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Background: Patients with anterior cruciate ligament (ACL) revision report lower outcome scores on validated knee questionnaires postoperatively compared to cohorts with primary ACL reconstruction. In a previously active population, it is unclear if patient-reported outcomes (PROs) are associated with a return to activity (RTA) or vary by sports participation level (higher level vs. recreational athletes). Hypotheses: Individual RTA would be associated with improved outcomes (ie, decreased knee symptoms, pain, function) as measured using validated PROs. Recreational participants would report lower PROs compared with higher level athletes and be less likely to RTA. Study Design: Cohort study; Level of evidence, 2. Methods: There were 862 patients who underwent a revision ACL reconstruction (rACLR) and self-reported physical activity at any level preoperatively. Those who did not RTA reported no activity 2 years after revision. Baseline data included patient characteristics, surgical history and characteristics, and PROs: International Knee Documentation Committee questionnaire, Marx Activity Rating Scale, Knee injury and Osteoarthritis Outcome Score, and the Western Ontario and McMaster Universities Osteoarthritis Index. A binary indicator was used to identify patients with same/better PROs versus worse outcomes compared with baseline, quantifying the magnitude of change in each direction, respectively. Multivariable regression models were used to evaluate risk factors for not returning to activity, the association of 2-year PROs after rACLR surgery by RTA status, and whether each PRO and RTA status differed by participation level. Results: At 2 years postoperatively, approximately 15% did not RTA, with current smokers (adjusted odds ratio [aOR] = 3.3; P = .001), female patients (aOR = 2.9; P < .001), recreational participants (aOR = 2.0; P = .016), and those with a previous medial meniscal excision (aOR = 1.9; P = .013) having higher odds of not returning. In multivariate models, not returning to activity was significantly associated with having worse PROs at 2 years; however, no clinically meaningful differences in PROs at 2 years were seen between participation levels. Conclusion: Recreational-level participants were twice as likely to not RTA compared with those participating at higher levels. Within a previously active cohort, no RTA was a significant predictor of lower PROs after rACLR. However, among patients who did RTA after rACLR, approximately 20% reported lower outcome scores. Most patients with rACLR who were active at baseline improved over time; however, patients who reported worse outcomes at 2 years had a clinically meaningful decline across all PROs.

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: A primary goal of anterior cruciate ligament reconstruction (ACLR) is to reduce pathologically increased anterior and rotational laxity of the knee, but the effects of residual laxity on patient-reported outcomes (PROs) after ACLR remain unclear. Hypothesis: Increased residual laxity at 2 years postoperatively is predictive of a higher risk of subsequent ipsilateral knee surgery and decreases in PRO scores from 2 to 6 years after surgery. Study Design: Cohort study; Level of evidence, 2. Methods: From a prospective multicenter cohort, 433 patients aged 6 mm) in laxity at 2 years postoperatively. Multiple linear regression models were built to determine the relationship between 2-year postoperative knee laxity and 2- to 6-year change in PROs while controlling for age, sex, body mass index, smoking status, meniscal and cartilage status, and graft type. Results: A total of 381 patients (87.9%) were available for follow-up 6 years postoperatively. There were no significant differences in risk of subsequent knee surgery based on residual knee laxity. Patients with a difference >6 mm in side-to-side anterior laxity at 2 years postoperatively were noted to have a larger decrease in PROs from 2 to 6 years postoperatively ( P < .05). No significant differences in any PROs were noted among patients with a difference Conclusion: The presence of a residual side-to-side KT-1000 arthrometer difference 6 mm in side-to-side anterior laxity were noted to have significantly decreased PROs at 6 years after ACLR.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

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)

