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Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments.We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment.data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin0.8 x admission value at day 7), 'static' (bilirubin of0.9 -1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p.001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores.We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.

Background: The incidence of posttraumatic osteoarthritis (PTOA) based on clinical radiographic grading criteria at 10 years after anterior cruciate ligament (ACL) reconstruction (ACLR) has not been well-defined in a prospective cohort of young athletic patients. Hypothesis: Among young athletic patients, there is a high incidence of clinical radiographic PTOA at 10 years after ACLR. Additionally, there is a significant difference in clinical radiographic osteoarthritis (OA) changes (joint space narrowing and osteophyte formation) between ACL-reconstructed and contralateral knees at 10 years. Study Design: Case series; Level of evidence, 4. Methods: The first 146 patients in an ongoing nested cohort study of the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort presented for a minimum 10-year follow-up. Included patients had a sports-related ACL injury, were aged Results: Interrater reliability was substantial for the IKDC (Gwet Agreement Coefficient [AC] 1 = 0.71), moderate for the KL (0.48), and almost perfect for the OARSI (0.84) grading systems. Among patients with a contralateral radiographically normal knee, the 10-year incidence of clinical radiographic PTOA after ACLR was 37% as defined by osteophytes and 23% as defined by joint space narrowing. The maximum side-to-side difference in the OARSI osteophyte grade in the medial or lateral compartment was 0 in 65% of patients, 1 in 20%, and ≥2 in 15%. The maximum side-to-side difference in the OARSI joint space narrowing grade was 0 in 77% of patients, 1 in 19%, and ≥2 in 4%. Conclusion: In young active patients, the 10-year incidence of clinical radiographic PTOA after ACLR was 37% as defined by osteophytes and 23% as defined by joint space narrowing. The mean difference in the degree of osteophyte formation (≤1 grade in 85%) and joint space narrowing (≤1 grade in 96%) between the ACL-reconstructed and contralateral knees was small. Registration: NCT02717559 (ClinicalTrials.gov identifier)

Background & aims Liver fibrosis is the critical determinant of liver-related outcomes in persons with nonalcoholic fatty liver disease. The rate that fibrosis develops determines the time taken to reach cirrhosis and consequent clinical outcomes. Estimates of the fibrosis progression rate (FPR) are uncertain having been defined in small observational series that rely largely on nonstandardised repeat biopsy in selected patients. The aim of this study was to evaluate the FPR in placebo-treated participants with nonalcoholic steatohepatitis (NASH) in randomised controlled trials (RCTs). Methods Systematic review and meta-analysis of RCTs in NASH with data on fibrosis change extracted. Calculated fibrosis progression rates were pooled in meta-analysis. The pooled estimate was then used to model the proportion of hypothetical cohorts starting with no fibrosis at the age of 30 who develop cirrhosis. Results A total of 35 trials including 1419 placebo-treated participants who underwent repeat liver biopsy were evaluated. Considering all trials, the overall FPR was 0.00 stages per year, increasing to 0.03 stages per year in both trials at low risk of bias and trials including >50 placebo-treated participants. This estimate was markedly lower than the value derived from previously pooled analyses of observational data. Using a FPR of 0.03 resulted in a substantial reduction in the proportion of patients developing cirrhosis compared with the FPR derived from observational studies (13% vs 28%). Conclusions The FPR in placebo-treated participants in RCTs is lower than that described from observational data. Slower fibrosis progression predicts fewer persons with NASH will progress to cirrhosis than previously estimated.

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient- and surgeon- dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting post-operative infections. Allografts had a higher risk of infection than autografts (odds ratio=6.8; 95% CI: 0.9-54.5; p=0.045). Diabetes (odds ratio=28.6; 95% CI: 5.5-149.9; p=0.004) was a risk factor for infection. Patient age, sex, BMI and smoking status were not associated with risk of infection after rACLR. STATEMENT OF CLINICAL SIGNIFICANCE: While there is a low rate of infection following rACLR, use of allograft and comorbidity with diabetes are associated with a higher risk of infection following this surgery.

Purpose of review This review will describe the natural history of alcohol-related liver disease (ArLD) in light of recent data that have synthesized existing knowledge on this topic and described new research cohorts to improve our understanding of progression and outcomes in ArLD. Recent findings ArLD occurs after a threshold of alcohol consumption, but this threshold is lowered by the presence of comorbid factors of which obesity is the most common. The most common stage of ArLD is alcohol-related steatosis: this is associated with a low rate of progression to cirrhosis (3%/year) and nonliver-related morbidity is more likely (4 versus 1%/year). In contrast, alcohol-related steatohepatitis or cirrhosis is more dangerous with higher rates of both nonliver and liver-related mortality. Hepatocellular carcinoma occurs at approximately 3%/year amongst people with ArLD cirrhosis. Summary These data allow an understanding of ArLD to accurately counsel patients and also to guide public health policies. Awareness of the shortcomings of the available data, highlighted in a recent systematic review, will inform the design of further research in particular to describe the multiple interacting factors that may cause ArLD to regress or progress.

Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Although hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+ metabolome in alcohol‐related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+ metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham National Health Service Foundation Trust. The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests and histology. NAD‐targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography–tandem mass spectrometry. Seventy‐two human liver specimens were analyzed, including 43 with ArLD. The NAD+ metabolome differed significantly between different types of liver disease (two‐way analysis of variance [ANOVA], P = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+ (432 μM vs. 616 μM in normal liver) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+ metabolome between ArLD samples with and without steatohepatitis (two‐way ANOVA, P = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+ (mean, 462 μM vs. 322 μM; P, Here we show that NAD+, NADP+, nicotinic acid and nicotinamide riboside are depressed in the livers of patients with alcohol‐related liver diseases, that the hepatic NAD metabolome correlates with clinical presentations, and that hepatic NAD status correlates with markers of immune function. These first‐in‐people clinical data reinforce preclinical insights in support of potential NAD‐boosting interventions in alcohol‐related liver diseases.

Background and aims Non-alcoholic fatty liver disease is common and there are a number of treatments in development. Patients with non-alcoholic steatohepatitis (NASH) and significant fibrosis are thought to be the population most in need of treatment. Identification of this group requires liver biopsy. The aim of this study was to identify the proportion of patients screened for phase 2 randomised controlled trials who subsequently entered these studies. Methods Large, multicentre, phase 2 randomised controlled trials of pharmacological therapies for NASH were identified by systematic review. The pooled proportion of potential participants who entered the trials was estimated by meta-analysis. The reasons for trial ineligibility were separately extracted and analysed. Results Thirteen reports of 14 trials were included. Overall, there were 4014 screened individuals included in the quantitative analyses and 53% were subsequently enrolled in a trial. Considering trials in which the entry criteria matched the current paradigm for treatment, that is, the presence of NASH and significant fibrosis, only 35% of screened individuals were eligible for trial entry. More than half of ineligible individuals were excluded on the basis of liver histology most often due to insufficient disease activity with or without insufficient fibrosis. Conclusion The majority of patients considered at risk of NASH and fibrosis sufficient for treatment in randomised controlled trials are ineligible for trial entry. Most often, this is due to ineligible liver histology. These findings have implications for the design of future trials in NASH and for the applicability of treatments after licensing.

