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Background Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown. Methods This multicenter, retrospective analysis evaluated the significance of comorbidities, as assessed by the Cumulative Illness Rating Scale (CIRS), among patients with CLL treated with ibrutinib. Results One hundred forty-five patients received ibrutinib (80% in a relapsed/refractory setting). A high burden of comorbidities (CIRS score ≥ 7) was associated with inferior median event-free survival (EFS; 24 vs 37 months; P = .003) and 2-year overall survival (OS; 79% vs 100%; P = .005). In an adjusted Cox model, both EFS and OS worsened with an incremental increase in the CIRS score. Furthermore, comorbidities were associated with an increased risk of ibrutinib dose reduction and therapy discontinuation. CIRS was predictive in both frontline and relapsed CLL, regardless of patient age. Conclusions Comorbidities portend a poor prognosis among patients with CLL treated with ibrutinib. Prospective studies are needed to optimize the treatment of patients with CLL who have comorbidities. Cancer 2018. © 2018 American Cancer Society.

Few studies have assessed which biomarkers influence mortality risk among those with peripheral arterial disease (PAD). We analyzed data from 556 individuals identified to have PAD (i.e. ankle–brachial index ⩽0.9) with available measurements of C-reactive protein, the neutrophil-to-lymphocyte ratio (NLR), homocysteine, and the urinary albumin-to-creatinine ratio (UACR) in the 1999–2004 National Health and Nutrition Examination Survey. We investigated whether a combination of these biomarkers improved the prediction of all-cause and cardiovascular mortality beyond conventional risk factors. During follow-up (median, 8.1 years), 277 of 556 participants died; 63 deaths were attributed to cardiovascular disease. After adjusting for conventional risk factors, Cox proportional-hazards models showed the following to be most strongly associated with all-cause mortality (each is followed by the adjusted hazard ratio [HR] per 1 standard deviation increment in the log values): homocysteine (1.31), UACR (1.21), and NLR (1.20). UACR alone significantly predicted cardiovascular mortality (1.53). Persons in the highest quintile of multimarker scores derived from regression coefficients of significant biomarkers had elevated risks of all-cause mortality (adjusted HR, 2.45; 95% CI, 1.66–3.62; p for trend

Introduction Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95%UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95%UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), andWest Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5%(95%UI, 42.8%to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5%of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.

BACKGROUND: Light smoking, consuming a few cigarettes daily, and intermittent, or nondaily, smoking patterns are increasingly common but carry health risks comparable to heavier smoking patterns. Nearly all smokers begin smoking as adolescents, who are at risk for developing these smoking patterns. Previous research suggests that smokers underestimate the risks associated with smoking. The extent to which adolescents perceive light and intermittent smoking as harmful has not been previously assessed. METHODS: Data from 24 658 US adolescents sampled by the 2012 National Youth Tobacco Survey, a national, school-based, cross-sectional survey, were examined. Cross-tabulations and multivariate ordered probit regression models were constructed to describe correlates of US adolescents’ perception of light and intermittent smoking. RESULTS: Although most adolescents (88.0%; 95% confidence interval [CI], 87.2% to 88.8%) reported beliefs that a heavier smoking pattern is very harmful, only 64.3% (95% CI; 63.2% to 65.3%) and 33.3% (95% CI; 32.0% to 34.6%) reported that light and intermittent smoking, respectively, are very harmful. Conversely, nearly one-quarter of US adolescents believed intermittent smoking causes little or no harm. Males, younger adolescents, Hispanics, and non-Hispanic blacks were more likely than their peers to view light and intermittent smoking patterns as less harmful. Those who were already light or intermittent smokers, those who used other tobacco products, and those who had a family member who used tobacco were also less likely to view their smoking patterns as harmful. CONCLUSIONS: Misconceptions about the safety of light and intermittent smoking are widespread among US adolescents. Significant public health attention is needed to redress these misperceptions.

Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients.We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance.In adjusted analyses, women were less likely than men to achieve treated LDL-C of100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90).In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.

Morbidity and mortality from peripheral arterial disease (PAD) continues to increase. Traditional cardiovascular risk factors are implicated in the development of PAD, yet the extent to which those risk factors correlate with mortality in such patients remains insufficiently assessed. Using data from the 1999 to 2004 National Health and Nutrition Examination Survey, Cox proportional hazards models were used to examine the association of cardiovascular risk factors and all-cause and cardiovascular mortality. A total of 647 individuals ≥40 years old with PAD (i.e., ankle-brachial index [ABI] ≤ 0.9) were followed for a median of 7.8 years. There were 336 deaths, of which 98 were attributable to cardiovascular disease. Compared with never smokers, current (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.62 to 3.71) and former (HR 1.62, 95% CI 1.14 to 2.29) smokers with PAD had higher rates of death. Moderate or vigorous physical activity of ≥10 minutes monthly was associated with lower death rates (HR 0.63, 95% CI 0.44 to 0.91). Also associated with increased rates of cardiovascular death were an ABI of0.5 (HR 2.56, 95% CI 1.28 to 5.15, compared with those with an ABI of 0.7 to 0.9) and diabetes mellitus (HR 2.50, 95% CI 1.33 to 4.73). Neither C-reactive protein nor body mass index was associated with mortality. In conclusion, tobacco use increased the risk of all-cause and cardiovascular death, whereas physical activity was associated with a decreased mortality risk. A low ABI and diabetes were also predictive of cardiovascular death.

Leptin and C-reactive protein (CRP) have each been linked to adverse cardiovascular events, and prior cross-sectional research suggests that increased levels of both biomarkers pose an even greater risk. The effect of increased levels of both leptin and CRP on mortality has not, however, been previously assessed.We used data from the third National Health and Nutrition Examination Survey (NHANES III) to estimate the mortality effect of high leptin and high CRP levels. Outcomes were compared with the use of inverse-probability-weighting adjustment. Among 6259 participants included in the analysis, 766 were in their sex-specific, population-weighted highest quartiles of both leptin and CRP. Median follow-up time was 14.3 years.There was no significant difference in adjusted all-cause mortality between the groups (risk ratio 1.22, 95% confidence interval [CI], 0.97-1.54). Similar results were noted with the use of several different analytic methods and in many subgroups, though high leptin and CRP levels may increase all-cause mortality in males (hazard ratio, 1.80, 95% CI, 1.32-2.46; P for interaction, 0.011). A significant difference in cardiovascular mortality was also noted (risk ratio, 1.54, 95% CI, 1.08-2.18), though that finding was not confirmed in all sensitivity analyses..In this observational study, no significant difference in overall all-cause mortality rates in those with high leptin and high CRP levels was found, though high leptin and CRP levels appear associated with increased mortality in males. High leptin and CRP levels also likely increase risk for cardiovascular death..

Introduction: U.S. adolescents increasingly use e-cigarettes. The perceived harm of e-cigarettes has not been described, nor has the correlation between harm perception and e-cigarette use been assessed. This study examines correlates of e-cigarette harm perception and use of e-cigarettes in a national survey. Methods: Cross-sectional, nationally representative data from the 2012 National Youth Tobacco Survey were used (n = 24,658). Cross-tabulations and multivariate ordered probit and logistic regression models were employed to assess relative harm perception and e-cigarette use. Results: Half of U.S. adolescents had heard of e-cigarettes. Of these, 13.2% (95% confidence interval (CI) = 11.7-14.9) and 4.0% (95% CI = 3.4-4.7) reported ever or currently using e-cigarettes, respectively. Of those aware of e-cigarettes, 34.2% (95% CI = 32.8-35.6) believed e-cigarettes were less harmful than cigarettes. Among those trying e-cigarettes, 71.8% (95% CI = 69.0-74.5) believed e-cigarettes were comparatively less harmful. Females and those ≥17 years old were more likely to perceive e-cigarettes as more harmful relative to cigarettes, while, on average, Whites, users of other tobacco products, and those with family members who used tobacco were more likely to perceive e-cigarettes as comparatively safer. Among cigarette-naive e-cigarette users, use of other tobacco products and perceived harm reduction by e-cigarettes were, respectively, on average associated with 1.6 and 4.1 percentage-point increases in e-cigarette use. Conclusions: Perception of e-cigarettes as less harmful than conventional cigarettes was associ- ated with increased e-cigarette use, including among cigarette-naive e-cigarette users. These find- ings should prompt further scientific investigation and merit attention from regulators.

