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In part 1 of a phase 2–3 trial, a 50-μg dose of mRNA-1273 vaccine was safe and immunogenic. In part 2, nearly 4000 6-to-11-year-olds received two doses of vaccine or placebo and were followed for a median of 82 days. The vaccine had mainly mild adverse effects and was immunogenic in 99%, similar to the results in 18-to-25-year-olds. Vaccine efficacy during a delta-variant period was 88%.

Hypoplastic left heart syndrome is a complex congenital heart lesion that requires a three-stage procedure for surgical palliation. This clinical trial examines two approaches to the first stage of the procedure, and the results provide important guidance for the most appropriate surgical management of this serious lesion. This clinical trial examines two approaches to the first stage of the Norwood procedure, and the results provide important guidance for the most appropriate surgical management of this serious lesion. Hypoplastic left heart syndrome and related anomalies involving a single right ventricle are characterized by hypoplasia of the left heart and the aorta, with compromised systemic cardiac output (Figure 1). Infants with the syndrome generally undergo a three-stage reconstruction culminating in the Fontan procedure. The first operation (stage I) is the Norwood procedure, in which the right ventricle is connected to a reconstructed aorta with the use of the proximal main pulmonary artery for systemic outflow. Pulmonary blood flow is reestablished by means of a shunt from the pulmonary artery to the systemic circulation. In the second operation (stage II), . . .

Children with Kawasaki disease are at risk for the development of coronary-artery aneurysms. Standard therapy for this disorder includes intravenous immune globulin and aspirin. This study shows that, as compared with placebo, the addition of a single pulsed dose of intravenous methylprednisolone has no further beneficial effect over that of standard therapy and therefore cannot be recommended for routine treatment. This study shows that the addition of a single pulsed dose of intravenous methylprednisolone has no further beneficial effect over that of standard therapy and therefore cannot be recommended for routine treatment. The standard of care for children with acute Kawasaki disease is treatment with high-dose intravenous immune globulin and aspirin. 1 Despite receiving high-dose intravenous immune globulin within the first 10 days of illness, approximately 5% of children with Kawasaki disease have subsequent coronary aneurysms and 1% have giant aneurysms, as classified on the basis of criteria of the Japanese Ministry of Health. 2 – 4 Moreover, when coronary-artery dimensions are adjusted for body-surface area, a far greater proportion of children with Kawasaki disease have coronary-artery dilation than would be detected with the use of unadjusted dimensions. 5 The role of corticosteroids in the primary . . .

The practice of coiling aortopulmonary collaterals (APCs) before Fontan completion is controversial, and published data are limited. We sought to compare outcomes in subjects with and without pre-Fontan coil embolization of APCs using the Pediatric Heart Network Fontan Cross-Sectional Study database which enrolled survivors of prior Fontan palliation. We compared hospital length of stay after Fontan in 80 subjects who underwent APC coiling with 459 subjects who did not. Secondary outcomes included post-Fontan complications and assessment of health status and ventricular performance at cross-sectional evaluation (mean 8.6 ± 3.4 years after Fontan). Centers varied markedly in frequency of pre-Fontan APC coiling (range 0%-30% of subjects, P < .001). The coil group was older at Fontan ( P = .004) and more likely to have single right ventricular morphology ( P = .054) and pre-Fontan atrioventricular valve regurgitation ( P = .03). The coil group underwent Fontan surgery more recently ( P < .001), was more likely to have a prior superior cavopulmonary anastomosis ( P < .001), and more likely to undergo extracardiac Fontan connection ( P < .001) and surgical fenestration ( P < .001). In multivariable analyses, APC coiling was not associated with length of stay (hazard ratio for remaining in-hospital 0.91, 95% CI 0.70-1.18, P = .48) or postoperative complications, except more post-Fontan catheter interventions (hazard ratio 1.74, 95% CI 1.04-2.91, P = .03), primarily additional APC coils. The groups had similar outcomes at cross-sectional evaluation. Management of APCs before Fontan shows marked practice variation. We did not find an association between pre-Fontan coiling of APCs and shorter postoperative hospital stay or with better late outcomes. Prospective studies of this practice are needed.

Obesity is an increasingly alarming public health threat, with nearly 20% of children classified as obese in the United States today. Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically‐based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity‐induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2 μg/kg/h) starting at an earlier age (6 years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady‐state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (CYP)2B6*6/*6 virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically‐based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity.

