Distinct microglial transcriptomic signatures within the hippocampus.

Microglia, the resident immune cells of the brain, are crucial in the development of the nervous system. Recent evidence demonstrates that microglia modulate adult hippocampal neurogenesis by inhibiting cell proliferation of neural precursors and survival both in vitro and in vivo, thus maintaining a balance between cell division and cell death in the neural stem cell pool. There are increasing reports suggesting these microglia found in neurogenic niches differ from their counterparts in non-neurogenic areas. Here, we present evidence that hippocampal microglia exhibit transcriptomic heterogeneity, with some cells expressing genes associated with neurogenesis. By comprehensively profiling myeloid lineage cells in the hippocampus using single cell RNA-sequencing, we have uncovered a small, yet distinct population of microglia which exhibit depletion in genes associated with homeostatic microglia and enrichment of genes associated with phagocytosis. Intriguingly, this population also expresses a gene signature with substantial overlap with previously characterized phenotypes, including disease associated microglia (DAM), a particularly unique and compelling microglial state.

Delphi Process for Validation of Fluid Treatment Algorithm for Critically Ill Pediatric Trauma Patients.

INTRODUCTION: While intravenous fluid therapy is essential to re-establishing volume status in children who have experienced trauma, aggressive resuscitation can lead to various complications. There remains a lack of consensus on whether pediatric trauma patients will benefit from a liberal or restrictive crystalloid resuscitation approach and how to optimally identify and transition between fluid phases. METHODS: A panel was comprised of physicians with expertise in pediatric trauma, critical care, and emergency medicine. A three-round Delphi process was conducted via an online survey, with each round being followed by a live video conference. Experts agreed or disagreed with each aspect of the proposed fluid management algorithm on a five-level Likert scale. The group opinion level defined an algorithm parameter's acceptance or rejection with greater than 75% agreement resulting in acceptance and greater than 50% disagreement resulting in rejection. The remaining were discussed and re-presented in the next round. RESULTS: Fourteen experts from five Level 1 pediatric trauma centers representing three subspecialties were included. Responses were received from 13/14 participants (93%). In round 1, 64% of the parameters were accepted, while the remaining 36% were discussed and re-presented. In round 2, 90% of the parameters were accepted. Following round 3, there was 100% acceptance by all the experts on the revised and final version of the algorithm. CONCLUSIONS: We present a validated algorithm for intavenous fluid management in pediatric trauma patients that focuses on the de-escalation of fluids. Focusing on this time point of fluid therapy will help minimize iatrogenic complications of crystalloid fluids within this patient population.

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

BACKGROUND: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized ArcCreERT2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

Characterization of the responses of brain macrophages to focused ultrasound-mediated blood-brain barrier opening.

The opening of the blood-brain barrier (BBB) by focused ultrasound (FUS) coupled with intravenously injected microbubbles can be leveraged as a form of immunotherapy for the treatment of neurodegenerative disorders. However, how FUS BBB opening affects brain macrophages is not well understood. Here by using single-cell sequencing to characterize the distinct responses of microglia and central nervous system-associated macrophages (CAMs) to FUS-mediated BBB opening in mice, we show that the treatment remodels the immune landscape via the recruitment of CAMs and the proliferation of microglia and via population size increases in disease-associated microglia. Both microglia and CAMs showed early and late increases in population sizes, yet only the proliferation of microglia increased at both timepoints. The population of disease-associated microglia also increased, accompanied by the upregulation of genes associated with gliogenesis and phagocytosis, with the depletion of brain macrophages significantly decreasing the duration of BBB opening.

Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by ( R,S )-ketamine.

INTRODUCTION: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized the ArcCreER T2 x enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact (CCI) model of TBI. Mice were then administered a contextual fear discrimination (CFD) paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if ( R,S )-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the DG, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, ( R,S )-ketamine facilitated fear discrimination and this behavioral improvement was reflected in DG memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces, and that this deficit can be improved with a single injection of ( R,S )-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

Building consensus for the medical management of children with moderate and severe acute spinal cord injury: a modified Delphi study.

