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BACKGROUND: With epigenome-wide mapping of DNA methylation, a number of novel smoking-associated loci have been identified. OBJECTIVES: We aimed to assess dose-response relationships of methylation at the top hits from the epigenome-wide methylation studies with smoking exposure as well as with total and cause-specific mortality. METHODS: In a population-based prospective cohort study in Germany, methylation was quantified in baseline blood DNA of 1,000 older adults by the Illumina 450K assay. Deaths were recorded during a median follow-up of 10.3 years. Dose-response relationships of smoking exposure with methylation at nine CpGs were modeled by restricted cubic spline regression. Associations of individual and aggregate methylation patterns with all-cause, cardiovascular, and cancer mortality were assessed by multiple Cox regression. RESULTS: Clear dose-response relationships with respect to current and lifetime smoking intensity were consistently observed for methylation at six of the nine CpGs. Seven of the nine CpGs were also associated with mortality outcomes to various extents. A methylation score based on the top two CpGs (cg05575921 and cg06126421) showed the strongest associations with all-cause, cardiovascular, and cancer mortality, with adjusted hazard ratios (95% CI) of 3.59 (2.10, 6.16), 7.41 (2.81, 19.54), and 2.48 (1.01, 6.08), respectively, for participants with methylation levels in the lowest quartile at both CpGs. Adding methylation at those two CpGs into a model that included the variables of the Systematic Coronary Risk Evaluation chart for fatal cardiovascular risk prediction improved the predictive discrimination. CONCLUSION: The novel methylation biomarkers are highly informative for both smoking exposure and smoking-related mortality outcomes. In particular, these biomarkers may substantially improve cardiovascular risk prediction. Nevertheless, the findings of the present study need to be further validated in additional large longitudinal studies. http://dx.doi.org/10.1289/ehp.1409020, Introduction Tobacco smoking has been recognized as a risk factor for a variety of complex diseases (CDC 2014), including cardiovascular diseases (CVDs) (Ezzati et al. 2005b), at least 15 types [...]

Objective: In the SENSCIS trial in subjects with systemic sclerosis–associated interstitial lung disease (SSc‐ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. This study was undertaken to investigate the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. Methods: In post hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC of ≥5% predicted or death and absolute decline in FVC of ≥10% predicted or death. Results: A total of 288 subjects received nintedanib and 288 subjects received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had a decline in FVC of >5% to ≤10% predicted, and 3.5% and 5.2% had a decline in FVC of >10% to ≤15% predicted; 34.5% and 43.8% had a decrease in FVC of ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC of ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66−1.06) (P = 0.14), and the HR for an absolute decline in FVC of ≥10% predicted was 0.64 (95% CI 0.43−0.95) (P = 0.029). Conclusion: These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc‐ILD. [ABSTRACT FROM AUTHOR]

Abstract Background The standardisation of the assessment methodology and case definition represents a major precondition for the comparison of study results and the conduction of meta-analyses. International guidelines provide recommendations for the standardisation of falls methodology; however, injurious falls have not been targeted. The aim of the present article was to review systematically the range of case definitions and methods used to measure and report on injurious falls in randomised controlled trials (RCTs) on fall prevention. Methods An electronic literature search of selected comprehensive databases was performed to identify injurious falls definitions in published trials. Inclusion criteria were: RCTs on falls prevention published in English, study population ≥ 65 years, definition of injurious falls as a study endpoint by using the terms "injuries" and "falls". Results The search yielded 2089 articles, 2048 were excluded according to defined inclusion criteria. Forty-one articles were included. The systematic analysis of the methodology applied in RCTs disclosed substantial variations in the definition and methods used to measure and document injurious falls. The limited standardisation hampered comparability of study results. Our results also highlight that studies which used a similar, standardised definition of injurious falls showed comparable outcomes. Conclusions No standard for defining, measuring, and documenting injurious falls could be identified among published RCTs. A standardised injurious falls definition enhances the comparability of study results as demonstrated by a subgroup of RCTs used a similar definition. Recommendations for standardising the methodology are given in the present review.

Na+/H+ exchangers (NHEs) are expressed in virtually all human tissues and organs. Two major tasks of those NHE isoforms that are located in plasma membranes are cell volume control by Na+-uptake and cellular pH regulation by H+-extrusion. Several NHEs, particularly NHE 1–4 and 8, are involved in the pathogenesis of diseases of the digestive system such as inflammatory bowel disease (ulcerative colitis, Crohn's disease) and gastric and colorectal tumorigenesis. In the present review, we describe the physiological purposes, possible malfunctions and pathophysiological effects of the different NHE isoforms along the alimentary canal from esophagus to colon, including pancreas, liver and gallbladder. Particular attention is paid to the functions of NHEs in injury repair and to the role of NHE1 in Barrett's esophagus. The impact of NHEs on gut microbiota and intestinal mucosal integrity is also dealt with. As the hitherto existing findings are not always consistent, sometimes even controversial, they are compared and critically discussed. [ABSTRACT FROM AUTHOR]