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Objectives: (1) To quantify hospital-level variation in use of neuroimaging to screen for intracranial injury (ICI) among infants without overt signs or symptoms of head trauma undergoing subspecialty evaluations for physical abuse; (2) to assess for disproportionality in neuroimaging based on race/ethnicity and insurance type., Methods: This was a cross-sectional study of infants age <12 months receiving subspecialty child abuse evaluations from 02/2021 - 12/2022 at 10 sites in CAPNET, a multicenter child abuse research network. Infants were included if they underwent a skeletal survey and lacked overt signs of possible ICI or blunt head injury. Outcome was completion of neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]). Multivariable logistic regression was used to assess associations between demographic, clinical, and hospital factors with neuroimaging use., Results: Of 1,114 infants, 746 (67%) underwent neuroimaging ranging from 51% to 80% across CAPNET hospitals. In multivariable analysis, young age, presence of rib fracture(s), and site had significant associations with neuroimaging. Insurance type and race/ethnicity did not contribute significantly to the model. After adjustment for case-mix, there was significant variation across hospitals, with neuroimaging use ranging from 51% (95% CI: 43%, 59%) to 79% (95% CI 71%, 88%) CONCLUSION: We identified significant variation in neuroimaging use across CAPNET hospitals, highlighting the need for guideline development and care standardization during the care of infants undergoing abuse evaluations., Competing Interests: Declaration of Competing Interest Dr. Berger, Dr. Brink, Dr. Campbell, Dr. Harper, Dr. Henry, Dr. Frasier, Dr. Melville, and Dr. Wood have provided testimony in cases with concern for child physical abuse for which their institutions received payment. Dr. Lindberg and Dr. Frasier have provided paid expert witness testimony in cases with concern for child physical abuse., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Childhood asthma is characterized by pervasive disparities, including 3-fold higher hospitalization rates and 7-fold higher death rates for Black children compared with White children. To address asthma disparities, one must intervene in all lived environments., Objective: To determine if a community health worker (CHW) intervention to connect the primary care, home, and school for low-income minoritized school-aged children with asthma and their caregivers improves asthma control., Design, Setting, and Participants: This study was a hybrid effectiveness/implementation trial using a 2 × 2 factorial, cluster randomized clinical trial design of 36 schools crossed with participant-level randomization into a clinic-based CHW intervention. The study was conducted from May 2018 to June 2022. The intervention took place in primary care offices, homes, and 36 West Philadelphia, Pennsylvania, public and charter schools. Children aged 5 to 13 years with uncontrolled asthma were recruited from local primary care practices., Interventions: Asthma management, trigger remediation, and care coordination occurred in school, home, and primary care settings. Children were followed up for 12 months. The Yes We Can Children's Asthma Program, Open Airways For Schools Plus, and school-based asthma therapy were implemented., Main Outcomes and Measures: Improvement in asthma control, as measured by the Asthma Control Questionnaire, comparing the mean difference between groups 1 year after randomization with their baseline (difference in differences). Both primary care and school interventions were dramatically disrupted by the COVID-19 pandemic; therefore, stratified analyses were performed to assess per-protocol intervention efficacy before the pandemic disruptions., Results: A total of 1875 participants were approached, 1248 were excluded, and 1 was withdrawn. The 626 analyzed study participants (mean [SD] age, 8.7 [2.4] years; 363 male [58%]) self-identified as Black race (96%) and non-Hispanic ethnicity (98%). Although all groups had statistically significant improvements in asthma control from baseline to 12 months (P- group: -0.46; 95% CI, -0.58 to -0.33; P+ group: -0.57; 95% CI, -0.74 to -0.44; S- group: -0.47; 95% CI, -0.58 to -0.35; S+ group: -0.59; 95% CI, -0.74 to -0.44), none of the difference-in-differences estimates from the primary prespecified models showed a clinically meaningful improvement in asthma control. Analysis from the prepandemic interval, however, demonstrated that children in the combined clinic-school intervention had a statistically significant improvement in asthma control scores compared with control (-0.79; 95% CI, -1.40 to -0.18)., Conclusions and Relevance: This randomized clinical trial provides preliminary evidence that connecting all lived environments for care of children can be accomplished through linkages with CHWs.

Objective: Aicardi Goutières Syndrome (AGS) is a rare genetic interferonopathy associated with diverse multisystemic complications. A critical gap exists in our understanding of its longitudinal, systemic disease burden, complicated by delayed diagnosis. To address this need, real-world data extracted from existing medical records were used to characterize the longitudinal disease burden., Methods: All subjects (n = 167) with genetically confirmed AGS enrolled in the Myelin Disorders Biorepository Project (MDBP) were included. As available in medical records, information was collected on subject demographics, age of onset, and disease complications. Information from published cases of AGS (2007-2022; n = 129) with individual-level data was also collected. Neurologic severity at the last available encounter was determined by retrospectively assigning the AGS Severity Scale [severe (0-3), moderate (4-8), and mild (9-11)]., Results: The genotype frequency in the natural history cohort was TREX1 (n = 26, 15.6 %), RNASEH2B (n = 50, 29.9 %), RNASEH2C (n = 3, 1.8 %), RNASEH2A (n = 7, 4.2 %), SAMHD1 (n = 25, 15.0 %), ADAR (n = 34, 20.4 %), IFIH1 (n = 19, 11.4 %), and RNU7-1 (n = 3, 1.8 %). The median age of systemic onset was 0.15 years [IQR = 0.67 years; median range by genotype: 0 (TREX1) - 0.62 (ADAR) years], while the median neurological onset was 0.33 years [IQR = 0.82 years; median range by genotype: 0.08 (TREX1) - 0.90 (ADAR) year]. The most common early systemic complications were gastrointestinal, including dysphagia or feeding intolerance (n = 124) and liver abnormalities (n = 67). Among postnatal complications, thrombocytopenia appeared earliest (n = 29, median 0.06 years). Tone abnormalities (axial hypotonia: n = 145, 86.8 %; dystonia: n = 123, 73.7 %), irritability (n = 115, 68.9 %), and gross motor delay (n = 112, 7.1 %) emerged as the most prevalent neurological symptoms. Previously published case reports demonstrated similar patterns. The median AGS score for the entire cohort was 4 (IQR = 7). The most severe neurologic phenotype occurred in TREX1-related AGS (n = 19, median AGS severity score 2, IQR = 2). Time to feeding tube placement, chilblains, early gross motor delay, early cognitive delay, and motor regression were significantly associated with genotype (Fleming-Harrington log-rank: p = 0.0002, p < 0.0001, p = 0.0038, p < 0.0001, p = 0.0001, respectively). Microcephaly, feeding tube placement, and seizures were associated with lower AGS scores (All: Wilcoxon rank sum test, p < 0.0001). Among the qualifying case reports (n = 129), tone abnormalities were the most prevalent disease feature, with spastic quadriplegia reported in 37 of 96 cases (38.5 %) and dystonia in 30 of 96 cases (31.2 %)., Conclusions: AGS is a heterogeneous disease with multi-organ system dysfunction that compounds throughout the clinical course, resulting in profound neurological and extra-neurological disease impact. Systemic symptoms precede neurologic disease features in most cases. Disease onset before the age of one year, microcephaly, feeding tube placement, and seizures were associated with worse neurological outcomes. This work will inform evidence-based clinical monitoring guidelines and clinical trial design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that influence the work reported in this paper. AV receives research support from Gilead Sciences Inc., Homology Medicines, Eli Lilly and Company, Shire/Takeda, Ionis, Biogen, and Ilumina Inc. She is a consultant to Orchard Pharmaceutical. She has provided unpaid scientific advisory services to Illumina, Shire/Takeda, Ionis, and Biogen, in addition to the research support she receives. AV receives grants and in-kind support for research from Eli Lilly, Gilead, Takeda, Illumina, Biogen, Boehringer Ingelhiem, Sanofi, Sana, Myrtelle, Affinia, Homology, Ionis, Passage Bio, and Orchard Therapeutics. AV serves on the scientific advisory boards of the MLD Foundation, European Leukodystrophy Association, and the United Leukodystrophy Foundation and in an unpaid capacity for Takeda, Ionis, Biogen, and Illumina. LAA is a consultant for Takeda, Biogen, and Orchard Therapeutics. LE serves on the Ionis Pharmaceuticals Board of Directors., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Explore pediatric staff experiences administering the second influenza vaccine dose., Study Design: Qualitative focus groups/interviews., Methods: As part of the National Institutes of Health-funded Flu2Text randomized control trial of text message reminders for second influenza vaccine dose, we conducted seven focus groups and four individual interviews (n = 39 participants total) with clinicians and staff from participating practices from the American Academy of Pediatrics' Pediatric Research in Office Settings (PROS) Network. Of 37 participating practices, 10 were selected through stratified sampling of practices with highest (n = 5) and lowest (n = 5) randomized controlled trial effect sizes. A semi-structured discussion guide included questions that addressed parental, practice, and health system barriers/facilitators to second influenza vaccine dose administration. Using the Systems Model of Clinical Preventive Care as a conceptual framework, two investigators independently coded transcripts (Κ = 0.86, high agreement) with NVivo 12 Plus. Coding inconsistencies were resolved by consensus., Results: Clinicians/staff reported that administering the second influenza vaccine dose in a season was more complex than other childhood vaccines. They highlighted parental uncertainty about the need for the second dose and the difficulty and inconvenience of bringing children back to the office as important barriers. Caregiver-staff relationships were perceived as helpful in getting children vaccinated with their second dose and vaccine reminders were seen as important cues-to-action., Conclusions: Ensuring receipt of two doses of the influenza vaccine in a given season presents unique challenges. Themes identified provide a framework for understanding opportunities to bolster second dose receipt, including explaining why two doses are needed, offering flexible hours for vaccination, and sending vaccine reminders., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Objective: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease., Methods: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years., Results: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years)., Interpretation: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions., Competing Interests: Declaration of competing interest Dr. Adang is an advisor to Takeda Pharmaceuticals (enzyme replacement study for MLD), Orchard Therapeutics (gene therapy development for MLD), and is a site sub-investigator for the Takeda trial (enzyme replacement study); Dr. Gröschel is an advisor Takeda and Orchard Therapeutics; Dr. Bonkowsky is a site principal investigator for the Takeda trial; Dr. Bernard is a site principal investigator for the Takeda trial; Dr. Weller Grønborg is a consultant to Orchard Therapeutics; Dr. Orchard is a consultant to Orchard Therapeutics. Dr. Krägeloh-Mann is an advisor to Takeda, Orchard Therapeutics; Dr. Vanderver is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial; Dr. Escolar is an advisor to Takeda, Janssen; she is employed by Forge Biologics; Dr. Fumagalli is the license holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard. Dr. Eichler, Dr. Fatemi, Dr. Gavazzi, Dr. Sevagamoorthy, Ms. Mutua, Ms. Muirhead, Ms. Schmidt, Ms. Pizzino, Ms. Yu, Ms. Jin, Mr. Vincent, Ms. Grzyb, Mr. D'Aiello, Mr. Sherbini, Mr. Bronner, Mr. Patel, Dr. Fraser, Dr. Emrick, Dr. Van Haren, Dr. Ruzhnikov, Dr. Keller, Ms. Uebergang, Ms. Poe, Dr. Yazdani, Dr. Bernat, Dr. Lindstrom, Dr. Stutterd, Dr. Gupta, Dr. Boulanger, Dr. Sylvain, Dr. Nguyen, Dr. Potic, Dr. Ljungberg, Dr. Zambon, Ms. Locatelli, Ms. Elgün, Dr. Kehrer, and Dr. Shults have no relevant disclosures., (Copyright © 2024. Published by Elsevier Inc.)