OBJECTIVE: The focus of this modified Delphi study was to investigate and build consensus regarding the medical management of children with moderate and severe acute spinal cord injury (SCI) during their initial inpatient hospitalization. This impetus for the study was based on the AANS/CNS guidelines for pediatric SCI published in 2013, which indicated that there was no consensus provided in the literature describing the medical management of pediatric patients with SCIs. METHODS: An international, multidisciplinary group of 19 physicians, including pediatric neurosurgeons, orthopedic surgeons, and intensivists, were asked to participate. The authors chose to include both complete and incomplete injuries with traumatic as well as iatrogenic etiologies (e.g., spinal deformity surgery, spinal traction, intradural spinal surgery, etc.) due to the overall low incidence of pediatric SCI, potentially similar pathophysiology, and scarce literature exploring whether different etiologies of SCI should be managed differently. An initial survey of current practices was administered, and based on the responses, a follow-up survey of potential consensus statements was distributed. Consensus was defined as ≥ 80% of participants reaching agreement on a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree). A final meeting was held virtually to generate final consensus statements. RESULTS: Following the final Delphi round, 35 statements reached consensus after modification and consolidation of previous statements. Statements were categorized into the following eight sections: inpatient care unit, spinal immobilization, pharmacological management, cardiopulmonary management, venous thromboembolism prophylaxis, genitourinary management, gastrointestinal/nutritional management, and pressure ulcer prophylaxis. All participants stated that they would be willing or somewhat willing to change their practices based on consensus guidelines. CONCLUSIONS: General management strategies were similar for both iatrogenic (e.g., spinal deformity, traction, etc.) and traumatic SCIs. Steroids were recommended only for injury after intradural surgery, not after acute traumatic or iatrogenic extradural surgery. Consensus was reached that mean arterial pressure ranges are preferred for blood pressure targets following SCI, with goals between 80 and 90 mm Hg for children at least 6 years of age. Further multicenter study of steroid use following acute neuromonitoring changes was recommended.

Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-ß as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.

Risk Variants in the Exomes of Children With Critical Illness.

Importance: Diagnostic genetic testing can lead to changes in management in the pediatric intensive care unit. Genetic risk in children with critical illness but nondiagnostic exome sequencing (ES) has not been explored. Objective: To assess the association between loss-of-function (LOF) variants and pediatric critical illness. Design, Setting, and Participants: This genetic association study examined ES first screened for causative variants among 267 children at the Morgan Stanley Children's Hospital of NewYork-Presbyterian, of whom 22 were otherwise healthy with viral respiratory failure; 18 deceased children with bronchiolitis from the Office of the Chief Medical Examiner of New York City, of whom 14 were previously healthy; and 9990 controls from the Institute for Genomic Medicine at Columbia University Irving Medical Center. The ES data were generated between January 1, 2015, and December 31, 2020, and analyzed between January 1, 2017, and September 2, 2022. Exposure: Critical illness. Main Outcomes and Measures: Odds ratios and P values for genes and gene-sets enriched for rare LOF variants and the loss-of-function observed/expected upper bound fraction (LOEUF) score at which cases have a significant enrichment. Results: This study included 285 children with critical illness (median [range] age, 4.1 [0-18.9] years; 148 [52%] male) and 9990 controls. A total of 228 children (80%) did not receive a genetic diagnosis. After quality control (QC), 231 children harbored excess rare LOF variants in genes with a LOEUF score of 0.680 or less (intolerant genes) (P = 1.0 × 10-5). After QC, 176 children without a diagnosis harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 1.8; 95% CI, 1.3-2.5). After QC, 25 children with viral respiratory failure harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 2.8; 95% CI, 1.1-6.6). A total of 114 undiagnosed children were enriched for de novo LOF variants in genes without a known disease association (observed, 14; expected, 6.8; enrichment, 2.05). Conclusions and Relevance: In this genetic association study, excess LOF variants were observed among critically ill children despite nondiagnostic ES. Variants lay in genes without a known disease association, suggesting future investigation may connect phenotypes to causative genes.

A Single-Centered Randomized Controlled Trial of Primary Pediatric Intensivists and Nurses.

