Associations of steps per day and step intensity with the risk of cancer: Findings from the Women's Health Accelerometry Collaboration cohort.

OBJECTIVE: Accumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers. METHODS: This study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011-2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer. RESULTS: On average, women were 73.4 years old, accumulated 4993 steps/day, and had 7.9 years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR = 0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR = 0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR = 0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at ≥40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day. CONCLUSIONS: Among women 62-97 years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.

How Generalizable Are Findings from a Community-Based Prospective Cohort Study? Extending Estimates from the Adult Changes in Thought Study to Its Source Population.

Background: The Adult Changes in Thought (ACT) study is a cohort of Kaiser Permanente Washington members ages 65+ that began in 1994. Objective: We wanted to know how well ACT participants represented all older adults in the region, and how well ACT findings on eye disease and its relationship with Alzheimer's disease generalized to all older adults in the Seattle Metropolitan Region. Methods: We used participation weights derived from pooling ACT and Behavioral Risk Factor Surveillance System (BRFSS) data to estimate prevalences of common eye diseases and their associations with Alzheimer's disease incidence. Cox proportional hazards models accounted for age, education, smoking, sex, and APOE genotype. Confidence intervals for weighted analyses were bootstrapped to account for error in estimating the weights. Results: ACT participants were fairly similar to older adults in the region. The largest differences were more self-reported current cholesterol medication use in BRFSS and higher proportions with low education in ACT. Incorporating the weights had little impact on prevalence estimates for age-related macular degeneration or glaucoma. Weighted estimates were slightly higher for diabetic retinopathy (weighted 5.7% (95% Confidence Interval 4.3, 7.1); unweighted 4.1% (3.6, 4.6)) and cataract history (weighted 51.8% (49.6, 54.3); unweighted 48.6% (47.3, 49.9)). The weighted hazard ratio for recent diabetic retinopathy diagnosis and Alzheimer's disease was 1.84 (0.34, 4.29), versus 1.32 (0.87, 2.00) in unweighted ACT. Conclusions: Most, but not all, associations were similar after participation weighting. Even in community-based cohorts, extending inferences to broader populations may benefit from evaluation with participation weights.

The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

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.

Systolic Blood Pressure and Survival to Very Old Age: Results From the Women's Health Initiative.

BACKGROUND: The relationship between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine which SBP levels in women ≥65 years of age with or without blood pressure medication were associated with the highest probability of surviving to 90 years of age. METHODS: The study population consisted of 16 570 participants enrolled in the Women's Health Initiative who were eligible to survive to 90 years of age by February 28, 2020, without a history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993 through 1998) and then annually through 2005. The outcome was defined as survival to 90 years of age with follow-up. Absolute probabilities of surviving to 90 years of age were estimated for all combinations of SBP and age using generalized additive logistic regression modeling. The SBP that maximized survival was estimated for each age, and a 95% CI was generated. RESULTS: During a median follow-up of 19.8 years, 9723 of 16 570 women (59%) survived to 90 years of age. Women with an SBP between 110 and 130 mm Hg at attained ages of 65, 70, 75, and 80 years had a 38% (95% CI, 34%-48%), 54% (52%-56%), 66% (64%-67%), or 75% (73%-78%) absolute probability to survive to 90 years of age, respectively. The probability of surviving to 90 years of age was lower for greater SBP levels. Women at the attained age of 80 years with 0%, 20%, 40%, 60%, 80%, or 100% time in therapeutic range (defined as an SBP between 110 and 130 mm Hg) had a 66% (64%-69%), 68% (67%-70%), 71% (69%-72%), 73% (71%-74%), 75% (72%-77%), or 77% (74%-79%) absolute survival probability to 90 years of age. CONCLUSIONS: For women >65 years of age with low cardiovascular disease and other chronic disease risk, an SBP level <130 mm Hg was found to be associated with longevity. These findings reinforce current guidelines targeting an SBP target <130 mm Hg in older women.

Correlates of physical activity and sedentary behavior among cancer survivors and cancer-free women: The Women's Health Accelerometry Collaboration.