Objective Questions persist as to which dimensions of child mental health are most associated with parental mental health status and if these associations differ by parental gender. We assessed associations between parental psychological distress and children's mental health. Methods Pooled data from the 2001, 2002, and 2004 National Health Interview Surveys (NHIS), a nationally representative, cross-sectional survey of US children aged 4 to 17 (n = 21,314), were used. Multivariate logistic regression was performed assessing associations between parental psychological distress, measured by the Kessler 6 scale, and the extended-form Strengths and Difficulties Questionnaire (SDQ) scales. Results Logistic regression demonstrated associations between parental psychological distress and increased likelihood of child mental health problems. Children aged 4 to 11 were more likely to have mental health problems if they had a psychologically distressed father (odds ratio [OR] 7.5, 95% confidence interval [CI] 2.3–24.3) or mother (OR 6.7, 95% CI 2.7–16.7). Children aged 12 to 17 with a psychologically distressed father (OR 4.53, 95% CI 1.18–17.47) or mother (OR 3.90, 95% CI 1.34–11.37) were also more likely than those without to have mental health problems. In parents of both genders, associations existed between parental psychological distress, and abnormal emotional symptoms in younger children, conduct disorder in older children, and hyperactivity in children of all ages. Conclusions Parental psychological distress appears similarly associated with adverse child mental health outcomes, regardless of parental gender. These findings corroborate limited prior research and demonstrate that associations between child mental health and parental mental illness are similar in magnitude for fathers and mothers.

Youth indoor tanning rates remain high despite the potential for increased melanoma risk. No previous study has assessed the prevalence of unhealthy weight control behaviors in both male and female adolescent indoor tanning users using a nationally representative survey.Pooled data on high school students from the 2009 and 2011 Youth Risk Behavior Survey were used (n = 26,951). Multivariate logistic regression was used to assess associations between the recent indoor tanning use and recently doing the following to lose weight: fasting for more than 24 hours; taking a pill, powder, or liquid without a doctor's consent; and vomiting or taking a laxative.Pooled data showed 23.3% of females reported indoor tanning within the past year; 6.5% of males did so as well. Adjusted multivariate results show that females who indoor tan were, on average, more likely to have fasted (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.5), taken a pill, powder, or liquid (OR, 2.4; 95% CI, 1.9-3.0), and vomited or taken a laxative to lose weight (OR, 1.4; 95% CI, 1.1-1.7) within the past 30 days than those who did not. Males who indoor tanned within the past year were, on average, more likely to have fasted (OR, 2.3; 95% CI, 1.7-3.1), taken a pill, powder, or liquid (OR, 4.4; 95% CI, 3.3-6.0), and vomited or taken a laxative to lose weight (OR, 7.1; 95% CI, 4.4-11.4) within the past 30 days.Significant associations between indoor tanning use and unhealthy weight control behaviors exist for both male and female adolescents, with a stronger association observed among males.

