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Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p 0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p = 0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p = 0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5 years (CHLT 82.1% vs. HA 80.9% [p = 0.73]; CHLT 82.1% vs. HA 80.9% [p = 0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.

Purpose of review This review explores trends in the United States (US) transplant surgery workforce with a focus on historical demographics, post-fellowship job market, and quality of life reported by transplant surgeons. Ongoing efforts to improve women and racial/ethnic minority representation in transplant surgery are highlighted. Future directions to create a transplant workforce that reflects the diversity of the US population are discussed. Recent findings Representation of women and racial and ethnic minorities among transplant surgeons is minimal. Although recent data shows an improvement in the number of Black transplant surgeons from 2% to 5.5% and an increase in women to 12%, the White to Non-White transplant workforce ratio has increased 35% from 2000 to 2013. Transplant surgeons report an average of 4.3 call nights per week and less than five leisure days a month. Transplant ranks 1st among surgical sub-specialties in the prevalence of three well-studied facets of burnout. Concerns about lifestyle may contribute to the decreasing demand for advanced training in abdominal transplantation by US graduates. Summary Minimal improvements have been made in transplant surgery workforce diversity. Sustained and intentional recruitment and promotion efforts are needed to improve the representation of women and minority physicians and advanced practice providers in the field.

Varied access to deceased donors across the globe has resulted in differential living donor liver transplant (LDLT) practices and lack of consensus over the influence of models for end stage liver disease (MELD), renal function, sarcopenia, or recent infection on short-term outcomes.Consider these risk factors in relation to patient selection and provide recommendations.Ovid MEDLINE, Embase, Scopus, Google Scholar, Cochrane Central.PRIMSA systematic review and GRADE.RD42021260809 RESULTS: MELD25-30 alone is not a contraindication to LDLT, and multiple studies found no increase in short term mortality in high MELD patients. Contributing factors such as muscle mass, acute physiologic assessment and chronic health evaluation score, donor age, graft weight/recipient weight ratio, and inclusion of the middle hepatic vein in a right lobe graft influence morbidity and mortality in high MELD patients. Higher mortality is observed with pretransplant renal dysfunction, but short-term mortality is rare. Sarcopenia and recent infection are not contraindications to LDLT. Morbidity and prolonged LOS are common, and more frequent in patients with renal dysfunction, nutritional deficiency or recent infection.When individual risk factors are studied mortality is low and graft loss is infrequent, but morbidity is common. MELD, especially with concomitant risk factors, had the greatest influence on short term outcome, and recent infection had the least. A multidisciplinary team of experts should carefully assess patients with multiple risk factors, and an optimal graft is recommended.

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6-29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and three post-LT. Overall, transplant free survival was 42.8% at 4 years and post-LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.

BACKGROUND: Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility. METHODS: Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement. RESULTS: The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or 1 μg/kg per minute and a serum lactate level >9 mmol/L. CONCLUSIONS: Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented., SCOPUS: ar.j, info:eu-repo/semantics/published

The effect of low health literacy (HL) on outcomes in end-stage liver disease (ESLD) is largely unknown. The association of low HL on clinical outcomes was investigated in a prospective cohort of outpatients with ESLD undergoing liver transplantation (LT) evaluation. From 2014 to 2017, 276 patients underwent LT evaluation with assessments of liver disease severity, medical and psychosocial comorbidities, physical frailty, and malnutrition. Literacy was measured with the Newest Vital Sign, a brief validated assessment. Multivariate models assessed relationships between HL and clinical outcomes adjusting for clinical and psychosocial variables. The median Model for End-Stage Liver Disease–sodium score of the study sample was 15 (interquartile range, 11–19), 71 (25.7%) of candidates were frail, 117 (42.4%) had malnutrition, 151 (54.7%) had hepatic encephalopathy, 104 (37.7%) had low HL, and 85 (39.2%) had marginal or poor social support. Adjusting for education level, socioeconomic factors, and severity of illness, low HL was independently associated with physical frailty (adjusted odds ratio [aOR], 3.59; 95% confidence interval [CI], 1.50–8.59; P = 0.004) and not being wait-listed (aOR 1.96; 95% CI, 1.03–3.75; P = 0.04). Strong social support attenuated the relationship between low HL and not being wait-listed (aOR, 1.58; 95% CI, 0.74–3.36; P = 0.24). Low HL is common and a largely unrecognized risk factor for poor health outcomes among patients with ESLD. Patient-oriented infrastructure and support are needed at the health system level to ensure all patients can successfully navigate the complex process of LT evaluation and wait-listing.

