The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women's Health Initiative clinical trials.

OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

The severity of vasomotor symptoms and number of menopausal symptoms in postmenopausal women and select clinical health outcomes in the Women's Health Initiative Calcium and Vitamin D randomized clinical trial.

OBJECTIVE: This study evaluated whether vasomotor symptom (VMS) severity and number of moderate/severe menopausal symptoms (nMS) were associated with health outcomes, and whether calcium and vitamin D (CaD) modified the risks. METHODS: The Women's Health Initiative CaD study was a double blind, randomized, placebo-controlled trial, which tested 400 IU of 25-hydroxyvitamin-D and 1,000 mg of calcium per day in women aged 50 to 79 years. This study included 20,050 women (median follow-up of 7 y). The outcomes included hip fracture, colorectal cancer, invasive breast cancer, all-cause mortality, coronary heart disease, stroke, cardiovascular death, and total cardiovascular disease (CVD). MS included: hot flashes, night sweats, dizziness, heart racing, tremors, feeling restless, feeling tired, difficulty concentrating, forgetfulness, mood swings, vaginal dryness, breast tenderness, migraine, and waking up several times at night. Associations between VMS severity and nMS with outcomes were tested. RESULTS: No association between VMS severity and any outcome were found. In contrast, nMS was associated with higher stroke (hazard ratio [HR] 1.40 95% confidence interval [CI] 1.04-1.89 for ≥ 2 MS vs none; HR 1.20 95% CI 0.89-1.63 for 1 MS vs none, P trend = 0.03) and total CVD (HR 1.35, 95% CI, 1.18-1.54 for ≥ 2 MS vs none; HR 0.99, 95% CI, 0.87-1.14 for 1 MS vs none P trend < 0.001). CaD did not modify any association. CONCLUSION: Severity of VMS was not associated with any outcome. Having ≥2 moderate or severe MS was associated with an increased risk for CVD. The number of moderate/severe MS may be a marker for higher CVD risk. : Video Summary:http://links.lww.com/MENO/A669.

Video Summary:http://links.lww.com/MENO/A669.

Higher albumin:creatinine ratio and lower estimated glomerular filtration rate are potential risk factors for decline of physical performance in the elderly: the Cardiovascular Health Study.

INTRODUCTION: Mildly reduced renal function and elevated urine protein levels are each prospectively associated with hip fracture risk in older adults. Here we determine whether these markers are associated with reduced appendicular muscle performance. METHODS: We prospectively examined the associations of urine albumin:creatinine ratio (ACR) and reduced estimated glomerular filtration rate (eGFR) with longitudinal changes in grip strength and gait speed >2 years in 2317 older community-dwelling men and women (median age 77 years). The median ACR was 9.8 [interquartile range (IQR) 5.40-21.50] mg/g creatinine and the median eGFR was 71.6 (IQR 59.1-83.56) mL/min/1.73 m2. Models were adjusted for demographic factors, clinical history and biochemical measures in four candidate pathways: diabetes, oxidative stress, inflammation and fibrosis. RESULTS: In demographic- and covariate-adjusted models, a 2-fold higher baseline urine ACR was associated with longitudinal changes of -0.17 kg [95% confidence interval (CI) -0.29 to -0.06) in grip strength and -1.10 cm/s (95% CI -1.67 to -0.53) gait speed per year. Corresponding estimates for a 10 mL/min/1.73 m2 lower baseline eGFR were -0.13 kg (95% CI -0.23 to -0.04) and -0.89 cm/s (95% CI -1.37 to -0.40), respectively. The associations of a 2-fold higher baseline ACR and a 10 mL/min/1.73 m2 lower baseline eGFR using cystatin C with grip strength and gait speed were equivalent to ∼1.2-1.9 additional years of age. Adjustment for covariates in candidate pathways did not attenuate these estimates. CONCLUSIONS: In older adults, higher ACR and lower eGFR are potential risk factors for a decline of physical performance >2 years.

Development of a comprehensive health-risk prediction tool for postmenopausal women.

