Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Impact of Social Determinants of Health on Predictive Models for Outcomes After Congenital Heart Surgery.

BACKGROUND: Despite documented associations between social determinants of health and outcomes post-congenital heart surgery, clinical risk models typically exclude these factors. OBJECTIVES: The study sought to characterize associations between social determinants and operative and longitudinal mortality as well as assess impacts on risk model performance. METHODS: Demographic and clinical data were obtained for all congenital heart surgeries (2006-2021) from locally held Congenital Heart Surgery Collaborative for Longitudinal Outcomes and Utilization of Resources Society of Thoracic Surgeons Congenital Heart Surgery Database data. Neighborhood-level American Community Survey and composite sociodemographic measures were linked by zip code. Model prediction, discrimination, and impact on quality assessment were assessed before and after inclusion of social determinants in models based on the 2020 Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model. RESULTS: Of 14,173 total index operations across New York State, 12,321 cases, representing 10,271 patients at 8 centers, had zip codes for linkage. A total of 327 (2.7%) patients died in the hospital or before 30 days, and 314 children died by December 31, 2021 (total n = 641; 6.2%). Multiple measures of social determinants of health explained as much or more variability in operative and longitudinal mortality than clinical comorbidities or prior cardiac surgery. Inclusion of social determinants minimally improved models' predictive performance (operative: 0.834-0.844; longitudinal 0.808-0.811), but significantly improved model discrimination; 10.0% more survivors and 4.8% more mortalities were appropriately risk classified with inclusion. Wide variation in reclassification was observed by site, resulting in changes in the center performance classification category for 2 of 8 centers. CONCLUSIONS: Although indiscriminate inclusion of social determinants in clinical risk modeling can conceal inequities, thoughtful consideration can help centers understand their performance across populations and guide efforts to improve health equity.

Severe Features of Systemic Juvenile Idiopathic Arthritis in Patients With Congenital Heart Disease.

OBJECTIVE: To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA). METHODS: We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory, and radiographic data were collected from the medical record and reviewed with each patient's primary medical team. RESULTS: Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy, but all the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n = 5), rash (n = 5), and arthritis (n = 4) developed after surgical intervention in all the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n = 5), elevated interleukin 18 levels (n = 5), baseline eosinophilia prior to initiation of biologic disease-modifying antirheumatic drugs (n = 4), and positivity for HLA-DRB1*15:01 alleles (n = 4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease. CONCLUSION: We identified an association between CHD and severe forms of sJIA. Although these findings will need to be confirmed in larger, multicenter cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD.

Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types.

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.

Child Opportunity Index and Pediatric Extracorporeal Membrane Oxygenation Outcomes; the Role of Diagnostic Category.

OBJECTIVES: To study the impact of social determinants of health (SDoH) on pediatric extracorporeal membrane oxygenation (ECMO) outcomes. DESIGN, SETTING, AND PATIENTS: Retrospective study of children (< 18 yr) supported on ECMO (October 1, 2015 to March 1, 2021) using Pediatric Health Information System (44 U.S. children's hospitals). Patients were divided into five diagnostic categories: neonatal cardiac, pediatric cardiac, neonatal respiratory, pediatric respiratory, and sepsis. SDoH included the Child Opportunity Index (COI; higher indicates social advantage), race, ethnicity, payer, and U.S. region. Children without COI were excluded. Diagnostic category-specific clinical variables related to baseline health and illness severity were collected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children supported on ECMO experienced a 33% in-hospital mortality (2863/8710). Overall, children with lower COI, "other" race, Hispanic ethnicity, public insurance and from South or West regions had greater mortality. Associations between SDoH and ECMO outcomes differed between diagnostic cohorts. Bivariate analyses found that only pediatric cardiac patients had an association between COI or race and mortality. Multivariable logistic regression analyses examined relationships between SDoH, clinical variables and mortality within diagnostic categories. Pediatric cardiac patients had 5% increased odds of death (95% CI, 1.01-1.09) for every 10-point decrement in COI, while Hispanic ethnicity was associated with higher survival (adjusted odds ratio [aOR] 0.72 [0.57-0.89]). Children with heart disease from the highest COI quintile had less cardiac-surgical complexity and earlier cannulation. Independent associations with mortality were observed in sepsis for Black race (aOR 1.62 [1.06-2.47]) and other payer in pediatric respiratory patients (aOR 1.94 [1.23-3.06]). CONCLUSIONS: SDoH are statistically associated with pediatric ECMO outcomes; however, associations differ between diagnostic categories. Influence of COI was observed only in cardiac patients while payer, race, and ethnicity results varied. Further research should investigate differences between diagnostic cohorts and age groups to understand drivers of inequitable outcomes.

Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery.

While genome sequencing has transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we used artificial intelligence (AI) technologies to explore the predictive value of genome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a cohort of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes were associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes was further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes was also informative, reducing the risk for adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Preoperative Hemodynamics Impact the Benefit of Fenestration on Fontan Postoperative Length of Stay.

BACKGROUND: Utilization of Fontan fenestration varies considerably by center. OBJECTIVES: Using a multicenter Pediatric Heart Network dataset linking surgical and preoperative hemodynamic variables, the authors evaluated factors associated with use of Fontan fenestration and the impact of fenestration on post-Fontan length of stay (LOS). METHODS: Patients 2 to 6 years old at Fontan surgery from 2010 to 2020 with catheterization<1 year prior were included. Factors associated with fenestration were evaluated using multivariable logistic regression adjusting for key covariates. Restrictive cubic spline analysis was used to evaluate potential cut-points for hemodynamic variables associated with longer postoperative LOS stratified by fenestration with multivariable linear regression to evaluate the magnitude of effect. RESULTS: Fenestration was used in 465 of 702 patients (66.2%). Placement of a fenestration was associated with center (range 27%-93% use, P < 0.0001) and Fontan type (OR: 14.1 for lateral tunnel vs extracardiac conduit, P < 0.0001). No hemodynamic variable was independently associated with fenestration. In a multivariable linear model adjusting for center, a center-fenestration interaction, prematurity, preoperative mean pulmonary artery pressure (mPAP), and cardiac index, fenestration was associated with shorter hospital LOS after Fontan (P = 0.0024). The benefit was most pronounced at mPAP ≥13 mm Hg (median LOS: 9 vs 12 days, P = 0.001). CONCLUSIONS: There is wide center variability in use of Fontan fenestration that is not explained by preoperative hemodynamics. Fenestration is independently associated with shorter LOS, and those with mPAP ≥13 mm Hg at pre-Fontan catheterization benefit the most. We propose this threshold as minimal criteria for fenestration.

De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

Neurodevelopmental Outcomes for Individuals With Congenital Heart Disease: Updates in Neuroprotection, Risk-Stratification, Evaluation, and Management: A Scientific Statement From the American Heart Association.

Over the past decade, new research has advanced scientific knowledge of neurodevelopmental trajectories, factors that increase neurodevelopmental risk, and neuroprotective strategies for individuals with congenital heart disease. In addition, best practices for evaluation and management of developmental delays and disorders in this high-risk patient population have been formulated based on literature review and expert consensus. This American Heart Association scientific statement serves as an update to the 2012 statement on the evaluation and management of neurodevelopmental outcomes in children with congenital heart disease. It includes revised risk categories for developmental delay or disorder and an updated list of factors that increase neurodevelopmental risk in individuals with congenital heart disease according to current evidence, including genetic predisposition, fetal and perinatal factors, surgical and perioperative factors, socioeconomic disadvantage, and parental psychological distress. It also includes an updated algorithm for referral, evaluation, and management of individuals at high risk. Risk stratification of individuals with congenital heart disease with the updated categories and risk factors will identify a large and growing population of survivors at high risk for developmental delay or disorder and associated impacts across the life span. Critical next steps must include efforts to prevent and mitigate developmental delays and disorders. The goal of this scientific statement is to inform health care professionals caring for patients with congenital heart disease and other key stakeholders about the current state of knowledge of neurodevelopmental outcomes for individuals with congenital heart disease and best practices for neuroprotection, risk stratification, evaluation, and management.

