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To investigate the biological mechanisms underlying the higher risk for psychosis in those that use cannabis, we conducted a genome-wide environment-interaction study (GWEIS). In a sample of individuals without a psychiatric disorder (N = 1262), we analyzed the interactions between regular cannabis use and genotype with psychotic-like experiences (PLE) as outcome. PLE were measured using the Community Assessment of Psychic Experiences (CAPE). The sample was enriched for those at the extremes of both cannabis use and PLE to increase power. A single nucleotide polymorphism in the P2RX7 gene (rs7958311) was associated with risk for a high level of psychotic experiences in regular cannabis users (p = 1.10 x10 -7 ) and in those with high levels of lifetime cannabis use (p = 4.5 × 10 -6 ). This interaction was replicated in individuals with high levels of lifetime cannabis use in the IMAGEN cohort (N = 1217, p = 0.020). Functional relevance of P2RX7 in cannabis users was suggested by in vitro experiments on activated monocytes. Exposure of these cells to tetrahydrocannabinol (THC) or cannabidiol (CBD) reduced the immunological response of the P2X7 receptor, which was dependent on the identified genetic variant. P2RX7 variants have been implicated in psychiatric disorders before and the P2X7 receptor is involved in pathways relevant to psychosis, such as neurotransmission, synaptic plasticity and immune regulation. We conclude that P2RX7 plays a role in vulnerability to develop psychotic symptoms when using cannabis and point to a new pathway that can potentially be targeted by newly developed P2X7 antagonists., (Copyright © 2020. Published by Elsevier Inc.)

Background & Aims: Liver stiffness measured with 2-dimensional shear wave elastography by Supersonic Imagine (2DSWE-SSI) is well-established for fibrosis diagnostics, but non-conclusive for portal hypertension., Methods: We performed an individual patient data meta-analysis of 2DSWE-SSI to identify clinically significant portal hypertension (CSPH), severe portal hypertension and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta-analytical integration of diagnostic accuracies with optimized rule-out (sensitivity-90%) and rule-in (specificity-90%) cut-offs., Results: Five studies from seven centres shared data on 519 patients. After exclusion, we included 328 patients. Eighty-nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE-SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of patients, with minimal between-study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE-SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut-off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral aetiology or BMI < 25 kg/m 2 . 2DSWE-SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in., Conclusion: Liver stiffness using 2-dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE-SSI cannot predict varices needing treatment., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The legalization of recreational cannabis across Canada has revealed the importance of medical education on cannabis-related topics. A recent study has indicated that Canadian physicians report a significant gap in current versus desired knowledge regarding the therapeutic use of cannabis. However, the state of education on cannabis has never been studied in Canadian medical schools. This article presents the preliminary findings of a survey conducted to understand the perceptions of Quebec's medical students regarding cannabis-related teachings in their current curriculum. Overall, students reported very low to low levels of exposure to, knowledge of, and comfort levels with cannabis-related subjects. The majority of students reported that they felt that their medical curricula did not prepare them to face cannabis-related issues in their future practices. Strategies need to be developed for improving medical school curriculum regarding cannabis-related issues. These findings provide potential key strategies to improve curricula., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Anticoagulant therapy has been recommended in patients with cirrhosis and portal vein thrombosis especially in candidates for liver transplantation. These patients are also likely to need variceal band ligation. This study aimed to assess the incidence of upper gastrointestinal bleeding after elective variceal band ligation in patients with cirrhosis receiving anticoagulant therapy for portal vein thrombosis., Methods: Patients with cirrhosis and nontumoral portal vein thrombosis treated with anticoagulant therapy undergoing elective variceal band ligation were retrospectively included. We recorded upper gastrointestinal bleeding events occurring within two weeks after variceal band ligation. Postvariceal band ligation bleeding was defined as active bleeding on at least one site of previous ligation at endoscopy., Results: Between 2014 and 2017, 32 patients with cirrhosis had scheduled variceal band ligations while on anticoagulant therapy [men 75%; median age 59 years; aetiology of cirrhosis: alcohol (50%), viral (34%), alcohol and viral (16%); and Child-Pugh score: A (31%), B (44%), and C (25%)]. Three (9%) patients presented postvariceal band ligation bleeding during the follow-up. None of these events led to haemorrhagic shock or death. Factors associated with postvariceal band ligation bleeding included variceal band ligation performed as secondary prophylaxis (P = 0.05) and previous decompensation of cirrhosis (P = 0.03)., Conclusion: In this small group of patients under anticoagulation therapy undergoing variceal band ligation, only a minority presented postendoscopic bleeding of minor importance. Nevertheless, particular attention should be paid to patients with previous decompensation of cirrhosis.

In patients with idiopathic noncirrhotic portal hypertension (INCPH), data on morbidity and mortality of abdominal surgery are scarce. We retrospectively analyzed the charts of patients with INCPH undergoing abdominal surgery within the Vascular Liver Disease Interest Group network. Forty-four patients with biopsy-proven INCPH were included. Twenty-five (57%) patients had one or more extrahepatic conditions related to INCPH, and 16 (36%) had a history of ascites. Forty-five procedures were performed, including 30 that were minor and 15 major. Nine (20%) patients had one or more Dindo-Clavien grade ≥ 3 complication within 1 month after surgery. Sixteen (33%) patients had one or more portal hypertension-related complication within 3 months after surgery. Extrahepatic conditions related to INCPH (P = 0.03) and history of ascites (P = 0.02) were associated with portal hypertension-related complications within 3 months after surgery. Splenectomy was associated with development of portal vein thrombosis after surgery (P = 0.01). Four (9%) patients died within 6 months after surgery. Six-month cumulative risk of death was higher in patients with serum creatinine ≥ 100 μmol/L at surgery (33% versus 0%, P < 0.001). An unfavorable outcome (i.e., either liver or surgical complication or death) occurred in 22 (50%) patients and was associated with the presence of extrahepatic conditions related to INCPH, history of ascites, and serum creatinine ≥ 100 μmol/L: 5% of the patients with none of these features had an unfavorable outcome versus 32% and 64% when one or two or more features were present, respectively. Portal decompression procedures prior to surgery (n = 10) were not associated with postoperative outcome. Conclusion: Patients with INCPH are at high risk of major surgical and portal hypertension-related complications when they harbor extrahepatic conditions related to INCPH, history of ascites, or increased serum creatinine., (© 2019 by the American Association for the Study of Liver Diseases.)