Background and AimsObesity is closely associated with non-alcoholic fatty liver disease (NAFLD). We investigated expression of the CC-chemokine CCL25 in adipose tissue (AT) and its relation to hepatic inflammation.MethodsPrimary human tissue was used for all experiments. CCL25 concentration in serum was measured with enzyme-linked immunosorbent assay (ELISA). Gene expression of CCL25 was measured with polymerase chain reaction. Protein expression was assessed with ELISA and immunohistochemistry. Leukocyte trafficking was investigated in a dynamic assay to model the hepatic sinusoid. Expression of CCR9 on liver-infiltrating leukocytes analysed with flow cytometry.ResultsCirculating CCL25 was increased in obesity. Gene expression of CCL25 in AT was several-fold higher than in liver, although protein levels of CCL25 were comparable. Soluble CCL25 in flow media increased leukocyte trafficking across hepatic endothelium. Greater numbers of CCR9+ cells were seen in liver tissue from patients with NAFLD, where the greatest difference was in the number of CD14+CD16+ monocytes.ConclusionsCCL25 and its cognate receptor CCR9 mediate a novel pathway of inflammatory crosstalk between adipose and liver tissue in NAFLD.

Background & Aims Liver histology is the primary endpoint in phase III trials in nonalcoholic steatohepatitis (NASH). There is an appreciable response to placebo that confounds endpoint assessment. The aim of this study was to quantify contributors to the placebo response and its impact on liver fibrosis improvement. Methods Estimates of fibrosis improvement in placebo-treated participants were made using probabilistic simulation. Each simulated trial included 120 participants. Parameters considered in the model included sampling and observer variability, regression to the mean, and net fibrosis progression calibrated to reported trial outcomes. Results In large phase IIb and III trials, 22% of placebo-treated participants with fibrosis stage 2 or 3 NASH at baseline improved by at least 1 fibrosis stage with minimal net disease progression. Estimates of sampling and observer variability in simultaneous biopsy studies highlighted an imbalance where apparent fibrosis improvement was more likely than worsening. Using these estimates and known trial outcomes, net fibrosis progression was estimated at 0.05 stages per year. Simulations of the placebo response rate showed a rate of 22% with 80% of trials falling between 15 and 30%, in keeping with trials reported to date. Additional increases in observer variability further increased the placebo response. Conclusions The analyses presented simply define the placebo response in liver fibrosis in trials in NASH in terms of sampling and observer variability, regression to the mean, and fibrosis progression. Factors relating to liver biopsy are largely unmodifiable, and the variation in placebo response rates, both simulated and observed, challenges the role of biopsy in trial endpoint assessment.

Advancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated with severe lung disease and pneumonia. Genome-wide association studies have also recently identified 3p21.31, encompassing theCXCR6gene, as a susceptibility locus for severe COVID-19. We assessed numbers T cells expressing the chemokine receptor CXCR6 and plasma levels of CXCL16, in control and COVID-19 patients. Results demonstrated that circulating CD8+CXCR6+T cells were significantly elevated with advancing age, yet virtually absent in patients with severe COVID-19. Peripheral levels of CXCL16 were significantly upregulated in severe COVID-19 patients compared to either mild COVID-19 patients or SARS-CoV-2 negative controls. This study supports a significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19.

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH. Methods: We performed a retrospective, international multi-center cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method. Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p 51. The type of corticosteroids used (prednisone, pred-nisolone, or methylprednisolone) was not associated with sur-vival benefit (p = 0.247). Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39. Lay summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90-or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51). (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction The clinical course of cirrhosis does not follow a predictable trajectory. Multistate models of disease progression have been adopted to assess its’ natural history, mainly in cohorts with biopsy proven cirrhosis. Transient elastography (TE) is commonly used in clinical practice to diagnose liver fibrosis. The aim of this study was to assess survival and competing risk of liver and non-liver related events in a cohort of patients with advanced chronic liver disease (ACLD) defined by TE using electronic health record (EHR) data. Method TE data was collected from St James’s University Hospital in Leeds and the Queen Elizabeth Hospital in Birmingham between 2008 and 2019. Patients with a liver stiffness measurement (LSM) of >10 kPa were included. Disease and procedural coding information sent to NHS Digital and held in EHR was analysed. Validation of the coding information was done in a subset of patients using the full clinical record. Clinical events including decompensation (ascites, variceal bleeding, hepatic encephalopathy), hepatocellular carcinoma and death were identified. The cumulative incidence of these events was calculated using a competing risk regression model. Results 2926 patients were included, 1608 with LSM ≥ 15 kPa. Median follow up was 38.4 months. 351 patients (12%) died and 109 patients (3.7%) received liver transplantation. Decompensation was the commonest liver event: 240 (8%) of patients had a liver event as their first clinical event of interest, 81 (3%) developed HCC. Cumulative incidence rates at 3 years are shown in table 1. The cumulative incidence of liver-related morbidity and mortality increased with liver stiffness. Multivariable analysis showed that increasing age, male gender and baseline LSM were independent predictors of survival (all p Conclusions Transient elastography is strongly associated with outcomes in two large contemporary cohorts of patients with ACLD. EHR data can be used to accurately define clinical progression in these patients. The outcomes described above are comparable to landmark descriptions of patients diagnosed using liver biopsy. Identification of ACLD using TE is a rational basis for a national cirrhosis registry to facilitate quality improvement and clinical trials in patients with liver disease.

Background: The Knee injury and Osteoarthritis Outcome Score (KOOS) has demonstrated inferior psychometric properties when compared with the International Knee Documentation Committee (IKDC) subjective knee form when assessing outcomes after anterior cruciate ligament (ACL) reconstruction. The KOOS, Joint Replacement (KOOS, JR) is a validated short-form instrument to assess patient-reported outcomes (PROs) after knee arthroplasty, and the purpose of this study was to determine if augmenting the KOOS, JR with additional KOOS items would allow for the creation of a short-form KOOS-based global knee score for patients undergoing ACL reconstruction, with psychometric properties similar to those of the IKDC. Hypothesis: An augmented version of the KOOS, JR could be created that would demonstrate convergent validity with the IKDC but avoid the ceiling effects and limitations previously noted with several of the KOOS subscales. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Based on preoperative and 2-year postoperative responses to the KOOS questionnaires from a sample of 1904 patients undergoing ACL reconstruction, an aggregate score combining the KOOS, JR and the 4 KOOS Quality of Life subscale questions, termed the KOOSglobal, was developed. Psychometric properties of the KOOSglobal were then compared with those of the IKDC subjective score. Convergent validity between the KOOSglobal and IKDC was assessed with a Spearman correlation (ρ). Responsiveness of the 2 instruments was assessed by calculating the pre- to postoperative effect size and relative efficiency. Finally, the presence of a preoperative floor or postoperative ceiling effect was defined with the threshold of 15% of patients reporting either the worst possible (0 for KOOSglobal and IKDC) or the best possible (100 for KOOSglobal and IKDC) scores, respectively. Results: The newly developed KOOSglobal was responsive after ACL reconstruction and demonstrated convergent validity with the IKDC. The KOOSglobal significantly correlated with the IKDC scores (ρ = 0.91, P < .001), explained 83% of the variability in IKDC scores, and was similarly responsive (relative efficiency = 0.63). While there was a higher rate of perfect postoperative scores with the KOOSglobal (213 of 1904, 11%) than with the IKDC (6%), the KOOSglobal was still below the 15% ceiling effect threshold. Conclusion: The large ceiling effects limit the ability to use several of the KOOS subscales with the younger, more active ACL population. However, by creating an aggregate score from the KOOS, JR and 4 KOOS Quality of Life subscale questions, the 11-item KOOSglobal offers a responsive PRO tool after ACL reconstruction that converges with the information captured with the IKDC. Also, by offering the ability to calculate multiple scores from a single questionnaire, the KOOSglobal may provide the orthopaedic community a single PRO platform to be used across knee-related subspecialties. Registration: NCT00478894 ( ClinicalTrials.gov identifier).