Background: For long-stay patients (LSP) in pediatric intensive care units (PICU), frequently rotating providers can lead to ineffective information sharing and retention, varying goals and timelines, and delayed decisions, likely contributing to prolonged admissions. Primary intensivists (one physician serves as a consistent resource for the patient/family and PICU providers) and primary nurses (a small team of PICU nurses provide consistent bedside care) seek to augment usual transitory PICU care, by enhancing continuity and, potentially, decreasing length of stay (LOS). Methods: A single-centered, partially blinded randomized controlled trial of primary intensivists and nurses versus usual care. PICU patients admitted for or expected to be admitted for >10 days and who had ≥1 complex chronic condition were eligible. A block randomization with 1:1 allocation was used. The primary outcome was PICU LOS. Multiple secondary outcomes were explored. Results: Two hundred LSPs were randomized-half to receive primaries and half to usual care. The two groups were not significantly different in their baseline and admission characteristics. LSPs randomized to receive primaries had a shorter, but non-significant, mean LOS than those randomized to usual care (32.5 vs. 37.1 days, respectively, p = .19). Compared to LSPs in the usual care group, LSPs in the primary group had fewer unplanned intubations. Among LSPs that died, DNR orders were more prevalent in the primary group. Other secondary outcome and balance metrics were not significantly different between the two groups. Conclusion: Primary intensivists and nurses may be an effective strategy to counteract transitory PICU care and serve the distinctive needs of LSPs. However, additional studies are needed to determine the ways and to what extent they may accomplish this.

Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice.

Polymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer's disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we generated a conditional knockout system whereby functional ApoE from astrocytes was ablated prior to injury. While successfully ablating ApoE just prior to TBI in mice, we observed an attenuation in the development of the spines in the newborn neurons. Intriguingly, animals with a double-hit, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury.

Multisystem Inflammatory Syndrome in Children Associated With Coronavirus Disease 2019 in a Children's Hospital in New York City: Patient Characteristics and an Institutional Protocol for Evaluation, Management, and Follow-Up.

OBJECTIVES: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome. DATA SOURCES: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods. DATA SYNTHESIS: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay. CONCLUSIONS: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

A Hybrid Model of Pediatric and Adult Critical Care During the Coronavirus Disease 2019 Surge: The Experience of Two Tertiary Hospitals in London and New York.

OBJECTIVES: The current novel severe acute respiratory syndrome coronavirus 2 outbreak has caused an unprecedented demand on global adult critical care services. As adult patients have been disproportionately affected by the coronavirus disease 2019 pandemic, pediatric practitioners world-wide have stepped forward to support their adult colleagues. In general, standalone pediatric hospitals expanded their capacity to centralize pediatric critical care, decanting patients from other institutions. There are few units that ran a hybrid model, managing both adult and pediatric patients with the same PICU staff. In this report, we describe the hybrid model implemented at our respective institutions with shared experiences, pitfalls, challenges, and adjustments required in caring for both young and older patients. DESIGN: Retrospective cohort study. SETTING: Two PICUs in urban tertiary hospitals in London and New York. PATIENTS: Adult and pediatric patients admitted to the PICU in roughly a 6-week period during the coronavirus disease 2019 surge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The PICU at King's College Hospital admitted 23 non-coronavirus disease adult patients, while whereas the PICU at Morgan Stanley's Children Hospital in New York admitted 46 adults, 30 of whom were coronavirus disease positive. The median age of adult patients at King's College Hospital was higher than those admitted in New York, 53 years (19-77 yr) and 24.4 years (18-52 yr), respectively. Catering to the different physical, emotional, and social needs of both children and adults by the same PICU team was challenging. One important consideration in both locations was the continued care of patients with severe non-coronavirus disease-related illnesses such as neurosurgical emergencies, trauma, and septic shock. Furthermore, retention of critical specialists such as transplant services allowed for nine and four solid organ transplants to occur in London and New York, respectively. CONCLUSIONS: This hybrid model successfully allowed for the expansion into adult critical care while maintaining essential services for critically ill children. Simultaneous care of adults and children in the ICU can be sustained if healthcare professionals work collaboratively, show proactive insight into anticipated issues, and exhibit clear leadership.

Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children's Hospital in New York City, New York.

