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Metabolic dysfunction-associated steatotic liver disease affects 1 in 4 people in the United States and western Europe, with an important proportion developing metabolic dysfunction-associated steatohepatitis (MASH), the progressive subtype of metabolic dysfunction-associated steatotic liver disease. Cirrhosis caused by MASH is a leading indication for liver transplantation and the most common cause of hepatocellular carcinoma. Hitherto, there have been no specific pharmacotherapies for MASH. The recent conditional approval by the Food and Drug Administration of resmetirom for the treatment of moderate or advanced MASH presents a much-anticipated therapeutic option for patients with noncirrhotic advanced MASH. Specifically, the intended population for resmetirom are patients with MASH and fibrosis stages 2 or 3. The approval of resmetirom also presents important challenges, including how to noninvasively identify patients with fibrosis stages 2-3, and how to exclude patients with more advanced disease who should not be treated until further data emerge on the use of resmetirom in this population. Herein we consider the available literature with regard to identifying the intended population for treatment with resmetirom and in proposing criteria for stopping treatment., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: As of March 2024, resmetirom is the first and only therapy approved in the United States (US) for the treatment of adults with non-cirrhotic nonalcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis (MALF) consistent with stages F2/F3 fibrosis. Estimates of the diagnosed, treatment-eligible NASH population are poorly understood due to diagnostic variability. This study provides a contemporary estimate of the size of the US resmetirom treatment-eligible population., Methods: A dynamic population calculator was developed combining literature, screening guidelines, resmetirom study criteria, and analyses of the NHANES 2017-March 2020 cycle. It computes NASH prevalence, proportion non-cirrhotic NASH with MALF, Year 1 diagnosis, and new diagnoses in Years 2 and 3. NASH prevalence was estimated by applying the American Association of Clinical Endocrinology screening algorithm and recommended NIT cut-offs in the NHANES dataset. The proportion of non-cirrhotic NASH with MALF was informed by analyses of the Forian US integrated medical claims database using NASH and cirrhosis-specific ICD-10-CM codes and FIB-4 scores. NASH diagnosis rates were obtained from published estimates and NHANES responses. Treatment-eligible population growth was projected using published incidence data. Estimates were compared to a NASH budget-impact-analysis (BIA) from the Institute for Clinical and Economic Review (ICER)., Results: In the base case, a NASH prevalence of 4.6% was modeled (range 1.3-14.2%). This value was multiplied by the proportion estimated to have non-cirrhotic MALF (i.e., 35%). Published analyses suggest a diagnosis rate of ~ 10% (range 3.3-14.3%) and ~ 16% year-over-year growth in the treatment-eligible population. Assuming a 1-million commercial-member population, the resmetirom treatment-eligible population was estimated as 1255-1699 in Years 1-3 following approval. Sensitivity analyses were conducted and comparison to the ICER BIA was influenced by different diagnosis rates., Conclusion: Estimation of the treatment-eligible population for resmetirom depends importantly on NASH diagnosis rates, which are predicted to be < 15% in the 3 years after drug approval. Nonalcoholic steatohepatitis (NASH) is an advanced form of nonalcoholic fatty liver disease. Previously there were no treatments for NASH in the United States (US), but as of March 2024, the US Food and Drug Administration (FDA) approved resmetirom (REZDIFFRA™), a once-daily, oral therapy, in conjunction with diet and exercise, under accelerated approval for the treatment of adults (aged 18 years or older) with non-cirrhotic NASH with moderate-to-advanced liver fibrosis (MALF), consistent with stages F2-F3. It is not well understood how many diagnosed patients with NASH would be eligible for treatment with resmetirom; thus, this study aimed to estimate the size of the US resmetirom treatment-eligible population. To do so, we created a flexible population calculator that considers how many people have NASH, what proportion would be eligible for resmetirom treatment-i.e., have non-cirrhotic NASH with MALF-and of those how many people would be diagnosed. We used published literature, screening guidelines, resmetirom study criteria, and analyses of national surveys to inform our range of estimates. In the main analysis, we modeled a NASH prevalence of 4.6% (range 1.3-14.2%), which was then limited to the proportion estimated to have non-cirrhotic NASH with MALF (i.e., 35%) and diagnosed (i.e., 10%, range 3.3-14.3%). A year-over-year growth of approximately 16% in the treatment-eligible population was modeled in years following approval. Assuming a population of 1 million commercial insurance enrollees, the resmetirom treatment-eligible population was estimated to be 1255-1699 in Years 1-3 following approval. We assessed alternative scenarios and have compared our results to existing models., (© 2024. The Author(s).)

