Care Navigation Increases Initiation of Hepatitis C Treatment After Release From Prison in a Prospective Randomized Controlled Trial: The C-LINK Study.

Background: Prison-based hepatitis C treatment is safe and effective; however, many individuals are released untreated due to time or resource constraints. On community re-entry, individuals face a number of immediate competing priorities, and in this context, linkage to hepatitis C care is low. Interventions targeted at improving healthcare continuity after prison release have yielded positive outcomes for other health diagnoses; however, data regarding hepatitis C transitional care are limited. Methods: We conducted a prospective randomized controlled trial comparing a hepatitis C care navigator intervention with standard of care for individuals released from prison with untreated hepatitis C infection. The primary outcome was prescription of hepatitis C direct-acting antivirals (DAA) within 6 months of release. Results: Forty-six participants were randomized. The median age was 36 years and 59% were male. Ninety percent (n = 36 of 40) had injected drugs within 6 months before incarceration. Twenty-two were randomized to care navigation and 24 were randomized to standard of care. Individuals randomized to the intervention were more likely to commence hepatitis C DAAs within 6 months of release (73%, n = 16 of 22 vs 33% n = 8 of 24, P < .01), and the median time between re-entry and DAA prescription was significantly shorter (21 days [interquartile range {IQR}, 11-42] vs 82 days [IQR, 44-99], P = .049). Conclusions: Care navigation increased hepatitis C treatment uptake among untreated individuals released from prison. Public policy should support similar models of care to promote treatment in this high-risk population. Such an approach will help achieve hepatitis C elimination as a public health threat.

Non-invasive fibrosis algorithms are clinically useful for excluding cirrhosis in prisoners living with hepatitis C.

BACKGROUND AND AIMS: Prison-based HCV treatment rates remain low due to multiple barriers, including accessing transient elastography for cirrhosis determination. The AST-to-platelet ratio index (APRI) and FIB-4 scores have excellent negative predictive value (NPV) in hospital cohorts to exclude cirrhosis. We investigated their performance in a large cohort of prisoners with HCV infection. METHODS: This was a retrospective cohort study of participants assessed by a prison-based hepatitis program. The sensitivity, specificity, NPV and positive predictive value (PPV) of APRI and FIB-4 for cirrhosis were then analysed, with transient elastography as the reference standard. The utility of age thresholds as a trigger for transient elastography was also explored. RESULTS: Data from 1007 prisoners were included. The median age was 41, 89% were male, and 12% had cirrhosis. An APRI cut-off of 1.0 and FIB-4 cut-off of 1.45 had NPVs for cirrhosis of 96.1% and 96.6%, respectively, and if used to triage prisoners for transient elastography, could reduce the need for this investigation by 71%. The PPVs of APRI and FIB-4 for cirrhosis at these cut-offs were low. Age ≤35 years alone had a NPV for cirrhosis of 96.5%. In those >35 years, the APRI cut-off of 1.0 alone had a high NPV >95%. CONCLUSION: APRI and FIB-4 scores can reliably exclude cirrhosis in prisoners and reduce requirement for transient elastography. This finding will simplify the cascade of care for prisoners living with hepatitis C.

Achieving Hepatitis C Elimination By Using Person-Centered, Nurse-Led Models of Care: A Discussion of Four International Case Studies.

Nurse-led models of care are an important strategy in the management of patients with chronic disease because of the person-centered approach that allows the needs of the individual to be prioritized and addressed in accessible settings. Hepatitis C is caused by a blood-borne virus that can cause liver disease and liver cancer; it predominantly affects marginalized populations, including people who inject drugs. Since 2013, all oral, direct-acting antiviral regimens have been available to cure hepatitis C. Nurses are well placed to be involved in the delivery of hepatitis C testing and treatment because of their extensive reach within marginalized communities and holistic approach to patient care. Four case studies of nurse-led models of care operating in Australia, Canada, the United Kingdom, and the United States are presented to illustrate the important role nurses have in delivering accessible, person-centered hepatitis C testing and treatment. Each case study demonstrates the success of overcoming barriers to hepatitis C testing and treatment such as geographic isolation, incarceration, social marginalization, and inflexible healthcare systems. Achieving the global target to eliminate hepatitis C by 2030 will require the nursing profession to embrace its role as the first point of contact to the healthcare system for many members of marginalized communities potentially at risk of hepatitis C. Nurses are well placed to reduce barriers and facilitate access to healthcare by scaling up activities focused on hepatitis C testing and treatment.

Outcomes of treatment for hepatitis C in prisoners using a nurse-led, statewide model of care.

