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Objective: To assess the outcomes of health behavior interventions, focusing on the elementary school environment, classroom curricula, and home programs, for the primary prevention of cardiovascular disease.Design: A randomized, controlled field trial at four sites with 56 intervention and 40 control elementary schools. Outcomes were assessed using prerandomization measures (fall 1991) and follow-up measures (spring 1994).Participants: A total of 5106 initially third-grade students from ethnically diverse backgrounds in public schools located in California, Louisiana, Minnesota, and Texas.Intervention: Twenty-eight schools participated in a third-grade through fifth-grade intervention including school food service modifications, enhanced physical education (PE), and classroom health curricula. Twenty-eight additional schools received these components plus family education.Main Outcome Measures: At the school level, two primary end points were changes in the fat content of food service lunch offerings and the amount of moderate-to-vigorous physical activity in the PE programs. At the level of the individual student, serum cholesterol change was the primary end point and was used for power calculations for the study. Individual level secondary end points included psychological factors, recall measures of eating and physical activity patterns, and other physiologic measures.Results: In intervention school lunches, the percentage of energy intake from fat fell significantly more (from 38.7% to 31.9%) than in control lunches (from 38.9% to 36.2%)(P<.001). The intensity of physical activity in PE classes during the Child and Adolescent Trial for Cardiovascular Health (CATCH) intervention increased significantly in the intervention schools compared with the control schools (P<.02). Self-reported daily energy intake from fat among students in the intervention schools was significantly reduced (from 32.7% to 30.3%) compared with that among students in the control schools (from 32.6% to 32.2%)(P<.001). Intervention students reported significantly more daily vigorous activity than controls (58.6 minutes vs 46.5 minutes; P<.003). Blood pressure, body size, and cholesterol measures did not differ significantly between treatment groups. No evidence of deleterious effects of this intervention on growth or development was observed.Conclusion: The CATCH intervention was able to modify the fat content of school lunches, increase moderate-to-vigorous physical activity in PE, and improve eating and physical activity behaviors in children during 3 school years. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas)., Methods and Results: To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone., Conclusions: This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2014 American Heart Association, Inc.)

Background: Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality., Methods and Results: Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16-2.00), elevated left ventricular filling pressure (E/E'; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02-1.07), and higher pulmonary artery pressure assessed by the tricuspid regurgitation velocity (hazard ratio, 1.23 per 0.5 m/s increase; 95% confidence interval, 1.02-1.49) were associated with the composite outcome and heart failure hospitalization alone after adjusting for clinical and laboratory variables. The risk of adverse outcome associated with left ventricular hypertrophy was additive to the risk associated with elevated E/E'., Conclusions: Among heart failure with preserved ejection fraction patients enrolled in TOPCAT, left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors. These features, both alone and in combination, identify heart failure with preserved ejection fraction patients at particularly high risk for cardiovascular morbidity and mortality., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00094302., (© 2014 American Heart Association, Inc.)

Background: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction., Methods: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure., Results: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis., Conclusions: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with substantial morbidity and mortality. Existing data on cardiac structure and function in HFpEF suggest significant heterogeneity in this population., Methods and Results: Echocardiograms were obtained from 935 patients with HFpEF (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial before initiation of randomized therapy. Average age was 70±10 years, 49% were women, 14% were of African descent, and comorbidities were highly prevalent. Centralized quantitative analysis in a blinded core laboratory demonstrated a mean left ventricular ejection fraction of 59.3±7.9%, with prevalent concentric left ventricular remodeling (34%) and hypertrophy (43%), and left atrial enlargement (53%). Diastolic dysfunction was present in 66% of gradable participants and was significantly associated with greater left ventricular hypertrophy and a higher prevalence of left atrial enlargement. Doppler evidence of pulmonary hypertension was present in 36%. At least 1 measure of structural heart disease was present in 93% of patients., Conclusions: Patients enrolled in TOPCAT demonstrated heterogeneous patterns of ventricular remodeling, with high prevalence of structural heart disease, including left ventricular hypertrophy and left atrial enlargement, in addition to pulmonary hypertension, each of which has been associated with adverse outcomes in HFpEF. Diastolic function was normal in approximately one third of gradable participants, highlighting the heterogeneity of the cardiac phenotype in this syndrome. These findings deepen our understanding of the TOPCAT trial population and expand our knowledge of the diversity of the cardiac phenotype in HFpEF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Background: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease., Purpose: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies., Methods: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint., Results: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation., Limitations: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers., Lessons Learned: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size., Conclusions: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