BACKGROUND: Liver transplantation (LT) is an accepted therapeutic option for hepatocellular carcinoma (HCC) in patients with cirrhosis. Despite careful candidate selection, HCC recurrence occurs. We aimed to describe the predictors of recurrence, clinical presentation, and predictors of survival after HCC recurrence post-LT. METHODS: Patients with recurrent HCC after LT between January 1996 and December 2017 were retrospectively reviewed. RESULTS: Of 711 patients, 96 (13.5%) patients had post-LT HCC recurrence. The median time to recurrence was 17.1 months, and the median survival was 10.1 months. Initial recurrence was more often in the graft (34.4%), and most (60.4%) had multiple recurrent lesions, and 26% were in multiple sites. In multivariate analysis, factors associated with shorter survival were poorly differentiated histology in explant (Hazard ratio [HR] = 1.96; p = 0.027), bilirubin ≥1.2 mg/dL (HR = 2.47; p = 0.025), and albumin

Kidney transplant recipients (KTRs) and liver transplant recipients (LTRs) have significant post-transplant weight gain and low physical activity. We conducted a home-based, remotely-monitored intervention using wearable accelerometer devices to promote post-transplant physical activity. We randomized 61 KTRs and 66 LTRs within 24 months of transplant to: 1) control, 2) accelerometer, or 3) intervention: accelerometer paired with financial incentives and health engagement questions to increase steps by 15% from baseline every 2 weeks. The primary outcome was weight change. A co-primary outcome for the two accelerometer arms was steps. Participants were recruited at a median of 9.5 [3-17] months post-transplant. At 3 months, there were no significant differences in weight change across the 3 arms. The intervention arm was more likely to achieve ≥7000 steps compared to control with device (OR 1.99, 95% CI:1.03-3.87); effect remained significant after adjusting for demographics, allograft, time from transplant, and baseline weight. Adherence to target step goals was 74% in the intervention arm, 84% of health engagement questions were answered correctly. A pilot study with financial incentives and health engagement questions was feasible and led KTRs and LTRs to walk more, but did not affect weight. A definitive trial is warranted. (ClinicalTrials.gov number: NCT03221465).

Summary It would be impossible to summarise all of the significant developments in the surgical management of hepatocellular carcinoma (HCC), even just over the past year, in a manuscript of this scope. Thus, we have selected topics for discussion that are the subject of current controversy and have attempted to present balanced points of view. Hepatic resection and transplantation are both mature modalities, and for the most part technical advances and improvements in candidate selection are incremental. The ability to readily cure hepatitis C stands out as the most impactful development in the field over recent years, especially in Western countries where hepatitis C has long been the chief aetiology underlying HCC and a predictor of poor outcomes after surgery, but its full implications remain to be clarified. The rising incidence of non-alcoholic steatohepatitis-related HCC and what it means with regard to surgical HCC management is an area of great current interest. With advancing technology, non-surgical locoregional treatments are gaining increasing application as potentially curative therapies. In addition, the advances in molecular and genomic assessment of HCC hold promise for personalising treatment and prognostication. The possible role of immunotherapy as an adjuvant to resection is being aggressively investigated. While liver surgery maintains an important role, the care of patients with HCC is more and more a team effort and needs to take place in the context of a well-integrated interdisciplinary programme to achieve the best outcomes for patients.

