Making computed tomography safer for patients with Crohn's disease.

Background and aims: Computed tomography (CT), often more accessible than magnetic resonance imaging (MRI), remains widely used though radiation exposure is an obvious disadvantage. We previously showed that modern CT technology can achieve over 70% reduction in radiation-dose without loss of accuracy. Here, we compare low- versus conventional-dose CT in patients with known Crohn's disease to assess clinical confidence and accuracy of the low-dose procedure in the semi-acute setting.Methods: A comparative study of low-dose CT with full iterative reconstruction (IR) versus conventional-dose CT was conducted in 50 consecutive outpatients with Crohn's disease. Clinicians were provided with the low-dose images and reports, whereas conventional-dose images were reviewed after 4 weeks.Results: The clinical question was adequately addressed with low-dose IR imaging in all cases. Complications of Crohn's were detected in 37/50 (74%) with no disagreement between low- and conventional-dose imaging. The effective radiation dose reduction was 76.5% (low-dose mean 2.15 mSv versus conventional-dose CT 6.99 mSv).Conclusion: Low-dose IR CT is safe and accurate for evaluating distribution and complications of known Crohn's disease in the outpatient setting. We propose that low-dose radiation imaging should be adopted as standard-of-care for the evaluation of Crohn's disease and an acceptable alternative to MR particularly in the acute setting. ClinicalTrials.gov: NCT03140306.

Macronutrients, microbiome and precision nutrition.

PURPOSE OF REVIEW: Precision nutrition and personalized diets are gaining popularity in nutritional science and medicine. To fully appreciate their potential benefits, a deep understanding of both macronutrients and nutrient-microbe interactions is required. RECENT FINDINGS: Microbiome science has reaffirmed the importance of dietary fiber in microbial and host health. Additional macronutrients, digestible carbohydrate, protein and fat also influence the composition and diversity of the microbiome and, therefore, microbial response to dietary intervention. Attention to macronutrient source, dose, microbial effect and metabolite production allows the development of more established links between diet and health. SUMMARY: The degree to which human diets need to be personalized for optimal health is still uncertain but a one-size-fits-all diet seems unlikely. However, for personal or precision nutrition to fulfill its promise, greater attention to the details of nutrient-microbe interactions will be required.

Liver transplantation for critically ill cirrhotic patients: Stratifying utility based on pretransplant factors.

The aim of this study was to produce a prognostic model to help predict posttransplant survival in patients transplanted with grade-3 acute-on-chronic liver failure (ACLF-3). Patients with ACLF-3 who underwent liver transplantation (LT) between 2007 and 2017 in 5 transplant centers were included (n = 152). Predictors of 1-year mortality were retrospectively screened and tested on a single center training cohort and subsequently tested on an independent multicenter cohort composed of the 4 other centers. Four independent pretransplant risk factors were associated with 1-year mortality after transplantation in the training cohort: age ≥53 years (P = .044), pre-LT arterial lactate level ≥4 mml/L (P = .013), mechanical ventilation with PaO2 /FiO2  ≤ 200 mm Hg (P = .026), and pre-LT leukocyte count ≤10 G/L (P = .004). A simplified version of the model was derived by assigning 1 point to each risk factor: the transplantation for Aclf-3 model (TAM) score. A cut-off at 2 points distinguished a high-risk group (score >2) from a low-risk group (score ≤2) with 1-year survival of 8.3% vs 83.9% respectively (P < .001). This model was subsequently validated in the independent multicenter cohort. The TAM score can help stratify posttransplant survival and identify an optimal transplantation window for patients with ACLF-3.

Bifidobacteriumbreve Bif195 Protects Against Small-Intestinal Damage Caused by Acetylsalicylic Acid in Healthy Volunteers.