This paper presents analyses from perhaps the largest and most comprehensive prospective cohort study of mid-aged women--the Massachusetts Women's Health Study (MWHS)--with numbers sufficient to provide, for the first time, stable estimates of parameters in the normal menopause transition. The three questions addressed in this analysis are (i) what are the natural menopause transitions and when do they occur, (ii) what factors affect these transitions and (iii) what signs and/or symptoms accompany these transitions? The data were obtained primarily from 5 years of follow-up of 2570 women in Massachusetts who were aged 45-55 years as of January 1, 1982. An initial baseline cross-sectional survey (T0) yielded a total of 8050 completed responses with an overall response rate of 77%. From this cross-sectional sample a cohort of approximately 2570 women was identified, consisting of women who had menstruated in the preceding 3 months and who had not undergone removal of the uterus and/or ovaries. Prospective study of the cohort consisted of six telephone contacts (T1-T6) at 9-month intervals with excellent retention of the respondents. A subset of the full cohort was defined that consisted of women who were premenopausal (rather than perimenopausal) at baseline (T0) (n = 1178). Confirming prior reports, the age at natural menopause occurred at 51.3 years with a highly significant median difference (1.8 years) between current smokers and non-smokers. The new analyses reported here on median age at inception of perimenopause (47.5 years) and factors affecting it are consistent with findings for age at last menstrual period, particularly the overwhelming effect of smoking. Smokers tend to have not only an earlier but also a shorter perimenopause. The length of the perimenopausal transition (estimated at nearly 4 years) has not been previously reported. Moreover, the highest rate of physician consultations is observed among those with longer perimenopause transitions. The relationship between menopause transitions and symptom reporting appears to be transitory, with reported rates showing an increase in the perimenopause and a compensatory decrease in the postmenopause. The implications of combined hormone replacement therapy for future research on menopause in industrial societies is discussed in relation to these findings.

Background: Patients with prior stroke represent a substantial proportion of patients presenting with acute ST-segment elevation myocardial infarction (STEMI). However, the impact of prior stroke on prognosis has not been rigorously examined in the reperfusion era., Methods: The baseline characteristics, treatments, and clinical outcomes of patients with prior stroke enrolled in the Magnesium in Coronaries (MAGIC) trial were evaluated and compared to those of patients without prior stroke., Results: MAGIC enrolled 6213 patients with STEMI, of whom 558 (9.0%) had prior stroke. Patients with prior stroke were more likely to have a history of hypertension (88.0% vs 70.3%), diabetes (19.9% vs 14.5%), myocardial infarction (38.2% vs 25.1%), and congestive heart failure (15.6% vs 9.7%). The mean Thrombolysis in Myocardial Infarction Risk Score was higher in patients with prior stroke compared to those without prior stroke (4.37 vs 3.93, P < .0001). Patients with prior stroke were less likely to receive reperfusion therapy, even among those considered eligible at presentation (66.3% vs 80.6%, P < .0001). Compared to patients without prior stroke, inhospital stroke (3.0% vs 1.0%, P < .0001), severe congestive heart failure (23.3% vs 18.2%, P = .003), and 30-day mortality (21.0% vs 14.7%, P < .0001) were higher among patients with prior stroke. On multivariable analysis, prior stroke was independently associated with a significantly higher risk of death at 30 days (odds ratio 1.44, P = .0023)., Conclusions: Patients with prior stroke who present with STEMI are at very high risk for short-term morbidity and mortality. Aggressive treatment of these patients appears warranted.

Background: The leading cause of death in patients hospitalized for acute myocardial infarction is cardiogenic shock. We conducted a randomized trial to evaluate early revascularization in patients with cardiogenic shock., Methods: Patients with shock due to left ventricular failure complicating myocardial infarction were randomly assigned to emergency revascularization (152 patients) or initial medical stabilization (150 patients). Revascularization was accomplished by either coronary-artery bypass grafting or angioplasty. Intraaortic balloon counterpulsation was performed in 86 percent of the patients in both groups. The primary end point was mortality from all causes at 30 days. Six-month survival was a secondary end point., Results: The mean age of the patients was 66+/-10 years, 32 percent were women and 55 percent were transferred from other hospitals. The median time to the onset of shock was 5.6 hours after infarction, and most infarcts were anterior in location. Ninety-seven percent of the patients assigned to revascularization underwent early coronary angiography, and 87 percent underwent revascularization; only 2.7 percent of the patients assigned to medical therapy crossed over to early revascularization without clinical indication. Overall mortality at 30 days did not differ significantly between the revascularization and medical-therapy groups (46.7 percent and 56.0 percent, respectively; difference, -9.3 percent; 95 percent confidence interval for the difference, -20.5 to 1.9 percent; P=0.11). Six-month mortality was lower in the revascularization group than in the medical-therapy group (50.3 percent vs. 63.1 percent, P=0.027)., Conclusions: In patients with cardiogenic shock, emergency revascularization did not significantly reduce overall mortality at 30 days. However, after six months there was a significant survival benefit. Early revascularization should be strongly considered for patients with acute myocardial infarction complicated by cardiogenic shock.

