Estrogen alone and joint symptoms in the Women's Health Initiative randomized trial.

OBJECTIVE: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial. METHODS: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms. RESULTS: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling. CONCLUSIONS: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.

An analysis of the effect of statins on the risk of Non-Hodgkin's Lymphoma in the Women's Health Initiative cohort.

Statins have been shown to induce a phosphoprotein signature that modifies MYC (myelocytomatosis viral oncogene) activation and to have anti-inflammatory activity that may impact the risk of Non-Hodgkin's lymphoma (NHL). We analyzed the relationship between statins and risk of NHL using data from the Women's Health Initiative (WHI). The study population included 161,563 postmenopausal women ages 50-79 years from which 712 cases of NHL were diagnosed after 10.8 years of follow-up. Information on statin use and other risk factors was collected by self- and interviewer-administered questionnaires. Multivariable-adjusted HR and 95% CI evaluating the relationship between statin use at baseline, as well as in a time-dependent manner and risk of NHL, were computed from Cox proportional hazards analyses. A separate analysis was performed for individual NHL subtypes: diffuse large B-Cell lymphoma (DLBCL) (n = 228), follicular lymphoma (n = 169), and small lymphocytic lymphoma (n = 74). All statistical tests were two-sided. There was no significant association between use of statins at baseline and risk of NHL (HR 0.85, 95% C.I. 0.67-1.08). However, in the multivariable-adjusted time-dependent models, statin use was associated with a borderline lower risk of NHL (HR 0.81, 95% C.I. 0.66-1.00). Considering subtypes of NHL, statin use was associated with a lower risk of DLBCL (HR 0.62, 95% C.I. 0.42-0.91). This effect was driven by lipophilic statins (HR 0.62, 95% C.I. 0.40-0.96). In the WHI, statins were associated with a lower overall risk of DLBCL, particularly attributable to lipophilic statins. These results may have impact on primary or secondary prevention of NHL, particularly DLBCL.

Predictors of Continued Smoking and Interest in Cessation Among Older Female Smokers.

OBJECTIVES: Older female smokers are highly vulnerable, yet little is known about their attitudes, beliefs, and behaviors regarding smoking cessation. METHODS: Southeast region Women's Health Initiative participants identified as smokers on at least one prior assessment were surveyed in 2012 regarding current tobacco use. RESULTS: Most of these current and former smokers ( N = 409, 63% response) were non-Hispanic White (81.7%) and had some college (80%), with mean age of 75.1 years. Current smoking was confirmed by 56%, and while 61% of these reported a past-year quit attempt, less than half used quit aids. Of current smokers, 57.5% intended to quit within 6 months (26.6% within 30 days), and 68% were interested in joining a cessation study. CONCLUSIONS: Older female smokers were highly motivated to quit, yet profoundly underutilized proven quit aids. Results support high acceptability of cessation interventions for this undertreated population.

Survey of Living Organ Donors' Experience and Directions for Process Improvement.

INTRODUCTION: Understanding living organ donors' experience with donation and challenges faced during the process is necessary to guide the development of effective strategies to maximize donor benefit and increase the number of living donors. METHODS: An anonymous self-administered survey, specifically designed for this population based on key informant interviews, was mailed to 426 individuals who donated a kidney or liver at our institution. Quantitative and qualitative methods including open and axial coding were used to analyze donor responses. FINDINGS: Of the 141 survey respondents, 94% would encourage others to become donors; however, nearly half (44%) thought the donation process could be improved and offered numerous suggestions. Five major themes arose: (1) desire for greater convenience in testing and scheduling; (2) involvement of previous donors throughout the process; (3) education and promotion of donation through social media; (4) unanticipated difficulties, specifically pain; and (5) financial concerns. DISCUSSION: Donor feedback has been translated into performance improvements at our hospital, many of which are applicable to other institutions. Population-specific survey development helps to identify vital patient concerns and provides valuable feedback to enhance the delivery of care.

