CI 0.73–0.99; ptrend = 0.06) subscales. Associations were attenuated and not significant after adjustment for depressive symptom severity. Objective: Perceived social support, emotional/information support, and positive social interaction were associated with incident MCI/dementia among older women. Results were not significant after adjustment for depressive symptom severity. Improving social support may reduce risk of MCI and dementia in older women.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Little is known about the relationships between annual visit-to-visit blood pressure variability and heart failure subphenotypes. The aim of this analysis was to examine the association between blood pressure variability and incident heart failure with preserved and reduced ejection fraction.Data from 23,918 postmenopausal women enrolled in the Women's Health Initiative Hormone Therapy Trials were analyzed. Blood pressure was measured at baseline (1993‒1998) and then annually through 2005. Variability was defined as the SD of the mean blood pressure across visits or the SD of the participant's regression line for blood pressure across visits. The outcome was the first heart failure hospitalization. Heart failure ascertainment and adjudications were through March 31, 2018.During a mean follow-up of 15.8 years, 913 incident cases of heart failure with preserved ejection fraction and 421 cases of heart failure with reduced ejection fraction were identified. In fully adjusted models, including mean longitudinal systolic and diastolic blood pressure and time-varying coronary events interim to heart failure hospitalization, women in the highest versus in the lowest quartile of SD of the mean systolic blood pressure were at a statistically significantly higher risk of heart failure with preserved ejection fraction (hazard ratio [95% CI]=1.61 [1.12, 2.31]) but not of heart failure with reduced ejection fraction (1.18 [0.70,1.96]). Conversely, the hazard ratio (95% CI) for the highest versus lowest quartile of SD of the mean diastolic blood pressure was 1.56 (0.89, 2.74) for heart failure with reduced ejection fraction and 1.19 (0.85,1.65) for heart failure with preserved ejection fraction. Results attenuated for SD of the participant's regression line when additionally adjusted for the temporal trend of systolic and diastolic blood pressure.Greater systolic blood pressure variability was associated with a higher risk of heart failure with preserved ejection fraction independent of mean blood pressure and coronary events interim to heart failure hospitalization.

PurposeThis study estimated associations between neighborhood socioeconomic status (NSES), walkability, green space, and incident falls among postmenopausal women and evaluated modifiers of these associations, including study arm, race and ethnicity, baseline household income, baseline walking, age at enrollment, baseline low physical functioning, baseline fall history, climate region, and urban-rural residence.MethodsThe Women's Health Initiative recruited a national sample of postmenopausal women (50-79years) across 40 U.S. clinical centers and conducted yearly assessments from 1993 to 2005 (n=161,808). Women reporting a history of hip fracture or walking limitations were excluded, yielding a final sample of 157,583 participants. Falling was reported annually. NSES (income/wealth, education, occupation), walkability (population density, diversity of land cover, nearby high-traffic roadways), and green space (exposure to vegetation) were calculated annually and categorized into tertiles (low, intermediate, high). Generalized estimating equations assessed longitudinal relationships.ResultsNSES was associated with falling before adjustment (high vs. low, odds ratio,1.01; 95% confidence interval, 1.00-1.01). Walkability was significantly associated with falls after adjustment (high vs. low, odds ratio,0.99; 95% confidence interval, 0.98-0.99). Green space was not associated with falling before or after adjustment. Study arm, race and ethnicity, household income, age, low physical functioning, fall history, and climate region modified the relationship between NSES and falling. Race and ethnicity, age, fall history, and climate region modified relationships between walkability and green space and falling.ConclusionsOur results did not show strong associations of NSES, walkability, or green space with falling. Future research should incorporate granular environmental measures that may directly relate to physical activity and outdoor engagement.

