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1.  Chronic Venous Disease in an Ethnically Diverse Population The San Diego Population Study 
American journal of epidemiology  2003;158(5):448-456.
In a 1994–1998 cross-sectional study of a multiethnic sample of 2,211 men and women in San Diego, California, the authors estimated prevalence of the major manifestations of chronic venous disease: spider veins, varicose veins, trophic changes, and edema by visual inspection; superficial and deep functional disease (reflux or obstruction) by duplex ultrasonography; and venous thrombotic events based on history. Venous disease increased with age, and, compared with Hispanics, African Americans, and Asians, non-Hispanic Whites had more disease. Spider veins, varicose veins, superficial functional disease, and superficial thrombotic events were more common in women than men (odds ratio (OR) = 5.4, OR = 2.2, OR = 1.9, and OR = 1.9, respectively; p < 0.05), but trophic changes and deep functional disease were less common in women (OR = 0.7 for both; p < 0.05). Visible (varicose veins or trophic changes) and functional (superficial or deep) disease were closely linked; 92.0% of legs were concordant and 8.0% discordant. For legs evidencing both trophic changes and deep functional disease, the age-adjusted prevalences of edema, superficial events, and deep events were 48.2%, 11.3%, and 24.6%, respectively, compared with 1.7%, 0.6%, and 1.3% for legs visibly and functionally normal. However, visible disease did not invariably predict functional disease, or vice versa, and venous thrombotic events occurred in the absence of either.
PMCID: PMC4285442  PMID: 12936900
cross-sectional studies; diagnostic imaging; ethnic groups; population; thrombosis; ultrasonics; veins
2.  Association of morning illumination and window covering with mood and sleep among post-menopausal women 
Sleep and biological rhythms  2004;2(3):174-183.
The antidepressant and sleep-promoting effects of light exposure might be useful for treating age-related mood and sleep disorders. In view of recent evidence suggesting beneficial effects of morning light, this study examined the associations of mood and sleep with morning light exposure, 24 h environmental illumination, and the degree to which the volunteers’ bedroom windows were covered in the morning. We examined 459 postmenopausal women participating an ancillary study of the Women’s Health Initiative conducted at the University of California, San Diego Clinical Center, San Diego, CA, USA. At baseline, volunteers completed a 4-week sleep-recall questionnaire. Volunteers were then assessed for 5–7 days in their home environments with actigraphic wrist monitors. During home recording, self-reported mood was assessed. Morning illumination during the first 4 h after arising, 24-h illumination mesor (cosine-fitted mean), and illumination acrophase (cosine-fitted peak time) were calculated. Sleep was scored each night using validated wrist actigraphic methods. A sleep diary was completed each morning. During two 24-h periods, urine was collected approximately every 2 h during wakefulness and following any voidings during the sleep period. Cosine-fitting established the acrophase of urinary 6-sulfatoxymelatonin (aMT6s) excretion. Morning illumination and 24-h illumination were modestly associated with better mood and sleep. Associations of light with mood and sleep were consistently greater for subjects whose body clocks were delayed relative to the group median. Less morning window covering in the subjects’ bedrooms was associated with more morning light and less depressed mood. The results suggest that both morning and 24-h light exposure may be beneficial for older adults.
PMCID: PMC4217703  PMID: 25374475
Actigraphy; bright light; Circadian phase; older adults
3.  Light exposure is related to social and emotional functioning and to quality of life in older women 
Psychiatry research  2006;143(1):35-42.
While there are data supporting the use of light in clinical populations, there has been less investigation of relationships among light and psychological variables in non-clinical samples. Subjects were 459 ethnically diverse women (mean age 67.68) recruited as part of the Women's Health Initiative. Light exposure and sleep were measured with an Actillume wrist actigraph. Subjects completed questionnaires, investigating Social Support, Social Functioning, Social Strain, Quality of Life, Satisfaction with Life, Emotional Well-being, Optimism, Negative Emotional Expressiveness, and Role Limitation Due to Emotional Problems. Significant partial correlations (controlling for age, education and ethnicity) were found between mesor light exposure and Social Functioning, Quality of Life, Satisfaction with Life, and Emotional Well-Being. Quality of Life and Satisfaction with Life were also found to be significantly correlated with morning light. The most parsimonious model to account for the variance shared between mesor light and the predictors included only Quality of Life. The variance shared between mesor light exposure and social and emotional functioning could be subsumed under the variance shared between mesor light exposure and Quality of Life. Increased light exposure is related to improved quality of life and social and emotional functioning. Increased light exposure is related to improved quality of life and social and emotional functioning.
PMCID: PMC3685148  PMID: 16725207
Phototherapy; Circadian rhythm; Interpersonal relations; Emotional disturbances; Sleep
4.  New-onset breast tenderness after initiation of estrogen plus progestin therapy and breast cancer risk 
Archives of internal medicine  2009;169(18):1684-1691.
