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BackgroundAcute kidney injury (AKI) that improves in the pediatric intensive care unit (PICU) is associated with better outcomes compared to AKI that persists, but no study has investigated whether this also occurs in children undergoing cardiopulmonary bypass (CPB).MethodsA retrospective study of children ≤18 years who underwent CPB in three children’s hospitals was conducted. Patients were classified into groups by kidney recovery after AKI according to Acute Disease Quality Initiative (ADQI) guidelines. Adjusted regression models evaluated associations between kidney recovery group and hospital outcomes.ResultsAmong 3620 children, AKI developed in 701 (19.4%): 610 transient AKI, 47 persistent AKI, and 44 acute kidney disease (AKD). Mortality increased with severity of kidney recovery group: 4.5% in the never developed AKI group, 8.9% in the transient AKI group, 25.5% in the persistent AKI group, and 31.8% in the AKD group (p <0.0001). In adjusted analysis, transient AKI (HR 1.4, CI 1.02, 2), persistent AKI (HR 22.4, CI 10.2, 49.2), and AKD (HR 3.7, CI 1.7, 7.9) had a greater hazard of mortality when compared to the never developed AKI group. Patients with transient AKI had a longer length of PICU stay than those with never developed AKI (HR 5.1, CI 2.9, 7.3).ConclusionsPatterns of kidney recovery after AKI were associated with worse PICU outcomes in children after CPB compared to those who did not develop AKI, even after rapid AKI recovery. Identification of factors that increase risk for these AKI patterns is necessary for prevention of AKI during CPB in children.

Complex congenital heart disease (CHD) is associated with neurodevelopmental impairment, the mechanism of which is unknown. Cerebral cortical dysmaturation in CHD is linked to white matter abnormalities, including developmental vulnerability of the subplate, in relation to oxygen delivery and metabolism deficits. In this study, we report associations between subcortical morphology and white matter metabolism in neonates with CHD using quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS). Multi-modal brain imaging was performed in three groups of neonates close to term-equivalent age: (1) term CHD (n = 56); (2) preterm CHD (n = 37) and (3) preterm control group (n = 22). Thalamic volume and cerebellar transverse diameter were obtained in relation to cerebral metrics and white matter metabolism. Short echo single-voxel MRS of parietal and frontal white matter was used to quantitate metabolites related to brain maturation (n-acetyl aspartate [NAA], choline, myo-inositol), neurotransmitter (glutamate), and energy metabolism (glutamine, citrate, creatine and lactate). Multi-variate regression was performed to delineate associations between subcortical morphological measurements and white matter metabolism controlling for age and white matter injury. Reduced thalamic volume, most pronounced in the preterm control group, was associated with increased citrate levels in all three group in the parietal white matter. In contrast, reduced cerebellar volume, most pronounced in the preterm CHD group, was associated with reduced glutamine in parietal grey matter in both CHD groups. Single ventricle anatomy, aortic arch obstruction, and cyanotic lesion were predictive of the relationship between reduced subcortical morphometry and reduced GLX (particularly glutamine) in both CHD cohorts (frontal white matter and parietal grey matter). Subcortical morphological associations with brain metabolism were also distinct within each of the three groups, suggesting these relationships in the CHD groups were not directly related to prematurity or white matter injury alone. Taken together, these findings suggest that subplate vulnerability in CHD is likely relevant to understanding the mechanism of both cortical and subcortical dysmaturation in CHD infants. Future work is needed to link this potential pattern of encephalopathy of CHD (including the constellation of grey matter, white matter and brain metabolism deficits) to not only abnormal fetal substrate delivery and oxygen conformance, but also regional deficits in cerebral energy metabolism.

Objective: Term congenital heart disease (CHD) neonates display abnormalities of brain structure and maturation, which are possibly related to underlying patient factors and perioperative insults. Our primary goal was to delineate associations between clinical factors and postnatal brain microstructure in term CHD neonates using diffusion tensor imaging (DTI) magnetic resonance (MR) acquisition combined with complementary data-driven connectome and seed-based tractography quantitative analysis. Our secondary goal was to delineate associations between mild dysplastic structural abnormalities and connectome and seed-base tractography as our primary goal. Methods: Neonates undergoing cardiac surgery for CHD were prospectively recruited from two large centers. Both pre- and postoperative magnetic resonance (MR) brain scans were obtained. DTI in 42 directions was segmented to 90 regions using neonatal brain template and three weighted methods. Seed- based tractography was performed in parallel. Clinical data :18 patient-specific and 9 preoperative variables associated with preoperative scan and 6 intraoperative and 12 postoperative variables associated with postoperative scan. A composite Brain Dysplasia Score (BDS) was created including cerebellar, olfactory bulbs, and hippocampus abnormalities. The outcomes included (1) connectome metrics: cost and global/nodal efficiency (2) seed-based tractography: fractional anisotropy. Statistics: multiple regression with false discovery rate correction (FDR). Results: A total of 133 term neonates with complex CHD were prospectively enrolled and 110 had analyzable DTI. Multiple patient-specific factors including d-transposition of the great arteries physiology and severity of impairment of fetal cerebral substrate delivery were predictive of preoperative reduced cost (p<0.0073), reduced global/nodal efficiency (p <0.03). Multiple postoperative factors (extracorporeal membrane oxygenation [ECMO], seizures, cardiopulmonary resuscitation) were predictive of postoperative reduced cost, reduced global/nodal efficiency (p < 0.05). All three subcortical structures of the BDS (including olfactory bulb/sulcus, cerebellum, and hippocampus) predicted distinct patterns of altered nodal efficiency (p<0.05). Conclusion: Patient-specific and postoperative clinical factors were most predictive of diffuse postnatal microstructural dysmaturation in term CHD neonates. In contrast, subcortical components of a structurally based- brain dysplasia score, predicted more regional based postnatal microstructural differences. Collectively, these findings suggest that brain DTI connectome may facilitate deciphering the mechanistic relative contribution of clinical and genetic risk factors related to poor neurodevelopmental outcomes in CHD.