e24031 Background: Older survivors of leukemia and lymphoma often experience long-term and late effects of chemotherapy, worsened by aging-related conditions such as functional and cognitive impairment, which may be inadequately addressed. In this study, we described common concerns in older survivors of leukemia and lymphoma, and assessed demographic and clinical factors associated with these concerns. Methods: We utilized data from the WHI LILAC study that recruited post-menopausal women aged 50 and 79 years. Participants who were diagnosed with leukemia and lymphoma after enrollment in WHI and answered at least half of the questions on current concerns in LILAC were included (n = 420). Participants were asked about 14 areas of current concerns common in cancer survivorship and to rate each from 0 (no concern) to 2 (major concern), with total score ranging 0-28. Linear regression was used to assess demographic and clinical factors associated with the concern score, and logistic regression for factors associated with the three most common concerns, with backward variable selection methods. Results: Mean age at assessment was 81 years (range 69-99) and 73% had non-Hodgkin lymphomas. Median time since diagnosis was 8.8 years (range 2.5-20.8 years). Seventy-two percent reported any concern; median concern score among these survivors was 3.5 (Q1-Q3, 2-5) (Table). Factors significantly correlated with the concern score were sadness, pain, loneliness, worse quality of life (QoL), lower physical functioning, more comorbidities, and greater prior symptom count (all p < 0.05). Significant factors correlated with common concerns were: 1) Fatigue/sleep: leukemia diagnosis, greater prior symptom count, feeling sad or depressed, reported distress, lower physical functioning; 2) Physical functioning/activity: public health insurance, older age, greater prior symptom count, reported pain, worse QoL, higher BMI; 3) Memory/concentration: prior chemotherapy or radiation, loneliness, worse QoL, greater prior symptom count (all p < 0.05). Conclusions: Almost three-quarter of survivors of leukemia and lymphoma reported at least one concern, with common concerns being fatigue/sleep, physical functioning/activity, and memory/concentration. A multicomponent intervention is needed to address these common concerns in older cancer survivors.[Table: see text]

Growing evidence suggests that impairment in rest-activity rhythms may be a risk factor for cognitive decline and impairment in the aging population. However, previous studies included only a limited set of rest-activity metrics and produced mixed findings. We studied a comprehensive set of parametric and nonparametric characteristics of rest-activity rhythms in relation to mild cognitive impairment (MCI) and probable dementia in a cohort of older women.The prospective analysis included 763 women enrolled in two ancillary studies of the Women's Health Initiative (WHI): the WHI Memory Study-Epidemiology of Cognitive Health Outcomes and Objective Physical Activity and Cardiovascular Health studies. The association between accelerometry-based rest-activity parameters and centrally adjudicated MCI and probable dementia were determined using Cox regression models adjusted for sociodemographic characteristics, lifestyle factors, and comorbidities.Overall, the results support a prospective association between weakened rest-activity rhythms (e.g., reduced amplitude and overall rhythmicity) and adverse cognitive outcomes. Specifically, reduced overall rhythmicity (pseudo F statistic), lower amplitude and activity level (amplitude/relative amplitude, mesor, and activity level during active periods of the day [M10]), and later activity timing (acrophase and midpoint of M10) were associated with a higher risk for MCI and probable dementia. Women with lower amplitude and mesor also exhibited faster cognitive decline over follow-up.Weakened rest-activity rhythms may be predictive markers for cognitive decline, MCI, and dementia among older women.

