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The intervention phase ran from December 1, 1993, to February 29, 2004. The postintervention phase began on March 1, 2004, the day participants were instructed to stop study medication use (conjugated equine estrogens or placebo) and continued through the original trial completion date (March 31, 2005). The postintervention extension phase began on April 1, 2005, and includes follow-up for participants who provided additional consent (78% of those eligible) through August 14, 2009.
The hazard ratios (HRs) are derived from proportional hazards models stratified by prior disease (for outcomes in which women were eligible for enrollment with and without the prevalent condition), age, and dietary modification randomization group. The P values for differences between the intervention and postintervention phases were calculated from models for the overall mean follow-up period that also included a time-dependent term for trial phase. For the intervention and overall phases, time to event equals 0 on date of randomization. For the postintervention phase, time to event equals 0 on February 29, 2004. CABG indicates coronary artery bypass graft; CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction; and PTCA, percutaneous transluminal coronary angioplasty.
Vertical dotted lines represent quintiles of duration of intended intervention and follow-up in the study population (elapsed time from randomization until the end of the intervention on February 29, 2004). CEE indicates conjugated equine estrogens.aIncludes events from randomization to August 14, 2009.bIncludes events from March 1, 2004, to August 14, 2009.
Annualized incidence rates were estimated for the overall follow-up period by dividing the number of events by the corresponding person-time for participants in each age stratum. The black squares indicate the HRs for the overall follow-up period. For comparison, the HRs for the intervention phase are shown as blue bars. CEE indicates conjugated equine estrogen; CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction.
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LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial. JAMA. 2011;305(13):1305–1314. doi:10.1001/jama.2011.382
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Author Affiliations: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington (Dr LaCroix and Mr Aragaki); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California (Dr Chlebowski); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts (Dr Manson); Health Science Center, Department of Preventive Medicine, University of Tennessee, Memphis (Dr Johnson); Department of Cardiology, George Washington University, Washington, DC (Dr Martin); Berman Center for Clinical Research, University of Minnesota, Minneapolis (Dr Margolis); Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California (Dr Stefanick); Health Science Center, University of Texas, San Antonio (Dr Brzyski); John A. Burns School of Medicine, University of Hawaii and Pacific Health Research Institute, Honolulu (Dr Curb); MedStar Research Institute, Hyattsville, Maryland (Dr Howard); Division of Preventive Medicine, University of Alabama, Birmingham (Dr Lewis); and Department of Social and Preventive Medicine, State University of New York, Buffalo (Dr Wactawski-Wende).
Context The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.
Objective To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.
Design, Setting, and Participants The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.
Main Outcome Measures The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.
Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).
Conclusions Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.
Trial Registration clinicaltrials.gov Identifier: NCT00000611
The Women's Health Initiative (WHI) Estrogen-Alone Trial was a double-blind, placebo-controlled, randomized clinical trial evaluating the effects of conjugated equine estrogens (CEE) on chronic disease incidence among postmenopausal women with prior hysterectomy. The trial intervention was stopped 1 year early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned termination date. Analyses of outcomes during the intervention period suggested that treatment effects differed by age; compared with older women, younger women receiving CEE had a lower risk of coronary heart disease (CHD), colorectal cancer, total death, and the global index of chronic diseases.1 However, the tests for interaction of age with treatment were only statistically significant for colorectal cancer.1
All previous reports of this trial were limited to outcomes occurring during the intervention phase. Herein, we report data on postintervention outcomes through a mean of 10.7 years of follow-up. This preplanned analysis had 3 objectives: (1) to assess the long-term effects of the CEE intervention on health outcomes; (2) to determine whether effects of CEE on health outcomes differed between the intervention and postintervention periods; and (3) to determine if previously identified suggestions of age-specific differences in effects of CEE on health outcomes persisted after stopping the intervention.
Details of the WHI Estrogen-Alone Trial have been published.1,2 Briefly, postmenopausal women aged 50 to 79 years were recruited at 40 US clinical centers between 1993 and 1998. Women were eligible if they had a prior hysterectomy, were not taking hormone therapy, and had an anticipated 3-year survival. Women were excluded if they had prior breast cancer or other cancer within 10 years (except non–melanoma skin cancer), or prior venous thromboembolism (if screened after 1997). The study protocol was approved by institutional review boards at the participating institutions and all participants provided written informed consent.
A total of 10 739 women were randomly assigned to receive orally either 0.625 mg/d of CEE (Premarin, Wyeth Ayerst, Philadelphia, Pennsylvania) or matching placebo. Randomization was implemented at the WHI Clinical Coordinating Center using a permuted block algorithm, stratified by clinical center and age group.1 The clinical trial target size of 12 375 was calculated to provide 81% power to detect a 21% reduction in CHD at 9 years of follow-up. With the actual randomized sample size, the power estimate was 72% for a 21% reduction in CHD.