Nonalcoholic fatty liver disease (NAFLD) is a common disease, closely associated with obesity and insulin resistance. We investigated the presence of a subset of myeloid cells associated with metabolic disturbance in the liver of patients with NAFLD and a murine model of obesity-induced liver disease. Gene and protein expression in liver and serum was investigated with RT-PCR or ELISA and correlated to clinical disease. Liver-infiltrating immune cells were isolated from normal or diseased human liver for flow cytometric analysis. In animal experiments, mice were fed a high-fat diet (60% of calories from fat) for 16 wk, or high-fat diet with 30% fructose for 32 wk to induce steatohepatitis and fibrosis. A small molecule inhibitor of CC chemokine receptor 2 (CCR2), CCX872, was administered to some mice. A subset of CD11c+CD206+ immune cells was enriched in human liver tissue, and greater infiltration was observed in NAFLD. The presence of CD11c+CD206+ myeloid cells correlated with systemic insulin resistance. CD11c+CD206+ cells expressed high levels of CCR2, and liver CC chemokine ligand 2 (CCL2) expression was increased in nonalcoholic steatohepatitis and correlated with disease activity. In mice, CCR2 inhibition reduced infiltration of liver CD11b+CD11c+F4/80+ monocytes, which are functional homologs of human CD11c+CD206+ cells, and improved liver injury and glycemic control. A role for CCR2/CCL2 in human NAFLD has long been postulated. These data confirm a role for this chemokine/receptor axis, through mediating adipose and hepatic infiltration of myeloid cells. Inhibition of CCR2 improved hepatic inflammation and fibrosis in murine models of NAFLD. These data confirm the rationale for targeting CCR2 to treat NAFLD. NEW & NOTEWORTHY These data show for the first time that CD11c+CD206+ myeloid cells, previously associated with human adipose tissue inflammation, infiltrate into liver tissue in nonalcoholic fatty liver disease. These cells express CCR2. Inhibition of CCR2 in mice inhibits hepatic inflammation caused by a murine homolog of these myeloid cells and improves experimental liver disease.

Fatty liver disease is almost always a consequence of obesity or alcohol abuse. In both cases significant changes to adipose tissue (AT) occur, which are remarkably similar despite their different causes. Hypertrophic and hypoxic adipocytes develop an inflammatory phenotype and become necrotic, secreting inflammatory cytokines into circulation, principally but not limited to tumor necrosis factor (TNF) α. The secretion of adipokines is altered in obesity and alcohol abuse. Fatty acids, instead of being stored in adipocytes are delivered to the liver. These multiple pathways of adipose-liver crosstalk contribute to the development and progression of liver disease: TNFα induces hepatocyte death and modulates hepatic immune function. Fatty acids promote hepatic steatosis and are pro-inflammatory, whilst adipokines mediate and exacerbate liver injury, for example leptin enhances fibrotic responses to injury. In non-alcoholic fatty liver disease (NAFLD) reducing adipose inflammation through weight loss or thiazolidinediones (TZDs) both improve liver injury. Experimental data that suggest that this might also be of benefit in alcoholic liver disease (ALD) but human studies are lacking at present. Keywords: Fatty liver disease, Adipose tissue (AT), Leptin, Adiponectin, Tumor necrosis factor (TNF) α

Background: Anterior cruciate ligament (ACL) reconstruction can effectively return athletes to the playing field, but they are still at risk of developing posttraumatic osteoarthritis (PTOA). No studies have used multivariable analysis to evaluate the predictors of radiographic PTOA in the lateral compartment of the knee at short-term follow-up after ACL reconstruction. Purpose: To determine the predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in a young, active cohort. Study Design: Cohort study; Level of evidence, 2. Methods: A nested cohort of 358 patients from the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort who were aged ≤33 years, were injured playing a sport, and had never undergone surgery on the contralateral knee were followed up 2 years after ACL reconstruction with questionnaires and with weightbearing knee radiographs using the metatarsophalangeal (MTP) joint technique. The joint space width in the lateral compartment was measured using a semiautomatic computerized method, and multivariable predictive modeling was used to evaluate the relationship between meniscus treatment, cartilage injury, graft type, and joint space while adjusting for age, sex, body mass index, and Marx activity score. Results: The mean lateral joint space width was 0.11 mm narrower on the ACL-reconstructed knee compared with the contralateral healthy knee (7.69 mm vs 7.80 mm, respectively; P < .01). Statistically significant predictors of a narrower joint space width on the ACL-reconstructed knee included lateral meniscectomy ( P < .001) and a Marx activity score less than 16 points ( P < .001). Conclusion: This study identifies lateral meniscectomy and a lower baseline Marx activity score to be predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in young, active patients without a prior knee injury.

Aims The UK has a socialized healthcare system that provides treatment that is free at the point of care for acute and chronic health disorders (the National Health Service-NHS), which is currently experiencing a period of unprecedented challenge. Methods A narrative review that discusses present and future arrangements for transplantation of alcohol-related liver disease (ArLD) in the UK. Results Liver disease in the UK is reaching epidemic proportions due to obesity and metabolic disease compounding alcohol-mediated liver damage. Unfortunately, hepatology services in the UK are geographically disparate and subject to significant variations in liver morbidity and mortality, prompting concerns that this may negatively impair access to transplantation. In an attempt to improve referrals to tertiary liver services, the UK listing criteria for alcohol-associated liver disease were revised in 2016 by a working party under the aegis of the UK-Liver Advisory Group with the ambition of increasing opportunities for disease evaluation and improving the condition of candidates referred for assessment. Conclusion Liver transplantation for ArLD is well established in the UK. Recent organizational changes seek to reduce inequities in access to transplant services. Short summary Liver disease in the UK is reaching epidemic proportions. Concerns over equity of access to liver transplantation prompted revision of the UK listing criteria for alcohol-associated liver disease in 2016, to improve to the availability of tertiary hepatology services. Transplanting patients with alcohol-related liver disease in the National Health System: New Rules and Decisions '…The second property of your excellent sherris is, the warming of the blood; which, before cold and settled, hath left the liver white and pale…'Falstaff; Henry IV Part 2: Act 4, Scene 3.