IFN-signaling gene (ISG) expression scores are potential markers of inflammation with significance from cancer to genetic syndromes. In Aicardi Goutières Syndrome (AGS), a disorder of abnormal DNA and RNA metabolism, this score has potential as a diagnostic biomarker, although the approach to ISG calculation has not been standardized or validated. To optimize ISG calculation and validate ISG as a diagnostic biomarker, mRNA levels of 36 type I IFN response genes were quantified from 997 samples (including 334 AGS), and samples were randomized into training and test data sets. An independent validation cohort (n = 122) was also collected. ISGs were calculated using all potential combinations up to 6 genes. A 4-gene approach (IFI44L, IFI27, USP18, IFI6) was the best-performing model (AUC of 0.8872 [training data set], 0.9245 [test data set]). The majority of top-performing gene combinations included IFI44L. Performance of IFI44L alone was 0.8762 (training data set) and 0.9580 (test data set) by AUC. The top approaches were able to discriminate individuals with genetic interferonopathy from control samples. This study validates the context of use for the ISG score as a diagnostic biomarker and underscores the importance of IFI44L in diagnosis of genetic interferonopathies.

Parents of children in the pediatric cardiac intensive care unit (CICU) are often unprepared for family meetings (FM). Clinicians often do not follow best practices for communicating with families, adding to distress. An interprofessional team intervention for FM is feasible, acceptable, and positively impacts family preparation and conduct of FM in the CICU. We implemented a family- and team-support intervention for conducting FM and conducted a pretest-posttest study with parents of patients selected for a FM and clinicians. We measured feasibility, fidelity to intervention protocol, and parent acceptability via questionnaire and semi-structured interviews. Clinician behavior in meetings was assessed through semantic content analyses of meeting transcripts tracking elicitation of parental concerns, questions asked of parents, and responses to parental empathic opportunities. Logistic and ordinal logistic regression assessed intervention impact on clinician communication behaviors in meetings comparing pre- and post-intervention data. Sixty parents (95% of approached) were enrolled, with collection of 97% FM and 98% questionnaire data. We accomplished > 85% fidelity to intervention protocol. Most parents (80%) said the preparation worksheet had the right amount of information and felt positive about families receiving this worksheet. Clinicians were more likely to elicit parental concerns (adjusted odds ratio = 3.42; 95%CI [1.13, 11.0]) in post-intervention FM. There were no significant differences in remaining measures. Implementing an interprofessional team intervention to improve family preparation and conduct of FM is locally feasible, acceptable, and changes clinician behaviors. Future research should assess broader impact of training on clinicians, patients, and families., (© 2024. The Author(s).)

