Elimination of 15N-thymidine after oral administration in human infants.

BACKGROUND: We have developed a new clinical research approach for the quantification of cellular proliferation in human infants to address unanswered questions about tissue renewal and regeneration. The approach consists of oral 15N-thymidine administration to label cells in S-phase, followed by Multi-isotope Imaging Mass Spectrometry for detection of the incorporated label in cell nuclei. To establish the approach, we performed an observational study to examine uptake and elimination of 15N-thymidine. We compared at-home label administration with in-hospital administration in infants with tetralogy of Fallot, a form of congenital heart disease, and infants with heart failure. METHODS: We examined urine samples from 18 infants who received 15N-thymidine (50 mg/kg body weight) by mouth for five consecutive days. We used Isotope Ratio Mass Spectrometry to determine enrichment of 15N relative to 14N (%) in urine. RESULTS/FINDINGS: 15N-thymidine dose administration produced periodic rises of 15N enrichment in urine. Infants with tetralogy of Fallot had a 3.2-fold increase and infants with heart failure had a 4.3-fold increase in mean peak 15N enrichment over baseline. The mean 15N enrichment was not statistically different between the two patient populations (p = 0.103). The time to peak 15N enrichment in tetralogy of Fallot infants was 6.3 ± 1 hr and in infants with heart failure 7.5 ± 2 hr (mean ± SEM). The duration of significant 15N enrichment after a dose was 18.5 ± 1.7 hr in tetralogy of Fallot and in heart failure 18.2 ± 1.8 hr (mean ± SEM). The time to peak enrichment and duration of enrichment were also not statistically different (p = 0.617 and p = 0.887). CONCLUSIONS: The presented results support two conclusions of significance for future applications: (1) Demonstration that 15N-thymidine label administration at home is equivalent to in-hospital administration. (2) Two different types of heart disease show no differences in 15N-thymidine absorption and elimination. This enables the comparative analysis of cellular proliferation between different types of heart disease.

Increased Cerebello-Prefrontal Connectivity Predicts Poor Executive Function in Congenital Heart Disease.

BACKGROUND: Children and adolescents with congenital heart disease (CHD) are at risk for cognitive impairments, such as executive function deficits and motor delays, which can impact their academic and adaptive functioning as well as their quality of life. We investigated whether alterations in connectivity between the prefrontal and cerebellar brain structures exist between CHD and control cohorts and if these alterations could predict cognitive or motor impairment among youths with CHD. METHODS: 53 participants with CHD and 73 healthy control participants completed multi-modal magnetic resonance imaging (MRI) of the brain, including high-resolution diffusion tensor imaging at 3T. We measured connectivity from masked regions of interest in the cerebellum to the frontal cortex using a probabilistic tractography method. Participants also completed neuropsychological tests of cognitive and motor skills using the NIH Toolbox. RESULTS: In the CHD group, fractional anisotropy (FA) was increased in the cognitive loop connectivity pathways, including from the right cerebellum to the left thalamus (p = 0.0002) and from the left thalamus to the left medial frontal gyrus (MFG) (p = 0.0048) compared with the healthy control group. In contrast, there were no differences between CHD and controls in motor loop connectivity pathways. An increase in FA from the right thalamus to the MFG tract in the cognitive loop (posterior subdivision) predicted (p = 0.03) lower scores on the NIHTB tests, including those of executive functioning. A transient increase in connectivity of the cognitive loop in the adolescent group was observed relative to the child and adult groups. CONCLUSIONS: Our results suggest that selective alteration of cerebellum-cerebral connectivity circuitry within the cognitive loops predicts cognitive dysfunction in CHD youth. Our study suggests a critical period of cerebellar circuitry plasticity in the adolescent period in CHD subjects that drives neurocognitive function. Further replication and validation in other pediatric CHD cohorts is warranted for future work.

Multimodality Imaging in Ebstein Anomaly.