BACKGROUND & AIMS: Enteropathy and small-intestinal ulcers are common adverse effects of nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (ASA). Safe, cytoprotective strategies are needed to reduce this risk. Specific bifidobacteria might have cytoprotective activities, but little is known about these effects in humans. We used serial video capsule endoscopy (VCE) to assess the efficacy of a specific Bifidobacterium strain in healthy volunteers exposed to ASA. METHODS: We performed a single-site, double-blind, parallel-group, proof-of-concept analysis of 75 heathy volunteers given ASA (300 mg) daily for 6 weeks, from July 31 through October 24, 2017. The participants were randomly assigned (1:1) to groups given oral capsules of Bifidobacterium breve (Bif195) (≥5 × 1010 colony-forming units) or placebo daily for 8 weeks. Small-intestinal damage was analyzed by serial VCE at 6 visits. The area under the curve (AUC) for intestinal damage (Lewis score) and the AUC value for ulcers were the primary and first-ranked secondary end points of the trial, respectively. RESULTS: Efficacy data were obtained from 35 participants given Bif195 and 31 given placebo. The AUC for Lewis score was significantly lower in the Bif195 group (3040 ± 1340 arbitrary units) than the placebo group (4351 ± 3195) (P = .0376). The AUC for ulcer number was significantly lower in the Bif195 group (50.4 ± 53.1 arbitrary units) than in the placebo group (75.2 ± 85.3 arbitrary units) (P = .0258). Twelve adverse events were reported from the Bif195 group and 20 from the placebo group. None of the events was determined to be related to Bif195 intake. CONCLUSIONS: In a randomized, double-blind trial of healthy volunteers, we found oral Bif195 to safely reduce the risk of small-intestinal enteropathy caused by ASA. ClinicalTrials.gov no: NCT03228589.

Longterm Survival After Liver Transplantation for Autoimmune Hepatitis: Results From the European Liver Transplant Registry.

The aim of this study was to analyze longterm patient and graft survival after liver transplantation for autoimmune hepatitis (AIH-LT) from the prospective multicenter European Liver Transplant Registry. Patient and liver graft survival between 1998 and 2017 were analyzed. Patients after AIH-LT (n = 2515) were compared with patients receiving LT for primary biliary cholangitis (PBC-LT; n = 3733), primary sclerosing cholangitis (PSC-LT; n = 5155), and alcohol-related cirrhosis (AC-LT; n = 19,567). After AIH-LT, patient survival was 79.4%, 70.8%, and 60.3% and graft survival was 73.2%, 63.4%, and 50.9% after 5, 10, and 15 years of follow-up. Overall patient survival was similar to patients after AC-LT (P = 0.44), but worse than after PBC-LT (hazard ratio [HR], 1.48; P < 0.001) and PSC-LT (HR, 1.19; P = 0.002). AIH-LT patients were at increased risk for death (HR, 1.37-1.84; P < 0.001) and graft loss (HR, 1.35-1.80; P < 0.001) from infections compared with all other groups and had a particularly increased risk for lethal fungal infections (HR, 3.38-4.20; P ≤ 0.004). Excluding patients who died within 90 days after LT, risk of death after AIH-LT was superior compared with AC-LT (HR, 0.84; P = 0.004), worse compared with PBC-LT (HR, 1.38; P < 0.001) and similar compared with PSC-LT (P = 0.93). Autoimmune hepatitis (AIH) patients with living donor liver transplantation (LDLT) showed reduced survival compared with patients receiving donation after brain death (HR, 1.96; P < 0.001). In AIH-LT patients, overall survival is inferior to PBC-LT and PSC-LT. The high risk of death after AIH-LT is caused mainly by early fatal infections, including fungal infections. Patients with LDLT for AIH show reduced survival.

A Model to Predict 1-Month Risk of Transplant or Death in Hepatitis A-Related Acute Liver Failure.

