Agency for Healthcare Research and Quality.

Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10−12 at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10−9 at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, P=0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.

Background: Sepsis represents a significant public health burden, costing the NHS £2.5 billion annually, with 35% mortality in 2006. The aim of this exploratory study was to investigate risk factors predictive of 30-day mortality amongst patients with sepsis in Nottingham. Methods: Data were collected prospectively from adult patients with sepsis in Nottingham University Hospitals NHS Trust as part of an ongoing quality improvement project between November 2011 and March 2014. Patients admitted to critical care with the diagnosis of sepsis were included in the study. In all, 97 separate variables were investigated for their association with 30-day mortality. Variables included patient demographics, symptoms of systemic inflammatory response syndrome, organ dysfunction or tissue hypoperfusion, locations of early care, source of sepsis and time to interventions. Results: A total of 455 patients were included in the study. Increased age (adjOR ¼ 1.05 95%CI ¼ 1.03-1.07 p < 0.001), thrombocytopenia (adjOR ¼ 3.10 95%CI ¼ 1.23-7.82 p ¼ 0.016), hospital-acquired sepsis (adjOR ¼ 3.34 95%CI ¼ 1.78-6.27 p < 0.001), increased lactate concentration (adjOR ¼ 1.16 95%CI ¼ 1.06-1.27 p ¼ 0.001), remaining hypotensive after vasopressors (adjOR ¼ 3.89 95%CI ¼ 1.26-11.95 p ¼ 0.02) and mottling (adjOR ¼ 3.80 95%CI ¼ 1.06-13.55 p ¼ 0.04) increased 30-day mortality odds. Conversely, fever (adjOR ¼ 0.46 95%CI ¼ 0.28-0.75 p ¼ 0.002), fluid refractory hypotension (adjOR ¼ 0.29 95%CI ¼ 0.10-0.87 p ¼ 0.027) and being diagnosed in surgical wards (adjOR ¼ 0.35 95%CI ¼ 0.15-0.81 p ¼ 0.015) were protective. Treatment timeliness were not significant factors. Conclusion: Several important predictors of 30-day mortality were found by this research. Retrospective analysis of our sepsis data has revealed mortality predictors that appear to be more patient-related than intervention-specific. With this information, care can be improved for those identified most at risk of death.

Sepsis Six can reduce physiological impairment, monitored by the National Early Warning Scores. Consistent delivery of the bundle can lead to better patient outcomes.