BACKGROUND: Describing correlates of physical activity (PA) and sedentary behavior (SB) among postmenopausal cancer survivors can help identify risk profiles and can be used to support development of targeted interventions to improve PA and reduce SB in this population. OBJECTIVE: To describe PA/SB and identify correlates of PA/SB among cancer and cancer-free post-menopausal women. METHODS: Women from the Women's Health Study (N = 16,629) and Women's Health Initiative/Objective Physical Activity and Cardiovascular Health Study (N = 6,079) were asked to wear an accelerometer on the hip for 7 days. Multiple mixed-effects linear regression models were used to identify sociodemographic-, health-, and chronic condition-related correlates (independent variables) associated with PA and SB (dependent variables) among women with (n = 2,554) and without (n = 20,154) a history of cancer. All correlates were mutually adjusted for each other. RESULTS: In unadjusted analyses, women with a history of cancer took fewer mean daily steps (4,572 (standard deviation 2557) vs 5,029 (2679) steps/day) and had lower mean moderate-to-vigorous PA (74.9 (45.0) vs. 81.6 (46.7) minutes/day) than cancer-free women. In adjusted analyses, for cancer and cancer-free women, age, diabetes, overweight, and obesity were inversely associated with all metrics of PA (average vector magnitude, time in moderate-to-vigorous PA, step volume, time at ≥40 steps/minutes, and peak 30-minute step cadence). In unadjusted analyses, mean SB was similar for those with and without cancer (529.7 (98.1) vs. 521.7 (101.2) minutes/day). In adjusted analyses, for cancer and cancer-free women, age, diabetes, cardiovascular disease, current smoking, overweight, and obesity were positive correlates of SB, while Black or Hispanic race/ethnicity, weekly/daily alcohol intake, and excellent/very good/good self-rated health were inverse correlates of SB. CONCLUSION: Several sociodemographic, health, and chronic conditions were correlates of PA/SB for postmenopausal women with and without cancer. Future studies should examine longitudinal relationships to gain insight into potential determinants of PA/SB.

Validating a model for predicting breast cancer and nonbreast cancer death in women aged 55 years and older.

BACKGROUND: To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models. METHODS: We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics. RESULTS: When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC. CONCLUSIONS: Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model.

Feasibility of a Health Coach Intervention to Reduce Sitting Time and Improve Physical Functioning Among Breast Cancer Survivors: Pilot Intervention Study.

BACKGROUND: Sedentary behavior among breast cancer survivors is associated with increased risk of poor physical function and worse quality of life. While moderate to vigorous physical activity can improve outcomes for cancer survivors, many are unable to engage in that intensity of physical activity. Decreasing sitting time may be a more feasible behavioral target to potentially mitigate the impact of cancer and its treatments. OBJECTIVE: The purpose of this study was to investigate the feasibility and preliminary impact of an intervention to reduce sitting time on changes to physical function and quality of life in breast cancer survivors, from baseline to a 3-month follow-up. METHODS: Female breast cancer survivors with self-reported difficulties with physical function received one-on-one, in-person personalized health coaching sessions aimed at reducing sitting time. At baseline and follow-up, participants wore the activPAL (thigh-worn accelerometer; PAL Technologies) for 3 months and completed physical function tests (4-Meter Walk Test, Timed Up and Go, and 30-Second Chair Stand) and Patient-Reported Outcomes Measurement Information System (PROMIS) self-reported outcomes. Changes in physical function and sedentary behavior outcomes were assessed by linear mixed models. RESULTS: On average, participants (n=20) were aged 64.5 (SD 9.4) years; had a BMI of 30.4 (SD 4.5) kg/m2; and identified as Black or African American (n=3, 15%), Hispanic or Latina (n=4, 20%), and non-Hispanic White (n=14, 55%). Average time since diagnosis was 5.8 (SD 2.2) years with participants receiving chemotherapy (n=8, 40%), radiotherapy (n=18, 90%), or endocrine therapy (n=17, 85%). The intervention led to significant reductions in sitting time: activPAL average daily sitting time decreased from 645.7 (SD 72.4) to 532.7 (SD 142.1; ß=-112.9; P=.001) minutes and average daily long sitting bouts (bout length ≥20 min) decreased from 468.3 (SD 94.9) to 366.9 (SD 150.4; ß=-101.4; P=.002) minutes. All physical function tests had significant improvements: on average, 4-Meter Walk Test performance decreased from 4.23 (SD 0.95) to 3.61 (SD 2.53; ß=-.63; P=.002) seconds, Timed Up and Go performance decreased from 10.30 (SD 3.32) to 8.84 (SD 1.58; ß=-1.46; P=.003) seconds, and 30-Second Chair Stand performance increased from 9.75 (SD 2.81) to 13.20 completions (SD 2.53; ß=3.45; P<.001). PROMIS self-reported physical function score improved from 44.59 (SD 4.40) to 47.12 (SD 5.68; ß=2.53; P=.05) and average fatigue decreased from 52.51 (SD 10.38) to 47.73 (SD 8.43; ß=-4.78; P=.02). CONCLUSIONS: This 3-month pilot study suggests that decreasing time spent sitting may be helpful for breast cancer survivors experiencing difficulties with physical function and fatigue. Reducing sitting time is a novel and potentially more feasible approach to improving health and quality of life in cancer survivors.

