Implementing pragmatic clinical trials in hepatology.

Patients with chronic liver disease would benefit from pragmatic trial designs. A pragmatic trial seeks to inform clinical decision-making by providing evidence for the adoption of an intervention into real-world clinical practice. A trial's pragmatism is based on the efficiency by which it identifies, recruits, and follows patients, the degree to which the interventions and design mirror the usual clinical care, and the importance of the outcomes to the patients. We review the promise, trade-offs, and purpose of pragmatic trials in hepatology.

Real-world evidence for factors associated with maintenance treatment practices among US adults with autoimmune hepatitis.

BACKGROUND AND AIMS: While avoidance of long-term corticosteroids is a common objective in the management of autoimmune hepatitis (AIH), prolonged immunosuppression is usually required to prevent disease progression. This study investigates the patient and provider factors associated with treatment patterns in US patients with AIH. APPROACH AND RESULTS: A retrospective cohort of adults with the incident and prevalent AIH was identified from Optum's deidentified Clinformatics Data Mart Database. All patients were followed for at least 2 years, with exposures assessed during the first year and treatment patterns during the second. Patient and provider factors associated with corticosteroid-sparing monotherapy and cumulative prednisone use were identified using multivariable logistic and linear regression, respectively.The cohort was 81.2% female, 66.3% White, 11.3% Black, 11.2% Hispanic, and with a median age of 61 years. Among 2203 patients with ≥1 AIH prescription fill, 83.1% received a single regimen for >6 months of the observation year, which included 52.2% azathioprine monotherapy, 16.9% azathioprine/prednisone, and 13.3% prednisone monotherapy. Budesonide use was uncommon (2.1% combination and 1.9% monotherapy). Hispanic ethnicity (aOR: 0.56; p = 0.006), cirrhosis (aOR: 0.73; p = 0.019), osteoporosis (aOR: 0.54; p =0.001), and top quintile of provider AIH experience (aOR: 0.66; p = 0.005) were independently associated with lower use of corticosteroid-sparing monotherapy. Cumulative prednisone use was greater with diabetes (+441 mg/y; p = 0.004), osteoporosis (+749 mg/y; p < 0.001), and highly experienced providers (+556 mg/y; p < 0.001). CONCLUSIONS: Long-term prednisone therapy remains common and unexpectedly higher among patients with comorbidities potentially aggravated by corticosteroids. The greater use of corticosteroid-based therapy with highly experienced providers may reflect more treatment-refractory disease.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

A Nonheme Iron(III) Superoxide Complex Leads to Sulfur Oxygenation.

A new alkylthiolate-ligated nonheme iron complex, FeII(BNPAMe2S)Br (1), is reported. Reaction of 1 with O2 at -40 °C, or reaction of the ferric form with O2•- at -80 °C, gives a rare iron(III)-superoxide intermediate, [FeIII(O2)(BNPAMe2S)]+ (2), characterized by UV-vis, 57Fe Mössbauer, ATR-FTIR, EPR, and CSIMS. Metastable 2 then converts to an S-oxygenated FeII(sulfinate) product via a sequential O atom transfer mechanism involving an iron-sulfenate intermediate. These results provide evidence for the feasibility of proposed intermediates in thiol dioxygenases.

Axial Ligation Impedes Proton-Coupled Electron-Transfer Reactivity of a Synthetic Compound-I Analogue.

