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ImportanceThe 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.ObjectiveTo 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 ParticipantsThis cohort was a nationwide analysis of heart transplants in the US that used data from the UNOS database. Participants were children (ExposuresUNOS-defined donor risk status.Main Outcomes and MeasuresTrend 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.ResultsOf 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 RelevanceIn 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.

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.

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.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.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%, p0.001), and longer median postoperative length of stay among survivors (45 vs 22 days, p0.001).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.

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.

Bicuspid aortic valve (BAV) disease is the most common congenital defect with a prevalence of 1–2% in the population. Patients with BAV are at risk to develop a number of conditions including aortic complications, aortic valve stenosis and aortic valve insufficiency (AI). Patients with severe, symptomatic aortic insufficiency experienced increased risk of heart failure and death. While aortic valve replacement is a highly effective treatment that remains the criterion standard, aortic valve repair (AVR) offers a number of potential advantages. The development of effective and durable techniques, for leaflet repair and aortic annulus reconstruction, has enabled the repair of the regurgitant aortic valve in selected patients. The primary goal of AVR is to restore a durable surface of coaptation to the regurgitant valve. A detailed understanding of the functional anatomy of the aortic root and mechanisms of AI are critical. A number of techniques have been developed to reconstruct these valves including annuloplasty and leaflet repairs. A number of experienced centers have reported durable long-term results, with good long-term survival and freedom from reoperation beyond 15 years in at some centers. Long term comparison between repair and biological valve replacements have shown that beyond approximately 11 years, patients with repairs have a lower risk of both reoperation and mortality.

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.

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.

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).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.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%, p0.001). Despite this difference in the rate of complications, survival in patients with a postoperative complication was similar across the volume tertiles.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.

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.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.After patients with missing MELD-XI scores were excluded, 2,939 patients met the inclusion criteria. Unconditional 30-day (93.1% vs 98.0%, p0.001), 1-year (85.9% vs 92.9%, p0.001), and 5-year (71.2% vs 79.5%, p0.001) 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; p0.001), 1 year (hazard ratio, 1.88; 95% confidence interval, 1.42 to 2.48, p0.001), and 5 years (hazard ratio, 1.41; 95% confidence interval, 1.19 to 1.77; p0.001). 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 (p0.001). The MELD-XI was not predictive of conditional mortality at 1 year or 5 years.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.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is the most frequent indication for lung transplantation. The pathophysiology of IPF is unknown and effective treatments other than transplantation are not available. It has been speculated that proteasomes, the major non-lysosomal proteases in eukaryotes, are involved in IPF pathophysiology. However, information on 26S/20S proteasomes in normal human lungs and lungs from patients with IPF is lacking. Therefore, we studied whether lung 20S/26S proteasome content, activity and biochemical characteristics are altered in patients with IPF.