Background: Cardiogenic shock (CS) is the leading cause of death in patients hospitalized with acute myocardial infarction (MI). Nonrandomized studies suggest reduced mortality rate with revascularization., Trial Design: The SHOCK trial is a multicenter, randomized, and unblinded study with a Registry for trial-eligible and ineligible nonrandomized patients. The trial is testing the hypothesis that a direct invasive strategy of emergency revascularization for patients with cardiogenic shock complicating acute MI will reduce 30-day all-cause mortality rate by 20 absolute percentage points compared with initial medical stabilization. Eligibility criteria include development of CS within 36 hours of an acute transmural MI as evidenced by ST elevation or new left bundle branch block MI; clinical criteria for CS with hemodynamic confirmation; absence of a mechanical, iatrogenic, or other cause of shock; and enrollment within 12 hours of CS diagnosis. Patients randomly assigned to emergency revascularization immediately undergo coronary angiography, with percutaneous transluminal coronary angioplasty or coronary artery bypass grafting depending on the coronary anatomy. Patients assigned to initial medical stabilization may undergo revascularization >/=54 hours after randomization., End Points: The primary end point is all-cause 30-day mortality after randomization. Secondary end points include death at trial termination, changes in left ventricular dimensions and function measured by echocardiography at randomization and 2 weeks later, and changes in quality of life and physical functioning from 2 weeks after discharge to 6 months after MI.

Objective: To assess the ability of the level of follicle-stimulating hormone (FSH) to distinguish among premenopausal, perimenopausal, and postmenopausal women., Methods: We examined cross-sectional and longitudinal data from the second phase of the Massachusetts Women's Health Study (1986 to 1995), a population-based cohort of 427 premenopausal and perimenopausal women identified from the first phase of the Massachusetts Women's Health Study (1981 to 1986)., Results: Boxplots of FSH levels throughout the menopausal transition displayed considerable overlap. Logistic regressions and their resulting receiver operating characteristic curves further demonstrated that, although FSH is a statistically significant predictor of menopausal status, no single value of FSH is expedient for distinguishing premenopausal from perimenopausal or perimenopausal from postmenopausal women., Conclusion: FSH alone is not an effective predictor of transition into the perimenopausal or postmenopausal period. Specifically, the frequently recommended FSH cutoff of 40 IU/L is inappropriate by itself for clinical determination of postmenopausal status.

Despite wide variation in the reporting of hot flashes and night sweats among menopausal women, what differentiates symptomatic from asymptomatic women is not well understood. In this article, we use longitudinal data from a large cohort of initially premenopausal women to address premenopausal factors predictive of length of the perimenopause, frequency of hot flash/night sweat (HF/NS) reporting, bothersomeness of HF/NS, and treatment seeking during menopause. The sample for analysis consists of 454 women from the Massachusetts Women's Health Study who were premenopausal at baseline and postmenopausal by the sixth and last study follow-up. Each of the four study outcomes was modeled as a function of premenopausal characteristics using logistic regression. Results confirm a wide range of symptom reporting, with 23% of women not reporting HF/NS at any of the six interviews. Variables related to greater frequency of HF/NS reporting included a longer perimenopause, more psychological and physical symptoms prior to menopause, lower education, and more negative attitudes toward menopause prior to menopause. Symptom bothersomeness was related to greater frequency of HF/NS reporting, smoking, and being divorced. Variables that predicted medical doctor consultation were greater frequency and bothersomeness of symptoms, higher education, and greater health care utilization. We conclude that general symptom reporting, attitudes toward menopause, and lifestyle factors can explain some of the individual variation in symptom reporting.

Background: The Child and Adolescent Trial for Cardiovascular Health (CATCH) was the first multicenter school-based research study to employ the fundamentals of clinical trials including the standardized protocol and Manuals of Operation, a steering committee for study governance, a distributed data system, an extensive quality control system, and a Data and Safety Monitoring Board., Method: CATCH tested the effectiveness of changes in school lunches, physical education, smoking policy, curricula, and family activities. Ninety-six elementary schools in four states were randomized to intervention or control conditions. The baseline cohort comprised 5, 106 ethnically diverse third graders followed through fifth grade., Results: The percentages of calories from fat and saturated fat were reduced significantly more in the intervention school lunches than among the controls. Significant increases in moderate to vigorous activity levels in existing physical education classes were made as well. Changes in self-reported dietary, physical activity, and psychosocial measures were significant. There were no significant differences in the physiological measures. Measurement error was generally low for all physiologic measures except skinfolds, indicating a high level of reliability. Across all sites, the coefficients of variation for lipids, height, and weight were less than 3%, whereas for skinfolds, they were considerably higher, ranging from 6 to 8%. Intraclass correlations for lipid studies were also uniformly high at 0.99. Interobserver agreement scores for SOFIT were greater than 90% for 9 of the 11 activities observed. Data entry error rates were low with less than five errors per 1,000 fields for all forms., Conclusions: The CATCH results provided more scientific evidence on the importance of schools in the population approach to health promotion. Many of the strategies used in this complex multicenter trial in the areas of design and analysis, measurement, training, data management, and quality control protocols might be appropriate for adoption in other studies.

Experiments involving large social units, such as schools, work sites, or whole cities, are commonly limited in statistical power because the number of randomized units is small, leaving few degrees of freedom for residual (between-unit) error. The authors describe a method for increasing residual degrees of freedom in a community experiment without substantially increasing cost or difficulty. In brief, they propose that the experimental units should be divided into random subsamples (batches). Batch sampling can improve statistical power if the community endpoint means are stable over time or if their temporal variation is comparable in period to the batch-sampling schedule. The authors demonstrate the theoretical advantages of the batch system and illustrate its use with data from the Pawtucket Heart Health Program, in which such a design was implemented.

Objectives: This review emphasizes results from population based studies in order to provide a reliable knowledge base and define major knowledge gaps for future research., Methods: The review systematically addresses the following aspects of menopause research: definition of menopause and menopause transitions; age at natural menopause and at inception of perimenopause; factors affecting timing and length of menopause transitions; concurrent hormone, menstrual and vascular changes. Under each substantive heading, available reports of original research are reviewed, assessed for reliability and summarized with respect to their contribution to the knowledge base., Results: From this review, the following reliable information can be summarized: median age at natural menopause in Caucasian women occurs between 50 and 51-55 years of age, is not affected by timing of surgical menopause and is affected by cigarette smoking, with current smokers having an earlier menopause by 1.5-2.0 years. No other factors appear to have an independent effect on age at menopause. There is no evidence of any secular trend in age at menopause. Evidence is accumulating that most physiological change associated with menopause either occurs or begins before the final menstrual period., Conclusions: We lack reliable information on the following: estimates of age at menopause from non-industrialized countries and diverse ethnic groups; information on perimenopause; differing perceptions of menopause, cross culturally; multi-disciplinary prospective data that can link various processes into coherent patterns.

Measuring levels of steroid hormones in epidemiologic studies is difficult because pulsatile release can cause the levels of many hormones to vary markedly over short intervals, leading to a loss of precision in between-subject comparisons. Clinicians often control this variation by collecting several samples from each subject at defined intervals and pooling these samples for assay. The number of samples per subject that would adequately control such variation in an epidemiologic study has not been fully investigated. This study examines the effects of collecting 1, 2, or 3 samples per subject on the variances of 11 hormones and sex hormone binding globulin in men and 6 hormones in women. Three samples were collected at 30-minute intervals from each of 20 men and 59 women and were assayed separately. Variances that would be obtained in studies collecting one, two, or three samples per subject were then estimated. Collecting more than one sample substantially reduced the variances of several hormones in men but not in women.

This paper describes some statistical considerations for the Child and Adolescent Trial for Cardiovascular Health (CATCH), a large-scale community health trial sponsored by the National Heart, Lung, and Blood Institute. The trial involves randomization of entire schools rather than individual students to the experimental arms. The paper discussed the implications of this form of randomization for the design and analysis of the trial. The power calculations and analysis plan for the trial are presented in detail. The handling of outmigrating and immigrating students is also discussed.

This paper presents findings from the Massachusetts Women's Health Study (MWHS), one of the largest population-based studies of mid-aged women. A longitudinal study that followed a population-based cohort of women as they proceeded through menopause, the MWHS's goal was to describe their responses and to identify health-related, life-style, and other social factors that affect this transition. Findings indicate that natural menopause appears to have no major impact on health or health behavior. The majority of women do not seek additional help concerning menopause, and their attitudes toward it are, overwhelmingly, positive or neutral. Physicians treating mid-aged women must be careful not to confuse "menopausal" symptoms with indicators of underlying disease or conditions unrelated to menopause.

In this summary, the authors provide the background of and proposed protocol for a clinical evaluation of the safety and efficacy of the Novacor N120 Left Ventricular Assist System, sponsored by the National Heart, Lung, and Blood Institute. Although the clinical trial was never carried out, the protocol developed for this trial may be useful to other investigators considering a clinical trial of a circulatory support device. The protocol is summarized here and in five more detailed articles in this issue.

The development of a multidimensional quality of life protocol to be used in a clinical trial of an LVAS was presented. The complexity of the new LVAS technology being evaluated added a unique dimension for HQL assessment. The rationale and procedures used in developing this protocol were described. Although we have elucidated the development of a protocol for a specific clinical trial, the principles and procedures employed are widely applicable. To summarize, these procedures are as follows: 1. Determine what quality of life domains are important to measure. This decision should be based upon the domains expected to be affected by treatment, those expected to change as a result of the natural course of the disease or condition, and those that may be affected by changes in the primary domains. 2. Once the domains are selected, identify specific measures for these domains. Where possible, the measures chosen should be standardized, well validated, and appropriate to the study population. Instrument length and mode of administration are additional considerations. 3. Consider any unique aspects of the study population or intervention and develop specific questions to address them. 4. Identify and measure important variables that may moderate or influence quality of life. 5. Test the protocol on an appropriate population for length, flow, and ease of administration. Copies of the complete HQL protocol are available by writing to: Dr. Nancy Avis, New England Research Institute, 9 Galen Street, Watertown, MA 02172.

The authors present a method for defining the inception of perimenopause that is based on self-reported data. The study sample (n = 1,550) was obtained from a 5-year longitudinal study of 2,569 Massachusetts women aged 45-55 years that began in 1981. The definition was derived from the ability of responses to questions concerning timing of the last menstrual period, menstrual regularity, and presence of menopausal symptoms (hot flashes/sweats) to predict menopause 3 years later. The two items that best defined the inception of perimenopause were 3-11 months of amenorrhea and increased menstrual irregularity for those without amenorrhea. This definition can easily be used in large epidemiologic investigations.

Background: Large field trials that randomize naturally occurring clusters such as communities, worksites, or schools are becoming widely accepted for evaluating complex interventions. The within-cluster measurement of individuals typically uses a cohort, followed throughout the trial or cross-sectional samples selected independently at each time point. The relative costs of these approaches is of concern in designing such trials., Methods: This paper takes the unified model for analyzing large cluster unit trials developed by Feldman and McKinlay (Stat Med 1993) and combines the resulting expression for the variance of the treatment effect with a simple cost function into an algorithm that produces the optimal trial design in terms of the number of clusters and the number of observations per cluster. Using the unified model developed in the prior paper, this algorithm also allows direct comparison of the cost of designs with equivalent precision. In particular, designs that use cohorts in each cluster unit and observe cohort members over time are contrasted with designs that draw independent cross-sectional samples from each cluster at each time point., Results: Using the algorithm and a realistic design problem, it is demonstrated that cohort designs are more cost efficient for short trials and high (> or = 0.75) autocorrelations., Conclusions: The power of the algorithm in designing cost-efficient cluster unit trials is well demonstrated. Estimates of variance and cost components from prior trials need to be readily accessible for use in the algorithm, for planning subsequent trials.

The present article prospectively examines the effect of change in menopause status on depression, while controlling for prior depression. This is a longitudinal follow-up of previous cross-sectional analyses reported by McKinlay, McKinlay, and Brambilla who examined the relative contribution of menopause to depression. The data derive from the Massachusetts Women's Health Study, a 5-year longitudinal study of a cohort of 2565 women aged 45 to 55 years at baseline (1981 to 1982). Results show that prior depression is the variable most predictive of subsequent depression, as measured by the Center for Epidemiologic Studies-Depression (CES-D) scale. Onset of natural menopause was not associated with increased risk of depression. Experiencing a long perimenopausal period (at least 27 months), however, was associated with increased risk of depression. The association between a long perimenopause and depression appeared to be explained by increased menopausal symptoms rather than by the menopause status itself. The observed increase in depression during a lengthy perimenopause appears to be transitory.