When the intervention phase ended after a mean of 7.1 years on February 29, 2004, vital status was known for 95% of participants, of whom 5.4% were deceased. By this time, 54% of participants had stopped taking their study medication. Median time receiving treatment was 5.9 years in the CEE group vs 5.8 years in the placebo group (interquartile range, 2.5-7.3 years). The median adherent time receiving treatment (ingestion of >80% of study pills) was 3.5 years in both groups (interquartile range, 1.5-6.5 years).
Clinical outcomes were collected through semiannual mailed questionnaires and annual clinic visits. Outcomes were verified3 initially by trained physician adjudicators at the local clinical centers by medical record review, followed by final adjudication at the WHI Clinical Coordinating Center. All adjudicators were blinded to treatment assignment.
Demographic characteristics and medical history were collected by self-report using standardized questionnaires. Race/ethnicity was reported by participants within predefined categories matching the US Census. This information was required by the funding agency to monitor nonwhite representation in the trial.
The postintervention period began on March 1, 2004, when participants were instructed to discontinue taking the study pills. The current report reflects a mean (SD) postintervention follow-up duration of 47.2 (20.7) months through August 14, 2009. After the protocol-specified termination date of March 31, 2005, subsequent participant follow-up required additional written consent, which was obtained from 77.9% of surviving participants in the CEE group (n = 3778) and 78.4% of surviving participants in the placebo group (n = 3867). The outcomes identified from the annual mailed questionnaires were verified by medical record review as described.3 Annual mammograms were encouraged and tracked by annual mammography report review. During the postintervention period, 3.6% to 4.7% of women from the CEE group and 2.7% to 3.0% of women from the placebo group reported estrogen-alone use (any route of administration) on annual questionnaires.
The primary analyses included all randomized participants using time-to-event methods and were based on the intention-to-treat principle as described previously.4 Thus, all participants were included in the analyses according to their randomized group assignment until they provided their last follow-up information (Figure 1). Baseline characteristics for women who provided additional consent were compared by randomization group using χ2 and t test statistics.
Annualized rates of clinical events were estimated for the intervention period, the postintervention period, and the entire follow-up period by dividing the number of events by the corresponding person-time in each phase. Cumulative incidence curves were drawn for each trial phase with quintiles of intended duration of intervention (ie, elapsed time from randomization until the intervention ended on February 29, 2004). The hazard ratios (HRs) were estimated using Cox proportional hazards models5 stratified by age, prior disease (if appropriate), and randomization status in the WHI Dietary Modification Trial.6 Models were constructed for each clinical end point in which women contributed follow-up time until the end of the interval, the date of their first relevant clinical event, or the date of death or withdrawal from the study (whichever came first). Formal tests of the differences between the HRs in the intervention compared with the postintervention phase were calculated by inclusion of a binary term for trial phase as a time-dependent variable as described.4 Absolute rates and attributable risks (rate differences between CEE and placebo groups) also were calculated. All statistical tests were 2-sided.
Nominal P values are reported without adjustment for multiple outcomes or sequential looks during the clinical trial follow-up period. Age-stratified subgroup analyses are reported for 10 outcomes. At the .05 level of significance, 0 to 1 interaction P values could be statistically significant based on chance alone.
To determine whether not providing consent to postintervention follow-up influenced risk estimates, inverse-probability weighting analyses were conducted using the methods described.4 Adherence sensitivity analyses also were conducted by censoring follow-up at 6 months after participants became nonadherent (ingestion of <80% of study pills or starting nonprotocol hormone therapy). For these analyses, participants who provided additional consent or were adherent were included in analyses that used the inverse of the participant's estimated reconsent or adherence probability as a weighting factor.
All statistical analyses were conducted using SAS software version 9.2 (SAS Institute Inc, Cary, North Carolina) and R software version 2.11 (R Foundation for Statistical Computing, http://www.r-project.org/).
Participant movement through the study is outlined in Figure 1. Among the women who provided additional consent, baseline characteristics remained similar to those previously published1 and were evenly distributed by randomized treatment assignment (Table). Small differences were observed for parity and bilateral oophorectomy between randomization groups. A comparison of the percentage of trial participants who consented to additional follow-up by treatment group is provided in eTable 1.
Incident clinical events by randomization assignment and corresponding HRs for the intervention, postintervention, and overall follow-up periods are summarized in Figure 2 and eTable 2. The HRs for CHD during the postintervention follow-up period were close to unity and similar to those observed during the intervention (Figure 2 and Figure 3). The increased stroke risk seen during the intervention phase was not present during the postintervention phase (0.36% [n = 66] in the CEE group vs 0.41% [n = 77] in the placebo group; HR, 0.89 [95% confidence interval {CI}, 0.64-1.24]; P = .05 for difference). Similarly, the increase in deep vein thrombosis and pulmonary embolism with CEE use compared with placebo during the intervention phase was not maintained during the postintervention phase (0.28% [n = 52] vs 0.39% [n = 74], respectively; HR, 0.72 [95% CI, 0.51-1.03]). For all cardiovascular events, the cumulative HR associated with CEE use was 1.06 (95% CI, 0.98-1.15) (2.26% in the CEE group [n = 1146] vs 2.12% in the placebo group [n = 1113]; Figure 2).