Importance: Liver disease is a leading cause of mortality in the US. Liver transplant can be a lifesaving procedure for patients with severe liver disease., Objective: To assess temporal trends and geographic variance in liver-related mortality (LRM) and liver transplant in the US., Design, Setting, and Participants: In this cohort study, the frequencies and geographic variance of LRM in 2018 and 2021 were obtained in a cross-sectional analysis of the Underlying Cause of Death data available on the Centers for Disease Control and Prevention's Epidemiologic Research database. The number of livers donated and transplanted according to the state of residence of each donor and recipient were obtained from the United Network for Organ Sharing., Main Outcomes and Measures: Liver-related mortality in 2018 and 2021, overall and by state, as well as the liver transplant rate according to state of residence of recipient and donor., Results: Overall LRM in the US was 93 418 in 2021, with a crude rate of 28.1 per 100 000 individuals, an increase of 19.1% compared with rates seen immediately prior to the COVID-19 pandemic in 2018 (77 282 [23.6 per 100 000 individuals]). Liver-related mortality in 2021 varied several-fold between states, from 18.4 per 100 000 individuals per year in Utah to 65.9 per 100 000 individuals per year in New Mexico. The mean number of liver-related deaths per transplant from all donor sources (in state and out of state) was 7.2 in the lowest LRM quintile compared with 21.5 in the highest (95% CI, 12.1-16.6; SE, 1.1; P < .001). Ten states had no liver transplant center. Paradoxically, residents of states with the highest LRM had a much lower rate of liver transplant (at any location) from organs procured from in-state residents than states with the lowest LRM quintile (13.0% vs 35.2% in-state donors; 95% CI, 14.1%-30.3%; SE, 3.9%; P < .001)., Conclusions and Relevance: This study suggests that rates of LRM have increased dramatically since the COVID-19 pandemic and vary several-fold between states. Rates of liver transplant are paradoxically lowest among residents living in states with the highest LRM. These findings highlight apparent geographic disparities in access to liver transplant that allocation policy cannot address.

Background & Aims: Acute-on-chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes patients with decompensated cirrhosis to the development of ACLF., Methods: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (body mass index [BMI] <30), obese class I-II (BMI 30-39.9) and obese class III (BMI ≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence., Results: Among 387,884 patient records of decompensated cirrhosis, 116,704 (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (hazard ratio 1.24; 95% CI 1.09-1.41; p <0.001). This finding was confirmed using the NIS (odds ratio 1.30; 95% CI 1.25-1.35; p <0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had a greater prevalence of renal failure., Conclusion: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly high prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF., Lay Summary: In this study, we identify that among patients with decompensated cirrhosis, class III obesity (severe/morbid obesity) is a modifiable risk factor for the development of acute-on-chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent in obese patients, particularly those with class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Long-term survival following liver transplantation is profoundly affected by conditions unrelated to graft function. Many causes of mortality are contributed to by the metabolic syndrome. The approach to metabolic syndrome in liver transplant recipients requires consideration of transplant-specific factors, particularly immunosuppression. Enhancing long-term outcomes for liver transplant recipients necessitates minimizing the amount of immunosuppression required to prevent rejection. Studies to determine the optimal approach to minimize the impact of metabolic syndrome and complications of immunosuppression in transplant recipients are needed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background & Aims: The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood., Methods: We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to 2009., Results: From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009. NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older (58.5±8.0 vs 53.0±8.9 years; P<.001), have a larger body mass index (>30 kg/m2) (63% vs 32%; P<.001), are more likely to be female (47% vs 29%; P<.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P<.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P=.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index., Conclusions: NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Although mortality rates following liver transplantation (LT) are well described, there is a lack of detailed, prospective studies determining patterns of and risk factors for long-term mortality. We analyzed the multicenter, prospectively obtained The National Institute of Diabetes and Digestive and Kidney Diseases LT Database of 798 transplant recipients from 1990 to 1994 (follow-up 2003). Overall, 327 recipients died. Causes of death >1 year: 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, 6% renal failure. Renal-related death increased dramatically over time. Risk factors for death >1 year (univariate): male gender, age/decade, pre-LT diabetes, post-LT diabetes, post-LT hypertension, post-LT renal insufficiency, retransplantation >1 year, pre-LT malignancy, alcoholic disease (ALD) and metabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation, post-LT diabetes, hypertension and renal insufficiency were significant risk factors for liver-related death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre-LT hypertension and post-LT renal insufficiency. In summary, the leading causes of late deaths after transplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age, diabetes and renal insufficiency identified patients at highest risk of poor survival overall. Diligent management of modifiable post-LT factors including diabetes, hypertension and renal insufficiency may impact long-term mortality.

Background & Aims: The percentage of Lens culinaris agglutinin-reactive (alpha)-fetoprotein (AFP-L3%) is proposed as a diagnostic and prognostic marker for hepatocellular carcinoma (HCC). We evaluated the utility of AFP-L3% for diagnosis of HCC in a US referral population., Methods: This retrospective study included 272 patients: 166 with HCC and 106 with benign liver disease (chronic liver disease, 77; benign liver mass, 29). The AFP-L3% was measured using a clinical auto-analyzer., Results: The AFP-L3% is not reported for a total alpha-fetoprotein (AFP) less than 10 ng/mL, and all patients with an AFP greater than 200 ng/mL had HCC; thus the AFP-L3% was noninformative for these patients. In patients with a total AFP of 10-200 ng/mL, an AFP-L3% greater than 10% had a sensitivity of 71% and a specificity of 63% for diagnosis of HCC. An AFP-L3% greater than 35% had a reduced sensitivity of 33%, but an increased specificity of 100%. The high specificity of the AFP-L3% cut-off of 35% allowed the confident diagnosis of an additional 10% of HCCs not diagnosed using an AFP cut-off of 200 ng/mL. After adjustment for AFP level, no association was observed between AFP-L3% and tumor size, stage, vascular invasion, grade, or survival., Conclusions: Patients with indeterminate total AFP values of 10-200 ng/mL present a diagnostic dilemma. We found that an AFP-L3% greater than 35% has 100% specificity for HCC in these patients. AFP-L3%, used in combination with AFP, may be a clinically useful adjunct marker for the diagnosis of HCC.