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts., Competing Interests: Declaration of competing interest Adeline Vanderver and Laura Adang have received research support from IONIS pharmaceuticals, Takeda, Sanofi, Eli Lilly, Boehringer Ingelheim, Affinia and Orchard Therapeutics. In addition, Dr. Vanderver has received research support from Illumina, Sana, Passage Bio, Homology and PMD foundation. Dr. Adang from Biogen, MSD Foundation, Don't Forget Morgan, Legacy of Angels and Orphan Disease Center. Dr. Vanderver and Dr. Adang hold the license for the AGS Severity Scale and Dr. Vanderver the patent of ASO in TUBB4A. Dr. Vanderver participates on the advisory board of ELA and United Leukodystrophy Foundation. Dr. Adang is the scientific advisor for CureMLD, MLD Foundation, Don't Forget Morgan, Yaya Foundation and MLDi. Dr. Vanderver is a site Principal Investigator (PI) for Takeda Pharmaceutical's clinical trial for Metachromatic Leukodystrophy NCT03771898 and is an advisor to Passagebio. Dr. Adang also serves as an advisor to Biogen. Dr. Vanderver, Dr. Adang, Dr. Fatemi, Dr. Eichler, Dr. Bonkowsky, Dr. Fraser, Dr. Keller, Dr. Emrick and Dr. Van Haren are recipients of NIH funding through the NINDS (National Institute of Neurological Disorders and Stroke) and/or NCATS (National Center for Advancing Translational Sciences). Dr. Eichler is a recipient of grants through Kennedy Krieger Institute Inc. and Children's Hospital Corporation dba Boston Children's Hospital, and has <1% equity in Swan Bio, and royalties from AAV9 license for AMN. Dr. Eichler receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures. Dr. Eichler is the founder and consultant of Swan Bio, is the ALD connect chair, and serves on the chair on the advisory board of European Leukodystrophy Association, board member at United Leukodystrophy Foundation, and as a scientific advisor for National Tay Sachs and Allied Diseases Association. Dr. Fatemi is a PI for Viking Therapeutics and Minoryx Therapeutics and receives research support from CureLBSL, Brian's Hope Foundation, SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund. Also, Dr. Fatemi was former Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and serves as the ALD Connect Board member. Dr. Fatemi co-invented a patent currently licensed to Ashvattha. All other authors have no conflicts of interest. Dr. Bonkowsky receives research support through grant from European Leukodystrophy Association, and consults for Ionis, Sanofi, Autobahn, Denali, Passage Bio, Bluebird, Calico. He also serves on the ALD connect board. Dr. Keller is the site PI for Ionis Pharmaceuticals Alexander Disease trial and Biomarin Pharmaceuticals Brineura extension study. Dr. Keller consults for Veristat and serves on United Leukodystrophy Foundation and Leukodystrophy Care Network Certified Center. Dr. Emrick serves on the advisory board for Ionis pharmaceuticals. Dr. Van Haren receives research support from United Leukodystrophy Foundation and Stanford MCHRI. He consults for Bluebird Bio, Poxel, Autobahn Therapeutics and Viking, and has participated in the Calico Board. He also serves in the leadership capacity at ALD connect, United Leukodystrophy Foundation and Global Leukodystrophy Alliance. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Children with trisomy 21 often have anatomic and physiologic features that may complicate tracheal intubation (TI). TI in critically ill children with trisomy 21 is not well described. We hypothesize that in children with trisomy 21, TI is associated with greater odds of adverse airway outcomes (AAOs), including TI-associated events (TIAEs), and peri-intubation hypoxemia (defined as > 20% decrease in pulse oximetry saturation [Sp o2 ])., Design: Retrospective database study using the National Emergency Airway Registry for Children (NEAR4KIDS)., Setting: Registry data from 16 North American PICUs and cardiac ICUs (CICUs), from January 2014 to December 2020., Patients: A cohort of children under 18 years old who underwent TI in the PICU or CICU from in a NEAR4KIDS center. We identified patients with trisomy 21 and selected matched cohorts within the registry., Interventions: None., Measurements and Main Results: We included 8401 TIs in the registry dataset. Children with trisomy 21 accounted for 274 (3.3%) TIs. Among those with trisomy 21, 84% had congenital heart disease and 4% had atlantoaxial instability. Cervical spine protection was used in 6%. The diagnosis of trisomy 21 (vs. without) was associated with lower median weight 7.8 (interquartile range [IQR] 4.5-14.7) kg versus 10.6 (IQR 5.2-25) kg ( p < 0.001), and more higher percentage undergoing TI for oxygenation (46% vs. 32%, p < 0.001) and ventilation failure (41% vs. 35%, p = 0.04). Trisomy 21 patients had more difficult airway features (35% vs. 25%, p = 0.001), including upper airway obstruction (14% vs. 8%, p = 0.001). In addition, a greater percentage of trisomy 21 patients received atropine (34% vs. 26%, p = 0.004); and, lower percentage were intubated with video laryngoscopy (30% vs. 37%, p = 0.023). After 1:10 (trisomy 21:controls) propensity-score matching, we failed to identify an association difference in AAO rates (absolute risk difference -0.6% [95% CI -6.1 to 4.9], p = 0.822)., Conclusions: Despite differences in airway risks and TI approaches, we have not identified an association between the diagnosis of trisomy 21 and higher AAOs., Competing Interests: Drs. Nishisaki and Nadkarni and Ms. Napolitano’s institution received funding from the National Institute of Child Health and Development, Agency for Healthcare Research and Quality (AHRQ), and Chiesi, USA. They received support for article research from the AHRQ. Dr. Nadkarni serves as President of the Society of Critical Care Medicine (SCCM) 2023–2024. The views presented in this article are his own, and are not intended to represent the views of the SCCM. Dr. Al-Subu received funding from the American Physician Institute. Dr. Krawiec received funding from NEJM Healer Cases and Elsevier Osmosis. Dr. Napolitano received funding from Drager Medical; their institution received funding from Drager, Timpel, Actuated Medical, and Vero-Biotech. Dr. Shults’ institution received funding from the National Institutes of Health (NIH) (R18HS024511); they received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To assess the presence and timing of furosemide diuretic tolerance in infants with bronchopulmonary dysplasia (BPD), and to determine if tolerance is modified by thiazide co-administration., Study Design: We performed a retrospective cohort study among infants born very preterm with BPD exposed to repeated-dose furosemide for 72 hours, measuring net fluid balance (total intake minus total output) as a surrogate of diuresis in the 3 days before and after exposure. The primary comparison was the difference in fluid balance between the first and third 24 hours of furosemide exposure. We fit a general linear model for within-subject repeated measures of fluid balance over time, with thiazide co-administration as an interaction variable. Secondary analyses included an evaluation of weight trajectories over time., Results: In 83 infants, median fluid balance ranged between + 43.6 and + 52.7 ml/kg/d in the 3 days prior to furosemide exposure. Fluid balance decreased to a median of + 29.1 ml/kg/d in the first 24 hours after furosemide, but then increased to +47.5 ml/kg/d by the third 24-hour interval, consistent with tolerance (P < .001). Thiazides did not modify the change in fluid balance during furosemide exposure for any time-period. Weight decreased significantly in the first 24 hours after furosemide and increased thereafter (P < .001)., Conclusions: The net fluid balance response to furosemide decreases rapidly during repeated-dose exposures in infants with BPD, consistent with diuretic tolerance. Clinicians should consider this finding in the context of an infant's therapeutic goals. Further research efforts to identify safe and effective furosemide dosage strategies are needed., Competing Interests: Declaration of Competing Interest The authors have no financial interests to disclose. This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K23HD10165 to Dr Bamat and National Institutes of Health National Heart Lung Blood InstituteK24HL143283 to Dr Laughon. The funding sources had no role in the study design; the collection, analysis and interpretation of the data; the writing of the report or the decision to submit for publication. Dr Bamat wrote the first draft of the manuscript. No compensation honorarium, grant, or other form of payment was given to produce the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ketamine has traditionally been avoided for tracheal intubations (TIs) in patients with acute neurological conditions. We evaluate its current usage pattern in these patients and any associated adverse events., Methods: We conducted a retrospective observational cohort study of critically ill children undergoing TI for neurological indications in 53 international pediatric intensive care units and emergency departments. We screened all intubations from 2014 to 2020 entered into the multicenter National Emergency Airway Registry for Children (NEAR4KIDS) registry database. Patients were included if they were under the age of 18 years and underwent TI for a primary neurological indication. Usage patterns and reported periprocedural composite adverse outcomes (hypoxemia < 80%, hypotension/hypertension, cardiac arrest, and dysrhythmia) were noted., Results: Of 21,562 TIs, 2,073 (9.6%) were performed for a primary neurological indication, including 190 for traumatic brain injury/trauma. Patients received ketamine in 495 TIs (23.9%), which increased from 10% in 2014 to 41% in 2020 (p < 0.001). Ketamine use was associated with a coindication of respiratory failure, difficult airway history, and use of vagolytic agents, apneic oxygenation, and video laryngoscopy. Composite adverse outcomes were reported in 289 (13.9%) Tis and were more common in the ketamine group (17.0% vs. 13.0%, p = 0.026). After adjusting for location, patient age and codiagnoses, the presence of respiratory failure and shock, difficult airway history, provider demographics, intubating device, and the use of apneic oxygenation, vagolytic agents, and neuromuscular blockade, ketamine use was not significantly associated with increased composite adverse outcomes (adjusted odds ratio 1.34, 95% confidence interval CI 0.99-1.81, p = 0.057). This paucity of association remained even when only neurotrauma intubations were considered (10.6% vs. 7.7%, p = 0.528)., Conclusions: This retrospective cohort study did not demonstrate an association between procedural ketamine use and increased risk of peri-intubation hypoxemia and hemodynamic instability in patients intubated for neurological indications., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Objectives: Extremes of patient body mass index are associated with difficult intubation and increased morbidity in adults. We aimed to determine the association between being underweight or obese with adverse airway outcomes, including adverse tracheal intubation (TI)-associated events (TIAEs) and/or severe peri-intubation hypoxemia (pulse oximetry oxygen saturation < 80%) in critically ill children., Design/setting: Retrospective cohort using the National Emergency Airway for Children registry dataset of 2013-2020., Patients: Critically ill children, 0 to 17 years old, undergoing TI in PICUs., Interventions: None., Measurements and Main Results: Registry data from 24,342 patients who underwent TI between 2013 and 2020 were analyzed. Patients were categorized using the Centers for Disease Control and Prevention weight-for-age chart: normal weight (5th-84th percentile) 57.1%, underweight (< 5th percentile) 27.5%, overweight (85th to < 95th percentile) 7.2%, and obese (≥ 95th percentile) 8.2%. Underweight was most common in infants (34%); obesity was most common in children older than 8 years old (15.1%). Underweight patients more often had oxygenation and ventilation failure (34.0%, 36.2%, respectively) as the indication for TI and a history of difficult airway (16.7%). Apneic oxygenation was used more often in overweight and obese patients (19.1%, 19.6%) than in underweight or normal weight patients (14.1%, 17.1%; p < 0.001). TIAEs and/or hypoxemia occurred more often in underweight (27.1%) and obese (24.3%) patients ( p < 0.001). TI in underweight children was associated with greater odds of adverse airway outcome compared with normal weight children after adjusting for potential confounders (underweight: adjusted odds ratio [aOR], 1.09; 95% CI, 1.01-1.18; p = 0.016). Both underweight and obesity were associated with hypoxemia after adjusting for covariates and site clustering (underweight: aOR, 1.11; 95% CI, 1.02-1.21; p = 0.01 and obesity: aOR, 1.22; 95% CI, 1.07-1.39; p = 0.002)., Conclusions: In underweight and obese children compared with normal weight children, procedures around the timing of TI are associated with greater odds of adverse airway events., Competing Interests: Ms. Napolitano’s, Dr. Shults’s, Dr. Nadkarni’s, and Dr. Nishisaki’s institution received funding from the Agency for Healthcare Research and Quality (R18HS024511). Ms. Napolitano’s institution received funding from Dräger, Actuated Medical, and Philips Respironics; they received support for article research from Timpel and VERO-Biotech. Dr. Krawiec received funding from New England Journal of Medicine Healer Cases and Carle Illinois School of Medicine Admissions Committee. Dr. Polikoff received funding from Novavax. Dr. Lee’s institution received funding from National Research Medical Council, Singapore. Dr. Shenoi is an elected member of the Society of Critical Care Medicine (SCCM) Council of the SCCM. Dr. Peihl disclosed that he is founder and Chief Medical Officer of 410 Medical; his institution received funding the Department of Defense (grants: USSOCOM W81XWH-22-C-0002, USAF SBIR AF212-CSO1 Phase II, F2-15653 USAF, SBIR AF211-CSO1 Phase II, F2-15254). Dr. Hasegawa disclosed work for hire. Dr. Nishisaki’s institution received funding from Chiesi USA, AHRA, and the National Institute of Child Health and Human Development. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To describe tracheal intubation (TI) practice by Advanced Practice Registered Nurses (APRNs) in North American PICUs, including rates of TI-associated events (TIAEs) from 2015 to 2019., Design/setting: Retrospective study using the National Emergency Airway Registry for Children with all TIs performed in PICU and pediatric cardiac ICU between January 2015 and December 2019. The primary outcome was first attempt TI success rate. Secondary outcomes were TIAEs, severe TIAEs, and hypoxemia., Subjects: Critically ill children requiring TI in a PICU or pediatric cardiac ICU., Interventions: None., Measurements and Main Results: Among 11,012 TIs, APRNs performed 1,626 (14.7%). Overall, TI by APRNs, compared with other clinicians, occurred less frequently in patients with known difficult airway (11.1% vs. 14.3%; p < 0.001), but more frequently in infants younger than 1 year old (55.9% vs. 44.4%; p < 0.0001), and in patients with cardiac disease (26.3% vs. 15.9%; p < 0.0001).There was lower odds of success in first attempt TI for APRNs vs. other clinicians (adjusted odds ratio, 0.70; 95% CI, 0.62-0.79). We failed to identify a difference in rates of TIAE, severe TIAE, and oxygen desaturation events for TIs by APRNs compared with other clinicians. The TI first attempt success rate improved with APRN experience (< 1 yr: 54.2%, 1-5 yr: 59.4%, 6-10 yr: 67.6%, > 10 yr: 63.1%; p = 0.021)., Conclusions: TI performed by APRNs was associated with lower odds of first attempt success when compared with other ICU clinicians although there was no appreciable difference in procedural adverse events. There appears to be a positive relationship between experience and success rates. These data suggest there is an ongoing need for opportunities to build on TI competency with APRNs., Competing Interests: Dr. Polikoff received funding from Novavax. Drs. Napolitano’s and Shults’s institutions received funding from the Agency for Healthcare Research and Quality (AHRQ) (R18HS024511). Dr. Napolitano’s institution received funding from Drager, Timpel, Respironics, Actuated Medical, and Vero-Biotech. Dr. Shults received support for article research from the AHRQ (R18HS024511). Dr. Berkenbosch received funding from Pfizer. Dr. Nishisaki’s institution received funding from the AHRQ, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Chiesi USA; she received support for article research from the AHRQ. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: Suspicion for child abuse is influenced by implicit biases. Evaluation by a Child Abuse Pediatrician (CAP) may reduce avoidable child protective services (CPS) referrals. Our objective was to investigate the association of patient demographic, social and clinical characteristics with CPS referral before consultation by a CAP (preconsultation referral)., Methods: Children<5years-old undergoing in-person CAP consultation for suspected physical abuse from February 2021 through April 2022 were identified in CAPNET, a multicenter child abuse research network. Marginal standardization implemented with logistic regression analysis examined hospital-level variation and identified demographic, social, and clinical factors associated with preconsultation referral adjusting for CAP's final assessment of abuse likelihood., Results: Among the 61% (1005/1657) of cases with preconsultation referral, the CAP consultant had low concern for abuse in 38% (384/1005). Preconsultation referrals ranged from 25% to 78% of cases across 10 hospitals (P < .001). In multivariable analyses, preconsultation referral was associated with public insurance, caregiver history of CPS involvement, history of intimate partner violence, higher CAP level of concern for abuse, hospital transfer, and near-fatality (all P < .05). The difference in preconsultation referral prevalence for children with public versus private insurance was significant for children with low CAP concern for abuse (52% vs 38%) but not those with higher concern for abuse (73% vs 73%), (P = .023 for interaction of insurance and abuse likelihood category). There were no differences in preconsultation referral based on race or ethnicity., Conclusions: Biases based on socioeconomic status and social factors may impact decisions to refer to CPS before CAP consultation., Competing Interests: Declaration of Competing Interest Drs Anderst, Lindberg and Letson have provided paid expert witness testimony in cases with concern for child physical abuse. Drs Berger’s, Campbell’s, Harper’s, Henry’s, Melville’s, and Wood’s institutions have been paid in cases with concern for child physical abuse for which they have provided expert testimony. The other authors report no conflicts of interest., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Nasal tracheal intubation (TI) represents a minority of all TI in the pediatric intensive care unit (PICU). The risks and benefits of nasal TI are not well quantified. As such, safety and descriptive data regarding this practice are warranted., Methods: We evaluated the association between TI route and safety outcomes in a prospectively collected quality improvement database (National Emergency Airway Registry for Children: NEAR4KIDS) from 2013 to 2020. The primary outcome was severe desaturation (SpO 2  > 20% from baseline) and/or severe adverse TI-associated events (TIAEs), using NEAR4KIDS definitions. To balance patient, provider, and practice covariates, we utilized propensity score (PS) matching to compare the outcomes of nasal vs. oral TI., Results: A total of 22,741 TIs [nasal 870 (3.8%), oral 21,871 (96.2%)] were reported from 60 PICUs. Infants were represented in higher proportion in the nasal TI than the oral TI (75.9%, vs 46.2%), as well as children with cardiac conditions (46.9% vs. 14.4%), both p  < 0.001. Severe desaturation or severe TIAE occurred in 23.7% of nasal and 22.5% of oral TI (non-adjusted p  = 0.408). With PS matching, the prevalence of severe desaturation and or severe adverse TIAEs was 23.6% of nasal vs. 19.8% of oral TI (absolute difference 3.8%, 95% confidence interval (CI): - 0.07, 7.7%), p  = 0.055. First attempt success rate was 72.1% of nasal TI versus 69.2% of oral TI, p  = 0.072. With PS matching, the success rate was not different between two groups (nasal 72.2% vs. oral 71.5%, p  = 0.759)., Conclusion: In this large international prospective cohort study, the risk of severe peri-intubation complications was not significantly higher. Nasal TI is used in a minority of TI in PICUs, with substantial differences in patient, provider, and practice compared to oral TI.A prospective multicenter trial may be warranted to address the potential selection bias and to confirm the safety of nasal TI., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2024.)

