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The Next-Generation Sequencing (NGS) Quality Initiative addresses laboratory challenges faced when performing NGS by developing tools and resources to build a robust quality management system. Here, we illustrate how those products support laboratories in navigating complex regulatory environments and quality-related challenges while implementing NGS effectively in an evolving landscape.

The central nervous system has a very high energy requirement. Accord- ingly, despite representing only 2% of the body＇s mass, the brain uses 20% of the total oxygen consumption. Importantly, because most of this energy is used to maintain synaptic activity, even a mild decrease in its supply to the brain has deleterious implications for synaptic function.

The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known. We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute–sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction were ascertained. Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer–determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to ≤5 at 101 (35.1%) laboratories, >5 to ≤10 at 34 (11.8%) laboratories, and >10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays. There is substantial hospital-level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications for both the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials.

Tissue-type plasminogen activator (tPA) is a serine proteinase released by the presynaptic terminal of cerebral cortical neurons following membrane depolarization (Echeverry et al., 2010). Recent studies indicate that the release of tPA triggers the synaptic vesicle cycle and promotes the exocytosis (Wu et al., 2015) and endocytic retrieval (Yepes et al., 2016) of glutamate-containing synaptic vesicles. Here we used electron microscopy, proteomics, quantitative phosphoproteomics, biochemical analyses with extracts of the postsynaptic density (PSD), and an animal model of cerebral ischemia with mice overexpressing neuronal tPA to study whether the presynaptic release of tPA also has an effect on the postsynaptic terminal. We found that tPA has a bidirectional effect on the composition of the PSD of cerebral cortical neurons that is independent of the generation of plasmin and the presynaptic release of glutamate, but depends on the baseline level of neuronal activity and the extracellular concentrations of calcium (Ca ). Accordingly, in neurons that are either inactive or incubated with low Ca concentrations tPA induces phosphorylation and accumulation in the PSD of the Ca /calmodulin-dependent protein kinase IIα (pCaMKIIα), followed by pCaMKIIα-mediated phosphorylation and synaptic recruitment of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast, in neurons with previously increased baseline levels of pCaMKIIα in the PSD due to neuronal depolarization or incubation with high concentrations of either Ca or glutamate , tPA induces pCaMKIIα and pGluR1 dephosphorylation and their subsequent removal from the PSD. We found that these effects of tPA are mediated by synaptic N-methyl-D-aspartate (NMDA) receptors and cyclin-dependent kinase 5 (Cdk5)-induced phosphorylation of the protein phosphatase 1 (PP1) at T320. Our data indicate that by regulating the pCaMKIIα/PP1 balance in the PSD tPA acts as a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate.

Population based metaheuristic can benefit from explicit parallelization in order to address complex numerical optimization problems. Typical realistic problems usually involve non-linear functions and many constraints, making the identification of global optimal solutions mathematically challenging and computationally expensive. In this work, a GPU based parallelized version of the Particle Swarm Optimization technique is proposed. The main contribution is the explicit consideration of equality and inequality constraints of general type, rather than addressing only box constrained models as typically done in acceleration studies of optimization algorithms. The implementation is tested on a set of optimization problems that serve as benchmark. Speedups averaging 299x were obtained with a single GPU on a standard PC using the PyCUDA technology. Satisfactory feasibility and optimality rates are also achieved, although a standard parameterization was adopted for all the experiments. Additional results are reported on a small set of difficult problems involving bilinear non-linearities.

