SummaryBackgroundLow-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.MethodsWe did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FindingsIn the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.InterpretationIn current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being ...

BACKGROUND There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of “low” (<10%), “intermediate” (10% to <20%), and “high” (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. CONCLUSIONS In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)

Twelve antibiotic substances for human use, including trimethoprim and representatives of the fluoroquinolone (FQ), sulfonamide (SA), penicillin (PE), cephalosporin (CE), nitroimidazole (NI), tetracycline (TC), and macrolide (MA) groups, were subjected to a screening study at five Swedish sewage treatment plants (STPs) during one week in 2002 and one week in 2003. The analytes were extracted from raw sewage water, final effluent, and sludge by solid-phase extraction (SPE) or liquid-solid extraction (as appropriate) and then identified and quantified by liquid chromatography/tandem mass spectrometry. The mostfrequently detected antibiotics in the matrices considered in this study were norfloxacin, ofloxacin, ciprofloxacin, trimethoprim, sulfamethoxazole, and doxycycline. The other analytes were only detected in a few samples. Analysis of the weekly mass flows through each STP showed that FQs were partly eliminated from the water during sewage water treatment and the highest amounts of these substances were found in sludge. Sulfamethoxazole and trimethoprim were mainly found in raw sewage water and final effluent, but these substances had balancing mass flows, indicating that they too can withstand sewage water treatment. The mass flow patterns for doxycycline were more complex, with high amounts occurring in sludge in some cases, suggesting thatthe behavior of this analyte may be more strongly influenced by the treatment process and other variables at individual STPs. The environmental load (the sum of the amounts in the final effluent and sludge) normalized to the number of inhabitants in the catchment area of each investigated STP compared with theoretical predictions based on consumption data (in parentheses) showed good correlations: norfloxacin, 0.8 (0.9); ofloxacin, 0.3 (0.2); ciprofloxacin, 1.3 (3.5); sulfamethoxazole, 0.2 (0.4); trimethoprim, 1.1 (1.0); and doxycycline, 0.7 (0.4) mg per person per week. The results show that reasonably accurate predictions of environmental load of these antibiotics can be time-effectively derived from consumption data without additional measurements.

SummaryBackgroundPersistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.MethodsIn a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.FindingsThe minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.InterpretationLarge-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.FundingBritish Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

ObjectivesTo compare the acute effects of uninterrupted sitting with sitting interrupted by brief bouts of light-intensity walking on self-reported fatigue, cognition, neuroendocrine biomarkers and cardiometabolic risk markers in overweight/obese adults.DesignRandomised two-condition crossover trial.SettingLaboratory study conducted in Melbourne, Australia.Participants19 overweight/obese adults (45–75 years).InterventionsAfter an initial 2 h period seated, participants consumed a meal-replacement beverage and completed (on 2 days separated by a 6-day washout period) each condition over the next 5 h: uninterrupted sitting (sedentary condition) or sitting with 3 min bouts of light-intensity walking every 30 min (active condition).Primary outcome measuresSelf-reported fatigue, executive function and episodic memory at 0 h, 4 h and 7 h.Secondary outcome measuresNeuroendocrine biomarkers and cardiometabolic risk markers (blood collections at 0 h, 4 h and 7 h, blood pressure and heart rate measured hourly and interstitial glucose measured using a continuous glucose monitoring system).ResultsDuring the active condition, fatigue levels were lower at 4 h (−13.32 (95% CI −23.48 to −3.16)) and at 7 h (−10.73 (95% CI −20.89 to −0.58)) compared to the sedentary condition. Heart rate was higher at 4 h (4.47 (95% CI 8.37 to 0.58)) and at 7 h (4.32 (95% CI 8.21 to 0.42)) during the active condition compared to the sedentary condition. There were no significant differences between conditions by time for other variables. In the sedentary condition, changes in fatigue scores over time correlated with a decrease in heart rate and plasma dihydroxyphenylalanine (DOPA) and an increase in plasma dihydroxyphenylglycol (DHPG).ConclusionsInterrupting prolonged sitting with light-intensity walking breaks may be an effective fatigue countermeasure acutely. Fatigue levels corresponded with the heart rate and neuroendocrine biomarker changes in uninterrupted sitting in this pilot study. Further research is needed to identify potential implications, particularly for the occupational health context.Trial registration numberACTRN12613000137796; Results.