Early Ascertainment of Breast Cancer Diagnoses Comparing Self-Reported Questionnaires and Electronic Health Record Data Warehouse: The WISDOM Study.

PURPOSE: The goal of this study was to use real-world data sources that may be faster and more complete than self-reported data alone, and timelier than cancer registries, to ascertain breast cancer cases in the ongoing screening trial, the WISDOM Study. METHODS: We developed a data warehouse procedural process (DWPP) to identify breast cancer cases from a subgroup of WISDOM participants (n = 11,314) who received breast-related care from a University of California Health Center in the period 2012-2021 by searching electronic health records (EHRs) in the University of California Data Warehouse (UCDW). Incident breast cancer diagnoses identified by the DWPP were compared with those identified by self-report via annual follow-up online questionnaires. RESULTS: Our study identified 172 participants with confirmed breast cancer diagnoses in the period 2016-2021 by the following sources: 129 (75%) by both self-report and DWPP, 23 (13%) by DWPP alone, and 20 (12%) by self-report only. Among those with International Classification of Diseases 10th revision cancer diagnostic codes, no diagnosis was confirmed in 18% of participants. CONCLUSION: For diagnoses that occurred ≥20 months before the January 1, 2022, UCDW data pull, WISDOM self-reported data via annual questionnaire achieved high accuracy (96%), as confirmed by the cancer registry. More rapid cancer ascertainment can be achieved by combining self-reported data with EHR data from a health system data warehouse registry, particularly to address self-reported questionnaire issues such as timing delays (ie, time lag between participant diagnoses and the submission of their self-reported questionnaire typically ranges from a month to a year) and lack of response. Although cancer registry reporting often is not as timely, it does not require verification as does the DWPP or self-report from annual questionnaires.

Systolic Blood Pressure and Survival to Very Old Age. Results from the Women's Health Initiative.

Background: The association between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine survival probabilities to age 90 for various SBP levels among women aged ≥ 65 years with or without BP medication. Methods: We analyzed blood pressure data from participants in the Women's Health Initiative (n=16,570) who were aged 65 or older and without history of cardiovascular disease, diabetes or cancer. Blood pressure was measured at baseline (1993-1998) and then annually through 2005. The outcome was defined as survival to age 90 with follow-up until February 28, 2020. Results: During a follow-up of 18 years, 9,723 (59%) of 16,570 women survived to age 90. The SBP associated with the highest probability of survival was about 120mmHg regardless of age. Compared to an SBP between 110 and 130 mmHg, women with uncontrolled SBP had a lower survival probability across all age groups and with or without BP medication. A 65-year-old women on BP medication with an interpolated SBP between 110 and 130 mmHg in 80% of the first 5 years of follow-up had a 31% (95% confidence interval, 24%, 38%) absolute survival probability. For those with 20% time in range, the probability was 21% (95% confidence interval, 16%, 26%). Conclusions: An SBP level below 130 mmHg was found to be associated with longevity among older women. The longer SBP was controlled at a level between 110 and 130 mmHg, the higher the survival probability to age 90. Preventing age-related rises in SBP and increasing the time with controlled BP levels constitute important measures for achieving longevity.

Accelerometer-measured physical activity and postmenopausal breast cancer incidence in the Women's Health Accelerometry Collaboration.