Background & Aims While abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease. Methods We conducted a survey of primarily (89%) hepatology and gastroenterology providers within (80%) and outside the United States (20%). Surveys were sent to 921 providers with 408 complete responses (44%), of whom 343 (80%) work in a tertiary liver transplant center. Results While alcohol screening rates in liver disease patients was nearly universal, less than half of providers reported practicing with integrated addiction providers, using alcohol biomarkers and screening tools. Safe alcohol use by liver disease patients was felt to exist by 40% of providers. While 60% of providers reported referring AUD patients for behavioral therapy, 71% never prescribed AUD pharmacotherapy due to low comfort (84%). Most providers (77%) reported low addiction education and 90% desired more during GI/hepatology fellowship training. Amongst prescribers, baclofen was preferred, but with gaps in pharmacotherapy knowledge. Overall, there was low adherence to the 2019 AASLD practice guidance for ALD, although higher in hepatologists and experienced providers. Conclusions While our survey of hepatology and gastroenterology providers demonstrated higher rates of alcohol screening and referrals for behavioral therapy, we found low rates of prescribing AUD pharmacotherapy due to knowledge gaps from insufficient education. Further studies are needed to assess interventions to improve provider alignment with best practices for treating patients with AUD and ALD.

Alcoholic liver disease (ALD) is a leading cause of chronic liver disease with a wide spectrum of manifestations including simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Liver injury in ALD is caused by chronic inflammation, which has been actively investigated as a therapeutic target for the treatment of ALD for over the last four decades. In this review, we summarize a wide variety of inflammatory mediators that have been shown to contribute to the pathogenesis of ALD, and discuss the therapeutic potential of these mediators for the treatment of ALD.

Adipose tissue represents a large volume of biologically active tissue that exerts substantial systemic effects in health and disease. Alcohol consumption can profoundly disturb the normal functions of adipose tissue by inducing adipocyte death and altering secretion of adipokines, pro-inflammatory mediators and free fatty acids from adipose tissue, which have important direct and indirect effects on the pathogenesis of alcoholic liver disease (ALD). Cessation of alcohol intake quickly reverses inflammatory changes in adipose tissue, and pharmacological treatment that normalizes adipose tissue function improves experimental ALD. Obesity exacerbates liver injury induced by chronic or binge alcohol consumption, and obesity and alcohol can synergize to increase risk of ALD and progression. Physicians who care for individuals with ALD should be aware of the effects of adipose tissue dysfunction on liver function, and consider strategies to manage obesity and insulin resistance. This Review examines the effect of alcohol on adiposity and adipose tissue and the relationship between alcohol, adipose tissue and the liver.

Objectives Epidemiological data have shown that individuals with advanced fibrosis are at greatest risk of premature morbidity in NAFLD. Individuals included in clinical trials are often highly selected to remove confounding factors but selection can introduce bias and limit external validity. We examined the external validity of trials in non-alcoholic fatty liver disease (NAFLD) by examining characteristics of participants in observational studies (OS) and randomised controlled trials (RCT) in NAFLD. Design A systematic review was performed with structured literature searches for relevant OS and RCT using PubMed and Ovid Embase (1948 - 2016). Identified studies were screened for inclusion by the authors and data extracted. Study populations were compared using t-tests to compare means and variances, in each case weighted by the size of individual studies. Dichotomous data were compared by Chi-squared test. Results In total 148 studies were included: 67 RCT and 81 OS including data from 44,860 individuals . Fifteen RCT participants differed from individuals in OS with regard to age, BMI, prevalence of DM, and gender (p

Background Previous studies have described the clinical impact of infection in alcoholic hepatitis (AH) but none have comprehensively explored the aetiopathogenesis of infection in this setting. We examined the causes, consequences and treatment of infection in a cohort of patients with AH. Methods We undertook a retrospective cohort study of patients with AH admitted between 2009 and 2014 to seven centres in Europe and the USA. Clinical and microbiological data were extracted from medical records. Survival was analysed with Kaplan–Meier analysis and Cox proportional hazards analysis to control the data for competing factors. Propensity score matching was used to examine the efficacy of prophylactic antibiotics administered in the absence of infection. Results We identified 404 patients with AH. Of these, 199 (49%) showed clinical or culture evidence of infection. Gut commensal bacteria, particularly Escherichia coli and Enterobacter species, were most commonly isolated in culture. Fungal infection was rarely seen. Cultured organisms and antibiotic resistance differed markedly between centres. Infection was an independent risk factor for death (hazard ratio for death at 90 days 2.33, 95% confidence interval 1.63–3.35, p

Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Though hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+ metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+ metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham NHS Foundation Trust (UHB). The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests (LFT) and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry (LC-MS). Seventy-two human liver specimens were analyzed including 43 with ArLD. The NAD+ metabolome differed significantly between different types of liver disease (two-way ANOVA p = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+ (432 μM vs. 616 μM in NL) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+ metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA p = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+ (mean 451 μM vs. 381 μM, p = 0.045). NAD+ concentration was inversely related to serum bilirubin concentration (r2 −0.127, p = 0.04) and positively correlated with myeloperoxidase activity (r2 0.31, p = 0.003). The concentration of NAD+ and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+ and precursor levels as well as depressed myeloperoxidase activity.

Background: Multiple studies have shown that patients are susceptible to posttraumatic osteoarthritis (PTOA) after an anterior cruciate ligament (ACL) injury, even with ACL reconstruction (ACLR). Prospective studies using multivariable analysis to identify risk factors for PTOA are lacking. Purpose/Hypothesis: This study aimed to identify baseline predictors of radiographic PTOA after ACLR at an early time point. We hypothesized that meniscal injuries and cartilage lesions would be associated with worse radiographic PTOA using the Osteoarthritis Research Society International (OARSI) atlas criteria. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 421 patients who underwent ACLR returned on-site for standardized posteroanterior semiflexed knee radiography at a minimum of 2 years after surgery. The mean age was 19.8 years, with 51.3% female patients. At baseline, data on demographics, graft type, meniscal status/treatment, and cartilage status were collected. OARSI atlas criteria were used to grade all knee radiographs. Multivariable ordinal regression models identified baseline predictors of radiographic OARSI grades at follow-up. Results: Older age (odds ratio [OR], 1.06) and higher body mass index (OR, 1.05) were statistically significantly associated with a higher OARSI grade in the medial compartment. Patients who underwent meniscal repair and partial meniscectomy had statistically significantly higher OARSI grades in the medial compartment (meniscal repair OR, 1.92; meniscectomy OR, 2.11) and in the lateral compartment (meniscal repair OR, 1.96; meniscectomy OR, 2.97). Graft type, cartilage lesions, sex, and Marx activity rating scale score had no significant association with the OARSI grade. Conclusion: Older patients with a higher body mass index who have an ACL tear with a concurrent meniscal tear requiring partial meniscectomy or meniscal repair should be advised of their increased risk of developing radiographic PTOA. Alternatively, patients with an ACL tear with an articular cartilage lesion can be reassured that they are not at an increased risk of developing early radiographic knee PTOA at 2 to 3 years after ACLR.

