Study Objectives:The long-term effect of continuous positive airway pressure (CPAP) on health-related quality of life (HRQOL) in patients with high cardiovascular disease risk and obstructive sleep apnea (OSA) without severe sleepiness is uncertain. We aimed to determine the effect of CPAP treatment on HRQOL in individuals with moderate or severe OSA and cardiovascular disease (CVD) or multiple CVD risk factors without severe sleepiness.Methods:In this randomized, controlled, parallel group study, 169 participants were assigned to treatment with CPAP or the control group (conservative medical therapy [CMT] or CMT with sham CPAP). Analyses were based on an intention-to-treat approach. Linear mixed effect models were fitted to compare the changes in the Medical Outcomes Study Short Form-36 (SF-36) and in subjective sleepiness (Epworth Sleepiness Scale [ESS]) between groups from baseline to the average of 6- and 12-month measurements.Results:CPAP improved several domains of HRQOL including bodily pain (treatment effect 9.7 [95% confidence interval, CI 3.9 to 15.4]; p = .001), vitality (5.7 [95% CI 1.5 to 9.9]; p = .008), general health (8.2 [95% CI 3.7 to 12.7]; p < .001), physical functioning (5.5 [95% CI 1.1 to 10.0]; p = .016), and the physical health summary score (3.3 [95% CI 1.4 to 5.3]; p = .001). CPAP also resulted in less daytime sleepiness (mean change in ESS -1.0 point [95% CI -2.0 to -0.0]; p = .040).Conclusions:In patients with moderate-severe OSA at high risk of cardiovascular events and without severe sleepiness, CPAP improved daytime sleepiness and multiple domains of HRQOL over 6 to 12 months of follow-up, with the largest improvement observed for bodily pain.

The authors surveyed the types of statistical methods used in the Journal during 2015. Investigators used a greater variety statistical methods, and the methods were more sophisticated than those used in earlier epochs.

We evaluate properties of sample size re-estimation (SSR) designs similar to the promising zone design considered by Mehta and Pocock (2011). We evaluate these designs under the assumption of a true effect size of 1.1 down to 0.4 of the protocol-specified effect size by six measures: 1. The probability of a sample size increase, 2. The mean proportional increase in sample size given an increase; 3 and 4. The mean true conditional power with and without a sample size increase; 5 and 6. The expected increase in sample size and power due to the SSR procedure. These measures show the probability of a sample size increase and the cost/benefit for given true effect sizes, particularly when the SSR may either be pursuing a small effect size of little clinical importance or be unnecessary when the true effect size is close to the protocol-specified effect size. The results show the clear superiority of conducting the SSR late in the study and the inefficiency of a mid-study SSR. The results indicate that waiting until late in the study for the SSR yields a smaller, better targeted set of studies with a greater increase in overall power than a mid-study SSR.

Clinical trials are our best vehicle for turning medical information that we may think is true into evidence that we know, within reasonable limits, to be true. Since the introduction of random assignments to treatment in the 1930s,1 the clinical trial has been in continuous evolution. Among the major milestones have been the development of methods to perform randomization; the convening of data and safety monitoring committees; the formulation of stopping guidelines for safety, efficacy, and futility; and many others. Indeed, the clinical trial landscape is far different today from what it was over 80 years ago, when investigators first . . .