During the postintervention phase, 81.2% of women in the CEE group and 81.3% of women in the placebo group had at least 1 mammogram. The HRs comparing rates of invasive breast cancer in women randomized to CEE vs placebo were similar during the intervention (HR, 0.79; 95% CI, 0.61-1.02) and postintervention phases (HR, 0.75; 95% CI, 0.51-1.09) (Figure 2 and Figure 3). Consequently, a statistically significant lower cumulative breast cancer incidence of 0.27% was seen in the CEE group (n = 151) compared with 0.35% in the placebo group (n = 199) (HR, 0.77 [95% CI, 0.62-0.95]; P = .02). Colorectal cancer incidence did not differ between the women in the CEE group and the placebo group during the intervention or postintervention periods (Figure 2 and Figure 4).
The reduced hip fracture risk seen during the intervention phase with CEE was not maintained in the postintervention phase (0.36% in the CEE group [n = 66] vs 0.28% in the placebo group [n = 53]) (HR, 1.27 [95% CI, 0.88-1.82]; P = .01 for difference; Figure 2) resulting in an overall HR of 0.92 (95% CI, 0.71-1.18]; 0.20% in the CEE group [n = 114] vs 0.22% in the placebo group [n = 127]). During the postintervention phase, hip fracture incidence was slightly higher in the CEE group compared with the placebo group (Figure 4). Randomization to CEE did not influence total mortality or the global index of chronic diseases either during the intervention phase or during the postintervention phase (Figure 2 and Figure 4).
The age-specific intervention results for a mean follow-up of 10.7 years are displayed in Figure 5. The overall HRs for CHD differed among women aged 50 to 59 years (HR, 0.59 [95% CI, 0.38-0.90]; 0.18% [n = 33] in the CEE group vs 0.31% in the placebo group [n = 56]) compared with older women in which the HRs were near unity (P = .05 for interaction). For total myocardial infarction (MI), the HR was 0.54 (95% CI, 0.34-0.86; 0.15% in the CEE group [n = 27] vs 0.27% in the placebo group [n = 50]) for women aged 50 to 59 years; 1.05 (95% CI, 0.82-1.35; 0.51% [n = 126] vs 0.48% [n = 124], respectively) for women aged 60 to 69 years; and 1.23 (95% CI, 0.92-1.65; 0.82% [n = 101] vs 0.66% [n = 84], respectively) for women aged 70 to 79 years (P = .007 for interaction). A similar pattern was seen when time since menopause (as previously defined7) instead of age was examined for both coronary end points (data not shown). Overall, stroke risks were nonsignificantly elevated for all age groups (P = .91 for interaction). For deep vein thrombosis and pulmonary embolism, no age-specific differences emerged but the increased risks observed during the intervention phase subsided during the postintervention phase.
There were fewer invasive breast cancers in the CEE group compared with the placebo group in all 3 age groups (P = .96 for interaction). The previously observed age interaction for colorectal cancer was significant throughout the entire follow-up period. Women aged 70 to 79 years at entry experienced a nearly 2-fold increased risk of colorectal cancer in the CEE group (0.30% [n = 38] vs 0.16% in the placebo group [n = 21]) (HR, 1.83 [95% CI, 1.08-3.12]; P = .04 for interaction).
The HRs for total mortality and the global index of chronic diseases differed by age as previously suggested.7 Younger postmenopausal women (aged 50-59 years) who were randomized to CEE vs placebo had a lower risk of death (0.35% [n = 65] vs 0.48% [n = 89], respectively; HR, 0.73 [95% CI, 0.53-1.00]) compared with no increased risk among women in their 60s (1.00% [n = 254] vs 0.96% [n = 253], respectively; HR, 1.04 [95% CI, 0.88-1.24]), and a slight increased risk of death among women in their 70s (2.02% [n = 258] vs 1.83% [n = 239], respectively; HR, 1.12 [95% CI, 0.94-1.33]; P = .04 for interaction). A similar pattern was observed by age for women randomized to CEE vs placebo for the global index of chronic diseases with a possible overall benefit among younger women (aged 50-59 years: 1.04% [n = 184] vs 1.22% [n = 217], respectively; HR, 0.85 [95% CI, 0.70-1.03]) and possible harm among the oldest women (aged 70-79 years: 4.04% [n = 466] vs 3.56% [n = 423], respectively; HR, 1.15 [95% CI, 1.01-1.32]; P = .009 for interaction).
Expressed as absolute rates per 10 000 women annualized over the average follow-up period of 10.7 years, women aged 50 to 59 years who received CEE compared with women who received placebo had 12 fewer acute MIs, 13 fewer deaths, and 18 fewer adverse events in the global index of chronic diseases. In contrast, women aged 70 to 79 years who received CEE compared with women who received placebo had 16 excess MIs, 19 excess deaths, and 48 excess adverse events in the global index of chronic diseases.
