BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

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In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.

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Background Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25hydroxy-vitamin D (25(OH)-vitamin D) levels for potential cardiovascular health benefits remain unclear. Methods and Results We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6,123 CVD cases in 65,994 participants were included for a meta-analysis. Comparing the lowest to the highest 25(OH)-vitamin D categories, the pooled relative risks (RR) was 1.52 (95% CI: 1.30-1.77) for total CVD, 1.42 (95% CI: 1.19-1.71) for CVD mortality, 1.38 (95% CI: 1.21-1.57) for coronary heart disease, and 1.64 (95% CI: 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and had better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below approximately 60 nmol/L, with a RR of 1.03 (95% CI: 1.00-1.06) per 25 nmol/L decrement in 25(OH)-vitamin D. Conclusions This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D in the range of 20-60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.

Abstract-We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP) in predicting the risk of cardiovascular disease (CVD), stratifying results at age 60 years, when DBP decreases while SBP continues to increase. We prospectively followed 11 150 male physicians with no history of CVD or antihypertensive treatment through the 2-year questionnaire, after which follow-up began. Reported blood pressure was averaged from both the baseline and 2-year questionnaires. During a median follow-up of 10. Key Words: blood pressure Ⅲ coronary artery disease Ⅲ stroke Ⅲ epidemiology Ⅲ aging T he positive association between either systolic blood pressure (SBP) or diastolic blood pressure (DBP) and the risk of cardiovascular disease (CVD) is well established. 1 Blood pressure is also characterized by its pulsatile and steady components. [2][3][4] The pulsatile component, estimated by pulse pressure (PP), represents blood pressure variation and is affected by left ventricular ejection fraction, large-artery stiffness, early pulse wave reduction, and heart rate. 5 The steady component, estimated by mean arterial pressure (MAP), is a function of left ventricular contractility, heart rate, and vascular resistance and elasticity averaged over time. 2,6 It remains unclear which measures of blood pressure, either alone or in combination, best predict the risk of CVD. Data from the Framingham Heart Study 5,7,8 and other studies 9,10 indicate that SBP increases continuously across all age groups, whereas DBP increases until age 60 years and then begins to decrease steadily. As a result, PP may become a more important blood pressure measure associated with CVD in older individuals. 11 In addition, MAP has not been extensively studied, with positive associations in some, 12-14 but not all, 15 studies with CVD.Therefore, we considered the use of SBP, DBP, PP, and MAP in a large cohort of men aged 40 to 84 years at baseline with no history of antihypertensive treatment. Using selfreported average blood pressure values on the baseline and 2-year questionnaires, we compared the associations of each blood pressure measure with the risk of incident CVD. We further examined potential differences in CVD risk by age dichotomized at 60 years, when DBP levels decrease while SBP continues to increase. 3,5 Methods Study Population and Data CollectionThe subjects and methods of the Physicians' Health Study, a 2ϫ2 factorial trial of aspirin and ␤-carotene for the primary prevention of

Total physical activity and vigorous activities showed the strongest reductions in CHD risk. Moderate and light activities, which may be less precisely measured, showed nonsignificant inverse associations. The association between physical activity and a reduced risk of CHD also extends to men with multiple coronary risk factors.