OBJECTIVE: The aim of the study was to develop a web-based calculator that predicts the likelihood of experiencing multiple, competing outcomes prospectively over 5, 10, and 15 years. METHODS: Baseline demographic and medical data from a healthy and racially and ethnically diverse cohort of 161,808 postmenopausal women, aged 50 to 79 at study baseline, who participated in the Women's Health Initiative (WHI), were used to develop and evaluate a risk-prediction calculator designed to predict individual risk for morbidity and mortality outcomes. Women were enrolled from 40 sites arranged in four regions of the United States. The calculator predicts all-cause mortality, adjudicated outcomes of health events (ie, myocardial infarction [MI], stroke, and hip fracture), and disease (lung, breast, and colorectal cancer). A proportional subdistribution hazards regression model was used to develop the calculator in a training dataset using data from three regions. The calculator was evaluated using the C-statistic in a test dataset with data from the fourth region. RESULTS: The predictive validity of our calculator measured by the C-statistic in the test dataset for a first event at 5 and 15 years was as follows: MI 0.77, 0.61, stroke 0.77, 0.72, lung cancer 0.82, 0.79, breast cancer 0.60, 0.59, colorectal cancer 0.67, 0.60, hip fracture 0.79, 0.76, and death 0.74, 0.72. CONCLUSION: This study represents the first large-scale study to develop a risk prediction calculator that yields health risk prediction for several outcomes simultaneously. Development of this tool is a first step toward enabling women to prioritize interventions that may decrease these risks. : Video Summary:http://links.lww.com/MENO/A463.

Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease.

OBJECTIVE: Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation. METHODS: A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model. RESULTS: In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation. CONCLUSIONS: CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

Association of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study.

PURPOSE: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD). METHODS: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use. RESULTS: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10-2 g/cm2per 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10-2 g/cm2per 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10-2 g/cm2per 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women. CONCLUSIONS: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement.

Bone Turnover Markers Are Not Associated With Hip Fracture Risk: A Case-Control Study in the Women's Health Initiative.

Current guidelines recommend that serum C-terminal telopeptide of type I collagen (CTX) and serum procollagen type 1 aminoterminal propeptide (PINP), measured by standardized assays, be used as reference markers in observational and interventional studies. However, there are limited data to determine whether serum CTX and PINP are associated with hip fracture risk among postmenopausal women. We determined the associations of serum CTX and serum PINP with hip fracture risk among postmenopausal women aged 50 to 79 years at baseline. We performed a prospective case-control study (400 cases, 400 controls) nested in the Women's Health Initiative Observational Study, which enrolled participants at 40 US clinical centers. Cases were women with incident hip fracture not taking osteoporosis medication; hip fractures were confirmed using medical records. Untreated controls were matched by age, race/ethnicity, and date of blood sampling. Serum CTX and serum PINP were analyzed on 12-hour fasting blood samples. The main outcome measure was incident hip fracture risk (mean follow-up 7.13 years). After adjustment for body mass index, smoking, frequency of falls, history of fracture, calcium and vitamin D intake, and other relevant covariates, neither serum CTX level nor serum PINP level was statistically significantly associated with hip fracture risk (CTX ptrend = 0.22, PINP ptrend = 0.53). Our results do not support the utility of serum CTX level or PINP level to predict hip fracture risk in women in this age group. These results will inform future guidelines regarding the potential utility of these markers in fracture prediction. © 2018 American Society for Bone and Mineral Research.

Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study.

BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear. OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY. METHODS: We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 µm (PM10), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR. RESULTS: Increased PM10 was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 µg/m3), the middle (28.5-31.0 µg/m3; ß = -0.0044, p = 0.09) and highest (≥31 µg/m3; ß = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (ß = -0.00035, p = 0.06) and smoking pack-years (ß = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants. CONCLUSIONS: PM10 may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.

Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study.

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found. INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse. METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression. RESULTS: Mean (SD) age was 76.2 (4.8) years; 58% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0%; AAC 45.1 and 46.7%; MAC 42.8 and 39.5%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD = 1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant. CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

Physical Functioning Among Women Aged 80 Years and Older With Previous Fracture.

