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Background and Aims: The new steatotic liver disease (SLD) nomenclature introduced metabolic and alcohol-associated liver disease (MetALD), describing the intersection of metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease. Waitlisting and liver transplantation for MetALD are not well defined. We aimed to develop and validate an algorithm for identifying SLD phenotypes and assessing trends in waitlisting and transplant outcomes., Approach and Results: We conducted a retrospective cohort study using the United Network for Organ Sharing registry, supplemented with detailed single-center data. We developed 5 candidate algorithms for SLD classification and calculated their diagnostic performance. Trends in waitlist registrations and transplants were estimated, and competing risk analyses and Cox regression models were conducted to assess waitlist removal and posttransplant outcomes among SLD phenotypes. The best-performing algorithm demonstrated substantial agreement (weighted kappa, 0.62) for SLD phenotypes, with acceptable sensitivity (73%) for MetALD. Between 2002 and 2022, waitlist registrations and transplants for MetALD increased 2.9-fold and 3.3-fold, respectively. Since 2013, there has been a significant increase in the absolute number of waitlist registrations (122 per year; 95% CI, 111-133) and transplants (107 per year; 95% CI, 94-120) for MetALD. Patients with MetALD experienced higher waitlist removal (adjusted subdistribution hazard ratio, 1.10; 95% CI, 1.03-1.17), all-cause mortality (adjusted hazard ratio, 1.13; 95% CI, 1.03-1.23), and graft failure (adjusted hazard ratio, 1.12; 95% CI, 1.03-1.21) than those with alcohol-associated liver disease., Conclusions: We developed and validated an algorithm for identifying SLD phenotypes in UNOS. MetALD is the third leading etiology among those waitlisted and underwent transplantation, exhibiting worse pretransplantation and posttransplantation outcomes compared to alcohol-associated liver disease. Identifying and addressing factors determining poor outcomes is crucial in this patient population., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: Corticosteroids are recommended by multiple society guidelines for the treatment of severe alcohol-associated hepatitis (AH). However, their use remains controversial due to inconsistent studies regarding their survival benefit., Methods: This was a retrospective cohort study of first-time hospitalizations for severe AH (Maddrey discriminant function ≥ 32) admitted to the Veterans Health Administration between January 3, 2005, and December 5, 2020, (i) evaluating the effect of corticosteroid therapy on all-cause survival, (ii) characterizing the clinical and psychosocial factors associated with corticosteroid use, and (iii) determining the effect of duration of corticosteroid therapy on all-cause survival among treatment-responsive patients (Lille score < 0.45)., Results: During the study period, 2,618 patients were admitted with severe AH, of whom 1,083 (41.37%) received corticosteroids. Although corticosteroids were significantly associated with improved all-cause survival in the unadjusted model ( P = 0.022), no survival benefit was observed in the adjusted model after accounting for baseline and admission characteristics (adjusted hazard ratio [aHR] = 1.01, P = 0.818). Psychiatry consultation was the only factor evaluated that was protective against mortality (aHR = 0.67, P < 0.001). Among the 428 patients (49.7%) responsive to corticosteroids, duration of therapy was not associated with overall survival on unadjusted ( P = 0.696) or adjusted models (aHR = 1.12, P = 0.710 for a ≥28-day course compared with a ≤7-day reference)., Discussion: Despite being recommended by clinical guidelines for severe AH, corticosteroids have low utilization with no survival benefit after accounting for differences in patient characteristics and practice patterns. Among patients with treatment response per the Lille score, no difference was observed in overall survival between shorter and longer durations of corticosteroid therapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Patients with cirrhosis have an increased risk of postoperative mortality, which is partially attributable to portal hypertension. Preoperative TIPS placement may reduce operative risk. Studies suggesting the benefits of preoperative TIPS are limited by residual confounding and lack of longitudinal laboratory data. To address these limitations, we used granular longitudinal data from the Veterans Health Administration., Methods: This retrospective cohort study of Veterans Health Administration patients with cirrhosis who underwent major surgery from 2008 to 2022 identified patients who underwent TIPS placement within 6 months before surgery. Demographics, comorbidities, surgery type, and longitudinal laboratory data were incorporated into a propensity score using 5:1 caliper matching for receipt of TIPS. The propensity-matched cohort included 39 patients with preoperative TIPS and 171 without., Results: Baseline characteristics were similar between groups. In Cox regression, recent TIPS was associated with an increased risk of postoperative mortality (HR: 2.69, 95% CI: 1.37-5.30, p = 0.004), redemonstrated in 500 random resampling events (median HR: 1.71). TIPS and non-TIPS patients had similar albumin, bilirubin, and international normalized ratio 6 months before surgery; however, immediately before surgery, TIPS patients had lower albumin (p = 0.009), higher bilirubin (p = 0.001), and higher international normalized ratio (p = 0.001)., Conclusions: In a propensity-matched analysis of patients with cirrhosis undergoing major surgery, recent TIPS was associated with increased postoperative mortality and worsened liver synthetic function in the immediate preoperative period. TIPS placement should be carefully considered in patients with cirrhosis who may undergo surgery., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: Cirrhosis patients are at increased risk for postoperative complications. It remains unclear whether preoperative nonsurgical clinician visits improve postoperative outcomes. We assessed the impact of preoperative primary care physician (PCP) and/or gastroenterologist/hepatologist (GI/Hep) visits on postoperative mortality in cirrhosis patients undergoing surgery and explored differences in medication changes and paracentesis rates as potential mediators., Methods: This was a retrospective cohort study of cirrhosis patients in the Veterans Health Administration who underwent surgery between 2008 and 2016. We compared 1982 patients with preoperative PCP and/or GI/Hep visits with 1846 propensity-matched patients without preoperative visits. We used Cox regression and Fine and Gray competing risk regression to evaluate the association between preoperative visit type and postoperative mortality at 6 months., Results: Patients with preoperative GI/Hep and PCP visits had a 45% lower hazard of postoperative mortality compared with those without preoperative visits (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35-0.87). A smaller effect size was noted with GI/Hep preoperative visit alone (HR, 0.69; 95% CI, 0.48-0.99) or PCP visit alone (HR, 0.70; 95% CI, 0.53-0.93). Patients with preoperative PCP/GI/Hep visits were more likely to have diuretics, spontaneous bacterial peritonitis prophylaxis, and hepatic encephalopathy medications newly initiated and/or dose adjusted and more likely to receive preoperative paracentesis as compared with those without preoperative visits., Conclusions: Preoperative PCP/GI/Hep visits are associated with a reduced risk of postoperative mortality with the greatest risk reduction observed in those with both PCP and GI/Hep visits. This synergistic effect highlights the importance of a multidisciplinary approach in the preoperative care of cirrhosis patients., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: In 2015, the United Network for Organ Sharing implemented a policy introducing a 6-mo waiting period before granting model for end-stage liver disease exception points to liver transplant (LT) candidates with hepatocellular carcinoma (HCC). This study analyzes the policy impact on post-LT HCC recurrence., Methods: This was a United Network for Organ Sharing retrospective cohort study of patients with HCC who underwent LT from January 1, 2010, to May 31, 2019. HCC-specific data included alpha-fetoprotein, tumor characteristics, locoregional therapy (LRT), and explant data used to calculate the Risk Estimation of Tumor Recurrence After Transplant score. The primary exposure was pre-/post-policy era, divided on October 8, 2015. Survival analysis techniques were used to evaluate the unadjusted and sequentially adjusted association between policy era and HCC recurrence, accounting for competing risks., Results: A total of 7940 patients were included, 5879 (74.0%) pre-policy era and 2061 (26.0%) post-policy era. Post-policy patients were older, received more LRT, and had lower alpha-fetoprotein levels and smaller tumor sizes at transplant. Incidence rates of HCC recurrence were 19.8 and 13.7 events per 1000 person-years for pre- and post-policy eras, respectively. Post-policy era was associated with an unadjusted 35% reduction in the risk of HCC recurrence ( P  < 0.001). After adjusting for recipient, donor, and tumor characteristics at listing this association remained (subhazard ratio 0.69; 95% confidence interval, 0.55-0.86; P  = 0.001); however, after additionally adjusting for LRT episodes and Risk Estimation of Tumor Recurrence After Transplant score, there was no longer a statistically significant association (subhazard ratio 0.77; 95% confidence interval, 0.59-1.00; P  = 0.054)., Conclusions: We observed a significant reduction in post-LT HCC recurrence after policy implementation. This may be due to waitlist selection of healthier patients, increased LRT utilization, and potential selection of favorable tumor biology., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Diabetes is associated with HCC; however, the impact of longitudinal blood glucose (BG) control on HCC risk in cirrhosis is not well known. We investigated this knowledge gap in a cohort of United States Veterans with cirrhosis from 2015 to 2021., Methods: We used repeated hemoglobin A1c measurements to categorize follow-up time according to BG control (defined as hemoglobin A1c < 7%) state over time: uncontrolled, nonsustained control (≤2 y), or sustained control (>2 y). We performed a sensitivity analysis using hemoglobin A1c < 8% to define BG control. We used Fine and Gray Cox proportional hazards regression with death and transplant as competing events to compare rates of incident HCC., Results: Our study included 81,907 individuals, 56.2% of whom had diabetes at baseline. There were 8,002 incident HCCs. The rate of HCC was 18% higher in diabetes (95% CI: 13% - 24%), and the