BACKGROUND & AIMS: Treatment programs for people who inject drugs (PWID), including prisoners, are important for achieving hepatitis C elimination targets. There are multiple barriers to treatment of hepatitis C in prisons, including access to specialist physicians, testing and antiviral therapy, short prison sentences, and frequent inter-prison transfer. We aimed to assess the effectiveness of a nurse-led model of care for the treatment of prisoners with hepatitis C. METHODS: A statewide program for assessment and management of hepatitis C was developed in Victoria, Australia to improve access to care for prisoners. This nurse-led model of care is supported by telemedicine to provide decentralized care within all prisons in the state. We prospectively evaluated the feasibility and efficacy of this nurse-led model of care for hepatitis C within the 14 adult prisons over a 13-month period. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) using per protocol analysis. RESULTS: There were 416 prisoners included in the analysis. The median age was 41 years, 90% were male, 50% had genotype 3 and 44% genotype 1 hepatitis C and 21% had cirrhosis. Injecting drug use was reported by 68% in the month prior to prison entry, 54% were receiving opioid substitution therapy, and 86% reported never previously engaging with specialist HCV care. Treatment duration was 8 weeks in 24%, 12 weeks in 59%, and 24 weeks in 17% of treatment courses. The SVR12 rate was 96% (301/313) per protocol. Inter-prison transfer occurred during 26% of treatment courses but was not associated with lower SVR12 rates. No treatment-related serious adverse events occurred. CONCLUSION: Hepatitis C treatment using a decentralized, nurse-led model of care is highly effective and can reach large numbers of prisoners. Large scale prison treatment programs should be considered to support hepatitis C elimination efforts. LAY SUMMARY: There is a high burden of hepatitis C infection among prisoners worldwide. Prisoners who continue to inject drugs are also at risk of developing new infections. For this reason, the prison setting provides an opportunity to treat those people at greatest risk of infection and to stop transmission to others. We developed a new method of providing hepatitis C treatment to prisoners, in which nurses rather than doctors assessed prisoners locally at each prison site. Treatment was safe and most prisoners were cured. Such programs will contribute greatly to achieving the World Health Organization's hepatitis C elimination goals.

Sustained virological response halts fibrosis progression: A long-term follow-up study of people with chronic hepatitis C infection.

BACKGROUND/AIMS: Long-term follow-up studies validating the clinical benefit of sustained virological response (SVR) in people with chronic hepatitis C (CHC) infection are lacking. Our aim was to identify rates and predictors of liver fibrosis progression in a large, well characterized cohort of CHC patients in whom paired liver fibrosis assessments were performed more than 10 years apart. METHODS: CHC patients who had undergone a baseline liver biopsy pre-2004 and a follow up liver fibrosis assessment more than 10 years later (biopsy or liver stiffness measurement (LSM) using transient elastography [FibroScan]) were identified. Subjects who had undergone a baseline liver biopsy but had no follow up fibrosis assessment were recalled for LSM. Fibrosis was categorised as mild-moderate (METAVIR F0-2 / LSM result of ≤ 9.5 kPa) or advanced (METAVIR F3-4/ LSM >9.5 kPa). The primary objective was to assess the association between SVR and the rate of liver fibrosis progression over at least 10 years, defined as an increase from mild-moderate fibrosis at baseline liver biopsy (METAVIR F0-2) to advanced fibrosis at follow-up liver fibrosis assessment. RESULTS: 131 subjects were included in this analysis: 69% male, 82% Caucasian, 60% G1 HCV, 25% G3 HCV. The median age at F/U fibrosis staging was 57 (IQR 54-62) years with median estimated duration of infection 33-years (IQR 29-38). At F/U, liver fibrosis assessment was performed by LSM in 86% and liver biopsy in 14%. The median period between fibrosis assessments was 14-years (IQR 12-17). 109 (83%) participants had received interferon-based antiviral therapy. 40% attained SVR. At F/U, there was a significant increase in the proportion of subjects with advanced liver fibrosis: 27% at baseline vs. 46% at F/U (p = 0.002). The prevalence of advanced fibrosis did not change among subjects who attained SVR, 30% at B/L vs 25% at F/U (p = 0.343). However, advanced fibrosis became more common at F/U among subjects with persistent viremia: 10% at B/L vs 31% at F/U (p = 0.0001). SVR was independently associated with protection from liver fibrosis progression after adjustment for other variables including baseline ALT (p = 0.011), duration of HCV infection and mode of acquisition. CONCLUSION: HCV eradication is associated with lower rates of liver fibrosis progression. The data support early treatment to prevent long-term liver complications of HCV infection.

Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37.

Identification of methionine aminopeptidase-2 (MetAP-2) as the molecular target of the antiangiogenic compound TNP-470 has sparked interest in N-terminal Met excision's (NME) role in endothelial cell biology. In this regard, we recently demonstrated that MetAP-2 inhibition suppresses Wnt planar cell polarity (PCP) signaling and that endothelial cells depend on this pathway for normal function. Despite this advance, the substrate(s) whose activity is altered upon MetAP-2 inhibition, resulting in loss of Wnt PCP signaling, is not known. Here we identify the small G protein Rab37 as a MetAP-2-specific substrate that accumulates in the presence of TNP-470. A functional role for aberrant Rab37 accumulation in TNP-470's mode of action is demonstrated using a Rab37 point mutant that is resistant to NME, because expression of this mutant phenocopies the effects of MetAP-2 inhibition on Wnt PCP signaling-dependent processes.