Updated Case Definition of MIS-C and Implications for Clinical Care.

OBJECTIVES: A broad, surveillance case definition was implemented when multisystem inflammatory syndrome in children (MIS-C) emerged in 2020. In 2023, a revised MIS-C case definition was constructed to improve specificity and reduce misclassification with other pediatric inflammatory conditions. This study aims to describe the impact of the updated definition on the classification of patients with MIS-C and Kawasaki Disease (KD). METHODS: Patients hospitalized from March 2020 to November 2022 with clinician-diagnosed KD and MIS-C at a single center were studied retrospectively. Specificity and positive predictive value were assessed; McNemar test was used to compare specificity. RESULTS: Among 119 patients with MIS-C per the 2020 definition, 20 (17%) did not fulfill the 2023 definition. Six of these 20 (30%) had shock or cardiac involvement. Of 59 KD patients, 10 (17%) met the 2020 MIS-C definition. Five patients (8%) met the 2023 MIS-C definition. Specificity for the 2020 and 2023 MIS-C definitions among KD patients were 83.1% and 91.5% respectively (McNemar, P = .0736). Positive predictive value was higher for the 2023 MIS-C case definition compared with the 2020 MIS-C case definition (95.2% vs 92.2%). CONCLUSIONS: Approximately 1 in 5 patients diagnosed with MIS-C using the 2020 case definition did not meet the 2023 definition, including patients with cardiovascular dysfunction. Overlap persisted between patients meeting KD and 2023 MIS-C case definitions, with a false positive rate of 8%. Implications for treatment should be considered, particularly in settings where presumed MIS-C may be treated with corticosteroid monotherapy.

Stress Ulcer Prophylaxis Versus Placebo-A Blinded Pilot Randomized Controlled Trial to Evaluate the Safety of Two Strategies in Critically Ill Infants With Congenital Heart Disease.

OBJECTIVES: The routine use of stress ulcer prophylaxis (SUP) in infants with congenital heart disease (CHD) in the cardiac ICU (CICU) is controversial. We aimed to conduct a pilot study to explore the feasibility of performing a subsequent larger trial to assess the safety and efficacy of withholding SUP in this population (NCT03667703). DESIGN, SETTING, PATIENTS: Single-center, prospective, double-blinded, parallel group (SUP vs. placebo), pilot randomized controlled pilot trial (RCT) in infants with CHD admitted to the CICU and anticipated to require respiratory support for greater than 24 hours. INTERVENTIONS: Patients were randomized 1:1 (stratified by age and admission type) to receive a histamine-2 receptor antagonist or placebo until respiratory support was discontinued, up to 14 days, or transfer from the CICU, if earlier. MEASUREMENTS AND MAIN RESULTS: Feasibility was defined a priori by thresholds of screening rate, consent rate, timely drug allocation, and protocol adherence. The safety outcome was the rate of clinically significant upper gastrointestinal (UGI) bleeding. We screened 1,426 patients from February 2019 to March 2022; of 132 eligible patients, we gained informed consent in 70 (53%). Two patients did not require CICU admission after obtaining consent, and the remaining 68 patients were randomized to SUP (n = 34) or placebo (n = 34). Ten patients were withdrawn early, because of a change in eligibility (n = 3) or open-label SUP use (n = 7, 10%). Study procedures were completed in 58 patients (89% protocol adherence). All feasibility criteria were met. There were no clinically significant episodes of UGI bleeding during the pilot RCT. The percentage of patients with other nonserious adverse events did not differ between groups. CONCLUSIONS: Withholding of SUP in infants with CHD admitted to the CICU was feasible. A larger multicenter RCT designed to confirm the safety of this intervention and its impact on incidence of UGI bleeding, gastrointestinal microbiome, and other clinical outcomes is warranted.