Acute liver failure (ALF) caused by hepatitis A is a rare but fatal disease. Here, we developed a model to predict outcome in patients with ALF caused by hepatitis A. The derivation set consisted of 294 patients diagnosed with hepatitis A-related ALF (ALFA) from Korea, and a validation set of 56 patients from Japan, India, and United Kingdom. Using a multivariate proportional hazard model, a risk-prediction model (ALFA score) consisting of age, international normalized ratio, bilirubin, ammonia, creatinine, and hemoglobin levels acquired on the day of ALF diagnosis was developed. The ALFA score showed the highest discrimination in the prediction of liver transplant or death at 1 month (c-statistic, 0.87; 95% confidence interval [CI], 0.84-0.92) versus King's College criteria (KCC; c-statistic, 0.56; 95% CI, 0.53-0.59), U.S. Acute Liver Failure Study Group index specific for hepatitis A virus (HAV-ALFSG; c-statistic, 0.70; 95% CI, 0.65-0.76), the new ALFSG index (c-statistic, 0.79; 95% CI, 0.74-0.84), Model for End-Stage Liver Disease (MELD; c-statistic, 0.79; 95% CI, 0.74-0.84), and MELD including sodium (MELD-Na; c-statistic, 0.78; 95% CI, 0.73-0.84) in the derivation set (all P < 0.01). In the validation set, the performance of the ALFA score (c-statistic, 0.84; 95% CI, 0.74-0.94) was significantly better than that of KCC (c-statistic, 0.65; 95% CI, 0.52-0.79), MELD (c-statistic, 0.74; 95% CI, 0.61-0.87), and MELD-Na (c-statistic, 0.72; 95% CI, 0.58-0.85) (all P < 0.05), and better, but not statistically significant, than that of the HAV-ALFSG (c-statistic, 0.76; 95% CI, 0.61-0.90; P = 0.28) and new ALFSG indices (c-statistic, 0.79; 95% CI, 0.65-0.93; P = 0.41). The model was well-calibrated in both sets. Conclusion: Our disease-specific score provides refined prediction of outcome in patients with ALF caused by hepatitis A.

Influence of donor and recipient gender on liver transplantation outcomes in Europe.

BACKGROUND & AIMS: The impact of gender and donor/recipient gender mismatch on LT outcomes is controversial. The aim of this study was to compare outcomes of LT in Europe, using the ELTR database, between male and female recipients, including donor/recipient gender mismatch. METHODS: Recipient, donor and transplant characteristics were compared between male and female patients. Patient survival was compared between groups, and the impact of donor/recipient gender matching as well as donor and recipient anthropometric characteristics were evaluated as potential risk factors for post-LT death/graft loss. RESULTS: A total of 46,334 LT patients were evaluated (70.5% men and 29.5% women). Ten-year survival rate was significantly higher in female than in male recipients (66% vs 59%, P < .0001). At multivariate analysis, adjusted for indication to LT and type of graft, donor/recipient gender mismatch (HR 1.12, 95% CI 1.04-1.2; P = .003), donor age > 60 years (HR 1.09, 95% CI 1.01-1.18; P = .027) and recipient age (HR 1.02, 95% CI 1.1-1.02; P < .0001) were significantly associated with post-LT lower survival rate in men. Conversely in female recipients, donor BMI > 30 (HR 1.32, 95% CI 1.09-1.6; P = .005), donor age > 60 years (HR 1.15, 95% CI 1.01-1.32; P = .027) and recipient age (HR 1.02, 95% CI 1.01-1.02; P < .0001) were significantly associated with lower post-LT survival rate. CONCLUSIONS: Donor/recipient gender mismatch in male recipients and the use of obese donor in female recipients are associated with reduced survival after LT. Therefore, the incorporation of donor and recipient anthropometric quantities in the allocation process should be a matter of further studies, as their matching can significantly influence long-term outcomes.

Gaps in the assortment of rapid assays for microorganisms of interest to the dairy industry.

