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Background: Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. Objective: Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). Methods: POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. Results: Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy ( p = 0.016). Conclusions: B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.

The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis.Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays.AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p 0.001).MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2022.

Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery’s composite mean score or individual test scores ( ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite ( p = 0.03), Symbol Digit Modalities Test ( p = 0.02), Rey Auditory Verbal Learning Test ( p = 0.01), and Cogstate choice reaction time ( p Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Objective To determine if low household income is associated with disease severity following emergency department (ED) discharge in children with acute gastroenteritis (AGE). Methods We conducted a secondary analysis employing data collected in 10 US-based tertiary-care, pediatric EDs between 2014 and 2017. Participants were aged 3 to 48 months and presented for care due to AGE. Income status was defined based on 1) home ZIP Code median annual home income and 2) percentage of home ZIP Code households below the poverty threshold. The primary outcome was moderate-to-severe AGE, defined by a post-ED visit Modified Vesikari Scale (MVS) score ≥9. Secondary outcomes included in-person revisits, revisits with intravenous rehydration, hospitalization, and etiologic pathogens. Results About 943 (97%) participants with a median age of 17 months (interquartile range 10, 28) completed follow-up. Post-ED visit MVS scores were lower for the lowest household income group (adjusted: -0.60; 95% confidence interval [CI]: -1.13, -0.07). Odds of experiencing an MVS score ≥9 did not differ between groups (adjusted odds ratio: 0.91; 95% CI: 0.54, 1.52). No difference in the post-ED visit MVS score or the proportion of participants with scores ≥9 was observed using the national poverty threshold definition. For both income definitions, there were no differences in terms of revisits following discharge, hospitalizations, and intravenous rehydration. Bacterial enteropathogens were more commonly identified in the lowest socioeconomic group using both definitions. Conclusions Lower household income was not associated with increased disease severity or resource use. Economic disparities do not appear to result in differences in the disease course of children with AGE seeking ED care.

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk ( PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene ( PRF1, p = 2.70 × 10−3) and two MHC genes ( BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Objectives Wait time for emergency care is a quality measure that affects clinical outcomes and patient satisfaction. It is unknown if there is racial/ethnic variability in this quality measure in pediatric emergency departments (PEDs). We aim to determine whether racial/ethnic differences exist in wait times for children presenting to PEDs and examine between-site and within-site differences. Methods We conducted a retrospective cohort study for PED encounters in 2016 using the Pediatric Emergency Care Applied Research Network Registry, an aggregated deidentified electronic health registry comprising 7 PEDs. Patient encounters were included among all patients 18 years or younger at the time of the ED visit. We evaluated differences in emergency department wait time (time from arrival to first medical evaluation) considering patient race/ethnicity as the exposure. Results Of 448,563 visits, median wait time was 35 minutes (interquartile range, 17-71 minutes). Compared with non-Hispanic White (NHW) children, non-Hispanic Black (NHB), Hispanic, and other race children waited 27%, 33%, and 12% longer, respectively. These differences were attenuated after adjusting for triage acuity level, mode of arrival, sex, age, insurance, time of day, and month [adjusted median wait time ratios (95% confidence intervals): 1.11 (1.10-1.12) for NHB, 1.12 (1.11-1.13) for Hispanic, and 1.05 (1.03-1.06) for other race children compared with NHW children]. Differences in wait time for NHB and other race children were no longer significant after adjusting for clinical site. Fully adjusted median wait times among Hispanic children were longer compared with NHW children [1.04 (1.03-1.05)]. Conclusions In unadjusted analyses, non-White children experienced longer PED wait times than NHW children. After adjusting for illness severity, patient demographics, and overcrowding measures, wait times for NHB and other race children were largely determined by site of care. Hispanic children experienced longer within-site and between-site wait times compared with NHW children. Additional research is needed to understand structures and processes of care contributing to wait time differences between sites that disproportionately impact non-White patients.

