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Background: We aimed to prospectively evaluate the association between a diabetes risk reduction diet (DRRD) score and the risk of liver cancer development and chronic liver disease-specific mortality., Methods: We included 98,786 postmenopausal women from the Women's Health Initiative-Observational Study and the usual diet arm of the Diet Modification trial. The DRRD score was derived from eight factors: high intakes of dietary fiber, coffee, nuts, polyunsaturated fatty acids, low intakes of red and processed meat, foods with high glycemic index, sugar-sweetened beverages (SSBs), and trans fat based on a validated Food-Frequency Questionnaire administered at baseline (1993-1998). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for liver cancer incidence and chronic liver disease mortality were estimated using Cox proportional hazards regression models., Results and Conclusion: After a median follow-up of 22.0 years, 216 incident liver cancer cases and 153 chronic liver disease deaths were confirmed. A higher DRRD score was significantly associated with a reduced risk of developing liver cancer (HR Tertile 3 vs. Tertile 1  = 0.69; 95% CI: 0.49-0.97; P trend  = 0.03) and chronic liver disease mortality (HR T3 vs. T1  = 0.54; 95% CI: 0.35-0.82; P trend  = 0.003). We further found inverse associations with dietary fiber and coffee, and positive associations with dietary glycemic index, SSBs, and trans fat. A higher DRRD score was associated with reduced risk of developing liver cancer and chronic liver disease mortality among postmenopausal women., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Purpose: Menopausal hormone therapy's influence on ovarian and endometrial cancers remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone on ovarian and endometrial cancer incidence and mortality in the Women's Health Initiative randomized, placebo-controlled clinical trials., Materials and Methods: Postmenopausal women, age 50-79 years, were entered on two randomized clinical trials evaluating different menopausal hormone therapy regimens. In 16,608 women with a uterus, 8,506 were randomly assigned to once daily 0.625 mg of CEE plus 2.5 mg once daily of MPA and 8,102 placebo. In 10,739 women with previous hysterectomy, 5,310 were randomly assigned to once daily 0.625 mg of CEE-alone and 5,429 placebo. Intervention was stopped for cause before planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Outcomes include incidence and mortality from ovarian and endometrial cancers and deaths after these cancers., Results: After 20-year follow-up, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041%] v 17 [0.020%]; hazard ratio [HR], 2.04 [95% CI, 1.14 to 3.65]; P = .014) and ovarian cancer mortality ( P = .006). By contrast, CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] v 63 [0.045%]; HR, 1.14 [95% CI, 0.82 to 1.59]; P = .44) or ovarian cancer mortality but did significantly lower endometrial cancer incidence (106 cases [0.073%] v 140 [0.10%]; HR, 0.72 [95% CI, 0.56 to 0.92]; P = .01)., Conclusion: In randomized clinical trials, CEE-alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not. By contrast, CEE plus MPA significantly reduced endometrial cancer incidence.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report long-term colorectal cancer findings from the Women's Health Initiative trial where 16,608 postmenopausal women with a uterus were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg, plus medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. When intervention ended after 5.6 years, although there were 44% fewer colorectal cancers in the intervention group (43 v 72, P = .003), the cancers were more commonly lymph node-positive (59.0% v 29.4%, P = .003). Now after cumulative 24-year follow-up, with 431 colorectal cancers, CEE plus MPA no longer influenced colorectal cancer incidence (215 [0.15, annualized rate %] v 216 [0.15], hazard ratio [HR], 0.95 [95% CI, 0.79 to 1.15]). Although not statistically significant, there were more colorectal cancer deaths with CEE plus MPA (87 [0.049] v 69 [0.041] deaths, HR, 1.20 [95% CI, 0.87 to 1.65], P = .26). Vaginal bleeding (54.1% v 5.2% at 6 months) and breast changes were more frequent in the intervention group. After adjusting for postrandomization vaginal bleeding and breast changes, bowel examinations were significantly delayed in intervention group participants ( P = .005), potentially contributing to diagnostic delay. Taken together, the findings suggest no clinically meaningful benefit for about 5 years of CEE plus MPA use on colorectal cancer outcome.

Background: Obesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed "metabolic endotoxemia." We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women., Methods: Fifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm 2 ) and n = 25 with high VAT area (177.5 ± 31.3 cm 2 ). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks., Results: Women in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet., Conclusions: Increased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms. Video Abstract., (© 2024. The Author(s).)

Few studies have reported on the accuracy of self-reported hypertension history among older postmenopausal women, which was this study's objective. Participants were postmenopausal women enrolled in the Osteoporosis and Periodontal Disease (OsteoPerio) study, an ancillary investigation of the Women's Health Initiative Observational Study (WHI-OS) at the Buffalo, New York, clinical site. Participants self-reported their history of physician diagnosed hypertension treated with medication at WHI-OS enrollment (1993-1998; n = 1342, mean age 63 years), then 3 years later at OsteoPerio enrollment (1997-2001; n = 1342), and again at OsteoPerio Year 5 follow-up (2002-2005; n = 1020). At each time point, medication inventories were recorded and served as the criterion with which self-report was compared in the present study. Physician diagnosed-treated hypertension was also self-reported annually on mailed health update questionnaires in the WHI-OS and were compared against medication inventory at the subsequent clinic exam. Of those participants who self-reported a history of hypertension at WHI enrollment, OsteoPerio enrollment, and OsteoPerio Year 5 follow-up, 41.2%, 90.3%, and 94.4%, respectively, had anti-hypertensive pills in their medication inventory. Across the three time points, sensitivity and specificity ranged from 0.72 to 0.98 and from 0.85 to 0.95, and kappa coefficients ranged from 0.52 to 0.79 when comparing self-report with medication inventory. For self-reported newly physician-diagnosed and treated hypertension on the annual health update questionnaire, 88.4% and 95.2% of those reporting hypertension had anti-hypertensive pills in the subsequent medication inventory. In general, sensitivity and kappa were lower in women aged ≥70 versus < 70 years and in those with history of cardiovascular disease and diabetes compared to those without these comorbidities. In this cohort of postmenopausal women, self-reported physician diagnosed and treated hypertension demonstrated moderate to high accuracy when compared against anti-hypertensive medication use documented by pill inventory, particularly for those who were younger and managing fewer comorbidities., (© 2024 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Purpose: Long COVID-19 syndrome occurs in 10-20 % of people after a confirmed/probable SARS-COV-2 infection; new symptoms begin within three months of COVID-19 diagnosis and last > 8 weeks. Little is known about risk factors for long COVID, particularly in older people who are at greater risk of COVID complications., Methods: Data are from Women's Health Initiative (WHI) postmenopausal women who completed COVID surveys that included questions on whether they had ever been diagnosed with COVID and length and nature of symptoms. Long COVID was classified using standard consensus criteria. Using WHI demographic and health data collected at study enrollment (1993-98) through the present day, machine learning identified the top 20 risk factors for long COVID. These variables were tested in logistic regression models., Results: Of n = 37,280 survey respondents, 1237 (mean age = 83 years) reported a positive COVID-19 test and 425 (30 %) reported long COVID. Symptoms included an array of neurological, cardio-pulmonary, musculoskeletal, and general fatigue, and malaise symptoms. Long COVID risk factors included weight loss, physical and mobility limitations, and specific heath conditions (e.g., history of heart valve procedure, rheumatoid arthritis)., Conclusions: Knowledge of risk factors for long COVID may be the first step in understanding the etiology of this complex disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marian L Neuhouser reports financial support was provided by National Institutes of Health. Mara Vitolins reports financial support was provided by National Center for Advancing Translational Sciences. No other COI declared by any authors If there are other authors, they 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 Inc. All rights reserved.)