This review presents the results of a study into the offering of rapid microbial detection assays to the Irish dairy industry. At the outset, a consultation process was undertaken whereby key stakeholders were asked to compile a list of the key microorganisms of interest to the sector. The resultant list comprises 19 organisms/groups of organisms divided into five categories: single pathogenic species (Cronobacter sakazakii, Escherichia coli and Listeria monocytogenes); genera containing pathogenic species (Bacillus, Clostridium, Listeria, Salmonella; Staphylococcus); broad taxonomic groupings (Coliforms, Enterobacteriaceae, fecal Streptococci, sulfite reducing bacteria/sulfite reducing Clostridia [SRBs/SRCs], yeasts and molds); organisms displaying certain growth preferences or resistance as regards temperature (endospores, psychrotrophs, thermodurics, thermophiles); indicators of quality (total plate count, Pseudomonas spp.). A survey of the rapid assays commercially available for the 19 organisms/groups of organisms was conducted. A wide disparity between the number of rapid tests available was found. Four categories were used to summarize the availability of rapid assays per organism/group of organisms: high coverage (>15 assays available); medium coverage (5-15 assays available); low coverage (<5 assays available); no coverage (0 assays available). Generally, species or genera containing pathogens, whose presence is regulated-for, tend to have a good selection of commercially available rapid assays for their detection, whereas groups composed of heterogenous or even undefined genera of mainly spoilage organisms tend to be "low coverage" or "no coverage." Organisms/groups of organisms with "low coverage" by rapid assays include: Clostridium spp.; fecal Streptococci; and Pseudomonas spp. Those with "no coverage" by rapid assays include: endospores; psychrotrophs; SRB/SRCs; thermodurics; and thermophiles. An important question is: why have manufacturers of rapid microbiological assays failed to respond to the necessity for rapid methods for these organisms/groups of organisms? The review offers explanations, ranging from the technical difficulty involved in detecting as broad a group as the thermodurics, which covers the spores of multiple sporeforming genera as well at least six genera of mesophilic nonsporeformers, to the taxonomically controversial issue as to what constitutes a fecal Streptococcus or SRBs/SRCs. We review two problematic areas for assay developers: validation/certification and the nature of dairy food matrices. Development and implementation of rapid alternative test methods for the dairy industry is influenced by regulations relating to both the microbiological quality standards and the criteria alternative methods must meet to qualify as acceptable test methods. However, the gap between the certification of developer's test systems as valid alternative methods in only a handful of representative matrices, and the requirement of dairy industries to verify the performance of alternative test systems in an extensive and diverse range of dairy matrices needs to be bridged before alternative methods can be widely accepted and adopted in the dairy industry. This study concludes that many important dairy matrices have effectively been ignored by assay developers.

Interaction between tacrolimus, MELD score and acute kidney injury after liver transplantation. Analysis on a large contemporary bicenter meld-era series.

BACKGROUND: Acute kidney injury (AKI) after liver transplantation (LT) is a common problem with complex management. The aims were to analyze the profile of AKI-RIFLE categories in the post-transplant setting of a wide multicentre cohort of patients in the MELD era and to specifically determine the effect of tacrolimus-based (TACRO) immunosuppressive regimes on the development of AKI. METHODS: A retrospective analysis of 550 (2007-2012) consecutive patients transplanted at Reina Sofia, Cordoba, and King's College Hospital, London, was performed. Inclusion criterion was to have CNI as part of initial immunosuppression immediately after LT. RESULTS: After exclusion criteria, a total of 477 patients were analyzed. Incidence of AKI within the first 2 weeks after LT was 65.8% (AKI-Risk), 41.3% (AKI-Injury), and 12.3% (AKI-Failure). The development of any type of AKI had no impact on short- and/or long-term survival up to 3 years after the transplant. Moreover, AKI was almost universal in the early post-transplant period and TACRO trough concentrations during the first 2 weeks after the transplant were not predictors of AKI in none of its categories in the multivariate analyses. CONCLUSIONS: Low-TACRO-based regimes were not as useful as expected in the prevention of AKI when analyzed in the context of a large contemporary LT series.

ERCP and SARS-COV-2: an urgent procedure that should be immune.