Two broad classes of studies relating to menopause are reviewed: descriptive studies (cross-sectional or longitudinal); and comparative studies (observational or experimental). For descriptive studies the issues are: costs of sampling from a general population; measurement of last menstrual period (LMP) in the context of hormone therapy; unbiased symptom reporting in ethnically diverse populations; and in-home vs. clinic-based measurement. Comparative cohort studies of menopause-related therapies are somewhat more vulnerable to selection bias from medical care access than case-control studies with hospital or patient controls. Ideally, in clinical trials, no subjects should have previously used any of the trial therapies to ensure unbiased assessment of side effects and to maximize preservation of masking if a placebo is used. In terms of analysis, information (precision) depends on the proportion in the sample for whom LMP is defined, not the total number in the sample. The role of cigarette smoking as covariate in any analysis is of particular concern as it is the major determinant of the timing of LMP. These design and analysis issues, although identified from research to date, are still new. Some lack wide documentation and are thus not well understood. Others lack clear solutions.

In planning large longitudinal field trials, one is often faced with a choice between a cohort design and a cross-sectional design, with attendant issues of precision, sample size, and bias. To provide a practical method for assessing these trade-offs quantitatively, we present a unifying statistical model that embraces both designs as special cases. The model takes account of continuous and discrete endpoints, site differences, and random cluster and subject effects of both a time-invariant and a time-varying nature. We provide a comprehensive design equation, relating sample size to precision for cohort and cross-sectional designs, and show that the follow-up cost and selection bias attending a cohort design may outweigh any theoretical advantage in precision. We provide formulae for the minimum number of clusters and subjects. We relate this model to the recently published prevalence model for COMMIT, a multi-site trial of smoking cessation programmes. Finally, we tabulate parameter estimates for some physiological endpoints from recent community-based heart-disease prevention trials, work an example, and discuss the need for compiling such estimates as a basis for informed design of future field trials.

Purpose: The study design, research questions, and baseline data are presented from a multicenter longitudinal epidemiologic investigation of the impact of human immunodeficiency virus (HIV) infection on three areas of functioning in children and adolescents with hemophilia: physical growth and sexual maturation, immune function, and neurological and neuropsychological functioning., Patients and Methods: Sixty-nine percent (n = 333) of a population of males between the ages of 6 and 19 years with moderate to severe hemophilia participated in a comprehensive baseline examination. Approximately 62% of the study group was HIV seropositive and 38% HIV seronegative., Results: Adjusted for age, HIV-positive participants were three times as likely as HIV-negative participants to exhibit declines in height-for-age attainment (p = 0.05), twice as likely to have delays in sexual maturation (p = 0.414), and more than three times as likely to exhibit antibody levels that were not indicative of prior exposure or vaccination (p < 0.001). In addition, analysis of a comprehensive battery of neuropsychological tests showed that HIV-positive participants were 50% more likely to show scores approximately 1 SD below expected levels in three of nine functional areas (p = NS) compared with HIV-negative participants., Conclusions: Entry data for this study reveal a greater likelihood for HIV-positive children and adolescents with moderate to severe hemophilia to have abnormal growth, and to exhibit antibody levels not indicative of prior exposure to disease or vaccination, which could be attributed to HIV infection. Lowered neuropsychological test performance in both groups may be attributable to the deleterious effects of chronic illness. Data are being collected from a group of non-HIV infected non-hemophiliac siblings for comparison.

This study examines self-reported hypertension and its correlates in a random sample of 5539 African-American and white middle-aged women residing in Massachusetts. African-American women reported hypertension more frequently than did whites (38.2% vs 19.8%). African-American women were more likely than white women to have seen a doctor in the preceding year and to have had a hysterectomy. The African-American women were less likely to be current smokers and were less educated than white women. Stepwise logistic regression revealed that self-reported hypertension was associated with race, education, health care utilization, and the interaction of education and race. Prevalence differences between African Americans and whites declined with increasing education. However, the model indicates that after controlling for differences in socioeconomic status (based on education) and health care utilization, self-reported hypertension was still more prevalent among African-American women.