Abnormal height and adiposity are observed after the Fontan operation. These abnormalities may be associated with worse functional outcome. We analyzed data from the National Heart, Lung, and Blood Institute Pediatric Heart Network cross-sectional study of Fontan patients. Groups were defined by height ( z-score <−1.5 or ≥−1.5) and body mass index (body mass index [BMI] z-score <−1.5 or −1.5 to 1.5 or ≥1.5). Associations of anthropometric measures with measurements from clinical testing (exercise, echocardiography, magnetic resonance imaging) were determined adjusting for demographics, anatomy, and pre-Fontan status. Relationships between anthropometric measures and functional health status (FHS) were assessed using the Child Health Questionnaire. Mean age of the cohort (n = 544) was 11.9 ± 3.4 years. Lower height- z patients (n = 124, 23%) were more likely to have pre-Fontan atrioventricular valve regurgitation ( P = .029), as well as orthopedic and developmental problems (both P < .001). Lower height- z patients also had lower physical and psychosocial FHS summary scores (both P < .01). Higher BMI- z patients (n = 45, 8%) and lower BMI- z patients (n = 53, 10%) did not have worse FHS compared to midrange BMI- z patients (n = 446, 82%). However, higher BMI- z patients had higher ventricular mass-to-volume ratio ( P = .03) and lower % predicted maximum work ( P = .004) compared to midrange and lower BMI- z patients. Abnormal anthropometry is common in Fontan patients. Shorter stature is associated with poorer FHS and non-cardiac problems. Increased adiposity is associated with more ventricular hypertrophy and poorer exercise performance, which may have significant long-term implications in this at-risk population.

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Patients who have undergone the Fontan procedure are at risk for thrombosis, ventricular dysfunction, and valve regurgitation, but data to guide the medical treatment and prevention of these adverse outcomes in this population are lacking. This analysis examined medication usage among Fontan patients by putative indication and by study center. The medical history and current medications of 546 Fontan subjects, ages 6–18 years, were assessed in a Pediatric Heart Network multicenter cross-sectional study. Cardiac imaging was performed within 3 months of enrollment. The majority of the subjects (64%) were taking two or more medications. Antithrombotics were taken by 86% of those with a history of stroke, thrombosis, or both and 67% of those without such a history (P = 0.01). Conversely, 14% of those with a history of stroke, thrombosis, or both were taking no antithrombotic. Angiotensin-converting enzyme inhibitor (ACEi) therapy was independently associated with moderate or severe atrioventricular valve regurgitation (P = 0.004), right ventricular morphology (P < 0.001), and shorter time since Fontan (P = 0.004) but not with ventricular systolic dysfunction. Glycoside therapy and diuretic therapy each was associated with older age at Fontan (P = 0.001 and P = 0.023, respectively) and a history of post-Fontan arrhythmia (P < 0.001 and P = 0.003, respectively) but not with ventricular systolic dysfunction. Medication use rates varied widely among the centers, even with controls for center differences in patient characteristics. Prospective therapeutic trials are needed to guide the medical treatment of Fontan patients.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network’s Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO2) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO2 declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO2 tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO2 at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO2 at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO2 at VAT was better preserved than peak VO2 across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.

Mitral regurgitation is the most common indication for reoperation in children following repair of atrioventricular septal defect (AVSD). We hypothesized that angiotensin-converting enzyme inhibitor therapy would decrease the severity of mitral regurgitation and limit left ventricular volume overload in children following AVSD repair. The Pediatric Heart Network designed a placebo-controlled randomized trial of enalapril in this population. The primary aim was to test the effect of enalapril on the change in left ventricular end-diastolic dimension body surface area–adjusted z score. Before the launch of the trial, a feasibility study was performed to estimate the number of patients with at least moderate mitral regurgitation following AVSD repair. Seventeen months after the start of the study, 349 patients were screened, 8 were trial eligible, and only 5 were enrolled. The study was subsequently terminated because of low patient accrual. Several factors led to the problems with patient accrual, including (1) the use of criteria to assess disease severity in the feasibility study that were not identical to those used in the trial, (2) failure to achieve equipoise for the study among clinicians and referring physicians, (3) reliance on methodology developed in adult populations with different disease mechanisms, and (4) absence of adequate data to define the natural history of the disease process under study. Progress in the treatment of children with cardiovascular disease will depend on the future of multicenter collaborative clinical trials. The lessons learned from this study may contribute to improvements in this research.