Fine Motor Skill Mediates Visual Memory Ability with Microstructural Neuro-correlates in Cerebellar Peduncles in Prematurely Born Adolescents.

Adolescents born preterm (PT) with no evidence of neonatal brain injury are at risk of deficits in visual memory and fine motor skills that diminish academic performance. The association between these deficits and white matter microstructure is relatively unexplored. We studied 190 PTs with no brain injury and 92 term controls at age 16 years. The Rey-Osterrieth Complex Figure Test (ROCF), the Beery visual-motor integration (VMI), and the Grooved Pegboard Test (GPT) were collected for all participants, while a subset (40 PTs and 40 terms) underwent diffusion-weighted magnetic resonance imaging. PTs performed more poorly than terms on ROCF, VMI, and GPT (all P < 0.01). Mediation analysis showed fine motor skill (GPT score) significantly mediates group difference in ROCF and VMI (all P < 0.001). PTs showed a negative correlation (P < 0.05, corrected) between fractional anisotropy (FA) in the bilateral middle cerebellar peduncles and GPT score, with higher FA correlating to lower (faster task completion) GPT scores, and between FA in the right superior cerebellar peduncle and ROCF scores. PTs also had a positive correlation (P < 0.05, corrected) between VMI and left middle cerebellar peduncle FA. Novel strategies to target fine motor skills and the cerebellum may help PTs reach their full academic potential.

Tumors of the neural crest: Common themes in development and cancer.

The neural crest (NC) is a remarkable transient structure in the vertebrate embryo that gives rise to a highly versatile population of pluripotent cells that contribute to the formation of multiple tissues and organs throughout the body. In order to achieve their task, NC-derived cells have developed specialized mechanisms to promote (1) their transition from an epithelial to a mesenchymal phenotype, (2) their capacity for extensive migration and cell proliferation, and (3) their ability to produce diverse cell types largely depending on the microenvironment encountered during and after their migratory path. Following embryogenesis, these same features of cellular motility, invasion, and proliferation can become a liability by contributing to tumorigenesis and metastasis. Ample evidence has shown that cancer cells have cleverly co-opted many of the genetic and molecular features used by developing NC cells. This review focuses on tumors that arise from NC-derived tissues and examines mechanistic themes shared during their oncogenic and metastatic development with embryonic NC cell ontogeny.

Presence of intramucosal neuroglial cells in normal and aganglionic human colon.

The enteric nervous system (ENS) is composed of neural crest-derived neurons (also known as ganglion cells) the cell bodies of which are located in the submucosal and myenteric plexuses of the intestinal wall. Intramucosal ganglion cells are known to exist but are rare and often considered ectopic. Also derived from the neural crest are enteric glial cells that populate the ganglia and the associated nerves, as well as the lamina propria of the intestinal mucosa. In Hirschsprung disease (HSCR), ganglion cells are absent from the distal gut because of a failure of neural crest-derived progenitor cells to complete their rostrocaudal migration during embryogenesis. The fate of intramucosal glial cells in human HSCR is essentially unknown. We demonstrate a network of intramucosal cells that exhibit dendritic morphology typical of neurons and glial cells. These dendritic cells are present throughout the human gut and express Tuj1, S100, glial fibrillary acidic protein, CD56, synaptophysin, and calretinin, consistent with mixed or overlapping neuroglial differentiation. The cells are present in aganglionic colon from patients with HSCR, but with an altered immunophenotype. Coexpression of Tuj1 and HNK1 in this cell population supports a neural crest origin. These findings extend and challenge the current understanding of ENS microanatomy and suggest the existence of an intramucosal population of neural crest-derived cells, present in HSCR, with overlapping immunophenotype of neurons and glia. Intramucosal neuroglial cells have not been previously recognized, and their presence in HSCR poses new questions about ENS development and the pathobiology of HSCR that merit further investigation.

Arch watch: current approaches and opportunities for improvement.

Coarctation of the aorta (CoA) is a ductus arteriosus (DA)-dependent form of congenital heart disease (CHD) characterized by narrowing in the region of the aortic isthmus. CoA is a challenging diagnosis to make prenatally and is the critical cardiac lesion most likely to go undetected on the pulse oximetry-based newborn critical CHD screen. When undetected CoA causes obstruction to blood flow, life-threatening cardiovascular collapse may result, with a high burden of morbidity and mortality. Hemodynamic monitoring practices during DA closure (known as an "arch watch") vary across institutions and existing tools are often insensitive to developing arch obstruction. Novel measures of tissue oxygenation and oxygen deprivation may improve sensitivity and specificity for identifying evolving hemodynamic compromise in the newborn with CoA. We explore the benefits and limitations of existing and new tools to monitor the physiological changes of the aorta as the DA closes in infants at risk of CoA.