The nature of the axial ligand in high-valent iron-oxo heme enzyme intermediates and related synthetic catalysts is a critical structural element for controlling proton-coupled electron-transfer (PCET) reactivity of these species. Herein, we describe the generation and characterization of three new 6-coordinate, iron(IV)-oxo porphyrinoid-π-cation-radical complexes and report their PCET reactivity together with a previously published 5-coordinate analogue, FeIV(O)(TBP8Cz+•) (TBP8Cz = octakis(p-tert-butylphenyl)corrolazinato3-) (2) (Cho, K. A high-valent iron-oxo corrolazine activates C-H bonds via hydrogen-atom transfer. J. Am. Chem. Soc. 2012, 134, 7392-7399). The new complexes FeIV(O)(TBP8Cz+•)(L) (L = 1-methyl imidazole (1-MeIm) (4a), 4-dimethylaminopyridine (DMAP) (4b), cyanide (CN-)(4c)) can be generated from either oxidation of the ferric precursors or by addition of L to the Compound-I (Cpd-I) analogue at low temperatures. These complexes were characterized by UV-vis, electron paramagnetic resonance (EPR), and Mössbauer spectroscopies, and cryospray ionization mass spectrometry (CSI-MS). Kinetic studies using 4-OMe-TEMPOH as a test substrate indicate that coordination of a sixth axial ligand dramatically lowers the PCET reactivity of the Cpd-I analogue (rates up to 7000 times slower). Extensive density functional theory (DFT) calculations together with the experimental data show that the trend in reactivity with the axial ligands does not correlate with the thermodynamic driving force for these reactions or the calculated strengths of the O-H bonds being formed in the FeIV(O-H) products, pointing to non-Bell-Evans-Polanyi behavior. However, the PCET reactivity does follow a trend with the bracketed reduction potential of Cpd-I analogues and calculated electron affinities. The combined data suggest a concerted mechanism (a concerted proton electron transfer (CPET)) and an asynchronous movement of the electron/proton pair in the transition state.

Multivisceral transplantation utilizing hepatitis C virus-viremic donors for hepatitis C virus-negative recipients.

The advent of highly effective and well-tolerated direct-acting antiviral therapy has made it more feasible to transplant hepatitis C virus (HCV)-infected organs into HCV-negative recipients. This case report presents the outcomes of 4 patients who underwent multivisceral transplantation from HCV-nucleic acid test (NAT)-viremic donors, with 1 recipient also requiring a kidney transplant. All recipients received posttransplant direct-acting antiviral therapy with sofosbuvir/velpatasvir (SOF/VEL [Epclusa]). By the fourth week of therapy, none of the recipients exhibited detectable viral loads, and all achieved sustained virologic response at 12 weeks. Allograft function for HCV D+/R- recipients remained excellent throughout follow-up. One recipient died from posttransplant lymphoproliferative disorder and another developed end-stage renal disease; both outcomes were ostensibly unrelated to HCV-donor status. The other 2 patients are progressing well without any evidence of allograft rejection.

Variation in intention-to-treat survival by MELD subtypes: All models created for end-stage liver disease are not equal.

BACKGROUND & AIMS: Kidney dysfunction is a major determinant of prognosis in patients with decompensated cirrhosis awaiting transplantation. We hypothesized that for identical model for end-stage liver disease (MELD) scores at listing, outcomes before and after liver transplantation may vary if the predominant driver of the MELD score is serum creatinine (Cr) vs. serum bilirubin (Br) or international normalized ratio (INR). METHODS: We evaluated all adult patients registered for liver transplantation (LT) between 2016-2020 and excluded patients receiving MELD exceptions or undergoing dual organ transplantation. Using K-Means clustering analysis, we classified each patient as MELD-Br, MELD-INR or MELD-Cr depending on the dominant variable for their MELD score. The primary outcome was intent-to-treat (ITT) survival, defined as survival within 1 year from listing with or without LT. RESULTS: MELD scores of LT waitlist registrants were clustered into three subtypes: MELD-Br (n = 13,658), MELD-INR (n = 13,809), and MELD-Cr (n = 12,412). One-year ITT survival rates were 78% (MELD-Br), 75% (MELD-INR), and 65% (MELD-Cr), p <0.01. ITT survival was lower for each MELD subtype for females compared to males (e.g. MELD-Cr: 63% females vs. 67% males, p <0.0001). The MELD-Cr subtype had the highest MELD at listing (MELD-Cr 23.4 vs. MELD-Br 19.2 vs. MELD-INR 21.0) and the largest decline in MELD over 3 months (23% vs. 12% vs. 21%). In adjusted analyses including MELD-Na, MELD-Cr was associated with higher waitlist mortality (hazard ratio 1.339, 95% CI 1.279-1.402) and lower LT rates (hazard ratio 0.688, 95% CI 0.664-0.713) compaed to the other subtypes. CONCLUSIONS: For equivalent listing practices, registrants with the MELD-Cr subtype have lower ITT survival. MELD subtype may serve as a more sophisticated variable for dynamic assessment of mortality risk and to guide organ allocation. IMPACT AND IMPLICATIONS: The model for end-stage liver disease (MELD) score is an excellent predictor of waitlist mortality; however, our work highlights that the driver of a patient's MELD score matters and particularly those driven by elevated creatinine are associated with lower 1-year intent-to-treat survival. The 1-year intent-to-treat survival is also lower for women compared to men within the Cr-dominant subtype. These results are important for physicians and patients undergoing LT evaluation as creatinine may serve as a marker of prognosis and even if creatinine levels improve the prognosis remains poor, necessitating discussion about alternative pathways for transplant. Our work also highlights that the type of kidney injury matters, in that those with acute kidney injury were more likely to die or remain on the waitlist than those with chronic kidney disease within the creatinine-dominant subtype.