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

We sought to assess the relationship between sleep duration, sleep disturbance and leukemia incidence among postmenopausal women. This study included 130343 postmenopausal women 50-79 years, who were enrolled in the Women’s Health Initiative during 1993-1998. Variables of self-reported, typical sleep duration and sleep disturbance were obtained at baseline by questionnaire, and the sleep disturbance level was defined according to the WHI Insomnia Rating Scale (WHIIRS). WHIIRS 0-4, 5-8 and 9-20 comprised 37.0%, 32.6% and 30.4% of all women, respectively. After an average of 16.4 years (2,135,109 cumulative person-years) of follow-up, 930 of the participants were identified with incident leukemia in this study. Compared to women with the lowest sleep disturbance (WHIIRS 0-4), women having higher sleep disturbance level (WHIIRS 5-8 or 9-20) had a 22% (95% CI: 1.04-1.43) and 18% (95% CI: 1.00-1.40) excess risk of leukemia respectively, after multivariable adjustment. A significant dose-response trend was found for sleep disturbance and leukemia risk (P for trend 0.048). In addition, women with highest sleep disturbance had a higher risk of myeloid leukemia (WHIIRS 9-20 vs WHIIRS 0-4, HR: 1.39, CI: 1.05-1.83). Higher sleep disturbance level was associated with increased risk of leukemia, especially for myeloid leukemia among postmenopausal women.

Supplementary Table S1-S16

Though studies have observed inverse associations between use of analgesics (aspirin, NSAIDs, and acetaminophen) and the risk of several cancers, the potential biological mechanisms underlying these associations are unclear. We investigated the relationship between analgesic use and serum concentrations of estrogens, androgens, and their metabolites among postmenopausal women to provide insights on whether analgesic use might influence endogenous hormone levels, which could in turn influence hormone-related cancer risk. The study included 1,860 postmenopausal women from two case–control studies nested within the Women's Health Initiative Observational Study. Analgesic use was reported at study baseline. Fifteen estrogens and estrogen metabolites and 12 androgens and androgen metabolites were quantified in baseline serum by LC/MS-MS. Linear regression with inverse probability weighting, stratified by menopausal hormone therapy (MHT) use, was used to estimate adjusted geometric mean concentrations of each hormone by analgesic use. Among women not currently using MHT (n = 951), low-dose aspirin (Prevention relevance:This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed.

Supplementary Data from The Association of Predicted Resting Energy Expenditure with Risk of Breast Cancer among Postmenopausal Women in the Women's Health Initiative Cohort

Supplementary Figure from Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study

To evaluate the effect of vitamin D(3) supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86–1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D(3) group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78–0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91–1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D(3) therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D(3) supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D(3) did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D(3) administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Objectives A comprehensive examination of resilience by race, ethnicity, and neighborhood socioeconomic status (NSES) among women aged ≥80 is needed, given the aging of the U.S. population, increasing longevity, and growing racial and ethnic diversity. Methods Participants were women aged ≥80 enrolled in the Women’s Health Initiative. Resilience was assessed with a modified version of the Brief Resilience Scale. Descriptive statistics and multiple linear regression examined the association of demographic, health, and psychosocial variables with resilience by race, ethnicity, and NSES. Results Participants (n = 29,367, median age = 84.3) were White (91.4%), Black (3.7%), Hispanic (1.9%), and Asian (1.7%) women. There were no significant differences by race and ethnicity on mean resiliency scores (p = .06). Significant differences by NSES were observed regarding mean resiliency scores between those with low NSES (3.94 ± 0.83, out of 5) and high NSES (4.00 ± 0.81). Older age, higher education, higher self-rated health, lower stress, and living alone were significant positive correlates of resilience in the sample. Social support was correlated with resilience among White, Black, and Asian women, but not for Hispanic women. Depression was a significant correlate of lower resilience, except among Asian women. Living alone, smoking, and spirituality were significantly associated with higher resilience among women with moderate NSES. Discussion Multiple factors were associated with resilience among women aged ≥80 in the Women’s Health Initiative. Despite some differing correlates of resilience by race, ethnicity, and NSES, there were many similarities. These results may aid in the design of resilience interventions for the growing, increasingly diverse population of older women.