Comparative proteomics reveals evidence for evolutionary diversification of rodent seminal fluid and its functional significance in sperm competition.

During insemination, males of internally fertilizing species transfer a complex array of seminal fluid proteins to the female reproductive tract. These proteins can have profound effects on female reproductive physiology and behavior and are thought to mediate postcopulatory sexual selection and intersexual conflict. Such selection may cause seminal fluid to evolve rapidly, with potentially important consequences for speciation. Here we investigate the evolution of seminal fluid proteins in a major mammalian radiation, the muroid rodents, by quantifying diversity in seminal fluid proteome composition for the first time across a broad range of closely related species. Using comparative proteomics techniques to identify and cross-match proteins, we demonstrate that rodent seminal fluid is highly diverse at the level of both proteomes and individual proteins. The striking interspecific heterogeneity in seminal fluid composition revealed by our survey far exceeds that seen in a second proteome of comparable complexity, skeletal muscle, indicating that the complement of proteins expressed in seminal fluid may be subject to rapid diversification. We further show that orthologous seminal fluid proteins exhibit substantial interspecific variation in molecular mass. Because this variation cannot be attributed to differential glycosylation or radical differences in termination sites, it is strongly suggestive of rapid amino acid divergence. Sperm competition is implicated in generating such divergence for at least one major seminal fluid protein in our study, SVS II, which is responsible for copulatory plug formation via transglutaminase-catalyzed cross-linking after insemination. We show that the molecular mass of SVS II is positively correlated with relative testis size across species, which could be explained by selection for an increased number of cross-linking sites involved in the formation of the copulatory plug under sperm competition.

Sorry, You Can't Have That Information: Data Holder Confusion Regarding Privacy Requirements for Personal Health Information and the Potential Chilling Effect on Health Research.

This study, conducted in Newfoundland and Labrador, assessed the level of awareness, perceptions and concerns of healthcare providers, health researchers, data managers and the general public about the collection, use and disclosure of personal health information (PHI) for research purposes. Data collection involved surveys and follow-up focus groups with participants. Results indicate a poor understanding generally with regard to privacy rights and responsibilities. Many professionals are unfamiliar with the legislative environment for PHI, particularly as it pertains to the access and use of PHI for research purposes. Lack of familiarity with basic requirements for patient-based research, coupled with heightened sensitivity to privacy issues owing to various federal and provincial regulatory initiatives, could have a chilling effect on health research. Importantly, our results indicate that the public is much less concerned about the use of their PHI for health research purposes than are professionals who collect, store and share it.

Asparagine deamidation and the role of higher order protein structure.

The 'protein world' exhibits additional complexity caused by post-translational modifications. One such process is nonenzymic deamidation of asparagine which is controlled partly by primary sequence, but also higher order protein structure. We have studied the deamidation of an N-terminal peptide in muscle glyceraldehyde 3-phosphate dehydrogenase to relate three-dimensional structure, proteolysis, and deamidation. This work has significant consequences for identification of proteins using peptide mass fingerprinting.

Positional proteomics: preparation of amino-terminal peptides as a strategy for proteome simplification and characterization.

We describe a protocol for selective extraction of the amino (N)-terminal-most peptide of a protein or a mixture of proteins after proteolysis. The first stage of the protocol blocks the free amino groups alpha and epsilon (the latter being lysyl residues) on the intact proteins by acetylation. In the second stage, proteolysis of the acetylated proteins yields a mixture of N-terminally acetylated (true N-terminal) and non-acetylated (internal and carboxy-terminal) peptides. Affinity capture of peptides bearing free amino groups using an immobilized amine-reactive reagent removes internal peptides from the mixture. The unbound fraction is highly enriched in N-terminal peptides, which can be analyzed without further treatment. This method is compatible with a range of proteolytic enzymes and fragmentation methods, and should take 2 d to complete. The N-terminal peptides can then be analyzed by mass spectrometry. This low cost, rapid method is readily adopted using off the shelf reagents.

Positional proteomics: selective recovery and analysis of N-terminal proteolytic peptides.

Bottom-up proteomics is the analysis of peptides derived from single proteins or protein mixtures, and because each protein generates tens of peptides, there is scope for controlled reduction in complexity. We report here a new strategy for selective isolation of the N-terminal peptides of a protein mixture, yielding positionally defined peptides. The method is tolerant of several fragmentation methods, and the databases that must be searched are substantially less complex.