BackgroundWe previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.MethodsUsing a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence ofDRB1*15and the absence ofA*02,and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, includingIL-6(rs2069852),BCL-2(rs2187163) andNFKB1(rs7665090).Results490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, pNFKB1SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence ofHLA-A*02(AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products andNFKB1SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found withIL-6andBCL-2SNP GG genotypes.ConclusionsThe presence of gene–environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries.Severely injured children (0 up to 18A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified.Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA- DRB1*15, the strongest genetic variant associated with POMS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC’s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 ( DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother’s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

Children with sickle cell disease commonly experience vaso-occlusive pain episodes due to sickling of erythrocytes, which often requires care in the emergency department. Our objective was to assess the use and impact of intranasal fentanyl for the treatment of children with SCD-VOE on discharge from the emergency department in a multicenter study. We conducted a cross-sectional study at 20 academic pediatric emergency departments in the United States and Canada. We used logistic regression to test bivariable and multivariable associations between the outcome of discharge from the emergency department and candidate variables theoretically associated with discharge. There study included 400 patients; 215 (54%) were female. The median age was 14.6 (interquartile range 9.8, 17.6) years. Nineteen percent (n=75) received intranasal fentanyl in the emergency department. Children who received intranasal fentanyl had nearly nine-fold greater adjusted odds of discharge from the emergency department compared to those who did not (adjusted odds ratio 8.99, 95% CI 2.81-30.56, P0.001). The rapid onset of action and ease of delivery without IV access offered by intranasal fentanyl make it a feasible initial parenteral analgesic in the treatment of children with sickle cell disease presenting with vaso-occlusive pain episodes in the acute-care setting. Further study is needed to determine potential causality of the association between intranasal fentanyl and discharge from the emergency department observed in this multicenter study. This article is protected by copyright. All rights reserved.

Introduction: Acquiring parental consent is critical to pediatric clinical research, especially in interventional trials. In this study we investigated demographic, clinical, and environmental factors associated with likelihood of parental permission for enrollment in a study of therapies for diabetic ketoacidosis (DKA) in children. Methods: We analyzed data from patients and parents who were approached for enrollment in the Pediatric Emergency Care Applied Research Network (PECARN) Fluid Therapies Under Investigation in DKA (FLUID) trial at one major participating center. We determined the influence of various factors on patient enrollment, including gender, age, distance from home to hospital, insurance status, known vs new onset of diabetes, glycemic control (hemoglobin A1c), DKA severity, gender of the enroller, experience of the enroller, and time of enrollment. Patients whose parents consented to participate were compared to those who declined participation using bivariable and multivariable analyses controlling for the enroller. Results: A total of 250 patient/parent dyads were approached; 177 (71%) agreed to participate, and 73 (29%) declined. Parents of patients with previous episodes of DKA agreed to enroll more frequently than those with a first DKA episode (94.3% for patients with 1-2 previous DKA episodes, 92.3% for > 2 previous episodes, vs 64.9% for new onset diabetes and 63.2% previously diagnosed but no previous DKA). Participation was also more likely with more experienced enrollers (odds ratio [95% confidence interval] of participation for an enroller with more than two years’ experience vs less than two years: 2.46 [1.53, 3.97]). After adjusting for demographic and clinical factors, significant associations between participation and both DKA history and enroller experience remained. Patient age, gender, distance of home from hospital, glycemic control, insurance status, and measures of DKA severity were not associated with likelihood of participation. Conclusion: Familiarity with the disease process (previously diagnosed diabetes and previous experience with DKA) and experience of the enroller favorably influenced the likelihood of parental permission for enrollment in a study of DKA in children.

OBJECTIVE Fluid replacement to correct dehydration, acidosis, and electrolyte abnormalities is the cornerstone of treatment for diabetic ketoacidosis (DKA), but little is known about optimal fluid infusion rates and electrolyte content. The objective of this study was to evaluate whether different fluid protocols affect the rate of normalization of biochemical derangements during DKA treatment. RESEARCH DESIGN AND METHODS The current analysis involved moderate or severe DKA episodes (n = 714) in children age RESULTS The rate of change of pH did not differ by treatment arm, but Pco2 increased more rapidly in the fast versus slow fluid infusion arms during the initial 4 h of treatment. The anion gap also decreased more rapidly in the fast versus slow infusion arms during the initial 4 and 8 h. Glucose-corrected sodium levels remained stable in patients assigned to 0.90% saline but decreased in those assigned to 0.45% saline at 4 and 8 h. Potassium levels decreased, while chloride levels increased more rapidly with 0.90% versus 0.45% saline. Hyperchloremic acidosis occurred more frequently in patients in the fast arms (46.1%) versus the slow arms (35.2%). CONCLUSIONS In children treated for DKA, faster fluid administration rates led to a more rapid normalization of anion gap and Pco2 than slower fluid infusion rates but were associated with an increased frequency of hyperchloremic acidosis.