Ebstein anomaly is the most common form of tricuspid valve congenital anomalies. The tricuspid valve is abnormal with different degrees of displacement of the septal leaflet and abnormal rotation of the valve towards the right ventricular outflow tract. In severe forms, it results in significant tricuspid regurgitation and requires surgical repair. There is an increased interest in understanding the anatomy of the tricuspid valve in this lesion as the surgical repair has evolved with the invention and wide adoption of the cone operation. Multimodality imaging plays an important role in diagnosis, follow-up, surgical planning and post-operative care. This review provides anatomical tips for the cardiac imagers caring for patients with Ebstein anomaly and will help provide image-based personalized medicine.

Occlusion of the os of the left coronary artery by dysplastic aortic valve tissue presenting as progressive mitral insufficiency and cardiac arrest.

Mitral regurgitation in the neonatal period is relatively rare. It can be secondary to a congenital malformation of the valve apparatus or mitral valve dysfunction and deformation secondary to myocardial dysfunction or volume load of the left ventricle. Less commonly, it can be due to coronary artery abnormalities leading to mitral valve papillary muscle ischaemia and subsequent dysfunction. Such coronary artery abnormalities include anomalous left coronary artery from pulmonary artery, left main coronary artery atresia, or a thromboembolic phenomenon. In this study, we describe a newborn with a dysplastic aortic valve causing obstruction of the os of the left coronary artery leading to progressive mitral insufficiency.

Associations between Maternal Risk Factors and Intrinsic Placental and Fetal Brain Functional Properties in Congenital Heart Disease.

The relationship between maternal risk factors (MRFs) (particularly pre-gravid obesity, diabetes, and hypertension) and congenital heart disease (CHD) to placental and fetal brain outcomes is poorly understood. Here, we tested the hypothesis that MRF and CHD would be associated with reduced intrinsic placental and fetal brain function using a novel non-invasive technique. Pregnant participants with and without MRF and fetal CHD were prospectively recruited and underwent feto-placental MRI. Using intrinsic properties of blood oxygen level dependent imaging (BOLD) we quantified spatiotemporal variance of placenta and fetal brain. MRFs and CHD were correlated with functional characteristics of the placenta and fetal brain. Co-morbid MRF (hypertension, diabetes, and obesity) reduced spatiotemporal functional variance of placenta and fetal brain (p < 0.05). CHD predicted reduced fetal brain temporal variance compared to non-CHD (p < 0.05). The presence of both MRF and CHD was associated with reduced intrinsic pBOLD temporal variance (p = 0.047). There were no significant interactions of MRFs and CHD status on either temporal or spatial variance of intrinsic brain BOLD. MRF and CHD reduced functional characteristic of placenta and brain in fetuses. MRF modification and management during pregnancy may have the potential to not only provide additional risk stratification but may also improve neurodevelopmental outcomes.

Impaired Neurovascular Function Underlies Poor Neurocognitive Outcomes and Is Associated with Nitric Oxide Bioavailability in Congenital Heart Disease.