Background & Aims: To date, studies into the natural history of alcohol-related liver disease (ALD) have lacked long-term follow-up, large numbers of participants, or both. We performed a systematic review to summarise studies that describe the natural history of histologically proven ALD. Methods: PubMed and Medline were searched for relevant studies according to pre-specified criteria. Data were extracted to describe the prevalence of ALD, histological progression of disease and mortality. Single-proportion meta-analysis was used to combine data from studies regarding rates of progression or mortality. Results: Thirty-seven studies were included, reporting data from 7,528 participants. Amongst cohorts of hazardous drinkers, on average 15% had normal histological appearance, 27% had hepatic steatosis, 24% had steatohepatitis and 26% had cirrhosis. The annualised rates of progression of pre-cirrhotic disease to cirrhosis were 1% (0–8%) for patients with normal histology, 3% (2–4%) for hepatic steatosis, 10% (6–17%) for steatohepatitis and 8% (3–19%) for fibrosis. Annualised mortality was 6% (4–7%) in patients with steatosis and 8% (5–13%) in cirrhosis. In patients with steatohepatitis on biopsy a marked difference was seen between inpatient cohorts (annual mortality 15%, 8–26%) and mixed cohorts of inpatients and outpatients (annual mortality 5%, 2–10%). Only in steatosis did non-liver-related mortality exceed liver-specific causes of mortality (5% per year vs. 1% per year). Conclusions: These data confirm the observation that alcohol-related hepatic steatohepatitis requiring admission to hospital is the most dangerous subtype of ALD. Alcohol-related steatosis is not a benign condition as it is associated with significant risk of mortality. Lay summary: Knowledge of the natural history of a disease allows clinicians and patients to understand the risks that are associated with a medical condition. In this study we systematically gathered all the published data regarding the natural history of alcohol-related liver disease in people who had a liver biopsy. We used this data to define the prevalence of the disease, the annual risk of progression to cirrhosis and the annual risk of death at each stage of the disease.

The diagnostic reach of nonalcoholic fatty liver disease (NAFLD) is broad, stretching from simple steatosis to cirrhosis. Expanded disease definitions are an important cause of waste in health care. Now is the time to revise the definition of NAFLD to include only those who have developed advanced fibrosis.

Purpose To determine which patient and injury factors are associated with the detection of high-grade laxity on examination under anesthesia before anterior cruciate ligament (ACL) reconstruction. Methods We identified 2,318 patients who underwent primary ACL reconstruction without associated ligament injuries. Demographic data and information regarding meniscal tears were collected. Patients with high-grade Lachman (difference from contralateral side >10 mm), pivot-shift (International Knee Documentation Committee grade 3+), or anterior drawer (difference from contralateral side >10 mm) tests were identified by physical examination under anesthesia before ACL reconstruction. Logistic regression modeling was used to evaluate whether chronicity of the ACL injury, patient age, sex, body mass index, generalized ligamentous laxity, and presence of meniscal tears were associated with increased odds of high-grade laxity, while we controlled for examining surgeon. Results Patients with chronic tears (>6 months from injury) had greater than twice the odds of having high-grade Lachman, pivot-shift, and anterior drawer tests (all P P P P = .013) meniscus tears were associated with increased odds of a high-grade Lachman test. Age younger than 20 years (OR, 1.34; P = .023), female sex (OR, 1.49; P = .001), generalized ligamentous laxity (OR, 3.46; P P P = .041) meniscus tear were associated with increased odds of a high-grade pivot-shift test. Generalized ligamentous laxity (OR, 2.27; P P = .001) or lateral (OR, 1.50; P = .010) meniscus tear were associated with increased odds of a high-grade anterior drawer test. Conclusions Chronic ACL tears, generalized ligamentous laxity, and meniscus tears are associated with increased odds of high-grade laxity with all 3 tests. Female patients and age younger than 20 years are associated with increased odds of a high-grade pivot-shift test. Level of Evidence Level II, lesser-quality prospective study.

Background Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver. Methods A cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model. Findings Obesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1–4.3, p = .022) and underweight (HR 2.38, 1.00–5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver. Interpretation Obesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH. Fund This work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Background\ud Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7 days to assess “response”.\ud \ud Aim\ud To assess the prognostic and therapeutic implications of baseline neutrophil‐to‐lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis.\ud \ud Methods\ud Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the receiver operating curve (AUC) analysis was performed. Kaplan‐Meier analysis was used to assess survival. Log‐rank test and odds ratio (OR) were used for comparative analysis.\ud \ud Results\ud Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90‐day outcome (0.660), but was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety‐day survival was not affected by prednisolone treatment if NLR < 5 or > 8 but mortality was reduced with prednisolone treatment when the NLR was 5‐8 (21.0% cf. 34.5%; P = 0.012). Prednisolone treatment increased the chance of Lille response if the NLR was ≥ 5 (56.5% cf. 41.1%: P = 0.01; OR 1.86) but increased the risk of day 7 infection (17.3% cf. 7.4%: P = 0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P = 0.008; OR 3.46) if the NLR was > 8. Incorporation of NLR into a modified Glasgow alcoholic hepatitis score (mGAHS) improved the AUC to 0.783 and 0.739 for 28‐day and 90‐day outcome, respectively.\ud \ud Conclusion\ud The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5‐8). The mGAHS has a good predictive value for 28‐ and 90‐day outcomes.

Background: Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver. Methods: A cohort of patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model. Findings: Obesity was common amongst patients with AH, seen in 19% of individuals. cBMI correlated with volume AT (r2= 0.623, p