Living donor liver transplantation has expanded in recent years, particularly in North America. As experience with this procedure has matured over the last 25 years, centers are increasingly faced with potential living donors who are more medically complex. As donors move through the evaluation process, completing the informed consent process continues to be challenged by a paucity of granular data demonstrating long-term outcomes and overall safety specifically in the otherwise "healthy" living liver donor population. Two recently published studies examined long-term outcomes post-living liver donation using Korean registry data and reported similar results, with excellent overall survival when compared to appropriately matched controls. However, the authors of these studies were presented differently, with one reporting an alarmist view based on one aspect of a suboptimal analysis approach using an inappropriate comparator group. Herein, the North American Living Liver Donor Innovation Group (NALLDIG) consortium discusses these two studies and their potential impact on living liver donation in North America, ultimately highlighting the importance of scientific integrity in data presentation and dissemination when using transplant registry data.

Post-transplant diabetes mellitus (PTDM) is a complication which reduces allograft and recipient life-span. Polygenic risk scores (PRS) robustly show association with greater type 2 diabetes (T2D) development risk. We examined T2D-PRS in transplant recipients and donors using genome-wide genotyping in 1581 liver recipients, and 1555 donors and 2062 kidney recipients and 533 donors from four centers. Liver and kidney recipient T2D-PRS was associated with pre-transplant T2D and PTDM development. Liver donor, but not kidney donor, T2D-PRS was an independent risk factor for PTDM development. Inclusion of a combined liver recipient and donor T2D-PRS significantly improved PTDM prediction vs clinical characteristics-only models: AUC (95%CI): 67.6% (64.1% − 71.1%) vs. 62.3% (58.8% − 65.8%), p = 0.0001. Liver recipients in the highest quintile of recipient-donor combined T2D-PRS had the greatest PTDM risk: OR (95%CI) = 3.22 (2.07–5.00), p = 1.92E-07, compared to the lowest quintile. T2D-PRS allows identification of transplant candidates with high PTDM risk, for whom early preemptive diabetes management is warranted. Pre-transplant knowledge of donor T2D-PRS in the setting of living liver donation should optimized selection of donors to reduce PTDM.

Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10

Patients heterozygous for an abnormal α-1 antitrypsin (A1AT) mutation may have an increased risk of liver disease in the setting of a secondary contributing factor.This single-center retrospective cohort study compared donor and recipient outcomes of A1AT heterozygous versus normal phenotype adult living-donor liver transplants (LDLTs).Between 2010 and 2016, 11 A1AT heterozygous donors and 10 recipients were compared to 57 normal donors and 41 recipients. There were no significant differences in sex, age, or race/ethnicity by A1AT phenotype. Heterozygous donors had significantly lower serum A1AT (median 100 mg/dL versus 131 mg/dL; P0.001). Median liver volume at 3 months post-LDLT was not different among donors or their recipients (1164 mm in heterozygous versus 1257 mm in normal [P = 0.449] for donors; 1563 mm versus 1606 mm [P = 0.387], respectively, for recipients). Recipient serum alkaline phosphatase at 1 month and 1 year post-LDLT was significantly higher in recipients of A1AT heterozygous grafts (160 U/L versus 99.5 U/L; P = 0.025 at 1 mo) but did not persist at 2 years. In addition, there was no association between A1AT level and liver volume at 3 months posttransplant in donors or recipients.Patients with a heterozygous A1AT mutation should be considered for living-liver donation.

CHLT is successful and increasing, with excellent survival for both cardiac and liver grafts. Outcomes are equivalent to single‐organ transplants, and there are potential immunological benefits compared with heart transplant alone. Evaluation and decision to proceed for dual‐organ transplant requires careful assessment by both organ teams at experienced centers to choose the appropriate recipients.

Background Non-alcoholic steatohepatitis has emerged as a leading cause of cirrhosis, and obesity-associated comorbidities, including renal disease have increased in prevalence. Obesity predisposes the kidney to hyperfiltration injury, potentially impairing acute kidney injury recovery. Identification of patients at risk for renal dysfunction is impeded by poor performance of renal function estimating equations among cirrhotics. To better understand obesity among cirrhotics and renal disease progression, we examined likelihood of kidney transplantation (KT) waitlisting after liver transplant alone (LTA) by obesity class. Methods 68,607 LTA recipients were identified in SRTR (2005-2018). Fine and Gray competing risks models were used to analyze likelihood of KT waitlisting. Results 27.4% of recipients were obese (BMI>30kg/m2) and were 10% more likely to require KT waitlisting (aHR: 1.10, 95%CI: 1.01-1.20). Risk was highest among recipients with Classes II and III obesity (BMI: >35kg/m2 ) (aHR: 1.37, 95%CI: 1.17-1.56). Moreover, recipients with Classes II and III obesity were 57% more likely to require KT waitlisting within one year post-LTA (aHR: 1.57, 95%CI: 1.18-2.10) compared to non-obese recipients. Discussion These findings suggest obesity was a risk factor for renal recovery failure and/or renal disease progression post-LTA and may confound identification of renal dysfunction and/or prediction of renal recovery among cirrhotics.