Regional Social Vulnerability is Associated With Geographic Disparity in Waitlist Outcomes for Patients With Non-Hepatocellular Carcinoma Model for End-stage Liver Disease Exceptions in the United States.

OBJECTIVE: This study was undertaken to evaluate the role of regional social vulnerability in geographic disparity for patients listed for liver transplantation with non-hepatocellular carcinoma (HCC) model for end-stage liver disease (MELD) exceptions. SUMMARY AND BACKGROUND: Prior work has demonstrated regional variability in the appropriateness of MELD exceptions for diagnoses other than HCC. METHODS: Adults listed at a single center for first-time liver-only transplantation without HCC after June 18, 2013 in the Scientific Registry of Transplant Recipients database as of March 2021 were examined. Candidates were mapped to hospital referral regions (HRRs). Adjusted likelihood of mortality and liver transplantation were modeled. Advantaged HRRs were defined as those where exception patients were more likely to be transplanted, yet no more likely to die in adjusted analysis. The Centers for Disease Control's Social Vulnerability Index (SVI) was used as the measure for community health. Higher SVIs indicate poorer community health. RESULTS: There were 49,494 candidates in the cohort, of whom 4337 (8.8%) had MELD exceptions. Among continental US HRRs, 27.3% (n = 78) were identified as advantaged. The mean SVI of advantaged HRRs was 0.42 versus 0.53 in nonadvantaged HRRs ( P = 0.002), indicating better community health in these areas. Only 25.3% of advantaged HRRs were in spatial clusters of high SVI versus 40.7% of nonadvantaged HRRs, whereas 44.6% of advantaged HRRs were in spatial clusters of low SVI versus 38.0% of nonadvantaged HRRs ( P = 0.037). CONCLUSIONS: An advantage for non-HCC MELD exception patients is associated with lower social vulnerability on a population level. These findings suggest assigning similar waitlist priority to all non-HCC exception candidates without considering geographic differences in social determinants of health may actually exacerbate rather than ameliorate disparity.

Barriers to Community-Based Eradication of Helicobacter pylori Infection.

Helicobacter pylori (HP) is a causative agent in gastric cancer (GC).1 In the United States, HP is more prevalent in racial and ethnic minorities, including African Americans, Asian Americans, Latinos, and immigrants, the same groups that are more likely to develop and die from GC.2 Although screening for HP is not presently performed in the United States, there are plausible benefits to doing so, because HP is considered a group 1 carcinogen by the World Health Organization, and its link to GC parallels that of human papilloma virus and cervical cancer.1 HP eradication as a means of preventing GC also fulfils the Wilson and Jungner criteria for a successful screening program, and literature has consistently demonstrated that HP eradication reduces GC risk and death from GC.3 In fact, in countries with a high burden of GC, HP eradication is considered primary prevention for GC. As such, targeted HP testing in the United States may reduce GC burden in high-risk groups.4 We evaluate the results of community-based HP testing in an at-risk, underserved population.