Bone bruise patterns after anterior cruciate ligament (ACL) rupture may predict the presence of intra-articular pathology and help explain the mechanism of injury. Lateral femoral condyle (LFC) and lateral tibial plateau (LTP) bone bruises are pathognomic to ACL rupture. There is a lack of information regarding medial tibial plateau (MTP) and medial femoral condyle (MFC) bone bruises.To summarize the prevalence and location of MTP bone bruises with acute ACL rupture and to determine the predictors of MTP bone bruises.Cross-sectional study; Level of evidence, 3.Inclusion criteria were patients who underwent ACL reconstruction between February 2015 and November 2017, magnetic resonance imaging (MRI) within 90 days of injury, and participation in the database. Exclusion criteria included previous ipsilateral surgery, multiligamentous injuries, and incomplete imaging. Due to the large number of cases remaining (n = 600), 150 patients were selected randomly from each year included in the study, for a total of 300 patients. Two readers independently reviewed injury MRI scans using the Costa-Paz bone bruise grading system. Logistic regression was used to identify factors associated with MTP bone bruises.Included were 208 patients (mean age, 23.8 years; mean body mass index, 25.6). The mechanism of injury was noncontact in 59% of injuries, with over half from soccer, basketball, and football. The median time from injury to MRI scan was 12 days. Of the 208 patients, 98% (203/208) had a bone bruise, 79% (164/208) had an MTP bone bruise, and 83% (172/208) had bruises in both medial and lateral compartments. The most common pattern, representing 46.6% of patients (97/208), was a bruise in all 4 locations (MFC, LFC, MTP, and LTP). Of the 164 MTP bruises, 160 (98%) involved the posterior third of the plateau, and 161 were grade 1. The presence of an MFC bruise was the only independent risk factor for an MTP bruise (odds ratio, 3.71). The resulting nomogram demonstrated MFC bruise, sport, and mechanism of injury were the most important predictors of an MTP bruise.MTP bruise after acute ACL rupture was as prevalent as lateral bruises. The presence of a posterior MTP bruise suggested anterior tibial translation at the time of injury and could portend more medial compartment pathology at the time of injury than previously recognized.

It is unknown whether race- or insurance-based disparities in health care exist regarding baseline knee pain, knee function, complete meniscal tear, or articular cartilage damage in patients who undergo anterior cruciate ligament reconstruction (ACLR).Black patients and patients with Medicaid evaluated for ACLR would have worse baseline knee pain, worse knee function, and greater odds of having a complete meniscal tear.Cross-sectional study; Level of evidence, 3.A cohort of patients (N = 1463; 81% White, 14% Black, 5% Other race; median age, 22 years) who underwent ACLR between February 2015 and December 2018 was selected from an institutional database. Patients who underwent concomitant procedures and patients of undisclosed race or self-pay status were excluded. The associations of race with preoperative Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale, KOOS Function subscale, and intraoperatively assessed complete meniscal tear (tear that extended through both the superior and the inferior meniscal surfaces) were determined via multivariate modeling with adjustment for age, sex, insurance status, years of education, smoking status, body mass index (BMI), meniscal tear location, and Veterans RAND 12-Item Health Survey Mental Component Score (VR-12 MCS).The 3 factors most strongly associated with worse KOOS Pain and KOOS Function were lower VR-12 MCS score, increased BMI, and increased age. Except for age, the other two factors had an unequal distribution between Black and White patients. Univariate analysis demonstrated equal baseline median KOOS Pain scores (Black, 72.2; White, 72.2) and KOOS Function scores (Black, 68.2; White, 68.2). After adjusting for confounding variables, there was no significant difference between Black and White patients in KOOS Pain, KOOS Function, or complete meniscal tears. Insurance status was not a significant predictor of KOOS Pain, KOOS Function, or complete meniscal tear.There were clinically significant differences between Black and White patients evaluated for ACLR. After accounting for confounding factors, no difference was observed between Black and White patients in knee pain, knee function, or complete meniscal tear. Insurance was not a clinically significant predictor of knee pain, knee function, or complete meniscal tear.

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.