Venous thromboembolism incidence, recurrence, and mortality based on Women's Health Initiative data and Medicare claims.

INTRODUCTION: Our objective was to compare Medicare claims to physician review and adjudication of medical records for identifying venous thromboembolism (VTE), and to assess VTE incidence, recurrence, and mortality in a large national cohort of post-menopausal women followed up to 19years. MATERIALS AND METHODS: We used detailed clinical data from the Women's Health Initiative (WHI) linked to Medicare claims. Agreement between data sources was evaluated among 16,003 women during 1993-2010. A claims-based definition was selected to analyze VTE occurrence and impact among 71,267 women during 1993-2012. RESULTS: Our VTE definition had 83% sensitivity. Positive predictive value was 69% when all records were included, and 94% after limiting Medicare records to those with a WHI hospitalization adjudicated. Annualized VTE incidence was 4.06/1000person-years (PY), recurrence was 5.30/100PY, and both rates varied by race/ethnicity. Post-VTE mortality within 1year was 22.49% from all causes, including 1.01% from pulmonary embolism, 10.40% from cancer, and 11.08% from other causes. Cancer-related VTE compared to non-cancer VTE had significantly (p<0.001) higher recurrence (9.86/100PY vs. 4.43/100PY) and mortality from all causes (45.89% vs. 12.28%), but not from pulmonary embolism (0.40% vs. 1.27%). CONCLUSIONS: Medicare claims compared reasonably well to physician adjudication. The combined data sources provided new insights about VTE burden and prognosis in older women.

Mortality in Postmenopausal Women by Sexual Orientation and Veteran Status.

PURPOSE OF THE STUDY: To examine differences in all-cause and cause-specific mortality by sexual orientation and Veteran status among older women. DESIGN AND METHODS: Data were from the Women's Health Initiative, with demographic characteristics, psychosocial factors, and health behaviors assessed at baseline (1993-1998) and mortality status from all available data sources through 2014. Women with baseline information on lifetime sexual behavior and Veteran status were included in the analyses (N = 137,639; 1.4% sexual minority, 2.5% Veteran). The four comparison groups included sexual minority Veterans, sexual minority non-Veterans, heterosexual Veterans, and heterosexual non-Veterans. Cox proportional hazard models were used to estimate mortality risk adjusted for demographic, psychosocial, and health variables. RESULTS: Sexual minority women had greater all-cause mortality risk than heterosexual women regardless of Veteran status (hazard ratio [HR] = 1.20, 95% confidence interval [CI]: 1.07-1.36) and women Veterans had greater all-cause mortality risk than non-Veterans regardless of sexual orientation (HR = 1.14, 95% CI: 1.06-1.22), but the interaction between sexual orientation and Veteran status was not significant. Sexual minority women were also at greater risk than heterosexual women for cancer-specific mortality, with effects stronger among Veterans compared to non-Veterans (sexual minority × Veteran HR = 1.70, 95% CI: 1.01-2.85). IMPLICATIONS: Postmenopausal sexual minority women in the United States, regardless of Veteran status, may be at higher risk for earlier death compared to heterosexuals. Sexual minority women Veterans may have higher risk of cancer-specific mortality compared to their heterosexual counterparts. Examining social determinants of longevity may be an important step to understanding and reducing these disparities.

Monocytosis and a Low Lymphocyte to Monocyte Ratio Are Effective Biomarkers of Ulcerative Colitis Disease Activity.