The population of liver transplant recipients has increased in Switzerland over the last few years. Morbidity and mortality after liver transplantation are due, in the early post-transplant period, to surgical and infectious complications as well as to rejection, whereas cardiovascular, metabolic, renal and oncologic complications are the most frequent complications in the late post-transplant period. The role of the general practitioner in the long-term follow-up of liver transplant recipients is of the highest importance and can represent the first-line care of these patients as soon as 6 to 12 months post-transplantation, while maintaining a close and regular collaboration with the transplant center. Multidisciplinary and structured follow-up, along with some specific screening tests, is warranted in order to refine patient management in a timely manner and to optimize outcomes., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Abdominal surgery is sometimes needed in patients with portal hypertension. The indication may be related to the underlying liver disease, including liver resection for liver cancer and parietal surgery. Surgery may also be performed for another indication, unrelated to the liver disease. Portal hypertension increases both morbidity and mortality after abdominal surgery, and it should be taken into account when planning surgery timing and surgical strategy. This article provides an overview of the main etiologies of portal hypertension, and the post-operative outcomes after liver resection and non-hepatic abdominal surgery, underlining the importance of a multidisciplinary approach., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background & Aims: Bacterial infections are common and life-threatening in patients with cirrhosis. Little is known about the epidemiology of bacterial infections in different regions. We performed a multicenter prospective intercontinental study to assess the prevalence and outcomes of bacterial and fungal infections in patients with cirrhosis., Methods: We collected data from 1302 hospitalized patients with cirrhosis and bacterial or fungal infections at 46 centers (15 in Asia, 15 in Europe, 11 in South America, and 5 in North America) from October 2015 through September 2016. We obtained demographic, clinical, microbiology, and treatment data at time of diagnosis of infection and during hospitalization. Patients were followed until death, liver transplantation, or discharge., Results: The global prevalence of multidrug-resistant (MDR) bacteria was 34% (95% confidence interval 31%-37%). The prevalence of MDR bacteria differed significantly among geographic areas, with the greatest prevalence in Asia. Independent risk factors for infection with MDR bacteria were infection in Asia (particularly in India), use of antibiotics in the 3 months before hospitalization, prior health care exposure, and site of infection. Infections caused by MDR bacteria were associated with a lower rate of resolution of infection, a higher incidence of shock and new organ failures, and higher in-hospital mortality than those caused by non-MDR bacteria. Administration of adequate empirical antibiotic treatment was independently associated with improved in-hospital and 28-day survival., Conclusions: In a worldwide study of hospitalized patients, we found a high prevalence of infection with MDR bacteria in patients with cirrhosis. Differences in the prevalence of MDR bacterial infections in different global regions indicate the need for different empirical antibiotic strategies in different continents and countries. While we await new antibiotics, effort should be made to decrease the spread of MDR bacteria in patients with cirrhosis., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis., Methods: We performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18 clinical sites in France from April 2010 through November 2014. Patients were randomly assigned to groups given 400 mg norfloxacin (n = 144) or placebo (n = 147) once daily for 6 months. Patients were evaluated monthly for the first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan-Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up., Results: The Kaplan-Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (P = .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower in the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35-0.99). The subdistribution hazard ratio for death at 6 months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13-0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42-4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria., Conclusions: In a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan-Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose To determine whether quantification of liver surface nodularity (LSN) provides an estimate of the presence of clinically significant portal hypertension (CSPH) in patients with cirrhosis. Materials and Methods This retrospective study included a training cohort (n = 189) and separate external validation cohort (n = 78), both composed of patients with cirrhosis who underwent abdominal CT and hepatic venous pressure gradient (HVPG) measurement between 2010 and 2016. The LSN score, liver and spleen volumes, liver-to-spleen volume ratio, platelet count to spleen diameter ratio, Iranmanesh score, aspartate amino transferase-to-platelet ratio index, and Fibrosis-4 index were derived from CT images and serum laboratories. The accuracy of the various tests for predicting CSPH was evaluated with area under the receiver operating characteristic curve (AUROC) and compared by using the DeLong test. Student t test and Pearson correlation coefficient were used. Results One hundred eighty-nine patients were analyzed (119 men [mean age ± standard deviation, 57 years ± 11; range, 29-81 years] and 70 women [mean age, 61 years ± 10; range, 34-83 years]; overall mean age, 58 years ± 10; range, 29-83 years). A total of 102 patients (54%) had CSPH. LSN score correlated with HVPG (r = 0.75; P < .001). Patients with CSPH had a higher LSN score than did those without CSPH (3.2 ± 0.6 vs 2.4 ± 0.3; P < .001). A cutoff value of 2.8 had a positive predictive value of 88% for CSPH; the AUROC of LSN was 0.88 ± 0.03. This was higher than that of other available noninvasive tests (DeLong, all P < .001). In the validation cohort, LSN score of 2.8 had a positive predictive value of 86% for CSPH; the AUROC was 0.87 ± 0.04. Conclusion The CT-based liver surface nodularity score demonstrated high diagnostic performance for detecting clinically significant portal hypertension and outperformed multiple other noninvasive tests. © RSNA, 2018 Online supplemental material is available for this article.