To investigate the association of infertility with atherosclerotic cardiovascular disease (ASCVD) among postmenopausal participants in the Women's Health Initiative (WHI). We hypothesized that nulliparity and pregnancy loss may reveal more extreme phenotypes of infertility, enabling further understanding of the association of infertility with ASCVD.Prospective cohort study.Forty clinical centers in the United States.A total of 158,787 postmenopausal participants in the Women's Health Initiative cohort.Infertility, parity, and pregnancy loss.The primary outcome was risk of ASCVD among women with and without a history of infertility, stratified by history of live birth and pregnancy loss. Cox proportional-hazards models were adjusted for demographics and risk factors for ASCVD.Among 158,787 women, 25,933 (16.3%) reported a history of infertility; 20,427 (80%) had at least 1 live birth; and 9,062 (35%) had at least 1 pregnancy loss. There was a moderate overall association between infertility and ASCVD (adjusted hazard ratio, 1.02; 95% confidence interval [CI], 0.99-1.06) over 19 years of follow-up. Among nulliparous women, infertility was associated with a 13% higher risk of ASCVD (95% CI, 1.04-1.23). Among nulliparous women who had a pregnancy loss, infertility was associated with a 36% higher risk of ASCVD (95% CI, 1.09-1.71).Women with a history of infertility overall had a moderately higher risk of ASCVD compared with women without a history of infertility. Atherosclerotic cardiovascular disease risk was much higher among nulliparous infertile women and among nulliparous infertile women who also had a pregnancy loss, suggesting that in these more extreme phenotypes, infertility may be associated with ASCVD risk.

There is growing recognition that reproductive factors are associated with increased risk of future cardiovascular disease. Infertility has been less well studied, although emerging data support its association with increased risk of cardiovascular disease. Whether infertility is associated with future risk of heart failure (HF) is not known.This study sought to examine the development of HF and HF subtypes in women with and without history of infertility.We followed postmenopausal women from the Women's Health Initiative prospectively for the development of HF. Infertility was self-reported at study baseline. Multivariable cause-specific Cox models were used to evaluate the association of infertility with incident overall HF and HF subtypes (heart failure with preserved ejection fraction [HFpEF]: left ventricular ejection fraction of ≥50% vs heart failure with reduced ejection fraction [HFrEF]: left ventricular ejection fraction of 50%]).Among 38,528 postmenopausal women (mean age: 63 ± 7 years), 5,399 (14%) participants reported a history of infertility. Over a median follow-up of 15 years, 2,373 developed incident HF, including 807 with HFrEF and 1,133 with HFpEF. Infertility was independently associated with future risk of overall HF (HR: 1.16; 95% CI: 1.04-1.30; P = 0.006). Notably, when examining HF subtypes, infertility was associated with future risk of HFpEF (HR: 1.27; 95% CI: 1.09-1.48; P = 0.002) but not HFrEF (HR: 0.97; 95% CI: 0.80-1.18).Infertility was significantly associated with incident HF. This was driven by increased risk of HFpEF, but not HFrEF, and appeared independent of traditional cardiovascular risk factors and other infertility-related conditions. Future research should investigate mechanisms that underlie the link between infertility and HFpEF.

PURPOSE: Lifestyle factors such as smoking, alcohol, body weight, physical activity, and diet quality have been associated with the risk of pancreatic cancer. However, studies of their combined association in women are limited. METHODS: Data on smoking habits, alcohol intake, diet composition, recreational physical activity, body weight, and waist circumference, obtained at recruitment for 136,945 postmenopausal women (aged 50–79 years) participating in the Women’s Health Initiative study, were categorized separately, with higher scores for each variable assigned to the categories representing healthier behaviors. The combined healthy lifestyle index (HLI) score, created by summing the scores for each risk factor, was grouped into quartiles. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pancreatic cancer risk in association with the HLI. RESULTS: Over an average follow-up period of approximately 16.0 years, 1,119 incident cases of pancreatic cancer were ascertained. Compared to women in the lowest HLI quartile, those in the upper quartiles (qt) had a reduced risk of pancreatic cancer (multivariable-adjusted HRqt(3)(rd) 0.83, 95% CI 0.74–0.99; and HRqt(4)(th) 0.74, 95% CI 0.62–0.88, respectively, p trend = 0.001). Use of waist circumference instead of BMI in the HLI score yielded similar results. Among women who were either non-diabetic or non-smokers, high HLI was also associated with reduced risk HRqt(4)(th) 0.78, 95% CI 0.65–0.85 and HRqt(4)(th) 0.80, 95% CI 0.66–0.97, respectively). Stratification by BMI categories (18.5− < 25.0, 25.0− < 30.0 and > 30.0 kg/m(2)) showed similar results in all groups. CONCLUSIONS: Our findings suggest that in postmenopausal women, a healthy lifestyle is associated with reduced risk of pancreatic cancer.