relative increase in the rate of HCC varied by etiology of cirrhosis from nonsignificant (HCV) to an increase of 120% (HBV). Uncontrolled and nonsustained BG control was associated with 1.80 (95% CI: 1.70-1.91) and 2.34 (95% CI: 2.21-2.48) times the rate of HCC compared to sustained BG control, respectively. Using Hgb A1c < 8% to define BG control, HCC rates in uncontrolled and nonsustained BG control were 2.43 (2.28-2.58) and 2.23 (2.11-2.36) times that observed in sustained BG control., Conclusions: Associations between diabetes and HCC in cirrhosis vary according to the longitudinal BG control state. Inadequate BG control is consistently associated with a higher risk of HCC, and long-term BG control should be considered in comprehensive cirrhosis care., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Mental health diagnoses are common and known to impact key outcomes in patients with chronic illnesses including cirrhosis. However, the independent impact of psychiatric comorbidities on mortality in these patients and potential mitigating effects of outpatient mental health-related care has not been well characterized., Methods: This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2021. Adjusted Cox regression was performed to evaluate the association between mental health-related diagnoses [groups: alcohol use disorder (AUD)/substance use disorder (SUD) alone, non-AUD/SUD alone, and any mental health diagnosis (AUD/SUD or non-AUD/SUD)] and all-cause mortality. In subgroup analyses, the impact of regular outpatient mental health visits was also assessed., Results: We identified 115,409 patients, 81.7% of whom had any mental health diagnosis at baseline. During the study window there was a significant increase in the number of mental health clinic visits per person-year (β=0.078, 95% CI: 0.065-0.092, p < 0.001), but a decrease in AUD/SUD clinic utilization (p < 0.001). In regression models, there was a 54% increased hazard in all-cause mortality for any mental health diagnosis, 11% for non-AUD/SUD, and 44% for AUD/SUD (each p < 0.001). Regular mental health visits resulted in a 21% decreased risk in all-cause mortality for AUD/SUD diagnosis, compared with 3% and 9% for any mental health diagnosis and non-AUD/SUD diagnosis, respectively (each p < 0.001)., Conclusions: Mental illness is associated with an increased risk of all-cause mortality in veterans with cirrhosis. Regular outpatient mental health care may be protective against all-cause mortality, particularly among patients with AUD/SUD. Future studies should focus on relevant clinical practice changes, including implementing integrated care programs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The coronavirus disease 2019 (COVID-19) pandemic has disrupted health care delivery in the United States, with increased reliance on telemedicine visits as opposed to in-person outpatient appointments. We used national data to evaluate shifts in modes of hepatology outpatient care for patients with cirrhosis during the pandemic. This was a retrospective cohort study among U.S. veterans with cirrhosis. We used linear regression to evaluate absolute and percentage changes from baseline in hepatology in-person visits and telemedicine visits from January 1, 2020, to August 11, 2020. The proportion of in-person and telemedicine visits were plotted geographically to demonstrate state-level shifts in care delivery over time. Patient-level characteristics in the pre-COVID and during-COVID periods were also compared. We identified 5,618 in-person and 6,210 telemedicine hepatology visits among patients with cirrhosis. In-person visits significantly declined (-16.0% per week; 95% confidence interval [CI] -20.7, -11.2; P < 0.001), while telemedicine visits significantly increased (61.3% per week; 95% CI 45.1, 77.5; P < 0.001) in the early during-COVID period. At the U.S. state level, we found that nearly all states experienced a significant shift toward telemedicine over the course of several weeks. Patients over the age of 70 years and Black patients were less likely to receive telemedicine visits in the pre-COVID period (each P < 0.05), although these differences were eliminated in the during-COVID periods. Conclusion: Among patients with cirrhosis, hepatology outpatient care delivery has shifted heavily toward telemedicine due to COVID-19. This occurred across the United States, and changes have been sustained through August 2020. Expanded telemedicine visits among older patients and Black patients may reflect dedicated efforts to increased access to care among these groups., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background & Aims: Studies regarding acute-on-chronic liver failure (ACLF) among liver transplant (LT) candidates from the United Network for Organ Sharing (UNOS) database are being used to inform LT policy changes worldwide. We assessed the validity of identifying ACLF in UNOS., Methods: We performed stratified random sampling among 3 US LT centers between 2013-2019 to obtain a representative patient sample across ACLF grades. We compared the concordance of ACLF classification by UNOS vs. blinded manual chart review, according to EASL-CLIF., Results: Among 481 sampled LT registrants, 250 (52%) had no ACLF, 75 (16%) had ACLF grade 1, 79 (16%) had ACLF grade 2, and 77 (16%) had ACLF grade 3 per UNOS categorization. Concordance of ACLF grade by UNOS vs. chart review was: 72%, 64%, 56%, and 64% for no ACLF, grade 1, grade 2, and grade 