The use of estrogen plus progestin therapy increases both breast cancer incidence and breast tenderness. Whether breast tenderness during estrogen plus progestin therapy is associated with breast cancer risk is uncertain.
We analyzed data from the Women’s Health Initiative Estrogen plus Progestin Clinical Trial, which randomized postmenopausal women with an intact uterus to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily (CEE + MPA, N=8506) or placebo (N=8102). At baseline and annually, participants underwent mammography and clinical breast exam. Self-report of breast tenderness was assessed at baseline and 12 months. Invasive breast cancer incidence was confirmed by medical record review (mean 5.6 years of follow-up).
Among women without baseline breast tenderness (N=14538), significantly more women assigned to CEE + MPA than placebo experienced new-onset breast tenderness after 12 months (36.1% vs. 11.8%, P<0.001). Among women in the CEE + MPA group, breast cancer risk was significantly higher in those with new-onset breast tenderness compared to those without new-onset breast tenderness (Hazard Ratio 1.48, 95% confidence interval 1.08–2.03, P=0.02). Among women in the placebo group, breast cancer risk was not significantly associated with new-onset breast tenderness.
New-onset breast tenderness during use of CEE + MPA was associated with increased breast cancer risk. The sensitivity and specificity for the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model.
PMCID: PMC3670683  PMID: 19822825
5.  Live well: a practical and effective low-intensity dietary counseling intervention for use in primary care patients with dyslipidemia - a randomized controlled pilot trial 
BMC Family Practice  2013;14:59.
Diet is the first line of treatment for elevated cholesterol. High-intensity dietary counseling (≥360 minutes/year of contact with providers) improves blood lipids, but is expensive and unsustainable in the current healthcare settings. Low-intensity counseling trials (≤ 30 minutes/year) have demonstrated modest diet changes, but no improvement in lipids. This pilot study evaluated the feasibility and the effects on lipids and diet of a low-intensity dietary counseling intervention provided by the primary care physician (PCP), in patients at risk for cardiovascular diseases.
Six month study with a three month randomized-controlled phase (group A received the intervention, group B served as controls) followed by three months of intervention in both groups.
Sixty-one adults age 21 to 75 years, with LDL-cholesterol ≥ 3.37 mmol/L, possessing Internet access and active email accounts were enrolled. Diet was evaluated using the Rate-Your-Plate questionnaire. Dietary counseling was provided by the PCP during routine office visits, three months apart, using printed educational materials and a minimally interactive counseling website. Weekly emails were sent reminding participants to use the dietary counseling resources. The outcomes were changes in LDL-cholesterol, other lipid subclasses, and diet quality.
At month 3, group A (counseling started at month 1) decreased their LDL-cholesterol by −0.23 mmol/L, (−0.04 to −0.42 mmol/L, P = 0.007) and total cholesterol by −0.26 mmol/L, (−0.05 to −0.47 mmol/L, P = 0.001). At month 6, total and LDL-cholesterol in group A remained better than in group B (counseling started at month 3). Diet score in group A improved by 50.3 points (38.4 to 62.2, P < 0.001) at month 3; and increased further by 11.8 (3.5 to 20.0, P = 0.007) at month 6. Group B made the largest improvement in diet at month 6, 55 points (40.0 to 70.1, P < 0.001), after having a small but significant improvement at month 3, 22.3 points (12.9 to 31.7, P < 0.001). No significant changes occurred in HDL-cholesterol in either group.
A low-intensity dietary counseling provided by the PCP in patients at risk for cardiovascular diseases produced clinically meaningful improvements in both diet and lipids of magnitude similar to changes reported with high intensity interventions.
Trial registration NCT01695837
PMCID: PMC3662581  PMID: 23663789
Diet; Behavior change; Lipid management; Cardiovascular; Risk reduction; Primary care
6.  Usefulness of Baseline Lipids and C-Reactive Protein in Women Receiving Menopausal Hormone Therapy as Predictors of Treatment-Related Coronary Events 
The American journal of cardiology  2008;101(11):1599-1605.
Blood lipids and high sensitivity C-reactive protein (hsCRP) are altered by hormone therapy. The goal of the current study was to determine whether lipids and hsCRP have predictive value for hormone therapy benefit or risk for coronary heart disease (CHD) events in postmenopausal women without previous cardiovascular disease. A nested case-control study was performed in the Women’s Health Initiative hormone trials. Baseline lipids and hsCRP were obtained from 271 incident CHD cases and 707 controls. In a combined trial analysis, a favorable lipid status at baseline tended to predict better CHD outcomes when taking conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA). Women with a low density lipoprotein (LDL)/high density lipoprotein (HDL) ratio <2.5 had no increase in risk of CHD when taking CEE with or without MPA (OR 0.60, 95%CI=0.34–1.06), whereas women with an LDL/HDL ratio ≥2.5 had an increased risk of CHD (OR 1.73, 95%CI=1.18–2.53) (p-value for interaction = 0.02). Low hsCRP levels added marginally to the value of LDL/HDL<2.5 when predicting CHD benefit on hormone therapy. In conclusion, postmenopausal women with undesirable lipid levels had excess CHD risk when using CEE with or without MPA; however, women with favorable lipid levels, especially an LDL/HDL ratio < 2.5, did not have an elevated risk of CHD with CEE with or without MPA, irrespective of hsCRP levels.