Multicentre study protocol comparing standard NRP to deveLoped Educational Modules for Resuscitation of Neonates in the Delivery Room with Congenital Heart Disease (LEARN-CHD).

INTRODUCTION: Infants born with critical congenital heart defects (CCHDs) have unique transitional pathophysiology that often requires special resuscitation and management considerations in the delivery room (DR). While much is known about neonatal resuscitation of infants with CCHDs, current neonatal resuscitation guidelines such as the neonatal resuscitation programme (NRP) do not include algorithm modifications or education specific to CCHDs. The implementation of CCHD specific neonatal resuscitation education is further hampered by the large number of healthcare providers (HCPs) that need to be reached. Online learning modules (eLearning) may provide a solution but have not been designed or tested for this specific learning need. Our objective in this study is to design targeted eLearning modules for DR resuscitation of infants with specific CCHDs and compare HCP knowledge and team performance in simulated resuscitations among HCPs exposed to these modules compared with directed CCHD readings. METHODS AND ANALYSIS: In a prospective multicentre trial, HCP proficient in standard NRP education curriculum are randomised to either (a) directed CCHD readings or (b) CCHD eLearning modules developed by the study team. The efficacy of these modules will be evaluated using (a) individual preknowledge/postknowledge testing and (b) team-based resuscitation simulations. ETHICS AND DISSEMINATION: This study protocol is approved by nine participating sites: the Boston Children's Hospital Institutional Review Board (IRB-P00042003), University of Alberta Research Ethics Board (Pro00114424), the Children's Wisconsin IRB (1760009-1), Nationwide Children's Hospital IRB (STUDY00001518), Milwaukee Children's IRB (1760009-1) and University of Texas Southwestern IRB (STU-2021-0457) and is under review at following sites: University of Cincinnati, Children's Healthcare of Atlanta, Children's Hospital of Los Angeles and Children's Mercy-Kansas City. Study results will be disseminated to participating individuals in a lay format and presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals.

Rethinking Congenital Heart Disease in Preterm Neonates.

Congenital heart disease (CHD) and prematurity are the leading causes of infant mortality in the United States. Importantly, the combination of prematurity and CHD results in a further increased risk of mortality and significant morbidity. The key factors in these adverse outcomes are not well understood, but likely include maternal-fetal environment, perinatal and neonatal elements, and challenging postnatal care. Preterm neonates with CHD are born with "double jeopardy": not only do they experience challenges related to immaturity of the lungs, brain, and other organs, but they also must undergo treatment for cardiac disease. The role of the neonatologist caring for preterm infants with CHD has changed with the evolution of the field of pediatric cardiac critical care. Increasingly, neonatologists invested in the cardiovascular care of the newborn with CHD engage at multiple stages in their course, including fetal consultation, delivery room management, preoperative care, and postoperative treatment. A more comprehensive understanding of prematurity and CHD may inform clinical practice and ultimately improve outcomes in preterm infants with CHD. In this review, we discuss the current evidence surrounding neonatal and cardiac outcomes in preterm infants with CHD; examine the prenatal, perinatal, and postnatal factors recognized to influence these outcomes; identify knowledge gaps; consider research and clinical opportunities; and highlight the ways in which a neonatologist can contribute to the care of preterm infants with CHD.

Delivery room oxygen physiology and respiratory interventions for newborns with cyanotic congenital heart disease.

OBJECTIVE: To characterize pulse oxygen saturation (SpO2) trajectories and respiratory interventions after birth for newborns with cyanotic congenital heart disease (CCHD). STUDY DESIGN: Retrospective single-site study of newborns ≥32 weeks gestation with CCHD: single ventricle with critical aortic obstruction (SV-CAO), critical pulmonic obstruction (CPO), transposition of the great arteries (TGA). Minute-to-minute SpO2 values and respiratory interventions were summarized and compared. RESULTS: Two hundred infants were enrolled. SpO2 at each minute differed across groups (p < 0.01), with the lowest values in TGA. All interventions were most frequent in TGA (p < 0.01). Continuous positive airway pressure was provided in 22% SV-CAO, 23% CPO, and 66% TGA. Positive pressure ventilation occurred in 7% SV-CAO, 14% CPO, and 33% TGA. Intubation occurred in 4% SV-CAO, 10% CPO, and 53% TGA. CONCLUSION: We defined SpO2 trajectories and delivery room respiratory interventions for three CCHD phenotypes. These results inform delivery room management of these high-risk populations.