BACKGROUND: Radical changes to clinical and endoscopy practice have been rapidly introduced following the spread of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Urgent endoscopies are, however, intended to proceed as normal with additional personal protective procedures. A perceived reduction in hospital attendances may suggest a number of urgently indicated endoscopic retrograde cholangio-pancreatographies (ERCPs) are being missed. Objectives and Methods: A review of all ERCPs carried out in a large tertiary referral endoscopy unit under healthcare restrictions was compared to the same time period in previous years. The intention was to determine if ERCPs are proceeding as normal or if there is a difference in referral characteristics. RESULTS: Under service restrictions (13 March to the end of April 2020), 55 ERCPs were performed compared with 87 ERCPs in 2019. Similar numbers to 2019 were also recorded in the preceding years. One case of coronavirus disease 2019 (COVID-19) was reported in a patient in the days following ERCP, with no cases notified among staff related to endoscopy. CONCLUSIONS: A reduction in ERCP referrals raises concern that a cohort of patients with significant biliary disease remain undetected. Whether this results in later, and more severe, presentation remains to be seen but a potential surge in such cases could significantly burden all future endoscopy planning services.

Proximity to transplant center and outcome among liver transplant patients.

In the United States, distance from liver transplant center correlates with worsened outcomes; the effects of geography elsewhere are unassessed. We performed a national registry analysis of United Kingdom listings for liver transplantation (1995-2014) and assessed whether travel time to transplant center correlates with outcome. There were 11 188 listings assessed (8490 transplanted), with a median travel time to center of 60 minutes (range 36-86). Of the national population, 3.38 × 107 (55.1%) reside ≥60 minutes from a center, and 7.65 × 106 (12.5%) >119 minutes. After competing risk analysis, increasing travel time was associated with an increased risk of death after listing (subdistribution hazard ratios relative to <60 minutes of 1.33 for 60-119 and 1.27 for >119 minutes; P < 0.001) and reduced likelihood of transplantation or recovery (0.94 and 0.86; P < 0.001). Among those transplanted, travel time was not associated with retransplant-free survival (P = 0.532). We used our model to examine optimal placement of a new center and identify a single site with a total travel time reduction of ≈10%. Our findings of disparities in accessibility of liver transplantation showed worse outcomes following listing in those distant from their transplant center, and our description of a method to model a new center complement existing data and support similar analyses of other networks.

Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.

BACKGROUND & AIMS: Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. METHODS: We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. RESULTS: Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH - an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61-65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m2: HR 4.29, p = 0.048) or high (>40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. CONCLUSIONS: The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications. LAY SUMMARY: The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis.

Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK.

This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.

Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK.

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.

Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo-a Meta-analysis of Individual Data From Controlled Trials.

BACKGROUND & AIMS: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. METHODS: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. RESULTS: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48-0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43-0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P = .04) but not in multiple-imputation analysis (HR 0.71; P = .08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10-1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. CONCLUSIONS: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.

Prednisolone or pentoxifylline for alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

Validation of artificial neural networks as a methodology for donor-recipient matching for liver transplantation.

In 2014, we reported a model for donor-recipient (D-R) matching in liver transplantation (LT) based on artificial neural networks (ANNs) from a Spanish multicenter study (Model for Allocation of Donor and Recipient in España [MADR-E]). The aim is to test the ANN-based methodology in a different European health care system in order to validate it. An ANN model was designed using a cohort of patients from King's College Hospital (KCH; n = 822). The ANN was trained and tested using KCH pairs for both 3- and 12-month survival models. End points were probability of graft survival (correct classification rate [CCR]) and nonsurvival (minimum sensitivity [MS]). The final model is a rule-based system for facilitating the decision about the most appropriate D-R matching. Models designed for KCH had excellent prediction capabilities for both 3 months (CCR-area under the curve [AUC] = 0.94; MS-AUC = 0.94) and 12 months (CCR-AUC = 0.78; MS-AUC = 0.82), almost 15% higher than the best obtained by other known scores such as Model for End-Stage Liver Disease and balance of risk. Moreover, these results improve the previously reported ones in the multicentric MADR-E database. In conclusion, the use of ANN for D-R matching in LT in other health care systems achieved excellent prediction capabilities supporting the validation of these tools. It should be considered as the most advanced, objective, and useful tool to date for the management of waiting lists. Liver Transplantation 24 192-203 2018 AASLD.

Predictive Factors for Survival in Children Receiving Liver Transplants for Wilson's Disease: A Cohort Study Using European Liver Transplant Registry Data.