Background: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials., Methods: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status., Results: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m 2 ; p < .001)., Conclusions: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies., (© 2024 American Cancer Society.)

Background: While the Breast Cancer Risk Assessment Tool (BCRAT) predicts breast cancer incidence, the model's performance, re-purposed to predict breast cancer mortality, is uncertain. Therefore, we examined whether the BCRAT model predicts breast cancer mortality in postmenopausal women in the Women's Health Initiative (WHI)., Methods: BCRAT 5-year breast cancer incidence risk estimates were calculated for 145,408 women (aged 50-79 years) enrolled in the WHI at 40 US clinical centers to examine associations of BCRAT risk groups (< 1%, 1-< 3%, ≥ 3%) with breast cancer mortality using Cox proportional regression modeling in all participants and in those with incident breast cancer., Results: Women with BCRAT ≥ 3% risk, compared to women with BCRAT < 1% risk, were older (age 70-79 years: 38.3% versus 5.3%), less commonly Black (1.1% versus 40.2%), and had stronger breast cancer family history. With 20-years follow-up, considering all participants, with 8,849 breast cancers and 1,076 breast cancer deaths, breast cancer mortality in BCRAT group ≥ 3% was not higher versus BCRAT group < 1% (Hazard Ratio [HR] 1.06 95% Confidence Interval [CI] 0.80-1.40): percent without 20-year breast cancer mortality; 99.4% [group < 1%] and 98.8% [group ≥ 3%]. Considering women with incident breast cancer, breast cancer mortality was also not higher in BCRAT group ≥ 3% versus BCRAT group < 1% (HR 1.07 95% CI 0.79-1.45)., Conclusions: The BCRAT model, at ≥ 3% 5-year incidence risk (US guideline threshold for chemoprevention), does not identify women with higher breast cancer mortality risk, with implications for breast cancer prevention strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk., Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted., Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10-8 in the meta-analysis; Pinteraction = 2.1 × 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004)., Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer., Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers., (©2024 American Association for Cancer Research.)

Background: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years)., Methods: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates., Results: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age., Conclusions: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To examine the association of dietary patterns with periodontal disease (PD) and its progression over 5 years., Materials and Methods: Analyses involved 1197 post-menopausal women from the OsteoPerio cohort. Dietary patterns assessed include Healthy Eating Index-2015 (HEI), Alternative HEI (AHEI), Dietary Approaches to Stop Hypertension (DASH) and alternate Mediterranean Diet (aMed) at baseline (the average of two food frequency questionnaires administered between 1993 and 2001). At baseline and the 5-year follow-up, periodontal assessments evaluated alveolar crestal height (ACH), probing pocket depth (PPD), clinical attachment loss (CAL), percentage of gingival sites bleeding on probing (%BOP) and missing teeth due to PD. Linear and logistic regression were used to examine the associations., Results: Cross-sectionally, HEI and aMed were associated with smaller CAL and %BOP; along with DASH, they were associated with a decreased odds of teeth missing due to PD. AHEI and aMed were associated with a decreased odds of severe PD. Prospectively, AHEI was associated with greater ACH progression. This association was attenuated to the null after loss of ACH was imputed for teeth lost due to PD over follow-up, or after excluding participants with diabetes, osteoporosis, hypertension or heart disease at baseline., Conclusions: Better adherence to healthy dietary patterns was associated with better PD measures cross-sectionally but greater progression of ACH over 5 years. The latter might be explained by incident tooth loss due to PD and pre-existing comorbidities., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence., Methods: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP., Results: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002)., Conclusion: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences ≥ |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation., (© 2024. Springer Nature B.V.)

Long-term physical functioning trajectories following distal forearm fracture are unknown. We found that women with versus those without distal forearm fracture were more likely to experience a 5-year decline in physical functioning, independent of initial physical functioning level. This association was most evident among women 80 years and older., Introduction: Physical functioning trajectory following lower arm or wrist fracture is not well understood., Purpose: This study is to evaluate physical functioning trajectory before vs. after lower arm or wrist fracture, stratified by age., Methods: We performed a nested case-control study of prospective data from the Women's Health Initiative Study (n = 2097 cases with lower arm or wrist fracture, 20,970 controls). Self-reported fractures and the physical functioning subscale of the RAND 36-item Short-Form Health Survey were assessed annually. We examined three physical functioning trajectory groups: stable, improving, and declining., Results: Mean (SD) number of physical functioning measurements was 5.2 (1.5) for cases and 5.0 (1.4) for controls. Declining physical functioning was observed among 20.4% of cases and 16.0% of controls. Compared to women without lower arm or wrist fracture, women with lower arm or wrist fracture were 33% more likely to experience declining physical functioning (adjusted odds ratio [aOR] 1.33 95% confidence interval [CI] 1.19-1.49, reference group stable or improving physical functioning trajectory). Associations varied by age: age ≥ 80 years aOR 1.56 (95% CI 1.29-1.88); age 70-79 years aOR 1.29 (95% CI 1.09-1.52); age < 70 years aOR 1.15 (95% CI 0.86-1.53) (p interaction  = 0.06). Associations between lower arm or wrist fracture and odds of declining physical functioning did not vary by baseline physical functioning or physical activity level., Conclusions: Women with lower arm or wrist fracture, particularly those aged 80 and older, were more likely to experience declines in physical functioning than women without such fractures, independent of baseline physical functioning level., (© 2024. The Author(s).)

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years., Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up., Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Background: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors., Methods: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass., Discussion: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Banack et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited., Objective: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial., Design: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611)., Setting: A multicenter ( n = 40) trial across the United States., Participants: 36 282 postmenopausal women with no history of breast or colorectal cancer., Intervention: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D 3 daily or placebo., Measurements: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use., Results: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality., Limitation: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled., Conclusion: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality., Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2598.

