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Chronic alcohol (ethanol) use is increasing in the United States and has been linked to numerous health issues in multiple organ systems including neurological dysfunction and diseases. Ethanol toxicity is mainly driven by the metabolite acetaldehyde, which is generated through three pathways: alcohol dehydrogenase (ADH2), catalase (CAT), and cytochrome P450 2E1 (CYP2E1). ADH2, while the main ethanol clearance pathway in the liver, is not expressed in the mammalian brain, resulting in CAT and CYP2E1 driving local metabolism of ethanol in the central nervous system. CYP2E1 is known to generate reactive metabolites and reactive oxygen species and localizes to the mitochondria (mtCYP2E1) and endoplasmic reticulum (erCYP2E1). We sought to understand the consequences of mtCYP2E1 and erCYP2E1 in the nervous system during acute ethanol exposure. To answer this question, we generated transgenic Caenorhabditis elegans roundworms expressing human CYP2E1 in the mitochondria, endoplasmic reticulum, or both and exposed them to ethanol. We found that at lower concentrations, wild-type and mtCYP2E1-expressing worms had a small but significant inhibition of locomotion, whereas the erCYP2E1-expressing worms showed protection from this inhibition. At higher doses, all strains had reduced locomotion, but the erCYP2E1-expressing worms recovered faster than wild-type controls. CYP2E1 expression, regardless of organellar targeting, reduced mitochondrial respiration in response to ethanol. Similarly, transgenic expression of CYP2E1 in either organelle in PC-12 rat neuronal cell lines sensitized them to ethanol-induced cell death. Together, these findings suggest that subcellular localization of CYP2E1 impacts behavioral effects of ethanol and should be further studied in the mammalian central nervous system., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessica H Hartman reports financial support was provided by National Institutes of Health. Hyland C. Gonzalez reports financial support was provided by National Institutes of Health. Kacy L. Gordon reports financial support was provided by National Institutes of Health. Jessica H. Hartman reports a relationship with Surrozen Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Body mass index (BMI) >40 is considered a relative contraindication to liver transplant. However, there is little research regarding best practices for weight loss in this population. We hypothesized that providing multidisciplinary support, including the use of glucagon-like protein 1 receptor agonists would facilitate patients' achievement of weight loss necessary for transplant eligibility., Methods: Patients 18 y or older were referred to the Henry Ford Health Liver Metabolic Clinic from August 2019 to September 2023, with either BMI >40 or >35 with abdominal adiposity that would complicate surgery. Patients were provided individualized support from hepatologists, dieticians, and counselors, as well as prescribed antiobesity medication and monitored closely for weight loss progress., Results: Among 19 patients referred to the Liver Metabolic Clinic, median baseline BMI was 42 (range, 34.6-48.8) with median goal weight loss of 14.1 kg (range, 4.1-31.4). Sixteen patients (84%) had metabolic dysfunction-associated steatohepatitis and 3 patients had alcohol-associated liver disease. Seven had comorbid hepatocellular carcinoma. Median Model for End-stage Liver Disease score was 14 (range, 7-22). Fifteen patients were treated with a glucagon-like peptide 1 receptor agonist (6 patients received liraglutide, 8 received semaglutide, and 1 received tirzepatide) and 4 received phentermine. Median weight loss was 11.7 kg for all 19 patients (range, 0-33). Eight patients received a transplant and 4 more patients were waitlisted. Time from baseline to waitlisting was ~5.5 mo (median 166 d; range, 68-840). Three patients remained on treatment, whereas 4 were deceased due to progressive liver disease or infection., Conclusions: Providing high BMI patients with individualized dietary and medical support can facilitate weight loss necessary to achieve liver transplant eligibility., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Liver transplant (LT) using organs donated after circulatory death (DCD) has been increasing in the United States. We investigated whether transplant centers' receptiveness to use of DCD organs impacted patient outcomes., Methods: Transplant centers were classified as very receptive (group 1), receptive (2), or less receptive (3) based on the DCD acceptance rate and DCD transplant percentage. Using organ procurement and transplantation network/UNOS registry data for 20 435 patients listed for LT from January 2020 to June 2022, we compared rates of 1-y transplant probability and waitlist mortality between groups, broken down by model for end-stage liver disease-sodium (MELD-Na) categories., Results: In adjusted analyses, patients in group 1 centers with MELD-Na scores 6 to 29 were significantly more likely to undergo transplant than those in group 3 (aHR range 1.51-2.11, P  < 0.001). Results were similar in comparisons between groups 1 and 2 (aHR range 1.41-1.81, P  < 0.001) and between groups 2 and 3 with MELD-Na 15-24 (aHR 1.19-1.20, P  < 0.007). Likewise, patients with MELD-Na score 20 to 29 in group 1 centers had lower waitlist mortality than those in group 3 (scores, 20-24: aHR, 0.71, P  = 0.03; score, 25-29: aHR, 0.51, P  < 0.001); those in group 1 also had lower waitlist mortality compared with group 2 (scores 20-24: aHR0.69, P  = 0.02; scores 25-29: aHR 0.63, P  = 0.03). One-year posttransplant survival of DCD LT patients did not vary significantly compared with donation after brain dead., Conclusions: We conclude that transplant centers' use of DCD livers can improve waitlist outcomes, particularly among mid-MELD-Na patients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Eradication of hepatitis C virus (HCV) infection has been linked with improvement in neurocognitive function, but few studies have evaluated the effect of antiviral treatment/ response on risk of dementia. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we investigated how antiviral therapy impacts the risk of developing dementia among patients with HCV., Methods: A total of 17,485 HCV patients were followed until incidence of dementia, death, or last follow-up. We used an extended landmark modeling approach, which included time-varying covariates and propensity score justification for treatment selection bias, as well as generalized estimating equations (GEE) with a link function as multinominal distribution for a discrete time-to-event data. Death was considered a competing risk., Results: After 15 years of follow-up, 342 patients were diagnosed with incident dementia. Patients who achieved sustained virological response (SVR) had significantly decreased risk of dementia compared to untreated patients, with hazard ratios (HRs) of 0.32 (95% CI 0.22-0.46) among patients who received direct-acting antiviral (DAA) treatment and 0.41 (95% CI 0.26-0.60) for interferon-based (IFN) treatment. Risk reduction remained even when patients failed antiviral treatment (HR 0.38, 95% CI 0.38-0.51). Patients with cirrhosis, Black/African American patients, and those without private insurance were at significantly higher risk of dementia., Conclusion: Antiviral treatment independently reduced the risk of dementia among HCV patients, regardless of cirrhosis. Our findings support the importance of initiation antiviral therapy in chronic HCV-infected patients., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Hepatic encephalopathy-a common and debilitating complication of cirrhosis-results in major health care burden on both patients and caregivers through direct and indirect costs. In addition to risk of falls, inability to work and drive, patients with hepatic encephalopathy often require hospital admission (and often readmission), and many require subacute care following hospitalization. The costs and psychological impact of liver transplantation often ensue. As the prevalence of chronic liver disease increases throughout the United States, the health care burden of hepatic encephalopathy will continue to grow., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Using ursodeoxycholic acid as a standard treatment and for its ability to test for antimitochondrial antibody to accelerate diagnosis, survival of primary biliary cholangitis patients has approached that of the general population, leading to a change in nomenclature from primary biliary cirrhosis to primary biliary cholangitis to more accurately describe the disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We previously investigated the impact of the COVID-19 pandemic on alcohol-related liver disease (ARLD), finding that admissions for alcoholic hepatitis (AH) increased by 50% in the summer of 2020 compared to the same period in 2016-2019. We have now expanded our analysis to consider full years' data and evaluate how rates changed in 2021. We also sought to identify factors associated with ICU admissions, need for dialysis, liver transplant evaluations, and death., Methods: Using retrospective data, we identified patients admitted to our four Detroit, Michigan area hospitals for acute ARLD for three periods pre-COVID (2016-February 2020), early COVID (June-December 2020), and late COVID (2021). Clustered logistic regression was performed to study rates of AH admissions across the three eras, where the patient was defined as the cluster and the analysis accounted for multiple encounters per cluster. A similar regression approach, univariate followed by multivariable analysis, was also used to study associations between patient characteristics and outcomes during hospitalization for AH., Results: AH-related admissions declined significantly from the early COVID to late COVID eras (OR 0.68, 95% CL 0.52, 0.88), returning to levels similar to that of the pre- COVID period (OR 1.18, 95% CL 0.96, 1.47). In multivariable analysis, baseline MELD score was associated with ICU admission, initiation of dialysis, transplant evaluation, and death while hospitalized for AH. Female patients were at almost twice the risk of death during admission compared to male patients (aOR 1.81, 95% CL 1.1, 2.98). Increasing age was associated with slightly lower odds of transplant (aOR 0.97, 95% CL 0.94, 1) and higher odds of death (aOR 1.03, 95% CL 1.01. 1.06)., Conclusion: After a spike in AH-related admissions during the first summer of the COVID-19 pandemic, rates declined significantly in 2021, returning to pre-pandemic levels., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background: Early identification of alcohol use is crucial for informing recommendations of appropriate follow-up treatment pre-liver transplant and optimizing post-liver transplant outcomes. The purpose of the study was to investigate whether there are psychosocial factors associated with a positive PEth test., Methods: All patients who underwent a routine pre-surgical psychological evaluation for liver transplant listing (all etiologies, including acute liver failure, dual organ, and re-transplantation) at a single health care system in 2020 were included in a retrospective chart review. Data extraction included results from PEth testing and information from the psychological evaluation (i.e., demographic, psychiatric symptoms, and cognitive functioning)., Results: There were 158 patients (73.8%) who had a PEth test, of whom 21.5% had a positive result (n = 34). Younger age was associated with a positive PEth (p < .001). ALD status and type of ALD (hepatitis vs. cirrhosis) were also associated with a positive PEth test. Other demographic characteristics and psychiatric symptoms were not associated with a positive PEth result (p > .05)., Conclusion: Younger age was the only significant demographic variable associated with a positive PEth test. Given the difficulty of predicting who may be using alcohol, it may be useful to use PEth testing for all patients during the pre-liver transplant evaluation and while patients are listed for liver transplant. Early identification of alcohol use through routine PEth testing will help identify patients who are using alcohol and need further treatment for alcohol use to optimize health and post-transplant outcomes., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Polyploid cells contain more than two copies of each chromosome. Polyploidy has important roles in development, evolution, and tissue regeneration/repair, and can arise as a programmed polyploidization event or be triggered by stress. Cancer cells are often polyploid. C. elegans nematodes are typically diploid, but stressors such as heat shock and starvation can trigger the production of tetraploid offspring. In this study, we utilized a recently published protocol to generate stable tetraploid strains of C. elegans and compared their physiological traits and sensitivity to two DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. As prior studies have shown, tetraploid worms are approximately 30% longer, shorter-lived, and have a smaller brood size than diploids. We investigated the reproductive defect further, determining that tetraploid worms have a shorter overall germline length, a higher rate of germ cell apoptosis, more aneuploidy in oocytes and offspring, and larger oocytes and embryos. We also found that tetraploid worms are modestly protected from growth delay from the chemotherapeutics but are similarly or more sensitive to reproductive toxicity. Transcriptomic analysis revealed differentially expressed pathways that may contribute to sensitivity to stress. This study reveals phenotypic consequences of whole-animal tetraploidy that make C. elegans an excellent model for ploidy differences., (© 2023. Springer Nature Limited.)