We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes and nitric oxide bioavailability. In a prospective single-center study, resting-state blood-oxygen-level-dependent (BOLD) and arterial spin labeling (ASL) MRI scans were successfully obtained from 24 CHD patients (age = 15.4 ± 4.06 years) and 63 normal referents (age = 14.1 ± 3.49) years. Pnvf was computed on a voxelwise basis as the negative of the ratio of functional connectivity strength (FCS) estimated from the resting-state BOLD acquisition to regional cerebral blood flow (rCBF) as estimated from the ASL acquisition. Pnvf was used to predict end-tidal CO2 (PETCO2) levels and compared to those estimated from the BOLD data. Nitric oxide availability was obtained via nasal measurements (nNO). Pnvf was compared on a voxelwise basis between CHD patients and normal referents and correlated with nitric oxide availability and neurocognitive outcomes as assessed via the NIH Toolbox. Pnvf was shown as highly predictive of PETCO2 using theoretical modeling. Pnvf was found to be significantly reduced in CHD patients in default mode network (DMN, comprising the ventromedial prefrontal cortex and posterior cingulate/precuneus), salience network (SN, comprising the insula and dorsal anterior cingulate), and central executive network (CEN, comprising posterior parietal and dorsolateral prefrontal cortex) regions with similar findings noted in single cardiac ventricle patients. Positive correlations of Pnvf in these brain regions, as well as the hippocampus, were found with neurocognitive outcomes. Similarly, positive correlations between Pnvf and nitric oxide availability were found in frontal DMN and CEN regions, with particularly strong correlations in subcortical regions (putamen). Reduced Pnvf in CHD patients was found to be mediated by nNO. Mediation analyses further supported that reduced Pnvf in these regions underlies worse neurocognitive outcome in CHD patients and is associated with nitric oxide bioavailability. Impaired neuro-vascular function, which may be non-invasively estimated via combined arterial-spin label and BOLD MR imaging, is a nitric oxide bioavailability dependent factor implicated in adverse neurocognitive outcomes in pediatric and young adult CHD.

Relationships Between Regional Cerebral Blood Flow and Neurocognitive Outcomes in Children and Adolescents With Congenital Heart Disease.

To identify regional cerebral blood flow (rCBF) alterations in children and adolescents with congenital heart disease (CHD) in relation to neurocognitive outcomes using a nonbiased data-driven approach. This is a prospective, observational study of children and adolescents with CHD without brain injury and healthy controls using pseudo-continuous arterial spin labeling (pCASL) MRI. Quantitative rCBF was compared between participants with CHD and healthy controls using a voxelwise data-driven method. Mediation analysis was then performed on a voxelwise basis, with the grouping variable as the independent variable, neurocognitive outcomes (from the NIH Toolbox Cognitive Battery) as the dependent variables, and rCBF as the mediator. After motion correction, a total of 80 studies were analyzable (27 for patients with CHD, 53 for controls). We found steeper age-related decline in rCBF among those with CHD compared to normal controls in the insula/ventromedial prefrontal regions (salience network) and the dorsal anterior cingulate and precuneus/posterior cingulate (default mode network), and posterior parietal/dorsolateral prefrontal (central executive network) (FWE-corrected P< 0.05). The reduced rCBF in the default mode/salience network was found to mediate poorer performance on an index of crystallized cognition from the NIH Toolbox Cognitive Battery in those with CHD compared to controls. In contrast, reduced rCBF in the central executive network/salience network mediated reduced deficits in fluid cognition among patients with CHD compared to controls. Regional cerebral blood flow alterations mediate domain-specific differences in cognitive performance in children and adolescents with CHD compared to healthy controls, independent of injury, and are likely related to brain and cognitive reserve mechanisms. Further research is needed to evaluate the potential of interventions in CHD targeting regional cerebral blood flow across lifespan.

Control of cytokinesis by ß-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment.

One million patients with congenital heart disease (CHD) live in the United States. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. Here, analysis of heart tissue from an infant with tetralogy of Fallot with pulmonary stenosis (ToF/PS) labeled with isotope-tagged thymidine demonstrated that cardiomyocyte cytokinesis failure is increased in this common form of CHD. We used single-cell transcriptional profiling to discover that the underlying mechanism of cytokinesis failure is repression of the cytokinesis gene ECT2, downstream of ß-adrenergic receptors (ß-ARs). Inactivation of the ß-AR genes and administration of the ß-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the number of cardiomyocytes (endowment) and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes in vitro. These results suggest that ß-blockers could be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

Interpretation errors in focused cardiac ultrasound by novice pediatric emergency medicine fellow sonologists.

