Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.

We propose computational protocol ͑compressive shear reactive dynamics͒ utilizing the ReaxFF reactive force field to study chemical initiation under combined shear and compressive load. We apply it to predict the anisotropic initiation sensitivity observed experimentally for shocked pentaerythritol tetranitrate single crystals. For crystal directions known to be sensitive we find large stress overshoots and fast temperature increase that result in early bond-breaking processes whereas insensitive directions exhibit small stress overshoot, lower temperature increase, and little bond dissociation. These simulations confirm the model of steric hindrance to shear and capture the thermochemical processes dominating the phenomena of shear-induced chemical initiation. Experiments by Bridgman 1 demonstrated that chemical transformations occur far more readily under combined shear and pressure loads. Coupling between mechanical, thermal, and chemical effects is important for initiation of detonation in explosives under mechanical impact. Understanding how the detonation sensitivity depends on formulation and structural properties is a critical issue in explosive technology. A great deal of effort has gone into the development of experimental techniques to study these processes ͑e.g., time resolved emission spectroscopy 2-4 ͒ but they have not yet provided satisfactory resolution of initial steps of detonation. Little is known about how mechanical and chemical processes couple to initiate detonation.An ideal system to examine for hints on the atomistic origin of sensitivity, is single crystal of pentaerythritol tetranitrate ͑PETN, four CH 2 -O-NO 2 chains connected to a central carbon, see inset of Fig. 1͒. showed that shock compression of the single crystal in different directions leads to dramatic differences in the sensitivity. Thus the pressure threshold for detonation along the ͓100͔ direction is at least ϳ4 times that for ͓110͔ direction. 10 Such single crystal experiments eliminate many of the variables that complicate interpretations ͑grain boundaries, voids, and internal defects͒ providing an unambiguous challenge to any proposed mechanisms. Dick et al. 8,9 attributed the orientational anisotropy of PETN sensitivity to steric hindrance to the shear of molecules in the neighboring slip planes. Recently, Plaksin 11 showed clear-cut experimental evidence that initiation of detonation occurs preferentially in directions with the maximum shear stress.Here we use reactive dynamics ͑RD͒ simulations at constant shear rate on uniaxially compressed PETN single crystal to show that the physical and chemical responses depend dramatically on the compression direction and slip system. In contrast, RD simulations of pure uniaxial shock compression in various directions show no correlation of the reactive behavior with anisotropy of sensitivity in experiment. Key to our simulations is the ReaxFF reactive force field, 12,13 whose parameters are trained to match quantum mechanics descriptions of reaction barriers for all plausibl...

Objective To evaluate the efficacy and safety of standard term (12 months) or long term (>12 months) dual antiplatelet therapy (DAPT) versus short term (<6 months) DAPT after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Design Systematic review and network meta-analysis. Data sources Relevant studies published between June 1983 and April 2018 from Medline, Embase, Cochrane Library for clinical trials, PubMed, Web of Science, ClinicalTrials.gov, and Clinicaltrialsregister.eu. Review methods Randomised controlled trials comparing two of the three durations of DAPT (short term, standard term, and long term) after PCI with DES were included. The primary study outcomes were cardiac or non-cardiac death, all cause mortality, myocardial infarction, stent thrombosis, and all bleeding events. Results 17 studies (n=46 864) were included. Compared with short term DAPT, network meta-analysis showed that long term DAPT resulted in higher rates of major bleeding (odds ratio 1.78, 95% confidence interval 1.27 to 2.49) and non-cardiac death (1.63, 1.03 to 2.59); standard term DAPT was associated with higher rates of any bleeding (1.39, 1.01 to 1.92). No noticeable difference was observed in other primary endpoints. The sensitivity analysis revealed that the risks of non-cardiac death and bleeding were further increased for ≥18 months of DAPT compared with short term or standard term DAPT. In the subgroup analysis, long term DAPT led to higher all cause mortality than short term DAPT in patients implanted with newer-generation DES (1.99, 1.04 to 3.81); short term DAPT presented similar efficacy and safety to standard term DAPT with acute coronary syndrome (ACS) presentation and newer-generation DES placement. The heterogeneity of pooled trials was low, providing more confidence in the interpretation of results. Conclusions In patients with all clinical presentations, compared with short term DAPT (clopidogrel), long term DAPT led to higher rates of major bleeding and non-cardiac death, and standard term DAPT was associated with an increased risk of any bleeding. For patients with ACS, short term DAPT presented similar efficacy and safety with standard term DAPT. For patients implanted with newer-generation DES, long term DAPT resulted in more all cause mortality than short term DAPT. Although the optimal duration of DAPT should take personal ischaemic and bleeding risks into account, this study suggested short term DAPT could be considered for most patients after PCI with DES, combining evidence from both direct and indirect comparisons. Systematic review registration PROSPERO CRD42018099519.

Based on genetic, histological, and functional evidence, we identified a new gene associated with DCM and observed mutations in 3-4% of cases in a population of European descent.

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