Research suggests a possible link between chronic infection with hepatitis C virus (HCV) and the development of Parkinson's Disease (PD) and secondary Parkinsonism (PKM). We investigated the impact of antiviral treatment status (untreated, interferon [IFN] treated, direct-acting antiviral [DAA] treated) and outcome (treatment failure [TF] or sustained virological response [SVR]) on risk of PD/PKM among patients with HCV. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we applied a discrete time-to-event approach with PD/PKM as the outcome. We performed univariate followed by a multivariable modelling that used time-varying covariates, propensity scores to adjust for potential treatment selection bias and death as a competing risk. Among 17,199 confirmed HCV patients, we observed 54 incident cases of PD/PKM during a mean follow-up period of 17 years; 3753 patients died during follow-up. There was no significant association between treatment status/outcome and risk of PD/PKM. Type 2 diabetes tripled risk (hazard ratio [HR] 3.05; 95% CI 1.75-5.32; p < .0001) and presence of cirrhosis doubled risk of PD/PKM (HR 2.13, 95% CI 1.31-3.47). BMI >30 was associated with roughly 50% lower risk of PD/PKM than BMI <25 (HR 0.43; 0.22-0.84; p = .0138). After adjustment for treatment selection bias, we did not observe a significant association between HCV patients' antiviral treatment status/outcome on risk of PD/PKM. Several clinical risk factors-diabetes, cirrhosis and BMI-were associated with PD/PKM., (© 2023 John Wiley & Sons Ltd.)