We evaluated the influence of dietary, anthropomorphic, and hormonal factors on bone density in a cross-sectional sample of 281 pre- and perimenopausal women age 50-60 years living in Massachusetts. The sample included only women who had intact ovaries and were not currently using estrogen. Information on diet was obtained through a semiquantitative food frequency questionnaire. We measured bone density using single-photon absorptiometry in the non-dominant arm in two sites: the midshaft and the ultradistal radius. We observed no important associations between midshaft bone density and dietary variables but found linear relations between ultradistal radius bone density and body mass index [b = 1.10 gm/cm2 per kg/m2, standard error (SE) = 0.56], follicle-stimulating hormone (FSH) (b = -0.36 gm/cm2 per IU/liter, SE = 0.15), and several nutrients: calcium (b = 0.012 gm/cm2 per mg/day, SE = 0.007), retinol (b = 0.002 gm/cm2 per IU/day, SE = 0.0008), vitamin C (b = 0.025 gm/cm2 per mg/day, SE = 0.013), and vitamin D (b = 0.040 gm/cm2 per IU/day, SE = 0.018). We could not clearly distinguish the independent contribution of these micronutrients, however, because many were commonly ingested together in the form of supplements. Caffeine was inversely associated with bone density (b = -0.035, SE = 0.017) independent of dietary, anthropometric, and hormonal factors. Analyses of individual caffeinated beverages revealed consistent inverse associations for coffee (b = -3.42 gm/cm2 per cups/day, SE = 1.49), tea (b = -2.85 gm/cm2 per cups/day, SE = 1.56), and caffeinated cola (b = -14.0 gm/cm2 per cans/day, SE = 5.1), but not for decaffeinated coffee or decaffeinated cola [corrected]. [ABSTRACT TRUNCATED AT 250 WORDS)

This paper presents analyses from a comprehensive prospective cohort study of mid-aged women [the Massachusetts Women's Health Study (MWHS)], with numbers sufficient to provide stable estimates of parameters in the normal menopause transition. Three questions are addressed: what are the natural menopause transitions and when do they occur; what factors affect the transitions; and what signs and/or symptoms accompany the transitions? The data were obtained primarily from 5 years of follow-up of 2,570 women in Massachusetts who were aged 44-55 years as of January 1, 1982. Prospective study of the cohort consisted of six telephone contacts (T 1 -T 6 ) at 9 month intervals with excellent retention. A subset of the full cohort was defined that consisted of women who were premenopausal (rather than perimenopausal) at baseline (T o ) (n = 1,178). Confirming prior reports, the age at natural menopause occurred at 51.3 years with a highly significant median difference (1.8 years) between current smokers and non-smokers. The new analyses reported here on median age at inception of perimenopause (47.5 years) and factors affecting it are consistent with findings for age at last menstrual period. Smokers tend to have not only an earlier but also shorter perimenopause. The length of the perimenopausal transition, estimated at about 3.5 years, has not been previously reported. The relationship between menopause transitions and symptom reporting appears to be transitory, with reporting rates showing an increase in the perimenopause and a compensatory decrease in postmenopause. The implications of combined hormone replacement therapy for future research on menopause in industrial societies is discussed in relation to these findings., (Copyright © 1992 Wiley-Liss, Inc., A Wiley Company.)

Background: While health risk appraisals (HRAs) are becoming increasingly popular as tools for health assessment and health education, comparatively little is known about the accuracy of these risk estimates., Methods: A field trial among 732 randomly selected adults ages 25 to 65 years was conducted to assess the validity of the risk scores produced by four widely used HRAs., Results: Self-reported HRA risk scores for cigarette smoking and relative weight were generally accurate, but correlations between physiological measurements and scores for blood pressure, cholesterol, and physical activity were always lower than .51. Correlations between epidemiologic estimates of the probability of CHD death and HRA total risk scores ranged from .13 to .75; partial correlations adjusting for age, race, and gender ranged from .12 to .47., Conclusions: The HRAs chosen for the field trial exhibited modest correlations with the CHD mortality risk predicted by the epidemiologic model. Mathematical errors made by respondents completing self-scored instruments and lack of knowledge regarding physiologic status decrease the accuracy of HRA risk estimates.

This study describes estrogen use among 45- to 55-year-old white women in Massachusetts from 1981 to 1987. In a 1981 cross-sectional survey, 7705 white women (77 percent response rate) returned a questionnaire or were interviewed by phone. Premenopausal women were invited into a 4.5-year follow-up study including telephone interviews every nine months, and 2236 (approximately 91 percent of the eligible women) had a complete follow-up. In the cross-sectional survey, 7.9 percent had used oral estrogens in the last two weeks, but most (77 percent) had had a hysterectomy; use varied notably from one area to another. Vaginal estrogens were used by 2.9 percent. Users and nonusers of oral estrogens were quite similar in regard to sociodemographic background. Data from the follow-up surveys showed that estrogen use increased throughout the study period and by the final follow-up women with higher education status reported more estrogen use than those with lower education status. Most women used estrogens only for a short time.

