Perioperative Characteristics and Outcomes of Fontan Versus Non-Fontan Patients Undergoing Combined Heart-Liver Transplantation: A Retrospective Cohort Study.

OBJECTIVES: Combined heart-liver transplantation (CHLT) is becoming increasingly frequent as a maturing population of patients with Fontan-palliated congenital heart disease develop advanced liver fibrosis or cirrhosis. The authors present their experience with CHLT for congenital and noncongenital indications, and identify characteristics associated with poor outcomes that may guide intervention in high-risk patients. DESIGN: This was a single-center retrospective cohort study. SETTING: This study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee. PARTICIPANTS: The study included 16 consecutive adult recipients of CHLT at the authors' institution between April 2017 and February 2022. INTERVENTIONS: Eleven patients underwent transplantation for Fontan indications, and 5 were transplanted for non-Fontan indications. MEASUREMENTS AND MAIN RESULTS: Compared with non-Fontan patients, Fontan recipients had longer cardiopulmonary bypass duration (199 v 119 minutes, p =m0.002), operative times (786 v 599 minutes, p = 0.01), and larger blood product transfusions (15.4 v 6.3 L, p = 0.18). Six of 16 patients required extracorporeal membrane oxygenation (ECMO), of whom 4 were Fontan patients who subsequently died. Patients who required ECMO had lower 5-hour lactate clearance (0.0 v 3.5 mmol/L, p = 0.001), higher number of vasoactive infusions, lower pulmonary artery pulsatility indices (0.58 v 1.77, p = 0.03), and higher peak inspiratory pressures (28.0 v 18.5 mmHg, p = 0.01) after liver reperfusion. CONCLUSIONS: Combined heart-liver transplantation in patients with Fontan-associated end-organ disease is particularly challenging and associated with higher recipient morbidity compared with non-Fontan-related CHLT. Early hemodynamic intervention for signs of ventricular dysfunction may improve outcomes in this growing high-risk population.

Anticoagulation with Intravenous Direct Thrombin Inhibitors in Pediatric Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature.

Although intravenous (IV) direct thrombin inhibitors (DTI) have gained interest in pediatric extracorporeal membrane oxygenation (ECMO), dosing and safety information is limited. The objective of this systematic review was to characterize DTI types, dosing, monitoring, and outcomes (bleeding and thromboembolic) in pediatric ECMO patients managed with IV DTIs. We conducted searches of MEDLINE (Ovid) and Embase (Elsevier) from inception through December 2022. Case reports, retrospective studies, and prospective studies providing per-patients or summary data for patient(s) <18 years of age receiving IV DTI for ECMO anticoagulation were included. Study selection and data extraction were conducted independently by two reviewers. A total of 28 studies: 14 case reports, 13 retrospective studies, and 1 prospective study were included, totaling 329 patients. Bivalirudin was utilized in 318 (96.7%), argatroban in 9 (2.7%), and lepirudin in 2 (0.6%) patients. Infusion dosing included: bivalirudin 0.14 ± 0.37 mg/kg/h, argatroban 0.69 ± 0.73 µg/kg/min, lepirudin 0.14 ± 0.02 mg/kg/h. Laboratory monitoring tests utilized were the activated clotting time, activated partial thromboplastin time (aPTT), diluted thrombin time, and thromboelastography measures. The aPTT was utilized in most patients (95%). Thromboembolism, bleeding, or death were observed in 17%, 17%, and 23% of bivalirudin, argatroban, and lepirudin patients, respectively. Bivalirudin appears to be the most frequently used DTI in pediatric ECMO. Dosing and laboratory monitoring varied, and bleeding and thromboembolic events were reported in 17% of patients. Prospective studies are warranted to establish dosing, monitoring, safety, and efficacy of bivalirudin and other IV DTI in pediatric ECMO.

Exception-Status Listing: A Critical Pathway to Heart Transplantation for Adults With Congenital Heart Diseases.