Objective: To evaluate the European experience after Adult-to-adult living donor liver transplantation using the left liver (LL-aLDLT)., Summary Background Data: LL-aLDLT decreases donor risk but provides a smaller graft that increases recipient risk as compared with right liver (RL-aLDLT). However, there is little knowledge of results obtained after LL-aLDLT in Europe., Methods: This is a European multicenter retrospective study which aims to analyze donor and recipient outcomes after 46 LL-aLDLT., Results: Seventy-six percent of the grafts were harvested by minimally invasive approach. Mean donor hospital stay was 7.5 ± 3.5 days. Donor liver function was minimally impaired, with 36 donors (78.3%) without any 90-day complication, and 4 (8.7%) presenting major complications. One, 3, and 5-year recipient survival was 90.9%, 82.7%, and 82.7%, respectively. However, graft survival was of 59.4%, 56.9%, and 56.9% at 1, 3, and 5 years respectively, due to a 26.1% urgent liver retransplantation (ReLT) rate, mainly due to SFSS (n = 5) and hepatic artery thrombosis (HAT, n = 5). Risk factor analysis for ReLT and HAT showed an association with a graft to body weight ratio (GBWR) <0.6% (P = 0.01 and P = 0.024, respectively) while SFSS was associated with a recipient MELD ≥14 (P = 0.019). A combination of donor age <45 years, MELD <14 and actual GBWR >0.6% was associated with a lower ReLT rate (0% vs. 33%, P = 0.044)., Conclusions: Our analysis showed low donor morbidity and preserved liver function. Recipient outcomes, however, were hampered by a high ReLT rate. A strict selection of both donor and recipients is the key to minimize graft loss.

Background: An outbreak of Pneumocystis pneumonia (PCP) in liver transplant recipients occurred between 2009 and 2011 at the Beaujon University Hospital just after immediate-release tacrolimus was replaced by extended-release tacrolimus. We conducted a retrospective study to analyze the transmission mode of Pneumocystis, the role of the change in the immunosuppressive regimen, and the factors associated with PCP., Patients and Methods: To analyze transmission, we built a transmission map. Two control groups were built. First, to assess the role of the change from tacIR to tacER, cases were matched to controls transplanted before 2009 (tacIR control group). Tacrolimus trough concentrations were compared between the 2 groups. Then, to assess factors associated with PCP, each PCP case was matched to 2 control patients: the one transplanted just before and the one just after (PCPAsFact control group). No PCP prophylaxis was given to any patient., Results: Fifteen cases of PCP were recorded. A contact between a case and a patient who developed PCP afterward was identified in 4 occasions. The comparison of tacrolimus trough concentrations did not conclude to a difference in the exposure to the drug. Lymphopenia was the only factor independently associated with the occurrence of PCP (odds ratio 0.78, 95% confidence interval 0.61-0.99, P = .04)., Conclusion: Our results suggest that patient-to-patient transmission was not the main mode of transmission of PCP. We found no evidence that the switch from tacIR to tacER led to an overexposure to tacrolimus. Our results suggest the possibility of targeted prophylaxis in immunosuppressed liver transplant recipients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Increased hepatic venous pressure gradient (HVPG) plays a role in the clinical manifestations of alcoholic hepatitis (AH). The evolution of HVPG and the influence of alcohol use in the intermediate term are unclear., Aim: The aim of this study was to explore HVPG modifications following AH taking into consideration alcohol use and clinical manifestations., Patients and Methods: Patients with AH (n=37; age 52 years; model for end-stage liver disease: 18.5; Maddrey score: 43) and chronic excessive drinkers with compensated cirrhosis (n=19; age: 54 years; model for end-stage liver disease: 9.2) underwent HVPG measurement and liver biopsy. Ten long-standing abstinent alcoholic cirrhotics served as controls. After discharge, patients were monitored for alcohol use and clinical complications, with repeated HVPG after a median duration of 100 days. Inflammation was determined using plasma C-reactive protein., Results: At baseline, compared with chronic excessive drinkers and alcoholic cirrhotics, patients with AH had increased HVPG (18.1±0.6 vs. 13.8±1.4 vs. 15±1.3 mmHg, P<0.05). During follow-up, patients who became abstinent or reported occasional drinking were more likely to achieve a greater than 20% reduction in HVPG compared with those returning to harmful alcohol (45 vs. 0%, P<0.01), and suffered from fewer complications (25 vs. 68%, P<0.03). High baseline C-reactive protein levels correlated to the Maddrey (r=0.38), but no relationship was observed between changes in inflammation and HVPG., Conclusion: Elevated HVPG is a feature of AH, with a clinically significant reduction in values in abstinent or occasional drinkers after weeks of follow-up. A return to harmful alcohol has a negative impact on portal hemodynamics and associated clinical complications.

Extensive rodent literature suggests that the endocannabinoid (eCB) system present in the nucleus accumbens (NAc) modulates dopamine (DA) release in this area. However, expression patterns of the cannabinoid receptor type 1 (CB1R), the synthesizing enzyme N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), and the degradation enzyme fatty acid amide hydrolase (FAAH) in the NAc have not yet been described in non-human primates. The goal of this study is therefore to characterize the expression and localization of the eCB system within the NAc of vervet monkeys (Chlorocebus sabaeus) using Western blots and immunohistochemistry. Results show that CB1R, NAPE-PLD, and FAAH are expressed across the NAc rostrocaudal axis, both in the core and shell. CB1R, NAPE-PLD, and FAAH are localized in medium spiny neurons (MSNs) and fast-spiking GABAergic interneurons (FSIs). Dopaminergic projections and astrocytes did not express CB1R, NAPE-PLD, or FAAH. These data show that the eCB system is present in the vervet monkey NAc and supports its role in the primate brain reward circuit.

Background: Refractory ascites (RA) is a complication of cirrhosis which is treated with large volume paracentesis (LVP) as the standard of care. Alfapump® system is a fully implantable pump system which reduces the need for LVP. The aim was to assess health-related quality of life (HRQL) in patients treated with alfapump® versus LVP., Methods: The data were collected in a multicenter open-label randomized controlled trial (clinicaltrials.gov #NCT01528410). Subjects with cirrhosis Child-Pugh class B or C accompanied by RA were randomized to receive alfapump® or LVP. The SF-36v2 and CLDQ scores were compared between the two treatment arms at screening and monthly during treatment., Results: Of 60 subjects randomized, HRQL data were available for 58 (N = 27 received alfapump® and N = 31 received LVP only). At baseline, no differences were seen between the treatment arms (all p > 0.05): age 61.9 ± 8.4, 79.3% male, MELD scores 11.7 ± 3.3, 85.2% Child-Pugh class B, 70.7% had alcoholic cirrhosis. The mean number of LVP events/subject was lower in alfapump® than LVP (1.1 vs. 8.6, p < 0.001). The HRQL scores showed a moderate improvement from the baseline levels in subjects treated with alfapump® (p < 0.05 for abdominal and activity scores of CLDQ) but not with LVP (all one-sided p > 0.05) in the first 3 months. Multivariate analysis showed that treatment with alfapump® was independently associated with better HRQL at 3 months (total CLDQ score: beta = 0.67 ± 0.33, p = 0.05)., Conclusion: As compared to LVP, the use of alfapump® system is associated with both a reduction in the number of LVP events and improvement of health-related quality of life.