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both

Background: The cause of subsequent surgery after anterior cruciate ligament (ACL) reconstruction varies, but if risk factors for specific subsequent surgical procedures can be identified, we can better understand which patients are at greatest risk. Purpose: To report the incidence and types of subsequent surgery that occurred in a cohort of patients 6 years after their index ACL reconstruction and to identify which variables were associated with the incidence of patients undergoing subsequent surgery after their index ACL reconstruction. Study Design: Cohort study; Level of evidence, 2. Methods: Patients completed a questionnaire before their index ACL surgery and were followed up at 2 and 6 years. Patients were contacted to determine whether any underwent additional surgery since baseline. Operative reports were obtained, and all surgical procedures were categorized and recorded. Logistic regression models were constructed to predict which patient demographic and surgical variables were associated with the incidence of undergoing subsequent surgery after their index ACL reconstruction. Results: The cohort consisted of 3276 patients (56.3% male) with a median age of 23 years. A 6-year follow-up was obtained on 91.5% (2999/3276) with regard to information on the incidence and frequency of subsequent surgery. Overall, 20.4% (612/2999) of the cohort was documented to have undergone at least 1 subsequent surgery on the ipsilateral knee 6 years after their index ACL reconstruction. The most common subsequent surgical procedures were related to the meniscus (11.9%), revision ACL reconstruction (7.5%), loss of motion (7.8%), and articular cartilage (6.7%). Significant risk factors for incurring subsequent meniscus-related surgery were having a medial meniscal repair at the time of index surgery, reconstruction with a hamstring autograft or allograft, higher baseline Marx activity level, younger age, and cessation of smoking. Significant predictors of undergoing subsequent surgery involving articular cartilage were higher body mass index, higher Marx activity level, reconstruction with a hamstring autograft or allograft, meniscal repair at the time of index surgery, or a grade 3/4 articular cartilage abnormality classified at the time of index ACL reconstruction. Risk factors for incurring subsequent surgery for loss of motion were younger age, female sex, low baseline Knee injury and Osteoarthritis Outcome Score symptom subscore, and reconstruction with a soft tissue allograft. Conclusion: These findings can be used to identify patients who are at the greatest risk of incurring subsequent surgery after ACL reconstruction.

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: Articular cartilage and meniscal damage are commonly encountered and often treated at the time of anterior cruciate ligament reconstruction (ACLR). Our understanding of how these injuries and their treatment relate to outcomes of ACLR is still evolving. Hypothesis/Purpose: The purpose of this study was to assess whether articular cartilage and meniscal variables are predictive of 10-year outcomes after ACLR. We hypothesized that articular cartilage lesions and meniscal tears and treatment would be predictors of the International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS) (all 5 subscales), and Marx activity level outcomes at 10-year follow-up after ACLR. Study Design: Cohort study (prognosis); Level of evidence, 1. Methods: Between 2002 and 2008, individuals with ACLR were prospectively enrolled and followed longitudinally using the IKDC, KOOS, and Marx activity score completed at entry, 2, 6, and 10 years. A proportional odds logistic regression model was built incorporating variables from patient characteristics, surgical technique, articular cartilage injuries, and meniscal tears and treatment to determine the predictors (risk factors) of IKDC, KOOS, and Marx outcomes at 10 years. Results: A total of 3273 patients were enrolled (56% male; median age, 23 years at time of enrollment). Ten-year follow-up was obtained on 79% (2575/3273) of the cohort. Incidence of concomitant pathology at the time of surgery consisted of the following: articular cartilage (medial femoral condyle [MFC], 22%; lateral femoral condyle [LFC], 15%; medial tibial plateau [MTP], 4%; lateral tibial plateau [LTP], 11%; patella, 18%; trochlea, 8%) and meniscal pathology (medial, 37%; lateral, 46%). Variables that were predictive of poorer 10-year outcomes included articular cartilage damage in the patellofemoral ( P < .01) and medial ( P < .05) compartments and previous medial meniscal surgery (7% of knees; P < .04). Compared with no meniscal tear, a meniscal injury was not associated with 10-year outcomes. Medial meniscal repair at the time of ACLR was associated with worse 10-year outcomes for 2 of 5 KOOS subscales, while a medial meniscal repair in knees with grade 2 MFC chondrosis was associated with better outcomes on 2 KOOS subscales. Conclusion: Articular cartilage injury in the patellofemoral and medial compartments at the time of ACLR and a history of medial meniscal surgery before ACLR were associated with poorer 10-year ACLR patient-reported outcomes, but meniscal injury present at the time of ACLR was not. There was limited and conflicting association of medial meniscal repair with these outcomes.