Introduction U.S. adolescents increasingly use alternative tobacco products (ATPs), including hookah. No study has previously assessed correlates of adolescent hookah use in a nationally representative sample. Methods Cross-sectional, nationally representative data of adolescents from the 2011 National Youth Tobacco Survey (NYTS) were used. Student demographics and their use of, exposure to, and beliefs about tobacco were examined as correlates of hookah use. Results Of adolescents nationwide, 7.3% reported ever trying hookah and 2.6% reported using hookah within the past month. Increasing age was associated with trying hookah, but not current hookah use. Sex was unassociated with hookah use. Asians were most likely to have tried hookah; Hispanics and those of another race reported greater current hookah use. Hookah use increased with perceived ease of access to and willingness to try tobacco. Students with a hookah user at home were more likely to have tried hookah and to currently use hookah. Current cigarette use was not associated with current hookah use (odds ratio [OR] = 1.3, 95% CI = 0.8-2.1), but was associated with trying hookah (OR = 1.5, 95% CI = 1.1-2.2). Non-cigarette tobacco use was associated with trying hookah (OR = 2.7, 95% CI = 2.1-3.5) and current hookah use (OR = 4.8, 95% CI = 2.7-8.7). Conclusions A sizeable minority of U.S. adolescents use hookah, particularly those living with hookah users, those who use other ATPs, and those who perceive tobacco as easily accessible. Current cigarette use was not associated with current hookah use. Future studies assessing the dangers of hookah use and interventions to curb this emerging problem appear warranted.

Source at: http://doi.org/10.1056/NEJMoa1614362 Background: Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. Methods: We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. Restults: In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. Conclusions: The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem.

BACKGROUND: Electronic cigarettes (e-cigarettes) are now the most commonly used tobacco product among US youth. The extent to which perceptions of e-cigarettes’ harm and addictiveness differ from those of other products remains unknown, as does whether these perceptions have changed over time. METHODS: Data from the 2012 and 2014 National Youth Tobacco Survey, a repeated cross-sectional survey of grade 6 to 12 students, were used. Cross-tabulations and logistic regression models were used to describe correlates of perceptions of harm and addictiveness of e-cigarettes, cigars, and smokeless tobacco compared with cigarettes. Trends in perceptions of e-cigarettes’ harm among different demographic groups were also assessed. RESULTS: In 2014, 73.0% believed that e-cigarettes were less harmful than cigarettes, compared with 20.2% for smokeless tobacco and 25.8% for cigars. By comparison, 47.1% believed that e-cigarettes were less addictive than cigarettes, compared with only 14.0% for smokeless tobacco and 31.5% for cigars. Use of each product was associated with a perception of decreased harm and addictiveness in adjusted analyses, as was being male, being a non-Hispanic white, and residing with a household member who used that product. Between 2012 and 2014, increasing numbers of US youth thought they were able to assess the relative harm of e-cigarettes and increasingly believed that e-cigarettes are less harmful than cigarettes. CONCLUSIONS: Most US youth view e-cigarettes as less harmful and addictive than cigarettes. Far fewer think similarly about cigars and smokeless tobacco. Increases in e-cigarettes’ perceived safety mirrors rapid increases observed in their use. Perceived safety correlates with use of each tobacco product.

INTRODUCTION: Despite reductions in smoking rates, exposure to cigarette smoke remains common among US children and adolescents. In adults, active smoking and secondhand smoke (SHS) exposure have been linked to adverse changes in lipid profiles and increases in inflammatory markers. Evidence that such changes are present before adulthood remains limited, and the extent to which active smoking and SHS exposure affect these cardiovascular measures in children has not been thoroughly assessed. METHODS: We employed data from 2008 individuals aged 12-19 years from the 2005-2010 National Health and Nutrition Examination Survey. Comparisons of the lipid and inflammatory marker levels among active smokers, those exposed to SHS (as determined by serum cotinine levels), and those unexposed to tobacco smoke were made using linear regression with multiple propensity score adjustment. RESULTS: Compared to unexposed children, lipid and inflammatory marker profiles did not differ among those exposed to SHS exposure. Among active smokers, differences compared to unexposed children were observed in triglyceride levels ( β=8.5 mg/dL, P = .01), the ratio of triglycerides to high-density lipoprotein ( β=0.2, P = .045), and low-density lipoprotein cholesterol ( β-4.1 mg/dL , P = .03), though these did not reach levels of confirmatory statistical significance. CONCLUSIONS: After accounting for sociodemographic characteristics and medical comorbidities, serum lipids and markers of systemic inflammation were not associated with SHS exposure. Tobacco smoke exposure in children may require longer durations of compounded effect before serum lipid abnormalities are detected. IMPLICATIONS: This paper adds detail to the study of secondhand smoke's effects on lipid profiles of children and adolescents. Prior research on this topic for these age groups has been limited, and this study provides national, cross-sectional data to show that both secondhand smoke and active smoking in childhood and adolescence is not associated with changes in lipid profiles or markers of inflammation. Tobacco smoke exposure may require longer durations of compounded effect before abnormalities are detected.