Background The association of cognitive function with symptoms of psychological distress during the coronavirus disease 2019 (COVID-19) pandemic or adherence to COVID-19 protective health behaviors is not well-understood. Methods We examined 2 890 older women from the Women’s Health Initiative cohort. Prepandemic (ie, within 12 months prior to pandemic onset) and peripandemic global cognitive function scores were assessed with the modified Telephone Interview for Cognitive Status (TICS-m). Anxiety, stress, and depressive symptom severity during the pandemic were assessed using validated questionnaires. We examined adherence to protective behaviors that included safe hygiene, social distancing, mask wearing, and staying home. Multivariable models were adjusted for age, race, ethnicity, education, region of residence, alcohol intake, and comorbidities. Results Every 5-point lower prepandemic TICS-m score was associated with 0.33-point mean higher (95% confidence interval [CI], 0.20, 0.45) perceived stress and 0.20-point mean higher (95% CI, 0.07, 0.32) depressive symptom severity during the pandemic. Higher depressive symptom severity, but not anxiety or perceived stress, was associated with a 0.69-point (95% CI, −1.13, −0.25) mean decline in TICS-m from the prepandemic to peripandemic period. Every 5-point lower peripandemic TICS-m score was associated with 12% lower odds ratio (OR, 0.88; 95% CI, 0.80, 0.97) of practicing safe hygiene. Conclusions Among older women, we observed that: (a) lower prepandemic global cognitive function was associated with higher stress and depressive symptom severity during the pandemic; (b) higher depressive symptom severity during the pandemic was associated with cognitive decline; and (c) lower global cognitive function during the pandemic was associated with lower odds of practicing safe hygiene.

INTRODUCTION: Physical activity can attenuate cancer-related declines in physical functioning, improve emotional well-being, and prolong survival among older (≥65 years) breast cancer survivors. However, factors associated with physical activity among older breast cancer survivors are not well-understood. MATERIALS AND METHODS: Participants were enrolled in the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study. Descriptive statistics, multiple linear regression, and relative risk [RR] regression were used to assess the association of demographic, clinical, physical and psychosocial variables with the total duration of and participation in physical activity among postmenopausal breast cancer survivors. Age-specific correlates (65–74 years vs. 75–84 years vs. ≥85 years) of physical activity were also examined. RESULTS: The majority of participants (n = 3710, mean age = 78.8 ± 5.9) were white (90.7%) and had in situ/localized breast cancer (78.9%). Women who had higher education (RR = 1.47 for graduate/professional school versus high school or less, 95% CI: 1.32, 1.63), higher self-rated health (RR = 1.04 for 10 point increase, 95% CI:1.02, 1.07), higher physical functioning (RR = 1.03 for 5 point increase, 95% CI: 1.02, 1.04), and higher social support (RR = 1.41 for social support all of the time versus none of the time, 95% CI: 1.01, 1.96), were more likely to engage in any physical activity. Similar results were observed for duration of physical activity. Among women aged