The association of leukocyte telomere length (LTL) with survival to late life with intact mobility has not been adequately studied. This prospective cohort study consisted of 1451 postmenopausal women from a Women's Health Initiative ancillary study, who were eligible, because of birth year, to survive to age 90 as of March 6, 2021. LTL was measured by Southern blot at baseline (1993-1998). Associations between LTL and survival to age 90 were evaluated using logistic regression models adjusted for socio-demographic characteristics, health factors, and lifestyle factors. Multinominal logistic regression was utilized to examine associations of LTL with survival to age 90 with or without intact mobility. Mediation analysis examined the extent to which incident coronary heart disease and stroke-mediated the association between LTL and longevity. Overall, 76.7% of women were White, and 23.3% were Black; average age at baseline was 70.4±3.5 years. Relative to death before age 90, the odds of survival to age 90 were 60% higher (OR, 1.60; 95% CI, 1.28-2.01), the odds of survival to age 90 with mobility limitation were 72% higher (OR, 1.72; 95% CI, 1.33-2.21), and the odds of survival to age 90 with intact mobility were 44% higher (OR, 1.44; 95% CI, 1.06-1.95) for every one kilobase longer LTL. Absence of CHD, stroke, or CHD/stroke mediated the association of LTL with survival to age 90 by 11.1%, 37.4%, and 31.3%, respectively; however, these findings were not significant. Longer LTL was associated with higher odds of survival to age 90 among older women., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Context: Along the menstrual cycle, associations between inconsistent sleep duration and levels of metabolic biomarkers are uncertain and could involve fluctuations in estrogen concentrations., Objective: To examine associations between patterns of sleep duration and metabolic biomarkers across two menstrual cycles within a cohort of premenopausal women., Methods: The BioCycle Study was conducted in New York between 2005-2007, enrolling 259 premenopausal women over two menstrual cycles. This micro-longitudinal cohort study involved intensive data collection including daily sleep diaries and biomarker assessments of leptin, insulin, and glucose at 16 key points timed to menstrual cycle phases. We considered dynamic sleep duration, as hours slept one night or as mean hours slept during the two nights prior to each biomarker assessment. Variability in habitual sleep duration, i.e., reported daily sleep duration, summarized across both menstrual cycles. Variation in habitual sleep duration was computed using L-moments, a robust version of dispersion, skewness, and kurtosis. To examine associations between patterns of sleep duration and metabolic biomarkers, we fitted a series of linear mixed models with random intercepts and inverse probability weighting. These models were adjusted for potential demographic, lifestyle, health confounders, and menstrual cycle phase., Results: Sleep duration one night or two nights prior to clinic visits were not associated with metabolic biomarker measures we assessed. However, overall variability (dispersion) in habitual sleep duration was associated with lower mean insulin HOMA-IR levels, but not glucose. Moreover, extreme short or long bouts of sleep duration was associated with higher mean levels of leptin, insulin, and HOMA-IR., Conclusions: These data suggest that variation in habitual sleep duration along the menstrual cycle may be associated with metabolic function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Porphyromonas gingivalis, a Gram-negative anaerobic bacterium commonly found in human subgingival plaque, is a major etiologic agent for periodontitis and has been associated with multiple systemic pathologies. Many P. gingivalis strains have been identified and different strains possess different virulence factors. Current oral microbiome approaches (16S or shotgun) have been unable to differentiate P. gingivalis strains. This study presents a new approach that aims to improve the accuracy of strain identification, using a detection method based on sequencing of the intergenic spacer region (ISR) which is variable between P. gingivalis strains. Our approach uses two-step PCR to amplify only the P. gingivalis ISR region. Samples are then sequenced with an Illumina sequencer and mapped to specific strains. Our approach was validated by examining subgingival plaque from 153 participants with and without periodontal disease. We identified the avirulent strain ATCC33277/381 as the most abundant strain across all sample types. The W83/W50 strain was significantly enriched in periodontitis, with 13% of participants harboring that strain. Overall, this approach can have significant implications not only for the diagnosis and treatment of periodontal disease but also for other diseases where P. gingivalis or its toxins have been implicated, such as Alzheimer's disease., (© 2024. The Author(s).)

Background: Alcohol reduces neutrophil function and decreases salivary flow, which could affect the composition of the oral microbiome., Objective: We hypothesized that the α- and β-diversity of the oral microbiome and the relative abundance of bacterial taxa would differ by frequency and type of alcohol consumption., Methods: We used a food frequency questionnaire to assess the frequency of consumption of beer, wine, and liquor (drinks/week) in a sample of 1179 postmenopausal women in the Osteoporosis and Periodontal Disease Study. Women were categorized as nondrinkers, drinking <1 drink/wk, ≥1 to <7 drinks/wk, or ≥7 drinks/wk for total alcohol consumption and for beer, wine, and liquor consumption. The composition and diversity of the oral microbiome was assessed from subgingival plaque samples using 16S ribosomal RNA amplicon sequencing. Permutational multivariate analysis of variance (PERMANOVA) was used to examine β-diversity (between-sample diversity) in the microbiome between alcohol consumption categories. Analysis of covariance was used to examine the mean α-diversity (within-sample diversity), assessed by the Shannon index (species evenness), Chao1 index (species richness), and observed operational taxonomic unit (OTU) count and the mean relative abundance of 245 bacterial taxa across alcohol consumption categories., Results: Over half of the participants (67%) consumed alcohol, with 14% reporting ≥1 drink/d. The β-diversity across categories of total alcohol consumption, but not categories of alcohol type, was statistically significantly different (P for PERMANOVA = 0.016). Mean α-diversity measures were statistically significantly higher (P < 0.05) in the highest category of total alcohol and wine consumption compared to nondrinkers; no significant associations were found for beer or liquor consumption. The relative abundance of 1 OTU, Selenomonassp.&#95;oral&#95;taxon&#95;133, was significantly lower in the highest level of total alcohol consumption compared to nondrinkers after adjustment for multiple comparisons., Conclusions: Alcohol consumption was associated with the diversity and composition of the subgingival microbiome., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2023 American Society for Nutrition. All rights reserved.)

Background: Caregiving is commonly undertaken by older women. Research is mixed, however, about the impact of prolonged caregiving on their health, well-being, and mortality risk. Using a prospective study design, we examined the association of caregiving with mortality in a cohort of older women., Methods: Participants were 158,987 postmenopausal women aged 50-79 years at enrollment into the Women's Health Initiative (WHI) who provided information on current caregiving status and caregiving frequency at baseline (1993-1998) and follow-up (2004-2005). Mortality was ascertained from baseline through March of 2019. Cox regression with caregiving status defined as a time-varying exposure was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality, adjusting for sociodemographic factors, smoking, and history of diabetes, hypertension, cardiovascular disease (CVD), and cancer. Stratified analyses explored whether age, race-ethnicity, depressive symptoms, frequency of caregiving, optimism, and living status modified the association between caregiver status and mortality., Results: At baseline, 40.7% of women (mean age 63.3 years) self-identified as caregivers. During a mean 17.5-year follow-up, all-cause mortality (50,526 deaths) was 9% lower (multivariable-adjusted HR = 0.91, 95% CI: 0.89-0.93) in caregivers compared to non-caregivers. The inverse association between caregiving and all-cause mortality did not differ according to caregiving frequency or when stratified by age, race-ethnicity, depressive symptoms, optimism, or living status (interaction p > 0.05, all). Caregiving was inversely associated with CVD and cancer mortality., Conclusion: Among postmenopausal women residing across the United States, caregiving was associated with lower mortality. Studies detailing the type and amount of caregiving are needed to further determine its impact on older women., (© 2023 The American Geriatrics Society.)