Importance: Descriptions of the coronavirus disease 2019 (COVID-19) experience in pediatrics will help inform clinical practices and infection prevention and control for pediatric facilities. Objective: To describe the epidemiology, clinical, and laboratory features of patients with COVID-19 hospitalized at a children's hospital and to compare these parameters between patients hospitalized with and without severe disease. Design, Setting, and Participants: This retrospective review of electronic medical records from a tertiary care academically affiliated children's hospital in New York City, New York, included hospitalized children and adolescents (≤21 years) who were tested based on suspicion for COVID-19 between March 1 to April 15, 2020, and had positive results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exposures: Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription-polymerase chain reaction assay. Main Outcomes and Measures: Severe disease as defined by the requirement for mechanical ventilation. Results: Among 50 patients, 27 (54%) were boys and 25 (50%) were Hispanic. The median days from onset of symptoms to admission was 2 days (interquartile range, 1-5 days). Most patients (40 [80%]) had fever or respiratory symptoms (32 [64%]), but 3 patients (6%) with only gastrointestinal tract presentations were identified. Obesity (11 [22%]) was the most prevalent comorbidity. Respiratory support was required for 16 patients (32%), including 9 patients (18%) who required mechanical ventilation. One patient (2%) died. None of 14 infants and 1 of 8 immunocompromised patients had severe disease. Obesity was significantly associated with mechanical ventilation in children 2 years or older (6 of 9 [67%] vs 5 of 25 [20%]; P = .03). Lymphopenia was commonly observed at admission (36 [72%]) but did not differ significantly between those with and without severe disease. Those with severe disease had significantly higher C-reactive protein (median, 8.978 mg/dL [to convert to milligrams per liter, multiply by 10] vs 0.64 mg/dL) and procalcitonin levels (median, 0.31 ng/mL vs 0.17 ng/mL) at admission (P < .001), as well as elevated peak interleukin 6, ferritin, and D-dimer levels during hospitalization. Hydroxychloroquine was administered to 15 patients (30%) but could not be completed for 3. Prolonged test positivity (maximum of 27 days) was observed in 4 patients (8%). Conclusions and Relevance: In this case series study of children and adolescents hospitalized with COVID-19, the disease had diverse manifestations. Infants and immunocompromised patients were not at increased risk of severe disease. Obesity was significantly associated with disease severity. Elevated inflammatory markers were seen in those with severe disease.

Sparse Activity of Hippocampal Adult-Born Neurons during REM Sleep Is Necessary for Memory Consolidation.

The occurrence of dreaming during rapid eye movement (REM) sleep prompts interest in the role of REM sleep in hippocampal-dependent episodic memory. Within the mammalian hippocampus, the dentate gyrus (DG) has the unique characteristic of exhibiting neurogenesis persisting into adulthood. Despite their small numbers and sparse activity, adult-born neurons (ABNs) in the DG play critical roles in memory; however, their memory function during sleep is unknown. Here, we investigate whether young ABN activity contributes to memory consolidation during sleep using Ca2+ imaging in freely moving mice. We found that contextual fear learning recruits a population of young ABNs that are reactivated during subsequent REM sleep against a backdrop of overall reduced ABN activity. Optogenetic silencing of this sparse ABN activity during REM sleep alters the structural remodeling of spines on ABN dendrites and impairs memory consolidation. These findings provide a causal link between ABN activity during REM sleep and memory consolidation.

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury.

Various brain injuries lead to the activation of adult neural stem/progenitor cells in the mammalian hippocampus. Subsequent injury-induced neurogenesis appears to be essential for at least some aspects of the innate recovery in cognitive function observed following traumatic brain injury (TBI). It has previously been established that Apolipoprotein E (ApoE) plays a regulatory role in adult hippocampal neurogenesis, which is of particular interest as the presence of the human ApoE isoform ApoE4 leads to significant risk for the development of late-onset Alzheimer's disease, where impaired neurogenesis has been linked with disease progression. Moreover, genetically modified mice lacking ApoE or expressing the ApoE4 human isoform have been shown to impair adult hippocampal neurogenesis under normal conditions. Here, we investigate how controlled cortical impact (CCI) injury affects dentate gyrus development using hippocampal stereotactic injections of GFP-expressing retroviruses in wild-type (WT), ApoE-deficient and humanized (ApoE3 and ApoE4) mice. Infected adult-born hippocampal neurons were morphologically analyzed once fully mature, revealing significant attenuation of dendritic complexity and spine density in mice lacking ApoE or expressing the human ApoE4 allele, which may help inform how ApoE influences neurological diseases where neurogenesis is defective.