3, respectively, with an overall Cohen's kappa coefficient of 0.48 (95% CI 0.42-0.54). Absence of acute decompensation was the most common reason for overestimation, and discordant brain and respiratory failure categorization were the most common reasons for underestimation of ACLF by UNOS., Conclusions: In this retrospective multi-center study, ACLF categorization by UNOS showed weak agreement with manual chart review. These findings are informative for ongoing allocation policy discussions, highlight the importance of prospective studies regarding ACLF in LT, and should encourage UNOS reform., Lay Summary: Acute-on-chronic-liver-failure (ACLF) is a specific and common form of liver failure associated with high death rates. Studies have been published using the United States transplant registry (UNOS) to identify and describe outcomes of transplant candidates and recipients with ACLF, and these data are driving policy changes for transplant allocation around the world, but nobody has shown whether these data are reliable. We found that UNOS was not categorizing ACLF in concordance or accurately when compared to chart review, which shows the need for UNOS reform and non-UNOS studies to appropriately inform policies regarding the transplantation of patients with ACLF., Competing Interests: Conflict of interest The authors have no potential conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Importance: Two mRNA-based vaccines against coronavirus disease 2019 (COVID-19) were found to be highly efficacious in phase 3 clinical trials in the US. However, patients with chronic illnesses, including cirrhosis, were excluded from clinical trials. Patients with cirrhosis have immune dysregulation that is associated with vaccine hyporesponsiveness., Objective: To study the association of receipt of the Pfizer BNT162b2 mRNA or the Moderna mRNA-1273 vaccines in patients with cirrhosis compared with a propensity-matched control group of patients at similar risk of infection and severe disease from COVID-19., Design, Setting, and Participants: We performed a retrospective cohort study of patients with cirrhosis who received at least 1 dose of a COVID-19 mRNA vaccine at the Veterans Health Administration. Patients who received at least 1 dose of the vaccine (n = 20 037) were propensity matched with 20 037 controls to assess the associations of vaccination with new COVID-19 infection and COVID-19 hospitalization and death., Exposures: Receipt of at least 1 dose of the BNT162b2 mRNA or the mRNA-1273 vaccines between December 18, 2020, and March 17, 2021., Main Outcomes and Measures: COVID-19 infection as documented by a positive result for COVID-19 by polymerase chain reaction, hospitalization, and death due to COVID-19 infection., Results: The median (interquartile range) age of the vaccinated individuals in the study cohort was 69.1 (8.4) years and 19 465 (97.2%) of the participants in each of the vaccinated and unvaccinated groups were male, consistent with a US veteran population. The mRNA-1273 vaccine was administered in 10 236 (51%) and the BNT162b2 mRNA in 9801 (49%) patients. Approximately 99.7% of patients who received the first dose of either vaccine with a follow-up of 42 days or more received a second dose. The number of COVID-19 infections in the vaccine recipients was similar to the control group in days 0 to 7, 7 to 14, 14 to 21, and 21 to 28 after the first dose. After 28 days, receipt of 1 dose of an mRNA vaccine was associated with a 64.8% reduction in COVID-19 infections and 100% protection against hospitalization or death due to COVID-19 infection. The association of reduced COVID-19 infections after the first dose was lower among patients with decompensated (50.3%) compared with compensated cirrhosis (66.8%). Receipt of a second dose was associated with a 78.6% reduction in COVID-19 infections and 100% reduction in COVID-19-related hospitalization or death after 7 days., Conclusions and Relevance: This cohort study of US veterans found that mRNA vaccine administration was associated with a delayed but modest reduction in COVID-19 infection but an excellent reduction in COVID-19-related hospitalization or death in patients with cirrhosis.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have favourable neurohumoral and metabolic effects in patients with chronic liver disease. However, studies examining SGLT2i in this population have been limited to patients with non-alcoholic fatty liver disease and have focused on surrogate biomarkers. Our aim was to evaluate whether SGLT2i can reduce the incidence of ascites and death over a period of 36 months in patients with cirrhosis and diabetes mellitus. Using electronic health data from Veterans Affairs hospitals in the United States, we conducted a propensity score matched intention-to-treat analysis among veterans on metformin who subsequently received either SGLT2i or dipeptidyl peptidase-4 inhibitors. Among 423 matched pairs (in total, 846 patients), we found no significant difference in the risk for ascites (hazard ratio 0.68 for SGLT2i, 95% confidence interval 0.37-1.25; p = .22) but did find that SGLT2i users had a reduced risk for death (adjusted hazard ratio 0.33, 95% confidence interval 0.11-0.99; p < .05). In comparison with dipeptidyl peptidase-4 inhibitors, SGLT2i may improve survival for patients with cirrhosis who require additional pharmacotherapy for diabetes mellitus beyond metformin, but confirmatory studies are necessary., (© 2021 John Wiley & Sons Ltd.)

