Clinical and microbiological features of infection in alcoholic hepatitis: an international cohort study

BACKGROUND: Previous studies have described the clinical impact of infection in alcoholic hepatitis (AH) but none have comprehensively explored the aetiopathogenesis of infection in this setting. We examined the causes, consequences and treatment of infection in a cohort of patients with AH. METHODS: We undertook a retrospective cohort study of patients with AH admitted between 2009 and 2014 to seven centres in Europe and the USA. Clinical and microbiological data were extracted from medical records. Survival was analysed with Kaplan-Meier analysis and Cox proportional hazards analysis to control the data for competing factors. Propensity score matching was used to examine the efficacy of prophylactic antibiotics administered in the absence of infection. RESULTS: We identified 404 patients with AH. Of these, 199 (49%) showed clinical or culture evidence of infection. Gut commensal bacteria, particularly Escherichia coli and Enterobacter species, were most commonly isolated in culture. Fungal infection was rarely seen. Cultured organisms and antibiotic resistance differed markedly between centres. Infection was an independent risk factor for death (hazard ratio for death at 90 days 2.33, 95% confidence interval 1.63-3.35, p < 0.001). Initiation of antibiotic therapy on admission in the absence of infection did not reduce mortality or alter the incidence of subsequent infections. Corticosteroid use increased the incidence of infection but this did not impact on survival. CONCLUSIONS: In this large real-world cohort of patients with AH, infection was common and was associated with reduced short-term survival. Gram-negative, gut commensal bacteria were the predominant infective organisms, consistent with increased translocation of gut bacteria in AH; however, the characteristics of infection differ between centres. Infection should be actively sought and treated, but we saw no benefits of prophylactic antibiotics

Genomic footprints of activated telomere maintenance mechanisms in cancer

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX(trunc)) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX(trunc) tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer