Saturation variant interpretation using CRISPR prime editing.

High-throughput functional characterization of genetic variants in their endogenous locus has so far been possible only with methods that rely on homology-directed repair, which are limited by low editing efficiencies. Here, we adapted CRISPR prime editing for high-throughput variant classification and combined it with a strategy that allows for haploidization of any locus, which simplifies variant interpretation. We demonstrate the utility of saturation prime editing (SPE) by applying it to the NPC intracellular cholesterol transporter 1 gene (NPC1), mutations in which cause the lysosomal storage disorder Niemann-Pick disease type C.

Humility in medical practice: a qualitative study of peer-nominated excellent clinicians.

Background: Humility has recently been conceptualized as a positive, multifaceted attribute in fields outside of medicine, such as psychology and philosophy. In medicine, there has been limited study into the nature of humility and its role in clinical practice. We sought to develop a deeper understanding of humility in medical practice through the lived-experiences of peer-nominated excellent clinicians.

Assessing global developmental delay across instruments in minimally verbal preschool autistic children: The importance of a multi-method and multi-informant approach.

Intellectual assessment in preschool autistic children bears many challenges, particularly for those who have lower language and/or cognitive abilities. These challenges often result in underestimation of their potential or exclusion from research studies. Understanding how different instruments and definitions used to identify autistic preschool children with global developmental delay (GDD) affect sample composition is critical to advance research on this understudied clinical population.

Development and Implementation of a Pilot Integrative Day Hospital Program for Youth with Severe Obesity and Mental Health Issues.

Adolescents with severe obesity and comorbid mental health issues are the most resistant to traditional weight management approaches and have poor treatment outcomes. Our objective was to implement and evaluate a pilot day hospital treatment program for adolescents with severe obesity, or risk for severe obesity, and significant mental health comorbidities. This was a prospective cohort study of adolescents 12-18 years of age with severe obesity (BMI >99th percentile), or at risk for severe obesity, and comorbid mental health issues.

The dimensions of white matter injury in preterm neonates.

White matter injury (WMI) represents a frequent form of parenchymal brain injury in preterm neonates. Several dimensions of WMI are recognized, with distinct neuropathologic features involving a combination of destructive and maturational anomalies. Hypoxia-ischemia is the main mechanism leading to WMI and adverse white matter development, which result from injury to the oligodendrocyte precursor cells.

Predictors of Invasive Herpes Simplex Virus Infection in Young Infants.

Objectives: To identify independent predictors of and derive a risk score for invasive herpes simplex virus (HSV) infection.

Methods: In this 23-center nested case-control study, we matched 149 infants with HSV to 1340 controls; all were ≤60 days old and had cerebrospinal fluid obtained within 24 hours of presentation or had HSV detected. The primary and secondary outcomes were invasive (disseminated or central nervous system) or any HSV infection, respectively.

Higher concentrations of vitamin D in Canadian children with juvenile idiopathic arthritis compared to healthy controls are associated with more frequent use of vitamin D supplements and season of birth.

A number of studies have demonstrated that patients with autoimmune disease have lower levels of vitamin D prompting speculation that vitamin D might suppress inflammation and immune responses in children with juvenile idiopathic arthritis (JIA).  The objective of this study was to compare vitamin D levels in children with JIA at disease onset with healthy children. We hypothesized that children and adolescents with JIA have lower vitamin D levels than healthy children and adolescents.

Effects of Maternal Vitamin D Supplementation During Pregnancy and Lactation on Infant Acute Respiratory Infections: Follow-up of a Randomized Trial in Bangladesh.

Background: We examined the effect of maternal vitamin D supplementation during pregnancy and lactation on risk of acute respiratory infection (ARI) in infants up to 6 months of age in Bangladesh.

Methods: This study was nested in a randomized, double-blind, placebo-controlled, 5-arm dose-ranging trial of prenatal and postpartum vitamin D supplementation. One group of women received 0 IU vitamin D per week during pregnancy and for 26 weeks post delivery ("placebo" group), one group received high-dose prenatal vitamin D supplementation of 28 000 IU per week and 26 weeks post delivery, and there were 3 additional dose-ranging groups receiving vitamin D supplementation during pregnancy only (4200, 16 800, and 28 000 IU per week, respectively).

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

Background: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).

Methods: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included.

American College of Rheumatology Guidance for the Management of Pediatric Rheumatic Disease During the COVID-19 Pandemic: Version 2.

Objective: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic.

Methods: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD.

Retention of Critical Procedural Skills After Simulation Training: A Systematic Review.

Objective: While short-term gains in performance of critical emergency procedures are demonstrated after simulation, long-term retention is relatively uncertain. Our objective was to determine whether simulation of critical emergency procedures promotes long-term retention of skills in nonsurgical physicians.

Methods: We searched multiple electronic databases using a peer-reviewed strategy.

Pain Reported by Chinese Children During Cancer Treatment: Prevalence, Intensity, Interference, and Management.

Background: Pain is a frequently reported and distressing symptoms during cancer treatment. However, there is limited evidence on pain reported by Chinese children with cancer.

Objectives: This study aimed to investigate the prevalence, intensity, interference, and management of pain reported by Chinese children during cancer treatment and explore the predictors of pain interference.

Morbidity in Late Preterm Birth: A Retrospective Cohort Study Assessing the Role of Immaturity versus Antecedent Factors.

Introduction: Late preterm infants (LPIs) are infants born between 340/7 and 366/7 weeks gestation. Morbidities in these infants are commonly considered a result of prematurity; however, some research has suggested immaturity may not be the sole cause of morbidities. We hypothesize that antecedents leading to late preterm birth are associated with different patterns of morbidities and that morbidities are the result of gestational age superimposed by the underlying etiologies of preterm delivery.

Haemodynamics and cerebral oxygenation of neonatal piglets in the immediate ex utero period supported by mechanical ventilation or ex utero oxygenator.

Key Points: The margin of human viability has extended to the extremes of gestational age (<24 weeks) when the lungs are immature and ventilator-induced lung injury is common. Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air-breathing environment. We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post-oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT).

Is social camouflaging associated with anxiety and depression in autistic adults?

Background: There is inconsistent evidence for a clear pattern of association between 'camouflaging' (strategies used to mask and/or compensate for autism characteristics during social interactions) and mental health.

Methods: This study explored the relationship between self-reported camouflaging and generalised anxiety, depression, and social anxiety in a large sample of autistic adults and, for the first time, explored the moderating effect of gender, in an online survey.

Results: Overall, camouflaging was associated with greater symptoms of generalised anxiety, depression, and social anxiety, although only to a small extent beyond the contribution of autistic traits and age.

Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency.

Hyperargininemia in patients with arginase 1 deficiency (ARG1-D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1-D patients (n = 16) from a Phase 1/2 study (101A) and the first 12 weeks of an open-label extension study (102A).

Examining volumetric gradients based on the frustum surface ratio in the brain in autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is accompanied by neurodevelopmental differences in regional cortical volume (CV), and a potential layer-specific pathology. Conventional measures of CV, however, do not indicate how volume is distributed across cortical layers. In a sample of 92 typically developing (TD) controls and 92 adult individuals with ASD (aged 18-52 years), we examined volumetric gradients by quantifying the degree to which CV is weighted from the pial to the white surface of the brain.