In addition to being the primary target of infections such as viral hepatitis, the liver may also be affected by systemic disease. These include bacterial, mycotic, and viral infections, as well as autoimmune and infiltrative diseases. These conditions generally manifest as abnormal liver biochemistries, often with a cholestatic profile, and may present with additional signs/symptoms such as jaundice and fever. A high index of suspicion and familiarity with potential causal entities is necessary to guide appropriate testing, diagnosis, and treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Serum phosphatidylethanol (PEth) is a highly sensitive test to detect alcohol use. We evaluated whether the availability of PEth testing impacted rates of liver transplant evaluation terminations and delistings., Methods: Medical record data were collected for patients who initiated transplant evaluation due to alcohol-related liver disease in the pre-PEth (2017) or PEth (2019) eras. Inverse probability weighting (IPW) was used to balance baseline patient characteristics. Outcomes included termination of evaluation or delisting due to alcohol use; patients were censored at receipt of transplant; death was considered a competing risk. The Fine-Gray method was performed to determine whether PEth testing affected risk of evaluation termination/ delisting due to alcohol use., Results: Three hundred and seventy-five patients with alcohol-related indications for transplant (157 in 2017; 210 in 2019) were included. The final IPW-adjusted model for the composite outcome of terminations/delisting due to alcohol use retained two significant variables (P < .05): PEth era and BMI category. Patients evaluated during the PEth era were almost three times more likely to experience an alcohol-related termination/delisting than those in the pre-PEth era (sHR = 2.86; 95%CI 1.67-4.97) CONCLUSION: We found that availability of PEth testing at our institution was associated with a higher rate of exclusion of patients from eligibility for liver transplant. Use of PEth testing has significant potential to inform decisions regarding transplant candidacy for patients with alcohol-related liver disease., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Early reports suggest that alcohol misuse increased in 2020 as a result of the COVID-19 pandemic. Using retrospective data from Henry Ford Health System in Detroit MI-an area that experienced an early and severe COVID-19 outbreak-we investigated the impact of the pandemic on alcohol-related liver disease (ARLD) in the summer of 2020 compared with the same period in 2016-2019. Both the number of ARLD admissions and the proportion of total admissions represented by ARLD patients increased significantly in 2020 compared with previous years. The number of ARLD admissions as a proportion of all hospitalizations was 50% higher in 2020 than in 2016-2019 (0.31% vs 0.21%; P = .0013); by September 2020, the number of admissions was 66% higher than previous years. Despite racial and geographical disparities in direct and indirect COVID-related stressors across the Detroit metropolitan area, the demographic profile of ARLD patients did not change compared with previous years., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Introduction and Objectives: Higher rates of psychiatric disorders are reported among cirrhotic patients. This study examines the demographic and clinical outcomes post-liver transplant (LT) among cirrhotic patients with a major psychiatric diagnosis (cases) compared to those without psychiatric diagnosis (controls)., Materials and Methods: Retrospective case control design was used among 189 cirrhotic patients who had undergone LT at Methodist University Hospital Transplant Institute, Memphis, TN between January 2006 and December 2014. Multivariable regression and Cox proportional hazard regression were conducted to compare allograft loss and all-cause mortality., Results: The study sample consisted of a matched cohort of 95 cases and 94 controls with LT. Females and those with Hepatic Encephalopathy (HE) were more likely to have psychiatric diagnosis. Patients with hepatocellular carcinoma (HCC) were twice as likely to have allograft loss. Psychiatric patients with HCC had two and a half times (HR 2.54; 95% CI: 1.20-5.37; p = 0.015) likelihood of all-cause mortality. Data censored at 1-year post-LT revealed that patients with psychiatric diagnosis have a three to four times higher hazard for allograft loss and all-cause mortality compared to controls after adjusting for covariates, whereas when the data is censored at 5 year, allograft loss and all-cause mortality have two times higher hazard ratio., Conclusions: The Cox proportional hazard regression analysis of censored data at 1 and 5 year indicate higher allograft loss and all-cause mortality among LT patients with psychiatric diagnosis. Patients with well-controlled psychiatric disorders who undergo LT need close monitoring and medication adherence., (Copyright © 2021 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Opioid medications are frequently used to address pain among patients with cirrhosis, including those on the liver transplant (LT) waitlist and after transplantation. However, opioid use has been associated with poor allograft outcomes and reduced transplant survival. We examined the impact of opioid use across the spectrum of advanced liver disease, from the initial hepatology consultation for cirrhosis through transplant referral, listing, and the post-LT process., Methods: The study includes all patients referred for cirrhosis management in a single healthcare system in the United States. Data were extracted retrospectively through medical chart review., Results: Of 414 patients included in the study, 104 (25%) were treated with opioid. Patients on opioids were more likely to be White, have body mass indices (BMI) >30, have HCV, suffer from hepatic encephalopathy, cigarette smokers, and use benzodiazepines concurrently. Higher doses of opioids were associated with multiple emergency department (ED). Eighty-nine underwent LT, including 20 opioid-treated patients. There was no difference found between the opioid and non-opioid groups with regard to allograft loss, ED visits, and hospital readmissions at 2 years post-LT follow-up., Conclusions: Opioid treatment was common among patients with cirrhosis. We did not find increased negative outcomes among opioid users across the spectrum of cirrhosis. However, the sample for LT patients was small., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life., Competing Interests: Disclosure S.C. Gordon receives grant/research support from AbbVie Pharmaceuticals, Conatus, CymaBay, Gilead Pharmaceuticals, Intercept Pharmaceuticals, and Merck. H.C. Gonzalez has served as a consultant/advisor for Gilead Pharmaceuticals. He also received grant/research support from Celenge., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The utility of ex vivo Magnetic resonance imaging proton density fat fraction (MRI-PDFF) in donor liver fat quantification is unknown., Purpose: To evaluate the diagnostic accuracy and utility in predicting early allograft dysfunction (EAD) of ex vivo MRI-PDFF measurement of fat in deceased donor livers using histology as the gold standard., Methods: We performed Ex vivo, 1.5 Tesla MRI-PDFF on 33 human deceased donor livers before implantation, enroute to the operating room. After the exclusion of 4 images (technical errors), 29 MRI images were evaluable. Histology was evaluable in 27 of 29 patients. EAD was defined as a peak value of aminotransferase >2000 IU/mL during the first week or an INR of ≥1.6 or bilirubin ≥10 mg/dL at day 7., Results: MRI-PDFF values showed a strong positive correlation (Pearson's correlation coefficient) when histology (macro-steatosis) was included (r = 0.78, 95% confidence interval 0.57-0.89, p<0.0001). The correlation appeared much stronger when macro plus micro-steatosis were included (r = 0.87, 95% confidence interval 0.72-0.94, p<0.0001). EAD was noted in 7(25%) subjects. AUC (Area Under the Curve) for macro steatosis (histology) predicted EAD in 73% (95% CI: 48-99), micro plus macro steatosis in 76% (95% CI: 49-100). AUC for PDFF values predicted EAD in 67(35-98). Comparison of the ROC curves in a multivariate model revealed, adding MRI PDFF values to macro steatosis increased the ability of the model in predicting EAD (AUC: 79%, 95% CI: 59-99), and addition of macro plus micro steatosis based on histology predicted EAD even better (AUC: 90%: 79-100, P = 0.054)., Conclusion: In this pilot study, MRI-PDFF imaging showed potential utility in quantifying hepatic steatosis ex-vivo donor liver evaluation and the ability to predict EAD related to severe allograft steatosis in the recipient., Competing Interests: The authors have declared that no competing interests exist.

