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 .)

Experiment: Adaptation of a globally important coccolithophore to ocean warming and acidification

Although oceanwarming and acidification are recognized as two major anthropogenic perturbations of today's oceanswe know very little about how marine phytoplankton may respond via evolutionary change.We tested for adaptation to ocean warming in combination with ocean acidification in the globally important phytoplankton species Emiliania huxleyi. Temperature adaptation occurred independently of ocean acidifcation levels. Exponential growth rates were were up to 16% higher in populations adapted for one year to warming when assayed at their upper thermal tolerance limit. Particulate inorganic (PIC) and organic (POC) carbon production was restored to values under present-day ocean conditions, owing to adaptive evolution, and were 101% and 55% higher under combined warming and acidification, respectively, than in non-adapted controls. Cells also evolved to a smaller size while they recovered their initial PIC:POC ratio even under elevated CO2. The observed changes in coccolithophore growth, calcite and biomass production, cell size and elemental composition demonstrate the importance of evolutionary processes for phytoplankton performance in a future ocean. At the end of a 1-yr temperature selection phase, we conducted a reciprocal assay experiment in which temperature-adapted asexual populations were compared to the respective non-adapted control populations under high temperature, and vice versa (1. Assay Data, Dataset #835336). Mean exponential growth rates m in treatments subjected to high temperature increased rapidly under all high temperature-CO2 treatment combinations during the temperature selection phase (2. time series, Dataset #835339)

Effects of rapid evolution on population cycles and extinction in predator–prey systems

Traditionally ecologists have tended to consider species as the smallest unit for understanding community dynamics. However, recent studies demonstrated that there is substantial amount of intraspecific genetic variation and the resultant microevolution can affect ecological dynamics. Here I introduce recent studies showing how adaptive phenotypic changes affect community dynamics, especially in predator–prey systems. First, I review the effects of rapid evolution on predator–prey cycles. Experimental and theoretical studies have demonstrated that the phase lag between predator and prey densities can be changed from the classic quarter to the half (“antiphase cycles”) or three-quarters (“clockwise cycles”) by prey defense evolution or coevolution, respectively. In addition, prey defense evolution can cause “cryptic cycles” where predator densities fluctuate whereas prey densities stay almost constant. Second, I explain how rapid adaptive evolution can prevent extinction (“evolutionary rescue”). Evolutionary rescue with interspecific interactions can create counterintuitive dynamics and will be important for understanding species coexistence in communities. Finally, I discuss future perspectives of empirical and theoretical studies on eco-evolutionary dynamics in complex communities

Marine invasion genomics: Revealing ecological and evolutionary consequences of biological invasions

Genomic approaches are increasingly being used to study biological invasions. Here, we first analyse how high-throughput sequencing has aided our understanding of the mechanisms associated with biological invasions. These include the transport of propagules to pre-invaded areas, an exploration of the consequences of hybridisation during range expansions, and the pre- and post- invasion adaptation of colonising populations. We then explore how contemporary genomic methods have been used to probe and monitor the spread of non-indigenous species. More specifically, we focus on the detection of species richness from environmental samples, measures of quantitative traits that may promote invasive- ness, analysis of rapid adaptation, and the study of phenotypic plasticity. Finally, we look to the future, exploring how genomic approaches will assist future biodiversity conservationists in their efforts to mitigate the spread and effects of biological invasions. Ultimately, although the use of genomic tools to study non-indigenous species has so far been rather limited, studies to date indicate that genomic tools offer unparalleled research opportunities to continually improve our understanding of marine biological invasion