PMCID: PMC3543778  PMID: 18489937
CHD; hormone therapy; lipids; cholesterol
7.  Serum Selenium, Genetic Variation in Selenoenzymes and Risk of Colorectal Cancer: Primary Analysis from The Women’s Health Initiative Observational Study and Meta-Analysis 
Selenium may prevent colorectal cancer. However, several previous studies are small and few investigated the associations between selenium and colorectal cancer among women, whose selenium metabolism may differ from men.
This nested case-control study investigated whether serum selenium concentration and genetic variants in five selenoenzymes (glutathione peroxidase 1-4 and selenoprotein P) were associated with colorectal cancer risk in 804 colorectal cancer cases and 805 matched controls from the Women’s Health Initiative (WHI) Observational Study. A meta-analysis was conducted to compare the WHI result with previous studies including 12 observational studies and two clinical trials on selenium.
Within the WHI, selenium concentrations were relatively high (mean = 135.6 μg/L) and were not associated with colorectal cancer risk (p for trend = 0.10); the adjusted odds ratio (OR) comparing the fifth with first quintile was 1.26 [95% confidence intervals (CI) = 0.91-1.73]. Moreover, genetic variants in selenoenzymes were not significantly associated with colorectal cancer risk. Consistent with the finding in WHI, our meta-analysis showed no association between selenium and colorectal tumor risk in women (OR = 0.97, 95% CI = 0.79-1.18 comparing the highest quantile with the lowest); however, in men, there was a significant inverse association (OR = 0.68, 95% CI = 0.57-0.82) (p = 0.01).
Consistent with previous studies, we observed no protective effect of selenium on colorectal cancer among women.
Our analyses suggest a population with relatively high selenium concentrations, especially women, would not benefit from increasing selenium intake.
PMCID: PMC3191200  PMID: 21765007
8.  Hypnotics' association with mortality or cancer: a matched cohort study 
BMJ Open  2012;2(1):e000850.
An estimated 6%–10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality.
A large integrated health system in the USA.
Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.
Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007.
Main outcome measures
Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity.
As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.
Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.
Article summary
Article focus
Estimate the mortality risks associated with specific currently popular hypnotics in a matched cohort design, using proportional hazards regression models.
Estimate the cancer risks associated with specific currently popular hypnotics.
Explore what risk associated with hypnotics can be attributed to confounders and comorbidity.
Key messages
Patients receiving prescriptions for zolpidem, temazepam and other hypnotics suffered over four times the mortality as the matched hypnotic-free control patients.
Even patients prescribed fewer than 18 hypnotic doses per year experienced increased mortality, with greater mortality associated with greater dosage prescribed.
Among patients prescribed hypnotics, cancer incidence was increased for several specific types of cancer, with an overall cancer increase of 35% among those prescribed high doses.
Strengths and limitations of this study
Design strengths included matching patient and control cohorts by age, gender and smoking. Through stratified statistical analyses, patients using hypnotics were matched with controls diagnosed with the exactly the same combination of 12 categories of comorbidity in up to 116 strata.
The major limitation was that residual confounding could not be fully excluded, due to possible biases affecting which patients were prescribed hypnotics and due to possible imbalances in surveillance.
Cohort studies demonstrating association do not necessarily imply causality, but the preferable randomised controlled trial method for assessing hypnotic risks may be impractical due to ethical and funding limitations.
PMCID: PMC3293137  PMID: 22371848
9.  Mortality Related to Actigraphic Long and Short Sleep 
Sleep medicine  2010;12(1):28-33.
The folk belief that we should sleep 8 hours seems to be incorrect. Numerous studies have shown that self-reported sleep longer than 7.5 hours or shorter than 6.5 hours predicts increased mortality risk. This study examined if prospectively-determined objective sleep duration, as estimated by wrist actigraphy, was associated with mortality risks.
From 1995–1999, women averaging 67.6 years of age provided one-week actigraphic recordings. Survival could be estimated from follow-up continuing until 2009 for 444, with an average of 10.5 years before censoring. Multivariate age-stratified Cox regression models were controlled for history of hypertension, diabetes, myocardial infarction, cancer, and major depression.
Adjusted survival functions estimated 61% survival (54%–69%, 95% C.I.) for those with sleep less than 300 min and 78% survival (73%–85%, 95% C.I.) for those with actigraphic sleep longer than 390 min, as compared with survival of 90% (85%–94%, 95% C.I.) for those with sleep of 300–390 min. Time-in-bed, sleep efficiency and the timing of melatonin metabolite excretion were also significant mortality risk factors.