Objectives: Previous studies have shown increasing hospitalizations for pediatric cholelithiasis, but recent trends are unknown. We conducted a national study of pediatric cholelithiasis to characterize recent hospitalization rate trends., Methods: Retrospective repeated cross-sectional analysis of pediatric (age < 18 years) cholelithiasis-associated hospitalizations combining data from the 2006 through 2019 Kids' Inpatient Database releases. The primary outcome of interest was the national hospitalization rate (per 100,000 children). We examined rates stratified by age group and sex and characterized hospitalization outcomes and characteristics for pediatric cholelithiasis., Results: Twenty-nine thousand one hundred two hospital records representing 42,282 gallstone-associated hospitalizations were identified. The hospitalization rate declined from 12.9 [95% confidence interval (CI): 12.6-13.2] in 2006 to 9.1 (95% CI: 8.8-9.3) in 2019. Consistent with the literature, hospitalizations occurred most often among teenagers (71%) and individuals with female sex (72%). The proportion of hospitalizations at freestanding children's hospitals increased significantly (from 18.2% to 35.1%). Finally, the proportion of hospitalizations involving a potentially medical predisposing condition increased significantly., Conclusions: The estimated US hospitalization rate for pediatric cholelithiasis declined by 30% between 2006 and 2019. Female patients and teenagers had the largest decline, and hospitalizations increasingly occurred at freestanding children's hospitals. Potential explanations include potential changes in delivery of care as well as changes in population disease burden., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: Practice guidelines from the American Academy of Pediatrics and Society for Developmental and Behavioral Pediatrics recommend evidence-based behavioral therapy (BT) as first-line treatment for preschool-age children with ADHD, prior to medication initiation. Thus, this study's objective is to present the frequency of physician-documented receipt of BT in preschool-age children with ADHD prior to medication initiation and to determine factors associated with receipt BT receipt., Methods: This retrospective medical record review was conducted across 7 Developmental Behavioral Pediatrics Research Network (DBPNet) sites. Data were abstracted for children <72 months old seen by a DBP clinician and initiated on ADHD medication between 1/1/2013-7/1/2017. From narrative text of the medical records, BT receipt was coded as: parent training in behavior management (PTBM), Applied Behavior Analysis (ABA), other, or did not receive., Results: Of the 497 children in this study; 225 children (45%) had reported receipt of any BT prior to ADHD medication initiation, with 15.9% (n = 79) receiving PTBM. Children with co-existing diagnoses of ASD or disruptive behavior disorder were more likely to receive BT than children without co-existing conditions (59.3% vs 69.0% vs 30.6%). There was significant site variability in reported receipt of BT, ranging from 22.4% to 74.1%, and sex and insurance were not associated with BT rates., Conclusion: The percentage of children with documented receipt of any BT, and particularly PTBM, was low across all sites and co-existing conditions. These findings highlight the universal need to increase receipt of evidence-based BT for all young children with ADHD., Competing Interests: Conflicts of Interest and Source of Funding: All phases of this study were conducted by DBPNet, which is supported by cooperative agreement UT5MC42432 from the Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services. This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. The authors have no other conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Traumatic injury is not evenly distributed by race and class in the USA. Black men are marginalized in the society, often reside in disadvantaged neighborhoods, and are at higher risk for injury mortality and ongoing physical and psychological problems following injury. Post-traumatic stress disorder (PTSD) and depressive symptom severity are among several problematic and disabling conditions faced by injury survivors. While much research has examined individual factors that lead to increased post-injury psychological symptom severity, the contribution of the social and physical environment has been relatively understudied., Objective: To examine the contribution of neighborhood characteristics to PTSD and depressive symptom severity in Black men following traumatic injury., Design: Prospective cohort study. Participant data were linked via GIS to neighborhood characteristics (constructs established by factor analysis) to spatially model factors associated with increased post-injury psychological symptom severity using a GEE regression analysis, adjusting for injury mechanism and severity, age, and insurance., Participants: Four hundred fifty-one adult Black males hospitalized for traumatic injury., Results: The 4 constructs were neighborhood disconnectedness, concentrated disadvantage/deprivation, crime/violence/vacancy, and race/ethnicity. High depressive and PTSD symptom severity was reported by 36.8% and 30.4% of participants, respectively. Higher PTSD symptom severity was associated with crime/violence/vacancy, and higher depressive symptom severity was associated with neighborhood disconnectedness. PTSD and depressive symptom severity were associated with intentional injury mechanisms and Medicaid/no insurance. Higher injury severity was associated with depressive symptoms., Conclusion: Neighborhood characteristics are associated with psychological symptom severity after injury., (© 2022. W. Montague Cobb-NMA Health Institute.)

Objectives: This study aimed to determine whether parent ratings of attention-deficit/hyperactivity disorder (ADHD) symptom severity or externalizing symptoms (EXT) or internalizing symptoms (INT) moderate response to stimulants (STIM) and alpha-2 adrenergic agonists (A2As) in preschool ADHD., Methods: Health records for children treated with medication for ADHD and with parent rating scale data available (N = 309; age <72 months) were reviewed at 7 Developmental-Behavioral Pediatric Research Network sites. Severity of ADHD was defined as the number of ADHD symptoms occurring often or very often on DSM-IV-based parent rating scales. EXT or INT from standardized rating scales were categorized as T score <60, 60 to <70, or ≥70. Ordinal logistic regression models predicting response to medication were calculated., Results: The median (interquartile range) age at ADHD diagnosis was 59 (54-65) months. One hundred eighty-three participants had ADHD symptom severity, and 195 had EXT or INT data. ADHD severity was not associated with medication response. Both EXT and INT were associated with medication response but with significant medication class by EXT/INT interactions. Children with higher EXT were less likely to respond to STIM, with percentage of nonresponders for T-score categories <60, 60 to <70, and ≥70 being 3.6%, 25.7%, and 33.3% (p = 0.016) and, for A2As, being 60%, 50%, and 33.3% (p = 0.55), respectively. A similar pattern was observed for INT categories: STIM 19.4%, 22.5%, and 50.0% (p = 0.002) and A2As 42.3%, 30%, and 42.3% (p = 0.48), respectively., Conclusion: For preschool ADHD, low ratings of EXT or INT are associated with a high likelihood of response to STIM. By contrast, response rates to STIM and A2As are more similar for children with high levels of EXT or INT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HIV increases the risk of atherosclerosis and cardiovascular diseases (CVD). This risk maybe even higher in adult survivors of perinatal HIV infection because of prolonged exposure to HIV and its treatments. Nutritional deprivation in early life may further increase CVD risk., Setting: Botswana-Baylor Children's Clinical Centre of Excellence, Gaborone., Methods: This study examined dyslipidemia in 18- to 24-year olds with perinatally-acquired HIV with and without linear growth retardation ("stunting"). Anthropometry and lipid profiles were measured following a minimum 8-hour fast. Stunting was defined by a height-for-age z-score of <2 SDs below the mean. Dyslipidemia was defined by non-high-density lipoprotein cholesterol (HDL-C) of ≥130 mg/dL, low-density lipoprotein cholesterol (LDL-C) of ≥100 mg/dL, or HDL of <40 mg/dL for male subjects and <50 mg/dL for female subjects. We used logistic regression to determine whether dyslipidemia was associated with stunting while adjusting for demographic and HIV treatment variables., Results: Of 107 young adults (46 males; 61 females) enrolled, 36 (33.6%) were stunted. Prevalence of dyslipidemia was 11.2%, 24.3%, and 65.4% for high non-HDL-C, high LDL-C, and low HDL-C, respectively. In univariable analysis, being stunted was associated with elevated LDL-C (odds ratio [OR], 2.52; 95% confidence interval [CI] =1.02 to 6.25) but not with elevated non-HDL-C (OR = 2.17; 95% CI: = 0.65 to 7.28) or with low HDL-C (OR = 0.75; 95% CI: = 0.33 to 1.73). The association between stunting and elevated LDL-C (OR = 4.40; 95% CI: = 1.49 to 12.98) remained significant after controlling for measured confounders., Conclusion: Dyslipidemia was common among perinatally HIV-infected youth and those with evidence of early nutritional deprivation who were more likely to have elevated LDL-C., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest No potential conflicts of interest.

Children with autism spectrum disorder (ASD) and intellectual disability (ID)/global delay (GD) frequently have symptoms of attention-deficit/hyperactivity disorder (ADHD). We describe the practice patterns of developmental behavioral pediatricians (DBPs) in the treatment of children with ASD and coexisting ADHD and compare medication classes for children with and without intellectual disability. In bivariate analyses, we compared demographic characteristics, co-occurring conditions, and medication classes for children with and without intellectual disability. Significantly more patients with ID/GD were prescribed α-agonists than patients without ID/GD, but the difference was no longer significant when controlling for age in logistic regression children with ID/GD had more comorbidities and were more likely to be prescribed more than on psychotropic medication. In conclusion, age rather than ID/GD was associated with medication choice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

TUBB4A pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset TUBB4A -related leukodystrophy cohort with existing gross motor outcome tools. Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification System (GMFCS-ER), and Gross Motor Function Classification-Metachromatic Leukodystrophy (GMFC-MLD) were selected through face validity. Subjects with a confirmed clinical and molecular diagnosis of TUBB4A -related leukodystrophy were enrolled. Participants' sex, age, genotype, and age at disease onset were collected, together with GMFM-88 and concurrent GMFCS-ER and GMFC-MLD. Performances on each measure were compared. GMFM-88 floor effect was defined as total score below 20%. A total of 35 subjects participated. Median performance by GMFM-88 was 16.24% (range 0-97.31), with 42.9% (n = 15) of individuals performing above the floor. GMFM-88 Dimension A (Lying and Rolling) was the best-performing dimension in the GMFM-88 (n = 29 above the floor). All levels of the Classification Scales were represented, with the exception of the GMFC-MLD level 0. Evaluation by GMFM-88 was strongly correlated with the Classification Scales (Spearman correlations: GMFCS-ER:GMFM-88 r  = 0.90; GMFC-MLD:GMFM-88 r  = 0.88; GMFCS-ER:GMFC-MLD: r  = 0.92). Despite overall observation of a floor effect, the GMFM-88 is able to accurately capture the performance of individuals with attenuated phenotypes. GMFM-88 Dimension A shows no floor effect. GMFC-MLD shows a strong correlation with GMFCS-ER and GMFM-88, supporting its use as an age-independent functional score in TUBB4A -related leukodystrophy.

Purpose: To examine the association between long-term use of dopamine agonists (DAs) and the risk of lung cancer in patients with restless legs syndrome (RLS)., Methods: We conducted a retrospective cohort study using Optum Clinformatics® database. We included adults ≥40 years diagnosed with RLS during the study period (1/2006-12/2016). Follow-up started with the first RLS diagnosis and ended on the earliest of: incident diagnosis of lung cancer, end of enrollment in the database or end of the study period. The exposure of interest was cumulative duration of DAs use, measured in a time-varying manner. We constructed a multivariable Cox regression model to estimate HRs and 95% CIs for the association between lung cancer and cumulative durations of DA use, adjusting for potential confounding variables., Results: We identified 295 042 patients with a diagnosis of RLS. The mean age of the cohort was 62.9; 66.6% were women and 82.3% were white. The prevalence of any DA exposure was 40.3%. Compared to the reference group (no use and ≤1 year), the crude HRs for lung cancer were 1.16 (95% CI 0.99-1.36) and 1.14 (95% CI 0.86-1.51) for 1-3 years and >3 years of cumulative DA use, respectively. The adjusted HR for lung cancer was 1.05 (95% CI 0.88-1.25) for 1-3 years and 1.02 (95% CI 0.76-1.37) for >3 years of cumulative DA use, respectively., Conclusions: At typical doses for the clinical management of RLS, long-term DA use was not associated with risk of lung cancer., (© 2023 John Wiley & Sons Ltd.)