Background: Although gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established., Objective: This study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women., Study Design: The Women's Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with medication from baseline (1993-1998) to March 2021. This study used logistic regression to examine the associations of any and individual adverse pregnancy outcomes with diabetes mellitus. Stratified analyses were performed to assess effect modification by body mass index, race and ethnicity, education, parity, breastfeeding, and age at first birth., Results: This analysis included 49,717 women without a history of diabetes mellitus at enrollment who had a least 1 pregnancy and responded to the questionnaire about adverse pregnancy outcomes. After adjusting for body mass index, demographic, lifestyle, and reproductive factors, gestational diabetes mellitus (odds ratio, 2.26; 95% confidence interval, 1.94-2.63), high birthweight (odds ratio, 1.30; 95% confidence interval, 1.18-1.44), and hypertensive disorders of pregnancy (odds ratio, 1.18; 95% confidence interval, 1.08-1.30) were independently associated with higher odds of type 2 diabetes mellitus, whereas preterm birth and low birthweight were not associated with diabetes mellitus risk. A history of ≥2 adverse pregnancy outcomes was associated with higher odds of type 2 diabetes mellitus (odds ratio, 1.55; 95% confidence interval, 1.28-1.88). This study further observed higher odds of type 2 diabetes mellitus (odds ratio, 3.69; 95% confidence interval, 2.38-5.70) among women with a history of both gestational diabetes mellitus and hypertensive disorders of pregnancy than those without any adverse pregnancy outcomes., Conclusion: Postmenopausal women with a history of gestational diabetes mellitus, those delivering high-birthweight infants, or those with hypertensive disorders of pregnancy are at risk of future type 2 diabetes mellitus. In addition, women with ≥2 conditions had an augmented risk and might be prioritized for screening and prevention efforts for type 2 diabetes mellitus., (Copyright © 2023. Published by Elsevier Inc.)

Background: Racial and ethnic disparities in coronavirus disease 2019 (COVID-19) risk are well-documented; however, few studies in older adults have examined multiple factors related to COVID-19 exposure, concerns, and behaviors or conducted race- and ethnicity-stratified analyses. The Women's Health Initiative (WHI) provides a unique opportunity to address those gaps., Methods: We conducted a secondary analysis of WHI data from a supplemental survey of 48 492 older adults (mean age 84 years). In multivariable-adjusted modified Poisson regression analyses, we examined predisposing factors and COVID-19 exposure risk, concerns, and behaviors. We hypothesized that women from minoritized racial or ethnic groups, compared to non-Hispanic White women, would be more likely to report: exposure to COVID-19, a family or friend dying from COVID-19, difficulty getting routine medical care or deciding to forego care to avoid COVID-19 exposure, and having concerns about the COVID-19 pandemic., Results: Asian women and non-Hispanic Black/African American women had a higher risk of being somewhat/very concerned about risk of getting COVID-19 compared to non-Hispanic White women and each was significantly more likely than non-Hispanic White women to report forgoing medical care to avoid COVID-19 exposure. However, Asian women were 35% less likely than non-Hispanic White women to report difficulty getting routine medical care since March 2020 (adjusted relative risk 0.65; 95% confidence interval 0.57, 0.75)., Conclusions: We documented COVID-related racial and ethnic disparities in COVID-19 exposure risk, concerns, and care-related behaviors that disfavored minoritized racial and ethnic groups, particularly non-Hispanic Black/African American women., (© The Author(s) 2023. 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.)

Objective: Observational studies have indicated that cocoa flavanol supplementation may be a promising strategy for type 2 diabetes (T2D) prevention. We aimed to directly evaluate its clinical efficacy in a large randomized clinical trial (RCT)., Research Design and Method: The Cocoa Supplement and Multivitamin Outcomes Study (COMSOS) was a 2 × 2 factorial RCT performed from June 2015 to December 2020 that tested cocoa extract and a multivitamin for the prevention of cardiovascular disease (CVD) and cancer. A total of 21,442 U.S. adults free of CVD and recent cancer, including 12,666 women aged ≥65 years and 8,776 men aged ≥60 years, were randomly assigned to receive cocoa extract [500 mg/day cocoa flavanols, including 80 mg (-)-epicatechin] or placebo. In this study, we included 18,381 participants without diabetes at enrollment and examined the effect of cocoa extract supplementation on incident self-reported T2D in intention-to-treat analyses., Results: During a median follow-up of 3.5 years, 801 incident T2D cases were reported. Compared with placebo, taking a cocoa extract supplement did not reduce T2D (adjusted hazard ratio 1.04, 95% CI 0.91-1.20, P = 0.58). Stratification analyses showed that the effect of cocoa extract supplementation was not significantly modified by sex, race, BMI, smoking, physical activity, dietary quality, flavanol status at baseline, or randomized multivitamin assignment., Conclusions: Middle-aged and older adults taking a cocoa extract supplement for a median of 3.5 years did not reduce their risk of incident T2D. Further studies of cocoa extract supplementation beginning earlier in adulthood and in populations with different background diets are warranted., (© 2023 by the American Diabetes Association.)