Purpose To evaluate differences in repair and nonoperatively managed grade III medial collateral ligament (MCL) injuries during anterior cruciate ligament (ACL) reconstruction. Methods Patients enrolled in a multicenter prospective longitudinal group who underwent unilateral primary ACL reconstruction between 2002 and 2008 were evaluated. Patients with concomitant grade III MCL injuries treated either operatively or nonoperatively were identified. Concurrent injuries, subsequent surgeries, surgical chronicity, and MCL tear location were analyzed. Patient-reported outcomes were measured at time of ACL reconstruction and 2-year follow-up. Results Initially, 3,028 patients were identified to have undergone primary ACL reconstruction during the time frame; 2,586 patients completed 2-year follow-up (85%). Grade III MCL tears were documented in 1.1% (27 of 2,586): 16 operatively managed patients and 11 nonoperatively treated MCLs during ACL reconstruction. The baseline Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee scores were lower in patients who underwent operative MCL treatment. Reoperation rates for arthrofibrosis were 19% after repair and 9% after conservative management (P = .48). At 2 years, both groups significantly improved; however, the nonoperative MCL group maintained superior patient-reported outcomes in terms of minimal clinically important differences, but these differences did not reach statistical significance (KOOS sports/recreation [88.2 vs 74.4, P = .10], KOOS knee-related quality of life [81.3 vs 68.4, P = .13], and International Knee Documentation Committee [87.6 vs 76.0, P = .14]). Tibial-sided MCL injuries were associated with clinically inferior baseline scores compared with femoral-sided MCL (KOOS knee-related quality of life, 34.4 vs 18.5, P = .09), but these differences resolved by 2 years. Surgical chronicity did not influence 2-year outcome. Conclusions Both operative and nonoperative management of MCL tears in our patient group demonstrated clinical improvements between study enrollment and 2-year follow-up. MCL surgery during ACL reconstruction was assigned to patients with worse symptoms at enrollment and was associated with worse outcomes at 2 years. A subset of patients with severe combined ACL and medial knee injuries may benefit from operative management; however, that population has yet to be defined. Level of Evidence Level III, retrospective cohort.

Background: The occurrence of physiologic knee hyperextension (HE) in the revision anterior cruciate ligament reconstruction (ACLR) population and its effect on outcomes have yet to be reported. Hypothesis/Purpose: The prevalence of knee HE in revision ACLR and its effect on 2-year outcome were studied with the hypothesis that preoperative physiologic knee HE ≥5° is a risk factor for anterior cruciate ligament (ACL) graft rupture. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing revision ACLR were identified and prospectively enrolled between 2006 and 2011. Study inclusion criteria were patients undergoing single-bundle graft reconstructions. Patients were followed up at 2 years and asked to complete an identical set of outcome instruments (International Knee Documentation Committee, Knee injury and Osteoarthritis Outcome Score, WOMAC, and Marx Activity Rating Scale) as well as provide information regarding revision ACL graft failure. A regression model with graft failure as the dependent variable included age, sex, graft type at the time of the revision ACL surgery, and physiologic preoperative passive HE ≥5° (yes/no) to assess these as potential risk factors for clinical outcomes 2 years after revision ACLR. Results: Analyses included 1145 patients, for whom 2-year follow-up was attained for 91%. The median age was 26 years, with age being a continuous variable. Those below the median were grouped as “younger” and those above as “older” (age: interquartile range = 20, 35 years), and 42% of patients were female. There were 50% autografts, 48% allografts, and 2% that had a combination of autograft plus allograft. Passive knee HE ≥5° was present in 374 (33%) patients in the revision cohort, with 52% being female. Graft rupture at 2-year follow-up occurred in 34 cases in the entire cohort, of which 12 were in the HE ≥5° group (3.2% failure rate) and 22 in the non-HE group (2.9% failure rate). The median age of patients who failed was 19 years, as opposed to 26 years for those with intact grafts. Three variables in the regression model were significant predictors of graft failure: younger age (odds ratio [OR] = 3.6; 95% CI, 1.6-7.9; P = .002), use of allograft (OR = 3.3; 95% CI, 1.5-7.4; P = .003), and HE ≥5° (OR = 2.12; 95% CI, 1.1-4.7; P = .03). Conclusion: This study revealed that preoperative physiologic passive knee HE ≥5° is present in one-third of patients who undergo revision ACLR. HE ≥5° was an independent significant predictor of graft failure after revision ACLR with a >2-fold OR of subsequent graft rupture in revision ACL surgery. Registration: NCT00625885 ( ClinicalTrials.gov identifier).

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV-infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX-treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype (GT) 1-infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1-infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies.

SummaryObjectiveThe prevalence of radiographic osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR) approaches 50%, yet the prevalence of significant knee pain is unknown. We applied three different models of Knee injury and Osteoarthritis Outcome Score (KOOS) thresholds for significant knee pain to an ACLR cohort to identify prevalence and risk factors.DesignMulticenter Orthopaedic Outcomes Network (MOON) prospective cohort patients with a unilateral primary ACLR and normal contralateral knee were assessed at 2 and 6 years. Independent variables included patient demographics, validated Patient Reported Outcomes (PRO; Marx activity score, KOOS), and surgical characteristics. Models included: (1) KOOS criteria for a painful knee = quality of life subscale

SummaryObjectiveTo identify risk factors for radiographic signs of post-traumatic osteoarthritis (OA) 2–3 years after anterior cruciate ligament (ACL) reconstruction through multivariable analysis of minimum joint space width (mJSW) differences in a specially designed nested cohort.MethodsA nested cohort within the Multicenter Orthopaedic Outcomes Network (MOON) cohort included 262 patients (148 females, average age 20) injured in sport who underwent ACL reconstruction in a previously uninjured knee, were 35 or younger, and did not have ACL revision or contralateral knee surgery. mJSW on semi-flexed radiographs was measured in the medial compartment using a validated computerized method. A multivariable generalized linear model was constructed to assess mJSW difference between the ACL reconstructed and contralateral control knees while adjusting for potential confounding factors.ResultsUnexpectedly, we found the mean mJSW was 0.35 mm wider in ACL reconstructed than in control knees (5.06 mm (95% CI 4.96–5.15 mm) vs 4.71 mm (95% CI 4.62–4.80 mm), P

Purpose/Background We aimed to describe changes in survival in alcoholic hepatitis (AH) over time by examining published data. Methods A systematic literature search of Ovid Embase and PubMed was undertaken using the MESH terms ‘hepatitis, alcoholic’ to identify randomised controlled trials (RCT) and observational studies (OS) in alcoholic hepatitis. Data were extracted from included studies regarding 28-day, 90-day, 180-day mortality, as well as biochemical and clinical data. Results After review of the literature search results, 77 studies published between 1971 and 2016 were analysed, which included data from a total of 8,184 patients. Overall mortality from AH was 26% at 28 days, 29% at 90 days and 44% at 180 days after admission. No changes in mortality over time were observed in univariable analysis at 28 days or 90 days after admission (Pearson correlation r -0.216, p = 0.098, and r 0.121 p = 0.503 respectively). A small but statistically significant increase in mortality was seen in 180-day mortality (r 0.461 p = 0.036). However, after meta-regression to adjust for other factors associated with mortality at each time point, no changes in mortality were seen. Sub-group analysis did not reveal any changes in mortality over time in different study types, or when only biopsy-proven or severe disease were considered. Conclusion There has been no improvement in mortality from AH. This is not explained by changes in severity of disease. This emphasises the urgent need for effective treatments for this alcoholic hepatitis.

