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Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. NCT03065699. • In a first-in-man, randomized-controlled trial of DIALIVE vs. standard of care, the primary endpoint of safety was met. • DIALIVE achieved acceptable performance characteristics for albumin exchange and reduction in endotoxin. • DIALIVE significantly reduced time to resolution of ACLF and improved prognostic scores compared with standard of care. • DIALIVE had a significantly greater impact on the pathophysiologically relevant biomarkers associated with ACLF. [Display omitted] [ABSTRACT FROM AUTHOR]

Offshore wave setup generated by wave breaking during coastal storms can create significant flow through tidal inlets and increase bay flooding. However, these flow contributions are not always considered when determining coastal flooding risk for engineering studies. This paper describes the wave-driven flow process at tidal inlets and demonstrates its impact on bay flooding on Long Island, New York. Numerical simulations using a coupled hydrodynamic and wave model are presented to show contributions to bay water level by wave-driven flow with respect to those by wind surge. These simulations include two major historical coastal storms and a small nor’easter in 2003, during which the model was validated using field measurements of water level. Finally, an approach is introduced for estimating wave-induced flow contributions to bay flooding as a function of inlet and storm characteristics, including tidal prism and wave conditions. The findings of this study indicate that wave-induced flow contributions make up 15–35% of the total storm surge, where the wave-induced flow contribution increases with increased inlet efficiency. [ABSTRACT FROM AUTHOR]

Abstract: Prediction of coupled storm hydrodynamics and morphodynamics is essential for accurately designing coastal flood protection measures. A numerical simulation methodology was developed and implemented to evaluate and assess engineering design solutions for storm damage reduction along the south shore of Long Island, New York, USA. This simulation methodology was applied to compute bay water levels for two major coastal storms taking into account contributions from storm surge, waves, wind, and barrier island overwash and breaching. Simulation results for breaching and bay flooding compare well to historically documented barrier island morphological change and bay high water marks. [Copyright &y& Elsevier]

Summary: The increased risk of cardiovascular disease (CVD) conferred by hepatitis C virus (HCV) is especially relevant after liver transplantation (LT), but its mechanism is still not well defined. This study aimed to evaluate the influence of HCV eradication in inflammatory and endothelial activation markers after LT. We evaluated inflammatory (TNF‐alfa, IL‐6, IL‐8, and MCP‐1) and endothelial activation (E‐selectin, ICAM‐1, VCAM‐1, and MMP‐9) markers before and after eradication in 45 LT recipients with HCV infection (LT+/HCV+) and 44 non‐transplanted HCV‐infected patients (LT‐/HCV+). We also considered an additional group of 40 LT recipients without HCV infection (LT+/HCV‐). LT+/HCV+ patients presented a higher endothelial activation status before eradication compared with LT+/HCV‐ patients. However, levels of E‐selectin, ICAM‐1, VCAM‐1, and MMP‐9 were comparable between LT+/HCV+ and LT‐/HCV+ patients before eradication. HCV eradication decreased ICAM‐1 (5466.55 pg/ml vs. 3354.88 pg/ml, P < 0.001) and VCAM‐1 (10456.52 pg/ml vs. 6658.85 pg/ml, P < 0.001) levels in LT+/HCV+ and LT‐/HCV+ patients. Remarkably, HCV eradication restored levels of endothelial activation markers of LT+/HCV+ patients compared with that of LT+/HCV‐ patients. HCV plays a major role in endothelial dysfunction after LT. Furthermore, HCV eradication restores endothelial activation despite the exposure to immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background: Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. Aims: To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. Methods: Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. Results: A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20–91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). Conclusion: Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH. [ABSTRACT FROM AUTHOR]

Background and Aim Assessment of the severity of liver disease following infection with hepatitis C virus ( HCV) is important in treatment selection and prognosis. As invasive liver biopsy procedures are regarded as the reference method to assess the stage of fibrosis, it is important to identify patient characteristics that are predictive of liver fibrosis severity. The aim of the study was to describe the distribution of liver severity scores, clinical characteristics, and physicians' assessment of fibrosis among HCV patients in five European countries. Methods This cross-sectional study retrospectively reviewed the medical records of patients who were chronically infected with HCV in 2006. Patients managed for HCV at any of 60 sites in France, Germany, Italy, Spain, and the UK were included. Data collected included patient demographics and clinical characteristics. A combination of univariate and multivariate regression analyses were used to identify predictors of fibrosis severity and factors associated with undergoing biopsy. Results Four thousand five hundred and ninety-four chronically infected HCV patients were included in this analysis. Management approaches differed between countries, with variations in biopsy use (59.3-18.4%) and preferred fibrosis scoring systems. Where histology results were available, 43.4%, 23.8%, and 32.9% had mild, moderate, and severe fibrosis, respectively. Factors associated with undergoing a biopsy included male gender and co-infection with hepatitis B virus. Chronic alcoholism, a lower first platelet count, and older age were predictors of increased liver fibrosis severity. Conclusions These data suggest that there are major differences in how specialists manage their HCV patients across five major European countries. [ABSTRACT FROM AUTHOR]