Objective: Our aim was to explore the risk of infection with all classes of inflammatory bowel disease (IBD) medications and the impact of these medications on the disease course in a nationwide cohort of patients with IBD., Design: This was a retrospective national cohort study of patients with IBD in the Veterans Affairs Healthcare System. We categorised IBD medication use immediately prior to the COVID-19 pandemic and used survival analysis methods to study associations with SARS-CoV-2 infection, as well as a combined secondary outcome of COVID-19 hospitalisation or COVID-19-related mortality., Results: The analytical cohort of 30 911 patients was primarily male (90.9%), white (78.6%) and with ulcerative colitis (58.8%). Over a median follow-up of 10.7 months, 649 patients (2.1%) were diagnosed with SARS-CoV-2 infection and 149 (0.5%) met the combined secondary outcome. In adjusted models, vedolizumab (VDZ) use was significantly associated with infection relative to mesalazine alone (HR 1.70, 95% CI 1.16 to 2.48, p=0.006). Patients on no IBD medications had increased risk of the combined secondary outcome relative to mesalazine alone (sub-HR 1.64, 95% CI 1.12 to 2.42, p=0.01), however, no other IBD medication categories were significantly associated with this outcome, relative to mesalazine alone (each p>0.05). Corticosteroid use was independently associated with both SARS-CoV-2 infection (HR 1.60, 95% CI 1.23 to 2.09, p=0.001) and the combined secondary outcome (sub-HR 1.90, 95% CI 1.14 to 3.17, p=0.01)., Conclusion: VDZ and corticosteroid were associated with an increased risk of SARS-CoV-2 infection. Except for corticosteroids no medications including mesalazine were associated with an increased risk of severe COVID-19., Competing Interests: Competing interests: NK has received an unrestricted research grant from Pfizer, Luitpold and Takeda Pharmaceuticals as well as Samsung BioEpis. NM and CT have nothing to disclose regarding conflicts of interest. WR has served (1) as a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, (2) as a consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Quell Tx, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC, (3) as an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia and 4SC, and (4) has received research funding from Abbott Laboratories, Abbvie, Aesca, Centocor, Falk Pharma, Immundiagnostik, MSD'. JDL has served as a consultant for Merck, AbbVie, Lilly, Janssen, Johnson & Johnson Consumer, and Takeda; has served on Data Safety Monitoring Boards for Pfizer, Gilead, and UCB; and has received research support from Takeda and Nestle Health Science., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Whether race/ethnicity plays a role in hematopoietic stem/progenitor cells (HSPC) mobilization in autologous donors has not been studied. We hypothesize that donor characteristic including race/ethnicity, age, sex, body mass index, and diagnostic groups influences HSPC mobilization. Diagnostic groups include healthy allogeneic donors, autologous multiple myeloma (MM) and non-MM donors., Study Design and Methods: Here, we conducted a single-center retrospective study in 64 autologous patients and 48 allogeneic donors. Autologous donors were patients diagnosed with MM or non-MM. All donors were grouped as African American (AA), White (W), or "Other"(O)., Results: Multivariate analysis demonstrated diagnostic group differences for CD34+ cell yields between race/ethnicity. Specifically, non-MM patients had the lowest CD34+ cell yields in AA and O, but not in W. For pre-apheresis peripheral blood (PB) CD34+ cell numbers, race/ethnicity had a significant effect both in bivariate and multivariate analyses. Non-MM patients had the lowest, and AA patients had the highest PB CD34+ cells. The results support the view that past therapies used in MM are likely more conducive of recovery of HSPC., Conclusions: Our study shows that race/ethnicity and diagnostic group differences influenced CD34+ cell mobilization response across donor types. Interestingly, autologous MM donors with the aid of plerixafor displayed comparable CD34 yields to allogeneic donors. Even though both MM and non-MM donors received plerixafor, non-MM donors had significantly lower CD34 yields among AA and O donors but not in W donors. Larger studies would be required to validate the role of diagnostic groups and race/ethnicity interactions., (© 2021 Wiley Periodicals LLC.)

