Using biomarkers to quantify problematic alcohol use.

Direct biomarkers detect alcohol even in small amounts shortly after ingestion. But which one is nearly 100% specific for alcohol use?

Hepatoid Adenocarcinoma Presenting as Pancreatitis.

Hepatoid adenocarcinoma (HAC) is an uncommon and aggressive type of adenocarcinoma, typically affecting the middle-aged and elderly. The morphological features of the HAC resemble hepatocellular carcinoma. Presenting symptoms may include upper abdominal pain, hematemesis, back pain, and palpable abdominal mass. HAC has no proven therapy, and the prognosis is extremely poor. Early surgical removal with chemotherapy remains the standard of care. We describe one of the youngest patients in the literature with HAC who presented with acute pancreatitis. The diagnostic workup was confused by diffuse lymphadenopathy and elevated ß-human chorionic gonadotropin making lymphoma and germ cell tumor likely possibilities until immunohistochemistry confirmed the diagnosis.

To avoid Hep B reactivation, screen before immunosuppression.

Universal HBV screening before immunosuppression is prudent and cost effective, even when local HBV prevalence is just 0.3%.

The gRNA-miRNA-gRNA Ternary Cassette Combining CRISPR/Cas9 with RNAi Approach Strongly Inhibits Hepatitis B Virus Replication.

The CRISPR/Cas9 system is a novel genome editing technology which has been successfully used to inhibit HBV replication. Here, we described a novel gRNA-microRNA (miRNA)-gRNA ternary cassette driven by a single U6 promoter. With an anti-HBV pri-miR31 mimic integrated between two HBV-specific gRNAs, both gRNAs could be separated from the long transcript of gRNA-miR-HBV-gRNA ternary cassette through Drosha/DGCR8 processing. The results showed that the gRNA-miR-HBV-gRNA ternary cassette could efficiently express two gRNAs and miR-HBV. The optimal length of pri-miRNA flanking sequence in our ternary cassette was determined to be 38 base pairs (bp). Besides, HBV-specific gRNAs and miR-HBV in gRNA-miR-HBV-gRNA ternary cassette could exert a synergistic effect in inhibiting HBV replication and destroying HBV genome in vitro and in vivo. Most importantly, together with RNA interference (RNAi) approach, the HBV-specific gRNAs showed the potent activity on the destruction of HBV covalently closed circular DNA (cccDNA). Since HBV cccDNA is an obstacle for the elimination of chronic HBV infection, the gRNA-miR-HBV-gRNA ternary cassette may be a potential tool for the clearance of HBV cccDNA.

Distinct features in natural history and outcomes of acute hepatitis C.

BACKGROUND: Acute hepatitis C (AHCV) provides a diagnostic challenge with diverse clinical presentations. GOALS: This study was aimed to examine the clinical and demographic features as well as outcomes in AHCV patients identified from inpatient and outpatient hospital settings. STUDY: Patients with suspected AHCV were recruited from Philadelphia VA Medical Center, Hospital of University of Pennsylvania and Brooklyn VA Medical Center between 2000 and 2010. AHCV was diagnosed by acute serum alanine aminotransferase elevation with anti-hepatitis C virus (HCV) seroconversion, HCV-RNA fluctuations above 1 log, and/or recent high-risk exposure without prior HCV infection, excluding those with human immunodeficiency virus infection. Clinical and therapeutic outcomes were monitored for at least 6 months. RESULTS: A total of 40 AHCV patients were enrolled with a median follow-up of 129 weeks. They were mostly men (68%) and whites (73%) with median age of 43 years, diverse risk factors (33% injection drugs, 20% health care-associated, 3% sexual, and 45% unknown), and wide variations in peak alanine aminotransferase (143 to 3435 U/L) and total bilirubin levels (0.4 to 19.3 mg/dL). Viremia resolved spontaneously in 23% and persisted without therapy in 27%, whereas 50% received interferon α-based therapy with 90% cure (18/20). Distinct clinical scenarios included: (1) wide viremic fluctuations >1 log (65%) and intermittent HCV-RNA negativity; (2) autoantibodies (25% antinuclear antibodies, 69% antismooth muscle antibodies) or autoimmune features; (3) delayed spontaneous viral clearance in 2 patients; (4) rapid cirrhosis progression in 2 patients. CONCLUSIONS: AHCV is a heterogenous disease that requires careful monitoring. The lack of apparent risk factor in high proportion of patients and its diverse presentations warrant diagnostic vigilance.