Adults with congenital heart diseases may not be candidates for conventional therapies to control ventricular systolic dysfunction, including mechanical circulatory support, which moves potential heart-transplantation recipients to a listing status of higher priority. This results in longer waitlist times and greater mortality rates. Exception-status listing allows a pathway for this complex and anatomically heterogenous group of patients to be listed for heart transplantation at appropriately high listing status. Our study queried the United Network for Organ Sharing registry to evaluate trends in the use of exception-status listing among adults with congenital heart diseases awaiting heart transplantation. Uptrend in the use of exception-status listing precedes the new allocation system, but it has been greatest since changes were made in the allocation system. It continues to remain a vital pathway for adults with congenital heart disease (whose waitlist mortality rates are often not characterized adequately by using the waitlist-status criteria) timely access to heart transplantation.

Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration.

Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.

BMP4 is a novel paracrine inhibitor of liver regeneration.

Transforming growth factor (TGF)-ß family members exert strong effects on restoration of liver mass after injury. Bone morphogenetic proteins (BMPs) are members of the TGF-ß family and are found in the liver, suggesting that these proteins may play a role in liver regeneration. We examined BMP signaling in the liver during hepatectomy. We found that BMP4 is constitutively expressed in the peribiliary stroma and endothelial cells of the liver and that expression is decreased after hepatectomy. Mice driven to maintain BMP4 expression in the liver display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration. Consistent with this finding, hepatocyte-specific deletion of the BMP receptor activin receptor-like kinase 3 (Alk3) enhances regeneration and reduces phosphorylation of SMAD1/5/8, a transducer of BMP signaling. In contrast to experiments in wild-type mice, maintaining BMP4 levels has no effect on liver regeneration in hepatocyte-specific Alk3 null mice, providing evidence that BMP4 signals through Alk3 to inhibit liver regeneration. Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration. Furthermore, high-dose BMP4 inhibits proliferation of primary hepatocytes and HepG2 cells in culture. These findings elucidate a new, potentially clinically relevant paradigm in which a constitutively expressed paracrine inhibitory factor plays a critical role in liver regeneration.

Association of Donors With US Public Health Service Risk Criteria and Outcomes After Adult vs Pediatric Cardiac Transplant.

Importance: The United Network for Organ Sharing (UNOS) evaluates donor risk for acute transmission of HIV, hepatitis B, or hepatitis C based on US Public Health Services (PHS)-specific criteria. However, recent data regarding use and outcomes of those donors with PHS risk criteria among pediatric and adult heart transplant recipients are lacking. Objective: To compare use and outcomes of graft from donors with PHS risk criteria vs those with a standard-risk donor (SRD) in children vs adults in a contemporary cohort. Design, Setting, and Participants: This cohort was a nationwide analysis of heart transplants in the US that used data from the UNOS database. Participants were children (<18 years old) and adults (≥18 years old) who received a heart transplant from January 1, 2010, to December 31, 2021. Exposures: UNOS-defined donor risk status. Main Outcomes and Measures: Trend analysis compared changes in PHS risk criteria use among children and adults. Patient survival was analyzed using Kaplan-Meier curves with log rank and Cox proportional hazards to compare PHS risk-criteria outcomes vs SRD-criteria outcomes in children and adult heart transplant recipients. Additional analysis was performed among adults who received a PHS-risk criteria graft that was previously declined for pediatric recipients. Results: Of 5115 pediatric transplant recipients (donor without PHS risk median [IQR] age, 5 [0-13] years and donor with PHS risk median [IQR] age, 8 [0-14] years) and 30 289 adult heart transplant recipients (donor without PHS risk median [IQR] age, 56 [46-63] years and donor with PHS risk median [IQR] age, 57 [47-63] years), PHS risk criteria comprised 8% in children vs 25% in adults. PHS criteria are being increasingly used over the past decade with the proportion of recipients transplanted with PHS risk-criteria donors being approximately 3 times greater among adult recipients than children recipients. Pediatric recipients of a PHS risk-criteria donor had greater pretransplant ventilatory support, whereas adult recipients of a PHS risk-criteria donor had greater pretransplant extracorporeal membrane oxygenation use. Patient survival was similar between pediatric recipients of PHS risk-criteria grafts vs SRD-criteria grafts and slightly higher among adult recipients of PHS risk-criteria grafts vs SRD-criteria grafts. The 1778 adult recipients who received a PHS criteria-risk donor that was previously declined for pediatric recipients had similar patient survival recipients compared with SRD-criteria donors (HR, 0.92; 95% CI, 0.81-1.03; P = .18). Conclusions and Relevance: In the current era, a 3-fold greater proportion of adult recipients receive a PHS risk-criteria graft compared with children despite similar posttransplant patient survival. The ongoing organ donor shortage underscores the need for consideration of PHS risk criteria where these donors remain underused.