This study confirms a U-shaped relationship between survival and actigraphically measured sleep durations, with the optimal objective sleep duration being shorter than the self-report optimums. People who sleep five or six hours may be reassured. Further studies are needed to identify any modifiable factors for this mortality and possible approaches to prevention.
PMCID: PMC3010336  PMID: 20870457
Sleep; Epidemiology; Duration; Mortality; Survival; Time-in-bed; Melatonin
10.  Cardiovascular Disease, its Risk Factors and Treatment, and Age-related Macular Degeneration: Women’s Health Initiative Sight Exam Ancillary Study 
American journal of ophthalmology  2007;143(3):473-483.
To examine the association of cardiovascular disease (CVD), CVD risk factors, and CVD treatment with age-related macular degeneration (AMD).
Observational analysis of a randomized clinical trial.
The Women’s Health Initiative Sight Examination (WHISE), an ancillary study to the Women’s Health Initiative’s (WHI) clinical trial of hormone replacement therapy.
Study Population
4,288 women aged 63 years and older.
Observation Procedures
Information on CVD and its risk factors were obtained from a standardized questionnaire and examination.
Main Outcome Measure
AMD as determined by standardized grading of fundus photographs.
Prevalence of any AMD was 21.4% (n=919). Of those with AMD, 5.8% (n=53) had signs of exudative AMD (n=39) or pure geographic atrophy (n=14), limiting the power to examine associations. Significant associations between late AMD and CVD risk factors were (odds ratio [OR], 95% confidence interval [CI]) older age (1.19, 1.13, 1.27, p < 0.0001), more pack years smoked (1.02 per pack-year smoked, 1.003, 1.03, p = 0.01), systolic blood pressure (0.84 per 10 mmHg, 0.71, 0.995, p = 0.04), report of taking calcium channel blockers (CCB) (2.49, 1.21, 5.12, p = 0.04), self-reported history of diabetes (2.00, 1.01, 3.96, p = 0.05), and greater body mass index (1.05 per 1 kg/m2, 1.001, 1.10, p = 0.05). History of myocardial infarction, stroke, use of statins, or white blood cell were not associated with AMD.
Results suggest that smoking, use of CCBs, diabetes, and obesity are risk factors for late AMD in women. However, the association of late AMD with systolic blood pressure and the effects of other CVD risk factors on early AMD need to be further explored.
PMCID: PMC2812860  PMID: 17317391
Menopause (New York, N.Y.)  2010;17(6):1136-1145.
We assessed whether vasomotor symptoms (VMS) were associated with coronary artery calcium (CAC) and how hormone therapy may influence this association.
Subjects were a subset of women aged 50 to 59 and a history of hysterectomy that enrolled in the Women’s Health Initiative (WHI) clinical trial of estrogen alone and underwent a computed tomography scan of the chest at the end of the trial to determine CAC. Participants provided information about VMS (hot flashes and/or night sweats), as well as HT use, on self-administered questionnaires at trial baseline.
The sample consisted of 918 women with a mean (SD) age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score > 0 was 46%, while the prevalence of a CAC score ≥ 10 and > 100 was 39 and 19%, respectively. At randomization, 77% reported a history of any VMS at any time prior to or at enrollment in the WHI while 20% reported any VMS only present at enrollment. Compared to those without a history of any VMS and after adjustment for potential confounders, a history of any VMS at any time up to and including WHI enrollment was associated with a significantly reduced odds for CAC > 0 (Odds Ratio 0.66, 95% CI 0.45 – 0.98). Moreover, as duration of HT increased the inverse association between any VMS and CAC moved toward the null.
A history of any VMS was significantly associated with a reduced odds for CAC independent of traditional CVD risk factors and other relevant covariates. This association appears to be influenced by duration of hormone therapy.
PMCID: PMC3037019  PMID: 20651617
calcium; coronary; vasomotor symptoms; women; menopause; atherosclerosis
12.  Calcium/Vitamin D Supplementation and Coronary Artery Calcification 
Menopause (New York, N.Y.)  2010;17(4):683-691.
Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared coronary artery calcium scores among women randomized to calcium/vitamin D supplementation versus placebo following trial completion.
In an ancillary substudy of women randomized to calcium carbonate (1000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) versus placebo, nested within the Women’s Health Initiative trial of estrogen among women with hysterectomy, we measured CAC with cardiac computed tomography in 754 women aged 50–59 years at randomization. Imaging for CAC was performed at 28 of 40 centers following a mean of 7 years of treatment and scans were read centrally. Coronary artery calcium scores were measured by a central reading center with masking to randomization assignments.