The results were similar when using inverse-probability weighting to account for censoring due to those not providing consent for postintervention follow-up. The HR for breast cancer for the cumulative follow-up period became 0.81 (95% CI, 0.64-1.01). Age-stratified results were virtually identical to those described herein with P values for interaction reflecting some loss of precision with the inverse-probability weights: CHD (P = .23); total MI (P = .01); colorectal cancer (P = .09); death (P = .13); and global index of chronic diseases (P = .02). In each case, women in their 50s had more favorable HRs than older women (aged 70-79 years).
The results also were similar when women were censored 6 months after becoming nonadherent to study medication during the intervention period. Adherence-adjusted HRs for the overall follow-up period using inverse-probability weighting showed an increased risk of stroke with CEE use (HR, 1.50; 95% CI, 1.11-2.05) and a lower risk of breast cancer (HR, 0.68; 95% CI, 0.49-0.95). No significant age interactions emerged for any outcome in the adherence-adjusted analyses; however, power was limited due to substantial censoring.
Among postmenopausal women with prior hysterectomy who stopped taking CEE after a median of 5.9 years of use, several patterns of health risks and benefits seen during the intervention period were not maintained during the postintervention period, while other trends persisted. For CHD (a primary trial end point), the HRs remained null after stopping the intervention and overall. The increases in risk of stroke and venous thromboembolism seen among women randomized to CEE during the intervention period rapidly dissipated during the postintervention period as did the protective effect on risk of hip fracture. The lower incidence of breast cancer seen among women randomized to CEE during the intervention period became statistically significant with extended follow-up. Considering the entire follow-up period, rates of total mortality and the global index of chronic diseases were essentially the same in the CEE and placebo groups. Statistically significant age interactions for CEE use, suggesting greater safety and possible benefit among women in their 50s and potential harm among older women, were observed for CHD, total MI, colorectal cancer, total mortality, and the global index of chronic diseases.
The statistically significant reduction in breast cancer incidence seen with CEE use continued a trend that emerged during the intervention period.8,9 This finding differs from the preponderance10-12 but not all13,14 observational studies that suggest CEE use, especially in lean women15,16 and after long duration of exposure,17 increases breast cancer incidence. We previously reported no significant differences by body mass index for CEE effects on breast cancer incidence among participants in this trial.8 Investigators from the Million Women Study have suggested,18 based on recent findings,9,19,20 that time from menopause (longer in the WHI vs shorter in usual clinical practice and observational study cohorts) may account for some of the differences in risk estimates from various studies. Alternatively, confounding by differential mammogram use in the observational studies (higher in estrogen users) may explain the finding of higher breast cancer incidence among hormone therapy users.20 Future subgroup analyses in this trial, which are beyond the scope of the current study, will explore this issue.
It is unlikely that diagnostic delay explains our breast cancer results because CEE only modestly influenced breast density21 and mammogram diagnostic performance.22 In terms of biological plausibility, preclinical23,24 and clinical25 studies suggest that the adaptive changes to gene expression profiles that occur during estrogen exposure and after estrogen deprivation26 may render mammary tumors susceptible to inhibition by estrogen. In contrast to these results from the Estrogen-Alone Trial, the WHI combined Estrogen Plus Progestin Trial showed that treatment impeded mammographic accuracy, and was associated with significant increase in rates of both breast cancer incidence and breast cancer mortality.27-29
With extended follow-up, hip fracture cumulative incidence was the same in the CEE and placebo groups. Rates of hip fracture were somewhat higher among women in the CEE group compared with those in the placebo group after stopping the intervention. These results are consistent with studies showing accelerated bone loss30 and a short-term increased risk of hip fracture among women who discontinue hormone therapy,31 and no fracture risk reduction or elevation in past hormone therapy users.32,33
Our results suggest that women randomized to CEE while in their 50s had fewer CHD events than those randomized to placebo, findings that are supported by preclinical34 and clinical data35-37 but are not applicable to older women. In a subset of WHI participants aged 50 to 59 years at study entry, coronary artery calcium measurements, which are markers for atherosclerotic plaque burden, were lower following trial completion among women randomized to CEE vs placebo.35 Other support derives from nonhuman primate models36 and observational studies.38-40 An important caveat is that study participants took unopposed estrogen for a median duration of less than 6 years and our results cannot be extrapolated to longer or shorter treatment durations.
Our results emphasize the need to counsel women about hormone therapy differently depending on their age and hysterectomy status. A postmenopausal woman who has had a hysterectomy and is considering initiation of CEE should be counseled about the increased risks of venous thromboembolism and stroke during treatment, which diminish with treatment cessation. Among younger women, no new safety concerns emerged and some risk reductions became apparent during the postintervention period. Among older women, risks of colorectal cancer, death, and the global index of chronic diseases were elevated over the cumulative follow-up period. The risks and benefits of CEE use for periods of longer than 5 to 6 years cannot be inferred from these data for any age group. Mechanisms underlying the reduced risks of breast cancer in all women, and coronary events in younger but not older women, warrant further study.
Corresponding Author: Andrea Z. LaCroix, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M3-A410, PO 19024, Seattle, WA 98109 (email@example.com).
Author Contributions: Dr LaCroix had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Manson, Margolis, Stefanick, Wactawski-Wende.