Nonalcoholic steatohepatitis (NASH) is one of the top 3 indications for liver transplantation (LT) in Western countries. It is unknown whether renal dysfunction at the time of LT has any effect on post-LT outcomes in recipients with NASH. From the United Network for Organ Sharing-Standard Transplant Analysis and Research data set, we identified 4088 NASH recipients who received deceased donor LT. We divided our recipients a priori into 3 categories: group 1 with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m 2 at the time of LT and/or received dialysis within 2 weeks preceding LT (n = 937); group 2 with recipients who had eGFR ≥30 mL/minute/1.73 m 2 and who did not receive renal replacement therapy prior to LT (n = 2812); and group 3 with recipients who underwent simultaneous liver-kidney transplantation (n = 339). We examined the association of pretransplant renal dysfunction with death with a functioning graft, all-cause mortality, and graft loss using competing risk regression and Cox proportional hazards models. The mean ± standard deviation age of the cohort at baseline was 58 ± 8 years, 55% were male, 80% were Caucasian, and average exception Model for End-Stage Liver Disease score was 24 ± 9. The median follow-up period was 5 years (median, 1816 days; interquartile range, 1090-2723 days). Compared with group 1 recipients, group 2 recipients had 19% reduced trend for risk for death with a functioning graft (subhazard ratio [SHR], 0.81; 95% confidence interval [CI], 0.64-1.02) and similar risk for graft loss (SHR, 1.25; 95% CI, 0.59-2.62), whereas group 3 recipients had similar risk for death with a functioning graft (SHR, 1.23; 95% CI, 0.96-1.57) and graft loss (SHR, 0.18; 95% CI, 0.02-1.37) using an adjusted competing risk regression model. In conclusion, recipients with preserved renal function before LT showed a trend toward lower risk of death with a functioning graft compared with SLKT recipients and those with pretransplant severe renal dysfunction in patients with NASH., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