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 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: Anterior cruciate ligament (ACL) revision cohorts continually report lower outcome scores on validated knee questionnaires than primary ACL cohorts at similar time points after surgery. It is unclear how these outcomes are associated with physical activity after physician clearance for return to recreational or competitive sports after ACL revision surgery. Hypotheses: Participants who return to either multiple sports or a singular sport after revision ACL surgery will report decreased knee symptoms, increased activity level, and improved knee function as measured by validated patient-reported outcome measures (PROMs) and compared with no sports participation. Multisport participation as compared with singular sport participation will result in similar increased PROMs and activity level. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 1205 patients who underwent revision ACL reconstruction were enrolled by 83 surgeons at 52 clinical sites. At the time of revision, baseline data collected included the following: demographics, surgical characteristics, previous knee treatment and PROMs, the International Knee Documentation Committee (IKDC) questionnaire, Marx activity score, Knee injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). A series of multivariate regression models were used to evaluate the association of IKDC, KOOS, WOMAC, and Marx Activity Rating Scale scores at 2 years after revision surgery by sports participation category, controlling for known significant covariates. Results: Two-year follow-up was obtained on 82% (986 of 1205) of the original cohort. Patients who reported not participating in sports after revision surgery had lower median PROMs both at baseline and at 2 years as compared with patients who participated in either a single sport or multiple sports. Significant differences were found in the change of scores among groups on the IKDC ( P < .0001), KOOS-Symptoms ( P = .01), KOOS–Sports and Recreation ( P = .04), and KOOS–Quality of Life ( P < .0001). Patients with no sports participation were 2.0 to 5.7 times more likely than multiple-sport participants to report significantly lower PROMs, depending on the specific outcome measure assessed, and 1.8 to 3.8 times more likely than single-sport participants (except for WOMAC-Stiffness, P = .18), after controlling for known covariates. Conclusion: Participation in either a single sport or multiple sports in the 2 years after ACL revision surgery was found to be significantly associated with higher PROMs across multiple validated self-reported assessment tools. During follow-up appointments, surgeons should continue to expect that patients who report returning to physical activity after surgery will self-report better functional outcomes, regardless of baseline activity levels.

Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes than primary ACL reconstruction. The reasons remain varied and not completely understood. METHODS: Patients undergoing revision ACL reconstruction were prospectively enrolled. Data collected included baseline demographics, surgical technique and pathological condition, prescribed rehabilitation instructions, and a series of validated patient-reported outcome instruments. Patients were followed for 2 years and asked to complete a set of outcome instruments identical to those completed at baseline. Subsequent surgical procedures on the ipsilateral knee were recorded. Regression analysis was used to control for age, sex, activity level, baseline outcome scores, and the above-mentioned rehabilitation-related variables in order to assess the factors affecting clinical outcomes 2 years after revision ACL reconstruction. RESULTS: A total of 843 patients met the inclusion criteria and were successfully enrolled, and 82% (695) were followed for 2 years. Two rehabilitation-related factors were found to influence outcome. First, patients who were prescribed an ACL brace for their return to sports had a significantly better Knee injury and Osteoarthritis Outcome Score (KOOS) for sports and recreational activities at 2 years (odds ratio [OR] =1.50, 95% confidence interval [CI] = 1.07 to 2.11; p = 0.019). Second, patients prescribed an ACL brace for the postoperative rehabilitation period were 2.3 times more likely to have subsequent surgery by 2 years (OR = 2.26, 95% CI = 1.11 to 4.60; p = 0.024). The odds of a graft rerupture were not affected by any type of brace wear. CONCLUSIONS: Rehabilitation-related factors that the physician can control at the time of an ACL reconstruction have the ability to influence clinical outcomes at 2 years. Weight-bearing and motion can be initiated immediately postoperatively. Bracing during the early postoperative period is not helpful. Use of a functional brace early in the postoperative period was associated with an increased risk of a reoperation. Use of a functional brace for a return to sports improved the KOOS on the sports/recreation subscale. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Background: Opioid use and public insurance have been correlated with worse outcomes in a number of orthopaedic surgeries. These factors have not been investigated with anterior cruciate ligament reconstruction (ACLR). Purpose/Hypothesis: To evaluate if narcotic use, physical therapy location, and insurance type are predictors of patient-reported outcomes after ACLR. It was hypothesized that at 1 year postsurgically, increased postoperative narcotic use would be associated with worse outcomes, physical therapy obtained within the authors’ integrated health care system would lead to better outcomes, and public insurance would lead to worse outcomes and athletic activity. Study Design: Cohort study; Level of evidence, 2. Methods: All patients undergoing unilateral, primary ACLR between January 2015 and February 2016 at a large health system were enrolled in a standard-of-care prospective cohort. Knee injury and Osteoarthritis Score (KOOS) and the Hospital for Special Surgery Pediatric–Functional Activity Brief Scale (HSS Pedi-FABS) were collected before surgery and at 1 year postoperatively. Concomitant knee pathology was assessed arthroscopically and electronically captured. Patient records were analyzed to determine physical therapy location, insurance status, and narcotic use. Multivariable regression analyses were used to identify significant predictors of the KOOS and HSS Pedi-FABS score. Results: A total of 258 patients were included in the analysis (mean age, 25.8; 51.2% women). In multivariable regression analysis, narcotic use, physical therapy location, and insurance type were not independent predictors of any KOOS subscales. Public insurance was associated with a lower HSS Pedi-FABS score (–4.551, P = .047) in multivariable analysis. Narcotic use or physical therapy location was not associated with the HSS Pedi-FABS score. Conclusion: Increased narcotic use surrounding surgery, physical therapy location within the authors’ health care system, and public versus private insurance were not associated with disease-specific KOOS subscale scores. Patients with public insurance had worse HSS Pedi-FABS activity scores compared with patients with private insurance, but neither narcotic use nor physical therapy location was associated with activity scores. Physical therapy location did not influence outcomes, suggesting that patients be given a choice in the location they received physical therapy (as long as a standardized protocol is followed) to maximize compliance.