Splanchnic vein thromboses include thrombosis of the portal venous system (including the portal, mesenteric and splenic vein) and hepatic vein thrombosis (also called Budd-Chiari syndrome). They are rare manifestations of venous thromboembolism. These thromboses are frequently associated with local or systemic factors. The therapeutic approach is often complex due to heterogeneity of patients and limited available data in the literature. The cornerstone of treatment is anticoagulation. However, the bleeding risk, related to portal hypertension, should be accurately assessed to individualize the treatment. A multidisciplinary consultation team including several specialists is provided at the University Hospitals of Geneva for the optimal management of those patients.

Purpose: Fetal alcohol spectrum disorder (FASD) is a developmental disease characterized by behavioral problems and physical defects including malformations of the eye and associated optical defects. How these malformations affect retinal functioning is not well known, although animal models have suggested that scotopic vision is particularly deficient. Age is also known to affect scotopic vision. Here, we determined the combined effects of age and fetal alcohol exposure (FAE) on retinal function using full-field electroretinograms (ERGs) in monkeys (Chlorocebus sabaeus)., Methods: ERGs were recorded in monkeys aged 3- to 12-years old, at multiple flash intensities under scotopic and photopic conditions, and functions were fit to the amplitudes of the a- and b-waves., Results: We found that both age and alcohol exposure affected ERGs. In photopic ERGs, amplitudes increased with age, and were higher in FAEs than controls, for data related to the OFF- and ON-pathways. In scotopic ERGs, amplitudes were decreased in young FAE compared with age-matched controls but only for the rod-dominated responses, while at brighter flashes, alcohol exposure led to an increase in the amplitude of the a- and b-waves., Conclusions: The ERGs from the FAE animals closely resembled the data from the older sucrose-control monkeys. This suggests that the FAE monkey retina ages more quickly than the control monkeys. This large sample of nonhuman primates, with carefully monitored ethanol exposure, demonstrates the critical interplay between age and alcohol when assessing the integrity of the retina. We suggest that ERGs might be an important adjunct to diagnosing human FASD.

Background and Aims: Patients with refractory ascites (RA) require repeated large volume paracenteses (LVP), which involves frequent hospital visits and is associated with a poor quality-of-life. This study assessed safety and efficacy of an automated, low-flow pump (alfapump® [AP]) compared with LVP standard of care [SoC]., Methods: A randomized controlled trial, in seven centers, with six month patient observation was conducted. Primary outcome was time to first LVP. Secondary outcomes included paracentesis requirement, safety, health-related quality-of-life (HRQoL), and survival. Nutrition, hemodynamics, and renal injury biomarkers were assessed in a sub-study at three months., Results: Sixty patients were randomized and 58 were analyzed (27 AP, 31 SoC, mean age 61.9years, mean MELD 11.7). Eighteen patients were included in the sub-study. Compared with SoC, median time to first LVP was not reached after six months in the AP group, meaning a significant reduction in LVP requirement for the AP patients (AP, median not reached; SoC, 15.0days (HR 0.13; 95%CI 13.0-22.0; p<0.001), and AP patients also showed significantly improved Chronic Liver Disease Questionnaire (CLDQ) scores compared with SoC patients (p<0.05 between treatment arms). Improvements in nutritional parameters were observed for hand-grip strength (p=0.044) and body mass index (p<0.001) in the sub-study. Compared with SoC, more AP patients reported adverse events (AEs; 96.3% vs. 77.4%, p=0.057) and serious AEs (85.2 vs. 45.2%, p=0.002). AEs consisted predominantly of acute kidney injury in the immediate post-operative period, and re-intervention for pump related issues, and were treatable in most cases. Survival was similar in AP and SoC., Conclusions: The AP system is effective for reducing the need for paracentesis and improving quality of life in cirrhotic patients with RA. Although the frequency of SAEs (and by inference hospitalizations) was significantly higher in the AP group, they were generally limited and did not impact survival. Lay summary: The alfapump® moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, the alfapump reduces the need for large volume paracentesis (manual fluid removal by needle) in patients with medically untreatable ascites. This can improve life quality for these patients. www.clinicaltrials.gov#NCT01528410., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: The use of human albumin for the management of cirrhosis has increased. Recommendations have been published for therapeutic paracentesis (TP), spontaneous bacterial peritonitis (SBP), and type 1 hepatorenal syndrome (HRS). The goal of this survey was to assess the prescription practices of French hepatogastroenterologists., Methods: All hepatogastroenterologists were contacted. The questionnaire evaluated (1) the use of albumin in validated indications and (2) the prescription of albumin for nonvalidated clinical situations., Results: Responses were analyzed from 451 (50.1%) practitioners. The mean age was 40 years (range, 24 to 67 y). Physicians practiced in a university hospital (47.7%) or a general hospital (45.8%). There were 56.7% senior practitioners. Overall 99.6% of the practitioners compensated for TP. Albumin was used by 87.8% of the physicians, with a fixed dose being used by 84.6%. For SBP, 94% of the physicians used albumin concomitantly with antibiotics. The recommended protocol was followed by 56.2% of the practitioners: more often by senior university hospital practitioners than by senior general hospital practitioners (P=0.015). About 66.5% used albumin infusion for the diagnosis of HRS: used more often by senior university hospital practitioners (P=0.0006). Albumin was used concomitantly with vasopressor treatment by 84%; the dose and the duration varied considerably. About 23.5% used albumin for severe bacterial infection, 47.9% for severe hyponatremia, 43.9% for severe hypoalbuminemia, and 65.9% for hydrothorax., Conclusions: In this large French survey, albumin is only prescribed in accordance with recommendations for TP. The schedule for SBP is followed by only 56% of the practitioners. The use of albumin for HRS is not adapted to recommendations, which are not well known, suggesting that they should be more diffused.