Post-trial CAC measurements were similar in women randomized to calcium/vitamin D supplementation (calcium/D) and those receiving placebo. The mean CAC score was 91.6 for calcium/D and 100.5 for placebo (rank test p-value=0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, ≥10, and ≥100) for calcium/D vs placebo were 0.92 (95% confidence interval, 0.64–1.34), 1.29 (0.88–1.87), and 0.90 (0.56–1.44), respectively. Corresponding odds ratios among women with >50% adherence to study pills and for higher levels of CAC (>300), were similar.
Treatment with moderate doses of calcium plus vitamin D3 did not appear to alter coronary artery calcified plaque burden among postmenopausal women.
PMCID: PMC2940244  PMID: 20551849
calcium; vitamin D; supplementation; coronary artery calcification; coronary heart disease; women’s health
13.  Estrogen Alone in Postmenopausal Women and Breast Cancer Detection by Means of Mammography and Breast Biopsy 
Journal of Clinical Oncology  2010;28(16):2690-2697.
As the influence of estrogen alone on breast cancer detection is not established, we examined this issue in the Women's Health Initiative trial, which randomly assigned 10,739 postmenopausal women with prior hysterectomy to conjugated equine estrogen (CEE; 0.625 mg/d) or placebo.
Screening mammography and breast exams were performed at baseline and annually. Breast biopsies were based on clinical findings. Effects of CEE alone on breast cancer detection were determined by using receiver operating characteristic (ROC) analyses of mammogram performance.
After a 7.1-year mean follow-up, fewer invasive breast cancers were diagnosed in the CEE than in the placebo group, but the difference was not statistically significant. Use of CEE alone increased mammograms with short-interval follow-up recommendations (cumulative, 39.2% v 29.6.3%; P < .001) but not abnormal mammograms (ie, those suggestive of or highly suggestive of malignancy; cumulative, 7.3% v 7.0%; P = .41). Breast biopsies were more frequent in the CEE group (cumulative, 12.5% v 10.7%; P = .004) and less commonly diagnosed as cancer (8.9% v 15.8%, respectively, with positive biopsies; P = .04). Mammographic breast cancer detection in the CEE group was significantly compromised only in the early years of use.
CEE alone use for 5 years results in approximately one in 11 and one in 50 women having otherwise avoidable mammograms with short-interval follow-up recommendations or breast biopsies, respectively. Although the breast biopsies on CEE were less commonly diagnosed as cancer, breast cancer detection was not substantially compromised. These findings differ from estrogen-plus-progestin use, for which significantly increased abnormal mammograms and a compromise in breast cancer detection are seen.
PMCID: PMC2881849  PMID: 20439627
14.  Relationships among dietary nutrients and subjective sleep, objective sleep, and napping in women 
Sleep medicine  2009;11(2):180.
To describe which dietary nutrient variables are related to subjective and objective habitual sleep and subjective and objective napping.
Participants were 459 postmenopausal women enrolled in the Women’s Health Initiative. Objective sleep was estimated using one week of actigraphy. Subjective sleep was prospectively estimated with a daily sleep diary. Dietary nutrients were calculated from food frequency questionnaires.
The most significant correlations were with subjective napping, including (from strongest to weakest): total fat, calories, saturated fat, monounsaturated fat, trans fat, water, proline, serine, tyrosine, phenylalanine, valine, cholesterol, leucine, glutamic acid, ash, isoleucine, histidine, sodium, tryptophan, protein, threonine, cystine, methionine, phosphorous, polyunsaturated fat, animal protein, aspartic acid, arginine, lysine, alanine, caffeine, riboflavin, gamma-tocopherol, glycine, retinol, delta-tocopherol, vitamin D, and selenium. Actigraphic nocturnal sleep duration was negatively associated with total fat, monounsaturated fat, trans fat, saturated fat, polyunsaturated fat, calories, gamma-tocopherol, cholesterol, and alpha-tocopherol-eq.
Actigraphic total sleep time was negatively associated with intake of fats. Subjective napping, which may be a proxy for subjective sleepiness, was significantly related to fat intake as well as intake of meat.
PMCID: PMC2819566  PMID: 20005774
Sleep; Diet; Nutrition; Obesity; Napping; Sleep Duration; Women
15.  Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause 
American Journal of Epidemiology  2009;170(1):12-23.
The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.
PMCID: PMC2733042  PMID: 19468079
clinical trial; cohort studies; estrogens; estrogen replacement therapy; hormone replacement therapy; medroxyprogesterone 17-acetate; postmenopause; progestins
16.  Aspirin Use, Dose, and Clinical Outcomes in Postmenopausal Women with Stable Cardiovascular Disease: The Women’s Health Initiative Observational Study 
Despite compelling evidence that aspirin reduces fatal and non-fatal vascular events among the overall population in various settings, women have frequently been underrepresented and their data underreported. We sought to evaluate the relationship between aspirin use, dose (81 or 325mg) and clinical outcomes among postmenopausal women with stable cardiovascular disease.
Women with cardiovascular disease (n=8928) enrolled in the Women’s Health Initiative Observational Study were used for this analysis. The primary outcome was the incidence of all-cause mortality and cardiovascular events (myocardial infarction, stroke and cardiovascular death).