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.

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.

Introduction The objectives of this study are (1) to develop a provider-friendly, evidence-based data capture system for lower-limb orthopaedic surgeries and (2) to assess the performance of the data capture system on the dimensions of agreement with operative note and implant log, consistency of data, and speed of provider input. Methods A multidisciplinary team developed a database and user interfaces for Android and iOS operating systems. Branching logic and discrete fields were created to streamline provider data input. One hundred patients were randomly selected from the first four months of data collection (February to June 2015). Patients were limited to those undergoing anterior cruciate ligament reconstruction, meniscal repair, partial meniscectomy, or a combination of these procedures. Duplicate data on these 100 patients were collected through chart review. These two data sets were compared. Cohen's kappa statistic was used to assess agreement. Results The database and smartphone data capture tool show almost perfect agreement (kappa > 0.81) for all data tested. In addition, data are more comprehensive with near-perfect provider completion (100% for all data tested). Furthermore, provider data entry is extremely efficient (median 151-second completion time). Conclusion A well-designed database and user-friendly interface have greater potential for research utility, clinical efficiency, and, thus, cost-effectiveness when compared with standard voice-dictated operative notes. Widespread utilization of such tools can accelerate the pace and improve the quality of orthopaedic clinical research. Level of evidence Level IV.

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).

Uncertainty sums up the Arctic of today, with significant implications for sovereignty and branding Canada. Climate change produces a level of interest in the North from a widening range of actors and confronts Canada with new challenges. The present study uses an expected utility forecasting model to assess the likely outcomes, under current conditions, across a range of substantively important issues in the Arctic. After an overview of the Arctic as an essential aspect of the Canadian brand, the work unfolds in four further stages. First, a forecasting model is introduced and linked to the present context. The second stage presents the expert-generated data used to forecast the future. Third, forecasts are produced and assessed in terms of implications for existing policy in areas ranging from search and rescue to transit of the Northwest Passage (NWP). The fourth and final stage offers conclusions about the Canadian brand in relation to the Arctic and suggests directions for future research.

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.

Background:When meniscal repair is performed during anterior cruciate ligament (ACL) reconstruction (ACLR), the effect of ACL graft type on meniscal repair outcomes is unclear.Hypothesis:The authors hypothesized that meniscal repairs would fail at the lowest rate when concomitant ACLR was performed with bone--patellar tendon--bone (BTB) autograft.Study Design:Cohort study; Level of evidence, 3.Methods:Patients who underwent meniscal repair at primary ACLR were identified from a longitudinal, prospective cohort. Meniscal repair failures, defined as any subsequent surgical procedure addressing the meniscus, were identified. A logistic regression model was built to assess the association of graft type, patient-specific factors, baseline Marx activity rating score, and meniscal repair location (medial or lateral) with repair failure at 6-year follow-up.Results:A total of 646 patients were included. Grafts used included BTB autograft (55.7%), soft tissue autograft (33.9%), and various allografts (10.4%). We identified 101 patients (15.6%) with a documented meniscal repair failure. Failure occurred in 74 of 420 (17.6%) isolated medial meniscal repairs, 15 of 187 (8%) isolated lateral meniscal repairs, and 12 of 39 (30.7%) of combined medial and lateral meniscal repairs. Meniscal repair failure occurred in 13.9% of patients with BTB autografts, 17.4% of patients with soft tissue autografts, and 19.4% of patients with allografts. The odds of failure within 6 years of index surgery were increased more than 2-fold with allograft versus BTB autograft (odds ratio = 2.34 [95% confidence interval, 1.12-4.92]; P = .02). There was a trend toward increased meniscal repair failures with soft tissue versus BTB autografts (odds ratio = 1.41 [95% confidence interval, 0.87-2.30]; P = .17). The odds of failure were 68% higher with medial versus lateral repairs ( P < .001). There was a significant relationship between baseline Marx activity level and the risk of subsequent meniscal repair failure; patients with either very low (0-1 points) or very high (15-16 points) baseline activity levels were at the highest risk ( P = .004).Conclusion:Meniscal repair location (medial vs lateral) and baseline activity level were the main drivers of meniscal repair outcomes. Graft type was ranked third, demonstrating that meniscal repairs performed with allograft were 2.3 times more likely to fail compared with BTB autograft. There was no significant difference in failure rates between BTB versus soft tissue autografts.Registration:NCT00463099 (ClinicalTrials.gov identifier).