Nearly half of living liver donors in North America are women of child-bearing age. Fetal and maternal outcomes after donation are unknown. We conducted a retrospective cohort study of female living liver donors (aged 18-50 years at donation) from 6 transplant centers. Participants were surveyed about their pregnancies and fertility. Outcomes were compared between predonation and postdonation pregnancies. Generalized estimating equations were clustered on donor and adjusted for age at pregnancy, parity, and pregnancy year. Among the 276 donors surveyed, 151 donors responded (54.7% response rate) and reported 313 pregnancies; 168/199 (68.8%) of the predonation pregnancies and 82/114 (71.9%) of the postdonation pregnancies resulted in live births, whereas 16.6% and 24.6% resulted in miscarriage, respectively. Women with postdonation pregnancies were older (32.0 versus 26.7 years; P < 0.001) and more frequently reported abnormal liver enzymes during pregnancy (3.5% versus 0.0%; P = 0.02) and delivery via cesarean delivery (35.4% versus 19.7%; P = 0.01). On adjusted analysis, there was no difference in cesarean delivery (odds ratio [OR], 2.44; 95% confidence interval [95% CI], 0.98-6.08), miscarriage (OR, 1.59; 95% CI, 0.78-3.24), combined endpoints of pregnancy-induced hypertension and preeclampsia (OR, 1.27; 95% CI, 0.36-4.49), or intrauterine growth restriction and preterm birth (OR, 0.91; 95% CI, 0.19-4.3). Of the 49 women who attempted pregnancy after donation, 11 (22.5%) self-reported infertility; however, 8/11 (72.7%) eventually had live births. Aside from increased reporting of abnormal liver enzymes and cesarean deliveries, there was no significant difference in pregnancy outcomes before and after living liver donation. One-fifth of women who attempt pregnancy after liver donation reported infertility, and although the majority went on to successful live births, further exploration is needed to understand the contributing factors. Future research should continue to monitor this patient-centered outcome across a large cohort of donors.

Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P

BACKGROUND Survival after living donor liver transplantation (LDLT) in the United States is excellent. However, the significance of pretransplant kidney disease on outcomes in this population is poorly understood. METHODS This was a retrospective cohort study of 2806 LDLT recipients nationally between January 2010 and June 2020. Recipients with estimated glomerular filtration rate

NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology.We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response.Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.

PURPOSE Hepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management. MATERIALS AND METHODS A prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory. RESULTS In the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2). CONCLUSION P/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are