Racial differences in hepatitis C treatment eligibility.

UNLABELLED: Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). CONCLUSION: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency.

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis.

BACKGROUND/AIMS: Interleukin-10 (IL-10) has been ascribed pro-viral but anti-fibrotic properties in chronic hepatitis C virus (HCV) infection. In this study, we examined the role of HCV-specific T-cell IL-10 response in patients with acute and chronic HCV infection. METHODS: Peripheral HCV-specific T-cell IL-10 and IFNgamma responses were measured in cytokine Elispot assay using overlapping HCV-derived peptides in patients with chronic (n=61), resolved (n=15) and acute (n=8) hepatitis C, looking for their onset, quantity, breadth and durability relative to clinical and virological outcomes. The source and effect of HCV-specific IL-10 response were determined in depletion and IL-10 neutralization experiments. RESULTS: Both HCV-specific IL-10 and IFNgamma responses were detected early within 1-2 months of acute clinical hepatitis C. However, only HCV-specific IL-10 response correlated with elevated liver enzymes, increased viremia and suppressed HCV-specific CD4(+) T-cell proliferation in acute infection. While these associations were lost in established chronic infection, HCV-specific IL-10 responses were increased in patients without cirrhosis while IL-10 blockade enhanced antiviral effector IFNgamma responses. CONCLUSIONS: HCV-specific IL-10 Tr1 responses may play a dual role in HCV infection, dampening effector T-cells to promote viral persistence in acute infection but also protecting against progressive fibrosis in chronic infection.

Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C.

BACKGROUND & AIMS: Acute hepatitis C virus (HCV) infection becomes chronic in the majority of patients. Although HCV-specific CD4 T-cell response is associated with HCV clearance, less is known about virus-specific CD8 T-cell or neutralizing antibody (nAb) responses and the role of CD4 help in their induction during acute infection. METHODS: HCV-specific CD4, CD8, and HCV pseudoparticle (HCVpp) nAb responses were monitored in acutely HCV-infected patients to define their relative contributions to viral clearance. RESULTS: Our results show that the outcome of acute hepatitis C is associated with a functional hierarchy in HCV-specific CD4 T-cell response and the scope of virus-specific, total T-cell interferon-gamma response. HCV-specific CD8 T-cell response was readily detectable in acutely HCV-infected patients regardless of virologic outcome or virus-specific CD4 T-cell response. In contrast, HCVpp-specific nAbs were readily detected in patients with chronic evolution and impaired virus-specific CD4 T-cell response but not in patients who cleared infection with robust virus-specific CD4 T-cell response. CONCLUSIONS: The outcome of acute hepatitis C is associated with efficient virus-specific CD4 T-cell response(s) without which HCV-specific CD8 T-cell and heterologous nAb responses may develop but fail to clear viremia. Furthermore, HCV-specific nAb responses may not be induced despite robust virus-specific CD4 T-cell response.