BACKGROUND: Few studies have examined accelerometer-measured physical activity and incident breast cancer (BC). Thus, this study examined associations between accelerometer-measured vector magnitude counts per 15 seconds (VM/15s) and average daily minutes of light physical activity (LPA), moderate-to-vigorous PA (MVPA), and total PA (TPA) and BC risk among women in the Women's Health Accelerometry Collaboration (WHAC). METHODS: The WHAC comprised 21,089 postmenopausal women (15,375 from the Women's Health Study [WHS]; 5714 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study [OPACH]). Women wore an ActiGraph GT3X+ on the hip for ≥4 days and were followed for 7.4 average years to identify physician-adjudicated in situ (n = 94) or invasive (n = 546) BCs. Multivariable stratified Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for tertiles of physical activity measures in association with incident BC overall and by cohort. Effect measure modification was examined by age, race/ethnicity, and body mass index (BMI). RESULTS: In covariate-adjusted models, the highest (vs. lowest) tertiles of VM/15s, TPA, LPA, and MVPA were associated with BC HRs of 0.80 (95% CI, 0.64-0.99), 0.84 (95% CI, 0.69-1.02), 0.89 (95% CI, 0.73-1.08), and 0.81 (95% CI, 0.64-1.01), respectively. Further adjustment for BMI or physical function attenuated these associations. Associations were more pronounced among OPACH than WHS women for VM/15s, MVPA, and TPA; younger than older women for MVPA; and women with BMI ≥30 than <30 kg/m2 for LPA. CONCLUSION: Greater levels of accelerometer-assessed PA were associated with lower BC risk. Associations varied by age and obesity and were not independent of BMI or physical function.

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

Importance: Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls. Objective: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls. Design, Setting, and Participants: This prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Women's Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n = 45 358) on age/year of enrollment and study arm. Exposures: Cancer diagnosis (site, stage, and treatment) via Medicare and medical records. Main Outcomes and Measures: Trajectories of self-reported physical function (RAND Short Form 36 [RAND-36] scale; range: 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis. Results: This study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls; after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, -5.3 [95% CI, -6.4 to -4.3] points per year in regional vs -2.8 [95% CI, -3.4 to -2.3] for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, -7.9 [95% CI, -12.2 to -3.6] points per year with any chemotherapy; -3.1 [95% CI, -6.0 to -0.3] with radiation therapy alone; and -2.6 [95% CI, -4.2 to -1.0] with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined -4.3 [95% CI, -5.9 to -2.6] points per year in the year following diagnosis vs -1.4 [95% CI, -1.7 to -1.0] points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis. Conclusions and Relevance: In this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

A RIEMANN MANIFOLD MODEL FRAMEWORK FOR LONGITUDINAL CHANGES IN PHYSICAL ACTIVITY PATTERNS.

Physical activity (PA) is significantly associated with many health outcomes. The wide usage of wearable accelerometer-based activity trackers in recent years has provided a unique opportunity for in-depth research on PA and its relations with health outcomes and interventions. Past analysis of activity tracker data relies heavily on aggregating minute-level PA records into day-level summary statistics in which important information of PA temporal/diurnal patterns is lost. In this paper we propose a novel functional data analysis approach based on Riemann manifolds for modeling PA and its longitudinal changes. We model smoothed minute-level PA of a day as one-dimensional Riemann manifolds and longitudinal changes in PA in different visits as deformations between manifolds. The variability in changes of PA among a cohort of subjects is characterized via variability in the deformation. Functional principal component analysis is further adopted to model the deformations, and PC scores are used as a proxy in modeling the relation between changes in PA and health outcomes and/or interventions. We conduct comprehensive analyses on data from two clinical trials: Reach for Health (RfH) and Metabolism, Exercise and Nutrition at UCSD (MENU), focusing on the effect of interventions on longitudinal changes in PA patterns and how different modes of changes in PA influence weight loss, respectively. The proposed approach reveals unique modes of changes, including overall enhanced PA, boosted morning PA, and shifts of active hours specific to each study cohort. The results bring new insights into the study of longitudinal changes in PA and health and have the potential to facilitate designing of effective health interventions and guidelines.

Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal: Secondary Analysis of a Randomized Clinical Trial.