Portal vein thrombosis is frequently encountered in patients with cirrhosis. Increased indication for non-invasive imaging in patients with cirrhosis has dramatically increased the recognition of PVT. This has led to a large amount of studies on pathogenesis as well as the prognostic impact of portal vein thrombosis on natural history of cirrhosis. However, in clinical practice, several aspects of the management of portal vein thrombosis remain unclear. This practical review discusses the most recent data toward the management of portal vein thrombosis in cirrhosis, especially regarding : a) the value of etiological workup ; b) the impact of portal vein thrombosis on the natural history of cirrhosis, and c) the indications and modalities of anticoagulation therapy., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Patients with severe alcoholic hepatitis (SAH) not responding to glucocorticoid therapy have higher mortality, though they do not differ in their baseline clinical characteristics and prognostic scores from those who respond to therapy. We hypothesized that the baseline hepatic gene expression differs between responders (R) and non-responders (NR). Baseline liver transcriptome was compared between R and NR in Indian (16 each) and French (5 NR, 3 R) patients with SAH. There were differentially expressed genes (DEGs) between NR and R, in Indian (1106 over-expressed, 96 under-expressed genes) and French patients (65 over-expressed, 142 under-expressed genes). Indian NR had features of hepatocyte senescence and French NR exhibited under-expression of genes involved in cell division, indicating a central defect in the capacity of hepatocytes for self-renewal in both populations. Markers of hepatic progenitor cell proliferation were either very few (Indian patients) or absent (French patients). No DEGs were enriched in inflammatory pathways and there were no differences in nuclear receptor subfamily 3 group C member 1 (NR3C1) transcript expression and splicing between NR and R. Our results reveal that baseline hepatic transcriptome is reflective of subsequent glucocorticoid non-response and indicate impaired regenerative potential of the liver as an underlying phenomenon in NR.

Objectives: We aimed to assess the performance of a new strip (Periscreen) for the rapid diagnosis of spontaneous bacterial peritonitis (SBP)., Methods: Ascitic fluid (AF) of cirrhotic patients hospitalized between March 2014 and August 2015 was independently tested by two readers using the new strip, which has four colorimetric graduations (negative, trace, small, and large). SBP was diagnosed on neutrophils in ascites>250/mm 3 . Ascites not related to portal hypertension were excluded., Results: Overall, 649 patients from 21 French centers were included and 1,402 AF (803 AF samples from 315 outpatients and 599 samples from 334 inpatients) were assessed. Eighty-four AF samples (17 AF in 9 outpatients and 67 AF in 31 inpatients) were diagnosed as SBP. The prevalence of SBP was 6% (2.1% in outpatients vs. 11.2% in inpatients; P<0.001) and 7.2% in patients with symptoms suggestive of SBP (3% in outpatients vs. 11.3% in inpatients; P<0.001). The κ value for inter-reader agreement was 0.81 (95% confidence interval: 0.77-0.84) when using the "trace" threshold. Considering discordant results (n=131) as positive to interpret the diagnostic performance of the strip at the "trace" threshold, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 91.7, 57.1, 12.0, and 99.1%, respectively. At this "trace" threshold, sensitivity and NPV were both 100% in outpatients, and 89.5 and 97.9% in inpatients, respectively. At the "small" threshold, sensitivity, specificity, PPV and NPV were 81.0, 85.9, 25.9 and 98.7%, respectively., Conclusions: The Periscreen strip is a rapid and highly efficient tool for excluding SBP in the outpatient setting.

Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver diseases. In patients with cirrhosis, diabetes can be either a classical type 2 diabetes mellitus or the so-called hepatogenous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contributing to peripheral insulin resistance through insulin receptors down-regulation. Moreover, cirrhosis is associated with increased levels of advanced-glycation-end products and hypoxia-inducible-factors, which may play a role in the development of diabetes. This review also focuses on the clinical implications of diabetes in patients with cirrhosis. First, diabetes is an independent factor for poor prognosis in patients with cirrhosis. Specifically, diabetes is associated with the occurrence of major complications of cirrhosis, including ascites and renal dysfunction, hepatic encephalopathy and bacterial infections. Diabetes is also associated with an increased risk of hepatocellular carcinoma in patients with chronic liver diseases. Last, the management of patients with concurrent diabetes and liver disease is also addressed. Recent findings suggest a beneficial impact of metformin in patients with chronic liver diseases. Insulin is often required in patients with advanced cirrhosis. However, the favourable impact of controlling diabetes in patients with cirrhosis has not been demonstrated yet., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Bleeding from gastric varices is more severe than that from esophageal varices, but its management remains debated. We aimed to determine how French hepatogastroenterologists manage cirrhotic patients with gastric varices., Methods: Hepatogastroenterologists (n=1163) working in general or university hospitals received a self-administered questionnaire., Results: Overall, 155 hepatogastroenterologists (13.3%) from 112 centers (33.3%; 39/40 university hospitals, 73/296 general hospitals) answered. Primary prophylaxis was used by 98.1% of hepatogastroenterologists as follows: β-blockers 96.1% (93.8 vs. 97.0%; university vs. general hospitals respectively; P=0.57), glue obliteration 16.9% (17.2 vs. 16.3%; P=0.88), and transjugular intrahepatic portosystemic shunt (TIPS) 8.0% (12.7 vs. 4.6%; P=0.12). To manage bleeding, university hospitals had greater local access to glue obliteration (95.4 vs. 68.2%; P<0.001) and TIPS (78.5 vs. 3.5%; P<0.001). Early TIPS was proposed by 53.6% (72.1 vs. 39.2%; P<0.001). Glue obliteration was performed under general anesthesia (86.1%) using Glubran (43.1%) or Histoacryl (52.9%), and lipiodol (78.8%) with varying degrees of dilution (1 : 10 to 3 : 4). The injected volume per varix varied widely (1-20 ml). Glue obliteration, band ligation, or both were used by, respectively, 64.2, 18.2, and 17.5% of practitioners. Almost all hepatogastroenterologists (98%) performed secondary prophylaxis: β-blockers 74.7% (75.0 vs. 74.4%, university vs. general hospitals; P=0.93), glue obliteration 66.0% (76.9 vs. 57.6%; P=0.013), and TIPS 30.0% (39.1 vs. 23.3%; P=0.037)., Conclusion: The management of gastric varices in France is heterogeneous across centers. University hospitals have better access to techniques such as glue obliteration and TIPS. As bleeding from gastric varices has a poor outcome, guidelines should be established to standardize clinical practices and design further studies.

