Association of different lipid measures for atherogenic lipid fractions and risk of coronary events in patients receiving combination antiretroviral therapy: the Swiss HIV Cohort Study

Background: Evidence for a better performance of different highly atherogenic versus traditional lipid parameters for coronary heart disease (CHD) risk prediction is conflicting. We investigated the association of the ratios of sma11 dense low density lipoprotein(LDL)/apoplipoprotein A, aolipoprotein B/apolipoprotein A-I and total cholesterol! HDL-cholesterol and CHD events in patients on combination antiretroviral therapy (cART).Methods: Case control study nested into the Swiss HIV Cohort Study: for each cART-treated patient with a first coronary event between April 1, 2000 and July 31, 2008 (case) we selected four control patients (1) that were without coronary events until the date of the event of the index case, (2) had a plasma sample within ±30 days of the sample date of the respective case, (3) received cART and (4) were then matched for age, gender and smoking status. Lipoproteins were measured by ultracentrifugation. Conditional logistic regression models were used to estimate the independent effects of different lipid ratios and the occurrence of coronary events.Results: In total, 98 cases (19 fatal myocardial infarctions [MI] and 79 non-fatal coronary events [53 definite MIs, 15 possible MIs and 11 coronary angioplasties or bypassesJ) were matched with 392 controls. Cases were more often injecting drug users, less likely to be virologically suppressed and more often on abacavir-containing regimens. In separa te multivariable models of total cholesterol, triglycerides, HDL-cholesterol, systolic blood pressure, abdominal obesity, diabetes and family history of CHD, small dense-LDL and apolipoprotein B were each statistically significantly associated with CHD events (for 1 mg/dl increase: odds ratio [OR] 1.05, 95% CI 1.00-1.11 and 1.15, 95% CI 1.01-1.31, respectively), but the ratiosof small dense-LDLlapolipoprotein A-I (OR 1.26, 95% CI 0.95-1.67), apolipoprotein B/apolipoprotein A-I (OR 1.02, 95% CI 0.97-1.07) and HDL-cholesterol! total cholesterol (OR 0.99 95% CI 0.98-1.00) were not. Following adjustment for HIV related and cART variables these associations were weakened in each model: apolipoprotein B (OR 1.27, 95% CI 1.00-1.30), sd-LDL (OR 1.04, 95% CI 0.99-1.20), small dense-LDLlapolipoprotein A-I (OR 1.17, 95% CI 0.87-1.58), apolipoprotein B/apolipoprotein A-I (OR 1.02, 95% CI 0.97-1.07) and total cholesterolJHDL- cholesterol (OR 0.99, 95% CI 0.99-1.00).Conclusions: In patients receiving cART, small dense-LDL and apolipoprotein B showed the strongest associations with CHD events in models controlling for traditional CHD risk factors including total cholesterol and triglycerides. Adding small dense LDLlapoplipoprotein A-l, apolipoprotein B/apolipoprotein A-I and total cholesterol! HDL-cholesterol ratios did not further improve models of lipid parameters and associations of increased risk for CHD events.

Estimating uncertainty of alcohol-attributable fractions for infectious and chronic diseases.

Background: Alcohol is a major risk factor for burden of disease and injuries globally. This paper presents a systematic method to compute the 95% confidence intervals of alcohol-attributable fractions (AAFs) with exposure and risk relations stemming from different sources.Methods: The computation was based on previous work done on modelling drinking prevalence using the gamma distribution and the inherent properties of this distribution. The Monte Carlo approach was applied to derive the variance for each AAF by generating random sets of all the parameters. A large number of random samples were thus created for each AAF to estimate variances. The derivation of the distributions of the different parameters is presented as well as sensitivity analyses which give an estimation of the number of samples required to determine the variance with predetermined precision, and to determine which parameter had the most impact on the variance of the AAFs.Results: The analysis of the five Asian regions showed that 150 000 samples gave a sufficiently accurate estimation of the 95% confidence intervals for each disease. The relative risk functions accounted for most of the variance in the majority of cases.Conclusions: Within reasonable computation time, the method yielded very accurate values for variances of AAFs.

Acute alcohol consumption and injury: risk associations and attributable fractions for different injury mechanisms.

OBJECTIVE: Most studies on alcohol as a risk factor for injuries have been mechanism specific, and few have considered several mechanisms simultaneously or reported alcohol-attributable fractions (AAFs)-which was the aim of the current study. METHOD: Data from 3,592 injured and 3,489 noninjured patients collected between January 2003 and June 2004 in the surgical ward of the emergency department of the Lausanne University Hospital (Switzerland) were analyzed. Four injury mechanisms derived from the International Classification of Diseases, 10th Revision, were considered: transportation-related injuries, falls, exposure to forces and other events, and interpersonal violence. Multinomial logistic regression models were calculated to estimate the risk relationships of different levels of alcohol consumption, using noninjured patients as quasi-controls. The AAFs were then calculated. RESULTS: Risk relationships between injury and acute consumption were found across all mechanisms, commonly resulting in dose-response relationships. Marked differences between mechanisms were observed for relative risks and AAFs, which varied between 15.2% and 33.1% and between 10.1% and 35.9%, depending on the time window of consumption (either 6 hours or 24 hours before injury, respectively). Low and medium levels of alcohol consumption generally were associated with the most AAFs. CONCLUSIONS: This study underscores the implications of even low levels of alcohol consumption on the risk of sustaining injuries through any of the mechanisms considered. Substantial AAFs are reported for each mechanism, particularly for injuries resulting from interpersonal violence. Observation of a so-called preventive paradox phenomenon is discussed, and prevention or intervention measures are described.

Screening of the inhibitory effect of xenobiotics on alcohol metabolism using S9 rat liver fractions.

The purpose of this work was to develop and optimize a simple and suitable method to detect the potential inhibitory effect of drugs and medicines on alcohol dehydrogenase (ADH) activity in order to evaluate the possible interactions between medicines and alcohol metabolism. Commonly used medicines that are often involved in court litigations related with driving under the influence of alcohol were selected. Alprazolam, flunitrazepam and tramadol were tested as drugs with no known effect on ADH activity. Cimetidine, reported previously as having inhibitory effect on ADH, and 4-methylpyrazole (4-MP), a well known ADH inhibitor, were tested as positive controls. Apart from 4-MP, tramadol was identified as having the higher inhibitory effect with an IC50 of 44.7×10(-3)mM, followed by cimetidine (IC50 of 122.9×10(-3)mM). Alprazolam and flunitrazepam also reduced liver ADH activity but to a smaller extent (inhibition of 11.8±5.0% for alprazolam 1.0mM and 34.5±7.1% for flunitrazepam 0.04mM). Apart from cimetidine, this is the first report describing the inhibitory effect of these drugs on ethanol metabolism. The results also show the suitability of the method to screen for inhibitory effect of drugs on ethanol metabolism helping to identify drugs for which further study is justified.