Importance: Half of women who are postmenopausal have genitourinary discomfort after menopause. Recommended therapies include low-dose vaginal estrogen. Individuals with a history of breast cancer or venous thromboembolism may have concerns about the safety of this intervention. Objective: To compare serum estrogen concentrations with the use of vaginal estrogen, 10 µg, tablet vs placebo in women who are postmenopausal. Design, Setting, and Participants: This is a secondary, post hoc analysis of data from a randomized clinical trial of treatment for moderate to severe genitourinary syndrome in women who are postmenopausal. The study was conducted at Kaiser Permanente Washington Health Research Institute and the University of Minnesota from April 11, 2016, to April 23, 2017. Measurements and data analysis were performed from November 3, 2020, to September 23, 2022. Interventions: Participants were randomly assigned to vaginal estradiol tablet (10 µg/d for 2 weeks and then twice weekly) plus placebo gel (3 times weekly) or dual placebo for 12 weeks. Main Outcomes and Measures: In this post hoc analysis, baseline and week 12 serum estradiol, estrone, and sex hormone-binding globulin (SHBG) concentrations were measured by a chemiluminescent assay. Week 12 values of the 3 analytes were compared by baseline participant characteristics. Linear models compared week 12 estradiol concentrations between treatment groups, adjusted for baseline characteristics. Results: A total of 174 women, mean (SD) age 61 (4) years, were included. Those in the estrogen group (n = 88) were more likely to have higher geometric mean (SD) week 12 serum estradiol concentrations (4.3 [2.2 pg/mL]) than those in the placebo group (n = 86) (3.5 [2.1] pg/mL) (P = .01). Adjusted for pretreatment hormone concentrations, age, clinical site, and body mass index, assignment to the estrogen vs placebo treatment group was significantly associated with higher week 12 estradiol concentrations (23.8% difference; 95% CI, 6.9%-43.3%). Most (121 of 174 [69.5%]) participants had enrollment serum estradiol concentrations higher than 2.7 pg/mL. Of women starting treatment at estradiol levels lower than or equal to 2.7 pg/mL, 38.1% (8 of 21) in the estrogen group and 34.4% (11 of 32) in the placebo group had estradiol concentrations higher than 2.7 pg/mL after 12 weeks of study participation (P = .78). Treatment assignment was not associated with week 12 estrone or SHBG concentrations. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a significant, although small, increase in serum estradiol levels was noted after 12 weeks of vaginal estrogen administration. The clinical relevance of this small increase is uncertain. Trial Registration: ClinicalTrials.gov Identifier: NCT02516202.

Changes in serum endogenous estrogen concentrations are mediators of the effect of low-dose oral estradiol on vasomotor symptoms.

OBJECTIVES: The aim of this study was to quantify changes in serum total estradiol (E2) and estrone (E1) concentrations with initiation of low-dose oral estradiol treatment and evaluate whether changes in concentrations mediate the effect of treatment in reducing vasomotor symptom (VMS) frequency. METHODS: We analyzed baseline and week 8 (W8) data from 171 perimenopausal and postmenopausal women with VMS enrolled in low-dose 17ß estradiol ( n = 72) and placebo ( n = 99) groups of a randomized clinical trial. RESULTS: From baseline to W8, women in the low-dose estradiol group had a fourfold increase in E2, resulting in a W8 E2 of 23 pg/mL, and a fivefold increase in E1, resulting in a W8 E1 of 110.7 pg/mL. In contrast, E2 and E1 among women in the placebo group were unchanged from baseline to W8. Changes in E2 and E1 from baseline to W8 met criteria for mediating the effect of low-dose estradiol treatment on VMS frequency. With change in estrogen concentration added to treatment assignment in a regression model predicting W8 VMS frequency, the effect of treatment with low-dose estradiol versus placebo was attenuated, with change in E2 representing a 44.1% reduction ( P = 0.03) and change in E1 representing a 69.5% reduction ( P = 0.02) in total intervention effect. CONCLUSION: Among perimenopausal and postmenopausal women with VMS, treatment with low-dose oral estradiol versus placebo results in four- to fivefold increases in serum E2 and E1. The increases in serum E2 and E1 with low-dose oral estradiol treatment seem to mediate in part the effect of treatment in reducing VMS frequency.

Markers of kidney function, genetic variation related to cognitive function, and cognitive performance in the UK Biobank.

