Recent Advances towards the Understanding of Secondary Acute Myeloid Leukemia Progression.

Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy related AML, tAML). sAML is diagnosed when the number of blasts is ≥20% in the bone marrow or peripheral blood, and it is characterized by poor prognosis, resistance to therapy and low overall survival rate. With the recent advances in next generation sequencing technologies, our understanding of the molecular events associated with sAML evolution has significantly increased and opened new perspectives for the development of novel therapies. The genetic aberrations that are associated with sAML affect genes involved in processes such as splicing, chromatin modification and genome integrity. Moreover, non-coding RNAs' emerged as an important contributing factor to leukemogenesis. For decades, the standard treatment for secondary AML has been the 7 + 3 regimen of cytarabine and daunorubicin which prolongs survival for several months, but modifications in either dosage or delivery has significantly extended that time. Apart from traditional chemotherapy, hematopoietic stem cell transplantation, CAR-T cell therapy and small molecule inhibitors have also emerged to treat sAML.

Impact of prolonged ischemic time on pediatric heart transplantation outcomes: Improved outcomes in the most recent era.

BACKGROUND: Impacts of ischemic time (IT) on pediatric heart transplant outcomes are multifactorial. We aimed to analyze the effect of prolonged IT on graft loss after pediatric heart transplantation. We hypothesized that graft survival with prolonged IT has improved across eras. METHODS: Patients <18 years old in the Pediatric Heart Transplant Society database were included (N=6,765) and stratified by diagnosis and era (1993-2004, 2005-2009, and 2010-2019). Severe graft failure (SGF) was defined as death, retransplant, or need for mechanical circulatory support in the first 7 days post-transplant. Descriptive statistical methods were used to compare differences between patient characteristics and IT. Kaplan-Meier survival analysis compared freedom from graft loss, rejection, and infection. Multivariable analysis was performed for graft loss and SGF (hazard and logistic regression modeling, respectively). RESULTS: Diagnoses were cardiomyopathy (N = 3,246) and congenital heart disease (CHD; N = 3,305). CHD were younger, more likely to have an IT ≥4.5 hours, and more likely to require extracorporeal membrane oxygenation or mechanical ventilation at transplant (all p < 0.001). Median IT was 3.6 hours (interquartile range 2.98-4.31; range 0-10.5). IT was associated with early graft loss (HR 1.012, 95% CI 1.005-1.019), but not when analyzed only in the most recent era. IT was associated with SGF (OR 1.016 95%CI 1.003-1.030). CONCLUSIONS: Donor IT was independently associated with an increased risk of graft loss, albeit with a small effect relative to other risk factors. Graft survival with prolonged IT has improved in the most recent era but the risk of SGF persists.

Anti-spike antibody durability after SARS-CoV-2 vaccination in adolescent solid organ transplant recipients.

BACKGROUND: Adolescent solid organ transplant recipients (aSOTRs) who received three doses of the COVID-19 mRNA vaccine experience high seroconversion rates and antibody persistence for up to 3 months. Long-term antibody durability beyond this timeframe following three doses of the SARS-CoV-2 mRNA vaccine remains unknown. We describe antibody responses 6 months following the third vaccine dose (D3) of the BNT162b2 mRNA vaccination among aSOTRs. METHODS: Participants in a multi-center, observational cohort who received the third dose of the vaccine were analyzed for antibodies to the SARS-CoV-2 spike protein receptor-binding domain (Roche Elecsys anti-SARS-CoV-2-S positive: ≥0.8, maximum: >2500 U/mL). Samples were collected at 1-, 3-, and 6-months post-D3. Participants were surveyed at each timepoint and at 12-months post-D3. RESULTS: All 34 participants had positive anti-RBD antibody titers 6 months post-D3. Variations in titers occurred between 3 and 6 months post-D3, with 8/28 (29%) having decreased antibody levels at 6 months compared to 3 months and 2/28 (7%) reporting increased titers at 6 months. The remaining 18/28 (64%) had unchanged antibody titers compared to 3-month post-D3 levels. A total of 4/34 (12%) reported breakthrough infection within 6 months and 3/32 (9%) reported infection after 6-12 months following the third dose of the SARS-CoV-2 mRNA vaccine. CONCLUSIONS: The results suggest that antibody durability persists up to 6 months following three doses of the SARS-CoV-2 mRNA in aSOTRs. Demography and transplant characteristics did not differ for those who experienced antibody weaning. Breakthrough infections did occur, reflecting immune-evasive nature of novel variants such as Omicron.

Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

BACKGROUND: The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. METHODS: The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. RESULTS: Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. SUMMARY: Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.

Omicron Infections in Vaccinated Pediatric Solid Organ Transplant Recipients.

SARS-CoV-2 infection during the Omicron period was frequent amongst a cohort of vaccinated pediatric solid organ transplant recipients (pSOTRs) despite robust anti-receptor-binding domain (anti-RBD) antibody response, suggesting poor neutralizing capacity against Omicron subvariants. Breakthrough infections among pSOTRs were overall limited in severity.

Changes in estimated glomerular filtration rate over the first year following repeat heart transplant in children and young adults.

BACKGROUND: Renal function is reduced in patients undergoing heart transplant due to hemodynamic compromise, cardiorenal syndrome, and nephrotoxin exposure. No current studies evaluate renal function in retransplants. METHODS: We reviewed all heart transplants at our center from 1995 to 2021 and matched first-time heart transplants with retransplants, based on age at transplant, sex, and race. Estimated glomerular filtration rate (eGFR) was derived from CKiD-U25 calculator using creatinine and measured prior to transplant, 1-week post-transplant, 1-3, 6, and 12 months post-transplant, and recent follow-up. Changes in eGFR were measured within and between patients using a piecewise linear mixed effect model with matching. Exploratory univariate analysis was performed to evaluate pre-transplant risk factors for decreased eGFR. RESULTS: The unmatched cohort included 393 heart transplant recipients, with 47 being retransplants. Thirty-eight patients in both groups with at least 1 year of follow-up underwent matching. Both retransplants and first-time transplants had an initial decline in eGFR. eGFR rebounded to baseline or above baseline at 1-3 months post-transplant, but eGFR in retransplants remained significantly lower. At 1-year post-transplant, the average eGFR was 67.8 ± 4.3 mL/min/1.73 m2 versus 104.7 ± 4.3 mL/min/1.73 m2 (p < .001) in the retransplants and first-time transplants group, respectively. CONCLUSION: This study provides data on anticipated renal trajectory following retransplantation.

Percutaneous Stenting of a Stenotic Berlin Heart Outflow Cannula Graft in a 2 Year Old Child.

Left ventricular assist device (LVAD) outflow obstruction is a rare complication of long-term LVAD support. We present the first case of successful percutaneous stent implantation in a pediatric patient with LVAD outflow obstruction.

Corrigendum: Tox21Enricher-Shiny: an R Shiny application for toxicity functional annotation analysis.

[This corrects the article DOI: 10.3389/ftox.2023.1147608.].

Widening care gap in VAD therapy.