Objectives: To evaluate implementation of a video laryngoscope (VL) as a coaching device to reduce adverse tracheal intubation associated events (TIAEs)., Design: Prospective multicenter interventional quality improvement study., Setting: Ten PICUs in North America., Patients: Patients undergoing tracheal intubation in the PICU., Interventions: VLs were implemented as coaching devices with standardized coaching language between 2016 and 2020. Laryngoscopists were encouraged to perform direct laryngoscopy with video images only available in real-time for experienced supervising clinician-coaches., Measurements and Main Results: The primary outcome was TIAEs. Secondary outcomes included severe TIAEs, severe hypoxemia (oxygen saturation < 80%), and first attempt success. Of 5,060 tracheal intubations, a VL was used in 3,580 (71%). VL use increased from baseline (29.7%) to implementation phase (89.4%; p < 0.001). VL use was associated with lower TIAEs (VL 336/3,580 [9.4%] vs standard laryngoscope [SL] 215/1,480 [14.5%]; absolute difference, 5.1%; 95% CI, 3.1-7.2%; p < 0.001). VL use was associated with lower severe TIAE rate (VL 3.9% vs SL 5.3%; p = 0.024), but not associated with a reduction in severe hypoxemia (VL 15.7% vs SL 16.4%; p = 0.58). VL use was associated with higher first attempt success (VL 71.8% vs SL 66.6%; p < 0.001). In the primary analysis after adjusting for site clustering, VL use was associated with lower adverse TIAEs (odds ratio [OR], 0.61; 95% CI, 0.46-0.81; p = 0.001). In secondary analyses, VL use was not significantly associated with severe TIAEs (OR, 0.72; 95% CI, 0.44-1.19; p = 0.20), severe hypoxemia (OR, 0.95; 95% CI, 0.73-1.25; p = 0.734), or first attempt success (OR, 1.28; 95% CI, 0.98-1.67; p = 0.073). After further controlling for patient and provider characteristics, VL use was independently associated with a lower TIAE rate (adjusted OR, 0.65; 95% CI, 0.49-0.86; p = 0.003)., Conclusions: Implementation of VL-assisted coaching achieved a high level of adherence across the PICUs. VL use was associated with reduced adverse TIAEs., Competing Interests: Ms. Napolitano’s, Dr. Shults’s, Dr. Nadkarni’s, and Dr. Nishisaki’s institutions received funding from the Agency for Healthcare Research and Quality (AHRQ) (R18HS024511). Ms. Napolitano’s institution received funding from Drager, Timpel, Philips/Respironics, Actuated Medical, and VERO-Biotech. Dr. Parsons institution received funding from Children’s Hospital of Philadelphia (CHOP) National Emergency Airway Registry for Children. Dr. Shults received support for article research from the AHRQ (R18HS024511). Dr. Yamada’s institution received funding from the AHRQ. Dr. Nishisaki’s institution received funding from Chiesi; she received funding from CHOP; and she received support for article research from the AHRQ. Dr. Nadkarni was supported by the Endowed Chair, Critical Care Medicine, and CHOP. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Mobile health (mHealth) is quickly expanding as a method of health promotion, but some interventions may not be familiar or comfortable for potential users. SMS text messaging has been investigated as a low-cost, accessible way to provide vaccine reminders. Most (97%) US adults own a cellphone and of those adults most use SMS text messaging. However, understanding patterns of SMS text message plan type and use in diverse primary care populations needs more investigation., Objective: We sought to use a survey to examine baseline SMS text messaging and data plan patterns among families willing to accept SMS text message vaccine reminders., Methods: As part of a National Institutes of Health (NIH)-funded national study (Flu2Text) conducted during the 2017-2018 and 2018-2019 influenza seasons, families of children needing a second seasonal influenza vaccine dose were recruited in pediatric primary care offices at the time of their first dose. Practices were from the American Academy of Pediatrics' (AAP) Pediatric Research in Office Settings (PROS) research network, the Children's Hospital of Philadelphia, and Columbia University. A survey was administered via telephone (Season 1) or electronically (Season 2) at enrollment. Standardized (adjusted) proportions for SMS text message plan type and texting frequency were calculated using logistic regression that was adjusted for child and caregiver demographics., Results: Responses were collected from 1439 participants (69% of enrolled). The mean caregiver age was 32 (SD 6) years, and most children (n=1355, 94.2%) were aged 6-23 months. Most (n=1357, 94.3%) families were English-speaking. Most (n=1331, 92.8%) but not all participants had an unlimited SMS text messaging plan and sent or received texts at least once daily (n=1313, 91.5%). SMS text messaging plan type and use at baseline was uniform across most but not all subgroups. However, there were some differences in the study population's SMS text messaging plan type and usage. Caregivers who wanted Spanish SMS text messages were less likely than those who chose English to have an unlimited SMS text messaging plan (n=61, 86.7% vs n=1270, 94%; risk difference -7.2%, 95% CI -27.1 to -1.8). There were no significant differences in having an unlimited plan associated with child's race, ethnicity, age, health status, insurance type, or caregiver education level. SMS text messaging use at baseline was not uniform across all subgroups. Nearly three-quarters (n=1030, 71.9%) of participants had received some form of SMS text message from their doctor's office; most common were appointment reminders (n=1014, 98.4%), prescription (n=300, 29.1%), and laboratory notifications (n=117, 11.4%). Even the majority (n=64, 61.5%) of those who did not have unlimited plans and who texted less than daily (n=72, 59%) reported receipt of these SMS text messages., Conclusions: In this study, most participants had access to unlimited SMS text messaging plans and texted at least once daily. However, infrequent texting and lack of access to an unlimited SMS text messaging plan did not preclude enrolling to receive SMS text message reminders in pediatric primary care settings., (©Chelsea S Wynn, Alexander G Fiks, Russell Localio, Justine Shults, Ekaterina Nekrasova, Laura P Shone, Alessandra Torres, Miranda Griffith, Rebecca Unger, Leigh Ann Ware, Mary Kate Kelly, Melissa S Stockwell. Originally published in JMIR Formative Research (https://formative.jmir.org), 30.06.2023.)

Objectives: To characterize and compare the type and frequency of a range of common and uncommon adverse effects (AEs) associated with α-2 adrenergic agonist (A2A) and stimulant treatment of attention-deficit/hyperactivity disorder at preschool-age as well as to evaluate the impact of age on common AEs., Study Design: This was a retrospective electronic medical record review of children <72 months of age (n = 497) evaluated at outpatient developmental-behavioral pediatric practices at 7 US academic medical centers within the Developmental-Behavioral Pediatrics Research Network. Data on AEs were abstracted for children who had treatment initiated by a developmental-behavioral pediatrician with an A2A or stimulant medication between January 2013 and July 2017; follow-up was complete by February 2019., Results: A2A and stimulants had distinctive AE profiles. A2A compared with stimulants had a greater proportion with daytime sleepiness and headaches; stimulants had significantly greater proportions for most other AE, including moodiness/irritability, difficulty with sleep, appetite suppression, stomachaches, skin picking/repetitive behaviors, withdrawn behavior, and weight loss. Younger age was associated with disruptive behavior and difficulty with sleep., Conclusions: Stimulants had a greater rate of most AEs compared with A2A. AE profiles, together with efficacy, should inform clinical decision-making. Prospective randomized clinical trials are needed to fully compare efficacy and AE profiles of A2A and stimulants., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Nearly half of neonatal intubations are complicated by severe desaturation (≥20% decline in pulse oximetry saturation (SpO 2 )). Apnoeic oxygenation prevents or delays desaturation during intubation in adults and older children. Emerging data show mixed results for apnoeic oxygenation using high-flow nasal cannula (NC) during neonatal intubation. The study objective is to determine among infants ≥28 weeks' corrected gestational age (cGA) who undergo intubation in the neonatal intensive care unit (NICU) whether apnoeic oxygenation with a regular low-flow NC, compared with standard of care (no additional respiratory support), reduces the magnitude of SpO 2 decline during intubation., Methods and Analysis: This is a multicentre, prospective, unblinded, pilot randomised controlled trial in infants ≥28 weeks' cGA who undergo premedicated (including paralytic) intubation in the NICU. The trial will recruit 120 infants, 10 in the run-in phase and 110 in the randomisation phase, at two tertiary care hospitals. Parental consent will be obtained for eligible patients prior to intubation. Patients will be randomised to 6 L NC 100% oxygen versus standard of care (no respiratory support) at time of intubation. The primary outcome is magnitude of oxygen desaturation during intubation. Secondary outcomes include additional efficacy, safety and feasibility outcomes. Ascertainment of the primary outcome is performed blinded to intervention arm. Intention-to-treat analyses will be conducted to compare outcomes between treatment arms. Two planned subgroup analyses will explore the influence of first provider intubation competence and patients' baseline lung disease using pre-intubation respiratory support as a proxy., Ethics and Dissemination: The Institutional Review Boards at the Children's Hospital of Philadelphia and the University of Pennsylvania have approved the study. Upon completion of the trial, we intend to submit our primary results to a peer review forum after which we plan to publish our results in a peer-reviewed paediatric journal., Trial Registration Number: ClinicalTrials.gov Registry (NCT05451953)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Determine if apneic oxygenation (AO) delivered via nasal cannula during the apneic phase of tracheal intubation (TI), reduces adverse TI-associated events (TIAEs) in children., Methods: AO was implemented across 14 pediatric intensive care units as a quality improvement intervention during 2016-2020. Implementation consisted of an intubation safety checklist, leadership endorsement, local champion, and data feedback to frontline clinicians. Standardized oxygen flow via nasal cannula for AO was as follows: 5 L/min for infants (< 1 year), 10 L/min for young children (1-7 years), and 15 L/min for older children (≥ 8 years). Outcomes were the occurrence of adverse TIAEs (primary) and hypoxemia (SpO 2  < 80%, secondary)., Results: Of 6549 TIs during the study period, 2554 (39.0%) occurred during the pre-implementation phase and 3995 (61.0%) during post-implementation phase. AO utilization increased from 23 to 68%, p < 0.001. AO was utilized less often when intubating infants, those with a primary cardiac diagnosis or difficult airway features, and patient intubated due to respiratory or neurological failure or shock. Conversely, AO was used more often in TIs done for procedures and those assisted by video laryngoscopy. AO utilization was associated with a lower incidence of adverse TIAEs (AO 10.5% vs. without AO 13.5%, p < 0.001), aOR 0.75 (95% CI 0.58-0.98, p = 0.03) after adjusting for site clustering (primary analysis). However, after further adjusting for patient and provider characteristics (secondary analysis), AO utilization was not independently associated with the occurrence of adverse TIAEs: aOR 0.90, 95% CI 0.72-1.12, p = 0.33 and the occurrence of hypoxemia was not different: AO 14.2% versus without AO 15.2%, p = 0.43., Conclusion: While AO use was associated with a lower occurrence of adverse TIAEs in children who required TI in the pediatric ICU after accounting for site-level clustering, this result may be explained by differences in patient, provider, and practice factors. Trial Registration Trial not registered., (© 2023. The Author(s).)