Background: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-related liver disease characterised by jaundice and liver failure. It is not known what might trigger an episode of AH. We interviewed patients to investigate changes in behaviour before the onset of AH. Methods: Structured interviews were performed with patients with AH to examine their alcohol use, diet, drug use and smoking habit. Clinical and laboratory results were noted. Patients were followed up for 12 months after interview. Results: Data from 39 patients was analysed. No single behavioural change occurred before the onset of jaundice, although reductions in alcohol and/or dietary intake were common. Reduction in alcohol use was seen to occur approximately 14 days before the onset of jaundice. Increased alcohol intake was not common. Clinical and laboratory data varied between types of behaviour changes, although these were not statistically significant. No changes in drug use or tobacco were reported before AH. Those who had not reduced alcohol intake or had increased their drinking had better survival. Conclusions: No single type of behaviour change is associated with AH. Contrary to previous assertions, increased alcohol intake was not common; in fact, participants were much more likely to have reduced their alcohol intake.

Introduction We aimed to describe changes in survival in alcoholic hepatitis (AH) over time by examining published data. Method A systematic literature search of Ovid Embase and PubMed was undertaken using the MESH terms ‘hepatitis, alcoholic’ to identify randomised controlled trials (RCT) and observational studies (OS) in alcoholic hepatitis. Data were extracted from included studies regarding 28 day, 90 day, 180 day mortality, as well as biochemical and clinical data. Results After review of the literature search results, 79 studies published between 1971 and 2016 were analysed, which included data from a total of 8318 patients. Overall mortality from AH was 25% at 28 days, 29% at 90 days and 38% at 180 days after admission. No changes in mortality over time were observed in univariable analysis at 28 days or 90 days after admission (Pearson correlation r −0.207, p=0.107, and r 0.109 p=0.553 respectively) (figure 1A and 1B). A statistically significant increase in mortality was seen in 180 day mortality (r 0.446 p=0.048) (figure 1C). However, after meta-regression to adjust for other factors associated with mortality at each time point, no changes in mortality were seen. Sub-group analysis of RCT and OS did not reveal any differences between type of study. Conclusion There has not been a significant improvement short-medium mortality from AH over the last four decades, despite much research and general medical innovation. This is not explained by changes in severity of disease. This emphasises the urgent need for effective treatments for this alcoholic hepatitis. Disclosure of Interest None Declared

Recent evidence that smaller hamstring graft diameter is associated with increased failure risk following anterior cruciate ligament (ACL) reconstruction has increased the popularity of graft configurations that increase graft diameter at the expense of graft length. A key question is how much graft needs to be in contact with the femoral tunnel to ensure that healing occurs. We hypothesize that no difference in two-year patient-reported outcomes or failure risk exists based on the amount of graft in the femoral tunnel. Through the use of prospectively collected cohort data augmented with retrospective chart review, 120 of 181 consecutive patients (66.3 %) undergoing primary ACL reconstruction with hamstring autograft were evaluated. Patient and surgical factors along with pre-operative and two-year postoperative knee injury and osteoarthritis outcome score (KOOS) and International Knee Documentation Committee (IKDC) scores and whether each patient underwent revision ACL reconstruction during the two-year follow-up period were recorded. No differences in two-year patient-reported outcome scores were noted between patients with graft length in the femoral tunnel less than 25 mm and those with graft length in the femoral tunnel of at least 25 mm. Controlling for age, sex, BMI, and femoral tunnel technique, no correlation was noted between KOOS or IKDC scores and either the length of graft in the femoral tunnel or the contact area between the graft and the tunnel. Variation of the length of hamstring autograft in the femoral tunnel between 14 and 35 mm does not predict KOOS or IKDC scores at 2 years postoperative.

Background: An initial anterior cruciate ligament (ACL) tear can be treated with surgical reconstruction or focused rehabilitation. The KANON (Knee Anterior cruciate ligament, NON-surgical versus surgical treatment) randomized controlled trial compared rehabilitation plus early ACL reconstruction (ACLR) to rehabilitation plus optional delayed ACLR and found no difference at 2 years by an intention-to-treat analysis of total Knee injury and Osteoarthritis Outcome Score (KOOS) results. Purpose: To compare the cost-effectiveness of early versus delayed ACLR. Study Design: Economic and decision analysis; Level of evidence, 2. Methods: A Markov decision model was constructed for a cost-utility analysis of early reconstruction (ER) versus rehabilitation plus optional delayed reconstruction (DR). Outcome probabilities and effectiveness were derived from 2 sources: the KANON study and the Multicenter Orthopaedic Outcomes Network (MOON) database. Collectively, these 2 sources provided data from 928 ACL-injured patients. Utilities were measured by the Short Form–6 dimensions (SF-6D). Costs were estimated from a societal perspective in 2012 US dollars. Costs and utilities were discounted in accordance with the United States Panel on Cost-Effectiveness in Health and Medicine. Effectiveness was expressed in quality-adjusted life-years (QALYs) gained. Principal outcome measures were average incremental costs, incremental effectiveness (as measured by QALYs), and net health benefits. Willingness to pay was set at $50,000, which is the currently accepted standard in the United States. Results: In the base case, the ER group resulted in an incremental gain of 0.28 QALYs over the DR group, with a corresponding lower overall cost to society of $1572. Effectiveness gains were driven by the low utility of an unstable knee and the lower utility for the DR group. The cost of rehabilitation and the rate of additional surgery drove the increased cost of the DR group. The most sensitive variable was the rate of knee instability after initial rehabilitation. When the rate of instability falls to 51.5%, DR is less costly, and when the rate of instability falls below 18.0%, DR becomes the preferred cost-effective strategy. Conclusion: An economic analysis of the timing of ACLR using data exclusively from the KANON trial, MOON cohort, and national average reimbursement revealed that early ACLR was more effective (improved QALYs) at a lower cost than rehabilitation plus optional delayed ACLR. Therefore, early ACLR should be the preferred treatment strategy from a societal health system perspective.

A transjugular intrahepatic portosystemic shunt (TIPS) is an expandable metal stent inserted via the jugular vein that creates a shunt from the portal vein to the systemic circulation via an artificial communication through the liver. It is used to treat complications of portal hypertension. In addition to rescue treatment in variceal bleeding, TIPS can play an important role in prevention of rebleeding. TIPS can improve symptoms if medical treatment of ascites or hepatic hydrothrorax has failed, but may not improve survival. Selected cases of Budd-Chiari syndrome improve with TIPS. This article discusses the indications, evidence, and complications of TIPS.

Objectives: Multiple studies have shown patients are susceptible to post-traumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) injury even with ACL reconstruction (ACLR). Prospective studies using multivariate analysis to identify risk factors for PTOA are lacking. This study aims to identify baseline predictors of radiographic PT OA after ACLR at an early time point and hypothesizes that meniscal injury and cartilage lesions will be associated with worse radiographic OA using the Osteoarthritis Research Society International (OARSI) atlas criteria. Methods: 421 patients who underwent ACLR returned onsite for standardized posteroanterior metatarsophalangeal radiographs a minimum of 2 years after surgery. At baseline, demographics, graft type, meniscal status/treatment, and cartilage status were collected. OARSI atlas criteria were used to grade all knee radiographs. Multivariable ordinal regression models identified baseline predictors of radiographic OARSI grades at follow-up. Results: The mean age was 19.8 years with 51.3% females. Higher age (odds ratio (OR) 1.06) and BMI (OR 1.05) were statistically significantly associated with higher OARSI grade in the medial compartment. Patients with a meniscal repair and a partial meniscectomy had statistically significantly higher OARSI grades in the medial compartment (meniscal repair OR 1.92 and meniscectomy OR 2.11) and in the lateral compartment (meniscal repair OR 1.96 and meniscectomy OR 2.97). Graft type, cartilage lesion, sex, and Marx activity scales had no significant association with OARSI grade. Conclusion: Older patients with a higher BMI who have an ACL tear with concurrent meniscal tear requiring partial meniscectomy or meniscal repair should be advised of their increased risk of developing radiographic OA. Alternatively, patients with an ACL tear with an articular cartilage lesion can be reassured that they are not at increased risk of developing radiographic knee OA at 2-3 years following ACLR.