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.)

Background and Aims: Patients with cirrhosis are at increased risk of postoperative mortality. Currently available tools to predict postoperative risk are suboptimally calibrated and do not account for surgery type. Our objective was to use population-level data to derive and internally validate cirrhosis surgical risk models., Approach and Results: We conducted a retrospective cohort study using data from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) cohort, which contains granular data on patients with cirrhosis from 128 U.S. medical centers, merged with the Veterans Affairs Surgical Quality Improvement Program (VASQIP) to identify surgical procedures. We categorized surgeries as abdominal wall, vascular, abdominal, cardiac, chest, or orthopedic and used multivariable logistic regression to model 30-, 90-, and 180-day postoperative mortality (VOCAL-Penn models). We compared model discrimination and calibration of VOCAL-Penn to the Mayo Risk Score (MRS), Model for End-Stage Liver Disease (MELD), Model for End-Stage Liver Disease-Sodium MELD-Na, and Child-Turcotte-Pugh (CTP) scores. We identified 4,712 surgical procedures in 3,785 patients with cirrhosis. The VOCAL-Penn models were derived and internally validated with excellent discrimination (30-day postoperative mortality C-statistic = 0.859; 95% confidence interval [CI], 0.809-0.909). Predictors included age, preoperative albumin, platelet count, bilirubin, surgery category, emergency indication, fatty liver disease, American Society of Anesthesiologists classification, and obesity. Model performance was superior to MELD, MELD-Na, CTP, and MRS at all time points (e.g., 30-day postoperative mortality C-statistic for MRS = 0.766; 95% CI, 0.676-0.855) in terms of discrimination and calibration., Conclusions: The VOCAL-Penn models substantially improve postoperative mortality predictions in patients with cirrhosis. These models may be applied in practice to improve preoperative risk stratification and optimize patient selection for surgical procedures (www.vocalpennscore.com)., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Gender disparities in authorship of heart failure (HF) guideline citations and clinical trials have not been examined., Methods: We identified authors of publications referenced in Class I Recommendations in United States (n=173) and European (n=100) HF guidelines and of publications of all HF trials with >400 participants (n=118) published between 2001 and 2016. Authors' genders were determined, and changes in authorship patterns over time were evaluated with linear regression and nonparametric testing., Results: The median proportion of women authors per publication was 20% (interquartile range [IQR], 8%-33%) in United States guidelines, 14% (IQR, 2%-20%) in European guidelines, and 11% (IQR, 4%-20%) in HF trials. The proportion of women authors increased modestly over time in United States and European guidelines' references (β=0.005 and 0.003, respectively, from 1986 to 2016; P <0.001) but not in HF trials (12.5% [IQR, 0%-20%] in 2001-2004 to 8.9% [IQR, 0%-20%] in 2013-2016; P >0.50). Overall proportions of women as first or last authors in HF trials (16%) did not change significantly over time ( P =0.60). North American HF trials had the highest likelihood of having a woman as first or senior author (24%). HF trials with a woman first or senior author were associated with a higher proportion of enrolled female participants (39% versus 26%, P =0.01)., Conclusions: In HF practice guidelines and trials, few women are authors of pivotal publications. Higher number of women authors is associated with higher enrollment of women in HF trials. Barriers to authorship and representation of women in HF guidelines and HF trial leadership need to be addressed.