Rapid exome sequencing in PICU patients with new-onset metabolic or neurological disorders.

BACKGROUND: Genomic assessment previously took months to result and was unable to impact clinical care in the pediatric intensive care unit (PICU). The advent of rapid exome sequencing potentially changes this. We investigated the impact of rapid exome sequencing in a pilot study on pediatric patients admitted to a single PICU with new-onset metabolic/neurologic disease. METHODS: Rapid exome sequencing (7 days to verbal result) was performed on (n = 10) PICU patients age < 6 years admitted with new-onset metabolic/neurologic disease. The primary outcome of interest was inpatient LOS, which served as a proxy for inpatient cost. RESULTS: A significant reduction in median LOS was identified when comparing PICU patients who underwent rapid exome sequencing to historical controls. From those patients who underwent rapid sequencing, five had likely pathogenic variants. In three cases with diagnostic genetic results, there was a modification to clinical care attributable to information provided by exome sequencing. CONCLUSIONS: This pilot study demonstrates that rapid exome sequencing is feasible to do in the PICU, that genetic results can be returned quickly enough to impact critical care decision-making and management. In a select population of PICU patients, this technology may contribute to a decrease in hospital length of stay. IMPACT: Ten prospectively enrolled PICU patients with defined clinical criteria and their parents underwent rapid exome sequencing. Fifty percent received a genetic diagnosis, and medical management was affected for 60% of those patients. Median hospital LOS was significantly decreased in this selective subset of PICU patients. Genetic disorders and congenital anomalies are a leading cause of pediatric mortality. Genomic assessment previously took weeks to months for results and was therefore unable to acutely impact clinical care in the pediatric intensive care unit (PICU). The recent advent of rapid exome sequencing changes this in selected patients. Rapid exome sequencing is feasible to do in a PICU. Genetic results can be returned quickly enough to impact critical care decision-making. When done in a carefully selected subset of pediatric patients, rapid exome sequencing can potentially decrease hospital LOS.

Child Abuse Taking Its Toll on the Emotional Well-Being of Pediatricians.

Pediatricians caring for patients with child abuse or neglect (CABN) may experience secondary traumatic stress (STS) from traumatized patients, or burnout (BO) from workplace stress. This may be buffered by compassion satisfaction (CS), positive meaning from one's work. For this study, STS, BO, and CS specific to a pediatrician's care of CABN were assessed for residents, hospitalists, intensivists, and outpatient physicians. Using the Professional Quality of Life Scale modified for CABN experiences, participants (n = 62) had a mean STS score at the 84th percentile, a mean BO score at the 66th percentile, and a mean CS score at the 17th percentile. Reporting one CABN patient as most emotionally impactful predicted STS, caring for all types of CABN predicted BO, and perceived knowledge no longer predicted CS when adjusting for the experience of mandated reporting or CABN fatality. These results highlight the need to support pediatricians involved with CABN.

Immune Regulation of Adult Neurogenic Niches in Health and Disease.

Microglia regulate neuronal development during embryogenesis, postnatal development, and in specialized microenvironments of the adult brain. Recent evidence demonstrates that in adulthood, microglia secrete factors which modulate adult hippocampal neurogenesis by inhibiting cell proliferation and survival both in vitro and in vivo, maintaining a balance between cell division and cell death in neurogenic niches. These resident immune cells also shape the nervous system by actively pruning synapses during critical periods of learning and engulfing excess neurons. In neurodegenerative diseases, aberrant microglial activity can impede the proper formation and prevent the development of appropriate functional properties of adult born granule cells. Ablating microglia has been presented as a promising therapeutic approach to alleviate the brain of maladaptive immune response. Here, we review key mechanisms through which the immune system actively shapes neurogenic niches throughout the lifespan of the mammalian brain in both health and disease. We discuss how interactions between immune cells and developing neurons may be leveraged for pharmacological intervention and as a means to preserve adult neurogenesis.