BACKGROUND: The removal of the HeartWare ventricular assist device (HVAD) due to pump malfunctions and inferior outcomes compared to HeartMate 3 (HM3) in adults has created a care gap for younger patients. It is unclear if the reported HVAD survival differs by age and if the initial experience with HM3 can bridge the gap. METHODS: Using the Society of Thoracic Surgeons (STS) Intermacs and Pedimacs registries, durable ventricular assist device (VAD) implants between September 2012 and December 2021 were identified. Young adults (YA) were defined as <40 years old in Intermacs. Patients were excluded if they had an isolated right VAD (RVAD) or were implanted as destination therapy (DT). Survival analysis by Kaplan-Meier (KM) and competing outcomes curves was performed, and 1-year survival is reported. RESULTS: The Intermacs cohort consisted of YA (n = 1226; HVAD 818; HM3 408) with a median age of YA of 32.07 (26.66-36.27) years and weight (wt) of 83.2 (68-104.2) kg. Most had cardiomyopathy (CM) (92.2%). The Pedimacs cohort was 668 patients (median age 9.47 [1.82-14.23] years, wt 27.2 [10-57.05] kg), and most also had CM (70.5%). Device breakdown included HVAD (n = 326), Berlin EXCOR (n = 277), and HM3 (n = 65). HVAD survival differed by age in adults, with YA fairing better than adults >40 years old (88.8% vs 79.4% at 1 year, p < 0.0001). YA survival was also better compared to Pedimacs patient (88.9% vs 83.7%, p = 0.0002), but when competing events were analyzed, mortality was similar to YA (9.2% vs 9.6%, p = 0.1) with a higher proportion of patient undergoing transplant at 1 year in Pedimacs (74% vs 31.3%, p < 0.0001). Survival by device differed between HVAD and HM3 in YA (88.8% vs 94.4%, p = 0.0025). This difference in device survival was not seen in all children (83.7% vs 87.3%, p = 0.21), including those ≥25 kg. Adverse event profiles also differed across the groups with adults seeing less adverse events with the HM3, but the same was not found (including stroke) in the pediatric cohort. Survival outcomes for patients between 10 and 25 kg were similar with the HVAD compared to the Berlin Heart EXCOR (p = 0.4290), with similarities in stroke risk. CONCLUSION: The removal of the HVAD device may result in a care gap in younger patient whose survival outcomes do not mirror that of older adults. The HM3 can fill a portion of this gap with good survival, but there remains a subset of pediatric patients that, based on initial HM3 use, will no longer have access to intracorporeal support and therefore, despite reasonable outcomes with the Berlin Heart EXCOR, will not be able to be discharged home. Lastly, it is essential that future changes to the availability of devices take into account the various patient populations that utilize the device to avoid unintended consequences of access inequality.

Tox21Enricher-Shiny: an R Shiny application for toxicity functional annotation analysis.

Inference of toxicological and mechanistic properties of untested chemicals through structural or biological similarity is a commonly employed approach for initial chemical characterization and hypothesis generation. We previously developed a web-based application, Tox21Enricher-Grails, on the Grails framework that identifies enriched biological/toxicological properties of chemical sets for the purpose of inferring properties of untested chemicals within the set. It was able to detect significantly overrepresented biological (e.g., receptor binding), toxicological (e.g., carcinogenicity), and chemical (e.g., toxicologically relevant chemical substructures) annotations within sets of chemicals screened in the Tox21 platform. Here, we present an R Shiny application version of Tox21Enricher-Grails, Tox21Enricher-Shiny, with more robust features and updated annotations. Tox21Enricher-Shiny allows users to interact with the web application component (available at http://hurlab.med.und.edu/Tox21Enricher/) through a user-friendly graphical user interface or to directly access the application's functions through an application programming interface. This version now supports InChI strings as input in addition to CASRN and SMILES identifiers. Input chemicals that contain certain reactive functional groups (nitrile, aldehyde, epoxide, and isocyanate groups) may react with proteins in cell-based Tox21 assays: this could cause Tox21Enricher-Shiny to produce spurious enrichment analysis results. Therefore, this version of the application can now automatically detect and ignore such problematic chemicals in a user's input. The application also offers new data visualizations, and the architecture has been greatly simplified to allow for simple deployment, version control, and porting. The application may be deployed onto a Posit Connect or Shiny server, and it uses Postgres for database management. As other Tox21-related tools are being migrated to the R Shiny platform, the development of Tox21Enricher-Shiny is a logical transition to use R's strong data analysis and visualization capacities and to provide aesthetic and developmental consistency with other Tox21 applications developed by the Division of Translational Toxicology (DTT) at the National Institute of Environmental Health Sciences (NIEHS).

Expanding use of the HeartMate 3 ventricular assist device in pediatric and adult patients within the Advanced Cardiac Therapies Improving Outcomes Network (ACTION).