Acquisition of data: LaCroix, Chlebowski, Manson, Johnson, Margolis, Stefanick, Brzyski, Curb, Howard, Wactawski-Wende.
Analysis and interpretation of data: LaCroix, Chlebowski, Manson, Aragaki, Johnson, Martin, Margolis, Curb, Howard, Lewis, Wactawski-Wende.
Drafting of the manuscript: LaCroix, Manson, Aragaki.
Critical revision of the manuscript for important intellectual content: LaCroix, Chlebowski, Manson, Johnson, Martin, Margolis, Stefanick, Brzyski, Curb, Howard, Lewis, Wactawski-Wende.
Statistical analysis: LaCroix, Aragaki.
Obtained funding: LaCroix, Chlebowski, Manson, Johnson, Stefanick, Curb, Howard, Lewis, Wactawski-Wende.
Administrative, technical, or material support: Chlebowski, Manson, Johnson, Brzyski, Curb, Lewis, Wactawski-Wende.
Study supervision: LaCroix, Johnson, Margolis, Curb, Howard, Wactawski-Wende.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr LaCroix reported serving on scientific advisory committees for research studies funded by Warner Chilcott and sanofi-aventis, Amgen, and Pfizer. Dr Chlebowski reported being a consultant for AstraZeneca, Novartis, Amgen, and Pfizer; receiving funding support from Amgen; and serving on speaker's bureaus for AstraZeneca and Novartis. Dr Howard reported receiving payment for lectures, serving on a speaker's bureau, and being a consultant for Merck/Schering-Plough Wyeth Research; and receiving research support through the donation of drugs from Merck/Schering-Plough. None of the other authors reported any financial disclosures.
Funding/Support: Wyeth Ayerst donated the study drugs. The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.
Role of the Sponsor: Committees of the Women's Health Initiative investigators that included representatives from the National Heart, Lung, and Blood Institute (the study's sponsor) had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript. The Women's Health Initiative Project Office at the National Heart, Lung, and Blood Institute approved the manuscript but had no other role.
Women's Health Initiative Investigators: A full listing of Women's Health Initiative investigators can be found at http://whiscience.org/publications/WHI_investigators_longlist_2005-2010.pdf.
Additional Contributions: We thank the Women's Health Initiative investigators and staff for their outstanding dedication and commitment.


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subset: commoncrawl


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LEXINGTON, Ky. -- Kentucky's starting lineup of three freshmen and two sophomores did most everything together. Now, they will go their separate ways in the NBA.
Freshmen Anthony Davis, Michael Kidd-Gilchrist and Marquis Teague, and sophomores Terrence Jones and Doron Lamb declared for the draft in a nationally televised news conference Tuesday night.
"We made it work," Jones said. "We all wanted to be there and do it together like we've done everything else together."
The group, all clad in similar blue UK golf shirts, came into the season largely untested before ascending to No. 1, winning the Southeastern Conference in dominating fashion and capping an NCAA tournament run with a 67-59 victory over Kansas in the title game for the school's eighth championship.
"It's been a great opportunity playing here. I'll miss this team, the way we played together. We all love each other," said Davis, who picked up every major player of the year award and is likely the No. 1 pick in June's draft. "I'm just going to miss this place. We won an NCAA championship here and did a lot. We all did a lot for this school and I'm going to miss it."
The five join seniors Darius Miller, who is also projected to be drafted, and Eloy Vargas in leaving the program.
"This is a players' first program. I said it three years ago. During the season, it's about our team. You saw it in this year's team, they were about each other," coach John Calipari said. "When the season is over, it's about moments like this."
The departures mean only freshman Kyle Wiltjer remains from the rotation with a new class of highly touted recruits joining Calipari next season. Calipari said he had never watched the final game of a season until this one.
Kidd-Gilchrist appeared emotional for a few moments at the podium and later said his mother, Cindy Richardson, wanted him to return to school since he was one of the youngest players in Division I after turning 18 in September. Instead, he has other plans for her.
"I want to spoil my mom. I think I'm going to spoil my mom to death. That's one thing I'm looking forward to," said Kidd-Gilchrist, who plans to buy her a watch for starters. "I'm ready, I think. I'm ready for anything that comes my way now."
Teague, the point guard, seemed to be the only player who might be a questionable first-round pick in Calipari's effort to match his 2010 draft class that saw five players go in the first round led by the No. 1 overall pick, John Wall. Teague said he felt like he did enough to be drafted in the first round by leading a "great team that's kind of like an NBA team" to a national championship.
"This is my lifelong dream to play in the NBA and to be doing it with these guys, we're all just making the decision together just makes it that much more special," Teague said. "I love every day knowing I played with these guys and that not being an option any more is tough to deal with. But we all decided we needed to move on, so this is something we've got to do."
Lamb said he really had only one goal after both he and Jones were projected first-round picks last season.
"The reason I stayed was to win a national championship," Lamb said. "Me and Terrence we talked together last year and we decided to come back this year to win a national championship and we did that. Our dreams came true."