Background: Existing research provides conflicting evidence regarding the relationship between estimated branched-chain amino acid (BCAA) intake and metabolic, glycemic markers, and anthropometric characteristics. This research seeks to examine the association between estimated dietary BCAA consumption and glycemic, and metabolic markers, as well as anthropometric parameters in adults classified as overweight or obese. Methods: In this cross-sectional analysis, we gathered data from 465 overweight and obese individuals aged between 18 and 37 years. To evaluate dietary data, we employed the food frequency questionnaire, and the BCAA content in foods was determined via the United States Department of Agriculture website. We utilized ELISA kits to measure fasting blood glucose (FBS) and lipid profile markers, and additionally calculated low-density lipoprotein (LDL) and insulin sensitivity markers. We assessed sociodemographic status, physical activity (PA), and anthropometric attributes through a method recognized as both valid and reliable. For statistical analysis, we conducted analyses of covariance (ANCOVA), making adjustments for variables including sex, PA, age, energy, and body mass index (BMI). Results: Upon adjusting for confounders, those in the highest tertiles of BCAA intake exhibited an increase in weight, BMI, waist circumference (WC), waist-to-hip ratio (WHR), and fat-free mass (FFM). Conversely, they demonstrated reduced fat mass (FM) (%) and FM (kg) compared to their counterparts in the lowest tertiles (P < 0.05). Additionally, there was a noted association between greater estimated BCAA intake and reduced LDL levels. Nonetheless, our findings did not reveal a significant relationship between dietary BCAA and glycemic indices. Conclusions: From our findings, an increased estimated intake of BCAA seems to correlate with diminished serum LDL concentrations. To gain a more comprehensive understanding of this association, it is imperative that further experimental and longitudinal studies be conducted. [ABSTRACT FROM AUTHOR]

Background: Patients with nonalcoholic steatohepatitis (NASH) are waitlisted at older ages than individuals with other liver diseases, but the effect of age on liver transplantation (LT) outcomes in this population and whether it differs from other etiologies is not known. We aimed to evaluate the impact of age on LT outcomes in NASH., Methods: The United Network for Organ Sharing database was used to identify adults with NASH, hepatitis C virus (HCV) infection, and alcohol-related liver disease (ALD) listed for LT during 2004-2017. Patients were split into age groups (18-49, 50-54, 55-59, 60-64, 65-69, ≥70), and their outcomes were compared., Results: From 2004 to 2017, 14 197 adults with NASH were waitlisted, and the proportion ≥65 increased from 15.8% to 28.9%. NASH patients ages 65-69 had an increased risk of waitlist and posttransplant mortality compared to younger groups, whereas the outcomes in ages 60-64 and 55-59 were similar. The outcomes of individuals with NASH were similar to patients of the same age group with ALD or HCV. Functional status and dialysis were predictors of posttransplant mortality in individuals ≥65 with NASH, and cardiovascular disease was the leading cause of death., Conclusions: Older NASH patients (≥65) have an increased risk of waitlist and posttransplant mortality compared to younger individuals, although outcomes were similar to patients with ALD or HCV of corresponding age. These individuals should be carefully evaluated prior to LT, considering their functional status, renal function, and cardiovascular risk. Further studies are needed to optimize outcomes in this growing population of transplant candidates.

Obesity has become a global epidemic, adding to the burden of chronic diseases and disabilities. Metabolic syndrome, especially obesity, is a significant risk factor for nonalcoholic fatty liver disease, which is the most common indication for liver transplant (LT). The prevalence of obesity among the LT population is growing. Obesity increases the necessity of LT by playing a role in the development of nonalcoholic fatty liver disease, decompensated cirrhosis, and hepatocellular carcinoma, and it can also coexist with other diseases requiring LT. Therefore, LT teams must identify key aspects required to manage this high-risk population, but there are currently no defined recommendations for managing obesity in LT candidates. Although body mass index is often used to assess the weight of patients and classify them as overweight or obese, this measure may be inaccurate to use in patients with decompensated cirrhosis, as fluid overload or ascites can significantly add to the weight of patients. Diet and exercise remain the cornerstone of obesity management. Supervised weight loss before LT, without worsening frailty and sarcopenia, may be beneficial in reducing surgical risks and improving long-term LT outcomes. Bariatric surgery is another effective treatment for obesity, with sleeve gastrectomy currently conferring the best outcomes in LT recipients. However, evidence supporting the timing of bariatric surgery is lacking. Long-term patient and graft survival data in individuals with obesity following LT are scarce. Class 3 obesity (body mass index ≥40) further complicates the treatment of this patient population. This article discusses the impact of obesity on the outcome of LT. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) affects 30% of adults in the United States. Transient elastography (TE) (Fibroscan, Echosens, Paris, France) with controlled attenuation parameter (CAP) is a noninvasive way to evaluate liver steatosis and liver stiffness. The primary objective of this study was to assess prevalence of elevated liver stiffness and steatosis immediately postpartum. Furthermore, we sought to evaluate whether there were differences in rates of metabolic disorders of pregnancy (gestational diabetes mellitus (GDM), gestational hypertension, and preeclampsia) and pre-pregnancy conditions (type 2 diabetes mellitus (DM), chronic hypertension, and obesity) in those with elevated postpartum liver steatosis/liver stiffness. IRB approved prospective cross-sectional study in which TE and liver function tests were performed 1–2 days postpartum. CAP ≥300 dB/m was classified as significant steatosis. Increased liver stiffness was defined as ≥7 kPa. Prevalence was determined by proportion of individuals undergoing TE/CAP who met criteria. Chi-square analysis was used to compare differences between groups. Eighty-nine patients were included: 20 (22%) had GDM, 13 (15%) had gestational hypertension, and 15 (17%) had preeclampsia. Women with kPa ≥7 were more likely to have ALT ≥25, type 2 diabetes, and preeclampsia (p <.05). Pre-gravid BMI, BMI at delivery, and GDM were not associated with increased kPa. Pregravid BMI ≥25 and chronic hypertension were associated with CAP ≥ 300 dB/m (p <.05). GDM, preeclampsia, and gestational hypertension were not associated with CAP ≥300 dB/m. Patients with preeclampsia, type 2 diabetes, and elevated ALT were more likely to have elevated postpartum liver stiffness. Pregravid BMI ≥25 and ≥30 were associated with increased liver steatosis, although did not impact liver stiffness. GDM was not associated with increased liver stiffness or steatosis. Consideration should be made for screening pregnant patients with preeclampsia, type 2 DM and overweight or obese BMI for liver disease in the postpartum period with potential for lifestyle intervention. [ABSTRACT FROM AUTHOR]

