The aim of this study was to assess the efficacy of end-ischemic hypothermic oxygenated perfusion (HOPE) used before liver transplantation (LT) with extended criteria donor (ECD) organs from donation after brain death (DBD) in reducing early allograft dysfunction (EAD) compared with static cold storage (SCS). Between 2019 and 2023, 262 ECD-DBD grafts from 8 French centers were randomly assigned for LT either after SCS (control group, n = 131) or after SCS and subsequent 1-4 h single portal HOPE before implantation (HOPE group, n = 131). The primary endpoint was the incidence of EAD. HOPE resulted in a significantly lower rate of EAD (17.6% vs 30.5%, P = .01). Severe complication rate (61.5% vs 52.4%, P = .15), comprehensive complication index (49 [34-65] vs 46 [35-65], P = .78), and 90-day mortality (5.3% vs 2.3%, P = .20) did not differ significantly between the control and HOPE groups, respectively. Four patients (4.9%) in the control group and 3 patients (3.3%) in the HOPE group experienced ischemic cholangiopathy at 1 year after LT (P = .71). In older patients receiving grafts with more than 6 hours of cold ischemia, HOPE was associated with a lower severe complication rate (26% vs72%, P = .005). HOPE in ECD grafts from DBD for LT reduces EAD with little clinical impact on morbidity and survival in recipients with low model for end-stage liver disease scores. Older recipients with long cold ischemia time might benefit the most. Clinical trial number: NCT03929523.

Background Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia–reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury. Methods HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage. Discussion We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing. Trial registration ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.

Abstract Background Drug consumption rooms (DCRs) have been developed in cities with open drug scenes, with the aim to reduce drug-related harm. In Lyon, France's second-largest city, there is no distinct drug use area, which raised doubts regarding the need for a DCR. Methods We conducted a face-to-face survey of 264 people who use drugs (PWUDs), recruited in harm reduction or addiction treatment centers, in the streets or in squats. We assess their willingness to use a DCR, and we collected sociodemographic and medical features. Bivariable comparisons and analyses adjusted for sociodemographic parameters explored the association between willing to use a DCR and other variables, thus providing crude (ORs) and adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Results In total, 193 (73.1%) PWUDs accepted to participate (mean age 38.5 ± 9.3 years; 80.3% men). Among them, 64.2% declared willing to use a DCR. Being treatment-seeker (aOR 0.20, 95% CI [0.08–0.51]; p < 0.001) and not living alone (aOR 0.29; 95% CI [0.10–0.86], p = 0.025) were negatively associated with willing to use a DCR. By contrast, receiving precarity social insurance (aOR 4.12; 95% CI [1.86–9.14], p < 0.001), being seropositive for hepatitis C (aOR 3.60; 95% CI [1.20–10.84], p = 0.022), being cannabis user (aOR 2.45; 95% CI [1.01–5.99], p = 0.049), and reporting previous problems with residents (aOR 5.99; 95% CI [2.16–16.58], p < 0.001) or with the police (aOR = 4.85; 95% CI [1.43–16.39], p = 0.011) were positively associated. Conclusions PWUDs, especially the most precarious ones, largely supported the opening of a DCR in Lyon, a city with no open drug scene.

There is a growing interest in the potentially deleterious impact of antibiotics on gut microbiota. Patients with bone and joint infection (BJI) require prolonged treatment that may impact significantly the gut microbiota. We collected samples from patients with BJI at baseline, end of antibiotics (EOT), and 2 weeks after antibiotic withdrawal (follow-up, FU) in a multicenter prospective cohort in France. Microbiota composition was determined by shotgun metagenomic sequencing. Fecal markers of gut permeability and inflammation as well as multi-drug-resistant bacteria (MDRB) and Clostridioides difficile carriage were assessed at each time point. Sixty-two patients were enrolled: 27 native BJI, 14 osteosynthesis-related BJI, and 21 prosthetic joint infections (PJI). At EOT, there was a significant loss of alpha-diversity that recovered at FU in patients with native BJI and PJI, but not in patients with osteosynthesis-related BJI. At EOT, we observed an increase of Proteobacteria and Bacteroidetes that partially recovered at FU. The principal component analysis (PCoA) of the Bray–Curtis distance showed a significant change of the gut microbiota at the end of treatment compared to baseline that only partially recover at FU. Microbiota composition at FU does not differ significantly at the genus level when comparing patients treated for 6 weeks vs. those treated for 12 weeks. The use of fluoroquinolones was not associated with a lower Shannon index at the end of treatment; however, the PCoA of the Bray–Curtis distance showed a significant change at EOT, compared to baseline, that fully recovered at FU. Levels of fecal neopterin were negatively correlated with the Shannon index along with the follow-up (r2 = 0.17; p < 0.0001). The PCoA analysis of the Bray–Curtis distance shows that patients with an elevated plasma level of C-reactive protein (≥5 mg/L) at EOT had a distinct gut microbial composition compared to others. MDRB and C. difficile acquisition at EOT and FU represented 20% (7/35) and 37.1% (13/35) of all MDRB/C. difficile-free patients at the beginning of the study, respectively. In patients with BJI, antibiotics altered the gut microbiota diversity and composition with only partial recovery, mucosal inflammation, and permeability and acquisition of MDRB carriage. Microbiome interventions should be explored in patients with BJI to address these issues.

in order to keep airways open, a PEEP of 7 cmH2O was appropriate in patients with healthy lungs and a normal BMI. However, this hypothesis remains unclear in patients undergoing robotic gynaecologic surgery. All points considered, a PEEP of 8 cmH2O, applied to a low tidal volume ventilation strategy in robotic gynaecologic surgical patients, is thought to have no benefit compared with 4 cmH2O with respect to intrapulmonary shunt.

BACKGROUND:The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.AIM:To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients.METHODS:A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.RESULTS:Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.CONCLUSION:The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

Abstract Background The widespread under-screening and under-treatment of alcohol use disorder (AUD) contributes to its health and socioeconomic burden. We conducted a mixed-methods (qualitative and qualitative) study in people with alcohol use disorder (PWAUD) to explore their expectations, as well as barriers and levers to AUD care. Methods Individuals with AUDIT > 15 (N = 179) were interviewed using computer-assisted interviews in several medical and non-medical sites (e.g., bars) (quantitative substudy). We also conducted semi-structured face-to-face interviews with 36 PWAUD (qualitative substudy). Using logistic regression, we explored factors associated with having previously received/sought care for AUD. Three major themes were identified in the qualitative textual analysis using a descending hierarchical classification. Results Not socializing with heavy drinkers (AOR [95%CI]:3.84[1.66–8.85]), regular smoking (9.72[3.91–24.15]) and feeling discriminated against (2.35[1.10–5.05]) were independent levers to having sought/received care for AUD, while being aged < 50 and employment were independent barriers. The five predominant themes in PWAUD discourses emerging from the textual analysis were: drinking context, medical care, alcohol treatment, tobacco/addiction and family. When triangulating results from the logistic regression and the textual analysis, two barriers (social drinking and difficulties with the medical care system), and two levers (family influence and tobacco addiction), emerged. Conclusion These results underline the need for interventions targeting families and the social network to increase awareness about AUD and related care. Simplified and novel comprehensive care trajectories are urgently needed to reduce the clinical and public health burden of AUD.

Abstract Background There is growing interest about the deleterious impact of antibiotics on loss of gut symbiosis, called dysbiosis. As patients with BJI require antibiotics usually during 6 to 12 weeks, it is of interest to determine whether dysbiosis is frequent in this population, and if it could potentially reversible or not. Methods Multicentric prospective cohort study in France (EudraCT 2016-003247-10) including patients with 3 categories of BJI: native, osteosynthesis-related and prosthetic joint infection (PJI). At the time of suspicion (V1), at the end of therapy (V2) and then 2 weeks after stopping therapy (V3), blood and fecal samples were collected. Extracted DNA from stool was sequenced using shotgun metagenomic sequencing based on illumina library and Iseq instrumentation. Data run through a dedicated pipeline in order to produce microbiome indexes such as Sympson or Shannon diversities indexes. Gut microbiome and inflammation markers were analyzed including fecal neopterin, a maker of gut inflammation. Results Concerning the 62 patients included (mean age, 60 years; mean duration of antibiotics, 66 days), 27 had native, 14 had osteosynthesis and 21 had PJI. The most frequently prescribed drug was a fluoroquinolone, followed by a third-generation cephalosporin and vancomycin. Stools from 42 of them were analyzed as per protocol. Overall, the mean Shannon richness index decreased from 0.904 at V1 to 0.845 at V2; the Bray-Curtis index underlined the difference in microbiome reconstitution at V3 in comparison with V1. We report significant microbiome loss of diversity at V2, that was reversible at V3 in patients with native BJI and osteosynthesis-related BJI, but not in patients with PJI (figure). Fecal neopterin increased between V1 and V2 (mean 221.6 and 698.1 pmol/g of feces, respectively) and then decreased at V3 (422.5 pmol/g), and could be a potential surrogate marker of gut dysbiosis. Of note, patients with abnormal CRP at the end of antibiotics had high neopterin values, that raises the hypothesis that abnormal CRP at the end of antibiotics could be in relation with gut dysbiosis rather than uncured BJI. Conclusion The impact of antibiotics on the gut microbiota of patients with BJI seems to be significant, especially in patients with PJI who could be candidate for fecal microbiota transplantation. Disclosures All authors: No reported disclosures.

Background Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. Methods We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. Findings Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33.4 months (IQR 24.0-40.7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2.77, 95% CI 2.07-3.71) and decompensated cirrhosis (3.83, 2.29-6.42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0.48, 95% CI 0.33-0.70) and hepatocellular carcinoma (0.66, 0.46-0.93), and was not associated with decompensated cirrhosis (1.14, 0.57-2.27). Interpretation Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

BACKGROUND:The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study. METHODS:HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates. RESULTS:1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4-49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2-6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p<0.0001), history of HCV treatment (aHR = 0.53 [0.32; 0.90], p = 0.01) and smoking (past (aHR = 5.69 [1.56; 20.78]) and current (3.22 [0.93; 11.09]) versus never, p = 0.01) were associated with all-cause mortality independently of SVR, age, sex, alcohol use and metabolic disorders. CONCLUSION:Any LSM >12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.

Background: Hepatitis C virus (HCV) and HIV infections are associated with higher risk of autoimmune diseases and T-cell dysfunction. Setting: We evaluate prevalence and factors associated with the presence of autoimmune antinuclear (ANA), anti-smooth muscle actin (aSMA), and anti-liver kidney microsome (aLKM1) antibodies (Ab) in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era. Methods: A cross-sectional observational study nested in the ANRS CO13 HEPAVIH cohort (NCT number: NCT03324633). We selected patients with both ANA testing and T-cell immunophenotyping determination during the cohort follow-up and collected aLKM1 and aSMA data when available. Logistic regression models were built to determine factors associated with the presence of autoAb. Results: Two hundred twenty-three HCV/HIV-coinfected patients fulfilled selection criteria. Prevalence of ANA and aSMA was 43.5% and 23.2%, respectively, and both were detected in 13.3% of patients. Isolated aSMA were detected in 9.9% and aLKM1 in 2 patients. In multivariable analysis, only a low nadir CD4 T-cell count was significantly associated with ANA detection. Conclusions: ANA and aSMA detection remain frequent in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era, despite fair immune restoration. These results advocate for a close monitoring of ANA before immune checkpoint inhibitor therapy in these patients with greater caution for those with a low nadir CD4 T-cell count.