Although biological evidence suggests that tea consumption may protect against non-Hodgkin lymphoma (NHL), epidemiological evidence has been unclear. The aim of this study was to examine the association between tea-drinking habits and the risk of NHL in a large nationwide prospective cohort of postmenopausal US women. 68 854 women who were enrolled from 1993 through 1998 in the Women’s Health Initiative Observational Study and responded to year 3 annual follow-up questionnaire comprised the analytic cohort. Newly diagnosed NHL cases after the year 3 visit were confirmed by medical and pathology reports. Multivariable-adjusted Cox proportional hazards models were performed to assess the associations of tea-drinking habits (specifically, the amounts of caffeinated/herbal/decaffeinated tea intake) with the overall risk of NHL and three major subtypes (diffuse large B-cell lymphoma (n 195, 0·3 %), follicular lymphoma (n 128, 0·2 %) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (n 51, 0·1 %)). Among 62 622 participants, a total of 663 (1·1 %) women developed NHL during a median follow-up of 16·51 (sd 6·20) years. Overall, different amounts of type-specific tea intake were not associated with the risk of NHL regardless of its histologic subtypes after adjustment for confounders. Our findings suggest that tea intake at the current consumption level does not influence the risk of NHL, regardless of its histologic types.

BackgroundTo investigate the association between walking pace and the risk of heart failure (HF) and HF sub-types.MethodsWe examined associations of self-reported walking pace with risk of incident HF and HF subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fractions, among 25,183 postmenopausal women, ages 50-79 years. At enrollment into the Women's Health Initiative cohort in 1993-1998, this subset of women was free of HF, cancer, or the inability to walk one block, with self-reported information on walking pace and walking duration. Multivariable Cox regression was used to examine associations of walking pace (casual 3 mph) with incident HF. We also examined the joint association of walking pace and duration with incident HF.ResultsThere were 1455 incident adjudicated acute decompensated HF hospitalization cases during a median of 16.9 years of follow-up. There was a strong inverse association between walking pace and overall risk of HF (HR=0.73, 95% CI [0.65, 0.83] for average vs. casual walking; HR=0.66, 95%CI [0.56, 0.78] for fast vs. casual walking). There were similar associations of walking pace with HFpEF (HR=0.73, 95%CI [0.62, 0.86] average vs. casual; HR=0.63, 95%CI [0.50, 0.80] for fast vs. casual) and with HFrEF (HR=0.72, 95%CI [0.57, 0.91] for average vs. casual; HR=0.74, 95%CI [0.54, 0.99] for fast vs. casual). The risk of HF associated with fast walking with less than 1h/week walking duration was comparable with the risk of HF among casual and average walkers with more than 2h/week walking duration.ConclusionWalking pace was inversely associated with risks of overall HF, HFpEF, and HFrEF in postmenopausal women. Whether interventions to increase the walking pace in older adults will reduce HF risk and whether fast pace will compensate for the short duration of walking warrants further study.

Introduction: Over 50% of US adults older than 75 live free of atherosclerotic cardiovascular disease (ASCVD) and diabetes (DM), yet data on incident statin use among this population are lacking. Our objective was to assess statin initiation by age among the Women’s Health Initiative cohort free of ASCVD and DM at baseline (1993). Hypothesis: Statin initiation is higher at older ages and differs by race/ethnicity. Methods: Exclusions were statin use at baseline, known ASCVD, DM, and no follow-up after baseline. Self-reported medication use was assessed in 1996 and 2008. Specific statin and dose prescribed at the time of initiation were identified using National Drug Codes and determined statin intensity, defined by the ACC/AHA guidelines. We estimated the adjusted association between age group ( Results: Over 12 years of follow-up, 27% of 99,631 women free of ASCVD and DM at baseline initiated a statin; initiation was lower with older age (Table). This association remained after adjustment for ASCVD risk factors and did not differ by race/ethnicity (p for interaction >0.5). Moderate intensity dose was most common at statin initiation overall, and moderate and high intensity dose were both lower with older age. Conclusion: Of women free of ASCVD and DM, women older than 75 were least likely to start a statin and most likely to start low intensity statin therapy at initiation than younger women. We identified a potential clinical gap for investigation: whether lower overall use of statins and lower intensity statin therapy among older women are associated with preventable ASCVD.