BACKGROUND: The oldest old are the fastest growing segment of the elderly population. Little is known regarding the associations of fracture history with physical functioning assessed after age 80. METHODS: Among 33,386 women surviving to age 80 years (mean ± SD years 84.6 ± 3.4), we examined the relationship between history of incident fracture after entry into the Women's Health Initiative (follow-up 15.2 ± 1.3 years) and their physical functioning assessed using the RAND-36 instrument most proximal to 2012 end of follow-up. RESULTS: Baseline mean (±SD) physical function score was 82 (± 18). After adjustment for demographic and medical characteristics, fracture at each site, including hip, upper limb, lower limb, and central body, was associated with significantly lower subsequent physical functioning (all p < .001). Hip, upper leg, spine, and pelvis fractures were particularly related with lower physical functioning scores, 11.7 (95% CI: 10.3, 13.1), 10.5 (8.8, 12.3), 9.8 (8.9, 10.8), and 8.7 (7.2, 10.2) units lower, respectively, compared with women without fracture (each p < .0001). Compared with women without central site fracture, women with central site fractures also had lower physical functioning scores (10.0 [9.3, 10.8] units lower]; p < .0001). In case-only analysis of fractures, older age, less than 1 year since fracture, one or more additional sites fractured, history of cardiovascular disease or cancer, higher body mass index, and no alcohol intake in the past 3 months also were independent predictors of lower physical functioning score (all p < .05). CONCLUSIONS: Among women surviving to 80 years and older, prior fracture is associated with lower current physical functioning, regardless of anatomical site of fracture, independent of other major predictors of disability.

Underuse and Overuse of Osteoporosis Screening in a Regional Health System: a Retrospective Cohort Study.

BACKGROUND: The United States Preventive Services Task Force (USPSTF) recommends screening for osteoporosis with dual-energy x-ray absorptiometry (DXA) for women aged ≥ 65 years and younger women with increased risk. "Choosing Wisely" initiatives advise avoiding DXA screening in women younger than 65 years without osteoporosis risk factors. OBJECTIVE: We aimed to determine the extent to which DXA screening is used in accordance with USPSTF recommendations within a regional health system. DESIGN: This was a retrospective longitudinal cohort study within 13 primary care clinics in the Sacramento, CA region. PATIENTS: The study included 50,995 women aged 40-85 years without prior osteoporosis screening, diagnosis, or treatment attending primary care visits from 2006 to 2012, observed for a mean of 4.4 years. MAIN MEASURES: We examined incidence of DXA screening. Covariates included age, race/ethnicity, and osteoporosis risk factors (body mass index < 20, glucocorticoid use, secondary osteoporosis, prior high-risk facture, rheumatoid arthritis, alcohol abuse, and current smoking). KEY RESULTS: Among previously unscreened women for whom the USPSTF recommends screening, 7-year cumulative incidence of DXA screening was 58.8 % among women aged 60-64 years with ≥ 1 risk factor (95 % CI: 51.9-65.8 %), 57.8 % for women aged 65-74 years (95 % CI: 55.6-60.0 %), and 42.7 % for women aged ≥ 75 years (95 % CI: 38.7-46.7 %). Among women for whom the USPSTF does not recommend screening, 7-year cumulative incidence was 45.5 % among women aged 50-59 years (95 % CI 44.1-46.9 %) and 58.6 % among women aged 60-64 years without risk factors (95 % CI 55.9-61.4 %). CONCLUSIONS: DXA screening was underused in women at increased fracture risk, including women aged ≥ 65 years. Meanwhile, DXA screening was common among women at low fracture risk, such as younger women without osteoporosis risk factors. Interventions may be needed to augment the value of population screening for osteoporosis.

Biomarkers of tobacco smoke exposure and asthma severity in adults.