Importance Differences in local organ supply and demand have introduced geographic inequities in the Model for End-stage Liver Disease (MELD) score–based liver allocation system, prompting national debate and patient-initiated lawsuits. No study to our knowledge has quantified the sex disparities in allocation associated with clinical vs geographic characteristics. Objective To estimate the proportion of sex disparity in wait list mortality and deceased donor liver transplant (DDLT) associated with clinical and geographic characteristics. Design, Setting, and Participants This retrospective cohort study used adult (age ≥18 years) liver-only transplant listings reported to the Organ Procurement and Transplantation Network from June 18, 2013, through March 1, 2018. Exposure Liver transplant waiting list. Main Outcomes and Measures Primary outcomes included wait list mortality and DDLT. Multivariate Cox proportional hazards regression models were constructed, and inverse odds ratio weighting was used to estimate the proportion of disparity across geographic location, MELD score, and candidate anthropometric and liver measurements. Results Among 81 357 adults wait-listed for liver transplant only, 36.1% were women (mean [SD] age, 54.7 [11.3] years; interquartile range, 49.0-63.0 years) and 63.9% were men (mean [SD] age, 55.7 [10.1] years; interquartile range, 51.0-63.0 years). Compared with men, women were 8.6% more likely to die while on the waiting list (adjusted hazard ratio [aHR], 1.11; 95% CI, 1.04-1.18) and were 14.4% less likely to receive a DDLT (aHR, 0.86; 95% CI, 0.84-0.88). In the geographic domain, organ procurement organization was the only variable that was significantly associated with increased disparity between female sex and wait list mortality (22.1% increase; aHR, 1.22; 95% CI, 1.09-1.30); no measure of the geographic domain was associated with DDLT. Laboratory and allocation MELD scores were associated with increases in disparities in wait list mortality: 1.14 (95% CI, 1.09-1.19; 50.1% increase among women) and DDLT: 0.87 (95% CI, 0.86-0.88; 10.3% increase among women). Candidate anthropometric and liver measurements had the strongest association with disparities between men and women in wait list mortality (125.8% increase among women) and DDLT (49.0% increase among women). Conclusions and Relevance Our findings suggest that addressing geographic disparities alone may not mitigate sex-based disparities, which were associated with the inability of the MELD score to accurately estimate disease severity in women and to account for candidate anthropometric and liver measurements in this study.

Summary The coronavirus disease 2019 (COVID-19) pandemic has shattered the meticulously developed processes by which we delivered quality care for patients with cirrhosis. Care has been transformed by the crisis, but enduring lessons have been learned. In this article, we review how COVID-19 will impact cirrhosis care. We describe how this impact unfolds over 3 waves; i) an intense period with prioritized high-acuity care with delayed elective procedures and routine care during physical distancing, ii) a challenging ‘return to normal’ following the end of physical distancing, with increased emergent decompensations, morbidity, and systems of care overwhelmed by the backlog of deferred care, and iii) a protracted period of suboptimal outcomes characterized by missed diagnoses, progressive disease and loss to follow-up. We outline the concrete steps required to preserve the quality of care provided to patients with cirrhosis. This includes an intensification of the preventative care provided to patients with compensated cirrhosis, proactive chronic disease management, robust telehealth programs, and a reorganization of care delivery to provide a full service of care with flexible clinical staffing. Managing the pandemic of a serious chronic disease in the midst of a global infectious pandemic is challenging. It is incumbent upon the entire healthcare establishment to be strong enough to weather the storm. Change is needed.

This article reviews the Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL). The findings show that the number of adult-to-adult living donor liver transplants is consistently increasing. Living donor liver transplantation has an important benefit for patients with acute liver failure, does not compromise donor safety, and has lower rates of acute cellular rejection in biologically related donor and recipient. The conclusions from the A2ALL consortium have been critical in transplant advancement, supporting increased use to help decrease waitlist death and improve long-term survival of transplant recipients.

The Model for End-Stage Liver Disease (MELD) score predicts higher transplant healthcare utilization and costs; however, the independent contribution of functional status towards costs is understudied. The study objective was to evaluate the association between functional status, as measured by Karnofsky Performance Status (KPS), and liver transplant (LT) costs in the first posttransplant year. In a cohort of 598 LT recipients from July 1, 2009 to November 30, 2014, multivariable models assessed associations between KPS and outcomes. LT recipients needing full assistance (KPS 10%-40%) vs being independent (KPS 80%-100%) were more likely to be discharged to a rehabilitation facility after LT (22% vs 3%) and be rehospitalized within the first posttransplant year (78% vs 57%), all P < .001. In adjusted generalized linear models, in addition to MELD (P < .001), factors independently associated with higher 1-year post-LT transplant costs were older age, poor functional status (KPS 10%-40%), living donor LT, pre-LT hemodialysis, and the donor risk index (all P < .001). One-year survival for patients in the top cost decile was 83% vs 93% for the rest of the cohort (log rank P < .001). Functional status is an important determinant of posttransplant resource utilization; therefore, standardized measurements of functional status should be considered to optimize candidate selection and outcomes.

This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 "low risk" cases, and may serve as reference to assess outcome of single or any groups of patients.To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups.Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative.Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ≤20 points, a balance of risk score ≤9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff.Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ≤4 days for ICU stay, ≤18 days for hospital stay, ≤59% for patients with severe complications (≥ Grade III) and ≤42.1 for 1-year CCI. Comparisons with the next higher risk group (model for end stage liver disease 21-30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values.Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.

PROBLEM Academic health centers face increasing challenges in pursuing and maintaining clinical excellence in their tripartite mission. At Penn Medicine, an institution-wide strategic planning process was initiated in 2012. Among the recommendations that arose from that process was to enhance the recognition of Penn Medicine's most outstanding clinicians. The Academy of Master Clinicians (AoMC) was founded in 2013. APPROACH The ad hoc committee charged with the development and implementation of the AoMC provided a mission statement, eligibility criteria, and a process for nomination and selection of AoMC members. This process was inclusive, extending to all entities of Penn Medicine. Various forms of institutional service were incorporated into the expectations for membership. OUTCOMES To date, 53 clinicians have been selected for membership in the AoMC. Members meet monthly to focus on significant institutional issues. Initiatives are identified for member leadership and participation. Members are engaged in activities and programs for medical students, residents, and faculty, focusing on areas such as career advising, faculty development, physician burnout, and practice operations. The executive vice president (EVP)/dean has commented that the AoMC is "highly visible and impactful." NEXT STEPS A yearly report on outcomes and impact of the AoMC is provided to the EVP and chief executive officer. In addition, at the end of each academic year, the members of the AoMC determine two to three new initiatives on which to work to formulate issues and potential actions.

Background Early extubation immediately following liver transplantation is increasingly common in adult practice. Some pediatric institutions have begun to adopt this strategy. Careful patient selection is essential in minimizing risk. Methods This retrospective cohort study evaluated infants and children who underwent liver transplantation between July 2011 and December 2014. Our primary objective was to determine early extubation rate. Secondary objectives were to identify clinical factors associated with successful early extubation compared with delayed extubation and to examine significant postoperative complications, intensive care unit length of stay, and hospital length of stay. Results The early extubation rate was 57.8% (37/64, confidence interval [CI] 44.8%-70.1%) over this 3.5-year period, increasing from 42% in 2012 to 58% by the end of 2014. The patients in the early extubation group were more likely to be older than the delayed extubation group (mean [SD], 7 [5.3] years vs 3.5 [5.5] years, difference between the mean [95% CI], 3.5 [0.8, 6.2] years); were to have come from home on the day of surgery (78.4% vs 25.9%); and were less likely to be listed as United Network for Organ Sharing status 1A (2.7% vs 25.9%). The early extubation group received less packed red blood cell volume (mean [SD], 9 [13.2] mL/kg vs 40.6 [48.5] mL/kg, difference between the mean [95% CI], 31.6 [95% CI 14.9, 48.3] mL/kg) and fresh-frozen plasma (mean 2.7 [SD 9.5] vs 13.3 [SD15.1], difference between the mean [95% CI], 10.5 [4.4,16.7] mL/kg). None of the patients in the early extubation group required reintubation in the first 24 hours following transplant and none experienced hepatic artery thrombosis. The early extubation group had a shorter average postoperative PICU stay (mean 3.8 [SD 2.1] days vs 17.6 [SD 31.3] days, difference between the mean [95% CI], 9.5 [4.3, 14.7] days) and a shorter postoperative hospital stay overall (mean 10.7 [SD 4.3] days vs 29.7 [SD 43.1] days, difference between the mean [95% CI], 19.1 [8.6, 29.6] days). Conclusion More than half of our pediatric liver transplant patients were successfully extubated in the operating room immediately following surgery. We believe early extubation to be safe when employed in selected subpopulations of pediatric patients undergoing liver transplantation.