Introduction: In 2022, the American Heart Association (AHA) introduced Life’s Essential 8 (LE8) as an updated definition of cardiovascular health (CVH). Sleep health was added to the original Life’s Simple 7 (LS7), and a new scoring system was developed. We evaluated how LE8 characterizes CVH among women in the WHI. Hypothesis: We hypothesized that the average LE8 score would be moderate, with only a small group of WHI participants having high CVH. Methods: The WHI recruited 161,808 post-menopausal women from 40 clinical centers in 1993-1998. This analysis included 116,514 women without self-reported CVD, with measured height, weight, and blood pressure, and self-reported smoking history, sleep duration, physical activity, diet, diabetes, and cholesterol at baseline. CVH components were scored from 0-100 based on participants’ achievement of each health factor or behavior. Scores were assigned per AHA guidance with some adaptations made based on data availability. Lacking measured values, glucose and lipid scores were calculated based on history and treatment status of diabetes and high cholesterol. Overall LE8 scores were calculated as the unweighted mean of all components. Scores were further categorized into high (80-100), moderate (50-79), or low (0-49), with higher scores indicating positive CVH. Results: The average LE8 score among WHI participants at baseline was 71.5 (standard deviation (SD): 12.5; range 20.6-100) ( Figure ). Overall, sleep scores were high (mean: 86.5, SD 19.1). The lowest scores were found in diet (mean: 39.5, SD 31.3) and physical activity (mean: 47.7, SD: 43.5). LE8 classified 28.1% of WHI participants (32,773/116,514) as having high CVH whereas a prior analysis of LS7 found that 17.7% and 6.1% had ideal levels of 5 and 6-7 CVH components, respectively. Conclusions: Based on the new LE8 definition, most women had moderate CVH at study baseline, with approximately a quarter having high CVH. Although sleep health was high, scores for other health behaviors demonstrated considerable room for improvement.

Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction. Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case–control samples: 404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and 440 pairs from the Women's Health Initiative (WHI) cohort. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication data sets using the area under the curve (AUC). Results: The meta-analysis identified associations (P < 4.7 × 10−5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P < 0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication data set in MCCS [N = 134; odds ratio per SD (OR) = 1.37; 95% CI, 1.00–1.90] after confounder adjustment; AUC = 0.66, compared with AUC = 0.64 without methylation information. Limited evidence of replication was found in the second testing data set in WHI (N = 440; OR = 1.09; 95% CI, 0.91–1.30). Conclusions: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger data sets. Impact: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.

Purpose This study examined associations between self-reported cognitive functioning and social support as well as social ties among women with breast cancer. Methods The study included 3351 women from the Women’s Health Initiative Life and Longevity After Cancer cohort who were diagnosed with breast cancer stages I–III. Social support was assessed using a modified Medical Outcomes Study (MOS) Social Support Survey, and marital status was obtained from the baseline questionnaire. We also assessed social ties (e.g., number of friends, relatives, living children) and cognitive function (Functional Assessment of Cancer Therapy-Cognitive Function [FACT-COG]) on the year-1-follow up questionnaire. Multivariable quantile regression was used to estimate the changes in median cognitive scores. Kruskal–Wallis tests were used to assess the association of cognitive function with social ties. Results The majority of participants were non-Hispanic White (93.3%), presently married (49%), with at least a 4-year college degree (53.2%), and had been diagnosed with localized breast cancer (79%). A 10-point higher social support score correlated to a 0.32 higher (better) median cognitive score (p p = 0.01). Significant associations were also present for having close relatives (p p Conclusion Women reporting higher social support and greater numbers of friends or relatives have higher cognitive functioning. Compared to divorced or separated women, married women were likely to have higher cognitive functioning. These findings suggest that social support assessments have the potential to help identify women at higher risk of cognitive decline.