BACKGROUND: Tobacco biomarkers including serum cotinine and urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) have been used in research settings. PURPOSE: The goal of the study was to examine the association of cotinine and NNAL with asthma outcomes in the U.S. adult population. METHODS: A cross-sectional design was used, using data from the National Health and Nutrition Examination Survey, 2007-2008, with participants aged >20 years with self-reported asthma (N=456). Past-year asthma exacerbations and emergency room/urgent care visits for asthma were examined. Analyses were conducted in 2013. RESULTS: Among adult asthmatics, 50.3% reported a past-year asthma attack (61.8% smokers, 46.6% nonsmokers, p=0.029). Among these, 24.7% reported a past-year emergency/urgent visit for asthma (34.7% smokers, 20.1% nonsmokers, p=0.034). Median concentrations of cotinine and creatinine-adjusted NNAL (NNAL/Cr) were significantly higher in those with a past-year asthma attack (0.43 ng/mL and 7.28 pg/mL) than in those without (0.06 ng/mL and 2.26 pg/mL), and highest in those with past-year emergency/urgent visits (0.93 ng/mL and 28.14 pg/mL). Among nonsmokers, increasing levels of log cotinine or log NNAL/Cr, adjusted for demographics, were significantly associated with past-year asthma exacerbation (log cotinine OR=1.46 [95% CI=1.1, 1.92]; log NNAL/Cr OR=1.42 [95% CI=1.07, 1.88]) and past-year emergency/urgent visit (log cotinine OR=1.95 [95% CI=1.32, 2.88]; log NNAL/Cr OR=1.58 [95% CI=1.23, 2.02]). Among smokers, increasing biomarker levels were not significantly associated with either outcome. CONCLUSIONS: In a population-based cross-sectional analysis, increased cotinine and NNAL were found to be associated with asthma exacerbation and healthcare use in nonsmokers with asthma. If these findings are confirmed in prospective studies, these biomarkers might be candidates for clinical indicators of risk of asthma.

Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: the Women's Health Initiative.

BACKGROUND: Clinical outcomes of the Women's Health Initiative (WHI) calcium plus vitamin D supplementation trial have been reported during 7.0 years of active intervention. We now report outcomes 4.9 years after the intervention stopped and cumulative findings. METHODS: Postmenopausal women (N=36,282) were randomized; postintervention follow-up continued among 29,862 (86%) of surviving participants. Primary outcomes were hip fracture and colorectal cancer. Breast cancer, all cancers, cardiovascular disease (CVD), and total mortality were predetermined major study outcomes. RESULTS: Hip fracture incidence was comparable in the supplement and the placebo groups, postintervention hazard ratio (HR)=0.95, 95% confidence interval (95% CI: 0.78, 1.15) and overall HR=0.91 (95% CI: 0.79, 1.05). Overall, colorectal cancer incidence did not differ between randomization groups, HR=0.95 (95% CI: 0.80, 1.13). Throughout, there also was no difference in invasive breast cancer, CVD, and all-cause mortality between groups. In subgroup analyses, the invasive breast cancer effect varied by baseline vitamin D intake (p=0.03 for interaction). Women with vitamin D intakes >600 IU/d, had an increased risk of invasive breast cancer, HR=1.28 (95% CI; 1.03, 1.60). Over the entire study period, in post hoc analyses, the incidence of vertebral fractures, HR=0.87 (95% CI: 0.76, 0.98) and in situ breast cancers, HR=0.82 (95% CI: 0.68, 0.99) were lower among women randomized to supplementation. CONCLUSION: After an average of 11 years, calcium and vitamin D supplementation did not decrease hip fracture or colorectal cancer incidence. Exploratory analyses found lower vertebral fracture and in situ breast cancer incidence in the supplement users. There was no effect on CVD or all-cause mortality.

Relationship between hysterectomy and admixture in African American women.