Among 8928 women with stable cardiovascular disease, 4101 (46%) reported taking aspirin, of whom 30% were on 81 and 70% were on 325mg. At 6.5 years of follow-up, no significant association was noted for aspirin use and all-cause mortality or cardiovascular events. However, after multivariate adjustment, aspirin use was associated with a significantly lower all-cause (adjusted HR 0.86, [0.75-0.99], P=0.04) and cardiovascular related mortality (adjusted HR 0.75, [0.60-0.95], P=0.01) compared with no aspirin. Aspirin use was associated with a lower risk of cardiovascular events (adjusted HR 0.90, [0.78-1.04], P=0.14) which did not meet statistical significance. Compared with 325mg, use of 81mg was not significantly different for all-cause mortality, cardiovascular events or any individual endpoint.
After multivariate adjustment, aspirin use was associated with significantly lower risk of all-cause mortality, specifically cardiovascular mortality, among postmenopausal women with stable cardiovascular disease. No significant difference was noted between 81 and 325mg of aspirin. Overall, aspirin use was low in this cohort of women with stable cardiovascular disease.
PMCID: PMC2801891  PMID: 20031819
Aspirin; Dose; Women; Cardiovascular Disease; Observational Study
17.  Oophorectomy, hormone therapy, and subclinical coronary artery disease in women with hysterectomy: the Women’s Health Initiative coronary artery calcium study 
Menopause (New York, N.Y.)  2008;15(4 Pt 1):639-647.
Surgical menopause has been associated with an increased risk of coronary heart disease events. In this study, we aimed to determine the associations between coronary artery calcium (CAC) and hysterectomy, oophorectomy, and hormone therapy use with a focus on the duration of menopause for which there was no hormone therapy use.
In a substudy of the Women’s Health Initiative placebo-controlled trial of conjugated equine estrogens (0.625 mg/d), we measured CAC by computed tomography 1.3 years after the trial was stopped. Participants included 1,064 women with previous hysterectomy, aged 50 to 59 years at baseline. The mean trial period was 7.4 years. Imaging was performed at a mean of 1.3 years after the trial was stopped.
Mean age was 55.1 years at randomization and 64.8 years at CAC measurement. In the overall cohort, there were no significant associations between bilateral oophorectomy, years since hysterectomy, years since hysterectomy without taking hormone therapy (HT), years since bilateral oophorectomy, and years of HT use before Women’s Health Initiative enrollment and the presence of CAC. However, there was a significant interaction between bilateral oophorectomy and prerandomization HT use for the presence of any CAC (P = 0.05). When multivariable analyses were restricted to women who reported no previous HT use, those with bilateral oophorectomy had an odds ratio of 2.0 (95% CI: 1.2–3.4) for any CAC compared with women with no history of oophorectomy, whereas among women with unilateral or partial oophorectomy, the odds of any CAC was 1.7 (95% CI: 1.0–2.8). Among women with bilateral oophorectomy, HT use within 5 years of oophorectomy was associated with a lower prevalence of CAC.
Among women with previous hysterectomy, subclinical coronary artery disease was more prevalent among those with oophorectomy and no prerandomization HT use, independent of traditional cardiovascular disease risk factors. The results suggest that factors related to oophorectomy and the absence of estrogen treatment in oophorectomized women may be related to coronary heart disease.
PMCID: PMC2751659  PMID: 18458645
Calcium; Coronary; Oophorectomy; Hormone therapy; Women; Coronary artery disease; Atherosclerosis
18.  FTO Polymorphisms Are Associated With Obesity but Not Diabetes Risk in Postmenopausal Women 
Obesity (Silver Spring, Md.)  2008;16(11):2472-2480.
The FTO gene was recently identified as a susceptibility locus for both obesity and type 2 diabetes by whole-genome association analyses of several European populations. We tested for an association between FTO risk alleles and obesity and diabetes in a well-characterized multiethnic cohort of postmenopausal women in the United States. We genotyped two most significantly associated single-nucleotide polymorphisms (SNPs) (rs9939609 and rs8050136) in intron 1 of FTO gene in a nested case–control study of 1,517 diabetes cases and 2,123 controls from the Women’s Health Initiative–Observational Study (WHI-OS). The allelic frequencies of either rs9939609 or rs8050136 differed widely across four ethnic groups. The frequency of the rare allele A of rs9939609 among controls was much lower in Asians/Pacific Islanders (17%) than in blacks (45%), whites (40%), and Hispanics (31%). We found significant associations of rs9939609 with BMI and waist circumference in white and Hispanic women, but not among black and Asian/Pacific Islander women. On average, each copy of the risk-allele A at rs9939609 was significantly associated with 0.45 kg/m2 increase in BMI (95% confidence interval (CI): 0.16–0.74; P = 0.004) and 0.97 cm increase in waist circumference (95% CI: 0.21–0.65; P = 0.0002). Similar results were observed for rs8050136. However, we found no significant genetic associations with diabetes risk, either within the full study sample or in any ethnic group. In conclusion, common genetic variants in the intron 1 of FTO gene may confer a modest susceptibility to obesity in an ethnicity-specific manner, but may be unlikely to contribute to a clinically significant diabetes risk.