BACKGROUND: Chronic kidney disease has been linked to worse cognition. However, this association may be dependent on the marker of kidney function used, and studies assessing modification by genetics are lacking. This study examined associations between multiple measures of kidney function and assessed effect modification by a polygenic score for general cognitive function. METHODS: In this cross-sectional study of up to 341,208 European ancestry participants from the UK Biobank study, we examined associations between albuminuria and estimated glomerular filtration rate based on creatinine (eGFRcre) or cystatin C (eGFRcys) with cognitive performance on tests of verbal-numeric reasoning, reaction time and visual memory. Adjustment for confounding factors was performed using multivariate regression and propensity-score matching. Interaction between kidney function markers and a polygenic risk score for general cognitive function was also assessed. RESULTS: Albuminuria was associated with worse performance on tasks of verbal-numeric reasoning (ß(points) = -0.09, p < 0.001), reaction time (ß(milliseconds) = 7.06, p < 0.001) and visual memory (ß(log errors) = 0.013, p = 0.01). A polygenic score for cognitive function modified the association between albuminuria and verbal-numeric reasoning with significantly lower scores in those with albuminuria and a lower polygenic score (p = 0.009). Compared to participants with eGFRcre ≥ 60 ml/min, those with eGFRcre < 60 ml/min had lower verbal-numeric reasoning scores and slower mean reaction times (verbal numeric reasoning ß = -0.11, p < 0.001 and reaction time ß = 6.08, p < 0.001 for eGFRcre < 60 vs eGFRcre ≥ 60). Associations were stronger using cystatin C-based eGFR than creatinine-based eGFR (verbal numeric reasoning ß = -0.21, p < 0.001 and reaction time ß = 11.21, p < 0.001 for eGFRcys < 60 vs eGFRcys ≥ 60). CONCLUSIONS: Increased urine albumin is associated with worse cognition, but this may depend on genetic risk. Cystatin C-based eGFR may better predict cognitive performance than creatinine-based estimates.

Are serum estrogen concentrations associated with menopausal symptom bother among postmenopausal women? Baseline results from two MsFLASH clinical trials.

OBJECTIVES: To evaluate whether single measurements of serum estradiol (E2), estrone (E1) and sex hormone-binding globulin (SHBG) concentration distinguishes between women with and without menopausal symptom bother. STUDY DESIGN: We analyzed baseline data from two clinical trials conducted in 2012-2017: MsFLASH 03 (178 peri-/post-menopausal women aged 40-62 years with bothersome vasomotor symptoms, mean age 54) and MsFLASH 05 (181 post-menopausal women aged 45-70 years with moderate-to-severe vulvovaginal symptoms, mean age 61). MAIN OUTCOME MEASURES: Symptom bother (hot flushes or flashes, night sweats, sweating, aching in muscles and joints, change in sexual desire, vaginal dryness during intercourse, and avoiding intimacy) in the past month was assessed using the Menopause-Specific Quality of Life questionnaire. Using logistic regression, we calculated the area under the receiver operating characteristic curve (AUC) values for E1, E2, and SHBG concentration in relation to being at least somewhat bothered (symptom bother score ≥3) by each symptom within each trial study population. RESULTS: AUC values (95% confidence interval) ranged between 0.51 (0.41-0.60) and 0.62 (0.53, 0.72) for MsFLASH 03 and between 0.51 (0.42, 0.59) and 0.64 (0.53, 0.75) for MsFLASH 05. There was little evidence of associations between serum hormone levels and bother by a given menopausal symptom. CONCLUSION: These findings do not support the clinical utility of a single measurement of serum of E1, E2, or SHBG concentrations in differentiating between women who are bothered by a given menopausal symptom and those who are not.

Sedentary Behavior and Atrial Fibrillation in Older Women: The OPACH Study.

Background Sedentary behavior is associated with cardiovascular disease, but its association with incident atrial fibrillation is not well studied. Our aim was to measure the association between objectively measured sedentary behavior and incident atrial fibrillation. Methods and Results Sedentary behavior was measured by a triaxial accelerometer worn on a belt for 1 week. Incident atrial fibrillation was ascertained from Medicare claims. The associations between total sedentary time (or patterns of sedentary behavior) and incident atrial fibrillation were assessed using Cox proportional hazards models adjusted for demographic and clinical covariates. Among 2675 participants (mean age, 78.2 years), there were 268 (10.0%) cases of incident atrial fibrillation at a rate of 31 cases per 1000 person-years. Greater total sedentary time was associated with a higher risk of incident atrial fibrillation after adjustment for age, race and ethnicity, body mass index, education, smoking history, hypertension, diabetes, stroke, heart disease, and other chronic conditions (quartile 4 versus quartile 1: hazard ratio, 1.20, [95% CI, 0.81-1.78]; P for trend=0.05). After adjusting for physical function and self-rated health, this was no longer statistically significant. Both longer mean sedentary bout duration and more continuous sedentary periods (versus frequent breaks in sedentary time) were also associated with higher risks of incident atrial fibrillation, but these associations were also attenuated with serial adjustment. Conclusions Total sedentary time and prolonged patterns of sedentary accumulation were associated with a higher risk of atrial fibrillation in this prospective study of community-dwelling older women, but these associations were attenuated by adjustment for physical function and self-reported health. This suggests that associations between sedentary behavior and atrial fibrillation may be attributable to global measures of overall function and health.