Background: The number of simultaneous liver-kidney (SLK) transplants has significantly increased in the United States. There has also been an increase in kidney-after-liver transplants associated with 2017 policy revisions aimed to fairly allocate kidneys after livers. SLK and kidney-after-liver candidates are prioritized in allocation policy for kidney offers ahead of kidney-alone candidates., Methods: We compared kidney graft outcomes of kidney-alone transplant recipients with SLK and kidney-after-liver transplants using paired kidney models to mitigate differences among donor risk factors. We evaluated recipient characteristics between transplant types and calculated differential graft years using restricted mean survival estimates., Results: We evaluated 3053 paired donors to kidney-alone and SLK recipients and 516 paired donors to kidney-alone and kidney-after-liver recipients from August 2017 to August 2022. Kidney-alone recipients were younger, more likely on dialysis, and Black race. One-year and 3-year post-transplant kidney graft survival for kidney-alone recipients was 94% and 86% versus SLK recipients 89% and 80%, respectively, P < 0.001. One-year and 3-year kidney graft survival for kidney-alone recipients was 94% and 84% versus kidney-after-liver recipients 93% and 87%, respectively, P = 0.53. The additional kidney graft years for kidney-alone versus SLK transplants was 21 graft years/100 transplants (SEM=5.0) within 4 years post-transplantation, with no significant difference between kidney-after-liver and kidney-alone transplants., Conclusions: Over a 5-year period in the United States, SLK transplantation was associated with significantly lower kidney graft survival compared with paired kidney-alone transplants. Most differences in graft survival between SLK and kidney-alone transplants occurred within the first year post-transplantation. By contrast, kidney-after-liver transplants had comparable graft survival with paired kidney-alone transplants., (Copyright © 2023 by the American Society of Nephrology.)

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC—1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years post-transplant was lower in NASH compared to non-NASH patients (5.80 vs. 9.41%, p = 0.01). Recurrence-free survival, however, was similar at 5 years between groups. Patients with NASH-related HCC were less likely to have post-transplant recurrence than their non-NASH counterparts, although recurrence free survival was similar at 5 years. [ABSTRACT FROM AUTHOR]

Background: Emerging data suggest disparities exist in liver transplantation (LT) for alcohol-associated liver disease (ALD). As the incidence of ALD increases, we aimed to characterize recent trends in ALD LT frequency and outcomes, including racial and ethnic disparities., Methods: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data (2015 through 2021), we evaluated LT frequency, waitlist mortality, and graft survival among US adults with ALD (alcohol-associated hepatitis [AH] and alcohol-associated cirrhosis [AAC]) stratified by race and ethnicity. We used adjusted competing-risk regression analysis to evaluate waitlist outcomes, Kaplan-Meier analysis to illustrate graft survival, and Cox proportional hazards modeling to identify factors associated with graft survival., Results: There were 1211 AH and 26 526 AAC new LT waitlist additions, with 970 AH and 15 522 AAC LTs performed. Compared with non-Hispanic White patients (NHWs) with AAC, higher hazards of waitlist death were observed for Hispanic (subdistribution hazard ratio [SHR] = 1.23, 95% confidence interval [CI]: 1.16-1.32), Asian (SHR = 1.22, 95% CI:1. 01-1.47), and American Indian/Alaskan Native (SHR = 1.42, 95% CI: 1.15-1.76) candidates. Similarly, significantly higher graft failures were observed in non-Hispanic Black (HR = 1.32, 95% CI: 1.09-1.61) and American Indian/Alaskan Native (HR = 1.65, 95% CI: 1.15-2.38) patients with AAC than NHWs. We did not observe differences in waitlist or post-LT outcomes by race or ethnicity in AH, although analyses were limited by small subgroups., Conclusions: Significant racial and ethnic disparities exist for ALD LT frequency and outcomes in the United States. Compared with NHWs, racial and ethnic minorities with AAC experience increased risk of waitlist mortality and graft failure. Efforts are needed to identify determinants for LT disparities in ALD that can inform intervention strategies., Competing Interests: M.C.M., T.G.C., and T.K. receive salary support from the National Institutes of Health (NIH) (U01 AA 026975). T.K. consults for Alexion. A.G.S.’s research is supported by R01 MD012565 and R01 CA256977. N.E.R. is supported by K08 CA259236. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript. W.M.L. is supported by U-01DK58369 and by research support from Intercept, Aurora, Gilead, Novo Nordisk, Alexion, Eiger, Camurus, and Lipocine, and consults for Forma, SeaGen, GSK, Karuna, and Cortexyme; none of these relationships pertain to alcohol-associated liver disease. L.B.V. consults for Gerson Lehrman Group and Noble Insights, receives grant support from W.L. Gore & Associates, and serves as an expert witness. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) patient‐derived xenograft (PDX) models hold potential to advance knowledge in HCC biology to help improve systemic therapies. Beside hepatitis B virus‐associated tumors, HCC is poorly established in PDX. Methods: PDX formation from fresh HCC biopsies were obtained and implanted intrahepatically or in subrenal capsule (SRC). Mouse liver injury was induced in immunodeficient Fah−/− mice through cycling off nitisinone after HCC biopsy implantation, versus continuous nitisinone as non‐liver injury controls. Mice with macroscopically detectable PDX showed rising human alpha1‐antitrypsin (hAAT) serum levels, and conversely, no PDX was observed in mice with undetectable hAAT. Results: Using rising hAAT as a marker for PDX formation, 20 PDX were established out of 45 HCC biopsy specimens (44%) reflecting the four major HCC etiologies most commonly identified at Memorial SloanKettering similar to many other institutions in the United States. PDX was established only in severely immunodeficient mice lacking lymphocytes and NK cells. Implantation under the renal capsule improved PDX formation two‐fold compared to intrahepatic implantation. Two out of 18 biopsies required murine liver injury to establish PDX, one associated with hepatitis C virus and one with alcoholic liver disease. PDX tumors were histologically comparable to biopsy specimens and 75% of PDX lines could be passaged. Conclusions: Using cycling off nitisinone‐induced liver injury, HCC biopsies implanted under the renal capsule of severely immunodeficient mice formed PDX with 57% efficiency as determined by rising hAAT levels. These findings facilitate a more efficient make‐up of PDX for research into subset‐specific HCC. [ABSTRACT FROM AUTHOR]