BACKGROUND: Current biomarkers in ulcerative colitis (UC) are limited by their performance, cost, and limited availability in daily practice. This study examined alterations in the leukocyte profiles as biomarkers of UC activity, including the effects of age, gender, and medications. METHODS: Case-control study that included 110 UC subjects, 75 subjects with Clostridium difficile infection, and 75 non-inflammatory bowel disease (IBD) subjects, randomly selected from a single-institution IBD database. Mean values of neutrophils (N), lymphocytes (L), monocytes (M) and their ratios were compared between groups. Receiver operator curve analyses assessed the performance of each biomarker in discriminating disease states. Subgroup analyses examined leukocytes profiles with endoscopic activity. RESULTS: Elevated monocyte counts and decreased L/M values significantly differed between subjects with active UC and UC in remission and performed better than the other leukocyte profiles. A monocyte count of 483 and L/M ratio of 3.1 were 60% sensitive and had a specificity of 61% and 53%, respectively for active UC. Monocyte count >860 and L/M value <1.6 had a 75% positive predictive value for UC activity. Those markers also correlated with endoscopically active disease. L/M and N/L values performed best at differentiating active UC from non-IBD controls, whereas N/L and N values performed best at differentiating from C. difficile controls. CONCLUSIONS: Monocytosis and a low L/M ratio might be effective, readily available, and low-cost biomarkers to identify disease activity in UC patients. N/L values were more effective in distinguishing active UC patients from patients without IBD and those with C. difficile infection.

Patient evaluation of an acute care pediatric telemedicine service in urban neighborhoods.

BACKGROUND: Telemedicine has enhanced care for children with illness in Rochester, NY, since May 2001, enabling 13,568 acute illness visits through December 2013. Prior findings included high parent satisfaction with childcare- and school-based telemedicine ("school telemedicine") and potential to replace 85% of office visits for illness. Urban neighborhood telemedicine ("neighborhood telemedicine") was designed to offer convenient care for illness episodes that school telemedicine often cannot serve because illness arises when children are at home or symptoms preclude attendance. This study was designed to characterize health problems prompting neighborhood telemedicine use and to assess parent perceptions of its value. MATERIALS AND METHODS: A parent satisfaction instrument was developed with input from parents and providers. Neighborhood telemedicine was initiated in January 2009 and totaled 1,362 visits through November 2013. During a 29-month survey period through January 2012, 3,871 acute illness telemedicine visits were completed, 908 (23.5%) of them via neighborhood telemedicine. Instruments were completed for 392 (43.2%) of the 908 visits. RESULTS: Neighborhood telemedicine comprised 27% of all telemedicine visits during the year of peak neighborhood activity. Almost all survey respondents were satisfied or highly satisfied with neighborhood visits (97.6%) and endorsed greater convenience than alternatives (94.5%). CONCLUSIONS: Family preferences and the high value placed on neighborhood telemedicine suggest such service is important, especially in health systems driven by patient values. Service provided by neighborhood telemedicine holds potential to meet a large demand for care of acute childhood illness. Financing reform to support patient-centered care (e.g., bundled payments) should encompass sustainable business models for this service.

Testing the proportional hazards assumption in case-cohort analysis.

BACKGROUND: Case-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess the assumption of proportional hazards of case-cohort Cox models have been proposed. METHODS: We extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define "case-cohort Schoenfeld residuals", and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer. RESULTS: Simulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches. CONCLUSIONS: The proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.

Estrogen alone and joint symptoms in the Women's Health Initiative randomized trial.

OBJECTIVE: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial. METHODS: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms. RESULTS: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling. CONCLUSIONS: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.

Restless legs syndrome and functional limitations among American elders in the Health and Retirement Study.