BACKGROUND: Established in 2000, Millennium Development Goal 4 (MDG4) catalysed extraordinary political, financial, and social commitments to reduce under-5 mortality by two-thirds between 1990 and 2015. At the country level, the pace of progress in improving child survival has varied markedly, highlighting a crucial need to further examine potential drivers of accelerated or slowed decreases in child mortality. The Global Burden of Disease 2015 Study (GBD 2015) provides an analytical framework to comprehensively assess these trends for under-5 mortality, age-specific and cause-specific mortality among children under 5 years, and stillbirths by geography over time. METHODS: Drawing from analytical approaches developed and refined in previous iterations of the GBD study, we generated updated estimates of child mortality by age group (neonatal, post-neonatal, ages 1-4 years, and under 5) for 195 countries and territories and selected subnational geographies, from 1980-2015. We also estimated numbers and rates of stillbirths for these geographies and years. Gaussian process regression with data source adjustments for sampling and non-sampling bias was applied to synthesise input data for under-5 mortality for each geography. Age-specific mortality estimates were generated through a two-stage age-sex splitting process, and stillbirth estimates were produced with a mixed-effects model, which accounted for variable stillbirth definitions and data source-specific biases. For GBD 2015, we did a series of novel analyses to systematically quantify the drivers of trends in child mortality across geographies. First, we assessed observed and expected levels and annualised rates of decrease for under-5 mortality and stillbirths as they related to the Soci-demographic Index (SDI). Second, we examined the ratio of recorded and expected levels of child mortality, on the basis of SDI, across geographies, as well as differences in recorded and expected annualised rates of change for under-5 mortality. Third, we analysed levels and cause compositions of under-5 mortality, across time and geographies, as they related to rising SDI. Finally, we decomposed the changes in under-5 mortality to changes in SDI at the global level, as well as changes in leading causes of under-5 deaths for countries and territories. We documented each step of the GBD 2015 child mortality estimation process, as well as data sources, in accordance with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). FINDINGS: Globally, 5·8 million (95% uncertainty interval [UI] 5·7-6·0) children younger than 5 years died in 2015, representing a 52·0% (95% UI 50·7-53·3) decrease in the number of under-5 deaths since 1990. Neonatal deaths and stillbirths fell at a slower pace since 1990, decreasing by 42·4% (41·3-43·6) to 2·6 million (2·6-2·7) neonatal deaths and 47·0% (35·1-57·0) to 2·1 million (1·8-2·5) stillbirths in 2015. Between 1990 and 2015, global under-5 mortality decreased at an annualised rate of decrease of 3·0% (2·6-3·3), falling short of the 4·4% annualised rate of decrease required to achieve MDG4. During this time, 58 countries met or exceeded the pace of progress required to meet MDG4. Between 2000, the year MDG4 was formally enacted, and 2015, 28 additional countries that did not achieve the 4·4% rate of decrease from 1990 met the MDG4 pace of decrease. However, absolute levels of under-5 mortality remained high in many countries, with 11 countries still recording rates exceeding 100 per 1000 livebirths in 2015. Marked decreases in under-5 deaths due to a number of communicable diseases, including lower respiratory infections, diarrhoeal diseases, measles, and malaria, accounted for much of the progress in lowering overall under-5 mortality in low-income countries. Compared with gains achieved for infectious diseases and nutritional deficiencies, the persisting toll of neonatal conditions and congenital anomalies on child survival became evident, especially in low-income and low-middle-income countries. We found sizeable heterogeneities in comparing observed and expected rates of under-5 mortality, as well as differences in observed and expected rates of change for under-5 mortality. At the global level, we recorded a divergence in observed and expected levels of under-5 mortality starting in 2000, with the observed trend falling much faster than what was expected based on SDI through 2015. Between 2000 and 2015, the world recorded 10·3 million fewer under-5 deaths than expected on the basis of improving SDI alone. INTERPRETATION: Gains in child survival have been large, widespread, and in many places in the world, faster than what was anticipated based on improving levels of development. Yet some countries, particularly in sub-Saharan Africa, still had high rates of under-5 mortality in 2015. Unless these countries are able to accelerate reductions in child deaths at an extraordinary pace, their achievement of proposed SDG targets is unlikely. Improving the evidence base on drivers that might hasten the pace of progress for child survival, ranging from cost-effective intervention packages to innovative financing mechanisms, is vital to charting the pathways for ultimately ending preventable child deaths by 2030. FUNDING: Bill & Melinda Gates Foundation. Erratum: Department of Error, The Lancet,Volume 389, Issue 10064, 2017, Page e1. DOI: 10.1016/S0140-6736(16)32608-3