BACKGROUND: Focused cardiac ultrasound (FOCUS) is a core competency for pediatric emergency medicine (PEM) fellows. The objectives of this study were (1) to evaluate test characteristics of PEM-fellow-performed FOCUS for pericardial effusion and diminished cardiac function and (2) to assess image interpretation independent of image acquisition. METHODS: PEM fellows performed and interpreted FOCUS on patients who also received cardiology service echocardiograms, the reference standard. Subsequently, eight different PEM fellows remotely interpreted a subset of the PEM-acquired and cardiology-acquired echocardiograms. RESULTS: Eight PEM fellows performed 54 FOCUS exams, of which two had pericardial effusion and four had diminished function. PEM fellow FOCUS had a sensitivity of 50.0% (95% CI 9.19-90.8) and specificity of 100.0% (95% CI 91.1-100.0) for detecting diminished function, and sensitivity of 50.0% (95% CI 2.67-97.33) and specificity of 98.1% (95% CI 88.42-99.9) for detecting pericardial effusions. When PEM fellows remotely interpreted 15 echocardiograms, the sensitivity was 81.3% (95% CI 70.7-88.8) and specificity 75% (95% CI 67.0-81.0) for detecting diminished function, and sensitivity of 76.3% (95% CI 65.0-85.0) and specificity 94.4% (95% CI 89.0-97.0) for detecting pericardial effusion. There were no differences in sensitivity and specificity of PEM fellows' interpretation of FOCUS studies compared to their interpretation of cardiology echocardiograms. Interrater reliability for interpretation of remote images (kappa) was 0.66 (95% CI 0.59-0.73) for effusion and 0.31 (95% CI 0.24-0.38) for function among the fellows. CONCLUSION: Novice PEM fellow sonologists (a physician who performs and interprets ultrasound) in the majority of instances were able to acquire and remotely interpret FOCUS images with limited training. However, they made real-time interpretation errors and likely need further training to incorporate real-time image acquisition and interpretation into their practice.

Comparison of Left Ventricular Hypertrophy by Electrocardiography and Echocardiography in Children Using Analytics Tool.

Left ventricular hypertrophy (LVH) is a common finding on pediatric electrocardiography (ECG) leading to many referrals for echocardiography (echo). This study utilizes a novel analytics tool that combines ECG and echo databases to evaluate ECG as a screening tool for LVH. SQL Server 2012 data warehouse incorporated ECG and echo databases for all patients from a single institution from 2006 to 2016. Customized queries identified patients 0-18 years old with LVH on ECG and an echo performed within 24 h. Using data visualization (Tableau) and analytic (Stata 14) software, ECG and echo findings were compared. Of 437,699 encounters, 4637 met inclusion criteria. ECG had high sensitivity (≥ 90%) but poor specificity (43%), and low positive predictive value (< 20%) for echo abnormalities. ECG performed only 11-22% better than chance (AROC = 0.50). 83% of subjects with LVH on ECG had normal left ventricle (LV) structure and size on echo. African-Americans with LVH were least likely to have an abnormal echo. There was a low correlation between V6R on ECG and echo-derived Z score of left ventricle diastolic diameter (r = 0.14) and LV mass index (r = 0.24). The data analytics client was able to mine a database of ECG and echo reports, comparing LVH by ECG and LV measurements and qualitative findings by echo, identifying an abnormal LV by echo in only 17% of cases with LVH on ECG. This novel tool is useful for rapid data mining for both clinical and research endeavors.

Surgical ligation of patent ductus arteriosus in premature infants: trends and practice variation.