Background: Text messages can be an effective and low-cost mechanism for patient reminders; however, they are yet to be consistently integrated into pediatric primary care., Objective: The aim of this study was to explore pediatric primary care clinician and staff perceptions of pediatric office text message communication with families., Methods: As part of the National Institutes of Health-funded Flu2Text randomized controlled trial of second-dose influenza vaccine text message reminders, we conducted 7 focus groups and 4 individual interviews in July-August 2019 with primary care pediatric clinicians and staff ( n = 39). Overall, 10 Pediatric Research in Office Settings (PROS) pediatric practices in 10 states were selected using stratified sampling. Semi-structured discussion guides included perspectives on possible uses, perceived usefulness, and ease of use of text messages; practices' current text messaging infrastructure; and perceived barriers/facilitators to future use of texting. Two investigators independently coded and analyzed transcripts based on the technology acceptance model using NVIVO 12 Plus (intercoder reliability, K = 0.86)., Results: Overall, participants were supportive of text reminders for the second-dose influenza vaccine, other vaccines, and appointments and perceived texting as a preferred method of communication for caregivers. Health information privacy and patient confidentiality were the main concerns cited. Only respondents from practices with no internal appointment text message reminder system prior to the study expressed concerns about technology implementation logistics, time, and cost., Conclusion: Text message reminders, for various uses, appear to be well accepted among a group of geographically widespread pediatric practices after participation in a trial of influenza vaccine text message reminders. Privacy, confidentiality, and resource barriers need to be addressed to facilitate successful implementation., Competing Interests: Conflict of Interest A.F. reported receiving an independent research grant from Pfizer for work unrelated to this project and unrelated to vaccination. No other disclosures were reported.

Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated., Competing Interests: Declaration of Competing Interest AV receives grant and in-kind support for translational research without personal compensation from Eli Lilly, Biogen, Takeda, Passage Bio, Homology, Illumina, Orchard therapeutics, and Ionis. In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, we report that DW is named on patents that describe the use of nucleoside-modified mRNA as a platform to deliver therapeutic proteins and vaccines. DW and MGA are also names on patents describing the use of lipids nanoparticles, and lipid compositions for nucleic acid delivery and vaccination. We have disclosed those interests fully to the University of Pennsylvania, and we have in place an approved plan for managing any potential conflicts arising from licensing of our patents., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clinical deterioration of hospitalized patients is common and can lead to critical illness and death. Rapid response teams (RRTs) assess and treat high-risk patients with signs of clinical deterioration to prevent further worsening and subsequent adverse outcomes. Whether activation of the RRT early in the course of clinical deterioration impacts outcomes, however, remains unclear. We sought to characterize the relationship between increasing time to RRT activation after physiologic deterioration and short-term patient outcomes., Design: Retrospective multicenter cohort study., Setting: Three academic hospitals in Pennsylvania., Patients: We included the RRT activation of a hospitalization for non-ICU inpatients greater than or equal to 18 years old., Interventions: None., Measurements and Main Results: The primary exposure was time to RRT activation after physiologic deterioration. We selected four Cardiac Arrest Risk Triage (CART) score thresholds a priori from which to measure time to RRT activation (CART score ≥ 12, ≥ 16, ≥ 20, and ≥ 24). The primary outcome was 7-day mortality-death or discharge to hospice care within 7 days of RRT activation. For each CART threshold, we modeled the association of time to RRT activation duration with 7-day mortality using multivariable fractional polynomial regression. Increased time from clinical decompensation to RRT activation was associated with higher risk of 7-day mortality. This relationship was nonlinear, with odds of mortality increasing rapidly as time to RRT activation increased from 0 to 4 hours and then plateauing. This pattern was observed across several thresholds of physiologic derangement., Conclusions: Increasing time to RRT activation was associated in a nonlinear fashion with increased 7-day mortality. This relationship appeared most marked when using a CART score greater than 20 threshold from which to measure time to RRT activation. We suggest that these empirical findings could be used to inform RRT delay definitions in further studies to determine the clinical impact of interventions focused on timely RRT activation., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Children with sickle cell disease (SCD) have an increased risk for gallstones due to chronic hyperbilirubinemia from hemolysis. Although gallstones are a known complication, there is variability in estimates of disease burden and uncertainty in the association between sex and gall bladder disease (GBD)., Methods: This was a retrospective cohort study of children with SCD using administrative claims data (January 1, 2014-December 31, 2018). Population-averaged multivariable panel-data logistic regression models were used to evaluate the association between GBD clinical encounters (outcome) and two exposures (age and sex). Annual GBD risk was calculated using predictive margins, adjusting for disease severity, transfusion frequency, and hydroxyurea exposure., Results: A total of 13,745 individuals (of 21,487 possible) met inclusion criteria. The population was evenly split across sex (49.5% female) with predominantly Medicaid insurance (69%). A total of 946 individuals (6.9%) had GBD, 432 (3.1%) had a gallstone complication, and 487 (3.5%) underwent cholecystectomy. The annual risk of GBD rose nonlinearly from 1 to 5% between ages 1 and 19 years with no difference between males and females. Cholecystectomy occurred primarily in individuals with GBD (87%), and neither age nor sex was associated with cholecystectomy in this population. High disease severity (compared with low) more than doubled the annual risk of GBD at all ages., Conclusions: GBD is associated with age but not sex in children with SCD. Neither age nor sex is associated with risk of cholecystectomy. High disease severity increases the rate of GBD at all ages., (© 2022 Wiley Periodicals LLC.)

Background: Intranasal corticosteroids (INCS) are frequently used to treat OSA syndrome (OSAS) in children. However, their efficacy has not been rigorously tested., Research Question: Do INCS result in improved OSAS symptoms, polysomnography findings, behavior, and quality of life compared with placebo?, Study Design and Methods: In this randomized, double-blind, placebo-controlled trial, children with OSAS aged 5 to 12 years (N = 134) were randomized 2:1 to receive 3 months of INCS or placebo. Children in the INCS arm were then re-randomized to receive 9 months of INCS or placebo. Polysomnography, symptoms, and neurobehavioral findings were measured at baseline, 3 months, and 12 months. The primary outcome was change in obstructive apnea hypopnea index (OAHI) at 3 months, available for 122 children. The secondary outcome was OAHI change at 12 months, available for 70 children., Results: Median (interquartile range) age and OAHI at baseline for the entire group were 7.9 (6.3 to 9.9) years and 5.8 (3.6 to 9.7) events per hour. OAHI changes at 3 months (-1.72 [-3.91 to 1.92] events per hour) and 12 months (-1.2 [-4.22 to 1.71] events per hour) were not different between the two groups (P = not significant). OSAS symptoms and neurobehavioral results did not differ between the INCS and placebo groups at 3 and 12 months. The 38 children who received INCS for 12 months reported a significant OAHI decrease from 7.2 (3.62 to 9.88) events per hour to 3.7 (1.56 to 6.4) events per hour (P = .039)., Interpretation: In children with OSAS, treatment with INCS did not result in significant polysomnography, neurobehavioral, or symptom changes at 3 and 12 months of treatment. Twelve months of INCS treatment resulted in a statistically significant but not clinically relevant OAHI reduction., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02180672; URL: www., Clinicaltrials: gov., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Among children requiring 2 influenza doses in a given season, second dose receipt nearly halves the odds of influenza. Nationally, many children do not receive both needed doses. This study sought to compare the effectiveness of text message reminders with embedded interactive educational information versus usual care on receipt and timeliness of the second dose of influenza vaccine., Methods: This trial took place over the 2017 to 2018 and 2018 to 2019 influenza seasons among 50 pediatric primary care offices across 24 states primarily from the American Academy of Pediatrics' Pediatric Research in Office Settings practice-based research network. Caregiver-child dyads of children 6 months to 8 years in need of a second influenza vaccination that season were individually randomized 1:1 into intervention versus usual care, stratified by age and language within each practice. Intervention caregivers received automated, personalized text messages, including educational information. Second dose receipt by April 30 (season end) and by day 42 (2 weeks after second dose due date) were assessed using Mantel Haenszel methods by practice and language. Analyses were intention to treat., Results: Among 2086 dyads enrolled, most children were 6 to 23 months and half publicly insured. Intervention children were more likely to receive a second dose by season end (83.8% versus 80.9%; adjusted risk difference (ARD) 3.8%; 95% confidence interval [0.1 to 7.5]) and day 42 (62.4% versus 55.7%; ARD 8.3% [3.6 to 13.0])., Conclusions: In this large-scale trial of primary care pediatric practices across the United States, text message reminders were effective in promoting increased and timelier second dose influenza vaccine receipt.