Objective: Hormone therapy can positively impact bone mineral density after menopause. We explored bone mineral density change in postmenopausal women who discontinued hormone therapy after the Women's Health Initiative landmark 2002 trial results were published. We secondarily explored whether usual physical activity modified the results., Methods: Postmenopausal women participating in the Buffalo OsteoPerio study with information on hip bone density, hormone therapy use, and self-reported physical activity at two time points (1997-2001; 2002-2007) were included (N = 961). Hormone therapy included three groups according to use at baseline and year 5 (non/non; current/non; current/current)., Results: At baseline (mean age, 65.9 years; SD, 6.7 years), 480 women were not using hormone therapy, while 481 were current users. Between the baseline and 5-year visits, 336 women using hormone therapy discontinued. Baseline total hip bone density was highest in current users. After 5 years, those who continued hormone therapy exhibited no bone loss; those who discontinued exhibited the greatest loss at the total hip of -0.021 gm/cm2. Women who never used hormone therapy exhibited some loss of -0.012 gm/cm2. Usual physical activity did not appreciably impact change in bone density in any group., Conclusions: This prospective observational study explored the 5-year change in bone mineral density among older postmenopausal women after the landmark 2002 hormone therapy trial findings were released. We found bone density decreased in never-users and in women who discontinued use. Bone density was maintained in current users. Although usual physical activity did not mitigate bone loss, targeted physical activity regimens should be investigated., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Background: Multimorbidity, defined as the presence of 2 or more chronic health conditions, is increasingly common among older adults. The combination of lifestyle characteristics such as diet quality, smoking status, alcohol intake, physical activity (PA), sleep duration, and body fat as assessed by body mass index (BMI) or waist circumference, and risk of multimorbidity are not well understood., Objectives: We investigated the association between the healthy lifestyle index (HLI), generated by combining indicators of diet quality, smoking, alcohol, PA, sleep amount, and BMI, and risk of multimorbidity, a composite outcome that included cardiovascular disease (CVD), diabetes, cancer, and fracture., Methods: We studied 62 037 postmenopausal women aged 50-79 years at enrollment in the Women's Health Initiative, with no reported history of CVD, diabetes, cancer, or fracture at baseline. Lifestyle characteristics measured at baseline were categorized and a score (0-4) was assigned to each category. The combined HLI (0-24) was grouped into quintiles, with higher quintiles indicating a healthier lifestyle. Multivariable adjusted estimates of hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the risk of developing multimorbidity were obtained using Cox proportional hazard models., Results: Over an average follow-up period of 16.3 years, 5 656 women developed multimorbidity. There was an inverse association between the HLI levels and risk of multimorbidity (compared to the HLI&#95;1st quintile: HR&#95;2nd quintile = 0.81 95% CI 0.74-0.83, HR&#95;3rd quintile = 0.77 95% CI 0.71-0.83, HR&#95;4th quintile = 0.70 95% CI 0.64-0.76, and HR&#95;5th quintile = 0.60 95% CI 0.54-0.66; p trend < .001). Similar associations were observed after stratification by age or BMI categories., Conclusions: Among postmenopausal women, higher levels of the HLI were associated with a reduced risk of developing multimorbidity., (© The Author(s) 2023. 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.)

Background: Associations of weight changes and intentionality of weight loss with longevity are not well described., Methods: Using longitudinal data from the Women's Health Initiative (N = 54 437; 61-81 years), we examined associations of weight changes and intentionality of weight loss with survival to ages 90, 95, and 100. Weight was measured at baseline, year 3, and year 10, and participants were classified as having weight loss (≥5% decrease from baseline), weight gain (≥5% increase from baseline), or stable weight (<5% change from baseline). Participants reported intentionality of weight loss at year 3., Results: A total of 30 647 (56.3%) women survived to ≥90 years. After adjustment for relevant covariates, 3-year weight loss of ≥5% vs stable weight was associated with lower odds of survival to ages 90 (OR, 0.67; 95% CI, 0.64-0.71), 95 (OR, 0.65; 95% CI, 0.60-0.71), and 100 (OR, 0.62; 95% CI, 0.49-0.78). Compared to intentional weight loss, unintentional weight loss was more strongly associated with lower odds of survival to age 90 (OR, 0.83; 95% CI, 0.74-0.94 and OR, 0.49; 95% CI, 0.44-0.55, respectively). Three-year weight gain of ≥5% vs stable weight was not associated with survival to age 90, 95, or 100. The pattern of results was similar among normal weight, overweight, and obese women in body mass index (BMI)-stratified analyses., Conclusions: Weight loss of ≥5% vs stable weight was associated with lower odds of longevity, more strongly for unintentional weight loss than for intentional weight loss. Potential inaccuracy of self-reported intentionality of weight loss and residual confounding were limitations., (© The Author(s) 2023. 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.)

Background: Circulating adiponectin and leptin have been associated with risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with patient survival has not been investigated., Methods: Adipokine levels were measured in prospectively collected samples from 472 patients with pancreatic cancer. Because of sex-specific differences in adipokine levels, associations were evaluated separately for men and women. In a subset of 415 patients, we genotyped 23 SNPs in adiponectin receptor genes (ADIPOR1 and ADIPOR2) and 30 SNPs in the leptin receptor gene (LEPR)., Results: Adiponectin levels were inversely associated with survival in women [HR, 1.71; 95% confidence interval (CI), 1.15-2.54]; comparing top with bottom quartile but not in men (HR, 0.89; 95% CI, 0.46-1.70). The SNPs rs10753929 and rs1418445 in ADIPOR1 were associated with survival in the combined population (per minor allele HR, 0.66; 95% CI, 0.51-0.84, and HR, 1.33; 95% CI, 1.12-1.58, respectively). Among SNPs in LEPR, rs12025906, rs3790431, and rs17127601 were associated with survival in the combined population [HRs, 1.54 (95% CI, 1.25-1.90), 0.72 (95% CI, 0.59-0.88), and 0.70 (95% CI, 0.56-0.89), respectively], whereas rs11585329 was associated with survival in men only (HR, 0.39; 95% CI, 0.23-0.66; Pinteraction = 0.0002)., Conclusions: High levels of adiponectin in the prediagnostic period were associated with shorter survival among women, but not among men with pancreatic cancer. Several polymorphisms in ADIPOR1 and LEPR are associated with patient survival., Impact: Our findings reveal the association between adipokine signaling and pancreatic cancer survival and demonstrate the importance of examining obesity-associated pathways in relation to pancreatic cancer in a sex-specific manner., (©2023 American Association for Cancer Research.)

Background: Positive affect and emotional resources, such as optimism, may play a major role in women's health and promote healthy well-being later in life. However, positive affect and optimism measures have not been psychometrically assessed in older women, despite relations to health. Therefore, the objective of this study was to psychometrically assess measures of positive affect and optimism and test their association with other measures of well-being. Methods: In a Women's Health Initiative subcohort of 58,810 women (mean age [standard deviation] 79.0 [6.1]; 89% White), positive affect and optimism were measured using the modified Differential Emotions Scale (mDES) and Life Orientation Test-Revised (LOT-R), respectively. Reliability was tested using Cronbach's alpha and McDonald's omega. Performance was assessed using item response theory. Factor analysis was used to explore the construct validity of the LOT-R. Convergent and divergent validity with other well-being measures was tested. Results: Results suggest good reliability (mDES: Cronbach's alpha = 0.90 and omega total = 0.92; LOT-R: Cronbach's alpha = 0.79, omega hierarchical = 0.61, and omega total = 0.83). Item response analyses indicate mDES's ability to discriminate across positive affect; LOT-R was skewed toward lower optimism levels. Exploratory factor analyses suggest a two-factor solution for the LOT-R. Significant, but small correlations in expected directions to well-being measures confirmed validity hypotheses. Conclusions: The mDES and LOT-R measured positive affect and optimism with good reliability, item performance, and validity in a large sample of older postmenopausal women, supporting use of these measures to quantify effects of positive affect and optimism-promoting interventions.