OBJECTIVE: We sought to analyse the variation in the incidence of patent ductus arteriosus over three recent time points and characterise ductal ligation practices in preterm infants in the United States, adjusting for demographic and morbidity factors. METHODS: Using the Kids' Inpatient Database from 2003, 2006, and 2009, we identified infants born at ⩽32 weeks of gestation with International Classification of Diseases, Ninth Revision diagnosis of patent ductus arteriosus and ligation code. We examined patient and hospital characteristics and identified patient and hospital variables associated with ligation. RESULTS: Of 182,610 preterm births, 30,714 discharges included a patent ductus arteriosus diagnosis. The rate of patent ductus arteriosus diagnosis increased from 14% in 2003 to 21% in 2009 (p<0.001). A total of 4181 ligations were performed, with an overall ligation rate of 14%. Ligation rate in infants born at ⩽28 weeks of gestation was 20% overall, increasing from 18% in 2003 to 21% in 2009 (p<0.001). The ligation rate varied by state (4-28%), and ligation was associated with earlier gestational age, associated diagnoses, hospital type, teaching hospital status, and region (p<0.001). CONCLUSION: The rates of patent ductus arteriosus diagnosis and ligation have increased in the recent years. Variation exists in the practice of patent ductus arteriosus ligation and is influenced by patient and non-patient factors.

The utility of handheld echocardiography for early rheumatic heart disease diagnosis: a field study.

AIMS: The World Heart Federation (WHF) guidelines for rheumatic heart disease (RHD) are designed for a standard portable echocardiography (STAND) machine. A recent study in a tertiary care centre demonstrated that they also had good sensitivity and specificity when modified for use with handheld echocardiography (HAND). Our study aimed to evaluate the performance of HAND for early RHD diagnosis in the setting of a large-scale field screening. METHODS AND RESULTS: STAND was performed in 4773 children in Gulu, Uganda, with 10% randomly assigned to also undergo HAND. Additionally, any child with mitral or aortic regurgitation also underwent HAND. Studies were performed by experienced echocardiographers and blindly reviewed by cardiologists using 2012 WHF criteria, which were modified slightly for HAND--due to the lack of spectral Doppler capability. Paired echocardiograms were performed in 1420 children (mean age 10.8 and 53% female), resulting in 1234 children who were normal, 133 who met criteria for borderline RHD, 47 who met criteria for definite RHD, and 6 who had other diagnoses. HAND had good sensitivity and specificity for RHD detection (78.9 and 87.2%, respectively), but was most sensitive for definite RHD (97.9%). Inter- and intra-reviewer agreement ranged between 66-83 and 71.4-94.1%, respectively. CONCLUSIONS: HAND has good sensitivity and specificity for diagnosis of early RHD, performing best for definite RHD. Protocols for RHD detection utilizing HAND will need to include confirmation by STAND to avoid over-diagnosis. Strategies that evaluate simplified screening protocols and training of non-physicians hold promise for more wide spread deployment of HAND-based protocols.

Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies.

PURPOSE: Data from two large phase III studies were analyzed to characterize the correlation between the occurrence of rash during treatment with the epidermal growth factor receptor inhibitor erlotinib and improved clinical outcomes. EXPERIMENTAL DESIGN: Overall survival, progression-free survival (PFS), and tumor response were compared between patients in a rash-evaluable subset who did or did not develop rash in National Cancer Institute of Canada Clinical Trials Group Studies BR.21 (single agent in non-small-cell lung cancer, n = 444 in erlotinib group and n = 229 in placebo group) and PA.3 (combination with gemcitabine in pancreatic cancer, n = 254 in erlotinib plus gemcitabine group and n = 245 in placebo plus gemcitabine group). RESULTS: Presence of rash strongly correlated with overall survival in both studies. In Study BR.21, these correlations increased with rash severity grade: grade 1 versus no rash [hazard ratio (HR), 0.41, P < 0.001] and grade >or=2 versus no rash (HR, 0.29, P < 0.001). Similar results were observed for PFS. Disease control (complete response + partial response + stable disease) seemed to increase with the presence and severity of rash. In Study PA.3, grade >or=2 rash (but not grade 1) strongly correlated with overall survival improvement: grade >or=2 versus no rash (HR, 0.47, P < 0.001). Similarly, grade >or=2 rash was strongly correlated with improvements in PFS and disease control. CONCLUSIONS: Physicians and patients should view rash development as a positive event indicative of greater likelihood of clinical benefit. Further studies are required to identify patients most likely to develop rash and to determine if dose escalation to induce rash can improve efficacy.