BACKGROUND: We report current outcomes in patients supported with the HeartMate 3 (HM3) ventricular assist device in a multicenter learning network. METHODS: The Advanced Cardiac Therapies Improving Outcomes Network database was queried for HM3 implants between 12/2017 and 5/2022. Clinical characteristics, postimplant course, and adverse events were collected. Patients were stratified according to body surface area (BSA) (<1.4 m2, 1.4-1.8 m2, and >1.8 m2) at device implantation. RESULTS: During the study period, 170 patients were implanted with the HM3 at participating network centers, with median age 15.3years; 27.1% were female. Median BSA was 1.68 m2; the smallest patient was 0.73 m2 (17.7 kg). Most (71.8%) had a diagnosis of dilated cardiomyopathy. With a median support time of 102.5days, 61.2% underwent transplantation, 22.9% remained supported on device, 7.6% died, and 2.4% underwent device explantation for recovery; the remainder had transferred to another institution or transitioned to a different device type. The most common adverse events included major bleeding (20.8%) and driveline infection (12.9%); ischemic and hemorrhagic stroke were encountered in 6.5% and 1.2% of patients, respectively. Patients with BSA <1.4 m2 had a higher incidence of infection, renal dysfunction, and ischemic stroke. CONCLUSIONS: In this updated cohort of predominantly pediatric patients supported with the HM3 ventricular assist device, outcomes are excellent with <8% mortality on device. Device-related adverse events including stroke, infection, and renal dysfunction were more commonly seen in smaller patients, highlighting opportunities for improvements in care.

Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity.

In a joint effort involving scientists from academia, industry and regulatory agencies, ECETOC's activities in Omics have led to conceptual proposals for: (1) A framework that assures data quality for reporting and inclusion of Omics data in regulatory assessments; and (2) an approach to robustly quantify these data, prior to interpretation for regulatory use. In continuation of these activities this workshop explored and identified areas of need to facilitate robust interpretation of such data in the context of deriving points of departure (POD) for risk assessment and determining an adverse change from normal variation. ECETOC was amongst the first to systematically explore the application of Omics methods, now incorporated into the group of methods known as New Approach Methodologies (NAMs), to regulatory toxicology. This support has been in the form of both projects (primarily with CEFIC/LRI) and workshops. Outputs have led to projects included in the workplan of the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) group of the Organisation for Economic Co-operation and Development (OECD) and to the drafting of OECD Guidance Documents for Omics data reporting, with potentially more to follow on data transformation and interpretation. The current workshop was the last in a series of technical methods development workshops, with a sub-focus on the derivation of a POD from Omics data. Workshop presentations demonstrated that Omics data developed within robust frameworks for both scientific data generation and analysis can be used to derive a POD. The issue of noise in the data was discussed as an important consideration for identifying robust Omics changes and deriving a POD. Such variability or "noise" can comprise technical or biological variation within a dataset and should clearly be distinguished from homeostatic responses. Adverse outcome pathways (AOPs) were considered a useful framework on which to assemble Omics methods, and a number of case examples were presented in illustration of this point. What is apparent is that high dimension data will always be subject to varying processing pipelines and hence interpretation, depending on the context they are used in. Yet, they can provide valuable input for regulatory toxicology, with the pre-condition being robust methods for the collection and processing of data together with a comprehensive description how the data were interpreted, and conclusions reached.

Vaccination-Associated Myocarditis and Myocardial Injury.

SARS-CoV-2 vaccine-associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types of viral myocarditis, and other vaccine-associated cardiac disorders. COVID-19 vaccine-associated myocardial injury can be caused by an inflammatory immune cell infiltrate, but other etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms and cardiac magnetic resonance imaging. Endomyocardial biopsy is confirmatory for myocarditis, but may not show an inflammatory infiltrate because of rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily with mRNA platform vaccines, which are also the most effective. In persons aged >16 or >12 years the myocarditis estimated crude incidences after the first 2 doses of BNT162b2 and mRNA-1273 are approximately 1.9 and 3.5 per 100 000 individuals, respectively. These rates equate to excess incidences above control populations of approximately 1.2 (BNT162b2) and 1.9 (mRNA-1273) per 100 000 persons, which are lower than the myocarditis rate for smallpox but higher than that for influenza vaccines. In the studies that have included mRNA vaccine and SARS-COVID-19 myocarditis measured by the same methodology, the incidence rate was increased by 3.5-fold over control in COVID-19 compared with 1.5-fold for BNT162b2 and 6.2-fold for mRNA-1273. However, mortality and major morbidity are less and recovery is faster with mRNA vaccine-associated myocarditis compared to COVID-19 infection. The reasons for this include vaccine-associated myocarditis having a higher incidence in young adults and adolescents, typically no involvement of other organs in vaccine-associated myocarditis, and based on comparisons to non-COVID viral myocarditis an inherently more benign clinical course.