Background: Advancements in medical technology and pharmacologic interventions have drastically improved survival of infants born preterm and low birth weight, but knowledge regarding the long-term health impacts of these individuals is limited and inconsistent., Aim: To investigate whether an individual's birthweight or history of being born preterm increases the risk of an adverse reproductive outcome., Study Design: Nested case-control study within the Women's Health Initiative., Subjects: 79,934 individuals who self-reported their personal birthweight category and/or preterm birth status., Outcomes Measures: Self-reported pregnancy outcomes: subfertility, miscarriage, stillbirth, preeclampsia, gestational diabetes, gestational hypertension, preterm birth, low birthweight infant, high birthweight infant. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR)., Results: After adjustments, individuals reporting their birthweight <6lbs. were 20 % more likely to have a stillbirth or 70 % more likely to have a low birthweight infant and were less likely to have a full-term birth or high birthweight infant during their pregnancy. Individuals reporting a birthweight ≥10 lbs. were more likely to have a high birthweight infant (OR 3.49, 95 % CI 2.73-4.39) and less likely to have a low birthweight infant (OR 0.64, 95 % CI 0.47-0.82). Individuals born preterm were at increased risk for infertility, miscarriage, preeclampsia, gestational diabetes, and delivering a preterm or low birthweight infant., Conclusions: As more individuals born preterm and/or low birthweight survive to adulthood, the incidence and prevalence of poor reproductive outcomes may increase. Women born at extremes of birthweight and prematurity may need to be monitored more closely during their own pregnancies., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The menopausal transition results in a progressive decrease in circulating estrogen levels. Experimental evidence in rodents has indicated that estrogen depletion leads to a reduction of energy expenditure and physical activity. It is unclear whether treatment with estrogen therapy increases physical activity level in postmenopausal women., Methods: A total of 27,327 postmenopausal women aged 50-79 years enrolled in the Women's Health Initiative randomized double-blind trials of menopausal hormone therapy. Self-reported leisure-time physical activity at baseline, and years 1, 3, and 6 was quantified as metabolic equivalents (MET)-h/wk. In each trial, comparison between intervention and placebo groups of changes in physical activity levels from baseline to follow-up assessment was examined using linear regression models., Results: In the CEE-alone trial, the increase in MET-h/wk was greater in the placebo group compared with the intervention group at years 3 ( P = 0.002) and 6 ( P < 0.001). Similar results were observed when analyses were restricted to women who maintained an adherence rate ≥80% during the trial or who were physically active at baseline. In the CEE + MPA trial, the primary analyses did not show significant differences between groups, but the increase of MET-h/wk was greater in the placebo group compared with the intervention group at year 3 ( P = 0.004) among women with an adherence rate ≥80%., Conclusions: The results from this clinical trial do not support the hypothesis that estrogen treatment increases physical activity among postmenopausal women., Competing Interests: Conflict of interest/financial disclosures: R.T.C. receives ongoing funding from UpToDate . M.S.L. received $1000 honorarium from the New England Bone Club for a plenary lecture at the 2022 New England Bone Club meeting. The other authors have nothing to disclose., (Copyright © 2023 by The North American Menopause Society.)

Background: A substantial observational literature relating specific fatty acid classes to chronic disease risk may be limited by its reliance on self-reported dietary data., Objectives: We aimed to develop biomarkers for saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acid densities, and to study their associations with cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) in Women's Health Initiative (WHI) cohorts., Methods: Biomarker equations were based primarily on serum and urine metabolomics profiles from an embedded WHI human feeding study (n = 153). Calibration equations were based on biomarker values in a WHI nutritional biomarker study (n = 436). Calibrated intakes were assessed in relation to disease incidence in larger WHI cohorts (n = 81,894). Participants were postmenopausal women, aged 50-79 when enrolled at 40 United States Clinical Centers (1993-1998), with a follow-up period of ∼20 y., Results: Biomarker equations meeting criteria were developed for SFA, MUFA, and PUFA densities. That for SFA density depended somewhat weakly on metabolite profiles. On the basis of our metabolomics platforms, biomarkers were insensitive to trans fatty acid intake. Calibration equations meeting criteria were developed for SFA and PUFA density, but not for MUFA density. With or without biomarker calibration, SFA density was associated positively with risk of CVD, cancer, and T2D, but with small hazard ratios, and CVD associations were not statistically significant after controlling for other dietary variables, including trans fatty acid and fiber intake. Following this same control, PUFA density was not significantly associated with CVD risk, but there were positive associations for some cancers and T2D, with or without biomarker calibration., Conclusions: Higher SFA and PUFA diets were associated with null or somewhat higher risk for clinical outcomes considered in this population of postmenopausal United States women. Further research is needed to develop even stronger biomarkers for these fatty acid densities and their major components. This study is registered with clinicaltrials.gov identifier: NCT00000611., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer., Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes., Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample., Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk., Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer., (©2023 American Association for Cancer Research.)

Background: The Women's Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here, we use WHI observational data for further insight into the chronic disease implications of adopting this type of low-fat dietary pattern., Objectives: We aimed to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction, to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error, and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately., Methods: Prospective disease association results are presented using WHI cohorts of postmenopausal women, aged 50-79 y when enrolled at 40 United States clinical centers. Biomarker equations were developed using an embedded human feeding study (n = 153). Calibration equations were developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes were associated with cancer, cardiovascular diseases, and diabetes incidence in WHI cohorts (n = 81,954) over an approximate 20-y follow-up period., Results: A biomarker for fat density was developed by subtracting protein, carbohydrate, and alcohol densities from one. A calibration equation was developed for fat density. Hazard ratios (95% confidence intervals) for 20% higher fat density were 1.16 (1.06, 1.27) for breast cancer, 1.13 (1.02, 1.26) for CHD, and 1.19 (1.13, 1.26) for diabetes, in substantial agreement with findings from the DM trial. With control for additional dietary variables, especially fiber, fat density was no longer associated with CHD, with hazard ratio (95% confidence interval) of 1.00 (0.88, 1.13), whereas that for breast cancer was 1.11 (1.00, 1.24)., Conclusions: WHI observational data support prior DM trial findings of low-fat dietary pattern benefits in this population of postmenopausal United States women., Trial Registration Number: This study is registered with clinicaltrials.gov identifier: NCT00000611., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Variability in sleep duration and cardiovascular health have been infrequently investigated, particularly among reproductive-age women. We examined these associations across the menstrual cycle among a cohort of 250 healthy premenopausal women, aged 18-44 years. The BioCycle study (New York, 2005-2007) collected cardiovascular biomarkers (serum high- and low-density lipoprotein (HDL, LDL), total cholesterol, triglycerides, and C-reactive protein (CRP)) at key time points along the menstrual cycle (follicular, ovulatory, and luteal phases). Women also recorded sleep duration in daily diaries. From these data, we computed L-moments, robust versions of location, dispersion, skewness, and kurtosis. We fitted linear mixed models with random intercepts and inverse probability weighting to estimate associations between sleep variability and cardiovascular biomarkers, accounting for demographic, lifestyle, health, and reproductive factors. Sleep dispersion (any deviation from mean duration) was associated with lower mean LDL for nonshift workers and non-White women. Skewed sleep duration was associated with higher mean CRP and lower mean total cholesterol. Sleep durations with extreme short and long bouts (kurtosis) were associated with a lower mean HDL, but not mean CRP, LDL, or triglycerides. Sleep duration modified associations between sleep dispersion and LDL, HDL, and total cholesterol. Even in young and healthy women, sleep duration variability could influence cardiovascular health., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI)., Methods: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates., Results: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively., Conclusions: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.