Wiltjer, who said earlier this year the thought of his teammates leaving was "scary," and the rest of the bench made up just six percent of the total minutes played this season. But the group will quickly be getting help as Calipari closes in on his fourth straight No. 1 recruiting class.
Kentucky already signed Willie Cauley, Alex Poythress and Archie Goodwin in the early period. Top prospect Nerlens Noel committed to the Wildcats on national television last week by shaving the school's initials in the back of his signature flat top hairstyle. Transfer Ryan Harrow is expected to take over as point guard with Wiltjer, giving the Wildcats the same projected starting mix of two sophomores and three freshmen.
The team is in the hunt for a few of the remaining top prospects who have until May 16 to make their final decisions.
All of Kentucky's new players will be thrust into major roles because with the departures, the Wildcats will lose 93.3 percent of their points, 94.5 percent of their individual rebounds and 96.2 percent of their assists.
Meanwhile, this group is about to begin their heady new lifestyle, something Davis couldn't help laughing about when he was reminded of his upcoming payday.
"I actually haven't thought about that yet. That's right, I am going to be rich," Davis said. "You've just got to manage your money well. Good thing is I like math. So I should be fine."


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Japan Still Sleeps
Ambitious projections that Tokyo will provide for more of its own security are overly hasty—and perhaps wishful thinking.
Michael Auslin of AEI writes at Foreign Policy that Japan is changing its defense posture in ways that "will have profound implications for the balance of power in Asia." I hope this is right, but I'm fairly sure it's wrong.
Last month, while I was in Japan meeting with industry and goverment leaders, including people close to the Ministry of Defense, I saw no evidence for this thesis. And Auslin's evidence is somewhat thin.
The article claims the Japanese government is laying the groundwork for a much larger military role in Asia over the next several decades. The evidence Auslin provides includes:
—A deal on realigning the U.S. military presence in Japan that avoids dealing with the biggest sticking point between the two sides (Futenma);
—A smattering of Japanese overseas deployments that Auslin claims have produced "a generation of [Self Defense Force] air, sea, and land officers with extensive operational experience";
—Japan's decision to buy the F-35;
—Tokyo's beginning of a process to revise the proscription on arms exports;
—and Japanese cooperation with the United States on missile defense.
These developments all indicate some militarization but nothing likely to produce "profound implications for the balance of power in Asia." Missile defense and experience conducting humanitarian-relief operations are all well and good, but they do not buy you the naval wherewithal to prevent China from taking over your sea lanes.
Auslin allows that the "overriding challenge" to a more normalized Japanese defense posture is the fact that these changes "lack a coherent political articulation and have not been supported by a national debate over Japan's role in Asia and in the world." Beyond that overriding challenge, however, there are a number of problems that could ground this vessel before it gets out of port.
First, demographics. Japan currently is swirling down the demographic drain. By 2040, 14 percent of the Japanese population is projected to be eighty years of age or older, with every five-year (i.e., ten-fourteen, fifteen-nineteen, etc) age cohort under sixty-five shrinking dramatically as compared to the same age group in 2010. Japan is likely to possess 40 percent fewer citizens under age fifteen and a 30 percent drop in working-age population by 2040, placing significant stress on its economy and its pension and health systems. This does not bode well for Japan's future economic performance and thus for its ability to generate the military investment that would underwrite a more assertive defense policy.
The demographic conundrum, coupled with expansive health-care and pension benefits for Japan's elderly, has built a tumor of structural debt into the Japanese economy. Meanwhile, the economic "lost decade" of the 1990s has turned into something that looks an awful lot like two lost decades. Maybe more. The attitude in Japan among young people is commensurately dyspeptic.
Relatedly, the big political issue in Japan today is whether to raise the consumption tax, which is essentially a value-added tax, from 5 percent to 10 percent in order to begin to close the gaping fiscal maw. What this would do, in essence, is redistribute money from high-consumption/low-earning Japanese (the large, politically powerful elderly cohort) toward lower-consumption/higher-earning Japanese (the smaller, politically weaker group of younger Japanese). But it is important to understand a) that whether this will happen is still anyone's guess, and b) even were it to pass, it would not come close to patching over the shortfalls in the Japanese welfare state.
In Tokyo, I heard a profound sense of resignation about Japan's ability to take a larger role in providing its own defense, even among defense intellectuals. When pressed on this point, Japanese-security scholars shrug and point at both public opinion and straight-trend-line projections of Chinese military spending and argue that they could not possibly keep up. True, but mostly irrelevant. They don't need to keep up, dollar for dollar; they need to do a limited number of things well. Some of those things they currently do well, like antisubmarine warfare and surveillance, but the China side of the China-Japan balance is shifting rapidly.
As I said, I'd like very much to believe that Japan is going to take on a much larger role in providing for its own security. But as long as Washington defines America's security as coextensive with Japan's, Tokyo would be foolish to stop free riding on America's exertions in Asia.
Image: An Honorable German


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U.S. cites thermal damage in 787 battery involved in Boston fire
The U.S. National Transportation Safety Board on Wednesday said its investigation into a fire on a Boeing Co 787 Dreamliner in Boston earlier this month had revealed some thermal damage to all eight cells in a special lithium-ion battery used to generate auxiliary power for the plane.
