Collier, J. | Search bioRxiv

bioRxiv2017

Hepatitis C Virus (HCV) diagnosis, epidemiology and access to treatment in a UK cohort

BackgroundAs direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment.\n\nMethodsWe performed a retrospective study of HCV infection in a UK teaching hospital to evaluate the performance of different diagnostic laboratory tests, to describe the population with active HCV infection, and to determine the proportion of these individuals who access clinical care.\n\nResultsOver a total time period of 33 months between 2013 and 2016, we tested 38,510 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag+ and/or HCV RNA+) in 359 (positive rate 0.9%). Our in-house HCV-Ab test had a positive predictive value of 87% when compared to repeat HCV-Ab testing in a regional reference laboratory, highlighting the potential for false positives to arise based on a single round of antibody-based screening. Of those confirmed Ab-positive, 70% were HCV RNA positive. HCV-Ag screening performed well, with 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p<0.0001). Among the 359 cases of infection, the median age was 37 years, 85% were male, and 36% were in prison. Among 250 infections for which genotype was available, HCV genotype-1 (n=110) and genotype-3 (n=111) accounted for the majority. 117/359 (33%) attended a clinic appointment and 48 (13%) had curative treatment defined as sustained virologic response at 12 weeks (SVR12).\n\nConclusionsHCV-Ab tests should be interpreted with caution as an indicator of population prevalence of HCV infection, both as a result of the detection of individuals who have cleared infection and due to false positive test results. We demonstrate that active HCV infection is over-represented among men and in the prison population. A minority of patients with a diagnosis of HCV infection access clinical care and therapy; enhanced efforts are required to target diagnosis and providing linkage to clinical care within high risk populations.\n\nABBREVIATIONS

epidemiology↗

bioRxiv2017

The cohesin ring uses its hinge to organize DNA using non-topological as well as topological mechanisms

As predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is a perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion in a large variety of mutants. In most cells where cohesin loads onto chromosomes but fails to form cohesion, loading is accompanied by entrapment of individual DNAs. However, cohesin with a hinge domain whose positively charged lumen has been neutralized not only loads onto and translocates along chromatin but also organizes it into chromatid-like threads, despite largely failing to entrap DNAs inside its ring. Thus, cohesin engages chromatin in a non-topological as well as a topological manner. Our finding that hinge mutations, but not fusions between Smc and kleisin subunits, abolish entrapment suggests that DNAs may enter cohesin rings through hinge opening. Lastly, mutation of three highly conserved lysine residues inside the Smc1 moiety of Smc1/3 hinges abolishes all loading without affecting cohesins initial recruitment to CEN loading sites or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesins hinge driven by cycles of ATP hydrolysis.

molecular biology↗