OBJECTIVE: We evaluated the acceptability of the Pediatric Quality of Life Inventory (PedsQL) and other outcomes as the primary outcomes for a pediatric hemorrhagic trauma trial (TIC-TOC) among clinicians. METHODS: We conducted a mixed-methods study that included an electronic questionnaire followed by teleconference discussions. Participants confirmed or rejected the PedsQL as the primary outcome for the TIC-TOC trial and evaluated and proposed alternative primary outcomes. Responses were compiled and a list of themes and representative quotes was generated. RESULTS: 73 of 91 (80%) participants completed the questionnaire. 61 (84%) participants agreed that the PedsQL is an appropriate primary outcome for children with hemorrhagic brain injuries. 32 (44%) participants agreed that the PedsQL is an acceptable primary outcome for children with hemorrhagic torso injuries, 27 (38%) participants were neutral, and 13 (18%) participants disagreed. Several themes were identified from responses, including that the PedsQL is an important and patient-centered outcome but may be affected by other factors, and that intracranial hemorrhage progression assessed by brain imaging (among patients with brain injuries) or blood product transfusion requirements (among patients with torso injuries) may be more objective outcomes than the PedsQL. CONCLUSIONS: The PedsQL was a well-accepted proposed primary outcome for children with hemorrhagic brain injuries. Traumatic intracranial hemorrhage progression was favored by a subset of clinicians. A plurality of participants also considered the PedsQL an acceptable outcome for selection for pediatric trauma clinical trial children with hemorrhagic torso injuries. Blood product transfusion requirement was favored by fewer participants.

Background Gastroenteritis is a common and impactful disease in childhood. Probiotics are often used to treat acute gastroenteritis (AGE); however, in a large multicenter randomized controlled trial (RCT) in 971 children, Lactobacillus rhamnosus GG (LGG) was no better than placebo in improving patient outcomes. Objectives We sought to determine whether the effect of LGG is associated with age, weight z score and weight percentile adjusted for age and sex, or dose per kilogram administered. Methods This was a preplanned secondary analysis of a multicenter double-blind RCT of LGG 1 × 1010 CFU twice daily for 5 d or placebo in children 3-48 mo of age with AGE. Our primary outcome was moderate to severe gastroenteritis. Secondary outcomes included diarrhea and vomiting frequency and duration, chronic diarrhea, and side effects. We used multivariable linear and nonlinear models testing for interaction effects to assess outcomes by age, weight z score and weight percentile adjusted for age and sex, and dose per kilogram of LGG received. Results A total of 813 children (84%) were included in the analysis; 413 received placebo and 400 LGG. Baseline characteristics were similar between treatment groups. There were no differential interaction effects across ranges of age (P-interaction = 0.32), adjusted weight z score (P-interaction = 0.43), adjusted weight percentile (P-interaction = 0.45), or dose per kilogram of LGG received (P-interaction = 0.28) for the primary outcome. Whereas we found a statistical association favoring placebo at the extremes of adjusted weight z scores for the number of vomiting episodes (P-interaction = 0.02) and vomiting duration (P-interaction = 0.0475), there were no statistically significant differences in other secondary outcome measures (all P-interactions > 0.05). Conclusions LGG does not improve outcomes in children with AGE regardless of the age, adjusted weight z score, and adjusted weight percentile of participants, or the probiotic dose per kilogram received. These results further strengthen the conclusions of low risk of bias clinical trials which demonstrate that LGG provides no clinical benefit in children with AGE.This trial was registered at clinicaltrials.gov as NCT01773967.