Deborah Hersman, chairman of the safety board, and other NTSB officials will provide an update on the investigation at a news conference on Thursday, according to an NTSB news release.
The agency on Sunday ruled out overcharging as the cause of the battery failure. The implications of the thermal damage cited by the NTSB on Wednesday were not immediately clear.
The NTSB said the battery, made by Japanese company GS Yuasa Corp, had eight cells of 3.7 volts each, and all eight had varying degrees of thermal damage.
Investigators have CT scanned and disassembled six of the eight cells, and their electrodes were being photographed and examined under a microscope, the agency said. The remaining two batteries would be examined in the same way in coming days at the agency's Washington laboratory.
Members of the investigative team had also been working in Arizona, Seattle and Japan, the NTSB said in a brief statement, without providing an additional details.
(Reporting By Andrea Shalal-Esa; Editing by Gary Hill)


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It's National Hobby Month — anyone have a hobby they want to kick-start?
I wanted to give you a heads up – – guess what I signed up for?? Cake Decorating Class!! I'm taking it through Michael's In-Store Classes and I can't wait! The heads up is because of this:
Yep, 50% off the class – – it ended up being around $22 – yes, for all 4 weeks total! I signed up for Course 1: Decorating Basics – – wanted to start at the beginning.
I have my kit and a cute apron – what else do I need, right?? It'll be every Saturday morning in February – I'll keep you posted on how it goes….
Has anyone taken this class before? Any tips or things I need to know?


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|The White House
President George W. Bush
|Print this document
For Immediate Release
Office of the Press Secretary
November 5, 2006
President's Statement on the Saddam Hussein Verdict
TSTC Airport
Waco, Texas
In Focus: Renewal in Iraq
THE PRESIDENT: Today, Saddam Hussein was convicted and sentenced to death by the Iraqi High Tribunal for the massacres committed by his regime in the town of Dujayl. Saddam Hussein's trial is a milestone in the Iraqi people's efforts to replace the rule of a tyrant with the rule of law -- it's a major achievement for Iraq's young democracy and its constitutional government.
During Saddam Hussein's trial, the court received evidence from 130 witnesses. The man who once struck fear in the hearts of Iraqis had to listen to free Iraqis recount the acts of torture and murder that he ordered against their families and against them. Today, the victims of this regime have received a measure of the justice which many thought would never come.
Saddam Hussein will have an automatic right to appeal his sentence; he will continue to receive the due process and the legal rights that he denied the Iraqi people. Iraq has a lot of work ahead as it builds its society that delivers equal justice and protects all its citizens. Yet history will record today's judgment as an important achievement on the path to a free and just and unified society.
The United States is proud to stand with the Iraqi people. We will continue to support Iraq's unity government as it works to bring peace to its great country. We appreciate the determination and bravery of the Iraqi security forces, who are stepping forward to defend their free nation. And we give our thanks to the men and women of America's Armed Forces, who have sacrificed so much for the cause of freedom in Iraq -- and they've sacrificed for the security of the United States. Without their courage and skill, today's verdict would not have happened. On behalf of the American people, I thank every American who wears the uniform, I thank their families -- and I thank them for their service and continued sacrifice.
Thank you very much.


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|Zucchini Lasagna inspired by Ordinary Vegetarian to use up faux mince meat
It seems to me that you do nothing for the whole of the month except bunker down reading blogs, with assistants, and still not get through all the posts. (Nor find time to participate in MoFo Iron Chef Challenges or other blog events or comment on all your favourite blogs.) For a while it was unsatisfying wading through lots of blogs that just didn't interest me. Not because they were terrible. They just weren't my cuppa tea.
|Tomato, Chickpea and Avocado Pasta from Limes and Lycopene
(next time I wont add spring onions and parsley)
Despite this, there were many wonderful discoveries on the blogosphere. I loved some of the MoFo themes on blogs. For example: Candies and Halloween ideas on Fork and Beans, Orange coloured recipes on Heathen Vegan, 1 recipe 5 ways on Veg-Am and A-Z on Veganise This. See my MoFo recipe round-ups for more interesting blogs. I have added quite a few new blogs to my feed reader.
|Excellent smoothie of kiwi fruit, blueberries, banana, avocado and soy milk
|Country grain and soy bread from Julie Stafford
Harder still for me is going without cheese. I was pleased to make my first cashew goat cheese. It was excellent. I was really pleased to find this led to a vegan pizza that worked well for me. I read a few people note that they found that home made vegan cheese sauce was better than anything they found in the stores. I think this would be the case for me, given that I prefer home made meat substitutes.
|Oven Baked Coconut Tofu adapted from French Fry Conundrum
(good with tomato sauce and pasta but needs some tweaking)
I was inspired by Scissors and Spice's Sun-dried Tomato and Roasted Red Pepper Pub Cream Cheese recipe but I wanted to use pumpkin and smoked paprika. I am doing better with making cashews into creamy sauce since I got my little blender attachment to my hand held blender. My problem with the dip was the overwhelming sweetness of pumpkin and cashews. I felt I added quite a bit of salt and smoked paprika to compensate. I am not sure I quite got the right balance but it was very moreish. In fact, it was all but gone at the end of the day after having family over for lunch.