Heart Transplantation for Pediatric and Congenital Cardiac Disease: A Comparison of Two Eras over 23 Years and 188 Transplants at a Single Institution.

BACKGROUND: To assess changes in patterns of practice and outcomes over time, we reviewed all patients who underwent heart transplantation (HTx) at our institution and compared two consecutive eras with significantly different immunosuppressive protocols (cohort 1 [80 HTx, June 1995-June 2006]; cohort 2 [108 HTx, July 2006-September 2018]). METHODS: Retrospective study of 180 patients undergoing 188 HTx (June 1995-September 2018; 176 first time HTx, 10 second HTx, and 2 third HTx). In 2006, we commenced pre-HTx desensitization for highly sensitized patients and started using tacrolimus as our primary postoperative immunosuppressive agent. The primary outcome was mortality. Survival was modeled by the Kaplan-Meier method. Univariable and multivariable Cox proportional hazard models were created to identify prognostic factors for survival. RESULTS: Our 188 HTx included 18 neonates, 85 infants, 83 children, and 2 adults (>18 years). Median age was 260.0 days (range: 5 days-23.8 years). Median weight was 7.5 kg (range: 2.2-113 kg). Patients in cohort 1 were less likely to have been immunosensitized preoperatively (12.5% vs 28.7%, P = .017). Nevertheless, Kaplan-Meier analysis suggested superior survival in cohort 2 (P = .0045). Patients in cohort 2 were more likely to be alive one year, five years, and ten years after HTx. Multivariable analysis identified the earlier era (hazard ratio [HR] [95% confidence interval] for recent era = 0.32 [0.14-0.73]), transplantation after prior Norwood operation (HR = 4.44 [1.46-13.46]), and number of prior cardiac operations (HR = 1.33 [1.03-1.71]) as risk factors for mortality. CONCLUSIONS: Our analysis of 23 years of pediatric and congenital HTx reveals superior survival in the most recent 12-year era, despite the higher proportion of patients with elevated panel reactive antibody in the most recent era. This improvement was temporally associated with changes in our immunosuppressive strategy.

Berlin Heart EXCOR and ACTION post-approval surveillance study report.

BACKGROUND: The Berlin Heart EXCOR Pediatric (EXCOR) ventricular assist device (VAD) was introduced in North America nearly 2 decades ago. The EXCOR was approved under Humanitarian Device Exemption status in 2011 and received post-market approval (PMA) in 2017 from Food and Drug Administration. Since the initial approval, the field of pediatric mechanical circulatory support has changed, specifically with regard to available devices, anticoagulation strategies, and the types of patients supported. This report summarizes the outcomes of patients supported with EXCOR from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry. These data were part of the PMA surveillance study (PSS) required by the Food and Drug Administration. METHODS: ACTION is a learning collaborative of over 40 pediatric heart failure programs worldwide, which collects data for all VAD implantations as one of its initiatives. All patients in North America with EXCOR implants reported to ACTION from 2018 to 2020 (n = 72) who had met an outcome were included in the EXCOR PSS group. This was compared with a historical, previously reported Berlin Heart EXCOR study group (Berlin Heart study [BHS] group, n = 320, 2007‒2014). RESULTS: Patients in the PSS group were younger, were smaller in weight/body surface area, were more likely to have congenital heart disease, and were less likely to receive a bi-VAD than those in the BHS group. Patients in the PSS group were less likely to be in Interagency Registry for Mechanically Assisted Circulatory Support Profile 1 and were supported for a longer duration. The primary anticoagulation therapy for 92% of patients in the PSS group was bivalirudin. Success, defined as being transplanted, being weaned for recovery, or being alive on a device at 180 days after implantation, was 86% in the PSS group compared with 76% in the BHS group. Incidence of stroke was reduced by 44% and the frequency of pump exchange by 40% in the PSS group compared with those in the BHS group. Similarly, all other adverse events, including major bleeding, were reduced in the PSS group. CONCLUSIONS: The PSS data, collected through ACTION, highlight the improvement in outcomes for patients supported with EXCOR compared with the outcomes in a historical cohort. These findings may be the result of changes in patient care practices over time and collaborative learning.