Abstract Aims Bromocriptine is thought to facilitate left ventricular (LV) recovery in peripartum cardiomyopathy (PPCM) through inhibition of prolactin secretion. However, this potential therapeutic effect remains controversial and was incompletely studied in diverse populations. Methods and results Consecutive women with new-onset PPCM (n = 76) between 1994 and 2015 in Quebec, Canada, were classified according to treatment (n = 8, 11%) vs. no treatment (n = 68, 89%) with bromocriptine. We assessed LV functional recovery at mid-term (6 months) and long-term (last follow-up) and compared outcomes among groups. Women treated with bromocriptine experienced better mid-term left ventricular ejection fraction (LVEF) recovery from 23 ± 10% at baseline to 55 ± 12% at 6 months, compared with a change from 30 ± 12% at baseline to 45 ± 13% at 6 months in women treated with standard medical therapy (P interaction < 0.01). At long-term, a similar positive association was found with bromocriptine (9% greater LVEF variation, P interaction < 0.01). In linear regressions adjusted for obstetrical, clinical, echocardiographic, and pharmacological variables, treatment with bromocriptine was associated with a greater improvement in LVEF [β coefficient (standard error), 14.1 (4.4); P = 0.03]. However, there was no significant association between bromocriptine use and the combined occurrence of all-cause death and heart failure events (hazard ratio, 1.18; 95% confidence interval, 0.15 to 9.31), using univariable Cox regressions based over a cumulative follow-up period of 285 patient-years. Conclusions In women newly diagnosed with PPCM, treatment with bromocriptine was independently associated with greater LV functional recovery.

Cystic ovarian disease (COD) is an important cause of abnormal estrous behavior and infertility in dairy cows. COD is mainly observed in high-yielding dairy cows during the first months post-partum, a period of high stress. We have previously reported that, in lower mammals, stress induces a cystic condition similar to the polycystic ovary syndrome in humans and that stress is a definitive component in the human pathology. To know if COD in cows is also associated with high sympathetic activity, we studied isolated small antral (5mm), preovulatory (10mm) and cystic follicles (25mm). Cystic follicles which present an area 600 fold greater compared with preovulatory follicles has only 10 times less concentration of NE as compared with small antral and preovulatory follicles but they had 10 times more NE in follicular fluid, suggesting a high efflux of neurotransmitter from the cyst wall. This suggestion was reinforced by the high basal release of recently taken-up 3 H-NE found in cystic follicles. While lower levels of beta-adrenergic receptor were found in cystic follicles, there was a heightened response to the beta-adrenergic agonist isoproterenol and to hCG, as measured by testosterone secretion. There was however an unexpected capacity of the ovary in vitro to produce cortisol and to secrete it in response to hCG but not to isoproterenol. These data suggest that, during COD, the bovine ovary is under high sympathetic nerve activity that in addition to an increased response to hCG in cortisol secretion could participate in COD development.

In the ISCHEMIA trial, patients with stable ischemic heart disease were randomly assigned to invasive or conservative treatment. As reported separately, the invasive strategy did not reduce clinical events. Improvements in health status were slightly greater with the invasive strategy, reflecting minimal effects in asymptomatic patients and larger effects in patients with angina symptoms at baseline.

Trandolapril is a well known angiotensin converting enzyme (ACE) inhibitor with many cardiovascular (CV) indications. The objectives of this article are to review the pharmacokinetics and pharmacodynamics properties of trandolapril and to focus on its clinical relevance in cardiovascular medicine. Various populations have been studied in large clinical trials including patients with congestive heart failure (CHF) after an acute myocardial infarction (AMI), diabetics, patients with hypertension (HTN), stable coronary artery disease (CAD) and prevention of proteinuria. Long-term treatment with trandolapril in patients with reduced left ventricular function soon after AMI significantly reduced the risk of overall mortality, mortality from CV causes, sudden death, and the development of severe CHF. Treatment with trandolapril after AMI complicated by left ventricular dysfunction appears to be of considerable importance in patients with diabetes mellitus by saving lives and substantially reducing the risk of progression to severe CHF as well. Moreover, trandolapril reduces progression to proteinuria in high-risk patients. Some of the advantages of trandolapril over other ACE inhibitors are the wide spectrum of patient populations studied, the well established dosage and its proven trough-to-peak effect ratios permitting a safe once-a-day administration.

Population based metaheuristics can benefit from parallelization in order to address complex numerical optimization problems. Typical realistic problems usually involve non-linear functions, integer variables and many constraints, making the identification of optimal solutions mathematically challenging and computationally expensive. In this work, a parallelized version of the Particle Swarm Optimization technique is proposed, whose main contribution is the explicit consideration of constraints. The implementation is tested on a classic set of optimization problems. Speedups up to 101x were obtained using a single GPU on a standard PC using the Py-Cuda technology.