Background and Purpose: The diagnosis of acute on chronic liver failure (ACLF) carries a high short-term mortality, making early identification of at-risk patients crucial. To date, there are no models that predict which patients with compensated cirrhosis will develop ACLF, and limited models exist to predict ACLF mortality. We sought to create novel risk prediction models using a large North American cohort., Methods: We performed a retrospective study of 75,922 patients with compensated cirrhosis from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) dataset. Using 70% derivation/30% validation sets, we identified ACLF patients using the Asian Pacific Association of Liver (APASL) definition. Multivariable logistic regression was used to derive prediction models (called VOCAL-Penn) for developing ACLF at 3, 6, and 12 months. We then created prediction models for ACLF mortality at 28 and 90 days., Results: The VOCAL-Penn models for ACLF development had very good discrimination [concordance (C) statistics of 0.93, 0.92, and 0.89 at 3, 6, and 12 months, respectively] and calibration. The mortality models also had good discrimination at 28 and 90 days (C statistics 0.89 and 0.88, respectively), outperforming the Model for End-stage Liver Disease (MELD), MELD-sodium, and the APASL ACLF Research Consortium ACLF scores., Conclusion: We have developed novel tools for predicting development of ACLF in compensated cirrhosis patients, as well as for ACLF mortality. These tools may be used to proactively guide patient follow-up, prognostication, escalation of care, and transplant evaluation. Receiver operating characteristic (ROC) curves for predicting development of APASL ACLF at 3 months (a), 6 months (b), and 1 year (c).

Background: In the United States, nearly 30% of liver transplants (LT) are performed for hepatocellular carcinoma (HCC). Although overall long-term survival is highest with LT, there are limited data on the incremental survival benefit of LT versus other curative options (resection or ablation) due to shunting of patients towards LT., Methods: We performed a retrospective cohort study of patients aged 50-69 with cirrhosis and HCC in the Veterans Health Administration (population enriched with 3 curative treatments) from 2008 to 2016. The cohort was restricted to patients who received LT, resection, or ablation and a calculated model for end-stage liver disease score <15 at HCC diagnosis., Results: Among 2129 veterans in the analytic cohort, 658 (26.7%) received LT, 244 (11.5%) underwent resection, and 1317 (61.59%) received ablation. In multivariable models, patients who underwent resection (hazard ratio: 5.42; 95% confidence interval: 4.15-7.08) or ablation (hazard ratio: 5.50; 95% confidence interval: 4.51-6.71) had significantly increased hazards of death. However, in absolute terms, the incremental survival benefit of LT over resection or ablation was small, between 0.02 and 0.03 years at 1 year, 0.32-0.42 years at 3 years, and 1.04-1.24 years at 5 years follow-up. These results were consistent in sensitivity analyses accounting for possible immortal time bias, as well as a cohort restricted to early/intermediate stage HCC., Conclusions: Although LT is associated with significantly increased survival compared to resection and ablation, the absolute incremental survival benefit is small over a 5-year time horizon. Optimal selection of patients for LT is critical for maximizing utilization of a scarce resource.

Background: Patients with cirrhosis have increased peri-operative mortality risk relative to non-cirrhotic patients, however, the impact of surgical procedure category on this risk is poorly understood., Methods: We performed a retrospective cohort study of cirrhosis surgery admissions using the National Inpatient Sample between 2012 and 2014 to estimate the adjusted odds of in-hospital mortality by surgical procedure category., Results: In-hospital mortality differed by surgical procedure category. Relative to major orthopedic surgeries, major abdominal surgeries had the highest odds of in-hospital mortality (odds ratio [OR] 8.27, 95% confidence interval [CI] 5.96-11.49), followed by major cardiovascular surgeries (OR 3.45, 95% CI 2.33-5.09). There was also a significant interaction term, whereby elective/non-elective admission status impacted in-hospital mortality risk differently for each surgical procedure category (P < 0.001)., Conclusion: In-hospital mortality varies substantially by surgical procedure type. Accounting for procedure type in models may improve risk prediction for peri-operative mortality in patients with cirrhosis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Patients listed for liver transplantation (LT) as status 1a currently receive the highest priority on the waiting list. The presence of acute on chronic liver failure (ACLF) with three or more organs failing (ACLF-3) portends low survival without transplantation, which may not be reflected by the Model for End-Stage Liver Disease-Sodium (MELD-Na) score. We compared short-term waitlist mortality for patients listed status 1a and those with ACLF-3 at listing. Data were analyzed from the United Network for Organ Sharing database, years 2002-2014, for 3,377 patients listed status 1a and 5,099 patients with ACLF-3. Candidates with ACLF were identified based on the European Association for the Study of the Liver Chronic Liver Failure Consortium criteria. MELD-Na score was treated as a categorical variable of scores <36, 36-40, and >40. We used competing risks regression to assess waitlist mortality risk. Evaluation of outcomes through 21 days after listing demonstrated a rising trend in mortality among ACLF-3 patients at 7 days (18.0%), 14 days (27.7%), and 21 days (32.7%) (P < 0.001) compared to a stable trend in mortality among individuals listed as status 1a at 7 days (17.9%), 14 days (19.3%), and 21 days (19.8%) (P = 0.709). Multivariable modeling with adjustment for MELD-Na category revealed that patients with ACLF-3 had significantly greater mortality (subhazard ratio, 1.45; 95% confidence interval, 1.31-1.61) within 14 days of listing compared to status-1a candidates. Analysis of the interaction between MELD-Na category and ACLF-3 showed that patients with ACLF-3 had greater risk of 14-day mortality than status-1a-listed patients, across all three MELD-Na categories. Conclusion: Patients with ACLF-3 at the time of listing have greater 14-day mortality than those listed as status 1a, independent of MELD-Na score; these findings illustrate the importance of early transplant evaluation and consideration of transplant priority for patients with ACLF-3., (© 2019 by the American Association for the Study of Liver Diseases.)

