Phillipsferguson8511

BACKGROUND/AIMS Treating hepatitis C virus (HCV) infection reduces overall mortality and reduces the risk of multiple extrahepatic complications. Whether the reduction in mortality is primarily due to reduction in liver-related causes or extrahepatic complications is unknown. METHODS We identified HCV+ persons treated for HCV, and propensity-score matched HCV+/untreated and HCV-uninfected persons in ERCHIVES between 2002-2016. We extracted cause of death data from the National Center for Health Statistics' National Death Index. Viral hepatitis associated liver-related mortality rates among treated and untreated HCV-infected persons were calculated by treatment and attainment of sustained virologic response (SVR). RESULTS Among 50,674 HCV+/treated (Group A), 31,749 HCV+/untreated (Group B) and 73,526 HCV-uninfected persons (Group C), 8.6% in Group A, 35.0% in Group B, and 14.3% in Group C died. Among those who died, viral hepatitis associated liver-related mortality rates per 100 patients years [95% CI] were 0.28[0.27,0.30] for Group A; 1.44 [1.38,1.49] for Group B; and 0.06[0.05,0.06] for Group C; (P less then 0.0001 for both comparisons). Among HCV+/treated persons, rates were 0.06[0.05,0.06] for those with SVR vs. 0.78[0.74,0.83] for those without SVR. Iodoacetamide order In competing risks Cox proportional hazards analysis, treatment with all-oral DAA regimens (adjusted hazard ratio 0.11[0.09,0.14] and SVR (adjusted hazard ratio 0.10[0.08, 0.11]) were associated with reduced hazards of liver-related mortality. CONCLUSIONS Treatment for HCV is associated with a significant reduction in viral hepatitis associated liver-related mortality which is particularly pronounced in those treated with DAA regimens and those who attain SVR. This may account for a significant proportion of reduction in all-cause mortality reported in previous studies. V.BACKGROUND & AIMS Severe forms of alcohol-related liver disease are associated with increased susceptibility to infections contributing to their poor prognosis. The cellular and molecular mechanisms responsible for this altered host defense are incompletely understood. METHODS We performed whole blood phenotypic analysis and ex vivo stimulation with various pathogen-associated molecular patterns (PAMPs). We included 34 patients with alcohol-related cirrhosis (18 of which had biopsy-proven severe alcoholic hepatitis [sAH]), 12 healthy controls and 11 patients with chronic alcohol consumption without significant liver disease. We also evaluated the transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles of CD14+ monocytes from a subset of patients. RESULTS Circulating monocytes and conventional dendritic cells (DCs) from patients with sAH displayed complex alterations characterized by increase of activation and inhibitory surface markers and impaired pro-inflammatory response upon stimulation with PAMPs representative of gram-negative bacteria (LPS, Pam3CSK4) or fungal pathogens (Zymosan). Their decreased ability to produce more than one cytokine (polyfunctionality) upon PAMPs stimulation was correlated with the risk of developing infection at 28 days or of mortality at 90 days. The presence of Acute-on-Chronic Liver Failure (ACLF) in patients with sAH did not significantly modify the immune profile of monocytes and DCs. Moreover, CD14+ monocytes of patients with sAH displayed altered transcriptional and epigenomic profiles characterized by downregulation of key innate immune and metabolic pathways and upregulation of important immunomodulatory factors. CONCLUSIONS The altered transcriptional program and functional properties of monocytes from sAH patients contributing to their susceptibility to infection have strong epigenetic determinants. BACKGROUND & AIMS Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current management era of pulmonary hypertension. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, the survival and the predictors of death in a large contemporary cohort of patients with PoPH. METHODS Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. Effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. RESULTS Six hundred and thirty-seven patients (mean age 55±10 years; 58% male) were included. Fifty seven percent had mild cirrhosis, i.e. Child-Pugh (CP) stage A. The median MELD score was 11 (Q1-Q3; 9-15). Most patients (n=474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n=336) or with an endothelin-receptor antagonist (n=128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p less then 0.001), 6-minute walk distance (6MWD) (p less then 0.0001) and pulmonary vascular resistance (p less then 0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD Score or CP stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively) CONCLUSION Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. BACKGROUND & AIMS The vitronectin receptor integrin alpha v beta 3 (αvβ3) drives fibrogenic activation of hepatic stellate cells (HSC). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in uptake of the [18F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis. METHODS PET with [18F]-Alfatide, non-enhanced computerized tomography (CT), histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvβ3 levels and liver fibrosis progression in carbon-tetrachloride (CCl4) and bile duct ligation (BDL) induced liver fibrosis mice model. The AUC liver 0-30 min to AUC blood 0-30 min contrast was used as an integrin αvβ3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings.