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Hospital-acquired infections (HAI) are common in cirrhosis with antibiotics frequently used to prevent infections, but their efficacy for this role is unknown. To investigate this, we used Albumin to Prevent Infection in Chronic Liver Failure (ATTIRE) data to evaluate whether antibiotic use in patients without infection prevented HAI.In ATTIRE patients without infection at baseline grouped by antibiotic prescription or not, we studied HAI during trial treatment period and mortality, with propensity score matching to account for differences in disease severity.Two hundred three of 408 patients prescribed antibiotics at enrollment did not have infection and they were more unwell than noninfected patients not given antibiotics. There were no differences in subsequent HAI comparing antibiotic treated (39/203, 19.2%) to nonantibiotic treated (73/360, 20.3%; P = 0.83). Twenty-eight-day mortality was higher in antibiotic-treated patients ( P = 0.004) likely reflecting increased disease severity. Matching groups using propensity scoring revealed no differences in HAI or mortality. In noninfected patients at enrollment treated with/without rifaximin, there were no differences in HAI ( P = 0.16) or mortality, confirmed with propensity matching. Patients given long-term antibiotic prophylaxis at discharge had no differences in 6-month mortality compared with nonantibiotic patients, although antibiotic-treated patients had more infections at trial entry, with numbers too small for matching.Half of antibiotics at study entry were given to patients without an infection diagnosis which did not reduce the overall risk of HAI or improve mortality. This supports prompt de-escalation or discontinuation of antibiotics guided by culture sensitivities at 24-48 hours after commencement if no infection and the patient is improving.

Albumin is recommended in decompensated cirrhosis, and studies have shown potential immunomodulatory effects. However, 2 large trials of repeated albumin infusions demonstrated contrasting results between outpatients and hospitalized patients. We investigated markers of systemic inflammation, immune function, albumin binding, and cardiovascular function using samples from Albumin To prevenT Infection in chronic liveR failurE (ATTIRE) taken at baseline, day 5, and day 10 of the trial to identify why targeted albumin infusions had no effect in hospitalized patients.Plasma samples were analyzed from 143 patients (n = 71 targeted albumin; n = 72 standard care at baseline) for cytokines, cardiovascular markers, prostaglandin E2, the effect of plasma on macrophage function, and albumin radioligand binding and oxidation status. The sample size was based on our feasibility study, and samples were selected by a trial statistician stratified by the serum albumin level and the presence of infection at randomization and analyses performed blinded to the study arm. Data were linked to 3-month mortality and treatment groups compared.Increased baseline model for end-stage liver disease score, white cell count, calprotectin, CD163, tumor necrosis factor, renin, atrial natriuretic peptide, and syndecan-1 were associated with 3-month mortality. Despite infusing substantially differing volumes of albumin, there were no significant differences in inflammatory markers, albumin-prostaglandin E2 binding, or cardiovascular markers between treatment arms.Contrary to many preclinical studies, targeted intravenous albumin therapy in hospitalized decompensated cirrhosis had no effect across a broad range of systemic inflammation, albumin function, and cardiovascular mediators and biomarkers compared with standard care, consistent with the null clinical findings.

INTRODUCTION Patients with decompensated cirrhosis and hyponatremia have a poor prognosis. We investigated Albumin to Prevent Infection in Chronic Liver Failure trial data to determine whether targeted albumin infusions improved outcome in patients with hyponatremia at baseline. METHODS We examined the interaction between targeted albumin and standard care for the composite primary end point, stratifying by baseline sodium ≥ and

Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.We conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment.A total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group.In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.).

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE)’ system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years’ time.

Background & Aims Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction. Methods Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production. Results We show that hepatic production of PGE2 via the cyclo-oxygenase 1–microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)–DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor. Conclusions PGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission. Lay summary Patients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation., Graphical abstract, Highlights • We demonstrate that monocyte dysfunction in patients with decompensated cirrhosis and refractory ascites is mediated by PGE2 through its EP4 receptor. • Monocyte HLA-DR expression was also reduced in both cohorts of patients with decompensated cirrhosis, at least in part, by elevated circulating PGE2. • Up to 55% of patients with ACLF have an infective precipitant. • Improving monocyte function in patients with pre-hospital cirrhosis and ascites could prevent development of ACLF. • PGE2-EP4 receptor antagonists might represent a treatment to improve monocyte dysfunction in outpatients with ascites.

BackgroundImprovements in the structure of endoscopy training programmes resulting in certification from the Joint Advisory Group in Gastrointestinal Endoscopy have been acknowledged to improve training experience and contribute to enhanced colonoscopy performance.ObjectivesThe 2016 British Society of Gastroenterology trainees’ survey of endoscopy training explored the delivery of endoscopy training - access to lists; level of supervision and trainee’s progression through diagnostic, core therapy and subspecialty training. In addition, the barriers to endoscopy training progress and utility of training tools were examined.MethodsA web-based survey (Survey Monkey) was sent to all higher specialty gastroenterology trainees.ResultsThere were some improvements in relation to earlier surveys; 85% of trainees were satisfied with the level of supervision of their training. But there were ongoing problems; 12.5% of trainees had no access to a regular training list, and 53% of final year trainees had yet to achieve full certification in colonoscopy. 9% of final year trainees did not feel confident in endoscopic management of upper GI bleeds.ConclusionsThe survey findings provide a challenge to those agencies tasked with supporting endoscopy training in the UK. Acknowledging the findings of the survey, the paper provides a strategic response with reference to increased service pressures, reduced overall training time in specialty training programmes and the requirement to support general medical and surgical on-call commitments. It describes the steps required to improve training on the ground: delivering additional training tools and learning resources, and introducing certification standards for therapeutic modalities in parallel with goals for improving the quality of endoscopy in the UK.

Background and study aims A universal European training program in gastroenterology and hepatology is currently not available. The European Board of Gastroenterology and Hepatology (EBGH) has produced guidance regarding expected competencies for European gastroenterology trainees but it is unclear whether these have been incorporated in national curricula. The aim of this study was to provide an in-depth assessment of training and research opportunities, professional activities and of socioeconomic aspects of gastroenterology training across Europe through a web-based 90-point questionnaire. Materials and methods Physicians in their last year or who had recently finished their training, from 16 European countries, were invited to answer the questionnaire. Results A total of 144 physicians answered the survey. A minimum number of procedures is required before completing training in nine of 16 countries (56 %). Overall, European trainees dedicate a median of 12 months (IQR 6–25) of their training period to endoscopy and a median of 3 months (IQR 0–6) to ultrasound. Training in interventional endoscopy was not always exhaustive, as about 50 % of participants performed fewer of several interventional procedures than was recommended by EBGH, most participants did not perform endoscopic hemostasis or endoscopic mucosal resection, and nearly a half of participants had no access to pancreatobiliary endoscopy training. Finally, up to 13 % of residents complete their training without the supervision of a mentor. Conclusion In this large European survey, deep gaps and considerable differences in several gastroenterology training activities were found both among and within 16 European countries. Homogenization of educational programs and training opportunities across Europe is therefore necessary.

ObjectiveAcademic medical training was overhauled in 2005 after the Walport report and Modernising Medical Careers to create a more attractive and transparent training pathway. In 2007 and 2016, national web-based surveys of gastroenterology trainees were undertaken to determine experiences, perceptions of and perceived barriers to out-of-programme research experience (OOP-R).Design, setting and patientsProspective, national web-based surveys of UK gastroenterology trainees in 2007 and 2016.Main outcome measureAttitudes to OOP-R of two cohorts of gastroenterology trainees.ResultsResponse rates were lower in 2016 (25.8% vs 56.7%) (p50% having already undertaken it. Doctor of Philosophy/medical doctorate remained the most popular OOP-R in both cohorts. Successful fellowship applications increased in 2016, and evidence of gender inequality in 2007 was no longer evident in 2016. In the 2016 cohort, 91.1% (n=144) felt the development of trainee-led research networks was important, with 74.7% (n=118) keen to get involved.ConclusionsThe majority of gastroenterology trainees who responded expressed a desire to undertake OOP-R, and participation rates in OOP-R remain high. Despite smaller absolute numbers responding than in 2007, 2016 trainees achieved higher successful fellowship application rates. Reassuringly more trainees in 2016 felt that OOP-R would be important in the future. Efforts are needed to tackle potential barriers to OOP-R and support trainees to pursue research-active careers.

Background & Aims Infection is a common cause of death in patients with cirrhosis. We investigated the association between the innate immune response and death within 3 months of hospitalization. Methods Plasma samples were collected on days 1, 5, 10, and 15 from participants recruited into the albumin to prevent infection in chronic liver failure feasibility study. Patients with acute decompensated cirrhosis were given albumin infusions at 10 hospitals in the United Kingdom. Data were obtained from 45 survivors and 27 non-survivors. We incubated monocyte-derived macrophages from healthy individuals with patients’ plasma samples and measured activation following lipopolysaccharide administration, determined by secretion of tumor necrosis factor and soluble mediators of inflammation. Each analysis included samples from 4 to 14 patients. Results Plasma samples from survivors vs non-survivors had different inflammatory profiles. Levels of prostaglandin E2 were high at times of patient hospitalization and decreased with albumin infusions. Increased levels of interleukin 4 (IL4) in plasma collected at day 5 of treatment were associated with survival at 3 months. Incubation of monocyte-derived macrophages with day 5 plasma from survivors, pre-incubated with a neutralizing antibody against IL4, caused a significant increase in tumor necrosis factor production to the level of non-survivor plasma. Although baseline characteristics were similar, non-survivors had higher white cell counts and levels of C-reactive protein and renal dysfunction. Conclusions We identified profiles of inflammatory markers in plasma that are associated with 3-month mortality in patients with acute decompensated cirrhosis given albumin. Increases in prostaglandin E2 might promote inflammation within the first few days after hospitalization, and increased levels of plasma IL4 at day 5 are associated with increased survival. Clinicaltrialsregister.eu: EudraCT 2014-002300-24

Background and Aims: Patients with cirrhosis are at a greatly increased risk of severe bacterial infection with survival directly related to extra-hepatic organ dysfunction. A defective innate immune response is considered to underlie this risk. There is however no medical strategy to restore immune competence in these patients. Elevated circulating Prostaglandin E2 (PGE2) levels contribute to immune suppression in acutely decompensated (AD) cirrhosis. PGE2 is more bioavailable because of decreased serum albumin levels in AD patients as albumin binds PGE2. The binding capacity of endogenous albumin is also known to be defective in cirrhosis. Human Albumin Solution (HAS), a safe and common intervention, could thus be repurposed as an immune restorative drug in AD patients. The primary aim of ATTIRE is to determine if raising serum albumin to >30 g/L in patients with decompensated cirrhosis will decrease rates of infection, extra hepatic organ dysfunction and death.