Practical Tips for Implementing a Student-Led Reflective Writing Workshop Series.

Reflective practice may ameliorate the burnout, empathy loss, and depression that medical students experience during clerkships. We describe a student-led reflective writing workshop in a safe and structured small group setting. We provide twelve tips for implementing such a workshop, informed by the existing literature on reflective writing and near-peer teaching, which include developing writing prompts, guiding student facilitators, and obtaining feedback. Common topics include patient suffering, workplace dynamics, and the joys of practicing medicine. Participants develop camaraderie with peers as well as tools they can carry forward as they continue to process the challenging experiences intrinsic to clinical medicine.

Colitis induces enteric neurogenesis through a 5-HT4-dependent mechanism.

BACKGROUND: The intestine is known to contain enteric neuronal progenitors, but their precise identity and the mechanisms that activate them remain unknown. Based on the evidence for the neurogenic role of serotonin (5-HT) in the postnatal gut and the observation of enteric neuronal hyperplasia in inflammatory bowel disease, we hypothesized that colitis induces a neurogenic response through 5-HT4 receptor signaling. METHODS: We examined the effects of 5-HT4 agonism on colonic neurogenesis and gliogenesis in vitro and in vivo in adult mice using dextran sodium sulfate to experimentally induce colitis. RESULTS: In vitro, 5-HT4 agonism led to increased neuronal proliferation and density. Induction of experimental colitis in vivo similarly resulted in increased numbers of myenteric neurons, and this was inhibited by 5-HT4 antagonism. Interestingly, both in vitro and in vivo, 5-HT4 signaling increased glial cell proliferation but did not increase glial cell numbers, leading us to hypothesize that glia may give rise to neurons. After induction of colitis in normal, Nestin-GFP and Sox2-GFP transgenic mice, it was revealed that multiple glial markers (Sox2, Nestin, and CD49b) became strongly expressed by enteric neurons. Immunoselected enteric glia were found to give rise to neurons in culture, and this was inhibited in the presence of 5-HT4 blockade. Finally, isolated glia gave rise to a neuronal network upon transplantation into aganglionic embryonic avian hindgut. CONCLUSIONS: These results show that colitis promotes enteric neurogenesis in the adult colon through a serotonin-dependent mechanism that drives glial cells to transdifferentiate into neurons.

Altered goblet cell differentiation and surface mucus properties in Hirschsprung disease.

Hirschsprung disease-associated enterocolitis (HAEC) leads to significant mortality and morbidity, but its pathogenesis remains unknown. Changes in the colonic epithelium related to goblet cells and the luminal mucus layer have been postulated to play a key role. Here we show that the colonic epithelium of both aganglionic and ganglionic segments are altered in patients and in mice with Hirschsprung disease (HSCR). Structurally, goblet cells were altered with increased goblet cell number and reduced intracellular mucins in the distal colon of biopsies from patients with HSCR. Endothelin receptor B (Ednrb) mutant mice showed increased goblet cell number and size and increased cell proliferation compared to wild-type mice in aganglionic segments, and reduced goblet cell size and number in ganglionic segments. Functionally, compared to littermates, Ednrb-/- mice showed increased transepithelial resistance, reduced stool water content and similar chloride secretion in the distal colon. Transcript levels of goblet cell differentiation factors SPDEF and Math1 were increased in the distal colon of Ednrb-/- mice. Both distal colon from Ednrb mice and biopsies from HSCR patients showed reduced Muc4 expression as compared to controls, but similar expression of Muc2. Particle tracking studies showed that mucus from Ednrb-/- mice provided a more significant barrier to diffusion of 200 nm nanoparticles as compared to wild-type mice. These results suggest that aganglionosis is associated with increased goblet cell proliferation and differentiation and subsequent altered surface mucus properties, prior to the development of inflammation in the distal colon epithelium. Restoration of normal goblet cell function and mucus layer properties in the colonic epithelium may represent a therapeutic strategy for prevention of HAEC.