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 %., Competing Interests: Declaration of Competing Interest All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years except for Julie E. Buring who declares an association to Pharmavite. All authors further declare no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women's Health Initiative ( n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.

Objectives: The relationship between optimism and cognitive functioning is not fully understood. We examined the association of optimism with risk of mild cognitive impairment (MCI) and dementia in the Women's Health Initiative Memory Study (WHIMS)., Methods: Optimism was measured by the Life Orientation Test-Revised (LOT-R) total score, and optimism and pessimism subscales. A panel of experts adjudicated cognitive endpoints based on annual cognitive assessments. We used cox proportional hazard regression models to examine the association of LOT-R total score and optimism and pessimism sub-scores with MCI/dementia. We also examined the relationship between vascular disease, LOT-R total score, optimism and pessimism, and cognition., Results: Mean age was 70.5 (SD = 3.9) years. The sample ( N  = 7249) was 87% white, and 29.8% of participants had < 12 years of education. Total LOT-R score (HR = 0.96, 95% CI: 0.94, 0.98, p  < 0.001) was associated with lower risk of combined MCI or dementia. More pessimism (HR = 1.08, 95% CI: 1.05, 1.11, p  < 0.0001) was associated with higher risk of MCI or dementia after adjustment for ethnicity, education, vascular disease, and depression. No significant relationships emerged from the optimism subscale., Conclusion: These data suggest that less pessimism, but not more optimism, was associated with a lower risk of MCI and dementia.

Introduction: Women with hypertensive disorders of pregnancy (HDP) have an increased risk of cardiovascular disease. Whether HDP is also associated with later-life dementia has not been fully explored., Methods: Using the Utah Population Database, we performed an 80-year retrospective cohort study of 59,668 parous women., Results: Women with, versus without, HDP, had a 1.37 higher risk of all-cause dementia (95% confidence interval [CI]: 1.26, 1.50) after adjustment for maternal age at index birth, birth year, and parity. HDP was associated with a 1.64 higher risk of vascular dementia (95% CI: 1.19, 2.26) and 1.49 higher risk of other dementia (95% CI: 1.34, 1.65) but not Alzheimer's disease dementia (adjusted hazard ratio = 1.04; 95% CI: 0.87, 1.24). Gestational hypertension and preeclampsia/eclampsia showed similar increased dementia risk. Nine mid-life cardiometabolic and mental health conditions explained 61% of HDP's effect on subsequent dementia risk., Discussion: Improved HDP and mid-life care could reduce the risk of dementia., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Helicobacter pylori infection may be a risk factor for pancreatic cancer, particularly infection by strains without the cytotoxin-associated gene A (CagA) virulence factor. Non-O blood type is a known risk factor for pancreatic cancer, and H. pylori gastric colonization occurs largely from bacterial adhesins binding to blood group antigens on gastric mucosa., Methods: We included 485 pancreatic cancer cases and 1,122 matched controls from 5 U.S. prospective cohorts. Prediagnostic plasma samples were assessed for H. pylori and CagA antibody titers. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer. ABO blood type was assessed using genetic polymorphisms at the ABO gene locus or self-report., Results: Compared with H. pylori -seronegative participants, those who were seropositive did not demonstrate an increased risk of pancreatic cancer (OR 0.83, 95% CI 0.65-1.06). This lack of association was similar among CagA-seropositive (OR 0.75, 95% CI 0.53-1.04) and -seronegative (OR 0.89, 95% CI 0.65-1.20) participants. The association was also similar when stratified by time between blood collection and cancer diagnosis ( P -interaction = 0.80). Consistent with previous studies, non-O blood type was associated with increased pancreatic cancer risk, but this increase in risk was similar regardless of H. pylori seropositivity ( P -interaction = 0.51)., Discussion: In this nested case-control study, history of H. pylori infection as determined by H. pylori antibody serology was not associated with pancreatic cancer risk, regardless of CagA virulence factor status. The elevated risk associated with non-O blood type was consistent in those with or without H. pylori seropositivity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Demographic and clinical factors influence the metabolome. The discovery and validation of disease biomarkers are often challenged by potential confounding effects from such factors. To address this challenge, we investigated the magnitude of the correlation between serum and urine metabolites and demographic and clinical parameters in a well-characterized observational cohort of 444 post-menopausal women participating in the Women's Health Initiative (WHI). Using LC-MS and lipidomics, we measured 157 aqueous metabolites and 756 lipid species across 13 lipid classes in serum, along with 195 metabolites detected by GC-MS and NMR in urine and evaluated their correlations with 29 potential disease risk factors, including demographic, dietary and lifestyle factors, and medication use. After controlling for multiple testing (FDR < 0.01), we found that log-transformed metabolites were mainly associated with age, BMI, alcohol intake, race, sample storage time (urine only), and dietary supplement use. Statistically significant correlations were in the absolute range of 0.2-0.6, with the majority falling below 0.4. Incorporation of important potential confounding factors in metabolite and disease association analyses may lead to improved statistical power as well as reduced false discovery rates in a variety of data analysis settings.