The effect of antiviral therapy (AVT) on kidney function in liver transplantation (LT) recipients has not been well described despite known association of hepatitis C virus (HCV) infection with chronic kidney disease (CKD). We compared the incidence of CKD and end-stage renal disease (ESRD) in 204 LT recipients with HCV based on treatment response to AVT. The mean estimated glomerular filtration rate (eGFR) at baseline (3 months after LT) was similar in the sustained virological response (SVR; n = 145) and non-SVR group (n = 59; 69 ± 21 versus 65 ± 33 mL/minute/1.73 m 2 ; P = 0.27). In the unadjusted Cox proportional regression analysis, the presence of SVR was associated with an 88% lower risk of CKD (hazard ratio, 0.12; 95% confidence interval [CI], 0.05-0.31) and 86% lower risk of ESRD (odds ratio, 0.14; 95% CI, 0.05-0.35). Similar results were found after adjusting for propensity score and time-dependent Cox regression analyses. The estimated slopes of eGFR based on a 2-stage mixed model of eGFR were calculated. Patients with SVR had a less steep slope in eGFR (-0.60 mL/minute/1.73 m 2 /year; 95% CI, -1.50 to 0.30; P = 0.190) than recipients without SVR (-2.53 mL/minute/1.73 m 2 /year; 95% CI, -3.99 to -1.07; P = 0.001), and the differences in the slopes were statistically significant (P = 0.026). In conclusion, in LT recipients with chronic HCV infection, achieving SVR significantly lowers the risk of decline in renal function and progression to ESRD independent of the AVT therapy used., (© 2018 by the American Association for the Study of Liver Diseases.)