Background:Articular cartilage health is an important issue following anterior cruciate ligament (ACL) injury and primary ACL reconstruction. Factors present at the time of primary ACL reconstruction may influence the subsequent progression of articular cartilage damage.Hypothesis:Larger meniscus resection at primary ACL reconstruction, increased patient age, and increased body mass index (BMI) are associated with increased odds of worsened articular cartilage damage at the time of revision ACL reconstruction.Study Design:Case-control study; Level of evidence, 3.Methods:Subjects who had primary and revision data in the databases of the Multicenter Orthopaedics Outcomes Network (MOON) and Multicenter ACL Revision Study (MARS) were included. Reviewed data included chondral surface status at the time of primary and revision surgery, meniscus status at the time of primary reconstruction, primary reconstruction graft type, time from primary to revision ACL surgery, as well as demographics and Marx activity score at the time of revision. Significant progression of articular cartilage damage was defined in each compartment according to progression on the modified Outerbridge scale (increase ≥1 grade) or >25% enlargement in any area of damage. Logistic regression identified predictors of significant chondral surface change in each compartment from primary to revision surgery.Results:A total of 134 patients were included, with a median age of 19.5 years at revision surgery. Progression of articular cartilage damage was noted in 34 patients (25.4%) in the lateral compartment, 32 (23.9%) in the medial compartment, and 31 (23.1%) in the patellofemoral compartment. For the lateral compartment, patients who had >33% of the lateral meniscus excised at primary reconstruction had 16.9-times greater odds of progression of articular cartilage injury than those with an intact lateral meniscus ( P < .001). For the medial compartment, patients who had Conclusion:Excision of the medial and lateral meniscus at primary ACL reconstruction increases the odds of articular cartilage damage in the corresponding compartment at the time of revision ACL reconstruction. Increased age is a risk factor for deterioration of articular cartilage in both tibiofemoral compartments, while increased BMI and the use of allograft for primary ACL reconstruction are associated with an increased risk of progression in the patellofemoral compartment.

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

Background: Understanding the risk factors for loss to follow-up in prospective clinical studies may allow for a targeted approach to minimizing follow-up bias and improving the generalizability of conclusions in anterior cruciate ligament reconstruction (ACLR) and other sports-related interventions. Purpose: To identify independent risk factors associated with failure to complete (ie, loss to follow-up) patient-reported outcome measures (PROMs) at 2 years after ACLR within a well-funded prospective longitudinal cohort. Study Design: Cohort study (prognosis); Level of evidence, 2. Methods: All patients undergoing primary or revision ACLR enrolled in the prospectively collected database of the multicenter consortium between 2002 and 2008 were included. Multivariate regression analyses were conducted to determine which baseline risk factors were significantly associated with loss to follow-up at a minimum of 2 years after surgery. Predictors assessed for loss to follow-up were as follows: consortium site, sex, race, marital status, smoking status, phone number provided (home or cell), email address provided (primary or secondary), years of school completed, average hours worked per week, working status (full-time, part-time, homemaker, retired, student, or disabled), number of people living at home, and preoperative PROMs (Knee injury and Osteoarthritis Outcome Score, Marx Activity Rating Scale, and International Knee Documentation Committee). Results: A total of 3202 patients who underwent ACLR were enrolled. The 2-year PROM follow-up rate for this cohort was 88% (2821 of 3202). Multivariate analyses showed that patient sex (male: odds ratio [OR], 1.80) and race (black: OR, 3.64; other nonwhite: OR, 1.81) were independent predictors of 2-year loss to follow-up of PROMs. Education level was a nonconfounder. Conclusion: While education level did not predict loss to follow-up, patients who are male and nonwhite are at increased risk of loss to follow-up of PROM at 2 years. Capturing patient outcomes with minimal loss depends on equitable, not equal, opportunity to maximize generalizability and mitigate potential population-level health disparities. Registration: NCT00478894 (ClinicalTrials.gov identifier).

