Tracheostomy after Surgery for Congenital Heart Disease: An Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database

Background Information concerning tracheostomy after operations for congenital heart disease has come primarily from single-center reports. We aimed to describe the epidemiology and outcomes associated with postoperative tracheostomy in a multi-institutional registry. Methods The Society of Thoracic Surgeons Congenital Heart Database (2000 to 2014) was queried for all index operations with the adverse event “postoperative tracheostomy” or “respiratory failure, requiring tracheostomy.” Patients with preoperative tracheostomy or weighing less than 2.5 kg undergoing isolated closure of patent ductus arteriosus were excluded. Trends in tracheostomy incidence over time from January 2000 to June 2014 were analyzed with a Cochran-Armitage test. The patient characteristics associated with operative mortality were analyzed for January 2010 to June 2014, including deaths occurring up to 6 months after transfer of patients to long-term care facilities. Results From 2000 to 2014, the incidence of tracheostomy after operations for congenital heart disease increased from 0.11% in 2000 to a high of 0.76% in 2012 (p < 0.0001). From 2010 to 2014, 648 patients underwent tracheostomy. The median age at operation was 2.5 months (25th, 75th percentile: 0.4, 7). Prematurity (n = 165, 26%), genetic abnormalities (n = 298, 46%), and preoperative mechanical ventilation (n = 275, 43%) were common. Postoperative adverse events were also common, including cardiac arrest (n = 131, 20%), extracorporeal support (n = 87, 13%), phrenic or laryngeal nerve injury (n = 114, 18%), and neurologic deficit (n = 51, 8%). The operative mortality was 25% (n = 153). Conclusions Tracheostomy as an adverse event of operations for congenital heart disease remains rare but has been increasingly used over the past 15 years. This trend and the considerable mortality risk among patients requiring postoperative tracheostomy support the need for further research in this complex population

Intronic Cis-Regulatory Modules Mediate Tissue-Specific and Microbial Control of angptl4/fiaf Transcription

The intestinal microbiota enhances dietary energy harvest leading to increased fat storage in adipose tissues. This effect is caused in part by the microbial suppression of intestinal epithelial expression of a circulating inhibitor of lipoprotein lipase called Angiopoietin-like 4 (Angptl4/Fiaf). To define the cis-regulatory mechanisms underlying intestine-specific and microbial control of Angptl4 transcription, we utilized the zebrafish system in which host regulatory DNA can be rapidly analyzed in a live, transparent, and gnotobiotic vertebrate. We found that zebrafish angptl4 is transcribed in multiple tissues including the liver, pancreatic islet, and intestinal epithelium, which is similar to its mammalian homologs. Zebrafish angptl4 is also specifically suppressed in the intestinal epithelium upon colonization with a microbiota. In vivo transgenic reporter assays identified discrete tissue-specific regulatory modules within angptl4 intron 3 sufficient to drive expression in the liver, pancreatic islet β-cells, or intestinal enterocytes. Comparative sequence analyses and heterologous functional assays of angptl4 intron 3 sequences from 12 teleost fish species revealed differential evolution of the islet and intestinal regulatory modules. High-resolution functional mapping and site-directed mutagenesis defined the minimal set of regulatory sequences required for intestinal activity. Strikingly, the microbiota suppressed the transcriptional activity of the intestine-specific regulatory module similar to the endogenous angptl4 gene. These results suggest that the microbiota might regulate host intestinal Angptl4 protein expression and peripheral fat storage by suppressing the activity of an intestine-specific transcriptional enhancer. This study provides a useful paradigm for understanding how microbial signals interact with tissue-specific regulatory networks to control the activity and evolution of host gene transcription

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Sources of Variation in Hospital-Level Infection Rates After Coronary Artery Bypass Grafting: An Analysis of The Society of Thoracic Surgeons Adult Heart Surgery Database

BACKGROUND: Patients undergoing coronary artery bypass grafting (CABG) are at risk for a variety of infections. Investigators have focused on predictors of these adverse sequelae, but less attention has been focused on characterizing hospital-level variability in these outcomes. METHODS: Between July 2011 and December 2013, The Society of Thoracic Surgeons Adult Cardiac Surgery Database shows 365,686 patients underwent isolated CABG in 1,084 hospitals. Hospital-acquired infections (HAIs) were defined as pneumonia, sepsis/septicemia, deep sternal wound infection/mediastinitis, vein harvest/cannulation site infection, or thoracotomy infection. Hospitals were ranked by their HAI rate as low (≤ 10th percentile), medium (10th to 90th percentile), and high (\u3e90th percentile). Differences in perioperative factors and composite morbidity and mortality end points across these groups were determined using the Wilcoxon rank sum and χ(2) tests. RESULTS: HAIs occurred among 3.97% of patients overall, but rates varied across hospital groups (low:8.41%). Pneumonia (2.98%) was the most common HAI, followed by sepsis/septicemia (0.84%). Patients at high-rate hospitals more often smoked, had diabetes, chronic lung disease, New York Heart Association Functional Classification III to IV, and received blood products (p \u3c 0.001); however, they less often were prescribed the appropriate antibiotics (p \u3c 0.001). Major morbidity and mortality occurred among 12.3% of patients, although this varied by hospital group (low: 8.6%, medium: 12.3%, high: 17.9%; p \u3c 0.001). CONCLUSIONS: Substantial hospital-level variation exists in postoperative HAIs among patients undergoing CABG, driven predominantly by pneumonia. Given the relatively small absolute differences in comorbidities across hospital groups, our findings suggest factors other than case mix may explain the observed variation in HAI rates

To ERV Is Human: A Phenotype-Wide Scan Linking Polymorphic Human Endogenous Retrovirus-K Insertions to Complex Phenotypes

Approximately 8% of the human genome is comprised of endogenous retroviral insertions (ERVs) originating from historic retroviral integration into germ cells. The function of ERVs as regulators of gene expression is well established. Less well studied are insertional polymorphisms of ERVs and their contribution to the heritability of complex phenotypes. The most recent integration of ERV, HERV-K, is expressed in a range of complex human conditions from cancer to neurologic diseases. Using an in-house computational pipeline and whole-genome sequencing data from the diverse 1,000 Genomes Phase 3 population (n = 2,504), we identified 46 polymorphic HERV-K insertions that are tagged by adjacent single nucleotide polymorphisms (SNPs). To test the potential role of polymorphic HERV-K in the heritability of complex diseases, existing databases were queried for enrichment of established relationships between the HERV-K insertion-associated SNPs (hiSNPs), and tissue specific gene expression and disease phenotypes. Overall, hiSNPs for the 46 polymorphic HERV-K sites were statistically enriched (p −16) for eQTLs across 44 human tissues. Fifteen of the 46 HERV-K insertions had hiSNPs annotated in the EMBL-EBI GWAS Catalog and cumulatively associated with >100 phenotypes. Experimental factor ontology enrichment analysis suggests that polymorphic HERV-K specifically contribute to neurologic and immunologic disease phenotypes, including traits related to intra cranial volume (FDR 2.00E-09), Parkinson's disease (FDR 1.80E-09), and autoimmune diseases (FDR 1.80E-09). These results provide strong candidates for context-specific study of polymorphic HERV-K insertions in disease-related traits, serving as a roadmap for future studies of the heritability of complex disease.</p