Elevation of IL-17 Cytokines Distinguishes Kawasaki Disease From Other Pediatric Inflammatory Disorders.

OBJECTIVE: Kawasaki disease (KD) is a systemic vasculitis of young children that can lead to development of coronary artery aneurysms. We aimed to identify diagnostic markers to distinguish KD from other pediatric inflammatory diseases. METHODS: We used the proximity extension assay to profile proinflammatory mediators in plasma samples from healthy pediatric controls (n = 30), febrile controls (n = 26), and patients with KD (n = 23), multisystem inflammatory syndrome in children (MIS-C; n = 25), macrophage activation syndrome (n = 13), systemic and nonsystemic juvenile idiopathic arthritis (n = 14 and n = 10, respectively), and juvenile dermatomyositis (n = 9). We validated the key findings using serum samples from additional patients with KD (n = 37) and febrile controls (n = 28). RESULTS: High-fidelity proteomic profiling revealed distinct patterns of cytokine and chemokine expression across pediatric inflammatory diseases. Although KD and MIS-C exhibited many similarities, KD differed from MIS-C and other febrile diseases in that most patients exhibited elevation in one or more members of the interleukin-17 (IL-17) cytokine family, IL-17A, IL-17C, and IL-17F. IL-17A was particularly sensitive and specific, discriminating KD from febrile controls with an area under the receiver operator characteristic curve of 0.95 (95% confidence interval 0.89-1.00) in the derivation set and 0.91 (0.85-0.98) in the validation set. Elevation of all three IL-17-family cytokines was observed in over 50% of KD patients, including 19 of 20 with coronary artery aneurysms, but was rare in all other comparator groups. CONCLUSION: Elevation of IL-17 family cytokines is a hallmark of KD and may help distinguish KD from its clinical mimics.

School age and adolescent heart failure following the Norwood procedure.

BACKGROUND: Heart failure results in significant morbidity and mortality for young children with hypoplastic left heart syndrome (HLHS) following the Norwood procedure. The trajectory in later childhood is not well described. METHODS: We studied the outcome into adolescence of participants enrolled in the Single Ventricle Reconstruction trial who underwent the Fontan procedure or survived to 6 years without having undergone Fontan procedure. The primary outcome was heart failure events, defined as heart transplant listing or death attributable to heart failure. Symptomatic heart failure for participants surviving 10 or more years was also assessed utilizing the Pediatric Quality of Life Inventory (PedsQL). RESULTS: Of the 345 participants who underwent a Fontan operation or survived to 6 years without Fontan, 25 (7.2%) had a heart failure event before the age of 12 years. Among these, 21 were listed for heart transplant, and 4 died from heart failure. Nineteen participants underwent heart transplant, all of whom survived to age 12 years. Factors associated with a heart failure event included longer Norwood hospital length of stay, aortic atresia, and no Fontan operation by age 6 years. Assessment of heart failure symptoms at 12 years of age revealed that 24 (12.2%) of 196 PedsQL respondents "often" or "almost always" had difficulty walking more than one block. CONCLUSIONS: Heart failure events occur in over 5% of children with palliated HLHS between preschool age and adolescence. Outcomes for children listed for transplant are excellent. However, a substantial portion of palliated HLHS children have significant symptoms of heart failure at 12 years of age.

Association of genetic and sulcal traits with executive function in congenital heart disease.

OBJECTIVE: Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. METHODS: We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. RESULTS: Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. INTERPRETATION: We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial.

BACKGROUND: Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population. METHODS: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete. FINDINGS: Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause). INTERPRETATION: PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding. FUNDING: Bristol Myers Squibb-Pfizer Alliance.

Postoperative Troponin Levels in Children Undergoing Open Heart Surgery With and Without Coronary Intervention.