Improvement in Survival After Transplantation for Critically Ill Patients With Cirrhosis in the United States.

INTRODUCTION: There is considerable debate over the indication of liver transplantation (LT) for critically ill patients with cirrhosis, in part due to their potentially poor post-LT prognosis. We analyzed the epidemiology and outcome of LT for critically ill patients with cirrhosis over 4 time periods of 4 years. METHODS: We included adult patients who underwent liver transplant alone between 2005 and 2020 using the United Network for Organ Sharing registry database. We defined critically ill patients with cirrhosis as being in the intensive care unit with 1 or more of the following characteristics at the time of LT: (i) grade III/IV hepatic encephalopathy, (ii) mechanical ventilation, (iii) dialysis, and (iv) vasopressors. RESULTS: A total of 85,594 LT recipients were included, 5,827 (6.8%) of whom were classified as being critically ill with cirrhosis at the time of LT. The number and percentage of critically ill LT recipients with cirrhosis increased over the study period: 819 (4.3%) in 2005-2008 vs 2,067 (7.9%) in 2017-2020, P < 0.001. There was a 17% absolute increase in 1-year survival after LT: 72.5% in 2005-2008 vs 89.5% in 2017-2020, P < 0.001. The 1-year post-LT survival gap between critically ill and noncritically ill patients with cirrhosis narrowed over the study period: 16.7 percentage points in 2005-2008 vs 4.6 percentage points in 2017-2020. The year of LT was independently associated with lower 1-year post-LT mortality (hazard ratio 0.92, 95% confidence interval 0.91-0.93, P < 0.001). DISCUSSION: The absolute number and relative percentage of LT recipients who were critically ill increased over time, as did 1-year post-LT survival. Meanwhile, the gap in survival between this group of patients and noncritically ill patients with cirrhosis decreased but persisted. Cautious access to selected LT candidates who are critically ill may be warranted, provided the gap in survival with noncritically ill patients remains as small as possible.

The Liver Cirrhosis Network Cohort Study: Cirrhosis Definition, Study Population, and Endpoints.

INTRODUCTION: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified. DISCUSSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion. REGISTRATION: NCT05740358.

Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database.

BACKGROUND: There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. OBJECTIVES: Identify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. METHODS: A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. RESULTS: We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75). CONCLUSIONS: After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Transplant center variability in utilizing nonstandard donors and its impact on the transplantation of patients with lower MELD scores.

There is a subset of patients with lower MELD scores who are at substantial risk of waitlist mortality. In order to transplant such patients, transplant centers must utilize "nonstandard" donors (eg, living donors, donation after circulatory death), which are traditionally offered to those patients who are not at the top of the waitlist. We used Organ Procurement and Transplantation data to evaluate center-level and region-level variability in the utilization of nonstandard donors and its impact on MELD at transplant among adult liver-alone non-status 1 patients transplanted from April 1, 2020, to September 30, 2022. The center-level variability in the utilization of nonstandard donors was 4-fold greater than the center-level variability in waitlisting practices (waitlistings with a MELD score of <20). While there was a moderate correlation between center-level waitlisting and transplantation of patients with a MELD score of <20 ( p = 0.58), there was a strong correlation between center-level utilization of nonstandard donors and center-level transplantation of patients with a MELD score of <20 ( p = 0.75). This strong correlation between center-level utilization of "nonstandard" donors and center-level transplantation of patients with a MELD score of <20 was limited to regions 2, 4, 5, 9, and 11. Transplant centers that utilize more nonstandard donors are more likely to successfully transplant patients at lower MELD scores. Public reporting of these data could benefit patients, caregivers, and referring providers, and be used to help maximize organ utilization.

Assessing LSAM's ability to account for changes in organ donation and transplant center behavior.

The Liver Simulated Allocation Model (LSAM) is used to evaluate proposed organ allocation policies. Although LSAM has been shown to predict the directionality of changes in transplants and nonused organs, the magnitude is often overestimated. One reason is that policymakers and researchers using LSAM assume static levels of organ donation and center behavior because of challenges with predicting future behavior. We sought to assess the ability of LSAM to account for changes in organ donation and organ acceptance behavior using LSAM 2019. We ran 1-year simulations with the default model and then ran simulations changing donor arrival rates (ie, organ donation) and center acceptance behavior. Changing the donor arrival rate was associated with a progressive simulated increase in transplants, with corresponding simulated decreases in waitlist deaths. Changing parameters related to organ acceptance was associated with important changes in transplants, nonused organs, and waitlist deaths in the expected direction in data simulations, although to a much lesser degree than changing the donor arrival rate. Increasing the donor arrival rate was associated with a marked decrease in the travel distance of donor livers in simulations. In conclusion, we demonstrate that LSAM can account for changes in organ donation and organ acceptance in a manner aligned with historical precedent that can inform future policy analyses. As Scientific Registry of Transplant Recipients develops new simulation programs, the importance of considering changes in donation and center practice is critical to accurately estimate the impact of new allocation policies.

Hospital readmission for acute kidney injury is independently associated with de novo end-stage renal disease after liver transplantation.

End-stage renal disease (ESRD) after liver transplantation (LT) is associated with high morbidity and mortality. The consequences of hospitalizations for post-LT acute kidney injury (AKI) are poorly understood. Using linked Medicare claims and transplant registry data, we analyzed adult liver alone recipients not receiving pre-transplant dialysis between 1/1/2007-12/31/2016. Covariate-adjusted Cox proportional hazards models stratified by center evaluated factors associated with AKI readmission during the first post-LT year, and whether AKI readmission was associated with de novo early (<1 y) or late (≥1 y) ESRD post-LT. The cohort included 10,559 patients and was 64.5% male, 72.5% White, 8.1% Black and 14.0% Hispanic with median age 62 years. Overall, 2,875 (27.2%) patients had ≥1 AKI hospitalization during the first year. eGFR at LT was associated with AKI readmission (aHR 1.16 per 10 mL/min/1.73m2 decrease; p<0.001). The aHR for early ESRD in patients with ≥1 AKI readmission <90 days post-LT was 1.90 (p<0.001). The aHRs for late ESRD with 1 and ≥2 prior AKI readmissions were 1.57 and 2.80 respectively (p<0.001). AKI readmissions in the first post-LT year impact over one-quarter of recipients. These increase the risk of subsequent ESRD, but may represent an opportunity to intervene and mitigate further renal dysfunction.

Use of HBsAg-positive donors in liver transplantation: An ILTS-EASL-AASLD multisociety survey.

The gap between organ supply and demand in liver transplantation remains large in most parts of the world. One strategy to increase the donor pool is to use grafts infected with HCV, HBV, and/or HIV viruses. We aimed to explore the current use of HBsAg-positive liver grafts worldwide. A prospective cross-sectional web-based survey was designed, with a total of 28 queries, assessing national and local regulations, center experience, and center-specific experience related to the topic, and sent to all members of International Liver Transplantation Society, European Association for the Study of the Liver, and American Association for the Study of the Liver, and promoted on social media. A total of 135 liver transplant centers answered the survey: 38% from WHO European Regions, 39% from American regions, and 9.7% from South-East Asian regions. Most of the participating centers (67.3%) had been performing liver transplantation for over 15 years, with a mean of 66.5 liver transplants per year, and 54% also performed living-donor liver transplants. HBV-related disease was the indication for liver transplantation in an average of 15% of all liver transplantation cases. Regarding national and/or regional regulations, 40% of the centers reported that the use of HBsAg-positive donors was permitted, and an additional 20% could use them under special circumstances. Thirty-two centers (31%) had previously used HBsAg-positive donors. Among these centers, 62.5% conducted living-donor liver transplants and showed an increased inclination toward the use of HBsAg-positive grafts in centers with elevated waitlist mortality. HBsAg-positive donors are underutilized worldwide. The use of HBsAg-positive liver grafts could help to increase the donor pool, particularly in highly endemic areas.

