Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

IntroductionAcute circulatory dysfunction in patients with sepsis can evolve rapidly into a progressive stage associated with high mortality. Early recognition and adequate resuscitation could improve outcome. However, since the spectrum of clinical presentation is quite variable, signs of hypoperfusion are frequently unrecognized in patients just admitted to the emergency department (ED). Hyperlactatemia is considered a key parameter to disclose tissue hypoxia but it is not universally available and getting timely results can be challenging in low resource settings. In addition, non-hypoxic sources can be involved in hyperlactatemia, and a misinterpretation could lead to over-resuscitation in an unknown number of cases. Capillary refill time (CRT) is a marker of peripheral perfusion that worsens during circulatory failure. An abnormal CRT in septic shock patients after ICU-based resuscitation has been associated with poor outcome. The aim of this study was to determine the prevalence of abnormal CRT in patients with sepsis-related hyperlactatemia in the early phase after ED admission, and its relationship with outcome.MethodsWe performed a prospective observational study. Septic patients with hyperlactemia at ED admission subjected to an initial fluid resuscitation (FR) were included. CRT and other parameters were assessed before and after FR. CRT-normal or CRT-abnormal subgroups were defined according to the status of CRT following initial FR, and major outcomes were registered.ResultsNinety-five hyperlactatemic septic patients were included. Thirty-one percent had abnormal CRT at ED arrival. After FR, 87 patients exhibited normal CRT, and 8 an abnormal one. Patients with abnormal CRT had an increased risk of adverse outcomes (88% vs. 20% p<0.001; RR 4.4 [2.7–7.4]), and hospital mortality (63% vs. 9% p<0.001; RR 6.7 [2.9–16]) as compared to those with normal CRT after FR. Specifically, CRT-normal patients required less frequently mechanical ventilation, renal replacement therapy, and ICU admission, and exhibited a lower hospital mortality.ConclusionsHyperlactatemic sepsis patients with abnormal CRT after initial fluid resuscitation exhibit higher mortality and worse clinical outcomes than patients with normal CRT.

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Tigecycline appears to be an effective therapy for severe infections due to CPKP in critically ill patients. Mortality is related to the severity of the underlying disease. We observed no benefit from a higher maintenance dose of tigecycline, although the number of patients included in the study was too small to draw any general conclusions in this regard.

A scheme for the numerical simulation of incompressible flows is presented. The modeling equations are written in conservation law form. The algorithm, written in a delta form, is very robust without resorting to any degree of relaxation. The well-known cumbersome numerical implementation related to staggered grids is totally removed. The scheme is second-order-accurate in space and first-order in time. An important novelty is the separation of the pressure terms in the physical equations in a pressure flux, facilitating the tackling of different fluids. The algorithm has been applied to laminar and turbulent flows. The results are truly encouraging.

SUMMARYWhen dealing with high-order numerical methods, an adequate treatment of curved surfaces is required not only to guarantee that the expected high-order is maintained in the vicinity of surfaces but also to avoid steady-state convergence issues. Among the variety of high-order surface treatment techniques that have been proposed, the ones employing NURBS (non-uniform rational B-splines) to describe curved surfaces can be considered superior both in terms of accuracy and compatibility with computer-aided design softwares. The current study describes in detail the integration of NURBS-based geometry description in a high-order solver based on the discontinuous Galerkin formulation. Particularly, this work also discusses how and why NURBS curves of very high order can be employed within standard NURBS-based boundary treatment techniques to yield reduced implementation complexity and computational overhead. Theoretical estimates are provided along with numerical experiments in order to support the proposed approach. Minding engineering applications in the context of compressible aerodynamics, additional simulations are addressed as numerical examples to illustrate the advantages of using higher-order NURBS in practical situations.

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