Objective: To determine the relationship between number of attempts and adverse events during neonatal intubation., Study Design: A retrospective study of prospectively collected data of intubations in the delivery room and NICU from the National Emergency Airway Registry for Neonates (NEAR4NEOS) in 17 academic centers from 1/2016 to 12/2019. We examined the association between tracheal intubation attempts [1, 2, and ≥3 (multiple attempts)] and clinical adverse outcomes (any tracheal intubation associated events (TIAE), severe TIAE, and severe oxygen desaturation)., Results: Of 7708 intubations, 1474 (22%) required ≥3 attempts. Patient, provider, and practice factors were associated with higher TI attempts. Increasing intubation attempts was independently associated with a higher risk for TIAE. The adjusted odds ratio for TIAE and severe oxygen desaturation were significantly higher in TIs with 2 and ≥3 attempts than with one attempt., Conclusion: The risk of adverse safety events during intubation increases with the number of intubation attempts., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In this work, we present a study of electronic health record (EHR) data that aims to identify pediatric obesity clinical subtypes. Specifically, we examine whether certain temporal condition patterns associated with childhood obesity incidence tend to cluster together to characterize subtypes of clinically similar patients. In a previous study, the sequence mining algorithm, SPADE was implemented on EHR data from a large retrospective cohort (n = 49 594 patients) to identify common condition trajectories surrounding pediatric obesity incidence. In this study, we used Latent Class Analysis (LCA) to identify potential subtypes formed by these temporal condition patterns. The demographic characteristics of patients in each subtype are also examined. An LCA model with 8 classes was developed that identified clinically similar patient subtypes. Patients in Class 1 had a high prevalence of respiratory and sleep disorders, patients in Class 2 had high rates of inflammatory skin conditions, patients in Class 3 had a high prevalence of seizure disorders, and patients in Class 4 had a high prevalence of Asthma. Patients in Class 5 lacked a clear characteristic morbidity pattern, and patients in Classes 6, 7, and 8 had a high prevalence of gastrointestinal issues, neurodevelopmental disorders, and physical symptoms respectively. Subjects generally had high membership probability for a single class (>70%), suggesting shared clinical characterization within the individual groups. We identified patient subtypes with temporal condition patterns that are significantly more common among obese pediatric patients using a Latent Class Analysis approach. Our findings may be used to characterize the prevalence of common conditions among newly obese pediatric patients and to identify pediatric obesity subtypes. The identified subtypes align with prior knowledge on comorbidities associated with childhood obesity, including gastro-intestinal, dermatologic, developmental, and sleep disorders, as well as asthma., Competing Interests: The authors declare that they have no conflict of interests., (Copyright: © 2022 Campbell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To determine whether conditions coexisting with attention-deficit/hyperactivity disorder (ADHD) in preschool-age children are associated with choice of stimulants or alpha-2 adrenergic agonists (A2As) and/or likelihood of improvement in ADHD symptoms. Methods: A retrospective electronic health record review of 497 children from 7 Developmental Behavioral Pediatrics Research Network (DBPNet) sites. Children were <72 months when treated with medication for ADHD from January 1, 2013 to July 1, 2017. We abstracted coexisting conditions, initial medication prescribed, and whether the medication was associated with improvement in symptoms. Analysis of improvement was adjusted for clustering by clinician and site. Results: The median (interquartile range) child age at the time of initiation of ADHD medication was 62 (54-67) months. The most common coexisting conditions included language disorders (40%), sleep disorders (28%), disruptive behavior disorders (22.7%), autism spectrum disorder (ASD; 21.8%), and motor disorders (19.9%). No coexisting conditions were present in 17.1%; 1 in 36.8%, 2 in 26.8%, and ≥3 in 19.3%. Stimulants were initially prescribed for 322 (64.8%) and A2A for 175 (35.2%) children. Children prescribed stimulants were more likely to have no coexisting conditions than those prescribed A2A (22.3% vs. 7.4%; p  < 0.001). Coexisting ASD and sleep disorder were associated with increased likelihood of starting A2As versus stimulants ( p  < 0.0005; p  = 0.002). The association between medication treatment and improvement varied by number of coexisting conditions for 0, 1, 2, or ≥3, respectively (84.7%, 73.8%, 72.9%, 64.6%; p  = 0.031). Children with ≥3 coexisting conditions were less likely to respond to stimulants than children with no coexisting conditions (67.4% vs. 79.9%; p  = 0.037). Conclusions: Among preschool-age children with ADHD, those with ≥3 coexisting conditions were less likely to respond to stimulants than those with no coexisting conditions. This was not found for A2A, but further research is needed as very few children with no coexisting conditions were treated with A2A.

Background: Because of the broad clinical spectrum, heritable autoinflammatory diseases present a management and therapeutic challenge. The most common genetic interferonopathy, Aicardi Goutières Syndrome (AGS), is associated with early onset neurologic disability and systemic inflammation. The chronic inflammation of AGS is the result of dysregulation of interferon (IFN) expression by one of nine genes within converging pathways. While each AGS subtype shares common features, distinct patterns of severity and potential for systemic complications amongst the genotypes are emerging. Multilineage cytopenias are a potentially serious, but poorly understood, complication of AGS. As immunomodulatory treatment options are developed, it is important to characterize the role of the disease versus treatment in hematologic abnormalities. This will allow for better understanding and management of cytopenia., Methods: In total, 142 individuals with molecularly-confirmed AGS were included. Information on genotype, demographics, and all available hematologic laboratory values were collected from existing medical records. As part of a clinical trial, a subset of this cohort (n = 52) were treated with a janus kinase inhibitor (baricitinib), and both pre- and post-treatment values were included. Abnormal values were graded based on Common Terminology Criteria for Adverse Events (CTCAE v5.0), supplemented with grading definitions for thrombocytosis, and were compared across genotypes and baricitinib exposure., Results: In total, 11,184 laboratory values were collected over a median of 2.54 years per subject (range 0-22.68 years). To reduce bias from repeated sampling within a limited timeframe, laboratory results were restricted to the most abnormal value within a month (n = 8485). The most common abnormalities were anemia (noted in 24% of subjects prior to baricitinib exposure), thrombocytopenia (9%), and neutropenia (30%). Neutropenia was most common in the SAMHD1 cohort and increased with baricitinib exposure (38/69 measurements on baricitinib versus 14/121 while not on baricitinib). Having an abnormality prior to treatment was associated with having an abnormality on treatment for neutropenia and thrombocytopenia., Conclusion: By collecting available laboratory data throughout the lifespan, we were able to identify novel patterns of hematologic abnormalities in AGS. We found that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. Moderate-severe graded events of neutropenia, anemia, and leukopenia were more common on baricitinib, but rarely of clinical consequence. Based on these results, we would recommend careful monitoring of hematologic parameters of children affected by AGS throughout the lifespan, especially while on therapy, and consideration of AGS as a potential differential diagnosis in children with neurologic impairment of unclear etiology with hematologic abnormalities. Trial registration ClinicalTrials.gov Identifier: NCT01724580 ClinicalTrials.gov Identifier: NCT03921554., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rationale & Objective: Concerns about nonadherent behaviors often prevent dialysis patients from entering waitlists for transplant even though there is an inconsistent association of these behaviors with posttransplant outcomes. We examined the association between plausible metrics of nonadherence related to dialysis treatment and posttransplant outcomes., Study Design: Retrospective cohort. We linked national dialysis treatment data with transplant registry data., Setting and Participants: Adult patients receiving maintenance hemodialysis from January 1, 2004, through December 31, 2014, who received a kidney transplant at a US center., Exposures: We examined 5 nonadherence metrics: serum potassium level (≥5.2 mEq/L), serum phosphorus level (>5.5 mg/dL), interdialytic weight gain (IDWG; ≥5 L), shortened treatments (≥30 min), and missed treatments (≥1); missed treatment data were available only for 2004-2009. These metrics were characterized per proportion of time under observation. Dialysis observation time was divided into 3-month intervals (quarters), and the number of nonadherent measurements in each domain was calculated for each quarter., Outcomes: Allograft loss, mortality, and acute rejection in the first posttransplant year., Analytical Approach: Using Cox proportional hazards and logistic regression, we estimated the hazard ratios for graft loss and mortality and odds ratios for rejection., Results: 9,543 patients met inclusion criteria. In our primary model, hyperphosphatemia (adjusted hazard ratio [aHR], 1.27 [95% CI, 1.08-1.49]), large IDWG (aHR, 1.39 [95% CI, 1.23-1.59]), and shortened treatments (aHR, 1.54 [95% CI, 1.12-2.13]) were associated with greater rates of allograft loss, but hyperkalemia was not. Large IDWG (aHR, 1.49 [95% CI, 1.29-1.73]) and shortened treatments (aHR, 1.34 [95% CI, 1.13-1.58]) were associated with mortality, whereas hyperkalemia and hyperphosphatemia were not. Only shortened treatments were associated with an increased risk of acute rejection (adjusted odds ratio, 3.88 [95% CI, 1.98-7.58]). In models limited to the years 2004-2009 that included missed treatments, missed treatments were associated only with mortality., Limitations: Unmeasured confounding (eg, dietary data); adherence metrics used may have multiple, complex causes., Conclusions: Plausible measures of dialysis nonadherence have long-term associations with allograft and patient survival. Behavioral metrics were more closely associated with outcomes than laboratory markers were. The implications of nonadherent behaviors for dialysis patients must be carefully considered before patients are excluded from transplantation., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Context: Youth with obesity and abnormal glucose tolerance have an increased risk for atherosclerosis but the relative contributions of insulin resistance and hyperglycemia to dyslipidemia and the development of subclinical atherosclerosis are unknown., Objective: This work aims to determine the association between insulin resistance, dyslipidemia, and carotid intimal thickness (cIMT) in adolescents with normal and abnormal glucose tolerance., Methods: An observational cohort study in 155 youth: 44 obese insulin sensitive (OIS; fasting insulin ≤ 20 µM/mL, body mass index [BMI] ≥ 95th percentile), 35 obese insulin resistant (OIR; fasting insulin > 20 µM/mL, BMI ≥ 95th percentile), 34 obese abnormal glucose tolerant (AGT; BMI ≥ 95th percentile), and 42 Lean (BMI 5th-85th percentile). Lipids, lipoprotein particle size and concentration (-P), insulin sensitivity (SI an intravenous glucose test), and CMIT were compared using linear models adjusted for age, race/ethnicity, biological sex, and Tanner stage. Lipid/lipoprotein profile and CMIT were reevaluated in a subset after 2 years., Results: Compared to OIS and Lean, OIR and AGT had elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) but similar total cholesterol and low-density lipoprotein cholesterol (LDL-C). Among OIS, OIR, AGT, lower SI was associated with atherogenic lipids (higher triglycerides, LDL-C, non-HDL-C, and lower HDL-C) and lipoproteins (higher total LDL-P and small HDL-P, and lower large HDL-P). There was a steeper decline in the association of SI with HDL-C and large HDL-P in AGT compared with OIR and OIS. cIMT was comparable across groups and inversely correlated with SI, with no change after 2 years., Conclusion: Among youth with obesity, insulin resistance was associated with an atherogenic lipoprotein/lipid profile and cIMT, regardless of glucose tolerance status. Insulin resistance in AGT youth was associated with a shift to smaller HDL-P compared to normoglycemic youth with obesity. Alterations in HDL-P metabolism may be early adverse manifestations of hyperglycemia in youth with obesity., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)

Background: Tracheal intubation (TI) practice across pediatric emergency departments (EDs) has not been comprehensively reported. We aim to describe TI practice and outcomes in pediatric EDs in contrast to those in intensive are units (ICUs) and use the data to identify quality improvement targets., Methods: Consecutive TI encounters from pediatric EDs and ICUs in the National Emergency Airway Registry for Children (NEAR4KIDS) database from 2015 to 2018 were analyzed for patient, provider, and practice characteristics and outcomes: adverse TI-associated events (TIAEs), oxygen desaturation (SpO 2 < 80%), and procedural success. A multivariable model identified factors associated with TIAEs in the ED., Results: A total of 756 TIs in 13 pediatric EDs and 12,512 TIs in 51 pediatric/cardiac ICUs were reported. Median (interquartile range [IQR]) patient age for ED TIs was higher (32 [7-108] months) than that for ICU TIs (15 [3-91] months; p < 0.001). Proportion of TIs for respiratory decompensation (52% of ED vs. 64% ICU), shock (26% vs. 14%), and neurologic deterioration (30% vs. 11%) also differed by location. Limited neck mobility was reported more often in the ED (16% vs. 6%). TIs in the ED were performed more often via video laryngoscopy (64% vs. 29%). Adverse TIAE rates (15.6% ED, 14% ICU; absolute difference = 1.6%, 95% confidence interval [CI] = -1.1 to 4.2; p = 0.23) and severe TIAE rates (5.4% ED, 5.8% ICU; absolute difference = -0.3%, 95% CI = -2.0 to 1.3; p = 0.68) were not different. Oxygen desaturation was less commonly reported in ED TIs (13.6%) than ICU TIs (17%, absolute difference = -3.4%, 95% CI = -5.9 to -0.8; p = 0.016). Among ED TIs, shock as an indication (adjusted odds ratio [aOR] = 2.15, 95% CI = 1.26 to 3.65) and limited mouth opening (aOR = 1.74, 95% CI = 1.04 to 2.93) were independently associated with TIAEs., Conclusions: While TI characteristics vary between pediatric EDs and ICUs, outcomes are similar. Shock and limited mouth opening were independently associated with adverse TI events in the ED., (© 2021 by the Society for Academic Emergency Medicine.)