Background & Aims: Data on the differences in ethnicity and race among patients with primary biliary cholangitis (PBC) awaiting liver transplantation (LT) are limited. We evaluated liver transplant waitlist trends and outcomes based on ethnicity and race in patients with PBC in the United States., Methods: Using the United Network for Organ Sharing (UNOS) registry, we collected data on patients with PBC on the liver transplant waitlist, and performed analysis with a focus on ethnicity and race-based variations clinical manifestations, waitlist mortality and LT rates from 2000 to 2014. Outcomes were adjusted for demographics, complications of portal hypertension, and Model for End-stage Liver Disease score at time of waitlist registration., Results: Although the number of white PBC waitlist registrants and additions decreased from 2000 to 2014, there were no significant changes in the number of Hispanic PBC waitlist registrants and additions each year. The proportion of Hispanic patients with PBC on the liver transplant waitlist increased from 10.7% in 2000 to 19.3% in 2014. Hispanics had the highest percentage of waitlist deaths (20.8%) of any ethnicity or race evaluated. After adjusting for demographic and clinical characteristics, Hispanic patients with PBC had the lowest overall rate for undergoing LT (adjusted hazard ratio, 0.71; 95% CI, 0. 60-0.83; P < .001) and a significantly higher risk of death while on the waitlist, compared to whites (adjusted hazard ratio, 1.41; 95% CI, 1.15-1.74; P < .001). Furthermore, Hispanic patients with PBC had the highest proportion of waitlist removals due to clinical deterioration., Conclusions: In an analysis of data from UNOS registry focusing on outcomes, we observed differences in rates of LT and liver transplant waitlist mortality of Hispanic patients compared with white patients with PBC. Further studies are needed to improve our understanding of ethnicity and race-based differences in progression of PBC., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Multimodal curricular assessment after adding standardized patient (SP) actor-based simulation to an advance care planning (ACP) facilitator training course and development of a formative feedback tool., Background: ACP represents a highly valued service requiring more and better trained facilitators., Methods: Participants were primarily nurses and social workers in a large multisite health system. The course included a precourse video demonstration of ACP, traditional lectures, and four 30-minute simulations with SPs. Knowledge was tested with a multiple choice question (MCQ) test. In addition to standard postcourse/postsimulation evaluations, learners were surveyed pre/post/30-90 days delayed for self-perceived confidence. A linear mixed-effects model was used to analyze changes over time. Trained faculty rated performance in simulations with an observational mini-clinical examination (mini-CEX)-type rating form with a checklist, global competency, and global communication rating. Inter-rater reliability (IRR) was calculated on randomly selected paired ratings., Results: Sixty-seven individuals consented to participate. MCQ scores improved from 83% ± 10% to 92% ± 8% (p < 0.001). Paired learner surveys of self-confidence across six domains were available for 65 pre, 65 post, and 40 delayed with a mean positive change on a 0 to 10 point scale from pre-post (2.32 ± 1.65; p < 0.001) and predelayed (2.34 ± 1.96; p < 0.001) time frames. For the faculty observation ratings of simulation performance, the average raw agreement for critical actions was 82% and IRR was 0.71., Conclusions: Learner feedback and self-assessment suggest that actor-based simulation contributed to improved confidence in conducting ACP. The mini-CEX observation form is adequate for formative feedback, with further testing needed to make judgments of competence.

Background/aims: Treatment of chronic hepatitis C (HCV) with newer direct acting antiviral (DAA) agents has been highly effective. Unfortunately, patients over 70 years old are underrepresented in studies. Given current recommendations to screen patients born between 1945 and 1965 for HCV, it is essential to determine the efficacy and safety of DAAs within the elderly population. This study aims to evaluate clinical outcomes of patients aged 70 years or older treated for HCV with DAAs at a single tertiary care center., Methods: We identified 25 patients aged 70 years or older who were treated for HCV with a sofosbuvir-based regimen. Baseline demographics, prior HCV treatment history, HCV treatment regimen, adverse effects, and interruption or discontinuation of therapy were collected. The primary endpoint was sustained virologic response at 12 weeks after end of treatment (SVR12). Secondary outcomes were self-reported side effects, drug interactions, and changes in medical regimen of treated patients., Results: All patients were genotype 1 (13 1a, 9 1b, 3 unspecified). Seventeen (68%) had cirrhosis including 1 Child's Pugh class B. Fifteen patients were treatment-naïve and 10 previously failed treatment with interferon. Seventeen patients were on ledipasvir/sofosbuvir, 4 on simeprevir/sofosbuvir/ribavirin, and 4 on simeprevir/sofosbuvir. Of 25 patients included, 96% (24/25) patients achieved SVR12. Two patients had a greater than 2 g/dL drop in hemoglobin from baseline and both were on ribavirin. Ribavirin was discontinued in 1 patient. One patient required a change in proton pump inhibitor. No patients discontinued therapy due to side effects., Conclusions: Patients aged 70 years or older with genotype 1 achieved high rates of sustained virologic response with treatment with newer sofosbuvir-based DAAs without any undue adverse events.

