Replication in Genome-Wide Association Studies

Replication helps ensure that a genotype-phenotype association observed in a genome-wide association (GWA) study represents a credible association and is not a chance finding or an artifact due to uncontrolled biases. We discuss prerequisites for exact replication, issues of heterogeneity, advantages and disadvantages of different methods of data synthesis across multiple studies, frequentist vs. Bayesian inferences for replication, and challenges that arise from multi-team collaborations. While consistent replication can greatly improve the credibility of a genotype-phenotype association, it may not eliminate spurious associations due to biases shared by many studies. Conversely, lack of replication in well-powered follow-up studies usually invalidates the initially proposed association, although occasionally it may point to differences in linkage disequilibrium or effect modifiers across studies.Comment: Published in at http://dx.doi.org/10.1214/09-STS290 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Towards Error Handling in a DSL for Robot Assembly Tasks

This work-in-progress paper presents our work with a domain specific language (DSL) for tackling the issue of programming robots for small-sized batch production. We observe that as the complexity of assembly increases so does the likelihood of errors, and these errors need to be addressed. Nevertheless, it is essential that programming and setting up the assembly remains fast, allows quick changeovers, easy adjustments and reconfigurations. In this paper we present an initial design and implementation of extending an existing DSL for assembly operations with error specification, error handling and advanced move commands incorporating error tolerance. The DSL is used as part of a framework that aims at tackling uncertainties through a probabilistic approach.Comment: Presented at DSLRob 2014 (arXiv:cs/1411.7148

Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice

Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The Gi protein Gα(i2) mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα(i2) exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα(i2) in megakaryocytes and platelets (Gna(i2)(fl/fl)/PF4-Cre mice) and found bleeding defects comparable to those in global Gα(i2)-deficient mice. To examine the impact of platelet Gα(i2) in postischemic thrombo-inflammatory infarct progression, Gna(i2)(fl/fl)/PF4-Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gna(i2)(fl/fl)/PF4-Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gna(i2)(fl/fl)/PF4-Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα(i2) not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo.Fil: Devanathan, Vasudharani. University of Tübingen; AlemaniaFil: Hagedorn, Ina. University Hospital; AlemaniaFil: Köhler, David. University of Tübingen; AlemaniaFil: Pexa, Katja. Universitat Dusseldorf; AlemaniaFil: Cherpokova, Deya. University Hospital; AlemaniaFil: Kraft, Peter. Universität Würzburg; AlemaniaFil: Singh, Madhurendra. Universitat Dusseldorf; AlemaniaFil: Rosenberger, Peter. University of Tübingen; AlemaniaFil: Stoll, Guido. Universität Würzburg; AlemaniaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Research Triangle Park; AlemaniaFil: Piekorz, Roland P.. Universitat Dusseldorf; AlemaniaFil: Beer-Hammer, Sandra. University of Tübingen; AlemaniaFil: Nieswandt, Bernhard. University Hospital; AlemaniaFil: Nürnberg, Bernd. University of Tübingen; Alemani

Posaconazole Tablet Pharmacokinetics: Lack of Effect of Concomitant Medications Altering Gastric pH and Gastric Motility in Healthy Subjects.

Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a ≥10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87-1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility

Self-assembly of Microcapsules via Colloidal Bond Hybridization and Anisotropy

Particles with directional interactions are promising building blocks for new functional materials and may serve as models for biological structures. Mutually attractive nanoparticles that are deformable due to flexible surface groups, for example, may spontaneously order themselves into strings, sheets and large vesicles. Furthermore, anisotropic colloids with attractive patches can self-assemble into open lattices and colloidal equivalents of molecules and micelles. However, model systems that combine mutual attraction, anisotropy, and deformability have---to the best of our knowledge---not been realized. Here, we synthesize colloidal particles that combine these three characteristics and obtain self-assembled microcapsules. We propose that mutual attraction and deformability induce directional interactions via colloidal bond hybridization. Our particles contain both mutually attractive and repulsive surface groups that are flexible. Analogous to the simplest chemical bond, where two isotropic orbitals hybridize into the molecular orbital of H2, these flexible groups redistribute upon binding. Via colloidal bond hybridization, isotropic spheres self-assemble into planar monolayers, while anisotropic snowman-like particles self-assemble into hollow monolayer microcapsules. A modest change of the building blocks thus results in a significant leap in the complexity of the self-assembled structures. In other words, these relatively simple building blocks self-assemble into dramatically more complex structures than similar particles that are isotropic or non-deformable

Under stochastic dominance Choquet-expected utility and anticipated utility are identical

The aim of this paper is to convince the reader that Choquet-expected utility, as initiated by Schmeidler (1982, 1989) for decision making under uncertainty, when formulated for decision making under risk naturally leads to anticipated utility, as initiated by Quiggin/Yaari. Thus the two generalizations of expected utility in fact are one

Lung transplantation for acute respiratory distress syndrome:A multicenter experience

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high-volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50-85) and waited for a median of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17-52.5), median length of ICU and hospital stay were 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2-7). 30-day mortality was 7.7%, 1 and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live-saving LTx to carefully selected ARDS patients

TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice

Objective: TRPM7 (transient receptor potential cation channel, subfamily M, member 7) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic alpha-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg2+ and Ca2+ permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. Approach and Results: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7(R/R)) causes a marked signaling defect in platelets. Trpm7(R/R) platelets showed an impaired PIP2 (phosphatidylinositol-4,5-bisphosphate) metabolism and consequently reduced Ca2+ mobilization in response to stimulation of the major platelet receptors GPVI (glycoprotein VI), CLEC-2 (C-type lectin-like receptor), and PAR (protease-activated receptor). Altered phosphorylation of Syk (spleen tyrosine kinase) and phospholipase C gamma 2 and beta 3 accounted for these global platelet activation defects. In addition, direct activation of STIM1 (stromal interaction molecule 1) with thapsigargin revealed a defective store-operated Ca2+ entry mechanism in the mutant platelets. These defects translated into an impaired platelet aggregate formation under flow and protection of the mice from arterial thrombosis and ischemic stroke in vivo. Conclusions: Our results identify TRPM7 kinase as a key modulator of phospholipase C signaling and store-operated Ca2+ entry in platelets. The protection of Trpm7(R/R) mice from acute ischemic disease without developing intracranial hemorrhage indicates that TRPM7 kinase might be a promising antithrombotic target