Introduction: Preterm delivery (PTD) contributes to significant neonatal morbidity and mortality. There is some evidence associating PTD with extreme climate, especially temperature. We examined PTD in relation to temperature and humidity in a Kuwait where extreme heat is common. Methods: We assessed 1893 pregnant women enrolled in a prospective study in Kuwait designed to assess the relation of environmental exposures in pregnancy with pregnancy and child health. We investigated the association of PTD with the 7-day mean temperature (Tm), heat index (HI), relative humidity (RH), dew point (Td), and specific humidity (SH) obtained from the national airport’s weather station. We defined PTD as birth prior to 37 weeks gestation based on the maternal last menstrual period. We used a logistic regression time series and case-crossover models to estimate the odds ratio (OR) and 95% confidence intervals (CI) for PTD per standard deviation change in exposure. Results: The incidence of PTD was 9.3%. During the weeks around delivery, the average Tm was 26.7 oC (range: 9.7 – 41) and average RH was 34.2% (range: 7.4 – 83.7). PTD was not associated with the Tm (OR: 0.94, 95% CI: 0.46 – 1.91), but there was a suggestive, albeit not statistically significant, association with RH (OR: 1.34, 95% CI: 0.94 – 1.89). During the hot season (Tm>22oC), RH was associated with PTD (OR: 1.52, 95% CI: 1.02 – 2.29). Associations with other humidity variables were also positive but lacked statistical significance and remained the same regardless of season. The case-crossover analysis results were similar to those from the time-series analysis. Conclusion: Our findings suggest that humidity during the hot season in the week prior to birth may increase the odds of PTD. Direct associations with Tm were not observed possibly due to the ubiquitous use of air conditioning. Public health advisories for pregnant women to avoid the outdoors should be considered during extremely humid and hot conditions.

AIMS A recent study demonstrated that intracoronary near-infrared spectroscopy (NIRS) findings in non-target vessels are associated with major adverse cardiovascular and cerebrovascular events (MACCE). It is unknown whether NIRS findings at non-stented sites in target vessels are similarly associated with future MACCE. This study evaluated the association between large lipid-rich plaques (LRP) detected by NIRS at non-stented sites in a target artery and subsequent MACCE. METHODS AND RESULTS This study evaluated 121 consecutive registry patients undergoing NIRS imaging in a target artery. After excluding stented segments, target arteries were evaluated for a large LRP, defined as a maximum lipid core burden index in 4 mm (maxLCBI4 mm) ≥400. Excluding events in stented segments, Cox regression analysis was performed to evaluate for an association between a maxLCBI4 mm ≥400 and future MACCE, defined as all-cause mortality, non-fatal acute coronary syndrome, and cerebrovascular events. NIRS detected a maxLCBI4 mm ≥400 in a non-stented segment of the target artery in 17.4% of patients. The only baseline clinical variable marginally associated with MACCE was ejection fraction (HR 0.96, 95% CI 0.93-1.00, P = 0.054). A maxLCBI4 mm ≥400 in a non-stented segment at baseline was significantly associated with MACCE during follow-up (HR 10.2, 95% CI 3.4-30.6, P < 0.001). CONCLUSION Detection of large LRP by NIRS at non-stented sites in a target artery was associated with an increased risk of future MACCE. These findings support ongoing prospective studies to further evaluate the ability of NIRS to identify vulnerable patients.

BACKGROUND: Motivational enhancement (ME) shows promise as a means of increasing adherence to CPAP for OSA.METHODS: We performed an open-label, parallel-arm, randomized controlled trial of CPAP only or CPAP + ME, recruiting individuals 45 to 75 years with moderate or severe OSA without marked sleepiness and with either established cardiovascular disease (CVD) or at risk for CVD. All participants received standardized CPAP support from a sleep technologist; those randomly assigned to CPAP + ME also received standardized ME delivered by a psychologist during two appointments and six phone calls over 32 weeks. Mixed-effect models with subject-specific intercepts and slopes were fitted to compare objective CPAP adherence between arms, adjusting for follow-up duration, randomization factors, and device manufacturer. All analyses were intention-to-treat.RESULTS: Overall, 83 participants (n = 42 CPAP only; n = 41 CPAP + ME) contributed 14,273 nights of data for 6 months. Participants were predominantly male (67%) and had a mean +/- SD age of 63.9 +/- 7.4 years, a BMI of 31.1 +/- 5.2 kg/m(2), and an apnea-hypopnea index of 26.2 +/- 12.9 events/h. In our fully adjusted model, average nightly adherence for 6 months was 99.0 min/night higher with CPAP + ME compared with CPAP only (P = .003; primary analysis). A subset of 52 participants remained in the study for 12 months; modeling these data yielded a consistent difference in adherence between arms of 97 min/night (P = .006) favoring CPAP + ME.CONCLUSIONS: ME delivered during brief appointments and phone calls resulted in a clinically significant increase in CPAP adherence. This strategy may represent a feasible approach for optimizing management of OSA.