Objective: To study the epidemiology of serious infections in patients hospitalized with gout.Methods: We identified patients with gout hospitalized with a primary diagnosis of pneumonia, sepsis/bacteremia, urinary tract infection (UTI), skin and soft tissue infections (SSTIs), or opportunistic infections (OIs) in a US National Inpatient Sample from 1998 to 2016 and examined factors associated with utilization and mortality.Results: We noted 1,140,085 hospitalizations of patients with serious infections and gout (11% of all hospitalizations of patients with gout; 1998-2000 [8.9%], 2015-2016 [14.5%]). Compared to patients without gout, patients with gout hospitalized with serious infections were older (median age 65 versus 74 years), more of them had a Charlson-Deyo comorbidity index score ≥2 (42% versus 65%), and fewer were female (53% versus 35%) or non-White (40% versus 35%), respectively. The most common infection was pneumonia (52%) in 1998-2000 and sepsis (52%) in 2015-2016. Median hospital charges and hospital stays were higher for patients with sepsis and OIs in 2015-2016 ($41,000-$42,000; 5.1-5.5 days) versus those with UTI, pneumonia, or SSTIs ($15,000-$17,000; 3.0-3.9 days). Compared to patients with sepsis, the multivariable-adjusted odds of health care utilization and in-hospital mortality were significantly lower for patients with UTI, SSTIs, and pneumonia, and non-home discharge or in-hospital mortality were lower in patients with OIs. Among patients hospitalized with infections, older age, Medicaid coverage, a higher Charlson-Deyo comorbidity index score, Black race, and Northeast and nonrural hospital location were associated with significantly higher health care utilization and mortality, while female sex, Medicare insurance, and lower income were associated with higher utilization.Conclusion: Given an increasing rate of serious infections, especially sepsis and pneumonia, in individuals with gout, development of effective interventions targeting factors associated with health care utilization and mortality will improve outcomes and reduce burden. [ABSTRACT FROM AUTHOR]

