Discovery of antivirulence agents against methicillin-resistant staphylococcus aureus

Antivirulence agents inhibit the production of disease-causing virulence factors but are neither bacteriostatic nor bactericidal. Antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, the most widespread community-associated MRSA strain in the United States, were discovered by virtual screening against the response regulator AgrA, which acts as a transcription factor for the expression of several of the most prominent S. aureus toxins and virulence factors involved in pathogenesis. Virtual screening was followed by similarity searches in the databases of commercial vendors. The small-molecule compounds discovered inhibit the production of the toxins alpha-hemolysin and phenol-soluble modulin α in a dose-dependent manner without inhibiting bacterial growth. These antivirulence agents are small-molecule biaryl compounds in which the aromatic rings either are fused or are separated by a short linker. One of these compounds is the FDA-approved nonsteroidal anti-inflammatory drug diflunisal. This represents a new use for an old drug. Antivirulence agents might be useful in prophylaxis and as adjuvants in antibiotic therapy for MRSA infections

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Development and validation of the Psychological Adaptation Scale (PAS): Use in six studies of adaptation to a health condition or risk

We introduce The Psychological Adaptation Scale (PAS) for assessing adaptation to a chronic condition or risk and present validity data from six studies of genetic conditions

Importance of copy number variants in childhood apraxia of speech and other speech sound disorders

Abstract Childhood apraxia of speech (CAS) is a severe and rare form of speech sound disorder (SSD). CAS is typically sporadic, but may segregate in families with broader speech and language deficits. We hypothesize that genetic changes may be involved in the etiology of CAS. We conduct whole-genome sequencing in 27 families with CAS, 101 individuals in all. We identify 17 genomic regions including 19 unique copy number variants (CNVs). Three variants are shared across families, but the rest are unique; three events are de novo. In four families, siblings with milder phenotypes co-inherited the same CNVs, demonstrating variable expressivity. We independently validate eight CNVs using microarray technology and find many of these CNVs are present in children with milder forms of SSD. Bioinformatic investigation reveal four CNVs with substantial functional consequences (cytobands 2q24.3, 6p12.3-6p12.2, 11q23.2-11q23.3, and 16p11.2). These discoveries show that CNVs are a heterogeneous, but prevalent, cause of CAS

Abstract P162: Racial and Gender Disparities in a Stroke Clinical Network

Introduction: Earlier studies have suggested that disparities in stroke care exist for racial and gender groups. Our objective was to examine compliance with defect free care for these groups in a stroke clinical network. Defect free care gauges compliance with the delivery of selected core metrics reflecting best practices. The stroke clinical network providers and stakeholders have been meeting for over 5 years to share best practices and perform improvement projects. The Stroke Clinical Network consists of nine stroke centers located in rural, suburban and urban geographical regions. Methods: Stroke coordinators at nine stroke centers (8 PSCs and 1 CSC) used the GWTG registry to obtain Defect-Free reports using the filters: male, female, African American and white. Populations included patients with a diagnosis of stroke, ICH and SAH. Data was collected for Jan 2016-December 2019. The proportion of defect free compliance was calculated for these subgroups: African American, white, male and female. Results: There was not a difference in defect free care compliance between African American and white stroke populations (AA defect free 90% 2355/2583; white defect free 89% 4176/4685). The range for defect free compliance for AA was 70-98%. The lowest score of 70% was in an urban hospital. The range for defect free compliance for whites was 82-97%. There was not a difference in defect free care between male and female patients (female defect free 92% 5311/5771; male defect free 90% 4646/5211). The range for defect free compliance for females was 78-98%. The range for defect free compliance for males was 70-98%. For all patients in the stroke clinical network defect free care compliance was 91% (9957/10982). Conclusions: In a geographically diverse Stroke Clinical Network there were no disparities in defect care compliance due to gender or race. Future plans include performing a deep dive of the individual care measures to identify opportunities for improvement. The results indicate having an effective Stroke Clinical Network in which best practices and standardization of care are achieved provides an effective strategy to improve defect-care compliance across a network of hospitals. </jats:p