Objectives Although common among patients coinfected with HIV and hepatitis C virus (HCV), sleep disturbances (SD) are still poorly documented in this population in the HCV cure era. This longitudinal study aimed at analysing SD in HIV-HCV coinfected patients and identifying their clinical and sociobehavioural correlates. Methods We used 5-year annual follow-up data from 1047 participants in the French National Agency for Research on Aids and Viral Hepatitis Cohort 13 'Hepatite et VIH' (ANRS C013 HEPAVIH) cohort of HIV-HCV coinfected patients to identify clinical (medical records) and behavioural (self-administered questionnaires) correlates of SD (mixed-effects logistic regression). SD were identified using one item documenting the occurrence of insomnia or difficulty falling asleep (ANRS 'Action Coordonnee 24' self-reported symptoms checklist), and two items documenting perceived sleep quality (Center for Epidemiologic Studies Depression and WHO Quality of Life HIV-specific brief scales). Results Seven hundred and sixteen (68.4%) patients with completed self-administered questionnaires reported SD at their most recent follow-up visit. In the multivariable model, hazardous alcohol consumption (Alcohol Use Disorders Identification Test-Consumption score 4 for men, 3 for women) (adjusted odds ratio =1.61; 95% confidence interval: 1.09-2.36), depressive symptoms (6.78; 4.36-10.55) and the number of other physical and psychological self-reported symptoms (1.10; 1.07-1.13) were associated independently with SD after adjustment for sex, age and employment status. HCV cure was not associated significantly with SD. Conclusion SD remain frequent in HIV-HCV coinfected patients and are associated with a series of modifiable behavioural risk factors. independent of HCV cure, improved screening and comprehensive management of alcohol use, physical and psychological self-reported symptoms and depression are essential in this population. Closer investigation of these risk factors of SDs may both increase sleep quality and indirectly improve patients' clinical outcomes. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.

Proton beam radiotherapy is used for the treatment of ocular diseases such as retinoblastoma and uveal melanoma, but despite its precision, patients can still experience radiation retinopathy. The retinopathic effects of radiation include endothelial cell injury, retinal ischemia, neovascularization, microaneurysms, and retinal detachment. We hypothesize that irradiation of retinal endothelial cells results in chronic inflammation of the endothelium and mitochondrial dysfunction leading to endothelial cell dysfunction and that administration of AP39, a mitochondrial-targeted hydrogen sulfide (H2S) donor will protect against IR-induced endothelial injury. Mouse retinal endothelial cells (mRECs) were irradiated with either protons (72.7 MeV to 131.1 MeV) using the ProteusONETM pencil beam system or photons (6 MV). AP39 was administered 45 minutes prior to IR and was present during irradiation. AP39 was removed 30-60 minutes after irradiation. The clonogenic assay was used to assess cell survival following irradiation +/- AP39 treatment. Mitochondrial damage and function was measured using mitochondrial copy number, mtDNA common deletion, and Seahorse XF24. RT-PCR and Western analysis were used to determine changes in RNA and protein levels. The relative biological effectiveness (RBE) of the ProteusONETM pencil proton beam was 1.1 compared to photons in mRECs. Intercellular adhesion molecule-1 (ICAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) RNA levels increased 72 hr after 10 Gy photon. There was also a 50% reduction in 3-mercaptopyruvate sulfurtransferase (3-MST) RNA, a predominantly mitochondrial H2S synthesis enzyme. There was no observed effect on mitochondrial DNA copy number or mtDNA deletion at 72 hr post-IR. However, there was a significant decrease in mitochondrial respiration and a corresponding increase in glycolysis following 10 Gy photons or protons that was rescued by AP39. AP39 also increased acetylation of mitochondrial proteins with no effect on SIRT3, the major mitochondrial deacetylase. Endothelial cells are critical for the establishment of barrier function in the eye and mitochondrial dysfunction could lead to barrier disruption and gradual development of radiation retinopathy following radiotherapy. We show that IR increases expression of adhesion molecules and decreases 3-MST, a major H2S synthesis enzyme in the mitochondria. In addition, mitochondrial function was markedly disrupted by 72 hours post-IR, but its rescue by AP39 suggests a novel role for H2S as a mitochondrial and endothelial radio-protectant following IR. Future studies will focus on identifying how AP39 and other mitochondria-targeted H2S delivery molecules restore mitochondrial function in irradiated retinal endothelial cells.

Introduction: Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naive or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy. Material and methods: We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon- free treatment with DAA +/- RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients. Results: A significant association was observed between presence of anti-E1E2 and HCV viral load < 61og10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level. Conclusions: The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (< 6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure. (C) 2018 Elsevier Masson SAS. All rights reserved.