This paper examines women's attitudes towards menopause in a large representative sample of middle-aged women. Data were derived from the Massachusetts Women's Health Study (MWHS) which is a prospective study of 2565 women aged 45-55, randomly sampled throughout Massachusetts. The paper addressed the following questions: (1) What are women's attitudes towards the menopause and how do attitudes change as a function of menopause? (2) What variables are related to attitudes towards menopause? and (3) Do attitudes towards menopause predict subsequent symptom reporting during menopause? Results showed that the majority of women reported relief or neutral feelings about the cessation of menses and that feelings became more positive as women experienced menopause. Negative attitudes towards menopause were related to general symptom reporting and depression. Additionally, negative attitudes prior to menopause were related to subsequent symptom reporting during menopause. These results suggest that the so-called menopause syndrome may be more related to personal characteristics than to menopause per se.

To determine whether there was a significant relationship between circulating lipids or lipoproteins and circulating estrogens or sex hormone-binding globulin (SHBG) in pre- and premenopausal women, 352 women were chosen randomly from communities in Eastern Massachusetts. These women had nonfasting blood samples drawn and analyzed for total cholesterol, high density lipoprotein cholesterol (HDL-C), HDL-2, HDL-3, apolipoprotein-A-I (apo-A-I), apo-B, triglycerides (TG), estrone, estradiol (E2), free E2, SHBG, and FSH. In addition, their body mass index (BMI; wt/ht2) was calculated, and a history of smoking, ethanol intake, current medication use, and the date of their last menstrual period was obtained. When the women were grouped according to the months from their last menses (less than 1, 1-3, and 4-11 months), those 4 months or longer since last menses had significantly lower E2 concentrations and significantly greater total cholesterol and FSH concentrations than the other two groups. However, when regressed on hormones, BMI, ethanol intake, and last menstrual period, total cholesterol was significantly related only to the time from last menses; TG, HDL-C, HDL-2, and apo-A-I were related to SHBG. Relationships between the lipids, with the exception of cholesterol and apo-B, were also noted with BMI and/or ethanol. Apo-B was related to the time from last menses. Differences in circulating estrogens appeared to be related only minimally, if at all, to the differences in total cholesterol that are seen in perimenopausal women. The relationships between lipids and lipoproteins and SHBG are probably epiphenomena as a result of similar sites of synthesis. Changes in lipids and lipoproteins that are seen at the time of the menopause are probably multifactorial in origin.

In the present study the antepartum relationship between maternal diabetic glucose control and fetal hypoxaemia was examined in 44 Type 1 (insulin-dependent) diabetic and 23 non-diabetic control pregnancies. Maternal HbA1C was used to assess maternal integrated blood glucose control while fetal metabolic control was evaluated by antepartum glucose, insulin, and C-peptide determinations in amniotic fluid at elective caesarean delivery. Fetal hypoxaemia was assessed indirectly by fetal umbilical vein plasma erythropoietin level at delivery. A prospectively developed statistical pathway model was used to examine the relationship of these variables. In applying forced stepwise multiple regression with this model, we observed in the diabetic subjects that mean maternal HbA1C during the last month of pregnancy correlated significantly with fetal umbilical venous erythropoietin at delivery (r = 0.57, p less than 0.001). Additional significant contributions to umbilical venous erythropoietin were found for amniotic fluid glucose and amniotic fluid insulin when these two independent variables were added in stepwise fashion (p less than 0.01). We conclude that in diabetic pregnancy, antepartum control of maternal hyperglycaemia is a significant factor associated with fetal hypoxaemia. We speculate that this effect is mediated through perturbations which accelerate fetal metabolism and which is expressed by amniotic fluid levels of glucose and insulin.

Abstract Health Risk Appraisals (HRAs) have been in increasingly wide use over the past 20 years as health education tools designed to encourage healthy behaviors. A major criticism of HRAs has been the error introduced by missing or incorrectly-specified responses by clients, especially regarding physiological measures such as blood pressure and cholesterol. Four HRAs were randomly assigned to members of a random sample of Massachusetts residents as part of a trial to assess the reliability and validity of HRA instruments. Two rules for substituting unknown physiological measures were evaluated: the existing rule for an HRA and a new rule, which simply substitutes the age- and gender-specific mean physiological values. Ordinary least squares regression was used to compare risk scores generated from known physiological measures, taken in respondents' homes, with risk scores generated by substitution. Regression slopes were mostly close to 1.0, most intercepts were relatively close to 0.0, and correlations were all extremely high, suggesting good performance of substitution rules on a group level. However, outliers from the regressions tended to be individuals at high risk whose risk was underestimated by the substitution rules. These results raise ethical questions about the use of substitution rules and reinforce the need for taking actual physiological measurements.