BackgroundClinical assessments are a primary method for ascertaining suicide risk, yet the language used across measures is inconsistent. The implications of these discrepancies for adolescent responding are unknown, which is troubling as multiple research areas (i.e. on culture, mental health language, and suicide communication) indicate individuals from varying sociodemographic backgrounds may communicate differently regarding mental health concerns. The aims of the current study are to investigate whether a geographically diverse sample of adolescents respond differently to directly and indirectly phrased suicide attempt questions (i.e. directly phrased includes the term ‘suicide’ and indirectly asks about suicidal behavior without using ‘suicide’), and to examine whether sociodemographic factors and history of mental health service usage relate to endorsement differences.MethodsParticipants were N = 5909 adolescents drawn from the Emergency Department Screening for Teens at Risk for Suicide multi-site study. The lifetime suicide attempt was assessed with two items from an adapted version of the Columbia Suicide Severity Rating Scale (C-SSRS; Posner et al., 2008): (1) a directly phrased question asking about ‘suicide attempts’ and (2) an indirectly phrased question providing the definition of an attempt.ResultsAn adolescent majority (83.7%) consistently reported no lifetime suicide attempt across items, 10.1% consistently reported one or more lifetime attempts across items, and 6.2% of adolescents responded discordantly to the items.ConclusionsMultivariable models indicated multiple demographic and mental health service variables significantly predicted discordant responding, with a notable finding being that father/stepfather education level at or below high school education predicted endorsing only the direct question.

Moderate to vigorous physical activity (MVPA), sports, and reduced screen time are associated with favorable youth risk profiles. We evaluated the association of MVPA, sports, and screen time with adolescent behaviors among pediatric emergency department youth. Adolescents were assessed for alcohol/drug use, risky behavior, conduct disorder, and depressive mood. MVPA was activity for ≥5 days/week and ≥60 minutes/day. Increased screen time was ≥3 hours/day computer/TV use for non-schoolwork. Multivariable regression studied association between MVPA, sports, and increased screen time and outcomes adjusting for demographics and academic achievement. Older age and lower academic achievement were significantly associated with risky behaviors, conduct disorder, and depression. Youth who endorsed MVPA and sports participation had less depression (odds ratio [OR] = 0.76; confidence interval [CI] = 0.66-0.87). Increased screen time was associated with conduct disorder (OR = 1.6; CI = 1.3-2.1), depression (OR = 1.2; CI = 1.0-1.4), and drug use (OR = 1.8; CI = 1.1-2.8). In pediatric emergency department youth, MVPA and sports participation is associated with less depression. Increased screen time is associated with conduct disorders, depression, and drug use.

OBJECTIVE This study assessed whether a single diabetic ketoacidosis (DKA) episode is associated with cognitive declines in children with newly diagnosed type 1 diabetes and whether the same is true in children who had previously been diagnosed after accounting for variations in glycemic control and other relevant factors. RESEARCH DESIGN AND METHODS We prospectively enrolled 758 children, 6–18 years old, who presented with DKA in a randomized multisite clinical trial evaluating intravenous fluid protocols for DKA treatment. DKA was moderate/severe in 430 children and mild in 328 children. A total of 392 children with DKA had new onset of type 1 diabetes, and the rest were previously diagnosed. Neurocognitive assessment occurred 2–6 months after the DKA episode. A comparison group of 376 children with type 1 diabetes, but no DKA exposure, was also enrolled. RESULTS Among all patients, moderate/severe DKA was associated with lower intelligence quotient (IQ) (β = −0.12, P < 0.001), item-color recall (β = −0.08, P = 0.010), and forward digit span (β = −0.06, P = 0.04). Among newly diagnosed patients, moderate/severe DKA was associated with lower item-color recall (β = −0.08, P = 0.04). Among previously diagnosed patients, repeated DKA exposure and higher HbA1c were independently associated with lower IQ (β = −0.10 and β = −0.09, respectively, P < 0.01) and higher HbA1c was associated with lower item-color recall (β = −0.10, P = 0.007) after hypoglycemia, diabetes duration, and socioeconomic status were accounted for. CONCLUSIONS A single DKA episode is associated with subtle memory declines soon after type 1 diabetes diagnosis. Sizable IQ declines are detectable in children with known diabetes, suggesting that DKA effects may be exacerbated in children with chronic exposure to hyperglycemia.