Hospital readmissions after liver transplantation (LT) are common and associated with increased morbidity and cost. High readmission rates at our center motivated a change in practice with adoption of a nurse practitioner (NP)-based posttransplant care program. We sought to determine if this program was effective in reducing 30- and 90-day readmissions after LT and to identify variables associated with readmission. We performed a retrospective cohort study of all patients undergoing LT from July 1, 2014, to June 30, 2017, at a tertiary LT referral center. A NP-based posttransplant care program with weekend in-house nurse coordination providers and increased outpatient NP clinic availability was instituted on January 1, 2016. Postdischarge readmission rates at 30 and 90 days were compared in the pre-exposure and postexposure groups, adjusting for associated risk factors. A total of 362 patients were included in the analytic cohort. There were no significant differences in demographics, comorbidities, or index hospitalization characteristics between groups. In the adjusted analyses, the risk of readmission in the postexposure group was significantly reduced relative to baseline at 30 days (hazard ratio [HR] 0.60, 95% confidence interval [CI], 0.39-0.90; P = 0.02) and 90 days (HR, 0.49; 95% CI, 0.34-0.71; P < 0.001). Risk factors positively associated with 30-day readmission included peritransplant dialysis (HR, 1.70; 95% CI, 1.13-2.58; P = 0.01) and retransplant on index hospitalization (HR, 10.21; 95% CI, 3.39-30.75; P < 0.001). Male sex was protective against readmission (HR, 0.66; 95% CI, 0.45-0.97; P = 0.03). In conclusion, implementation of expanded NP-based care after LT was associated with significantly reduced 30- and 90-day readmission rates. LT centers and other service lines using significant postsurgical resources may be able to reduce readmissions through similar programs., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

The term acute-on-chronic liver failure (ACLF) is intended to identify patients with chronic liver disease who develop rapid deterioration of liver function and high short-term mortality after an acute insult. The two prominent definitions (European Association for the Study of the Liver [EASL] and Asian Pacific Association for the Study of the Liver [APASL]) differ, and existing literature applies to narrow patient groups. We sought to compare ACLF incidence and mortality among a diverse cohort of patients with compensated cirrhosis, using both definitions. This was a retrospective cohort study of patients with incident compensated cirrhosis in the Veterans Health Administration from 2008 to 2016. First ACLF events were identified for each definition. Incidence rates were computed as events per 1,000 person-years, and mortality was calculated at 28 and 90 days. Among 80,383 patients with cirrhosis with 3.35 years median follow-up, 783 developed EASL and APASL ACLF, 4,296 developed EASL ACLF alone, and 574 developed APASL ACLF alone. The incidence rate of APASL ACLF was 5.7 per 1,000 person-years (95% confidence interval [CI]: 5.4-6.0), and the incidence rate of EASL ACLF was 20.1 (95% CI: 19.5-20.6). The 28-day and 90-day mortalities for APASL ACLF were 41.9% and 56.1%, respectively, and were 37.6% and 50.4% for EASL ACLF. The median bilirubin level at diagnosis of EASL-alone ACLF was 2.0 mg/dL (interquartile range: 1.1-4.0). Patients with hepatitis C or nonalcoholic fatty liver disease had among the lowest ACLF incidence rates but had the highest short-term mortality. Conclusion: There is significant discordance in ACLF events by EASL and APASL criteria. The majority of patients with EASL-alone ACLF have preserved liver function, suggesting the need for more liver-specific ACLF criteria., (© 2019 by the American Association for the Study of Liver Diseases.)