Sociodemographic and geographic differences in the US epidemiology of autoimmune hepatitis with and without cirrhosis.

BACKGROUND AND AIMS: Data on the epidemiology of autoimmune hepatitis (AIH) in the United States are limited. This study investigated the sociodemographic and geographic factors associated with AIH incidence and prevalence with and without cirrhosis. APPROACH AND RESULTS: In a retrospective cohort of adults in the Optum Clinformatics Data Mart (2009-2018), we identified AIH cases using a validated claims-based algorithm. Incidence and prevalence were compared between sociodemographic subgroups. Logistic regression evaluated the association of US Census Division with AIH incidence and the factors associated with incident AIH with cirrhosis. From 2009 to 2018, the age- and sex-standardized prevalence of AIH in the Optum cohort was 26.6 per 100,000 persons with an incidence of 4.0 per 100,000 person-years. AIH incidence increased earlier among Hispanics (age 50-59 years) and later among Asians (≥80 years). Adjusted AIH incidence was higher in the Mountain Division (odds ratio [OR] 1.17) and lower in the Pacific (OR 0.68), Middle Atlantic (OR 0.81), and West North Central Divisions (OR 0.86 vs. East North Central; p < 0.001). Male sex (OR 1.31, p = 0.003), Black race (OR 1.32, p = 0.022), and Hispanic ethnicity (OR 1.37 vs. non-Hispanic White, p = 0.009) were associated with incident AIH with cirrhosis. Incident AIH with cirrhosis was greater in the West South Central Division (OR 1.30 vs. South Atlantic; p = 0.008). CONCLUSIONS: AIH epidemiology differs according to sociodemographic and geographic factors in the United States. Studies are needed to determine the genetic, epigenetic, and environmental factors underlying the heterogeneity in AIH risk and outcomes.

Achieving Consensus: Severity-Graded Definitions of Fontan-Associated Complications to Characterize Fontan Circulatory Failure.

BACKGROUND: Fontan physiology leads to chronic changes in other organ systems that may affect long-term survival and the success of heart transplantation. Inadequate assessment and treatment of the extra-cardiac effects of Fontan may contribute to poor outcomes. Severity-graded/ordinal consensus definitions of Fontan complications are lacking, which limits understanding of how Fontan-specific morbidity affects patients' outcomes. METHODS AND RESULTS: A panel of Fontan patient and physiology experts, including pediatric, adult congenital, heart failure, and critical-care cardiology as well as pediatric nephrology, hepatology and psychology, convened to develop definitions of Fontan complications. Definitions were created by using a severity-graded ordinal scale: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, disabling or life threatening. Following definition creation, a second panel of 21 experts in Fontan circulatory failure used a modified Delphi methodology to modify and vote on definitions until consensus (> 90% agreement without recommended further modification) was reached on final definitions. After 3 rounds of modifications and voting, consensus agreement was achieved on all Fontan-specific definitions. The defined complications and morbidities of Fontan include: anatomic Fontan pathway obstruction, cyanosis, systemic venous abnormalities resulting from venous insufficiency, atrial arrhythmia, ventricular arrhythmia, bradycardia, chronic pleural effusions, chronic ascites, protein-losing enteropathy, plastic bronchitis, hemoptysis and pulmonary hemorrhage, sleep apnea, Fontan-associated liver disease, portal and hepatic variceal disease, acute kidney injury affecting clinical treatment, polycythemia, thrombotic disease, recurrent or severe bacterial infection, skin atrophy, adrenal insufficiency, physical impact of previous stroke, mood/behavior disorder, and neurodevelopmental disorder. CONCLUSION: Consensus and severity-graded definitions of Fontan-specific cardiac and extra-cardiac complications were achieved and are available for use in research. They will allow future robust analyses of Fontan patient outcomes.