OBJECTIVE: Most studies suggest that hysterectomies are more common in African American women than in other ethnic groups. To assess this ethnic surgical disparity in a novel way, our main goal was to determine whether admixture (the proportion of sub-Saharan African or European origin in individuals) is associated with hysterectomy frequency in African American women in the Women's Health Initiative. STUDY DESIGN: In this retrospective study, we used ancestry informative single nucleotide polymorphisms to estimate admixture proportions in >10,000 African American women from the Women's Health Initiative. Logistic regression models were used to assess the association between admixture and self-reported history of hysterectomy with and without controls for relevant covariates. Multinomial logistic regression models were used to assess the association between admixture and self-reported age of hysterectomy. We also considered other potential risk factors (adiposity, hypertension, and education) for hysterectomy accounting for admixture. RESULTS: African admixture was a strong risk factor after the adjustment for multiple covariates (odds ratio, 1.85; P < .0001). The admixture risk for hysterectomy was highest for those procedures that were performed in the 35-39 age range (odds ratio, 3.08; P < .0001) and least evident in oldest ages (≥45 years old). Our analyses also suggest that adiposity, hypertension, and education were associated independently with hysterectomy in this population group. CONCLUSION: These results suggest that higher African admixture is associated with higher frequencies of hysterectomy and that genetic studies that specifically target African American women and diseases that are associated with hysterectomy may be especially useful in understanding the pathogenesis and underlying cause of this disparity in health outcome.

A soluble form of the CSF-1 receptor contributes to the inhibition of inflammation in a teleost fish.

We previously reported on the identification of a novel soluble form of the CSF-1 receptor (sCSF-1R) in goldfish that induced dose-dependent down-regulation of macrophage proliferation. Herein, we report that sCSF-1R has a role beyond macrophage development, which extends into the control of cellular antimicrobial inflammatory responses in this lower vertebrate. Using an in vivo model of self-resolving peritonitis coupled to in vitro characterization of sCSF-1R activity, we show that sCSF-1R plays a role in the inhibition of inflammation which follows an initial acute phase of innate antimicrobial responses within an inflammatory site. In vitro, mature goldfish primary kidney macrophages but not monocytes up-regulated sCSF-1R expression upon direct contact with apoptotic cells. In vivo, sCSF-1R expression coincided with an increase in macrophage numbers that resulted from administration of apoptotic cells into the goldfish peritoneal cavity. This contrasted the decrease in sCSF-1R expression during zymosan-induced inflammatory responses in vivo. Subsequent experiments showed an anti-inflammatory effect for sCSF-1R. Leukocyte infiltration and ROS production decreased in a dose-dependent manner compared to zymosan-stimulated controls upon addition of increasing doses of recombinant sCSF-1R. Among others, sCSF-1R may contribute to the dual role that phagocytic macrophages play in the induction and regulation of inflammation. Overall, our results provide new insights into ancient mechanisms of inflammation control and, in particular, the evolutionary origins of the CSF-1 immune regulatory axis.

Relationship between gallbladder surgery and ethnic admixture in African American and Hispanic American women.

OBJECTIVES: The objective of this study was to investigate whether differences in admixture in African American and Hispanic American adult women are associated with differences in gallbladder surgery. METHODS: Gallbladder surgery history on entry to the Women's Health Initiative's (WHI) study was used as a dichotomous outcome measure for this study. The proportion of European, sub-Saharan African, and Amerindian (AMI) admixture was estimated for 10,841 African American and 4,620 Hispanic American women in WHI using 92 ancestry informative markers. Logistic regression analyses assessed the relationship between admixture and gallbladder surgery in WHI women (enrollment at ages >50, mean age 61 years) with or without adjusting for multiple covariates, including measures of adiposity, parity, alcohol use, and education. RESULTS: There was a significant positive association between AMI admixture and the frequency of gallbladder surgery in Hispanic Americans. The odds ratio (OR) and 95% confidence intervals (CIs) for AMI admixture group was OR=2.97, CI=2.01-4.38, P<10(-4). Although there were strong positive associations with parity and adiposity, and negative associations with alcohol consumption and education, accounting for these covariates did not remove the admixture association (OR=2.46, CI=1.62-3.73). In contrast, the effect of African admixture was nearly indistinguishable from that of the European admixture, both of which were protective in the Hispanic American group, and African admixture had a marginal association with decreased gallbladder surgery in the African American group. Measures of adiposity were associated with increased risk for gallbladder surgery and remained significant after accounting for admixture and each of the other covariates. Education level and alcohol use were associated with decreased risk for gallbladder disease. However, after accounting for the other covariates these variably remained significant. CONCLUSIONS: AMI admixture is strongly associated with gallbladder surgery in women, even after adjustment for selected risk factors for cholelithiasis. Additional studies to ascertain the specific genetic risk factors underlying these associations are warranted.

Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial.

BACKGROUND: Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. METHODS: In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. FINDINGS: 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002). INTERPRETATION: 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. FUNDING: Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).

Comparative long-term adverse effects elicited by invasive group B and C meningococcal infections.

BACKGROUND: Given the identity between Neisseria meningitidis serogroup B (MenB) capsular polysaccharide (polysialic acid; PSA) and PSA found on neural cell adhesion molecules, it has been proposed that infection with MenB or vaccination with PSA may be associated with subsequent autoimmune or neurological disease. METHODS: We conducted 2 studies. The first was a retrospective nationwide study of invasive meningococcal disease (IMD) in Iceland (with 541 subjects) during the period 1975-2004, and we cross referenced this cohort with databases with respect to subsequent diagnosis of autoimmune disorders. A follow-up study involving 120 survivors of IMD was performed. The study included 70 patients with a history of MenB and 50 patients with N. meningitidis serogroup C (MenC) infection, who served as control subjects. Participants answered standardized questionnaires (Beck's Depression Inventory [BDI] II, Depression Anxiety Stress Scales [DASS], and Patient Health Questionnaire [PHQ]), and serum levels of immunoglobulin (Ig) G against MenB and MenC capsular polysaccharides were measured. RESULTS: The nationwide cohort had 9166 patient-years of follow up. No evidence of increased autoimmunity was found to be associated with MenB, compared with MenC. In the follow-up study, patients were evaluated 16.6 years after the infection, representing 2022 patient-years of observation. Comparable rates of most complications were recorded, but MenC infections were associated with arthritis (P = .008) and migraine headaches (P = .01) more frequently than were MenB infections. No difference was observed with respect to scores on BDI-II, DASS, or PHQ. IgG anti-MenB and anti-MenC capsular polysaccharide levels were not related to patient complaints. CONCLUSIONS: This study does not support the hypothesis that MenB infection may predispose to autoimmunity. MenC infections are associated with a higher prevalence of arthritis and migraine headaches. No evidence of antibody-associated pathology was detected at long-term follow-up.

Exemestane for breast-cancer prevention in postmenopausal women.

BACKGROUND: Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. METHODS: In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. RESULTS: A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. CONCLUSIONS: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).

Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women's Health Initiative Observational Study.

BACKGROUND: Elective bilateral salpingo-oophorectomy (BSO) is routinely performed with hysterectomy for benign conditions despite conflicting data on long-term outcomes. METHODS: This is a prospective cohort of 25 448 postmenopausal women aged 50 to 79 years enrolled in the Women's Health Initiative Observational Study who had a history of hysterectomy and BSO (n = 14 254 [56.0%]) or hysterectomy with ovarian conservation (n = 11 194 [44.0%]) and no family history of ovarian cancer. Multivariable Cox proportional hazards regression models were used to examine the effect of BSO on incident cardiovascular disease, hip fracture, cancer, and death. RESULTS: Current or past use of estrogen and/or progestin was common irrespective of BSO status (78.6% of cohort). In multivariable analyses, BSO was not associated with an increased risk of fatal and nonfatal coronary heart disease (hazard ratio, 1.00 [95% confidence interval, 0.85-1.18]), coronary artery bypass graft/percutaneous transluminal coronary angioplasty (0.95 [0.82-1.10]), stroke (1.04 [0.87-1.24]), total cardiovascular disease (0.99 [0.91-1.09]), hip fracture (0.83 [0.63-1.10]), or death (0.98 [0.87-1.10]). Bilateral salpingo-oophorectomy decreased incident ovarian cancer (0.02% in the BSO group; 0.33% in the ovarian conservation group; number needed to treat, 323) during a mean (SD) follow-up of 7.6 (1.6) years, but there were no significant associations for breast, colorectal, or lung cancer. CONCLUSIONS: In this large prospective cohort study, BSO decreased the risk of ovarian cancer compared with hysterectomy and ovarian conservation, but incident ovarian cancer was rare in both groups. Our findings suggest that BSO may not have an adverse effect on cardiovascular health, hip fracture, cancer, or total mortality compared with hysterectomy and ovarian conservation.