Prospective and longitudinal studies have examined liver donors' medical outcomes beyond the first 1 to 2 years postdonation. There is no analogous longitudinal evidence on long-term psychosocial outcomes, including patient-reported clinically significant mental health problems and perceptions of physical well-being. We examined prevalence, descriptive characteristics, and predictors of diagnosable mental health conditions and self-reported physical health problems, including fatigue and pain, in the long-term years after liver donation.Donors from 9 centers who initially completed telephone interviews at 3 to 10 years postdonation (mean, 5.8 years; SD, 1.9) were reinterviewed annually for 2 years using validated measures. Outcomes were examined descriptively. Repeated-measures regression analyses evaluated potential predictors and correlates of outcomes.Of 517 donors initially interviewed (66% of those eligible), 424 (82%) were reassessed at least once. Prevalence rates of major depression and clinically significant pain were similar to general population norms; average fatigue levels were better than norms. All prevalence rates showed little temporal change. Anxiety and alcohol use disorder rates exceeded normative rates at 1 or more assessments. Longer postdonation hospitalization, female sex, higher body mass index, concerns about donation-related health effects, and burdensome donation-related financial costs were associated with increased risk for most outcomes (P's0.05). Men were at higher risk for alcohol use disorder (P0.001).Anxiety and alcohol use disorders were more common than would be expected; they may warrant increased research attention and clinical surveillance. Surveillance for long-term problems in the areas assessed may be optimized by targeting donors at higher risk based on identified predictors and correlates.

Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

Background Living donor transplantation is becoming increasingly popular as a modality for patients necessitating liver transplantation. Hepatic artery thrombosis (HAT) remains the most feared acute postoperative complication associated with living-donor liver transplantation. Preoperative planning, including scheduling reconstructive microsurgeons to perform the hepatic artery anastomosis using a surgical microscope or loupes, can decrease HAT rates. Methods A retrospective review of two reconstructive microsurgeons at a single institution was performed to analyze postoperative outcomes of adult and pediatric live donor liver transplants where reconstructive microsurgeons performed the hepatic artery anastomosis. One surgeon utilized the surgical microscope, while the other surgeon opted to use surgical loupes for the anastomosis. Results A total of 38 patients (30 adult and eight pediatric) met inclusion criteria for this study, and average patient age in the adult and pediatric population studied was 48.5 and 3.6 years, respectively. Etiologies of adult patients' liver failure were most commonly cholestatic (43%), followed by alcohol (23%), hepatitis C virus-related cirrhosis (17%), and nonalcoholic steatohepatitis (7%), while etiologies of pediatric liver failure were most commonly cholestatic (62.5%). None of the patients (0%) experienced acute postoperative HAT. On average, 22 and 25 months of postoperative follow-up was obtained for the adult and pediatric cohorts, respectively, and only one adult patient was found to have any liver-related complication. Conclusion A collaborative relationship between reconstructive microsurgeons and transplant surgeons mitigates the risk of HAT and improves patient outcomes in living donor liver transplantation.

To determine if patient liver derived organoids can in principle be a useful experimental model for non alcoholic staetohepatitis (NASH), we derived to our knowledge for the first time bipotent ductal organoids from endstage NASH patient livers, and for comparison from normal donor livers. We found that all tested NASH liver derived organoids exhibited a profound failure to dedifferentiate from the hepatic state back to the biliary state, consistent with the known poor regenerative capacity of NASH livers. Indeed, RNAseq on all tested NASH organoid populations confirmed down regulation of multiple cell cycle pathways. NASH liver derived hepatically differentiated organoids can slowly expand as monolayers, significantly simplifying microscopic quantitation: The monolayers show variable, but overall significantly increased lipid droplet accumulation in response to free fatty acids. Transcriptome analysis of NASH organoids reveals strong upregulation of a wide variety of pro inflammatory pathways in a NASH patient specific manner. Surprisingly, NASH liver derived organoids are highly diverse not only regarding their cytochrome cytochrome p450 metabolism and inflammatory response, but also react differentially to known antisteatotic, anti inflammatory and antifibrotic drugs, raising the possibility of using NASH patient liver biopsy derived organoids for personalized drug screening and therapy.One Sentence SummaryNASH patient liver derived organoids replicate NASH liver phenotypes in a patient specific manner and exhibit profound differences in their response to drugs that are currently used in NASH clinical trials.