Background & Aims: Racial/ethnic disparities in liver transplantation (LT) are well‐recognized. Although Hispanics represent the largest and youngest minority group in the United States, limited data exist on long‐term outcomes. We aimed to investigate long‐term post‐liver transplant outcomes in Hispanic patients and identify potential disparities compared to a baseline demographic of non‐Hispanic white patients. Methods: We performed a retrospective cohort study of first‐time liver transplant recipients using the United Network for Organ Sharing database from 2002 to 2013, with follow‐up through 2018. The primary outcomes of interest were overall patient and graft survival after LT. Results: 45 767 patients underwent LT (85.0% non‐Hispanic white, 15.0% Hispanic). Hispanics had lower socioeconomic status, higher prevalence of pretransplant comorbidities and more severe liver disease compared to non‐Hispanic whites. Hispanics had similar patient (76.6% vs 75.6%; P =.12) and graft (71.7% vs 70.8%; P =.28) survival at 5 years and significantly better patient (62.9% vs 59.7%; P <.001) and graft (58.6% vs 55.6%; P =.002) survival at 10 years. In multivariable analysis, Hispanics had lower associated all‐cause mortality (HR 0.86, 95% CI, 0.82‐0.91; P <.001) and graft failure (HR 0.89, 95% CI, 0.85‐0.93; P <.001) compared to non‐Hispanic whites. In etiology‐specific subanalysis, Hispanics transplanted for ALD, NASH and HCV had lower all‐cause mortality compared to non‐Hispanic whites. Conclusions: Hispanics have similar or better long‐term post‐LT outcomes compared to non‐Hispanic whites despite a worse pretransplant risk factor profile. Further research is needed to clarify if this survival advantage reflects uncaptured protective factors or more stringent transplant selection in the Hispanic population. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) continues to increase in frequency as an indication for liver transplantation (LT). Data on long-term outcomes for these patients are limited. We aimed to compare long-term patient and graft survival in patients undergoing LT for NASH in the United States to other indications., Methods: We analyzed data from the Scientific Registry of Transplant Recipients of adult patients who underwent primary deceased-donor LT from January 1, 2005, to December 31, 2019., Results: NASH has increased as an indication for LT by 4.5-fold, from 5.2% in 2005 to 23.4% in 2019. Patient (61.2%) and graft survival (59.2%) at 10 y are significantly poorer for NASH than for all other indications other than alcohol. Patients transplanted for NASH have higher body mass index (32.2 versus 27.6) and greater frequency of diabetes (13% versus 11.6%) than any other indication ( P < 0.001). Portal vein thrombosis, location in intensive care unit, dialysis, and pre-LT diabetes ( P < 0.001 for all) are independently predictive of patient death and graft loss. Body mass index is not predictive. NASH patients undergoing simultaneous liver kidney have markedly worse 10-y patient and graft survival than liver-only (52.3% versus 62.1%). Graft loss was attributed to recurrence of NASH in <1% of patients., Conclusions: LT for NASH is associated with relatively poor long-term patient and graft survival when compared with patients transplanted for other indications, NASH patients undergoing simultaneous liver kidney have the worst long-term outcomes., Competing Interests: S.P. received research/grant funding from Intercept, Target PharmaSolutions, and Genfit. M.C. has consulted for Gilead, AbbVie, Bristol Myers, AMRA, Terns, Madrigal, Novartis, Lipocene, Metacrine, NGM Bio, and Intercept. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Nonalcoholic steatohepatitis (NASH) is one of the most common etiologies of liver transplantation (LT) in the United States. We investigated regional trends in waitlist candidates, LT rates, and recipient survival among patients with NASH., Methods: Using the United Network for Organ Sharing database by Organ Procurement and Transplantation Network regions, we investigated waitlist registration, LT rates, and survival for NASH between January 2004 and December 2019., Results: The absolute number and percentage of total LT performed for NASH increased substantially in all Organ Procurement and Transplantation Network regions. In 2019, region 11 had the highest percentage of NASH-related LT with 31.4% followed by region 10 (25.3%) and region 8 (23.1%). Between 2015 and 2019, region 5 had the highest rising percentage in LT for NASH at 208%, followed by region 1 (194%) and region 4 (183%). The proportion of NASH hepatocellular carcinoma (NASH-HCC) was the highest in region 9 at 37.7% and lowest in region 10 (19.2%), region 3 (20.6%), and region 11 (20.8%). In multivariate analysis, diabetes (HR 1.18, P < 0.001), dialysis before LT (hazard ratio [HR] 1.53, P < 0.001), HCC (HR 1.19, P < 0.00), portal vein thrombosis (HR 1.24, P < 0.001), donor age (HR 1.026, P = 0.03), and recipient age (HR 1.24, P = <0.001) were associated with worse survival., Discussion: LT for patients with NASH has dramatically increased across all regions since 2004, but with substantial heterogeneity among regions in the proportion with HCC and post-LT survival. Identifying contributing factors to these regional differences is warranted., (Copyright © 2022 by The American College of Gastroenterology.)

We aimed to understand the contemporary changes in the characteristics and the determinants of outcomes among simultaneous liver-kidney transplantation (SLKT) recipients at 6 liver transplantation centers in the United States. We retrospectively enrolled SLKT recipients between 2002 and 2017 in the US Multicenter SLKT Consortium. We analyzed time-related trends in recipient characteristics and outcomes with linear regression and nonparametric methods. Clustered Cox regression determined the factors associated with 1-year and overall survival. We enrolled 572 patients. We found significant changes in the clinical characteristics of SLKT recipients: as compared with 2002, recipients in 2017 were older (59 versus 52 years; P < 0.001) and more likely to have chronic kidney disease (71% versus 33%; P < 0.001). There was a marked improvement in 1-year survival during the study period: 89% in 2002 versus 96% in 2017 (P < 0.001). We found that the drivers of 1-year mortality were SLKT year, hemodialysis at listing, donor distance, and delayed kidney allograft function. The drivers of overall mortality were an indication of acute kidney dysfunction, body mass index, hypertension, creatinine at SLKT, ventilation at SLKT, and donor quality. In this contemporary cohort of SLKT recipients, we highlight changes in the clinical characteristics of recipients. Further, we identify the determinants of 1-year and overall survival to highlight the variables that require the greatest attention to optimize outcomes., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Simultaneous liver-kidney transplantation (SLKT) is increasingly common in the United States. However, little is known about the renal-related outcomes following SLKT, which are essential to maximize the health of these allografts. We examined the factors impacting renal function following SLKT. This is an observational multicenter cohort study from the US Multicenter SLKT Consortium consisting of recipients of SLKT aged ≥18 years of transplantations performed between February 2002 and June 2017 at 6 large US centers in 6 different United Network for Organ Sharing regions. The primary outcome was incident post-SLKT stage 4-5 chronic kidney disease (CKD) defined as <30 mL/minute/1.73 m 2 or listing for kidney transplant. The median age of the recipients (n = 570) was 58 years (interquartile range, 51-64 years), and 37% were women, 76% were White, 33% had hepatitis C virus infection, 20% had nonalcoholic steatohepatitis (NASH), and 23% had alcohol-related liver disease; 68% developed ≥ stage 3 CKD at the end of follow-up. The 1-year, 3-year, and 5-year incidence rates of post-SLKT stage 4-5 CKD were 10%, 12%, and 16%, respectively. Pre-SLKT diabetes mellitus (hazard ratio [HR], 1.45; 95% CI, 1.00-2.15), NASH (HR, 1.58; 95% CI, 1.01-2.45), and delayed kidney graft function (HR, 1.72; 95% CI, 1.10-2.71) were the recipient factors independently associated with high risk, whereas the use of tacrolimus (HR, 0.44; 95% CI, 0.22-0.89) reduced the risk. Women (β = -6.22 ± 2.16 mL/minute/1.73 m 2 ; P = 0.004), NASH (β = -7.27 ± 3.27 mL/minute/1.73 m 2 ; P = 0.027), and delayed kidney graft function (β = -7.25 ± 2.26 mL/minute/1.73 m 2 ; P = 0.007) were independently associated with low estimated glomerular filtration rate at last follow-up. Stage 4-5 CKD is common after SLKT. There remains an unmet need for personalized renal protective strategies, specifically stratified by sex, diabetes mellitus, and liver disease, to preserve renal function among SLKT recipients., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