Accelerometer-Derived Daily Life Movement Classified by Machine Learning and Incidence of Cardiovascular Disease in Older Women: The OPACH Study.

Background Current physical activity guidelines focus on volume and intensity for CVD prevention rather than common behaviors responsible for movement, including those for daily living activities. We examined the associations of a machine-learned, accelerometer-measured behavior termed daily life movement (DLM) with incident CVD. Methods and Results Older women (n=5416; mean age, 79±7 years; 33% Black, 17% Hispanic) in the Women's Health Initiative OPACH (Objective Physical Activity and Cardiovascular Health) study without prior CVD wore ActiGraph GT3X+ accelerometers for up to 7 days from May 2012 to April 2014 and were followed for physician-adjudicated incident CVD through February 28th, 2020 (n=616 events). DLM was defined as standing and moving in a confined space such as performing housework or gardening. Cox models estimated hazard ratios (HR) and 95% CI, adjusting for age, race and ethnicity, education, alcohol use, smoking, multimorbidity, self-rated health, and physical function. Restricted cubic splines examined the linearity of the DLM-CVD dose-response association. We examined effect modification by age, body mass index, Reynolds Risk Score, and race and ethnicity. Adjusted HR (95% CIs) across DLM quartiles were: 1.00 (reference), 0.68 (0.55-0.84), 0.70 (0.56-0.87), and 0.57 (0.45-0.74); p-trend<0.001. The HR (95% CI) for each 1-hour increment in DLM was 0.86 (0.80-0.92) with evidence of a linear dose-response association (p non-linear>0.09). There was no evidence of effect modification by age, body mass index, Reynolds Risk Score, or race and ethnicity. Conclusions Higher DLM was independently associated with a lower risk of CVD in older women. Describing the beneficial associations of physical activity in terms of common behaviors could help older adults accumulate physical activity.

Toward a better measure of midlife sexual function: pooled analyses in nearly 1,000 women participating in MsFLASH randomized trials.

OBJECTIVE: Evaluate appropriateness of the current Female Sexual Function Index (FSFI)-19 value of <26.6 to designate female sexual dysfunction (FSD) in postmenopausal women, using the Female Sexual Distress-Revised (FSDS-R) scale to measure distress. METHODS: Participant-level data containing standardized measures from five completed Menopause Strategies: Finding Lasting Answers for Symptoms and Health trials was pooled. Baseline characteristics and FSFI-19 scores were compared across trials (F-test, homogeneity). FSFI-19 score associations with the FSDS-R were described. Receiver operating characteristic (ROC) curves were plotted to illustrate the choice of optimal FSFI-19 value to predict sexual distress. ROC curves were also estimated adjusting for trial number, clinical center, age, education, race, smoking, and BMI. RESULTS: Nine hundred ninety eight women (79.2% postmenopausal), mean age 55.9 (SD 4.8) had complete FSFI-19, FSDS-R, and covariate data. Baseline mean FSFI-19 score among all participants and sexually active participants was 18.7 (SD 9.5) and 22.0 (SD 7.2), respectively. There was a consistent pattern across the trials of inverse association between poorer sexual function (FSFI-19) and greater sexual distress. Based on the ROC curve showing the likelihood of FSDS-R frequent or greater distress according to cut points of FSFI, the optimal cut point for FSD was FSFI-19 <21 for all participants. This cut point corresponded to sensitivity 87.2% (95% CI, 83.4-91.0), specificity 57.9% (95% CI, 54.3-61.6) and adjusted area under the ROC curve 78.8% (95% CI, 75.8-81.8). CONCLUSIONS: A new FSFI-19 cut point of ≥21 should be considered to describe normal sexual function in periand postmenopausal women as opposed to the standard cut point of >26.6. VIDEO SUMMARY: http://links.lww.com/MENO/A915.