Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

DNA methylation and allergic sensitizations: A genome-scale longitudinal study during adolescence

Background: the presence of allergic sensitization has a major influence on the development and course of common childhood conditions such as asthma and rhinitis. The etiology of allergic sensitization is poorly understood and its underlying biological mechanisms are not well established. Several studies showed that DNA methylation (DNAm) at some CpGs is associated with allergic sensitization. However, no studies have focused on the critical adolescence period.Methods: we assessed the association of pre- and post-adolescence genome-wide DNAm with allergic sensitization against indoor, outdoor and food allergens, using linear mixed models. We hypothesized that DNAm is associated with sensitization in general, and with poly-sensitization status, and these associations are ageand gender-specific. We tested these hypotheses in the IoW cohort (n=376) and examined the findings in the BAMSE cohort (n=267).Results: via linear mixed models, we identified 35 CpGs in IoW associated with allergic sensitization (at false discovery rate of 0.05), of which 33 were available in BAMSE and replicated with respect to the direction of associations with allergic sensitization. At the 35 CpGs except for cg19210306 on C13orf27, a reduction in methylation among atopic subjects was observed, most notably for cg21220721 and cg11699125 (ACOT7). DNAm at cg10159529 was strongly correlated with expression of IL5RA in peripheral blood (p-value=6.76×10-20). Three CpGs (cg14121142, cg23842695, and cg26496795) were identified in IoW with age-specific association between DNAm and allergic sensitization.Conclusion: in adolescence, the status of allergic sensitization was associated with DNAm differentiation and at some CpGs the association is likely to be age-specific

Earth at rest. Aesthetic experience and students' grounding in science education

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