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P

ObjectiveTo characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS).MethodsThis was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005.ResultsIn total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previously published adult Multiple Sclerosis Severity Scores (MSSS) showed slower progression of Ped-MSSS with increasing gaps between higher EDSS score and years after diagnosis. Decile scores in our POMS cohort for EDSS of 2.0, 3.0, and 6.0 were 8.00/9.46/9.94, 7.86/9.39/9.91, and 7.32/9.01/9.86 at 2, 5, and 10 years, respectively. Notable predictors of disease progression in both EDSS and Ped-MSSS models were ever having a motor relapse and EDSS at year 1. Symbol Digit Modalities Test (SDMT) scores were inversely correlated with duration of disease activity and cerebral functional score.ConclusionsPersons with POMS exhibit lower EDSS scores compared to persons with adult-onset MS. Use of a Ped-MSSS model may provide an alternative to EDSS scoring in clinical assessment of disease severity and disability accrual.

OBJECTIVE: Differences in the quality of emergency department (ED) care are often attributed to nonclinical factors such as variations in the structure, systems, and processes of care. Few studies have examined these associations among children. We aimed to determine whether process measures of quality of care delivered to patients receiving care in children’s hospital EDs were associated with physician-level or hospital-level factors. METHODS: We included children (

Objective To measure the variability in discharge opioid prescription practices for children discharged from the emergency department (ED) with a long-bone fracture. Design A retrospective cohort study of pediatric ED visits in 2015. Setting Four pediatric EDs. Subjects Children aged four to 18 years with a long-bone fracture discharged from the ED. Methods A multisite registry of electronic health record data (PECARN Registry) was analyzed to determine the proportion of children receiving an opioid prescription on ED discharge. Multivariable logistic regression was performed to determine characteristics associated with receipt of an opioid prescription. Results There were 5,916 visits with long-bone fractures; 79% involved the upper extremity, and 27% required reduction. Overall, 15% of children were prescribed an opioid at discharge, with variation between the four EDs: A = 8.2% (95% confidence interval [CI] = 6.9–9.7%), B = 12.1% (95% CI = 10.5–14.0%), C = 16.9% (95% CI = 15.2–18.8%), D = 23.8% (95% CI = 21.7–26.1%). Oxycodone was the most frequently prescribed opioid. In the regression analysis, in addition to variation by ED site of care, age 12–18 years, white non-Hispanic, private insurance status, reduced fracture, and severe pain documented during the ED visit were associated with increased opioid prescribing. Conclusions For children with a long-bone fracture, discharge opioid prescription varied widely by ED site of care. In addition, black patients, Hispanic patients, and patients with government insurance were less likely to be prescribed opioids. This variability in opioid prescribing was not accounted for by patient- or injury-related factors that are associated with increased pain. Therefore, opioid prescribing may be modifiable, but evidence to support improved outcomes with specific treatment regimens is lacking.

Study objective This study aimed to explore oral ondansetron usage and impact on outcomes in clinical practice. Methods This observational study was a planned secondary analysis of 2 trials conducted in 10 US and 6 Canadian institutions between 2014 and 2017. Children 3 to 48 months old with gastroenteritis and ≥3 episodes of vomiting in the 24 hours preceding emergency department (ED) presentation were included. Oral ondansetron was administered at the discretion of the provider. The principal outcomes were intravenous fluid administration and hospitalization at the index visit and during the subsequent 72 hours and diarrhea and vomiting frequency during the 24 hours following the ED visit. Results In total, 794 children were included. The median age was 16.0 months (interquartile range 10.0 to 26.0), and 50.1% (398/794) received oral ondansetron. In propensity-adjusted analysis (n=528), children administered oral ondansetron were less likely to receive intravenous fluids at the index visit (adjusted odds ratio [aOR] 0.50; 95% confidence interval [CI] 0.29 to 0.88). There were no differences in the frequencies of intravenous fluid administration within the first 72 hours (aOR 0.65; 95% CI 0.39 to 1.10) or hospitalization at the index visit (aOR 0.31; 95% CI 0.09 to 1.10) or the subsequent 72 hours (aOR 0.52; 95% CI 0.21 to 1.28). Episodes of vomiting (aRR 0.86; 95% CI 0.63 to 1.19) and diarrhea (aRR 1.11; 95% CI 0.93 to 1.32) during the 24 hours following ED discharge also did not differ. Conclusion Among preschool-aged children with gastroenteritis seeking ED care, oral ondansetron administration was associated with a reduction in index ED visit intravenous fluid administration; it was not associated with intravenous fluids administered within 72 hours, hospitalization, or vomiting and diarrhea in the 24 hours following discharge.