Objectives: Recurrent hepatitis C is universal after liver transplant when viremia is present at the time of transplant, and this affects survival. Previous treatments with pegylated interferon and ribavirin with or without boceprevir or telaprevir have yielded modest sustained virologic response rates and frequent adverse effects. A combination of new antiviral agents has been used for recurrent hepatitis C. We aim to describe the outcomes of recurrent hepatitis C in liver transplant patients treated with simeprevir, sofosbuvir, and ribavirin., Materials and Methods: Fifty-three consecutive patients with recurrent hepatitis C genotype 1 were included. All patients had liver biopsy before enrollment if cirrhosis was not evident. Standard doses of simeprevir and sofosbuvir were used for 12 weeks. Ribavirin was adjusted based on hemoglobin levels. In 53 patients, 50 completed 12 weeks of treatment., Results: All 50 patients who completed 12 weeks of treatment achieved sustained virologic response. One patient who completed only 6 weeks also achieved sustained virologic response. Overall, the antiviral treatment was well tolerated, with no interactions with immunosuppressive drugs., Conclusions: The combination of simeprevir and sofosbuvir with or without ribavirin yields a high sustained virologic response rate of 96% in a historically difficult to treat patient population (recurrent hepatitis C genotype 1).

Drug-induced liver injury (DILI) can be predictable or idiosyncratic and has an estimated incidence of approximately 20 cases per 100,000 persons per year. DILI is a common cause of acute liver failure in the United States. No accurate tests for diagnosing DILI exist, and its diagnosis is based on exclusion of other conditions. Managing DILI includes discontinuing the suspected causative agent and in selected cases administering an antidote. Liver support systems are used for long-term support or as a bridge to transplantation and are effective for improving encephalopathy, hyperbilirubinemia, and other liver-related conditions, but whether they improve survival remains uncertain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Treatment with direct-acting antiviral agents has revolutionized the approach to hepatitis C. We are now able to obtain high sustained virological response (SVR) rates, even in the historically difficult-to-treat patient populations. SVR translates into improved clinical outcomes, particularly overall and liver-related mortality, and benefits are more striking in patients with cirrhosis. A 2.5- to 5-fold risk reduction in the incidence of hepatocellular carcinoma and improvement in complications derived from portal hypertension have been reported as well. It is hypothesized that the benefits from SVR occur largely due to regression of fibrosis, which arises from the halt on the fibrogenic stimuli and activation of extracellular matrix reabsorption signals. Non-invasive markers of fibrosis are being utilized to assess regression, but it is still unclear how accurate they are in this clinical scenario. Interventions aiming to improve liver wellness and screening for cirrhosis-related complications should continue to be the norm after SVR.

Objectives: Identifying barriers to access to hepatitis C virus (HCV) treatment among screen detected subjects is critical for any public health strategy aimed at controlling HCV infection in the general population., Methods: Data from the National Health and Nutrition Examination Survey HCV Follow-up study from 2001 to 2010 were used. Participants who tested positive for HCV were sent a letter informing them of their test results and advised to pursue further evaluation. Information on HCV transmission and its potential complications was also provided to all positive participants. These subjects were recontacted 6 months after notification to determine what action they had taken regarding the positive result., Results: Of 38,025 participants, 502 tested positive for HCV infection, giving a prevalence of 1.3% (95% confidence interval (CI) 0.8%, 1.8%). A total of 205 subjects participated in the 6-month follow-up interview. Those who could not be reached were more likely to be less educated, injecting drugs, and not to have health insurance. Half (50.2%) of the positive individuals were not aware of their status before notification. A total of 166 (81%) had pursued further evaluation. Only 18 (26.9%) received therapy. The main reason for not receiving treatment was high cost (19.4%). In adjusted analysis, the only barrier to pursuing downstream HCV care was the lack of health insurance (2.76, 95% CI 1.54, 7.69; P=0.007)., Conclusions: This study suggests that the lack of health insurance may attenuate the theoretical benefits of a screening program that identifies asymptomatic HCV-infected individuals who are less likely to pursue downstream care.