Deep Learning for Improved Risk Prediction in Surgical Outcomes.

The Norwood surgical procedure restores functional systemic circulation in neonatal patients with single ventricle congenital heart defects, but this complex procedure carries a high mortality rate. In this study we address the need to provide an accurate patient specific risk prediction for one-year postoperative mortality or cardiac transplantation and prolonged length of hospital stay with the purpose of assisting clinicians and patients' families in the preoperative decision making process. Currently available risk prediction models either do not provide patient specific risk factors or only predict in-hospital mortality rates. We apply machine learning models to predict and calculate individual patient risk for mortality and prolonged length of stay using the Pediatric Heart Network Single Ventricle Reconstruction trial dataset. We applied a Markov Chain Monte-Carlo simulation method to impute missing data and then fed the selected variables to multiple machine learning models. The individual risk of mortality or cardiac transplantation calculation produced by our deep neural network model demonstrated 89 ± 4% accuracy and 0.95 ± 0.02 area under the receiver operating characteristic curve (AUROC). The C-statistics results for prediction of prolonged length of stay were 85 ± 3% accuracy and AUROC 0.94 ± 0.04. These predictive models and calculator may help to inform clinical and organizational decision making.

Prediction of One-Year Transplant-Free Survival after Norwood Procedure Based on the Pre-Operative Data.

This paper discusses computational modeling of predictive risk factors for neonates undergoing a Norwood surgical procedure, a multi-stage cardiac procedure that restores functional systemic circulation in patients such as neonates with Hypoplastic Left Heart Syndrome (HLHS). In this model, we apply machine learning based binary classication to 549 cases reported by the Pediatric Heart Networks Single Ventricle Reconstruction Trial. We use neural networks classier to predict risk factors for individual patients undergoing a Norwood procedure for the repair of HLHS. Results indicate that independent risk can be calculated with 85% accuracy and 0.94 area under the receiver operating characteristics curve. This model may help physicians provide counseling for families and medically optimize patients prior to surgery by modifying individual risk factors.

Shunt Failure-Risk Factors and Outcomes: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.

BACKGROUND: Systemic-to-pulmonary shunt failure is a potentially catastrophic complication. We analyzed a large multicenter clinical registry to describe the prevalence and evaluate risk factors. METHODS: Infants (aged ≤365 days) undergoing shunt operations (systemic artery-to-pulmonary artery or systemic ventricle-to-pulmonary artery) in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) from 2010 to 2015 were included. Multivariable logistic regression was used to evaluate risk factors for in-hospital shunt failure. Model covariates included patient characteristics, preoperative factors, procedural factors including shunt type, and center effects. Centers with more than 15% missing data for key covariates were excluded. RESULTS: Shunt operations were performed in 9,172 infants (118 centers). In-hospital shunt failure occurred in 674 (7.3%). In multivariable analysis, risk factors for in-hospital shunt failure included lower weight at operation (odds ratio [OR], 1.35; p = 0.001), preoperative hypercoagulable state (OR, 2.47; p = 0.031), and the presence of any other STS-CHSD preoperative risk factors (OR, 1.24; p = 0.038). Shunt failure was less likely with a systemic ventricle-to-pulmonary artery shunt than a systemic artery-to-pulmonary artery shunt (OR, 0.65; p = 0.020). Neither cardiopulmonary bypass nor single-ventricle diagnosis was a risk factor for shunt failure. Patients with in-hospital shunt failure had significantly higher rates of operative mortality (31.9% vs 11.1%, p < 0.001) and major morbidity (84.4% vs 29.4%, p < 0.001), and longer median postoperative length of stay among survivors (45 vs 22 days, p < 0.001). CONCLUSIONS: In-hospital shunt failure is common, and associated mortality risk is high. These data highlight at-risk patients and procedural cohorts that warrant expectant surveillance and may benefit from enhanced antithrombotic prophylaxis or other management strategies to reduce shunt failure. These findings may inform planning of future clinical trials.

Risk Factors for Survival After Heart Transplantation in Children and Young Adults: A 22-Year Study of 179 Transplants.

BACKGROUND: This article reviews all patients who underwent heart transplantation (HTx) within a single institution (172 patients underwent 179 HTx [167 first-time HTxs, 10 second HTxs, 2 third HTxs]) to describe diagnostic characteristics, management protocols, and risk factors for mortality. METHODS: Descriptive analysis was performed for the entire cohort using mean, standard deviation, median, interquartile range, and overall range, as appropriate. Univariable and multivariable Cox proportional hazards models were performed to identify prognostic factors for outcomes over time. The primary outcome of interest was mortality, which was modeled by Kaplan-Meier analysis. RESULTS: Median age at HTx was 263 days (range, 5 days to 24 years; mean = 4.63 ± 5.95 years; 18 neonates, 79 infants). Median weight at HTx was 7.5 kg (range, 2.2-113 kg; mean = 19.36 ± 23.54). Diagnostic categories were cardiomyopathy (n = 62), primary transplantation for hypoplastic left heart syndrome (HLHS) or HLHS-related malformation (n = 33), transplantation after cardiac surgery for HLHS or HLHS-related malformation (n = 17), non-HLHS congenital heart disease (n = 55), and retransplant (n = 12). Operative mortality was 10.1% (18 patients). Cumulative total follow-up is 1,355 years. Late mortality was 18.4% (33 patients). Overall Kaplan-Meier five-year survival was 76.2%. One hundred twenty-one patients are alive with a mean follow-up of 7.61 ± 6.46 years. No survival differences were seen among the five diagnostic subgroups ( P = .064) or between immunosensitized patients (n = 31) and nonimmunosensitized patients (n = 141; P = .422). CONCLUSIONS: Excellent results are expected for children undergoing HTx with comparable results among diagnostic groups. Pretransplant mechanical circulatory support and posttransplant mechanical circulatory support are risk factors for decreased survival. Survival after transplantation for HLHS or HLHS-related malformation is better with primary HTx in comparison to HTx after prior cardiac surgery.

Modified Model for End-Stage Liver Disease eXcluding INR (MELD-XI) Score Predicts Early Death After Pediatric Heart Transplantation.

BACKGROUND: We sought to determine the ability of the Model for End-Stage Liver Disease eXcluding INR (MELD-XI) to predict short-term and long-term outcomes in pediatric patients undergoing orthotopic heart transplant. METHODS: The United Network for Organ Sharing Database was queried for all pediatric patients (aged 1 to 18 years) undergoing orthotopic heart transplant from 2000 to 2012. The logarithmic relationship between the serum creatinine and bilirubin was used to calculate the MELD-XI score. Lowess smoothing plots were referenced, and a score threshold of 12.2 was used to stratify patients into low (75%) and high (25%) MELD-XI cohorts. Patient-specific characteristics, intraoperative variables, and postoperative outcomes were compared between the two cohorts. Differences in survival at 30 days, 1 year, and 5 years between the MELD-XI cohorts were estimated by the Kaplan-Meier method. Cox proportional hazards modeling was used to determine the risk-adjusted effect of a high MELD-XI score on death. RESULTS: After patients with missing MELD-XI scores were excluded, 2,939 patients met the inclusion criteria. Unconditional 30-day (93.1% vs 98.0%, p < 0.001), 1-year (85.9% vs 92.9%, p < 0.001), and 5-year (71.2% vs 79.5%, p < 0.001) survivals were significantly worse in the high-score cohort. However, 1-year survival excluding 90-day deaths (94.9% vs 95.8%, p = 0.29) and 5-year survival excluding 1-year deaths (82.8% vs 85.6%, p = 0.09) were statistically equivalent. When modeled as a categoric variable, a high MELD-XI score was an independent predictor of death at 30 days (hazard ratio, 2.86; 95% confidence interval, 1.84 to 4.45; p < 0.001), 1 year (hazard ratio, 1.88; 95% confidence interval, 1.42 to 2.48, p < 0.001), and 5 years (hazard ratio, 1.41; 95% confidence interval, 1.19 to 1.77; p < 0.001). For every 1-point increase in the MELD-XI score, mortality increased 11% at 30 days, 7% at 1 year, and 4% at 5 years (p < 0.001). The MELD-XI was not predictive of conditional mortality at 1 year or 5 years. CONCLUSIONS: The MELD-XI scoring system can be used in pediatric orthotopic heart transplant to identify patients at risk for poor outcomes. Because long-term survival is largely driven by early death, renal insufficiency and congestive hepatopathy should be optimized before transplant.

The Effect of Institutional Volume on Complications and Their Impact on Mortality After Pediatric Heart Transplantation.

BACKGROUND: This study evaluated the potential association of institutional volume with survival and mortality subsequent to major complications in a modern cohort of pediatric patients after orthotopic heart transplantation (OHT). METHODS: The United Network of Organ Sharing database was queried for pediatric patients (aged ≤18 years) undergoing OHT between 2000 and 2010. Institutional volume was defined as the average number of transplants completed annually during each institution's active period and was evaluated as categoric and as a continuous variable. Logistic regression models were used to determine the effect of institutional volumes on postoperative outcomes, which included renal failure, stroke, rejection, reoperation, infection, and a composite complication outcome. Cox modeling was used to analyze the risk-adjusted effect of institutional volume on 30-day, 1-year, and 5-year mortality. Kaplan-Meier estimates were used to compare differences in unconditional survival. RESULTS: A total of 3,562 patients (111 institutions) were included and stratified into low-volume (<6.5 transplants/year, 91 institutions), intermediate-volume (6.5 to 12.5 transplants/year, 12 institutions), and high-volume (>12.5 transplants/year, 8 institutions) tertiles. Unadjusted survival was significantly different at 30 days (p = 0.0087) in the low-volume tertile (94.2%; 95% confidence interval, 92.7% to 95.4%) compared with the high-volume tertile (96.8%; 95% confidence interval, 95.7% to 97.7%). No difference was observed at 1 or 5 years. Risk-adjusted Cox modeling demonstrated that low-volume institutions had an increased rate of mortality at 30 days (hazard ratio, 1.91; 95% confidence interval, 1.02 to 3.59; p = 0.044), but not at 1 or 5 years. High-volume institutions had lower incidences of postoperative complications than low-volume institutions (30.3% vs 38.4%, p < 0.001). Despite this difference in the rate of complications, survival in patients with a postoperative complication was similar across the volume tertiles. CONCLUSIONS: No association was observed between institutional volume and adjusted or unadjusted long-term survival. High-volume institutions have a significantly lower rate of postoperative complications after pediatric OHT. This association does not correlate with increased subsequent mortality in low-volume institutions. Given these findings, strategies integral to the allocation of allografts in adult transplantation, such as regionalization of care, may not be as relevant to pediatric OHT.

Radiation proctitis: current strategies in management.

Radiation proctitis is a known complication following radiation therapy for pelvic malignancy. The majority of cases are treated nonsurgically, and an understanding of the available modalities is crucial in the management of these patients. In this paper, we focus on the current treatments of radiation proctitis.

Tob1 is a constitutively expressed repressor of liver regeneration.

How proliferative and inhibitory signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified transducer of ErbB2.1 (Tob1), a member of the PC3/BTG1 family of mito-inhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hepatectomy in mice secondary to posttranscriptional mechanisms. Deletion of Tob1 increases hepatocyte proliferation and accelerates restoration of liver mass after hepatectomy. Down-regulation of Tob1 is required for normal liver regeneration, and Tob1 controls hepatocyte proliferation in a dose-dependent fashion. Tob1 associates directly with both Caf1 and cyclin-dependent kinase (Cdk) 1 and modulates Cdk1 kinase activity. In addition, Tob1 has significant effects on the transcription of critical cell cycle components, including E2F target genes and genes involved in p53 signaling. We provide direct evidence that levels of an inhibitory factor control the rate of liver regeneration, and we identify Tob1 as a crucial check point molecule that modulates the expression and activity of cell cycle proteins.