Introduction: The majority of patients with chronic lymphocytic leukemia (CLL) present with comorbidities, commensurate with the median age at diagnosis of 71 years. The Cumulative Illness Rating Scale (CIRS) is a widely used index which has been incorporated into clinical research in CLL. CIRS consists of 14 categories related to different body systems and scores the severity of each condition from 0-4. We have previously reported in a single-center study that CIRS predicted outcomes in patients with CLL treated with chemo-immunotherapy (CIT). However, to date it is not yet known how comorbidities impact outcomes in the era of novel agents. We tested a hypothesis that CIRS and severe organ dysfunction would retain prognostic significance. Methods: We conducted a retrospective analysis of patients with CLL who underwent treatment at three academic medical centers between 2000 and 2016. CIRS score was calculated as in Salvi et al, 2008. Overall survival (OS) and progression-free survival (PFS) were assessed by Cox proportional hazards models adjusting for performance status (PS), age group, and chemotherapy regimen. Survival analysis in patients treated with ibrutinib was adjusted for age, PS, Rai stage, del17p and prior treatment. In addition, the impact of severe organ dysfunction (CIRS-3+, i.e. CIRS score ≥3 in single organ system) was assessed. Results: Median age in patients receiving CIT was 65 years (N=233). The most common comorbidities were hypertension, endocrine (e.g. diabetes mellitus) and vascular (e.g. deep vein thrombosis). Fludarabine-Rituximab (N=61), Fludarabine-Cyclophosphamide-Rituximab (N=67), Rituximab-Cyclophosphamide-Vincristine-Prednisone (N=35), Bendamustine-Rituximab (N=38) and chlorambucil (N=47) were the most commonly used regimens. 79.5% of treatments were administered in a frontline setting. Average total CIRS was 6.6 and 47% had CIRS-3+. Median OS among all patients receiving CIT was 112 months (95% CI: 105 - 128 months). CIRS≥7 and CIRS3+ were associated with inferior OS compared to patients without significant comorbidities (87, 92 and 129 months, respectively, p In patients treated with ibrutinib the median age was 71 years (N=83), which was significantly older than in the CIT cohort (p Conclusion: In this multicenter retrospective analysis we show that CIRS has prognostic significance in patients with CLL treated with either CIT or ibrutinib, where increased comorbidities correlate with shortened progression-free and overall survival. CIRS appears to carry prognostic value in both upfront and relapsed settings, including patients whose disease can be salvaged with ibrutinib. Larger prospective studies of patients with lymphoid malignancies who have comorbidities are necessary to better define the prognostic value of CIRS in the era of targeted agents and determine the optimal approach to therapy of such patients. Figure 1 Figure 1. Disclosures Persky: Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.