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.

Background: Lower socioeconomic status (SES) is associated with worse patient-reported outcome (PRO) after orthopaedic procedures. In patients with anterior cruciate ligament (ACL) reconstruction, evaluating SES by use of traditional measures such as years of education or occupation is problematic because this group has a large proportion of younger patients. We hypothesized that lower education level and lower values for SES would predict worse PRO at 2 years after ACL reconstruction and that the effect of education level would vary with patient age. Purpose: To compare the performance of multivariable models that use traditional measures of SES with models that use an index of neighborhood SES derived from United States (US) Census data. Study Design: Cohort study; Level of evidence, 3. Methods: A cohort of 675 patients (45% female; median age, 20 years), were prospectively enrolled and evaluated 2 years after ACL reconstruction with questionnaires including the International Knee Documentation Committee (IKDC) questionnaire, the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Marx activity rating scale (Marx). In addition, a new variable was generated for this study, the SES index, which used geocoding performed retrospectively to identify the census tract of residence for each participant at the time of enrollment and extract neighborhood SES measures from the 2000 US Census Descriptive Statistics. Multivariable models were constructed that included traditional measures of SES as well as the SES index, and the quality of models was compared through use of the likelihood ratio test. Results: Lower SES index was associated with worse PRO for all measures. Models that included the SES index explained more variability than models with traditional SES. In addition, a statistically significant variation was found regarding the impact of education on PRO based on patient age for the IKDC score, the Marx scale, and 4 of the 5 KOOS subscales. Conclusion: This study demonstrates that lower neighborhood SES is associated with worse PRO after ACL reconstruction and that age and education have a significant interaction in this patient population. Future studies in patients who have undergone ACL reconstruction should attempt to account for neighborhood SES when adjusting for confounding factors; further, targeting patients from areas with lower neighborhood SES with special interventions may offer an opportunity to improve their outcomes.

Background: Injuries to the posterolateral corner (PLC) may occur concurrently with anterior cruciate ligament (ACL) injury. Purpose/Hypothesis: This study evaluated the outcomes of patients who underwent operative management of PLC injuries concurrently with ACL reconstruction in a prospective multicenter cohort. We hypothesized that there would be no differences in outcomes between patients who were treated with PLC repair and PLC reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing ACL reconstruction were enrolled into a prospective longitudinal multicenter cohort between 2002 and 2008. Those with complete 6-year follow-up data (patient-reported outcomes and subsequent surgery information) were identified. Excluded from the study were patients with posterior cruciate ligament injuries. Patients who underwent PLC repair were compared with those who underwent PLC reconstruction with regard to interval from injury to surgery, need for revision surgery, and long-term outcomes at 6 years. Results: During the identified time frame, 3026 identified patients underwent primary ACL reconstruction; 34 (1.1%) also underwent concurrent PLC surgery (15 repairs, 19 reconstructions [18 allografts, 1 autograft]). With the numbers available, we did not detect significant differences between groups regarding the rate of meniscal or chondral injuries. Median time to PLC reconstruction was 121 days as compared with 19 days for concurrent ACL reconstruction and PLC repair ( P = .01). There were no between-group differences in Marx activity scores prior to surgery ( P = .4). At 6-year follow-up, there were no between-group differences in Knee injury and Osteoarthritis Outcome Score ( P = .36-.83) or International Knee Documentation Committee score ( P = .84); however, patients treated with PLC reconstructions had lower Marx activity scores (4.1 vs 9.4; P = .02). There was 1 ACL revision in the PLC reconstruction group, and 1 of the PLC repairs was revised to a reconstruction during the follow-up period. Conclusion: Good outcomes were achieved at 6-year follow-up with both repair and reconstruction of PLC injuries treated concurrently with ACL reconstruction. The PLC reconstruction group had lower activity levels 6 years after surgery. The present data suggest that, for appropriately selected patients undergoing acute surgical treatment of combined ACL and PLC injuries, PCL repair can achieve good long-term outcomes.