Considerations for application of benchmark dose modeling in radiation research: workshop highlights.

BACKGROUND: Exposure to different forms of ionizing radiation occurs in diverse occupational, medical, and environmental settings. Improving the accuracy of the estimated health risks associated with exposure is therefore, essential for protecting the public, particularly as it relates to chronic low dose exposures. A key aspect to understanding health risks is precise and accurate modeling of the dose-response relationship. Toward this vision, benchmark dose (BMD) modeling may be a suitable approach for consideration in the radiation field. BMD modeling is already extensively used for chemical hazard assessments and is considered statistically preferable to identifying low and no observed adverse effects levels. BMD modeling involves fitting mathematical models to dose-response data for a relevant biological endpoint and identifying a point of departure (the BMD, or its lower bound). Recent examples in chemical toxicology show that when applied to molecular endpoints (e.g. genotoxic and transcriptional endpoints), BMDs correlate to points of departure for more apical endpoints such as phenotypic changes (e.g. adverse effects) of interest to regulatory decisions. This use of BMD modeling may be valuable to explore in the radiation field, specifically in combination with adverse outcome pathways, and may facilitate better interpretation of relevant in vivo and in vitro dose-response data. To advance this application, a workshop was organized on June 3rd, 2022, in Ottawa, Ontario that brought together BMD experts in chemical toxicology and the radiation scientific community of researchers, regulators, and policy-makers. The workshop's objective was to introduce radiation scientists to BMD modeling and its practical application using case examples from the chemical toxicity field and demonstrate the BMDExpress software using a radiation dataset. Discussions focused on the BMD approach, the importance of experimental design, regulatory applications, its use in supporting the development of adverse outcome pathways, and specific radiation-relevant examples. CONCLUSIONS: Although further deliberations are needed to advance the use of BMD modeling in the radiation field, these initial discussions and partnerships highlight some key steps to guide future undertakings related to new experimental work.

ToxicR: A computational platform in R for computational toxicology and dose-response analyses.

The need to analyze the complex relationships observed in high-throughput toxicogenomic and other omic platforms has resulted in an explosion of methodological advances in computational toxicology. However, advancements in the literature often outpace the development of software researchers can implement in their pipelines, and existing software is frequently based on pre-specified workflows built from well-vetted assumptions that may not be optimal for novel research questions. Accordingly, there is a need for a stable platform and open-source codebase attached to a programming language that allows users to program new algorithms. To fill this gap, the Biostatistics and Computational Biology Branch of the National Institute of Environmental Health Sciences, in cooperation with the National Toxicology Program (NTP) and US Environmental Protection Agency (EPA), developed ToxicR, an open-source R programming package. The ToxicR platform implements many of the standard analyses used by the NTP and EPA, including dose-response analyses for continuous and dichotomous data that employ Bayesian, maximum likelihood, and model averaging methods, as well as many standard tests the NTP uses in rodent toxicology and carcinogenicity studies, such as the poly-K and Jonckheere trend tests. ToxicR is built on the same codebase as current versions of the EPA's Benchmark Dose software and NTP's BMDExpress software but has increased flexibility because it directly accesses this software. To demonstrate ToxicR, we developed a custom workflow to illustrate its capabilities for analyzing toxicogenomic data. The unique features of ToxicR will allow researchers in other fields to add modules, increasing its functionality in the future.

The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score.

BACKGROUND: Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. METHODS: The TEAMMATE trial (IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at 6 months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. CONCLUSION: The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Impact of race and health coverage on listing and waitlist mortality in pediatric cardiac transplantation.