Other great dips on Green Gourmet Giraffe:
Finnish green bean paté
Pea Paté
Roasted pumpkin and garlic hummus
Vegan queso dip
Voracious Vegan Paté
Smoky Pumpkin Dip
Adapted from Scissors and Spice
1 cup raw cashews, soaked 8-9 hours
1/2 cup water
1 cup diced roast pumpkin
1 tbsp tahini
1 tbsp nutritional yeast
1 tbsp lemon juice
1/4 tsp crushed garlic
1/4 - 1/2 tsp smoked paprika
1 - 1 1/2 tsp salt (according to taste)
dash cayenne pepper
Blend cashews and water until smooth. This took a while for me and even after minutes of blending it got better but still could be smoother. Blend with other ingredients or if you are using a tiny blender, blend cashews into cream separately and then blend other ingredients and mix cashew cream and other ingredients in a bowl.
On the Stereo:
Time Out: Dave Brubeck Quartet
Vegan Month of Food October 2011. Go to my Vegan MoFo list for more Vegan MoFo posts.


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Disney's Animal Kingdom Lodge welcomed the birth of two Ruppell's Griffon Vultures earlier this month. They are the first hatchings of this threatened species at Walt Disney World Resort. Each chick weighed less than six ounces and was about eight inches long when hatched.
Over the past twenty years, the population of Ruppell's Griffon Vultures has been declining. This reduction led the International Union for Conservation of Nature to raise the status of this species to threatened. Members of Disney's Animal Programs Team hope to increase the species population and generate more awareness of the challenges these birds face.
When grown, each new-born vulture could reach sizes close to three feet in height , with a wingspan of nearly eight feet, and can weigh 15-20 pounds. They are also known for their high-flying skills, being among the highest flying bird on record, once spotted at an altitude of over 37, 000 feet in the skies of West Africa. Ruppell's vultures can fly more than three miles in six minutes and are able to stay in the air for as many as six to seven hours a day.
Ruppell's vultures are highly social; they roost, nest and gather to feed in large flocks. While they are generally a quiet breed, they may become vocal at the nest and during feeding time. The Ruppell's vultures pair up for life, which may be forty or fifty years.
More about Disney's Animal Care Program on The Disney Blog


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Like, Share, Discover: Facebook For Scientists
A few years ago, while he was doing research at Harvard, Ijad Madisch could not figure out why his experiment wasn't working. His adviser didn't know what was wrong, nobody in his lab worked on the same stuff, and none of his researcher friends could help.
"I was so frustrated," Madisch said. "I said there has to be something online where I go, where people can present themselves as a scientist, and where they put their information about their research and their publications and you can search for it."
That's when Madisch got the idea for a scientist network: ResearchGate — a sort of Facebook for scientists. Instead of sharing favorite photos and videos, researchers could use the Web platform to connect with each other and share information that doesn't get published. Madisch thinks ResearchGate will make scientists more productive.
"My goal: to win the Nobel Prize," Madisch said. "And I really believe in that. If we think that ResearchGate will accelerate research in all the different fields, it will change the speed of science significantly in the future. I definitely think that ResearchGate could win the Nobel Prize for that one day."
That big idea ambition wowed investors. ResearchGate got funded by a former Facebook executive and the same venture capital firm that backed Twitter. So far, 900,000 people have signed up as members.
One of them is Caroline Moore-Kochlacs, a neuroscientist at Boston University. Her profile page shows her picture, her field of study, her adviser and publications. She can follow other researchers or click onto group pages that discuss specific topics.
Moore-Kochlacs says she uses Facebook, too, but on that site people feel like they have to be clever or have mass appeal. She likes ResearchGate because she can ask obscure questions about algorithms. She also gets up to date on recent publications.
"The scientific literature is so huge at this point, that it's really impossible to get through everything in your topic area. People really rely on hearing it from other people," Moore-Kochlacs said.
Not every ResearchGate user is seeing the network effect.
"Sometimes I get these emails that are like, 'Dear Sirs: I'm writing a dissertation on public health. Any suggestions? Please advise,' " said Kim Bertrand, an epidemiologist at the Harvard School of Public Health. "I don't need that."
Founder Madisch says he knows his site will only prove valuable if researchers use it to help each other, not just steal each other's ideas. But he says if he can build ResearchGate into an indispensable social network for scientists, he'll be making more of a contribution than he could as a lone researcher.
Copyright 2020 WBUR. To see more, visit WBUR.


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Mt Bromo TimeMotifs
Time Motifs shows the motifs/patterns of the sky. By overlaying images shot in certain intervals, it captures the rotation of the sky that occurs during the night. Instead of using all images, which would result in long light trails, it now shows certain moments that result in a rotating pattern. The effect reminds in some cases of the patterns on seashells.Read More