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 .)

0142 Automatic Detection of Cortical Arousals in Sleep using Bi-direction LSTM Networks

Cortical arousals are transient events that occur during sleep. Although they can occur naturally, arousals are often used to evaluate sleep-wake dysfunction. The gold standard for detecting arousals is visual inspection of polysomnography recordings. Manual annotation of arousals is time consuming and has been shown to have a high inter- and intra-scorer variation. This study proposes a method to fully automate detection of arousals using recent advances in machine learning.Methods:The proposed method in this study extracted features from electroencephalography (EEG), electrooculography (EOG) and chin electromyography (EMG) to compute a probability of arousals through a bi-directional long short-term memory neural network. The study used a dataset of 233 nocturnal PSGs of population-based samples from Wisconsin Sleep Cohort (WSC) and 30 nocturnal PSGs of clinical samples from the Stanford Sleep Cohort (SSC). The model was trained on 186 recordings from WSC and annotations from two scorers. The model was tested on 47 recordings from WSC and then compared to a set of 3 annotations from 9 independent scorers on 30 recordings from both cohorts by measure of Fleiss’ Kappa (level of agreement greater than chance).Results:The model obtained a precision of 0.79, a recall of 0.8 and F1-score of 0.79 on the 47 recordings from WSC. The model was robust to different sleep stages showing an F1-score of 0.71 ± 0.19, 0.8 ± 0.13, 0.89 ± 0.18 and 0.8 ± 0.17 (mean ± SD) for N1, N2, N3 and REM sleep, respectively. Preliminary results comparing the scorers show a Fleiss’ Kappa of 0.38 ± 0.12, while including the model predictions result in a Fleiss’ Kappa of 0.4 ± 0.1.Conclusion:Cortical arousals were detected automatically with the proposed algorithm with a high performance and robustness to different sleep stages. Preliminary results comparing nine independent scorers demonstrates a low inter-scorer reliability with a similar agreement to the model predictions.<br/

The genetic etiology of periodic leg movement in sleep.

STUDY OBJECTIVES: Periodic Limb Movement in Sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a Genome-Wide Association Study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of 4 cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6,843 total subjects.. METHODS: The MrOS study and Wisconsin Sleep Cohort Study (N=1,745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1,002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using mendelian randomization. RESULTS: We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 x 10 -12, beta=0.486), a SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 x10 -22, beta=0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS. CONCLUSIONS: Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings

Enhancing Participation in Disadvantaged Urban Neighbourhoods

Participation in neighbourhoods is a highly valued phenomenon. Participation is the basis of a shared social life, but it also makes everyday life, and the lived experience of people participating in it, political. From a public administration perspective, governance and formal policy-making are increasingly reaching out to citizens, instead of drawing solely on representative mechanisms of local government. This paper investigates how practitioners working in disadvantaged neighbourhoods in Dutch cities enhance participation. Using empirical data from research in disadvantaged neighbourhoods in The Netherlands, the paper shows that these practitioners either start projects that connect people in their own life world or connect policy-makers and policy to initiatives on the ground. As a result, they create the opportunity for many to develop their citizenship and become a more active participant in their local communities