PMCID: PMC2732012  PMID: 18787525
19.  Conjugated Equine Estrogens and Breast Cancer Risk in the Women’s Health Initiative Clinical Trial and Observational Study 
American journal of epidemiology  2008;167(12):1407-1415.
The Women’s Health Initiative randomized controlled trial found a trend (p = 0.09) toward a lower breast cancer risk among women assigned to daily 0.625-mg conjugated equine estrogens (CEEs) compared with placebo, in contrast to an observational literature that mostly reports a moderate increase in risk with estrogenalone preparations. In 1993–2004 at 40 US clinical centers, breast cancer hazard ratio estimates for this CEE regimen were compared between the Women’s Health Initiative clinical trial and observational study toward understanding this apparent discrepancy and refining hazard ratio estimates. After control for prior use of postmenopausal hormone therapy and for confounding factors, CEE hazard ratio estimates were higher from the observational study compared with the clinical trial by 43% (p = 0.12). However, after additional control for time from menopause to first use of postmenopausal hormone therapy, the hazard ratios agreed closely between the two cohorts (p = 0.82). For women who begin use soon after menopause, combined analyses of clinical trial and observational study data do not provide clear evidence of either an overall reduction or an increase in breast cancer risk with CEEs, although hazard ratios appeared to be relatively higher among women having certain breast cancer risk factors or a low body mass index.
PMCID: PMC2703736  PMID: 18448442
breast neoplasms; clinical trial; cohort studies; estrogens; hormone replacement therapy; postmenopause
20.  Risk Factors for Chronic Venous Disease: the San Diego Population Study 
The etiology of chronic venous disease in the lower limbs is unclear, and there are very limited data on potential risk factors from representative population studies.
Participants in the San Diego Population Study, a free-living adult population randomly selected from age, sex and ethnic strata, were systematically assessed for risk factors for venous disease. Categorization of normal, moderate disease and severe disease was determined hierarchically through clinical examination and ultrasound sonography by trained vascular technologists, who also performed anthropometric measures. An interviewer administered questionnaire and examination assessed potential risk factors for venous disease suggested by previous reports.
In multivariable models, moderate venous disease was independently related to age, a family history of venous disease, previous hernia surgery, and normotension in both sexes. In men, current walking, the absence of cardiovascular disease, and not moving after sitting were also predictive, while in women, additional predictors were weight, number of births, oophorectomy, flat feet, and not sitting. For severe disease, age, family history of venous disease, waist circumference, and flat feet were predictive in both sexes. In men, occupation as a laborer, cigarette smoking, and normotension were also independently associated with severe venous disease, while in women additional significant and independent predictors were hours standing, history of leg injury, number of births, and cardiovascular disease, while African-American ethnicity was protective. Multiple other postulated risk factors for venous disease were not significant in multivariable analysis in this population.
Although some risk factors for venous disease such as age, family history of venous disease, and findings suggestive of ligamentous laxity (hernia surgery, flat feet) are immutable, others can be modified, such as weight, physical activity, and cigarette smoking. Overall, these data provide modest support for the potential of behavioral risk factor modification to prevent chronic venous disease.
PMCID: PMC2023874  PMID: 17600666
veins; peripheral vascular diseases; risk factors; epidemiology; varicose veins; venous insufficiency
21.  Self-Reported Sleep Latency in Postmenopausal Women 
Journal of Korean Medical Science  2007;22(6):1007-1014.
The ain of this study was to access how self-reported sleep latency (SRSL) was affected by sleep habits, mood, and circadian rhythm in postmenopausal women. Subjects (n=384, 67.9±7.7 yr) completed sleep and mood questionnaires, sleep log and actigraphic data. The major urinary melatonin metabolite (6-sulphatoxymelatonin, aMT6s) was assayed in fractional urine specimens for two 24-hr intervals. Although SRSL (26.5±24.4 min) and actigraphic sleep latency (ASL; 27.8±20.0 min) were correlated (rs=0.361, p<0.001), the short SRSLs tended to be underestimated whereas the long SRSLs tended to be overestimated as compared to ASL. SRSL was positively correlated with the scales of insomnia, mood and hot flash, hypertension, use of anti-hypertensive drugs and the acrophase and the offset of aMT6s. SRSL was negatively correlated with the global assessment of functioning scale in DSM-IV (GAF scale), and light exposure and wrist activity. Multiple linear regression analysis showed that the best-fit model to predict SRSL was light exposure, GAF scale, and use of anti-hypertensive drugs. SRSL may be determined by psychophysiological factors as well as circadian rhythm function. Therapeutic approaches suggested for trouble falling asleep might include increased daylight exposure, improvements in general health, and modification of anti-hypertensive pharmacotherapy.