Background: Chronic hepatitis C virus (HCV) infection causes cirrhosis and hepatocellular carcinoma but is also etiologically linked to several extrahepatic medical conditions including renal disorders. HCV is also associated with extrahepatic malignancies and may be oncogenic. Whether HCV confers an increased risk of renal cell carcinoma (RCC) remains controversial., Aims: Prospectively determine whether chronic HCV is associated with an increased risk of RCC., Methods: At an integrated medical center in Detroit, Michigan, adult patients with suspected RCC or newly diagnosed colon cancer (controls) were screened for hepatitis C antibody (HCAB) and HCV RNA. Renal or colon cancers were confirmed histologically. The proportion of patients with HCAB and HCV RNA in each group was compared, and risk factors for renal cell carcinoma were determined by multivariable logistic regression analysis., Results: RCC patients had a higher rate of HCAB positivity (11/140, 8 %) than colon cancer patients (1/100, 1 %) (p < 0.01). Of the HCAB-positive patients, 9/11 RCC and 0/1 controls had detectable HCV RNA. HCV RNA positivity was a significant risk factor for RCC (OR 24.20; 95 % CL 2.4, >999.9; p = 0.043). Additionally, viremic RCC patients were significantly younger than RCC patients who were HCV RNA negative (p = 0.013)., Conclusions: Patients with chronic HCV are at heightened risk of RCC.

Donor genotype for polymorphisms near IFNL3 influences hepatitis C virus (HCV) therapy responsiveness. This relationship has not been studied in a sample of HCV-infected living donor liver transplantation (LDLT) recipients in the United States (US). We investigated the association of donor and recipient genotypes near the IFNL3 gene at a large US liver transplant center. Recipient homozygosity for rs12979860 C was associated with increased sustained virologic response (SVR) in antiviral treatment-experienced patients pretransplant (P = 0.055). Consistently, donor homozygosity for rs12979860 C was also associated with increased SVR in patients who received post-transplant antiviral therapy (P = 0.048). Transplantation of an rs12979860 CC graft confers a favorable post-transplant antiviral response among HCV-positive recipients in an LDLT setting. Recipients with the favorable rs12979860 genotype receiving antiviral therapy before transplant are also more likely to achieve SVR. The effect of genotype status in the era of direct-acting antiviral agents will require future study.

The benefits of using transgenic switchgrass with decreased levels of caffeic acid 3-O-methyltransferase (COMT) as biomass feedstock have been clearly demonstrated. However, its effect on the soil microbial community has not been assessed. Here we report metagenomic and metatranscriptomic analyses of root-associated soil from COMT switchgrass compared with nontransgenic counterparts., (Copyright © 2014 Chauhan et al.)

Dual-resolution approaches for molecular simulations combine the best of two worlds, providing atomic details in regions of interest and coarser but much faster descriptions of less-relevant parts of molecular systems. Given the abundance of water in biomolecular systems, reducing the computational cost of simulating bulk water without perturbing the solute's properties is a very attractive strategy. Here we show that the coarse-grained model for water called WatFour (WT4) can be combined with any of the three most used water models for atomistic simulations (SPC, TIP3P, and SPC/E) without modifying the characteristics of the atomistic solvent and solutes. The equivalence of fully atomistic and hybrid solvation approaches is assessed by comparative simulations of pure water, electrolyte solutions, and the β1 domain of streptococcal protein G, for which comparisons between experimental and calculated chemical shifts at (13)Cα are equivalent.

An accurate assessment of the degree of fibrosis or presence of cirrhosis is critical both for the appropriate management of, and to provide prognosis for, patients with chronic hepatitis C infection. In the new era of direct acting antivirals, large numbers of patients may enter therapy, and although liver biopsy remains the gold standard, it is not practical in all settings. In recent years, a variety of noninvasive methods have been developed that may obviate the need for liver biopsy in most settings. Indirect laboratory formulas, tests, panels of biomarkers and imaging modalities may accurately stage the degree of fibrosis in hepatitis C monoinfection, hepatitis C/HIV coinfection, and post-transplant recurrent hepatitis C.

Gastroparesis is a chronic disorder of gastric motility characterized by delayed gastric empting in the absence of mechanical obstruction, which can lead to symptoms of nausea, vomiting, bloating, abdominal pain, postprandial fullness and weight loss. Although there are many etiologies, the primary causes are diabetes or are idiopathic. The mainstay of treatment is dietary and drug therapies. However, many patients will continue to suffer intractable symptoms despite these treatments. Gastric neurostimulation with the Enterra Therapy system has been approved for use under the Humanitarian Device Exemption by the US FDA. The device produces pulses of electrical stimulation that are delivered to the stomach continuously. One randomized clinical trial and multiple nonrandomized unblinded clinical trials and case series have documented improvement of symptoms in intractable diabetic and idiopathic gastroparesis. The purpose of this article is to introduce the Enterra Therapy gastric neurostimulator. Gastroparesis and its pathophysiology will be discussed in this clinical context to enhance the understanding of the device and its development. We will analyze the device in detail, its placement and the results of studies evaluating its efficacy.