Background: Patient-reported outcome measures are commonly used to measure knee pain and functional impairment. When structural abnormality is identified on examination and imaging, arthroscopic partial meniscectomy and chondroplasty are commonly indicated for treatment in the setting of pain and decreased function. Purpose: To evaluate the relationship between patient characteristics, mental health, intraoperative findings, and patient-reported outcome measures at the time of knee arthroscopy. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Between February 2015 and October 2016, patients aged 40 years and older who were undergoing routine knee arthroscopy for meniscal and cartilage abnormality, without reconstructive or restorative procedures, were prospectively enrolled in this study. Routine demographic information was collected, and the Knee injury and Osteoarthritis Outcome Score (KOOS) Pain, Quality of Life (QoL), and Physical Function Short Form (PS) subscales and the mental and physical component subscales of the Veterans RAND 12-Item Health Survey (VR-12 MCS and VR-12 PCS) were administered preoperatively on the day of surgery. Intraoperative findings were collected in a standardized format. Patient demographics, intraoperative findings, and the VR-12 MCS were used as predictor values, and a multivariate analysis was conducted to assess for relationships with the KOOS and VR-12 as dependent variables. Results: Of 661 eligible patients, baseline patient-reported outcomes and surgical data were used for 638 patients (97%). Lower scores on both subscales of the VR-12 were predicted by female sex, positive smoking history, fewer years of education, and higher body mass index (BMI). All KOOS subscales were negatively affected by lower VR-12 MCS scores, female sex, lower education level, and higher BMI in a statistically meaningful way. Positive smoking history was associated with worse scores on the KOOS-PS. Abnormal synovial status was associated with worse KOOS-Pain. Conclusion: The demographic factors of sex, smoking status, BMI, and education level had an overwhelming impact on preoperative KOOS and VR-12 scores. Of interest, mental health as assessed by the VR-12 MCS was also a consistent predictor of KOOS scores. The only intraoperative finding with a significant association was abnormal synovial status and its effect on KOOS-Pain scores.

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.

Background: The length of most patient-reported outcome measures creates significant response burden, which hampers follow-up rates. The Patient Acceptable Symptom State (PASS) is a single-item, patient-reported outcome measure that asks patients to consider all aspects of life to determine whether the state of their joint is satisfactory; this measure may be viable for tracking outcomes on a large scale. Hypothesis: The PASS question would identify clinically successful anterior cruciate ligament reconstruction (ACLR) at 1-year follow-up with high sensitivity and moderate specificity. We defined “clinically successful” ACLR as changes in preoperative to postoperative scores on the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale and the KOOS knee-related quality of life subscale in excess of minimal clinically important difference or final KOOS pain or knee-related quality of life subscale scores in excess of previously defined PASS thresholds. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Patients enrolled in a prospective longitudinal cohort completed patient-reported outcome measures immediately before primary ACLR. At 1-year follow-up, patients completed the same patient-reported outcome measures and answered the PASS question: “Taking into account all the activity you have during your daily life, your level of pain, and also your activity limitations and participation restrictions, do you consider the current state of your knee satisfactory?” Results: A total of 555 patients enrolled in our cohort; 464 were eligible for this study. Of these, 300 patients (64.7%) completed 1-year follow-up, of whom 83.3% reported satisfaction with their knee after surgery. The PASS question demonstrated high sensitivity to identify clinically successful ACLR (92.6%; 95% CI, 88.4%-95.6%). The specificity of the question was 47.1% (95% CI, 35.1%-59.5%). The overall agreement between the PASS and our KOOS-based criteria for clinically successful intervention was 81.9%, and the kappa value indicated moderate agreement between the two methods (κ = 0.44). Conclusion: The PASS question identifies individuals who have experienced clinically successful ACLR with high sensitivity. The limitation of the PASS is its low specificity, which we calculated to be 47.1%. Answering “no” to the PASS question meant that a patient neither improved after surgery nor achieved an acceptable final state of knee health. The brevity, interpretability, and correlation of the PASS question with significant improvements on various KOOS subscales make it a viable option in tracking ACLR outcomes on a national or global scale.

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.