BACKGROUND: Social factors like race and insurance affect transplant outcomes. However, little is known in pediatric heart transplantation. We hypothesized that race and insurance coverage impact listing and waitlist outcomes across eras. METHODS: Data from the Pediatric Heart Transplant Society multi-center registry prospectively collected between January 1, 2000-December 31, 2019 were analyzed. Patients were divided by race as Black, White and other and by insurance coverage at listing (US governmental, US private and non-US single payer systems (UK, Canada). Clinical condition at listing and waitlist outcomes were compared across races and insurance coverages. Categorical variables were compared using a chi-square test and continuous variables using the Wilcoxon rank sum test. Risk factors for waitlist mortality were examined using multiphase parametric hazard modeling. A sensitivity analysis using parametric hazard explored the interaction between race and insurance. RESULTS: At listing, compared to Whites (n = 5391) and others (n = 1167), Black patients (n = 1428) were older, more likely on US governmental insurance and had cardiomyopathy as the predominant diagnosis (p < 0.0001). Black patients were more likely to be higher status at listing, in hospital, on inotropes or a ventricular assist device (p < 0.0001). Black patients had significantly shorter time on the waitlist compared to other races (p < 0.0001) but had higher waitlist mortality (p = 0.0091), driven by the earlier era (2000-2009) (p = 0.0005), most prominently within the US private insurance cohort (p = 0.015). Outcomes were not different in other insurance cohorts or in the recent era (2010-2019). CONCLUSION: Black children are older and sicker at the time of listing, deteriorate more often and face a higher wait list mortality, despite a shorter waitlist period and favorable clinical factors, with improvement in the recent era associated with the recent US healthcare reforms. The social construct of race appears to disadvantage Black children by limiting referral, consideration or access to pediatric cardiac transplantation.

Race and Socioeconomic Bias in Pediatric Cardiac Transplantation.

BACKGROUND: To date, no studies evaluated implicit bias among clinicians caring for children with advanced heart failure. OBJECTIVES: This study aims to evaluate implicit racial and socioeconomic bias among pediatric heart transplant clinicians. METHODS: A cross-sectional survey of transplant clinicians from the Pediatric Heart Transplant Society was conducted between June and August 2021. The survey consisted of demographic questions along with explicit and validated race and socioeconomic status (SES) implicit association tests (IATs). Implicit and explicit biases among survey group members were studied and associations were tested between implicit and explicit measures. RESULTS: Of 500 members, 91 (18.2%) individuals completed the race IAT and 70 (14%) completed the SES IAT. Race IAT scores indicated moderate levels of implicit bias (mean = 0.33, d = 0.76; P < 0.001; ie, preference for White individuals). SES IAT scores indicated strong implicit bias (mean = 0.52, d = 1.53; P < 0.001; ie, preference for people from upper SES). There were weak levels of explicit race and wealth bias. There was a strong level of explicit education bias (mean = 5.22, d = 1.19; P < 0.001; ie, preference for educated people). There were nonsignificant correlations between the race and the SES IAT and explicit measures (P > 0.05 for all). CONCLUSIONS: As observed across other health care disciplines, among a group of pediatric heart transplant clinicians, there is an implicit preference for individuals who are White and from higher SES, and an explicit preference for educated people. Future studies should evaluate how implicit biases affect clinician behavior and assess the impact of efforts to reduce such biases.

Initial multicenter experience with ventricular assist devices in children and young adults with muscular dystrophy: An ACTION registry analysis.

PURPOSE: Cardiac disease results in significant morbidity and mortality in patients with muscular dystrophy (MD). Single centers have reported their ventricular assist device (VAD) experience in specific MDs and in limited numbers. This study sought to describe the outcomes associated with VAD therapy in an unselected population across multiple centers. METHODS: We examined outcomes of patients with MD and dilated cardiomyopathy implanted with a VAD at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers from 9/2012 to 9/2020. RESULTS: A total of 19 VADs were implanted in 18 patients across 12 sites. The majority of patients had dystrophinopathy (66%) and the median age at implant was 17.2 years (range 11.7-29.5). Eleven patients were non-ambulatory (61%) and 6 (33%) were on respiratory support pre-VAD. Five (28%) patients were implanted as a bridge to transplant, 4 of whom survived to transplant. Of 13 patients implanted as bridge to decision or destination therapy, 77% were alive at 1 year and 69% at 2 years. The overall frequencies of positive outcome (transplanted or alive on device) at 1 year and 2 years were 84% and 78%, respectively. Two patients suffered a stroke, 2 developed sepsis, 1 required tracheostomy, and 1 experienced severe right heart failure requiring right-sided VAD. CONCLUSIONS: This study demonstrates the potential utility of VAD therapies in patients with muscular dystrophy. Further research is needed to further improve outcomes and better determine which patients may benefit most from VAD therapy in terms of survival and quality of life.