BackgroundLittle is known about how well postoperative pain is managed in living liver donors, despite pain severity being the strongest predictor of persistent pain with long-lasting disability.MethodsWe conducted a prospective multicenter study of 172 living liver donors. Self-reported outcomes fo

BACKGROUND: 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 post-transplant 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. METHODS: We performed a retrospective cohort study of all patients undergoing LT from 7/½014 to 6/30/2017 at a tertiary LT referral center. A nurse practitioner (NP)-based post-transplant care program with weekend in-house nurse coordination providers and increased outpatient NP clinic availability was instituted on 1/½016. Post-discharge readmission rates at 30 and 90 days were compared in the pre- and post-exposure groups, adjusting for associated risk factors. RESULTS: A total 362 patients were included in the analytic cohort. There were no significant differences in demographics, comorbidities, or index hospitalization characteristics between groups. In adjusted analyses, the risk of readmission in the post-exposure 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

Adult-to-adult living donor liver transplantation (LDLT) was introduced in response to the shortage of deceased donor liver grafts. The number of adult living donor transplants is increasing due to improved outcomes and increasing need. Advantages of LDLT include optimization of the timing of transplant, better organ quality, and lower rates of recipient mortality compared to staying on the wait list for deceased donor liver transplant. Donor safety remains the major focus when considering LDLT. Recent advancements have supported the increased use of LDLT to help decrease wait list death and improve long-term survival of transplant recipients.

Solid organ transplantation disrupts virus-host relationships, potentially resulting in viral transfer from donor to recipient, reactivation of latent viruses, and new viral infections. Viral transfer, colonization, and reactivation are typically monitored using assays for specific viruses, leaving the behavior of full viral populations (the “virome”) understudied. Here we sought to investigate the temporal behavior of viruses from donor lungs and transplant recipients comprehensively. We interrogated the bronchoalveolar lavage (BAL) and blood viromes during the peri-transplant period and 6–16 months post-transplant in 13 donor-recipient pairs using shotgun metagenomic sequencing. Anelloviridae, ubiquitous human commensal viruses, were the most abundant human viruses identified. Herpesviruses, parvoviruses, polyomaviruses and bacteriophages were also detected. Anelloviridae populations were complex, with some donor organs and hosts harboring multiple contemporaneous lineages. We identified transfer of Anelloviridae lineages from donor organ to recipient serum in 4 of 7 cases that could be queried, and immigration of lineages from recipient serum into the allograft in 6 of 10 such cases. Thus, metagenomic analyses revealed that viral populations move between graft and host in both directions, showing that organ transplantation involves implantation of both the allograft and commensal viral communities.

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

BACKGROUND AND AIMS: The five-year incidence of post-transplant hepatocellular carcinoma (HCC) recurrence is 8-20%. Several studies have evaluated pre-transplant risk factors for HCC recurrence, but nearly all data have treated HCC as a homogeneous condition across all etiologies of liver disease despite differences in tumor biology and baseline incidence of HCC. We sought to evaluate the impact of etiology of liver disease, maximum pre-transplant alpha fetoprotein (AFP), and the interaction of the two factors on the risk of HCC recurrence. METHODS: We performed a retrospective cohort study of HCC transplant recipients using United Network for Organ Sharing (UNOS) data from 2002-2016. Competing risks regression was performed to identify variables associated with HCC recurrence, and an interaction term between etiology and maximum AFP category. RESULTS: Among 18,406 recipients, 1,484 patients experienced HCC recurrence over 3.1 years of median follow-up time. There was a significant interaction between AFP category and etiology of liver disease (p < 0.001). Among patients with a maximum AFP 1,000ng/mL, those with alcoholic liver disease had the highest risk of HCC recurrence among all etiologies. CONCLUSION: Risk of HCC recurrence differs by etiology of liver disease, and the significance of elevated pre-transplant AFP varies by etiology. Patients with alcoholic liver disease and elevated maximum AFP are at uniquely high risk of HCC recurrence. These findings have potential UNOS policy implications, as the transplant selection process may ultimately benefit from etiology-specific criteria.