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

Simulation is a key component of training in the pediatric cardiac intensive care unit (CICU), a complex environment that lends itself to virtual reality (VR)-based simulations. However, VR has not been previously described for this purpose. Two simulations were developed to test the use of VR in simulating pediatric CICU clinical scenarios, one simulating junctional ectopic tachycardia and low cardiac output syndrome, and the other simulating acute respiratory failure in a patient with suspected coronavirus disease 2019. Six attending pediatric cardiac critical care physicians were recruited to participate in the simulations as a pilot test of VR's feasibility for educational and practice improvement efforts in this highly specialized clinical environment. All participants successfully navigated the VR environment and met the critical endpoints of the two clinical scenarios. Qualitative feedback was overall positive with some specific critiques regarding limited realism in some mechanical aspects of the simulation. This is the first described use of VR in pediatric cardiac critical care simulation.Simulation is a key component of training in the pediatric cardiac intensive care unit (CICU), a complex environment that lends itself to virtual reality (VR)-based simulations. However, VR has not been previously described for this purpose. Two simulations were developed to test the use of VR in simulating pediatric CICU clinical scenarios, one simulating junctional ectopic tachycardia and low cardiac output syndrome, and the other simulating acute respiratory failure in a patient with suspected coronavirus disease 2019. Six attending pediatric cardiac critical care physicians were recruited to participate in the simulations as a pilot test of VR's feasibility for educational and practice improvement efforts in this highly specialized clinical environment. All participants successfully navigated the VR environment and met the critical endpoints of the two clinical scenarios. Qualitative feedback was overall positive with some specific critiques regarding limited realism in some mechanical aspects of the simulation. This is the first described use of VR in pediatric cardiac critical care simulation.

Fibrous particles interact with cells and organisms in complex ways that can lead to cellular dysfunction, cell death, inflammation, and disease. The development of conductive transparent networks (CTNs) composed of metallic silver nanowires (AgNWs) for flexible touchscreen displays raises new possibilities for the intimate contact between novel fibers and human skin. Here, we report that a material property, nanowire-bending stiffness that is a function of diameter, controls the cytotoxicity of AgNWs to nonimmune cells from humans, mice, and fish without deterioration of critical CTN performance parameters: electrical conductivity and optical transparency. Both 30- and 90-nm-diameter AgNWs are readily internalized by cells, but thinner NWs are mechanically crumpled by the forces imposed during or after endocytosis, while thicker nano-wires puncture the enclosing membrane and release silver ions and lysosomal contents to the cytoplasm, thereby initiating oxidative stress. This finding extends the fiber pathology paradigm and will enable the manufacture of safer products incorporating AgNWs.

Rationale Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD). Objective We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment. Method A total of 148 children, 4–5 years old, were classified into groups as follows: ADHD group ( n  = 107, DSM-IV-TR criteria) and a control group (CG, n  = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0). Results Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive–impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms. Conclusions Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.

Purpose Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene–disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene–disease relationships. Methods The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene–disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss. Results The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ). Conclusion This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.

The vast majority of Attention-deficit/hyperactivity disorder (ADHD) patients have other associated pathologies, with depressive symptoms as one of the most prevalent. Among the mediators that may participate in ADHD, melatonin is thought to regulate circadian rhythms, neurological function and stress response. To determine (1) the serum baseline daily variations and nocturnal excretion of melatonin in ADHD subtypes and (2) the effect of chronic administration of methylphenidate, as well as the effects on symptomatology, 136 children with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: DSM-IV-TR criteria) were divided into subgroups using the “Children’s Depression Inventory” (CDI). Blood samples were drawn at 20:00 and 09:00 h, and urine was collected between 21:00 and 09:00 h, at inclusion and after 4.61 ± 2.29 months of treatment. Melatonin and its urine metabolite were measured by radioimmunoassay RIA. Factorial analysis was performed using STATA 12.0. Melatonin was higher predominantly in hyperactive-impulsive/conduct disordered children (PHI/CD) of the ADHD subtype, without the influence of comorbid depressive symptoms. Methylphenidate ameliorated this comorbidity without induction of any changes in the serum melatonin profile, but treatment with it was associated with a decrease in 6-s-melatonin excretion in both ADHD subtypes. Conclusions: In untreated children, partial homeostatic restoration of disrupted neuroendocrine equilibrium most likely led to an increased serum melatonin in PHI/CD children. A differential cerebral melatonin metabolization after methylphenidate may underlie some of the clinical benefit.

Fibrous particles interact with cells and organisms in complex ways that can lead to cellular dysfunction, cell death, inflammation, and disease. The development of conductive transparent networks (CTNs) composed of metallic silver nanowires (AgNWs) for flexible touchscreen displays raises new possibilities for the intimate contact between novel fibers and human skin. Here, we report that a material property, nanowire-bending stiffness that is a function of diameter, controls the cytotoxicity of AgNWs to nonimmune cells from humans, mice, and fish without deterioration of critical CTN performance parameters: electrical conductivity and optical transparency. Both 30- and 90-nm-diameter AgNWs are readily internalized by cells, but thinner NWs are mechanically crumpled by the forces imposed during or after endocytosis, while thicker nanowires puncture the enclosing membrane and release silver ions and lysosomal contents to the cytoplasm, thereby initiating oxidative stress. This finding extends the fiber pathology paradigm and will enable the manufacture of safer products incorporating AgNWs.