The endocannabinoid (eCB) system is widely expressed in various parts of the central nervous system, including the retina. The localization of the key eCB receptors, particularly CB1R and CB2R, has been recently reported in rodent and primate retinas with striking interspecies differences. Little is known about the distribution of the enzymes involved in the synthesis and degradation of these eCBs. We therefore examined the expression and localization of the main components of the eCB system in the retina of mice, tree shrews, and monkeys. We found that CB1R and FAAH distributions are well-preserved among these species. However, expression of NAPE-PLD is circumscribed to the photoreceptor layer only in monkeys. In contrast, CB2R expression is variable across these species; in mice, CB2R is found in retinal neurons but not in glial cells; in tree shrews, CB2R is expressed in Müller cell processes of the outer retina and in retinal neurons of the inner retina; in monkeys, CB2R is restricted to Müller cells. Finally, the expression patterns of MAGL and DAGLα are differently expressed across species. Overall, these results provide evidence that the eCB system is differently expressed in the retina of these mammals and suggest a distinctive role of eCBs in visual processing.

The beneficial effects of the use of albumin, either alone or combines with other treat- ments, have been demonstrated in patients with various complications of cirrhosis. Therefore, albumin should be administred in patients with spontaneous bacterial peritonitis in association with antibiotics, and in association with terlipressin in patients with type 1 hepatorenal syndrome. Albumin use reduces the occurrence of paracentesis-related circulatory dysfunction, in patients with large ascites undergoing paracentesis. So far, the beneficial effect of albumin has not been demonstrated, neither for infections other than spontaneous bacterial peritonitis nor for hepatic encephalopathy. This article provides an overview of the data evaluating the effects of albumin in patients with cirrhosis.

Purpose: To prospectively compare the technical success rate and accuracy of shear-wave elastography (SWE) and transient elastography (TE) for the detection of clinically significant portal hypertension (PH) in patients with advanced cirrhosis who are undergoing hepatic vein pressure gradient (HVPG) measurements., Materials and Methods: The institutional ethics committee approved the study, and written informed consent was obtained. Seventy-nine consecutive patients with cirrhosis who were undergoing SWE and TE at the time of HVPG measurement were studied. The technical success rate of SWE and TE was compared with the diagnostic value of liver stiffness (LS) and spleen stiffness (SS) measurements and composite scores (LS spleen-diameter-to-platelet-ratio score [LSPS] and PH risk score) by using SWE and TE to detect clinically significant PH (HVPG ≥ 10 mm Hg) and esophageal varices at high risk of bleeding. Areas under the receiver operating characteristic curve and the DeLong test were used., Results: The technical success rate of SWE was significantly better than that of TE for both LS and SS (97% and 97% vs 44% and 42%, respectively; P < .001). LS of more than 24.6 kPa with SWE had a sensitivity, specificity, and accuracy for clinically significant PH of 81%, 88%, and 82%, respectively. Diagnostic performance of LS by using SWE was significantly better than that for SS for the diagnosis of clinically significant PH (area under the receiver operating characteristic curve of 0.87 vs 0.64, P = .003). LS, SS, LSPS, and PH risk score (according to SWE or TE) did not differ between patients with and those without high-risk esophageal varices (P = .09-.42)., Conclusion: In patients with advanced cirrhosis who are undergoing HVPG measurements, LS measurements obtained by using SWE have a higher technical success rate and a better diagnostic value than TE for clinically significant PH., ((©) RSNA, 2014)

Background & Aims: The most serious complication of acute mesenteric vein thrombosis (MVT) is acute intestinal ischaemia requiring intestinal resection or causing death. Risk factors for this complication are unknown. To identify risk factors for severe intestinal ischaemia leading to intestinal resection in patients with acute MVT., Methods: We retrospectively analysed consecutive patients seen between 2002 and 2012 with acute MVT in 2 specialized units. Patients with cirrhosis were excluded. We compared patients who required intestinal resection to patients who did not., Results: Among 57 patients, a local risk factor was identified in 14 (24%) patients, oral contraceptive use in 16 (29%), and at least one or more other systemic prothrombotic condition in 25 (44%). Five (9%) patients had diabetes mellitus (DM), 33 (58%) had overweight or obesity, 9 (18%) had hypertriglyceridemia and 10 (19%) had arterial hypertension. Eleven patients (19%) underwent intestinal resection. DM was significantly associated with intestinal resection (P = 0.02) while local factors or prothrombotic conditions were not. Computed tomography (CT) scans performed at diagnosis found that occlusion of second order radicles of the superior mesenteric vein was more frequently observed in patients who underwent intestinal resection (P = 0.009)., Conclusions: In acute MVT, patients with underlying DM have an increased risk of requiring intestinal resection. Neither local factors nor systemic prothrombotic conditions are associated with intestinal resection. When CT scan shows the preservation of second order radicles of the superior mesenteric vein, the risk of severe resection is low., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Unlabelled: In patients with chronic hepatitis C (CHC), cirrhosis is associated with age, gender, diabetes, alcohol abuse, and coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV). The effect of these factors on the outcome of cirrhosis is unknown. This study in CHC patients with cirrhosis aimed to assess the influence of these factors on decompensation, liver transplantation, and death. Consecutive patients with CHC and cirrhosis hospitalized between January 1, 2006 and December 31, 2008 were followed up until death, transplantation, or study closure in March 2013. Gender, age, Model for End-Stage Liver Disease (MELD) score, diabetes, alcohol abuse, HIV, or HBV coinfection were collected at inclusion. The complications of cirrhosis, death, and liver transplantation were recorded at inclusion and during follow-up. The association between baseline factors and liver-related outcomes at inclusion and during follow-up were tested using logistic regression and Cox's model, respectively. A total of 348 patients with CHC and cirrhosis (68% men; median age: 59 years; median MELD: 10) were included. At baseline, 40% of the patients had diabetes, 29% alcohol abuse, and 6% HIV or HBV coinfection. Baseline MELD≥10 (P<0.001), diabetes (P=0.027), and HBV coinfection (P=0.001) were independently associated with transplantation-free survival. Baseline diabetes was independently associated with ascites (P=0.05), bacterial infections (P=0.001), and encephalopathy (P<0.001) at inclusion. Baseline diabetes was independently associated with development of ascites (P=0.057), renal dysfunction (P=0.004), bacterial infections (P=0.007), and hepatocellular carcinoma (P=0.016) during the follow-up., Conclusion: In patients with CHC and cirrhosis, diabetes is an independent prognostic factor. Improving diabetes control may improve the outcome of cirrhosis., (© 2014 by the American Association for the Study of Liver Diseases.)

Objective: To assess the value of the liver and spleen viscoelastic parameters at multifrequency MR elastography to determine the degree of portal hypertension and presence of high-risk oesophageal varices in patients with cirrhosis., Methods: From January to September 2012, 36 consecutive patients with cirrhosis evaluated for transplantation were prospectively included. All patients underwent hepatic venous pressure gradient (HVPG) measurements and endoscopy to assess oesophageal varices. Multifrequency MR elastography was performed within the liver and spleen. The shear, storage and loss moduli were calculated and compared to the HVPG with Spearman coefficients and multiple regressions. Patients with and without severe portal hypertension and high-risk varices were compared with Mann-Whitney tests, logistic regression and ROC analysis., Results: The liver storage and loss moduli and the spleen shear, storage and loss moduli correlated with the HVPG. At multiple regression, only the liver and the spleen loss modulus correlated with the HVPG (r = 0.44, p = 0.017, and r = 0.57, p = 0.002, respectively). The spleen loss modulus was the best parameter for identifying patients with severe portal hypertension (p = 0.019, AUROC = 0.81) or high-risk varices (p = 0.042, AUROC = 0.93)., Conclusions: The spleen loss modulus appears to be the best parameter for identifying patients with severe portal hypertension or high-risk varices., Key Points: 1. Noninvasive HVPG assessment can be performed with liver and spleen MR elastography 2. The spleen loss modulus enables the detection of high-risk oesophageal varices 3. The spleen loss modulus enables the detection of severe portal hypertension.

Background & Aims: Lipopolysaccharide (LPS)-expressing bacteria cause severe inflammation in cirrhotic patients. The global gene response to LPS is unknown in cirrhotic immune cells., Methods: Gene-expression profiling using Affymetrix Human Exon Array analyzed the expression of 14,851 genes in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from 4 patients with cirrhosis and 4 healthy subjects. We performed validation studies using RT-qPCR in LPS-stimulated PBMCs from 52 patients and 9 healthy subjects and investigated the association of gene induction with mortality in 26 patients., Results: Gene-expression profiling of LPS-stimulated cirrhotic cells showed 509 upregulated genes and 1588 downregulated genes. In LPS-stimulated "healthy" cells, 952 genes were upregulated and 838 genes downregulated. The 741 LPS-regulated genes shared by cirrhotic and "healthy" cells were involved in cytokine production/activity and induction of "immune paralysis". Comparison of functions associated with the 1356 genes, specifically regulated by LPS in cirrhotic cells, to functions of the 1049 genes, specifically regulated in "healthy" cells, allowed to define a cirrhosis-specific phenotype. Unlike in "healthy" cells, LPS failed to induce an interferon-mediated program in cirrhotic cells. In cirrhotic PBMCs, LPS specifically induced certain molecules involved in apoptosis and downregulated molecules involved in endocytic trafficking. RT-qPCR experiments showed that LPS-stimulated cirrhotic PBMCs had an enhanced induction of certain proinflammatory cytokines and chemokines. In the prognosis study, higher ex vivo LPS-induction of the inflammatory genes IL6 and CXCL5 was a significant predictor of mortality., Conclusions: Our results show that LPS-stimulated cirrhotic PBMCs exhibit an extensive and often unexpected transcriptional response., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Guidelines recommend antibiotic prophylaxis (AP) in well-selected groups of cirrhotic patients, but the impact of these recommendations has not been assessed in France., Aim: To evaluate AP prescription tendencies for gastrointestinal bleeding, and primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP)., Methods: Practitioners (n = 1,159) working in general hospitals (GH) or in university hospitals (UH) received a self-administered questionnaire., Results: Three hundred and eighty-nine (33.6%; GH 35% and UH 30.4%) practitioners responded. AP was prescribed by 97.7%, 72.3% and 94.8% of practitioners, without significant differences between UH and GH, respectively, for gastrointestinal bleeding (quinolones 48.2%, third-generation cephalosporins 27.7% and amoxicillin-clavulanic acid 22.2%), primary (quinolones 97.2%) and secondary prophylaxis of SBP (quinolones 99%). For gastrointestinal bleeding, ofloxacin (47.6%) and norfloxacin (37.4%) were the main quinolones prescribed, and ceftriaxone (77%) was the main third-generation cephalosporin prescribed. The principal reasons for prescribing AP were a decrease in bacterial infection (88.9% for gastrointestinal bleeding, 91.3% for primary and 94.3% for secondary prophylaxis of SBP), a recommendation by a consensus conference (83%, 38% and 74.4% respectively) and an improvement in survival (72.8%, 41.3% and 57.7% respectively). Only 31.7% of practitioners (39.6% for UH vs. 28.6% for GH; P = 0.038) believed that AP may reduce the risk of bleeding recurrence. Reported side effects (28%) of AP mainly concerned the risk of quinolone resistance (62% of cases)., Conclusion: Antibiotic prophylaxis is well-recognized by French practitioners, but its routine use depends on the expertise of practitioners. Quinolones remain the main antibiotic class prescribed irrespective of the type of prophylaxis., (© 2012 John Wiley & Sons A/S.)