BACKGROUND: Restless legs syndrome (RLS) is a common condition associated with decreased quality of life in older adults. This study estimates the prevalence, risk factors, and functional correlates of among U.S. elders. METHODS: Subjects (n = 1,008) were sub-sampled from the 2002 cross-sectional interview survey of the Health and Retirement Study (HRS), a nationally representative study of U.S. elders. Symptoms and sleep disturbances consistent with RLS were identified. Activities of daily living (ADL), instrumental activities of daily living (IADL), and limitations for mobility, large muscle groups, gross and fine motor function were measured using standardized questions. Incident functional limitations were detected over six years of observation. RESULTS: The prevalence of RLS among U.S. elders born before 1947 was 10.6%. Factors associated with increased prevalence RLS at baseline included: overweight body mass index (multivariate adjusted prevalence ratio = 1.77; 95% confidence interval (CI) 1.05-2.99); mild-to-moderate pain (2.67, 1.47-4.84) or pain inferring with activity (3.44, 2.00-5.93); three or more chronic medications (2.54, 1.26-5.12), highest quartile of out-of-pocket medical expenses (2.12, 1.17-3.86), frequent falls (2.63, 1.49-4.66), health limiting ability to work (2.91, 1.75-4.85), or problems with early waking or frequent wakening (1.69, 1.09-2.62 and 1.55, 1.00-2.41, respectively). Current alcohol consumption (0.59, 0.37-0.92) and frequent healthcare provider visits (0.49, 0.27-0.90) were associated with decreased RLS prevalence. RLS did not predict incident disability for aggregate measures but was associated with increased risk for specific limitations, including: difficulty climbing several stair flights (multivariate-adjusted hazard ratio = 2.38, 95% CI 1.39-4.06), prolonged sitting (2.17, 1.25-3.75), rising from a chair (2.54, 1.62-3.99), stooping (2.66, 1.71-4.15), moving heavy objects (1.79, 1.08-2.99), carrying ten pounds (1.61, 1.05-2.97), raising arms (1.76, 1.05-2.97), or picking up a dime (1.97, 1.12-3.46). CONCLUSIONS: RLS sufferers are more likely to have functional disability, even after adjusting for health status and pain syndrome correlates.

Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative.

OBJECTIVE: To determine the effect of hormone therapy on arthroplasty rates. METHODS: We examined data from the Women's Health Initiative placebo-controlled, double-blind, randomized trials. Community-dwelling women ages 50-79 years were enrolled at 40 US clinics. Women with prior arthroplasty were excluded, yielding a sample size of 26,321 subjects. Women who had had hysterectomies (n = 10,272) were randomly assigned to receive 0.625 mg/day conjugated equine estrogens (n = 5,076), or placebo (n = 5,196), with a mean followup of 7.1 years. Those who had not had hysterectomies (n = 16,049) were randomly assigned to receive estrogen plus progestin (n = 8,240), given as 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate, or placebo (n = 7,809), with a mean followup of 5.6 years. Participants reported hospitalizations, and arthroplasties were identified by procedure codes. Arthroplasties due to hip fracture were censored. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (95% CIs) using intent-to-treat methods and outcome of time to first procedure. RESULTS: In the estrogen-alone trial, women receiving hormone therapy had significantly lower rates of any arthroplasty (HR 0.84 [95% CI 0.70-1.00], P = 0.05). However, this effect was borderline statistically significant for hip arthroplasty (HR 0.73 [95% CI 0.52-1.03], P = 0.07), and not significant for knee arthroplasty (HR 0.87 [95% CI 0.71-1.07], P = 0.19). In the estrogen-plus-progestin trial, there was no association for total arthroplasty (HR 0.99 [95% CI 0.82-1.20], P = 0.92) or for individual hip (HR 1.14 [95% CI 0.83-1.57], P = 0.41) or knee (HR 0.91 [95% CI 0.72-1.15], P = 0.41) arthroplasties. CONCLUSION: These data suggest that hormone therapy may influence joint health, but this observed decrease in risk may be limited to unopposed estrogen and may possibly be more important in hip than in knee osteoarthritis.

Use of complementary medicine in older Americans: results from the Health and Retirement Study.

PURPOSE: The correlates of complementary and alternative medicine (CAM) utilization among elders have not been fully investigated. This study was designed to identify such correlates in a large sample of older adults, thus generating new data relevant to consumer education, medical training, and health practice and policy. DESIGN AND METHODS: A subsample from the 2000 Wave of the Health and Retirement Study (n = 1,099) aged 52 or older were surveyed regarding use of CAM (chiropractic, alternative practitioners, dietary and herbal supplements, and personal practices). RESULTS: Of respondents over 65 years of age, 88% used CAM, with dietary supplements and chiropractic most commonly reported (65% and 46%, respectively). Users of alternate practitioners and dietary supplements reported having more out-of-pocket expenses on health than nonusers of these modalities. Age correlated positively with use of dietary supplements and personal practices and inversely with alternative practitioner use. Men reported less CAM use than women, except for chiropractic and personal practices. Blacks and Hispanics used fewer dietary supplements and less chiropractic, but they reported more personal practices than Whites. Advanced education correlated with fewer chiropractic visits and more dietary and herbal supplement and personal practices use. Higher income, functional impairment, alcohol use, and frequent physician visits correlated with more alternative practitioner use. There was no association between CAM and number of chronic diseases. IMPLICATIONS: The magnitude and patterns of CAM use among elders lend considerable importance to this field in public health policy making and suggest a need for further epidemiological research and ongoing awareness efforts for both patients and providers.

Effect of estrogen therapy on gallbladder disease.

CONTEXT: Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than randomized trials. OBJECTIVE: To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes. DESIGN, SETTING, AND PARTICIPANTS: Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers. The volunteer sample was 22,579 community-dwelling women aged 50 to 79 years without prior cholecystectomy. INTERVENTION: Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E + P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14,203). MAIN OUTCOME MEASURES: Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures, with events ascertained through medical record review. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) using intention-to-treat and time-to-event methods. RESULTS: The CEE and the E + P groups were similar to their respective placebo groups at baseline. The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials, respectively. The annual incidence rate for any gallbladder event was 78 events per 10,000 person-years for the CEE group (vs 47/10,000 person-years for placebo) and 55 per 10,000 person-years for E + P (vs 35/10,000 person-years for placebo). Both trials showed greater risk of any gallbladder disease or surgery with estrogen (CEE: HR, 1.67; 95% CI, 1.35-2.06; E + P: HR, 1.59; 95% CI, 1.28-1.97). Both trials indicated a higher risk for cholecystitis (CEE: HR, 1.80; 95% CI, 1.42-2.28; E + P: HR, 1.54; 95% CI 1.22-1.94); and for cholelithiasis (CEE: HR, 1.86; 95% CI, 1.48-2.35; E + P: HR, 1.68; 95% CI, 1.34-2.11) for estrogen users. Also, women undergoing estrogen therapy were more likely to receive cholecystectomy (CEE: HR, 1.93; 95% CI, 1.52-2.44; E + P: HR, 1.67; 95% CI, 1.32-2.11), but not other biliary tract surgery (CEE: HR, 1.18; 95% CI, 0.68-2.04; E + P: HR, 1.49; 95% CI, 0.78-2.84). CONCLUSIONS: These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy. The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy.

Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey.

Studies considering the association between total cholesterol and noncardiovascular mortality, particularly from respiratory disease, yield inconclusive findings. To explore this question, the relation of lipids to pulmonary function, specifically forced expiratory volume in 1 second (FEV(1)), was investigated in the Third National Health and Nutrition Examination Survey. Conducted in the United States in 1988-1994 among adults aged > or =17 years, this survey measured serum lipids, FEV(1), and confounding factors including smoking and antioxidants. Multiple linear regression analysis explored the relation of FEV(1)/height(2) to low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and their respective apolipoproteins (apo) B and A-I. A standard deviation increase in HDL cholesterol or apo A-I was associated with an FEV(1) increase of 43 ml (95% confidence interval (CI): 30, 56) or 29 ml (95% CI: 11, 47), respectively, for an average-height adult. A standard deviation increase in LDL cholesterol or apo B was associated with an FEV(1) decrease of -24 ml (95% CI: -43, -5) or -53 ml (95% CI: -74, -32), respectively, adjusted for serum antioxidant status. The lipid subfractions were differentially associated with FEV(1) consistent with the possibility that LDL cholesterol contributes to endogenous oxidative burden while HDL cholesterol attenuates inflammatory tissue damage. Whether these associations are causal remains to be determined.