We aimed to characterize the ranges, temporal trends, influencing factors, and prognostic significance of postoperative troponin levels after congenital heart surgery. This single-center retrospective study included patients from 2006 to 2021 who had ≥ 1 postoperative troponin-T measurement collected within 96 h of congenital heart surgery (CHS). Patients were grouped as Anomalous Aortic Origin of the Coronary Artery-"AAOCA repair," or congenital heart surgery with "Other Coronary Interventions" other than AAOCA repair, or "No Coronary Intervention." In each group, information on concomitant surgery requiring one or more of the following-atriotomy, ventriculotomy, right ventricular muscle bundle resection, and/or septal myectomy-was collected. Clinical correlates of troponin values were analyzed in three postoperative windows: < 8, 8-24, and 24-48 h. The highest median [range] troponin levels (ng/mL) for the samples were 0.34 [0.06, 1.32] at < 8 h for "AAOCA repair," 1.35 [0.14, 12.0] at < 8 h for those undergoing CHS with "Other Coronary Interventions," and 0.87 [0.06, 25.1] at 8-24 h for those undergoing CHS with "No Coronary Interventions." Atriotomy was associated with higher median troponin levels in the AAOCA group at < 8 h (0.40 [0.31, 0.77] vs. 0.29 [0.17, 0.54], P = 0.043) and in the Other Coronary Intervention group at 8-24 h (1.67 [1.04, 2.63] vs. 0.40 [0.19, 1.32], P = 0.002). Patients experiencing major postoperative complications (vs. those who did not) had higher troponin levels in the AAOCA group as early as 8-24 h (0.36 [0.24, 0.57] vs. 0.21 [0.14, 0.33], P = 0.03). Similar findings were noted in the Coronary Intervention (2.20 [1.34, 3.90] vs. 1.11 [0.51, 2.90], P = 0.028) and No Coronary Intervention (2.2 [1.49, 15.1] vs. 0.74 [0.40, 2.34], P = 0.027) groups but earlier at < 8 h. In the AAOCA group, 2/18 (11%) troponin outliers experienced cardiac arrest in comparison to 0/80 (0%) non-outliers (P = 0.032). In the Other Coronary Intervention group, troponin outliers had longer median times to ICU discharge (10 vs. 4 days) and hospital discharge (21 vs. 10 days) (both P < 0.001). Postoperative troponin levels depend on a multitude of factors and may have prognostic value in patients undergoing congenital heart surgery with coronary interventions.

Social Drivers of Health and Pediatric Extracorporeal Membrane Oxygenation Outcomes.

BACKGROUND: Relationships between social drivers of health (SDoH) and pediatric health outcomes are highly complex with substantial inconsistencies in studies examining SDoH and extracorporeal membrane oxygenation (ECMO) outcomes. To add to this literature with emerging novel SDoH measures, and to address calls for institutional accountability, we examined associations between SDoH and pediatric ECMO outcomes. METHODS: This single-center retrospective cohort study included children (<18 years) supported on ECMO (2012-2021). SDoH included Child Opportunity Index (COI), race, ethnicity, payer, interpreter requirement, urbanicity, and travel-time to hospital. COI is a multidimensional estimation of SDoH incorporating traditional (eg, income) and novel (eg, healthy food access) neighborhood attributes ([range 0-100] higher indicates healthier child development). Outcomes included in-hospital mortality, ECMO run duration, and length of stay (LOS). RESULTS: 540 children on ECMO (96%) had a calculable COI. In-hospital mortality was 44% with median run duration of 125 hours and ICU LOS 29 days. Overall, 334 (62%) had cardiac disease, 92 (17%) neonatal respiratory failure, 93 (17%) pediatric respiratory failure, and 21 (4%) sepsis. Median COI was 64 (interquartile range 32-81), 323 (60%) had public insurance, 174 (34%) were from underrepresented racial groups, 57 (11%) required interpreters, 270 (54%) had urban residence, and median travel-time was 89 minutes. SDoH including COI were not statistically associated with outcomes in univariate or multivariate analysis. CONCLUSIONS: We observed no significant difference in pediatric ECMO outcomes according to SDoH. Further research is warranted to better understand drivers of inequitable health outcomes in children, and potential protective mechanisms.