End-stage liver disease secondary to hepatitis C virus (HCV) infection is the major indication for orthotopic liver transplantation (OLT) worldwide. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East, including Saudi Arabia, G4 infection is the most common genotype among transplant recipients. Due to the low prevalence of HC V-G4 in Europe and the United States, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant. The aim of this review is to summarize the natural history and treatment outcome of HCV-G4 following liver transplantation, with particular attention to new HCV therapies. This review incorporates all published studies and abstracts including HCV-G4 patients. [ABSTRACT FROM AUTHOR]

Background and Aims: We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population., Approach and Results: We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P < 0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P < 0.001), whereas HCV-ACLF declined by 45.2% (P < 0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (β = 0.90; P = 0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR] = 1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR = 1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3., Conclusions: NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality., (© 2020 by the American Association for the Study of Liver Diseases.)

Hepatitis E is considered rare in the United States (US) despite its widespread occurrence in Asian and African countries. The objective of this study was to describe the characteristics of hepatitis E-related pregnancies and acute-on-chronic liver failure and analyse trends for hepatitis E diagnosis among hospitalized patients in the US. We examined data from the 2010-2017 National Inpatient Sample from Healthcare Cost and Utilization Project to determine mortality, morbidity, pregnancy diagnoses, chronic liver disease diagnoses, and other conditions during hospitalization. Data were extracted for hospitalizations with hepatitis E as defined by ICD-9 codes 070.43 and 070.53 and ICD-10 code B17.2. Of 208,462,242 hospitalizations from 2010-2015, we identified 960 hepatitis E hospitalizations. The hospitalization rate of hepatitis E was 3.7 per 10 million in 2010 and 6.4 per 10 million in 2015 (β = 0.60, p = 0.011). From 2015 to 2017, the hospitalization appeared to increase with slope (β) of 0.50. Among those hospitalizations, 34 (4%) died and 85 (9%) had acute-on-chronic liver failure. Ninety-five (10%) had a diagnosis of pregnancy, there were no reports of maternal or foetus/neonate deaths, but there was a high proportion of adverse events for both during hospitalization. Having a chronic liver disease was associated with hepatic coma diagnosis (OR = 10.94, p = 0.002). Although the hospitalization rate of hepatitis E in the US is low, it appears to be increasing over time. Further studies are necessary in order to conclude a causal association of hepatitis E with adverse events and mortalities in pregnancy and chronic liver disease in the US., (© 2020 John Wiley & Sons Ltd.)

Diabetes mellitus (DM) significantly impacts long-term survival after liver transplantation (LT). We identified survival factors for LT recipients who had DM to inform preventive care using machine-learning analysis. We analyzed risk factors for mortality in patients from across the United States using the Scientific Registry of Transplant Recipients (SRTR). Patients had undergone LT from 1987 to 2019, with a follow-up of 6.47 years (standard deviation [SD] 5.95). Findings were validated on a cohort from the University Health Network (UHN) from 1989 to 2014 (follow-up 8.15 years [SD 5.67]). Analysis was conducted with Cox proportional hazards and gradient boosting survival. The training set included 84.67% SRTR data (n = 15,289 patients), and the test set included 15.33% SRTR patients (n = 2769) and data from UHN patients (n = 1290). We included 18,058 adults (12,108 [67.05%] men, average age 54.21 years [SD 9.98]) from the SRTR who had undergone LT and had complete data for investigated features. A total of 4634 patients had preexisting DM, and 3158 had post-LT DM. The UHN data consisted of 1290 LT recipients (910 [70.5%] men, average age 54.0 years [SD 10.4]). Increased serum creatinine and hypertension significantly impacted mortality with preexisting DM 1.36 (95% confidence interval [CI], 1.21-1.54) and 1.20 (95% CI, 1.06-1.35) times, respectively. Sirolimus use increased mortality 1.36 times (95% CI, 1.18-1.58) in nondiabetics and 1.33 times (95% CI, 1.09-1.63) in patients with preexisting DM. A similar effect was found in post-LT DM, although it was not statistically significant (1.38 times; 95% CI, 1.07-1.77; P = 0.07). Survival predictors generally achieved a 0.60 to 0.70 area under the receiver operating characteristic for 5-year mortality. LT recipients who have DM have a higher mortality risk than those without DM. Hypertension, decreased renal function, and sirolimus for maintenance immunosuppression compound this mortality risk. These predisposing factors must be intensively treated and modified to optimize long-term survival after transplant., (Copyright © 2020 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Introduction: There are limited data on repeated basal cell cancer (BCC) occurrences among patients with inflammatory bowel disease (IBD), especially the impact of continuing immunosuppressive medications., Methods: We conducted a retrospective cohort study of 54,919 patients with IBD followed in the Veterans Affairs Healthcare System. We identified patients who had an incident BCC after their IBD diagnosis. We defined patients' exposure based on their IBD medications use as follows: (i) only aminosalicylate (5-ASA) use, (ii) only active thiopurine (TP) use, (iii) past TP use (discontinued >6 months ago) and no antitumor necrosis factor (TNF) use, (iv) anti-TNF use after previous TP use, (v) only anti-TNF use, and (vi) active anti-TNF and TP use. The outcome of interest was the repeated occurrence of BCC. Adjusted and unadjusted hazard ratios with 95% confidence intervals were used to estimate the risk of repeated BCC occurrence., Results: A total of 518 patients developed BCC after their IBD diagnosis. The numbers of repeated BCC occurrences per 100 person-years were 12.8 (5-ASA use only), 34.5 (active TP use), 19.3 (past TP use and no anti-TNF use), 25.4 (anti-TNF use after previous TP use), 17.8 (only anti-TNF use), and 22.4 (active anti-TNF and TP use). Compared with 5-ASA use alone, only active TP use was associated with an increased risk for repeated BCC occurrence (adjusted hazard ratio 1.65, 95% confidence interval 1.24-2.19; P = 0.0005). However, the increased risk was no longer present for other exposure categories., Discussion: Among IBD patients who developed an incident BCC while taking a TP and continued it, there was an increased risk of repeated BCC occurrences.