Background: Identifying risk factors for inferior outcomes after anterior cruciate ligament reconstruction (ACLR) is important for prognosis and future treatment. Hypothesis: Articular cartilage lesions and meniscus tears/treatment would predict International Knee Documentation Committee (IKDC) score, Knee injury and Osteoarthritis Outcome Score (KOOS) (all 5 subscales), and Marx activity level at 6 years after ACLR. Study Design: Cohort study (prognosis); Level of evidence, 1. Methods: Between 2002 and 2004, a total of 1512 ACLR patients were prospectively enrolled and followed longitudinally, with the IKDC, KOOS, and Marx activity score completed at entry, 2 years, and 6 years. A logistic regression model was built incorporating variables from patient demographics, surgical technique, articular cartilage injuries, and meniscus tears/treatment to determine the predictors (risk factors) of IKDC and KOOS scores and Marx activity level at 6 years. Results: A minimum follow-up on 86% (1307/1512) of the cohort was completed at 6 years. The cohort was 56% male and had a median age of 23 years at the time of enrollment, with 76% reporting a noncontact injury mechanism. Incidence of concomitant injury at the time of surgery consisted of the following: articular cartilage (medial femoral condyle [MFC], 25%; lateral femoral condyle [LFC] 20%; medial tibial plateau [MTP], 6%; lateral tibial plateau [LTP], 12%; patella, 20%; trochlear, 9%) and meniscus (medial, 38%; lateral, 46%). Both articular cartilage lesions and meniscus tears were significant predictors of 6-year outcomes on the IKDC and KOOS. Grade 3 or 4 articular cartilage lesions (excluding patella) significantly reduced IKDC and KOOS scores at 6 years. The IKDC demonstrated worse outcomes with the presence of a grade 3 or 4 chondral lesion on the MFC, MTP, and LFC. Likewise, the KOOS score was negatively affected by cartilage injury. The sole significant predictor of reduced Marx activity level was the presence of a grade 4 lesion on the MFC. Lateral meniscus repairs did not correlate with inferior results, but medial meniscus repairs predicted worse IKDC and KOOS scores. Lateral meniscus tears left alone significantly improved prognosis. Small partial meniscectomies (50%) on either the medial or lateral menisci improved prognosis. Analogous to previous studies, other significant predictors of lower outcome scores were lower baseline scores, higher body mass index, lower education level, smoking, and anterior cruciate ligament revisions. Conclusion: Both articular cartilage injury and meniscus tears/treatment at the time of ACLR were significant predictors of IKDC and KOOS scores 6 years after ACLR. Similarly, having a grade 4 MFC lesion significantly reduced a patient’s Marx activity level score at 6 years.

BACKGROUND Prognostic scores are used to assess the likelihood of mortality in cirrhosis and the necessity of liver transplantation. These models are imperfect and refinement would allow more accurate prognostication and selection of patients for transplant. This study investigated association of red cell parameters and mortality in liver transplant candidates. METHODS Data from patients with cirrhosis assessed for transplantation from 2008 to 2010 at Queen Elizabeth Hospital Birmingham, UK were reviewed retrospectively. Kaplan-Meier analysis and Cox regression models were used to generate indices predicting mortality. Accuracy of existing and updated models was tested by calculation of c-statistics. Results were validated in a cohort of patients assessed for liver transplant in Jena, Germany. RESULTS Data were collected from 386 patients in the study cohort. Median follow-up was 15 months (0-45). During follow-up, 151 patients (39%) were transplanted, 138 (36%) died, and 97 (25%) survived without transplant. Abnormal reticulocyte count (P

This review focuses on alcohol and substance abuse in the context of solid-organ transplantation. Alcohol and substance abuse are common and may lead to a need for solid-organ transplantation and may also contribute to significant physical and psychologic problems that impact upon the recipient. Damaging levels of alcohol intake can occur in the absence of dependence. Alcohol or substance abuse after transplantation is associated with poor medication compliance and this may increase risk of graft loss. Intravenous drug use is associated with increased risk of infections (especially secondary to opportunistic organisms-bacterial, viral, protozoal, and others-and such infections may be more severe in the immunosuppressed), but there is only anecdotal evidence that such behavior has a worse outcome in transplant recipients. Whereas previous alcohol excess and drug use in kidney recipients are both associated with a small but statistically significantly increased risk of adverse outcomes (hazard ratio, 1.16-1.56), alcohol use within recommended guidelines after transplantation appears safe and possibly beneficial. Robust data are lacking for other organs, but those available suggest that heart transplantation is safe in individuals with a history of alcohol or substance abuse. Health specialists in drug or alcohol addiction should carefully screen all potential transplant candidates for these conditions, and where there is evidence of dependency or abuse, effective psychologic and physical treatment should be offered. Studies have shown that interventions such as psychologic intervention have improved alcohol behavior in the context of liver transplantation. Although there are no comparable studies with other solid-organ recipients, it is reasonable to expect transferable outcomes.

Hepatitis C virus (HCV) is a major cause of global morbidity, causing chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma. The liver is a large and complex organ containing multiple cell types, including hepatocytes, sinusoidal endothelial cells (LSEC), Kupffer cells, and biliary epithelial cells. Hepatocytes are the major reservoir supporting HCV replication; however, the role of nonparenchymal cells in the viral lifecycle remains largely unexplored. LSEC secrete factors that promote HCV infection and transcript analysis identified bone morphogenetic protein 4 (BMP4) as a candidate endothelial-expressed proviral molecule. Recombinant BMP4 increased HCV replication and neutralization of BMP4 abrogated the proviral activity of LSEC-conditioned media. Importantly, BMP4 expression was negatively regulated by vascular endothelial growth factor A (VEGF-A) by way of a VEGF receptor-2 (VEGFR-2) primed activation of p38 MAPK. Consistent with our in vitro observations, we demonstrate that in normal liver VEGFR-2 is activated and BMP4 expression is suppressed. In contrast, in chronic liver disease including HCV infection where there is marked endothelial cell proliferation, we observed reduced endothelial cell VEGFR-2 activation and a concomitant increase in BMP4 expression. Conclusion: These studies identify a role for LSEC and BMP4 in HCV infection and highlight BMP4 as a new therapeutic target for treating individuals with liver disease. (Hepatology 2014;59:375–384)