Background Under-five mortality is declining in Ghana and many other countries. Very few studies have measured under-five mortality—and its social and environmental risk factors—at fine spatial resolutions, which is relevant for policy purposes. Our aim was to estimate under-five mortality and its social and environmental risk factors at the district level in Ghana. Methods and Findings We used 10% random samples of Ghana’s 2000 and 2010 National Population and Housing Censuses. We applied indirect demographic methods and a Bayesian spatial model to the information on total number of children ever born and children surviving to estimate under-five mortality (probability of dying by 5 y of age, 5q0) for each of Ghana’s 110 districts. We also used the census data to estimate the distributions of households or persons in each district in terms of fuel used for cooking, sanitation facility, drinking water source, and parental education. Median district 5q0 declined from 99 deaths per 1,000 live births in 2000 to 70 in 2010. The decline ranged from <5% in some northern districts, where 5q0 had been higher in 2000, to >40% in southern districts, where it had been lower in 2000, exacerbating existing inequalities. Primary education increased in men and women, and more households had access to improved water and sanitation and cleaner cooking fuels. Higher use of liquefied petroleum gas for cooking was associated with lower 5q0 in multivariate analysis. Conclusions Under-five mortality has declined in all of Ghana’s districts, but the cross-district inequality in mortality has increased. There is a need for additional data, including on healthcare, and additional environmental and socioeconomic measurements, to understand the reasons for the variations in mortality levels and trends.

Obstructive sleep apnea (OSA) significantly impacts cardiovascular health, demonstrated by observational investigations showing an independently increased risk of ischemic heart disease, diabetes, hypertension, congestive heart failure, acute coronary syndrome, stroke, cardiovascular mortality, and all-cause mortality. Positive airway pressure (PAP), a medical therapy for sleep apnea, reverses airway obstruction and may help reduce cardiovascular risk. Prior to planning large phase III randomized controlled trials to test the impact of PAP on cardiovascular outcomes, several gaps in knowledge need to be addressed. This article describes 2 independent studies that worked collaboratively to fill these gaps. The populations, design features, and relative benefits/challenges of the 2 studies (SleepTight and BestAIR) are described. Both studies were encouraged to have multidisciplinary teams with expertise in behavioral interventions to improve PAP compliance. Both studies provide key information that will be useful to the research community in future large-scale, event-driven, randomized trials to evaluate the efficacy and/or effectiveness of strategies to identify and treat significant OSA for decreasing risk of major adverse cardiovascular events in high-risk patients.

In the latter half of the 20th century, Los Angeles had, by many measures, higher levels of photochemical air pollutants than any other major city in the United States (Figure 1). To address this problem, the California Air Resources Board and its partners became leaders in quantifying the health effects of air pollutants and in aggressively implementing pollution-control strategies. Even with these actions, air-pollution levels remained high. In 1993, “Health Advisories” were issued on 92 days.1 In that year, the prospective Children's Health Study was launched to examine the effects of air pollution on lung growth in children. Fourth-grade children . . .