Background: Familial hypercholesterolemia (FH) patients require aggressive lipid lowering therapies to reduce cardiovascular disease risk. In the US, treatment patterns remain poorly described, and it remains unclear whether sex or ethnic/racial disparities exist. In 2013, the FH Foundation launched

© 2016 Elsevier Ltd GBD 2015 HIV Collaborators. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015. Lancet HIV 2016; 3: e361–87—In this Article, Kerrie E Doyle and David M Pereira have been added to the list of collaborators and Claudia C Pereira has been removed. These corrections have been made as of Aug 22, 2016.

OBJECTIVE: In 2011, the Accreditation Council on Graduate Medical Education increased restrictions on resident duty-hours. Additional changes have been considered, including greater work-hours restrictions and lengthening residency. Program directors tend to oppose further restrictions; however, residents’ views are unclear. We sought to determine whether residents support these proposals, and if so why. METHODS: We surveyed US pediatric residents from a probability sample of 58 residency programs. We used multivariate logistic regression to determine predictors of support for (1) a 56-hour workweek and (2) the addition of 1 year to residency to achieve a 56-hour week. RESULTS: Fifty-seven percent of sampled residents participated (n = 1469). Forty-one percent of respondents supported a 56-hour week, with 28% neutral and 31% opposed. Twenty-three percent of all residents would be willing to lengthen training to reduce hours. The primary predictors of support for a 56-hour week were beliefs that it would improve education (odds ratio [OR] 8.6, P < .001) and quality of life (OR 8.7, P < .001); those who believed patient care would suffer were less likely to support it (OR 0.10, P < .001). Believing in benefits to education without decrement to patient care also predicted support for a 56-hour-week/4-year program. CONCLUSIONS: Pediatric residents who support further reductions in work-hours believe reductions have positive effects on patient care, education, and quality of life. Most would not lengthen training to reduce hours, but a minority prefers this schedule. If evidence mounts showing that reducing work-hours benefits education and patient care, pediatric residents’ support for the additional year may grow.