Importance: Infants who appear neurologically well and have fractures concerning for abuse are at increased risk for clinically occult head injuries. Evidence of excess variation in neuroimaging practices when abuse is suspected may indicate opportunity for quality and safety improvement., Objective: To quantify neuroimaging practice variation across children's hospitals among infants with fractures evaluated for abuse, with the hypothesis that hospitals would vary substantially in neuroimaging practices. As a secondary objective, factors associated with neuroimaging use were identified, with the hypothesis that age and factors associated with potential biases (ie, payer type and race or ethnicity) would be associated with neuroimaging use., Design, Setting, and Participants: This cross-sectional study included infants with a femur or humerus fracture or both undergoing abuse evaluation at 44 select US children's hospitals in the Pediatric Health Information System (PHIS) from January 1, 2016, through March 30, 2020, including emergency department, observational, and inpatient encounters. Included infants were aged younger than 12 months with a femur or humerus fracture or both without overt signs or symptoms of head injury for whom a skeletal survey was performed. To focus on infants at increased risk for clinically occult head injuries, infants with billing codes suggestive of overt neurologic signs or symptoms were excluded. Multivariable logistic regression was used to investigate demographic, clinical, and temporal factors associated with use of neuroimaging. Marginal standardization was used to report adjusted percentages of infants undergoing neuroimaging by hospital and payer type. Data were analyzed from March 2021 through January 2022., Exposures: Covariates included age, sex, race and ethnicity, payer type, fracture type, presentation year, and hospital., Main Outcomes and Measures: Use of neuroimaging by CT or MRI., Results: Of 2585 infants with humerus or femur fracture or both undergoing evaluations for possible child abuse, there were 1408 (54.5%) male infants, 1726 infants (66.8%) who were publicly insured, and 1549 infants (59.9%) who underwent neuroimaging. The median (IQR) age was 6.1 (3.2-8.3) months. There were 748 (28.9%) Black non-Hispanic infants, 426 (16.5%) Hispanic infants, 1148 (44.4%) White non-Hispanic infants. In multivariable analyses, younger age (eg, odds ratio [OR] for ages <3 months vs ages 9 to <12 months, 13.2; 95% CI, 9.54-18.2; P < .001), male sex (OR, 1.47; 95% CI, 1.22-1.78; P < .001), payer type (OR for public vs private insurance, 1.48; 95% CI, 1.18-1.85; P = .003), fracture type (OR for femur and humerus fracture vs isolated femur fracture, 5.36; 95% CI, 2.11-13.6; P = .002), and hospital (adjusted range in use of neuroimaging, 37.4% [95% CI 21.4%-53.5%] to 83.6% [95% CI 69.6%-97.5%]; P < .001) were associated with increased use of neuroimaging, but race and ethnicity were not. Publicly insured infants were more likely to undergo neuroimaging (62.0%; 95% CI, 60.0%-64.1%) than privately insured infants (55.1%; 95% CI, 51.8%-58.4%) (P = .001)., Conclusions and Relevance: This study found that hospitals varied in neuroimaging practices among infants with concern for abuse. Apparent disparities in practice associated with insurance type suggest opportunities for quality, safety, and equity improvement.

Objective: To assess parental decision-making preferences when caring for a child with serious illness and to evaluate for an association between preferences and parental trust in physicians, and potential modification of this association by parental anxiety or depression. Methods: We analyzed cross-sectional data from 200 parents of 158 children in the United States who had life-threatening illnesses and whose attending physicians thought that the parents would have to make major medical decision in the next 12 to 24 months. Parents completed measures of decision-making preferences, trust in physicians, anxiety, and depression. Results: Higher reported levels of trust were associated with lower preferences for autonomous decision making (Spearman correlation = -0.24; 95% confidence interval [CI] = -0.36 to -0.01; p  < 0.008). Among parents with higher levels of trust, increasing anxiety scores were associated with decreasing preference for autonomy, whereas among parents with lower levels of trust, increasing anxiety scores showed an increasing preference for autonomy (regression coefficient = -0.01; 95% CI = -0.02 to -0.001; p  ≤ 0.03). Conclusions: Decreasing trust in physicians is associated with a higher preference for autonomous decision making. Parents who have higher levels of anxiety exhibit this association more strongly. Decision support for parents of children with serious illness should use strategies to respect parental decision-making preferences, address potential distrust, and provide mental health support to parents who are anxious or depressed.

Rationale & Objective: Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined after kidney transplantation. We studied how measures of body composition change after receipt of a kidney allograft., Study Design: Prospective longitudinal cohort study., Setting & Participants: 60 kidney transplant recipients, aged 20-60 years, at the University of Pennsylvania., Exposure: Kidney transplantation., Outcome: Dual-energy x-ray absorptiometry measures of fat mass index (FMI) and appendicular lean mass index (ALMI, representing muscle mass), computed tomography measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALM FMI ) is an established index of relative sarcopenia., Analytical Approach: Measures expressed as age, sex, and race-specific z scores for transplant recipients were compared with 327 healthy controls. Regression models were used to identify correlates of change in outcome z scores and compare transplant recipients with controls., Results: At transplantation, ALMI, ALMI FMI , muscle strength, and muscle density z scores were lower versus controls (all P≤0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18% to 45%. Although ALMI increased after transplantation (P<0.001) and was comparable with the controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMI FMI deficits (mean z score of-0.31 at 24 months; P=0.02 vs controls). Muscle density improved after transplantation despite gains in FMI (P=0.02). Muscle strength relative to ALMI also improved (P=0.04) but remained low compared with controls (P=0.01). Exercise increased in the early months after transplantation (P<0.05) but remained lower than controls (P = 0.02)., Limitations: Lack of muscle biopsies precluded assessment of muscle histology and metabolism., Conclusions: The 2-year interval after kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass, resulting in persistent relative sarcopenia., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Black patients are less likely than white patients to receive pain treatment, especially opioids, for both acute and chronic pain. Black men are at higher risk than other populations of being "assumed criminal" regardless of any involvement in criminal activity. Additionally, certain injury and patient characteristics such as intentionality of injury and substance use history may lead providers to suspect criminal involvement and impact pain treatment decisions. The purpose of this study was to describe factors that predict receipt of opioid prescription at hospital discharge. We conducted a secondary analysis of data from a cohort of 623 seriously injured Black men treated at trauma centers in Philadelphia between 2013 and 2017. Regression models were used to examine relationships between discharge opioid prescriptions, injury intent, and substance use history. Controlling for age, injury severity, pain score, length of hospital stay (LOS), insurance type, and year of study, receipt of opioids was not impacted by injury intent. However, patients who self-reported substance overuse were less likely to receive opioids than those who did not. Patients with higher injury severity, pain scores, and longer LOS were more likely to receive opioids. Of patients who received opioids, patients with higher pain scores and longer LOS received higher dosages than those with lower scores and shorter LOS. While previous research highlights stigmatization experienced by intentionally injured patients, injury intent did not impact receipt of discharge opioid prescriptions in this study. Future research should continue to explore the effect of injury intent on patients' experiences in the healthcare system., (© 2020. W. Montague Cobb-NMA Health Institute.)

Aicardi-Goutières syndrome (AGS) is a monogenic type-I interferonopathy that results in neurologic injury. The systemic impact of sustained interferon activation is less well characterized. Liver inflammation is known to be associated with the neonatal form of AGS, but the incidence of AGS-related hepatitis across lifespan is unknown.We compared natural history data including liver enzyme levels with markers of inflammation, (liver-specific autoantibodies and interferon signaling gene expression[ISG] scores). Liver enzymes were classified as normal or elevated by the fold increase over the upper limit of normal (ULN). The highest increases were designated as hepatitis, defined as aspartate-aminotransferase or alanine-aminotransferase threefold ULN, or gamma-glutamyl transferase 2.5-fold ULN. A larger cohort was used to further characterize the longitudinal incidence of liver abnormalities and the association with age and genotype.Across the AGS cohort ( n  = 102), elevated liver enzymes were identified in 76 individuals (74.5%) with abnormalities at a level consistent with hepatitis in 29 individuals (28.4%). SAMHD1 mutations were less likely to be associated with hepatitis (log-rank test; p  = 0.011). Hepatitis was associated with early-onset disease and microcephaly (log-rank test; microcephaly p  = 0.0401, age onset p  = 0.0355). While most subjects ( n  = 20/33) were found to have liver-specific autoantibodies, there was no association between the presence of autoantibodies or ISG scores with hepatitis-level enzyme elevations.In conclusion, all genotypes of AGS are associated with transient elevations of liver enzymes and the presence of liver-associated autoantibodies. This adds to our growing understanding of the systemic pathology AGS., Competing Interests: Dr. Gavazzi reports grants from NINDS, 1 U01 NS106845-01A1, during the conduct of the study;Dr. Adang reports grants from NINDS, 1 U01 NS106845-01A1, during the conduct of the study;Dr. Vanderver reports grants from NINDS, 1 U01 NS106845-01A1, during the conduct of the study; nonfinancial support from Gilead, grants from Eli Lilly, nonfinancial support from Illumina, grants from Takeda, grants from Homology, grants from Biogen, outside the submitted work;Dr. Shults reports grants from NINDS, 1 U01 NS106845-01A1, during the conduct of the study;All other authors reported no conflict of interest., (Thieme. All rights reserved.)

Background: Leukodystrophies are a rare class of disorders characterized by severe neuromotor disability. There is a strong need for research regarding the functional status of people with leukodystrophy which is limited by the need for in-person assessments of mobility. The purpose of this study is to assess the reliability of the Gross Motor Function Measure-88 (GMFM-88) using telemedicine compared with standard in-person assessments in patients with leukodystrophy., Methods: A total of 21 subjects with a diagnosis of leukodystrophy (age range = 1.79-52.82 years) were evaluated by in-person and by telemedicine evaluations with the GMFM-88 by physical therapists. Inter-rater reliability was assessed through evaluation of the same subject by two independent raters within a three-week period (n = 10 encounters), and intrarater reliability was assessed through blinded rescoring of video-recorded assessments after a one-week time interval (n = 6 encounters)., Results: Remote assessments were performed by caregivers in all 21 subjects using resources found in the home with remote guidance. There was agreement between all paired in-person and remote measurements (Lin's concordance correlation ≥0.995). The Bland-Altman analysis indicated that the paired differences were within ±5%. Intrarater and inter-rater reliability demonstrated an intraclass correlation coefficient of >0.90., Conclusions: These results support that remote application of the GMFM-88 is a feasible and reliable approach to assess individuals with leukodystrophy. Telemedicine application of outcome measures may be of particular value in rare diseases and those with severe neurologic disability that impacts the ability to travel., (Copyright © 2021 Elsevier Inc. All rights reserved.)