PMCID: PMC2694625  PMID: 18162715
Sleep Latency; Postmenopause; Circadian Rhythm; Sleep Initiation and Maintenance Disorders; Depression
22.  Impact of Cyclooxygenase Inhibitors in the Women's Health Initiative Hormone Trials: Secondary Analysis of a Randomized Trial 
PLoS Clinical Trials  2006;1(5):e26.
We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials.
The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6.
The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States.
The trials enrolled 27,347 postmenopausal women, aged 50–79 y.
We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
Outcome Measures:
Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68–1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86–2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57–1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69–1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified.
Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results.
Editorial Commentary
Background: As part of a set of studies known as the Women's Health Initiative trials, investigators aimed to find out whether providing postmenopausal hormone therapy (estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced cardiovascular risk as compared to placebo. Earlier observational studies had suggested this might be the case. The trials found that postmenopausal hormone therapy did not reduce cardiovascular risk in the groups studied. However, there was a concern that medication use outside the trial with nonsteroidal anti-inflammatory drugs (NSAIDs), and specifically the type of NSAID known as COX-2 inhibitors, could have affected the findings. This concern arose because it is known that COX-2 inhibition lowers levels of prostacyclin, a molecule thought to be beneficial to cardiovascular health, whereas estrogen increases prostacyclin levels. Evidence from randomized trials and observational studies has also shown that patients treated with some COX-2 inhibitors are at increased risk of heart attacks and strokes; the cardiovascular safety of other NSAIDs is also the focus of great attention. Therefore, the authors of this paper aimed to do a statistical exploration of the data from the Women's Health Initiative hormone trials, to find out whether NSAID use by participants in the trials could have affected the trials' main findings.
What this trial shows: In this reanalysis of the original data from the trials, the investigators found that the effects of hormone therapy on cardiovascular outcomes were similar among users and non-users of NSAIDs, confirming that use of these drugs did not significantly affect the results from the Women's Health Initiative hormone trials.
Strengths and limitations: The original hormone trials were large, appropriately randomized studies that enrolled a diverse cohort of participants. Therefore, a large number of cardiovascular events occurred in the groups being compared, allowing this subsequent analysis to be done. One limitation is that use of COX-2 inhibitors in the trial was low; therefore, the investigators were not able to specifically test whether COX-2 inhibitor use (as opposed to NSAID use generally) might have affected their findings.
Contribution to the evidence: The investigators did not set out specifically to evaluate the cardiovascular safety of particular medications in this study. Rather, they wanted to see if these NSAIDs could have modified the effects of the hormone therapy. The secondary analysis done here shows that the main findings from the Women's Health Initiative hormone trials were not significantly affected by use of NSAIDs outside the trial.
PMCID: PMC1584256  PMID: 17016543
23.  Ethnicity, sleep, mood, and illumination in postmenopausal women 
BMC Psychiatry  2004;4:8.
This study examined how ethnic differences in sleep and depression were related to environmental illumination and circadian rhythms.
In an ancillary study to the Women's Health Initiative, 459 postmenopausal women were recorded for one week in their homes, using wrist monitors. Sleep and illumination experience were estimated. Depression was self-rated with a brief adjective check list. Affective diagnoses were made using the SCID interview. Sleep disordered breathing was monitored with home pulse oximetry.
Hispanic and African-American women slept less than European-American women, according to both objective recordings and their own sleep logs. Non-European-American women had more blood oxygen desaturations during sleep, which accounted for 26% of sleep duration variance associated with ethnicity. Hispanic women were much more depressed. Hispanic, African-American and Native-American women experienced less daily illumination. Less daily illumination experience was associated with poorer global functioning, longer but more disturbed sleep, and more depression.
Curtailed sleep and poor mood were related to ethnicity. Sleep disordered breathing was a factor in the curtailed sleep of minority women. Less illumination was experienced by non-European-American women, but illumination accounted for little of the contrasts between ethnic groups in sleep and mood. Social factors may be involved.
PMCID: PMC400740  PMID: 15070419
24.  TALMRS: Time-Affinity Linked Medical Record System 
Use of relational data base techniques allows the development of a three dimensional medical record system in which data relevant to multiple problems need only be entered once, but may be presented in an essentially unlimited number of contexts. This Time-Affinity Linked Medical Record System (TALMRS) builds upon and extends the concepts of the Problem Oriented Medical Record (POMR). Links which enable the user to view the data in many different ways make it possible for the same record to be productively used by persons with interest in very different, yet overlapping, data sets, such as an internist and a psychiatrist, without the need for duplication. Furthermore views may be used concurrently, retrospectively or even prospectively to evaluate the record for a pattern either provided by, or of interest to, an expert or subspecialist.
PMCID: PMC2245127

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