Tobacco use remains a pediatric disease because 9 of 10 smokers begin smoking before their 18th birthday.1 Nearly half a million US citizens die prematurely each year from smoking-related diseases, with substantial economic consequences.1 To address these continued problems, the Family Smoking Prevention and Tobacco Control Act was enacted in June 2009 and empowered the US Food and Drug Administration (FDA) to regulate the manufacture, sale, marketing, and distribution of tobacco products. Under the act, the FDA can restrict marketing and sales of tobacco products to youth, mandate reporting of ingredients and additives, ban cigarette flavorings, and review manufacturers’ claims regarding allegedly lower-risk products. The Tobacco Control Act marked a substantial advance to curb tobacco use among minors. Yet the FDA gained control only over cigarettes and smokeless tobacco products. Most alternative tobacco products (ATPs), including water pipe tobacco (ie, hookah or shisha) and e-cigarettes, were left unregulated. Others, like snus, a moist smokeless tobacco product popularized in Sweden for its alleged harm reduction, remain virtually unregulated.2 While taxes, regulation, and educational efforts have contributed to further declines in adolescent cigarette smoking rates, use of the less-regulated ATPs continues to rise.1 The increase in adolescent ATP use has occurred because of their widespread availability, lax regulation, targeted advertising, and perceptions that these products are relatively safe.3 Manufacturer claims of purported harm reduction with ATPs may be misleading but, given the current regulatory environment, remain unchecked. Results of observational research studies on the potential role for ATPs in harm reduction among adult cigarette smokers have been used, in effect, to promote their widespread availability, including to cigarette-naive children.4 Manufacturers of ATPs have aggressively marketed their products to youth through product flavoring, promotional material, and the distribution of free samples. Such behaviors mirror the long-standing practices of tobacco companies with cigarettes, behaviors banned under the Tobacco Control Act.3 The relationship between ATPs and traditional cigarettes is of critical importance, yet it has been insufficiently explored. Alternative tobacco products might serve as gateway products for adolescents, leading to subsequent use of other tobacco products, including traditional cigarettes. If true, failure to regulate ATPs has the potential to undermine antitobacco regulatory efforts regarding minors. Some ATPs may lead to subsequent cigarette use, as reported by Soneji and colleagues5 in the February 2015 issue of JAMA Pediatrics. In a national survey of 1596 young adults (15–23 years old), including 1048 who were cigarette-naive at baseline, both baseline water pipe tobacco and snus use were associated with increased interim cigarette initiation, current cigarette smoking, and high-intensity cigarette smoking after a 2-year follow-up period. These relationships persisted after adjusting for sociodemographic and behavioral covariates, including measures of sensation seeking and individuals’ other risk-taking behaviors. The authors estimated that baseline water pipe tobacco and snus use increased the odds of interim cigarette smoking initiation by 2.56 (95%CI, 1.46–4.47) and 3.73 (95%CI, 1.43–9.76), respectively, after accounting for other factors. Baseline water pipe tobacco use increased the odds of subsequent cigarette smoking by 2.48(95%CI, 1.01–6.06) as did use of snus (odds ratio, 6.19; 95%CI, 1.86–20.56). Although the study was limited by the caveats of observational data analysis, the authors’ robust findings provide a convincing link between use of the studied ATPs and subsequent cigarette use. A few specific limitations merit comment. The authors were unable to assess whether users of water pipe tobacco or snus had used other ATPs such as e-cigarettes. It remains plausible that use of another unmeasured ATP increased individuals’ subsequent cigarette use and influenced the reported findings. In addition, Soneji and colleagues5 were unable to characterize the time between ATP use and cigarette use; near-concurrent cigarette initiation cannot then be fully excluded by the authors’ study design. Nonetheless, a plausible conclusion is that tobacco use leads to tobacco use. Use of ATPs likely increases the risk of both concurrent and subsequent use of any other tobacco product, including cigarettes. Half of US adolescent tobacco users are polytobacco users and individuals’ tobacco use trajectories remain poorly characterized.6 Although much work is needed to help understand the increasing complexity of young adults’ tobacco use trajectories in order to promote effective public health planning, these findings corroborate limited prior research suggesting that precollege ATP use increases subsequent cigarette use.7 That such findings conflict with prior studies on adults, as with the case in studies of Swedish adults that suggested no link between snus use and subsequent cigarette uptake,8 highlights the important difference between tobacco uptake in childhood and potential harm-reduction strategies in adults even when considering the same product. The regulatory implications of the results by Soneji and colleagues5 have been underscored by recent developments. In April 2014, the FDA issued a proposed rule to extend its jurisdiction to include tobacco products not previously regulated by the FDA, including e-cigarettes, cigars, pipe tobacco, dissolvable and gel tobacco forms, and water pipe tobacco.9 Advocates have noted that the Tobacco Control Act enables the FDA to regulate snus more aggressively as well.2 The results of the FDA’s decision to “deem” these products as qualifying under existing law and to regulate the marketing, sale, and manufacturing of such products would mark a substantial advance in US tobacco control efforts. The FDA is currently reviewing public comments on the proposed rule. A second front in the war on tobacco has opened. As regulations on cigarette tobacco have tightened, adolescent cigarette use has decreased. Yet a burgeoning ATP problem may undermine those successes. Absent more stringent regulation, a robust market for such products has developed and ATPs have become widely available to adolescents. Adolescents are increasingly using these products, and such use is not experimentation but the beginnings of an addiction that can lead to later cigarette use.