Unlabelled: Cirrhosis is commonly accompanied by impaired defense functions of polymorphonuclear leucocytes (PMNs), increased patient susceptibility to infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity is dependent on a massive production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), termed respiratory burst (RB). Rapamycin, an antagonist of mammalian target of rapamycin (mTOR), may be used in the treatment of HCC and in transplanted patients. However, the effect of mTOR inhibition on the PMN RB of patients with cirrhosis remains unexplored and was studied here using the bacterial peptide, formyl-Met-Leu-Phe (fMLP), as an RB inducer. fMLP-induced RB of PMN from patients with decompensated alcoholic cirrhosis was strongly impaired (30%-35% of control) as a result of intracellular signaling alterations. Blocking mTOR activation (phospho-S2448-mTOR) with rapamycin further aggravated the RB defect. Rapamycin also inhibited the RB of healthy PMNs, which was associated with impaired phosphorylation of the NOX2 component, p47phox (phox: phagocyte oxidase), on its mitogen-activated protein kinase (MAPK) site (S345) as well as a preferential inhibition of p38-MAPK relative to p44/42-MAPK. However, rapamycin did not alter the fMLP-induced membrane association of p47phox and p38-MAPK in patients' PMNs, but did prevent their phosphorylation at the membranes. The mTOR contribution to fMLP-induced RB, phosphorylation of p47phox and p38-MAPK was further confirmed by mTOR knockdown in HL-60 cells. Finally, rapamycin impaired PMN bactericidal activity, but not bacterial uptake., Conclusion: mTOR significantly up-regulates the PMN RB of patients with cirrhosis by p38-MAPK activation. Consequently, mTOR inhibition by rapamycin dramatically aggravates their PMN RB defect, which may increase patients' susceptibility to infection. Thus, concerns should be raised about the use of rapamycin in immuno-depressed patients., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background & Aims: Circulating membrane-shed microparticles (MPs) participate in regulation of vascular tone. We investigated the cellular origins of MPs in plasma from patients with cirrhosis and assessed the contribution of MPs to arterial vasodilation, a mechanism that contributes to portal hypertension., Methods: We analyzed MPs from blood samples of 91 patients with cirrhosis and 30 healthy individuals (controls) using flow cytometry; their effects on the vascular response to vasoconstrictors were examined in vitro and in vivo., Results: Circulating levels of leuko-endothelial (CD31(+)/41(-)), pan-leukocyte (CD11a(+)), lymphocyte (CD4(+)), and erythrocyte (CD235a(+)) MPs were higher in patients with cirrhosis than in controls. Plasma of patients with cirrhosis contained hepatocyte-derived MPs (cytokeratin-18(+)), whereas plasma from controls did not. The severity of cirrhosis and systemic inflammation were major determinants of the levels of leuko-endothelial and hepatocyte MPs. MPs from patients with advanced cirrhosis significantly impaired contraction of vessels in response to phenylephrine, whereas MPs from healthy controls or from patients of Child-Pugh class A did not. This effect depended on cyclooxygenase type 1 and required phosphatidylserine on the surface of MPs. Intravenous injection of MPs from patients with cirrhosis into BALB/C mice decreased mean arterial blood pressure., Conclusions: Cirrhosis is associated with increases in circulating subpopulations of MPs, likely resulting from systemic inflammation and liver cell damage. The overall pool of circulating MPs from patients with advanced cirrhosis impairs vasoconstrictor responses and decreases blood pressure, contributing to the arterial vasodilation associated with portal hypertension., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with generally 4 and 11 N-linked glycans on E1 and E2, respectively. Studies using mutated recombinant HCV envelope glycoproteins incorporated into retroviral pseudoparticles (HCVpp) suggest that some glycans play a role in protein folding, virus entry, and protection against neutralization. The development of a cell culture system producing infectious particles (HCVcc) in hepatoma cells provides an opportunity to characterize the role of these glycans in the context of authentic infectious virions. Here, we used HCVcc in which point mutations were engineered at N-linked glycosylation sites to determine the role of these glycans in the functions of HCV envelope proteins. The mutants were characterized for their effects on virus replication and envelope protein expression as well as on viral particle secretion, infectivity, and sensitivity to neutralizing antibodies. Our results indicate that several glycans play an important role in HCVcc assembly and/or infectivity. Furthermore, our data demonstrate that at least five glycans on E2 (denoted E2N1, E2N2, E2N4, E2N6, and E2N11) strongly reduce the sensitivity of HCVcc to antibody neutralization, with four of them surrounding the CD81 binding site. Altogether, these data indicate that the glycans associated with HCV envelope glycoproteins play roles at different steps of the viral life cycle. They also highlight differences in the effects of glycosylation mutations between the HCVpp and HCVcc systems. Furthermore, these carbohydrates form a "glycan shield" at the surface of the virion, which contributes to the evasion of HCV from the humoral immune response.

Background: Assessing liver fibrosis is traditionally performed by biopsy, an imperfect gold standard. Non-invasive techniques, liver stiffness measurements (LSM) and biomarkers [FibroTest(R) (FT)], are widely used in countries where they are available. The aim was to identify factors associated with LSM accuracy using FT as a non-invasive endpoint and vice versa., Methods: The proof of concept was taken using the manufacturers recommendations for excluding patients at high risk of false negative/positive. The hypothesis was that the concordance between LSM and FT, would be improved by excluding high-risk patients. Thereafter, the impact of potential variability factors was assessed by the same methods. Liver biopsy and independent endpoints were used to validate the results., Results: Applying manufacturers' recommendations in 2,004 patients increased the strength of concordance between LSM and FT (P<0.00001). Among the 1,338 patients satisfying recommendations, the methodology identified a significant LSM operator effect (P = 0.001) and the following variability factors (all P<0.01), related to LSM: male gender, older age, and NAFLD as a cause of liver disease. Biopsy confirmed in 391 patients these results., Conclusion: This study has validated the concept of using the strength of concordance between non-invasive estimates of liver fibrosis for the identification of factors associated with variability and precautions of use.