Adaptive Coarse Spaces for FETI-DP and BDDC Methods

Iterative substructuring methods are well suited for the parallel iterative solution of elliptic partial differential equations. These methods are based on subdividing the computational domain into smaller nonoverlapping subdomains and solving smaller problems on these subdomains. The solutions are then joined to a global solution in an iterative process. In case of a scalar diffusion equation or the equations of linear elasticity with a diffusion coefficient or Young modulus, respectively, constant on each subdomain, the numerical scalability of iterative substructuring methods can be proven. However, the convergence rate deteriorates significantly if the coefficient in the underlying partial differential equation (PDE) has a high contrast across and along the interface of the substructures. Even sophisticated scalings often do not lead to a good convergence rate. One possibility to enhance the convergence rate is to choose appropriate primal constraints. In the present work three different adaptive approaches to compute suitable primal constraints are discussed. First, we discuss an adaptive approach introduced by Dohrmann and Pechstein that draws on the operator P_D which is an important ingredient in the analysis of iterative substructuring methods like the dual-primal Finite Element Tearing and Interconnecting (FETI-DP) method and the closely related Balancing Domain Decomposition by Constraints (BDDC) method. We will also discuss variations of the method by Dohrmann and Pechstein introduced by Klawonn, Radtke, and Rheinbach. Secondly, we describe an adaptive method introduced by Mandel and Sousedík which is also based on the P_D-operator. Recently, a proof for the condition number bound in this method was provided by Klawonn, Radtke, and Rheinbach. Thirdly, we discuss an adaptive approach introduced by Klawonn, Radtke, and Rheinbach that enforces a Poincaré- or Korn-like inequality and an extension theorem. In all approaches generalized eigenvalue problems are used to compute a coarse space that leads to an upper bound of the condition number which is independent of the jumps in the coefficient and depend on an a priori prescribed tolerance. Proofs and numerical tests for all approaches are given in two dimensions. Finally, all approaches are compared

Evidence of unidirectional gene flow in a fragmented population of Salmo trutta L

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Lung Surfactant Accelerates Skin Wound Healing : A Translational Study with a Randomized Clinical Phase I Study

Lung surfactants are used for reducing alveolar surface tension in preterm infants to ease breathing. Phospholipid films with surfactant proteins regulate the activity of alveolar macrophages and reduce inflammation. Aberrant skin wound healing is characterized by persistent inflammation. The aim of the study was to investigate if lung surfactant can promote wound healing. Preclinical wound models, e.g. cell scratch assays and full-thickness excisional wounds in mice, and a randomized, phase I clinical trial in healthy human volunteers using a suction blister model were used to study the effect of the commercially available bovine lung surfactant on skin wound repair. Lung surfactant increased migration of keratinocytes in a concentration-dependent manner with no effect on fibroblasts. Significantly reduced expression levels were found for pro-inflammatory and pro-fibrotic genes in murine wounds. Because of these beneficial effects in preclinical experiments, a clinical phase I study was initiated to monitor safety and tolerability of surfactant when applied topically onto human wounds and normal skin. No adverse effects were observed. Subepidermal wounds healed significantly faster with surfactant compared to control. Our study provides lung surfactant as a strong candidate for innovative treatment of chronic skin wounds and as additive for treatment of burn wounds to reduce inflammation and prevent excessive scarring. © 2020, The Author(s)

Effectiveness of a Long-term Home-Based Exercise Training Program in Patients With COPD After Pulmonary Rehabilitation: A Multicenter Randomized Controlled Trial

Background: Most patients with COPD do not maintain exercise training after pulmonary rehabilitation (PR). Research question: Does a 12-month home-based, minimal-equipment strength training program after PR have an effect on dyspnea, exercise capacity, and patient-reported outcomes in patients with COPD? Study design and methods: In a parallel-arm multicenter study across four Swiss PR clinics, patients with COPD were allocated randomly (1:1 ratio) into an intervention group (IG; home-based strength training program) or control group (CG; usual care). The primary outcome was change in Chronic Respiratory Questionnaire (CRQ) dyspnea scale score from baseline to 12 months. Secondary outcomes were change in exercise capacity (1-min sit-to-stand-test [1MSTST], 6-min walk test [6MWT]), health-related quality of life, exacerbations, and symptoms. We assessed the IG's experience by interviews at study end. Main analyses were based on the intention-to-treat approach, and adjusted linear regression models were used. Results: One hundred twenty-three patients with COPD (IG, n = 61; CG, n = 62) were randomized, 61 of whom were women and whose mean ± SD age was 66.8 ± 8.1 years and mean ± SD FEV1 was 39.3 ± 15.3% predicted. One hundred four participants completed 12 months of follow-up (IG, n= 53; CG, n= 51). Of the 53 IG participants, 37 participants (70%) conducted the training until study end. We found no difference in change in CRQ dyspnea scale score over 12 months (adjusted mean difference, 0.28; 95% CI, -0.23 to 0.80; P = .27). We found moderate evidence for a difference in 1MSTST repetitions favoring the IG (adjusted mean difference, 2.6; 95% CI, 0.22-5.03; P = .033), but no evidence for an effect in other outcomes. Seventy-nine percent of the IG reported positive effects that they attributed to the training. Interpretation: The home exercise program had no effect on dyspnea, but improved 1MSTST performance and patient-perceived fitness. The supported program was well accepted by patients with COPD and may facilitate continued exercise training at home. Trial registry: ClinicalTrials.gov; No.: NCT03461887; URL: www. Clinicaltrials: gov. Keywords: COPD; dyspnea; effectiveness; functional exercise capacity; home-based exercise training; long-term maintenance; minimal equipment; pulmonary rehabilitation; quality of life; randomized controlled tria

CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Purpose Large copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. Methods We developed a web-application combining >250,000 patient and population CNVs together with a large set of biomedical annotations and provide tools for CNV classification based on ACMG/ClinGen guidelines and gene-set enrichment analyses. Results Here, we introduce the CNV-ClinViewer (https://cnv-ClinViewer.broadinstitute.org), an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface. Conclusion Overall, this resource facilitates semi-automated clinical CNV interpretation and genomic loci exploration and, in combination with clinical judgment, enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research

Genotype-phenotype correlation at codon 1740 ofSETD2

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2

Intervenções via Internet para redução do consumo de álcool entre universitários : uma revisão sistemática

Objective: To identify the main modalities of Internet-based interventions to limit alcohol use among university students, and to describe the effects of these interventions on alcohol use and related consequences. Methods: A systematic review of PubMed, PsycINFO, and SciELO was performed using as search terms "alcohol drinking AND Internet," without date or language restrictions. Inclusion criteria were randomized controlled trial design, focus on college students and on Internet-based interventions, and evaluating the effects of the intervention on alcohol use or alcohol-related consequences. Results: Thirty-six articles were analyzed. Two main intervention modalities were identified: personalized normative feedback (PNF, n=28) and multicomponent interventions (n=8). Twelve studies with PNF reported reductions in alcohol use 3 months after the intervention. Multicomponent interventions reduced alcohol use and related consequences; most studies focused on the website AlcoholEdu, which reduced alcohol consumption and the consequences of alcohol use 6 months after the intervention. Conclusions: FNP and the AlcoholEdu website, the most frequently evaluated interventions among the selected studies, were effective in reducing alcohol use in university students. These strategies are an alternative to increase the access of university students to interventions aimed at limiting alcohol use

Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice.

Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/-) mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4f/fLysMCre+/0 (DLL4del) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can't be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis