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Background: Brain magnetic resonance imaging (MRI) of infants with congenital heart disease (CHD) shows brain immaturity assessed via a cortical-based semi-quantitative score. Our primary aim was to develop an infant paralimbic-related subcortical-based semi-quantitative dysmaturation score, termed brain dysplasia score (BDS), to detect abnormalities in CHD infants compared to healthy controls and secondarily to predict clinical outcomes. We also validated our BDS in a preclinical mouse model of hypoplastic left heart syndrome. Methods: A paralimbic-related subcortical BDS, derived from structural MRIs of infants with CHD, was compared to healthy controls and correlated with clinical risk factors, regional cerebral volumes, feeding, and 18-month neurodevelopmental outcomes. The BDS was validated in a known CHD mouse model named Ohia with two disease-causing genes, Sap130 and Pchda9. To relate clinical findings, RNA-Seq was completed on Ohia animals. Findings: BDS showed high incidence of paralimbic-related subcortical abnormalities (including olfactory, cerebellar, and hippocampal abnormalities) in CHD infants (n = 215) compared to healthy controls (n = 92). BDS correlated with reduced cortical maturation, developmental delay, poor language and feeding outcomes, and increased length of stay. Ohia animals (n = 63) showed similar BDS findings, and RNA-Seq analysis showed altered neurodevelopmental and feeding pathways. Sap130 mutants correlated with a more severe BDS, whereas Pcdha9 correlated with a milder phenotype. Conclusions: Our BDS is sensitive to dysmaturational differences between CHD and healthy controls and predictive of poor outcomes. A similar spectrum of paralimbic and subcortical abnormalities exists between human and Ohia mutants, suggesting a common genetic mechanistic etiology. [ABSTRACT FROM AUTHOR]

Introduction: In solid-organ transplantation, human leukocyte antigen (HLA) donor-specific antibodies (DSA) are strongly associated with graft rejection, graft loss, and patient death. The predominant tests used for detecting HLA DSA before and after solid-organ transplantation are HLA single antigen bead (SAB) assays. However, SAB assays may not detect antibodies directed against HLA epitopes that are not represented in the SAB. The prevalence and potential impact of unrepresented HLA epitopes are expected to vary by ethnicity, but have not been thoroughly investigated. To address this knowledge gap, HLA allele frequencies from seven ethnic populations were compared with HLA proteins present in SAB products from two manufacturers to determine unrepresented HLA proteins. Materials: Allele frequencies were obtained from the Common, Intermediate, and Well Documented HLA catalog v3.0, and frequencies of unrepresented HLA types were calculated. Next-generation sequencing was used to determine HLA types of 60 deceased solid-organ donors, and results were used to determine if their HLA-A, -B, -C, and -DRB1 proteins were not present in SAB reagents from two vendors. Unrepresented HLA proteins were compared with the most similar protein in SAB assays from either vendor and then visualized using modeling software to assess potential HLA epitopes. Results: For the seven ethnic populations, 0.5% to 11.8% of each population had HLA proteins not included in SAB assays from one vendor. Non-European populations had greater numbers of unrepresented alleles. Among the deceased donors, 26.7% (16/60) had at least one unrepresented HLA-A, -B, -C, or -DRB1 protein. Structural modeling demonstrated that a subset of these had potential HLA epitopes that are solvent accessible amino acid mismatches and are likely to be accessible to B cell receptors.Discussion: In conclusion, SAB assays cannot completely rule out the presence of HLA DSA. HLA epitopes not represented in those assays vary by ethnicity and should not be overlooked, especially in non-European populations. Allele-level HLA typing can help determine the potential for HLA antibodies that could evade detection. [ABSTRACT FROM AUTHOR]

Background: The US Pediatric Heart Allocation Policy (PHAP) was revised in March 2016, with the goal of reducing waitlist mortality. We evaluated the hypothesis that these changes, which increased status exceptions, have worsened racial disparities in waitlist outcomes. Methods: Children in the Pediatric Heart Transplant Study database listed for first heart transplant from January 2012 – June 2020 were included and stratified by listing before (Era 1) or after (Era 2) the PHAP revision. Results: A total of 4,089 children were listed during the study period. Compared with white children (n = 2648), non‐white children (n = 1441) were more likely to have an underlying diagnosis of cardiomyopathy in both eras. Waitlist mortality was similar in white and non‐white children in Era 1, but comparatively worse for non‐white children in Era 2. In multivariable analysis controlling for diagnosis, age, and severity markers, non‐white children had a significantly higher waitlist mortality only in Era 2 (Era 1: sHR 1.22 [95%CI 0.90 – 1.66] vs. Era 2: sHR 1.57 [95%CI 1.17 – 2.10]). Conclusions: Widening racial disparities in waitlist mortality may be an unintended consequence of the 2016 PHAP revision. Additional analyses may inform the degree to which this policy vs. unrelated changes in care differentially contribute to these disparities. [ABSTRACT FROM AUTHOR]

Advances in surgical technique and medical surveillance have improved outcomes of single ventricle (SV) palliation, particularly during the first interstage period. However, there remains a considerable mortality risk beyond this period. Patients born between January 2004 and December 2011 who required SV palliation were retrospectively identified. Patients who survived stage 1 palliation, were discharged home, and then were evaluated for Glenn candidacy, and continued care at our institution were included. Perioperative echocardiographic, hemodynamic, and operative data were analyzed at each surgical stage. The primary outcome was death or need for transplant. Univariate and multivariate analysis was completed using Cox proportional-hazards modeling. A total of 175 patients were included. Three patients died after pre-operative evaluation before Glenn. Glenn was completed in 168 patients, 16 died before Fontan. Fontan was completed in 149 patients; 117 were alive without need for transplant, 17 died post-Fontan, and 1 required transplantation. Twenty-one patients were lost to follow-up throughout the study period and were censored at time of last follow-up. Pre-Glenn moderate or severe atrioventricular valve regurgitation (AVVR) was an independent risk factor for death/transplant (HR 2.41; p -value.026). Pre-Glenn moderate ventricular dysfunction was also an independent risk factor (HR 5.29; p -value.012). Other risk factors included right ventricular (RV) dominant morphology and perinatal acidosis. Despite advances in SV palliation, a subset of these children remains at increased risk for poor outcomes. Early risk factors include RV dominant morphology and perinatal acidosis. Patients with substantial AVVR or ventricular dysfunction before Glenn palliation are also at significantly higher risk for death or requirement of transplantation later in childhood. [ABSTRACT FROM AUTHOR]

Post‐transplant lymphoproliferative disorders (PTLD) are the main malignancy seen after pediatric heart transplant and are a significant cause of morbidity and mortality. Prior to the development of detailed guidelines, we sought to identify trends in screening, diagnosis, and treatment of pediatric PTLD. All Pediatric Heart Transplant Society (PHTS) institutions were surveyed. No identifiable patient information was shared. From 56 PHTS centers, 22 responses were received (39.3%). 100% agree PTLD cannot be diagnosed solely based on elevated Epstein‐Barr virus (EBV) load. All respondents routinely screen for EBV by blood PCR, but frequency of screening varies. There was intermediate consensus regarding the use of computed tomography (CT) and/or positron emission tomography (PET) in surveillance management for PTLD. Most centers require a diagnostic biopsy before initiating new treatment for PTLD (14 of 18, 77.8%), but many reduce immune suppression based on elevated EBV without pathologic PTLD (16 of 22, 72.7%). Beyond immune modulation, rituximab is most commonly used (9 of 13, 69.2%). Consultation with oncology is common (17 of 17, 100%), but timing varies widely. Our survey highlights significant elements of agreement and significant practice variation among PHTS institutions regarding pediatric PTLD. Reduction of immune suppression prior to pathologic diagnosis of PTLD is a common management strategy. When this fails, rituximab is used, but is most often reserved until after confirmation of the diagnosis. Oncology subspecialists are commonly involved in these cases. Our findings highlight the need to develop improved guidelines for evaluation and treatment of pediatric PTLD. [ABSTRACT FROM AUTHOR]