Strain-specific T-cell suppression and protective immunity in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) frequently persists with an apparently ineffective antiviral T-cell response. We hypothesized that some patients may be exposed to multiple HCV subtypes and that strain-specific T cells could contribute to the viral dynamics in this setting. To test this hypothesis, CD4 T-cell responses to three genotype 1a-derived HCV antigens and HCV antibody serotype were examined in chronically HCV infected (genotypes 1a, 1b, 2, 3, and 4) and spontaneously HCV recovered subjects. Consistent with multiple HCV exposure, 63% of patients infected with genotypes 2 to 4 (genotypes 2-4) and 36% of those infected with genotype 1b displayed CD4 T-cell responses to 1a-derived HCV antigens, while 29% of genotype 2-4-infected patients showed serotype responses to genotype 1. Detection of 1a-specific T cells in patients without active 1a infection suggested prior self-limited 1a infection with T-cell-mediated protection from 1a but not from non-1a viruses. Remarkably, CD4 T-cell responses to 1a-derived HCV antigens were weakest in patients with homologous 1a infection and greater in non-1a-infected patients: proportions of patients responding were 19% (1a), 36% (1b), and 63% (2-4) (P = 0.0006). Increased 1a-specific CD4 T-cell responsiveness in non-1a-infected patients was not due to increased immunogenicity or cross-reactivity of non-1a viruses but directly related to sequence divergence. We conclude that the T-cell response to the circulating virus is either suppressed or not induced in a strain-specific manner in chronically HCV infected patients and that, despite their ability to clear one HCV strain, patients may be reinfected with a heterologous strain that can then persist. These findings provide new insights into host-virus interactions in HCV infection that have implications for vaccine development.

Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection.

Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCV-specific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P =.001) and scope (14/36 vs. 4/36 pools, P =.002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R = -0.51, P =.049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4(+)CD25(+) regulatory T cells (7.3% chronic vs. 2.5% recovered, P =.002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4(+)CD25(+) regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence.

The outcome of liver grafts procured from hepatitis C-positive donors.

BACKGROUND: The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in detail. METHODS: Two study populations were examined retrospectively to assess the survival of liver grafts procured from HCV+ donors. First, we evaluated the survival of all 13 HCV+ and 103 HCV- grafts that were transplanted at our institution to HCV+ recipients from January 1, 1995 to December 31, 1999. In parallel, we analyzed a subset of the United Network for Organ Sharing (UNOS) liver transplant database from the same 5-year time period that was comprised of 14,195 adult patients for whom donor and recipient HCV serologies were known. Kaplan-Meier graft survival for both patient populations was calculated based on donor and recipient HCV serologic status. A Cox proportional hazards analysis was performed on UNOS data to identify variables independently predicting graft survival. RESULTS: For transplants performed at our institution, we found no statistically significant difference in the Kaplan-Meier graft survival of HCV+ and HCV- grafts transplanted to HCV+ recipients (P=0.68). The incidence of biopsy-proven, recurrent HCV posttransplant was similar in recipients receiving either HCV+ or HCV- grafts (4/13 vs. 18/103, chi-square P=0.211). Analysis of UNOS data revealed that the survival of HCV+ grafts in HCV+ recipients was equivalent to the survival of HCV- grafts in HCV+ recipients. Unexpectedly, the survival of grafts in HCV+ recipients in general was significantly inferior to that of grafts in HCV- recipients. Multivariate analysis of all patients found recipient but not donor HCV status to be independently predictive of graft survival. CONCLUSIONS: Analysis of data from a single center and the national UNOS database suggests that transplantation of liver allografts from HCV+ donors to HCV+ recipients results in graft survival comparable to HCV- grafts transplanted to HCV+ recipients. In contrast, recipient HCV positivity is an independent predictor of graft failure compared with patients transplanted for other causes of liver disease.

Issues in Resource Management: A model hospital

This paper seeks to present the issues in resource management facing Health Administrators in the English Speaking Caribbean against a service delivery backdrop. Using a model 150 bed acute care general hospital, the authors would try to demonstrate the benefits and value of accountability management change and paradigm shifts in the management of hospitals. The model hospital is characterised by high quality, efficiency and effective delivery of service, continuous improvement and value added to the community. All aspects of the organization will be considered. * Financial Resources - Adequacy and Control; * Human Resources - Staffing, Development and Planning; * Technology - Appropriateness use and Relevance; * Information - Decision support Services, Decision Making; * Quality - Service standards, Continuous improvement; * Organizational Design and Development; * Management Systems Development; * Policies and Procedures; * Physical Plant and Equipment; * Aesthetics; * Public and Community Relations (AU)