Care of Diabetes and the Sacrifice of Evidence-Based Medicine and Health Equity.

The American Diabetes Association and the European Association for the Study of Diabetes published a 2022 consensus report recommending changes in diabetes care. This Perspective raises three concerns: with how the report summarizes evidence, how it frames the social determinants of health (SDOH), and with its transnational composition and conflicts of interest. The Perspective analyzes three new clinical recommendations that change the role of metformin from first-line therapy to a first-line option, for the inclusion of weight management as a co-primary treatment goal with glycemic control for patients without cardiac or renal complications, and for addition of the SDOH as a universal component of diabetes care together with lifestyle changes and self-management support. The Perspective considers how the poor evidence assessments of the recommendations and the imprecise framing of the SDOH introduce bias. The composition of the panel's membership poorly represents and accounts for the challenges faced by vulnerable US communities or safety net providers. The report is placed in a historical context for diabetes of organized medicine's failures to overcome prejudices and promote health equity. The Perspective concludes that the report perpetuates a pattern of prejudice within organized medicine at the expense of scientific precision and health equity.

Racial-ethnic differences in liver transplant waitlist outcomes in patients with hepatocellular carcinoma before and after recent changes to allocation policy.

BACKGROUND: In May 2019, liver transplant (LT) allocation policy changed to limit MELD exception points for hepatocellular carcinoma (HCC) to median MELD at transplant minus three (MMaT-3). We evaluated this policy's impact on waitlist outcomes for HCC candidates, by race and ethnicity, hypothesizing that the introduction of the MMaT-3 reduced inequities in waitlist outcomes. METHODS: Retrospective cohort study of the Scientific Registry for Transplant Recipients, including all adult LT candidates (N = 10 751) who received HCC exception points from May 17, 2017 to May 18, 2019 (pre-policy; N = 6627) to May 19, 2019 to March 1, 2021 (post-policy; N = 4124). We compared incidence of LT and waitlist removal for death or becoming too sick pre- and post-policy for non-Hispanic White, non-Hispanic Black, Hispanic/Latinx, and Asian patients using competing risk regression adjusted for candidate characteristics. RESULTS: One-year cumulative incidence of LT decreased significantly pre-/post-policy among White (77.4% vs. 64.5%; p < .01) and Black (76.2% vs. 63.1%; p < .01) candidates only, while a 1-year incidence of death/non-LT waitlist removal decreased significantly only among Hispanics (13.4% vs. 7.5%; p < .01). After covariate adjustment, the effect of the policy change was a significantly decreased incidence of LT for White (SHR: .63 compared to pre-policy; p < .001), Black (SHR: .62; p < .001), and Asian (SHR: .68; p = .002), but no change for Hispanic patients. Only Hispanic patients had a significant decrease in death/waitlist removal after the policy change (SHR:  .69; p = .04). Compared to White patients in the pre-policy era, Hispanic (SHR:  .88, p < .007) and Asian candidates (SHR:  .72; p < .001) had lower unadjusted incidence of LT. This disparity was mitigated in the post-policy era where Hispanic patients had higher likelihood of LT than Whites (SHR: 1.22; p = .002). For the outcome of death/non-LT waitlist removal, the only significant difference was a 42% lower incidence of waitlist removal for Asian compared to White patients in the post-policy era (SHR:  .58; p = .03). CONCLUSION: Among LT recipients with HCC, racial/ethnic subpopulations were differentially affected by the MMAT-3 policy, resulting in a post-policy reduction of some of the previous disparities.