Hepatitis E virus (HEV), of the family Herpesviridae, is a virus that infects nearly 20 million people per year throughout the world. HEV is most commonly transmitted via the fecal-oral route and has long been described as a virus that afflicts only those in resource-poor countries. However, HEV has been detected in numerous animal carriers, various food sources, and even in human blood products in resource-rich regions of the world. HEV is of importance in the transplant patient population because of its ability to cause chronic viral infection in these patients can lead to graft loss and cirrhosis. In this review, we discuss the current knowledge of HEV as it pertains to the liver transplant patient population and discuss diagnosis and treatment of this infection., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH., Methods: This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters., Results: At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits., Conclusions: The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956)., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To understand factors contributing to liver graft loss and patient death, we queried a national database designed to follow pediatric patients transplanted between 1987 and 1995 till adulthood. A comparison was made to a cohort transplanted between 2000 and 2014. The 5-, 10-, 15-, 20-, and 25-year patient survival and graft survival were 95.5%, 93.7%, 89.1%, 80.8%, and 73.1%, and 92.5%, 86.7%, 77.6%, 68.7%, and 62.2%, respectively. The twenty-year patient/graft survival was significantly worse in those transplanted between 5 and 17 years of age compared to those transplanted at <5 years of age (P < 0.001). For the modern era cohort, the 3-year patient survival was significantly lower in children transplanted at 16-17 years of age compared to those transplanted at <5 and 11-15 years of age (P ≤ 0.02). The 3-year graft survival was similarly lower in children transplanted at 16-17 years of age compared to those transplanted at <5, 5-10, and 11-15 years of age (P ≤ 0.001). Infection as a cause of death occurred either early or >15 years post-transplant. Chronic rejection remained the leading cause of graft loss in both cohorts and the commonest indication for retransplantation 20-25 years following primary transplant. Further research is required to identify modifiable factors contributing to development of chronic rejection., (© 2019 Wiley Periodicals, Inc.)

Background: In the United States, the physician assistant (PA) model has proven to be a cost-effective way to train quality primary care providers with a high degree of acceptance of the PA role by patients and other healthcare providers. Aim: Discuss PA model as it pertains to other countries. Methods: Review of relevant literature related to physician assistant education, practice and global interest. Results: Several countries including the United Kingdom, Scotland, Canada, the Netherlands, Taiwan, South Africa and Ghana are exploring or re-exploring the concept of the physician assistant as a way to quickly and efficiently train and employ autonomous and flexible health workers to address their nation's healthcare needs. Conclusions: Physician assistant education is efficient and flexible and the PA model can be easily adapted to the specific health system needs of other nations. In addition, many PA programs have affiliation agreements with institutions outside of the United States to host PA students for clinical rotations and there is an ever-growing interest by students in international rotations. The Physician Assistant Education Association along with the American Academy of Physician Assistants is actively involved with sharing information about the PA profession with other countries. [ABSTRACT FROM AUTHOR]

Our goal was to review the hypotheses in evolution that promise to elucidate the genetic bases of autoimmune hepatitis. DRB1*0301 and DRB1*0401 are the principal risk factors in Britain and the United States. Other susceptibility alleles in different ethnic groups commonly share the same or a similar motif at the critical DRbeta71 position of the HLA class II molecule. Disease severity may be determined by the number of alleles encoding lysine at the DRbeta1 position, the density of dimers presenting antigen, and the avidity of T-cell receptors for the displayed antigen. Concurrence on the same or different chromosomes of other nonspecific autoimmune promoters may also contribute. A negatively charged residue at the P4 position of antigenic peptides is preferred for binding to the disease-susceptibility alleles, and this complex may be recognized by promiscuous T cells. We conclude that autoimmune hepatitis is a model by which to study the genetic bases of autoimmunity. [ABSTRACT FROM AUTHOR]

The article presents views and insights of the author concerning the role of physician assistants (PA) in addressing medical workforce shortages in the U.S. The clinical versatility of PA makes them particularly valuable in supplementing doctors in a wide range of roles, as well as replacing doctors in areas of doctor shortage. In some systems, there may be reluctance to create a new category of practitioner, a concern sometimes raised by nurses.