While biomarkers have been proposed to identify individuals at risk for radiation-induced cardiovascular disease (RICVD), little is known about long-term associations with cardiac events. We examined associations of biomarkers of oxidative stress (myeloperoxidase, growth differentiation factor-15, 8-hydroxy-2'-deoxyguanosine [8-OH-dG], placental growth factor), cardiac injury (troponin I, cystatin-C), inflammation (interleukin-6, C-reactive protein), and myocardial fibrosis (transforming growth factor-ß) with long-term RICVD in breast cancer (BC) survivors. We conducted a nested case-control study within the Women's Health Initiative of postmenopausal women with incident BC stages I-III, who received radiation and had pre- and post-BC diagnosis serum samples. Cases (n = 55) were defined as developing incident, physician-adjudicated myocardial infarction, coronary heart disease death, other CVD death, heart failure, or stroke after BC. Cases were matched to three controls (n = 158). After adjustment, a higher 8-OH-dG ratio was significantly associated with an elevated long-term risk of RICVD, suggesting oxidative DNA damage may be a putative pathway for RICVD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We evaluated the influence of two endogenous hormones on bone health in older women. Higher FSH was associated with bone disease, especially in lower estradiol environments. FSH attenuated the relationship between estradiol and bone. This may provide a mechanism through which future clinical research intervenes on bone loss., Introduction/purpose: Despite preclinical evidence for an inverse association of follicle-stimulating hormone (FSH) and bone mineral density (BMD), no large epidemiologic studies have evaluated the separate and joint influences of FSH and estradiol on bone in postmenopausal women., Methods: In a cross-sectional study of 675 postmenopausal women, we evaluated associations of serum FSH and dual X-ray absorptiometry (DXA)-classified areal BMD as well as low bone mass or osteoporosis (T-score <  - 1.0) of the femoral neck and total hip. We stratified this analysis by serum estradiol (cut at the median). We tested whether FSH mediates the association of estradiol and BMD using the Sobel test., Results: In linear regression models, there was a significant inverse association of serum FSH with both femoral neck and total hip BMD (both p < 0.01) when adjusted for age, hormone therapy (HT) use, and diabetes. In fully adjusted logistic regression models, women in the highest FSH tertile had higher odds of low bone mass/osteoporosis at the femoral neck (OR = 2.98; 95% CI = 1.86-4.77) and at the total hip (OR = 1.74; 95% CI = 1.06-2.84) compared to those in the lowest FSH tertile. We report evidence of effect modification by estradiol in stratified models and an interaction term. FSH met all criteria of a mediator, including an estimated 70% attenuation of the estradiol-BMD relationship (Sobel p value < 0.001)., Conclusions: FSH is associated with higher odds of having low bone mass/osteoporosis even after accounting for HT use. FSH is a mediator of the relationship between estradiol and BMD in healthy postmenopausal women. Larger, prospective studies of FSH concentrations and bone health are needed., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Background & Aims: Incidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts., Methods: Concentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography-mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men., Results: Higher concentrations of total testosterone (OR per one-unit increase in log 2  = 1.77, 95% CI = 1.38-2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21-2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22-20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27-2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33-0.68)., Conclusions: Higher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk., Impact and Implications: This study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Objective: Older adults typically experience higher rates of severe disease and mortality than the general population after contracting an infectious disease. Vaccination is critical for preventing disease and severe downstream outcomes; however, vaccination rates among older adults are suboptimal. We assessed predictors associated with pneumococcal and seasonal influenza vaccination among older women., Methods: We used data from the Women's Health Initiative, a nationwide cohort of women. We ascertained seasonal influenza and pneumococcal vaccination status through a questionnaire administered in 2013. We limited analyses to women aged ≥65 years at questionnaire administration. We used logistic regression to estimate associations between demographic, lifestyle, and health-related factors and vaccination and explored stratification by race., Results: Of participants who responded to each question, 84.3% (n = 60 578) reported being vaccinated for influenza and 85.5% (n = 59 015) for pneumonia. The odds of reporting influenza vaccination were significantly lower among non-Hispanic Black participants than among non-Hispanic White participants (odds ratio [OR] = 0.53; 95% CI, 0.49-0.58), women with no health insurance versus private health insurance (OR = 0.61; 95% CI, 0.54-0.68), and women living in rural versus urban settings (OR = 0.84; 95% CI, 0.73-0.96). Current smoking, lower education levels, and having comorbid conditions were associated with lower likelihood of being vaccinated for influenza (than not); past pneumonia diagnosis and being currently married were associated with a higher likelihood. We observed similar associations for pneumococcal vaccination coverage., Conclusions: These findings reinforce the need to enact policy and implement programs to improve access to, education and awareness about, and provider recommendations for these critical disease-prevention tools. Results from our study should guide strategies for SARS-CoV-2 vaccination.

Background: Osteoporosis heavily affects postmenopausal women and is influenced by environmental exposures. Determining the impact of criteria air pollutants and their mixtures on bone mineral density (BMD) in postmenopausal women is an urgent priority., Methods: We conducted a prospective observational study using data from the ethnically diverse Women's Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, January 2020 to August 2022). We used log-normal, ordinary kriging to estimate daily mean concentrations of PM 10 , NO, NO 2 , and SO 2 at participants' geocoded addresses (1-, 3-, and 5-year averages before BMD assessments). We measured whole-body, total hip, femoral neck, and lumbar spine BMD at enrollment and follow-up (Y1, Y3, Y6) via dual-energy X-ray absorptiometry. We estimated associations using multivariable linear and linear mixed-effects models and mixture effects using Bayesian kernel machine regression (BKMR) models., Findings: In cross-sectional and longitudinal analyses, mean PM 10 , NO, NO 2 , and SO 2 averaged over 1, 3, and 5 years before the visit were negatively associated with whole-body, total hip, femoral neck, and lumbar spine BMD. For example, lumbar spine BMD decreased 0.026 (95% CI: 0.016, 0.036) g/cm 2 /year per a 10% increase in 3-year mean NO 2 concentration. BKMR suggested that nitrogen oxides exposure was inversely associated with whole-body and lumbar spine BMD., Interpretation: In this cohort study, higher levels of air pollutants were associated with bone damage, particularly on lumbar spine, among postmenopausal women. These findings highlight nitrogen oxides exposure as a leading contributor to bone loss in postmenopausal women, expanding previous findings of air pollution-related bone damage., Funding: US National Institutes of Health., Competing Interests: Most authors declare that they have no competing interest in any form. JWW declares funding from NHLBI/NIH to support the Women's Health Initiative (JWW is the PI of the northeast WHI regional center), which has occurred since 1993 and will go through 2027. WHI funding for JWW supports support travel to the annual WHI meeting. JWW is dean of the School of Public Health and Health Professions at the University at Buffalo and serves as a board member of several western New York community organizations (unpaid). GM receives royalties for his books (The exposome: a primer [2014]; The exposome: a new paradigm for health and disease [2020], published by Academic Press). GM also receives stipend for serving as Editor of Exposome, published by Oxford University Press. GM also has received honoraria from Kansas University Medical Center (speaker), Mayo Clinic (speaker), Foundation for Gender Specific Medicine (book chapter), AAAS (speaker), Vichy (speaker), University of Colorado (speaker), and the University of Arizona (speaker). When GM speaks at universities in the U.S. the travel is paid by them., (© 2023 The Author(s).)

Proton pump inhibitors (PPIs) have off-target activity on fatty acid synthase (FASN), a critical enzyme in energy balance and cancer growth. We evaluated risk of common obesity-related cancers: breast, colorectal (CRC), and endometrial, with use of PPI and histamine-2 receptor antagonists (H2RA) in 124,931 postmenopausal women enrolled in the Women's Health Initiative. Incident cancer cases were physician-adjudicated. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for cancer incidence after year 3. There were 7956 PPI ever users and 9398 H2RA only users. Ever use of either PPI or H2RA was not associated with risk of breast cancer ( n  = 9186) nor risk of endometrial cancer ( n  = 1231). The risk of CRC ( n  = 2280) was significantly lower in PPI users (HR = 0.75, 95% CI = 0.61-0.92), but not in H2RA users (HR = 1.13, 95% CI = 0.97-1.31). The association of PPI use with CRC was apparent regardless of BMI or NSAID use, and was stronger with longer PPI duration ( p  = 0.006) and potency ( p  = 0.005). The findings that PPI use, but not H2RA use, demonstrate an inverse dose-response relationship with risk of CRC is consistent with preclinical data showing FASN inhibition prevents colon cancer progression and supports a role of PPI in CRC prevention.