Liver transplantation (LT) is a rescue therapy for life-threatening complications of Wilson's disease (WD). However, data on the outcome of WD patients after LT are scarce. The aim of our study was to analyze a large pediatric WD cohort with the aim of investigating the longterm outcome of pediatric WD patients after LT and to identify predictive factors for patient and transplant survival. This is a retrospective cohort study using data of all children (<18 years) transplanted for WD enrolled in the European Liver Transplant Registry from January 1968 until December 2013. In total, 338 patients (57.6% female) transplanted at 80 different European centers (1-26 patients per center) were included in this study. The median age at transplantation was 14.0 years (interquartile range [IQR], 11.2-16.1 years); patients were followed up for a median of 5.4 years (IQR, 1.0-10.9 years) after LT. Overall patient survival rates were high with 87% (1-year survival), 84% (5-year survival), and 81% (10-year survival); survival rates increased considerably with the calendar year (P < 0.001). Early age at LT, living donation, and histidine tryptophan ketoglutarate preservation liquid were identified as risk factors for poor patient survival in the multivariate analysis. LT is an excellent treatment option for pediatric patients with WD and associated end-stage liver disease. Longterm outcome in these patients is similar to other pediatric causes for LT. Overall patient and graft survival rates improved considerably over the last decades. To improve future research in the field, the vast variability of allocation strategies should be harmonized and a generally accepted definition or discrimination of acute versus chronic WD needs to be found.

A retrospective analysis of post-transplant lymphoproliferative disorder following liver transplantation.

OBJECTIVE: To evaluate response rates and survival in adults developing post-transplant lymphoproliferative disorder (PTLD) following liver transplantation. METHODS: Patients were identified retrospectively and data collected through local liver and haematology electronic databases and pharmacy records. RESULTS: Forty-five patients were identified. The median age at first transplant and at development of PTLD was 48 and 54 years, respectively, with the median time from transplant to PTLD diagnosis of 56 months. The majority of cases (76%) were monomorphic B-cell lymphomas, and 36% of tumours were EBV positive. Treatment involved reduction in immune-suppression (RIS) in 30 (67%) with RIS the only treatment in 3. Ten (22%) patients were treated with rituximab alone, 13 (29%) with chemotherapy alone and 14 (31%) patients were treated with rituximab and chemotherapy. Twenty-six (58%) patients achieved a complete response (CR). At a median follow-up of 27 months, the median overall survival (OS) was 50 months. Response and OS were not associated with clinical factors or the use of rituximab. CONCLUSION: Outcomes reported in this study are favourable and comparable to those reported previously. The addition of rituximab did not appear to have improved outcomes in this series, although a significant proportion of patients were able to avoid chemotherapy.

Histopathology of 460 liver allografts removed at retransplantation: A shift in disease patterns over 27 years.

BACKGROUND AND AIM: Approximately 10%-19% of liver transplant recipients develop irreversible graft failure requiring retransplantation. We reviewed the histology of failed grafts removed at retransplantation in our center over 27 years. METHODS: Two hundred and seventy-six adults and 118 children underwent retransplantation from 1987 to 2014, receiving 321 and 139 liver grafts, respectively. We analyzed graft histology, recipient demographics, indications and time interval to retransplantation. We divided retransplantation in 3 eras: A (1987-1994), B (1995-2001), and C (2002-2014). RESULTS: A total of 3298 adult and 938 pediatric primary liver transplants were conducted in our center, and 8.4% of adults and 12.6% of children experienced retransplantation. Considering the changes throughout the eras, the proportion of chronic rejection declined, while that of unexplained chronic fibrosing hepatitis increased steadily, representing the main reason for retransplantation conducted >10 years after primary transplant in children, and second in adults in the most recent era. This chronic hepatitis of the graft might correspond to a slowly evolving form of rejection, possibly with a humoral component, associated with progressive graft fibrosis and eventually failure. CONCLUSIONS: We observed a shift in histopathology of failed liver grafts, with increasing relevance of chronic idiopathic hepatitis associated with progressive fibrosis and graft failure.