As part of a longitudinal study of the respiratory health effects of indoor and outdoor air pollutants, pulmonary function, respiratory illness history, and symptom history were recorded at 2 successive annual examinations of 10,106 white children living in 6 cities in the United States. Parental education, illness history, and smoking habits also were recorded, along with the fuel used for cooking in the child's home. Maternal cigarette smoking was associated with increases of 20 to 35% in the rates of 8 respiratory illnesses and symptoms investigated, and paternal smoking was associated with smaller but still substantial increases. Illness and symptom rates were linearly related to the number of cigarettes smoked by the child's mother. Illness rates were higher for children of current smokers than for children of ex-smokers. The associations between maternal smoking status and childhood respiratory illnesses and symptoms were reduced but not eliminated by adjustment for parental illness history. Levels of forced expiratory volume in one second (FEV1) were significantly lower for children of current smokers than for children of nonsmokers at both examinations and highest for children of ex-smokers. Levels of forced vital capacity (FVC) were lower for children of nonsmokers than for children of current smokers at both examinations, but the difference was statistically significant only at the first examination. Both the increase in mean FVC and the decrease in mean FEV1 among children of current smokers were linearly related to daily cigarette consumption. None of the respiratory illnesses and symptoms studied was significantly associated with exposure to gas cooking in the child's home.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic obstructive pulmonary disease (COPD) is among the five leading causes of death in the developed world and is a rapidly rising cause of death in most other countries.1 Cigarette smoking is clearly the predominant cause of the development of COPD, but there has been speculation for some time that other factors need to be considered in assessing risk of the disease. The report by Lange et al.2 in this issue of the Journal describes results obtained from three longitudinal cohort studies involving adults (age range, 25 to 40 years in two cohorts and 31 to 75 years in the . . .

STUDY OBJECTIVES A challenge in conducting randomized controlled trials of sleep apnea is the timely recruitment of participants to active and control arms. This study assesses the costs and efficiencies of alternative recruitment methods. DESIGN Analysis of recruitment data from the Best Apnea Intervention in Research planning study. SETTING Sleep clinics and cardiology practices. PARTICIPANTS One hundred forty-eight individuals with an apnea-hypopnea index > 15 and cardiovascular (CV) risk factors randomized from a pool of more than 30,000 potentially eligible patients. INTERVENTIONS Comparisons: (1) modes of recruitment: face-to-face (F2F) recruitment versus mail-based recruitment (MBR); (2) recruitment source (sleep versus cardiology clinics). MEASUREMENTS AND RESULTS Recruitment yield was defined as the ratio of the number of subjects randomized to the number of screened records. Recruitment costs were estimated based on staff time. Of the 148 randomized subjects, 25 were recruited from sleep clinics using F2F recruitment and 123 were recruited from cardiology using a F2F (n = 35) or MBR (n = 88) strategy. F2F recruitment yields were 0.17% and 0.30% for sleep versus cardiology sources, respectively (P = 0.04). A comparison of F2F to MBR showed recruitment yields of 1.11% and 0.90% and costs per randomized subject of $2,139 and $647, respectively. CONCLUSIONS Large resources may be needed to meet the recruitment goals of sleep apnea intervention trials. Recruitment source and mode influence efficiencies. For a trial comparing active versus sham continuous positive airway pressure in patients with CV risk factors, recruiting from cardiology was more efficient than from sleep clinics. MBR was three times less costly than F2F recruitment.

In the analysis of prevention and intervention studies, it is often important to investigate whether treatment effects vary among subgroups of patients defined by individual characteristics. These "subgroup analyses" can provide information about how best to use a new prevention or intervention program. However, subgroup analyses can be misleading if they test data-driven hypotheses, employ inappropriate statistical methods, or fail to account for multiple testing. These problems have led to a general suspicion of findings from subgroup analyses. This article discusses sound methods for conducting subgroup analyses to detect moderators. Multiple authors have argued that, to assess whether a treatment effect varies across subgroups defined by patient characteristics, analyses should be based on tests for interaction rather than treatment comparisons within the subgroups. We discuss the concept of heterogeneity and its dependence on the metric used to describe treatment effects. We discuss issues of multiple comparisons related to subgroup analyses and the importance of considering multiplicity in the interpretation of results. We also discuss the types of questions that would lead to subgroup analyses and how different scientific goals may affect the study at the design stage. Finally, we discuss subgroup analyses based on post-baseline factors and the complexity associated with this type of subgroup analysis.

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2–4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79–4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: −0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91–3.34, P = 0.10; risk difference, 0.010; 95% CI: −0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.