Building global collaborative research networks in paediatric critical care: a roadmap.

Paediatric critical care units are designed for children at a vulnerable stage of development, yet the evidence base for practice and policy in paediatric critical care remains scarce. In this Health Policy, we present a roadmap providing strategic guidance for international paediatric critical care trials. We convened a multidisciplinary group of 32 paediatric critical care experts from six continents representing paediatric critical care research networks and groups.

Association of Psychological Resilience, Cognitive Reserve, and Brain Reserve with Post-Concussive Symptoms in Children with Mild Traumatic Brain Injury and Orthopedic Injury: An A-CAP Study.

Protective factors, including psychological resilience, cognitive reserve, and brain reserve, may be positively associated with recovery after pediatric mild traumatic brain injury (mTBI) but are yet to be studied concurrently. We sought to examine these factors as moderators of post-concussive symptoms (PCS) in pediatric mTBI compared with mild orthopedic injury (OI). Participants included 967 children (633 mTBI, 334 OI) aged 8-16.

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy.

Do preinjury life events moderate the outcomes of mild traumatic brain injuries in children? An A-CAP Study.

Objective: To examine preinjury life events as moderators of postconcussive symptoms (PCS) and quality of life (QoL) in children with pediatric mild traumatic brain injury (mTBI) versus orthopedic injury (OI).

Methods: Participants were 633 children with mTBI and 334 with OI, ages 8-16.99, recruited from 5 pediatric emergency departments and followed for 6 months postinjury as part of a prospective cohort study.

Bisphosphonates in Glucocorticoid-Treated Patients With Duchenne Muscular Dystrophy: A Systematic Review and Grading of the Evidence.

Background And Objectives: Bisphosphonates are routinely used to treat osteoporosis in patients with Duchenne muscular dystrophy (DMD), a rare, severely debilitating neuromuscular disease. We sought to synthesize and grade benefits and harms evidence of bisphosphonates in glucocorticoid-treated patients with DMD.

Methods: In this systematic review (PROSPERO identifier: CRD42020157606), we searched MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, and CENTRAL for articles published from inception up to and including March 31, 2023, reporting results in any language from any study type.

Longitudinal Functional Connectome in Pediatric Concussion: An Advancing Concussion Assessment in Pediatrics Study.

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children.

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare germline missense variants in ; one identical variant was found in five individuals and another variant in two individuals.

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings.

NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice.

Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT.

Health Care Use, Costs, and Survival Trajectory of Home Mechanical Insufflation-Exsufflation.

Background: Despite expert recommendations for use, limited evidence identifies effectiveness of mechanical insufflation-exsufflation (MI-E) in addressing respiratory morbidity and resultant health care utilization and costs for individuals with neuromuscular disorders. We examined the impact of provision of publicly funded MI-E devices on health care utilization, health care costs, and survival trajectory.

Methods: This is a retrospective pre/post cohort study linking data on prospectively recruited participants using MI-E to health administrative databases to quantify outcomes.

Cutaneous granulomas as the presenting manifestation of Griscelli syndrome type 2.

Griscelli syndrome type 2 is a rare autosomal recessive disorder characterized by hypopigmentation, silvery hair, and immunological dysfunction with no primary neurological impairment. We report an 18-month-old girl with Griscelli syndrome type 2 who presented to the dermatology department for cutaneous granulomas that developed following live-attenuated vaccination. Two compound heterozygous variants in the RAB27A gene were subsequently identified.

Health-care practitioners' preferences for the return of secondary findings from next-generation sequencing: a discrete choice experiment.

Purpose: Health-care practitioners' (HCPs) preferences for returning secondary findings (SFs) will influence guideline compliance, shared decision-making, and patient health outcomes. This study aimed to estimate HCPs' preferences and willingness to support the return (WTSR) of SFs in Canada.

Methods: A discrete choice experiment estimated HCPs' preferences for the following attributes: disease risk, clinical utility, health consequences, prior experience, and patient preference.

Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.

Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency.

Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally.

Correction: Phenotate: crowdsourcing phenotype annotations as exercises in undergraduate classes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Characteristics of vomiting as a predictor of intracranial injury in pediatric minor head injury.

Objectives: Vomiting is common in children after minor head injury. In previous research, isolated vomiting was not a significant predictor of intracranial injury after minor head injury; however, the significance of recurrent vomiting is unclear. This study aimed to determine the value of recurrent vomiting in predicting intracranial injury after pediatric minor head injury.

Phenotate: crowdsourcing phenotype annotations as exercises in undergraduate classes.

Purpose: Computational documentation of genetic disorders is highly reliant on structured data for differential diagnosis, pathogenic variant identification, and patient matchmaking. However, most information on rare diseases (RDs) exists in freeform text, such as academic literature. To increase availability of structured RD data, we developed a crowdsourcing approach for collecting phenotype information using student assignments.

Fluid Biomarkers of Pediatric Mild Traumatic Brain Injury: A Systematic Review.

Public concern is growing about the short- and long-term effects of pediatric mild traumatic brain injury (mTBI). This concern is amplified because pediatric mTBI has the potential to go undiagnosed in acute care settings, placing children at increased risk for reinjury prior to complete recovery. The management of mTBI can be particularly challenging due to the lack of validated biomarkers that clinicians can use to objectively diagnose pediatric mTBI, predict risk for prolonged recovery, or demonstrate mTBI recovery.

De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism.

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 - A Prospective Observational Study.

Objective: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3.

Methods: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3.

Trends in incidence, prevalence, and mortality of neuromuscular disease in Ontario, Canada: A population-based retrospective cohort study (2003-2014).

Background: Population trends of disease prevalence and incidence over time measure burden of disease and inform healthcare planning. Neuromuscular disorders (NMD) affect muscle and nerve function with varying degrees of severity and disease progression.

Objective: Using health administrative databases we described trends in incidence, prevalence, and mortality of adults and children with NMD.

genotype explains 20% of phenotypic variability in GNE myopathy.

Objective: To test the hypothesis that common mutations influence disease severity; using statistical analysis of patient cohorts from different countries.

Methods: Systematic literature review identified 11 articles reporting 759 patients. GNE registry data were used as a second data set.

Validation and refinement of a clinical decision rule for the use of computed tomography in children with minor head injury in the emergency department.

Background: There is uncertainty about which children with minor head injury need to undergo computed tomography (CT). We sought to prospectively validate the accuracy and potential for refinement of a previously derived decision rule, Canadian Assessment of Tomography for Childhood Head injury (CATCH), to guide CT use in children with minor head injury.

Methods: This multicentre cohort study in 9 Canadian pediatric emergency departments prospectively enrolled children with blunt head trauma presenting with a Glasgow Coma Scale score of 13-15 and loss of consciousness, amnesia, disorientation, persistent vomiting or irritability.

The Benefits and Challenges of Involving Adolescents in Medical Education: A Qualitative Study.

Objective: To explore the potential benefits and challenges of involving adolescents in the education of medical students and residents from the perspectives of adolescents who are hospitalized with chronic health conditions.

Methods: We conducted qualitative interviews with adolescents at a Canadian pediatric hospital. Eligible participants were those between 13 and 18 years of age who had chronic health conditions lasting more than 3 months and were feeling well enough to participate in an interview.