Importance Diabetic kidney disease is among the most important causes of end-stage kidney disease worldwide. Risk factors for diabetic kidney disease remain incompletely defined. Recent studies document a high frequency of acute kidney injury (AKI) during diabetic ketoacidosis (DKA) in children, raising the question of whether these AKI episodes might contribute to future risk of diabetic kidney disease. Objective To determine whether episodes of AKI occurring during DKA in children are associated with increased risk of development of microalbuminuria. Design, setting, and participants This retrospective review of medical records included children with type 1 diabetes with 1 or more urine albumin levels measured during routine diabetes care from 2 university-affiliated urban tertiary children's hospitals in the United States from January 2006 to December 2019. Age at diagnosis of diabetes, hemoglobin A1c levels, episodes of DKA, pH and creatinine levels during DKA, and urine albumin and creatinine measurements were analyzed. Cox proportional hazards regression models were used to identify variables affecting the hazard rate for microalbuminuria development. Analyses began January 2021 and ended May 2021. Exposures Episodes of DKA and episodes of AKI occurring during DKA. Main outcomes and measures AKI occurrence and AKI stage were determined from serum creatinine measurements during DKA using Kidney Disease: Improving Global Outcomes criteria. Microalbuminuria was defined as urine albumin-to-creatinine ratio of 30 mg/g or more or excretion of 30 mg or more of albumin in 24 hours. Results Of 2345 children, the mean (SD) age at diagnosis was 9.4 (4.4) years. One or more episodes of DKA occurred in 963 children (41%), and AKI occurred during DKA in 560 episodes (47%). In multivariable models adjusting for the associations of age at diagnosis and mean hemoglobin A1c level since diagnosis, each episode of AKI during DKA was associated with a hazard ratio of 1.56 (95% CI, 1.3-1.87) for development of microalbuminuria. Four or more episodes increased the hazard rate by more than 5-fold. DKA episodes without AKI did not significantly increase the hazard rate for microalbuminuria development after adjusting for other covariates. Conclusions and relevance These data demonstrate that episodes of AKI occurring during DKA in children with type 1 diabetes are significantly associated with risk of developing microalbuminuria. Greater efforts are necessary to reduce the frequency of DKA.

BACKGROUND Alcohol and cannabis use frequently co-occur, which can result in problems from social and academic impairment to dependence (i.e., alcohol use disorder [AUD] and/or cannabis use disorder [CUD]). The Emergency Department (ED) is an excellent site to identify adolescents with alcohol misuse, conduct a brief intervention, and refer to treatment; however, given time constraints, alcohol use may be the only substance assessed due to its common role in unintentional injury. The current study, a secondary data analysis, assessed the relationship between adolescent alcohol and cannabis use by examining the National Institute of Alcohol Abuse and Alcoholism (NIAAA) two question screen's (2QS) ability to predict future CUD at one, two, and three years post-ED visit. Methods: At baseline, data was collected via tablet self-report surveys from medically and behaviorally stable adolescents 12-17 years old (n = 1,689) treated in 16 pediatric EDs for non-life-threatening injury, illness, or mental health condition. Follow-up surveys were completed via telephone or web-based survey. Logistic regression compared CUD diagnosis odds at one, two, or three-year follow-up between levels constituting a single-level change in baseline risk categorization on the NIAAA 2QS (nondrinker versus low-risk, low- versus moderate-risk, moderate- versus high-risk). Receiver operating characteristic curve methods examined the predictive ability of the baseline NIAAA 2QS cut points for CUD at one, two, or three-year follow-up. Results: Adolescents with low alcohol risk had significantly higher rates of CUD versus nondrinkers (OR range: 1.94-2.76, p < .0001). For low and moderate alcohol risk, there was no difference in CUD rates (OR range: 1.00-1.08). CUD rates were higher in adolescents with high alcohol risk versus moderate risk (OR range: 2.39-4.81, p < .05). Conclusions: Even low levels of baseline alcohol use are associated with risk for a later CUD. The NIAAA 2QS is an appropriate assessment measure to gauge risk for future cannabis use.

Background Federal exception from informed consent (EFIC) procedures allow studies to enroll patients with time-sensitive, life-threatening conditions when written consent is not feasible. Our objective was to compare enrollment rates with and without EFIC in a trial of tranexamic acid (TXA) for children with hemorrhagic injuries. Methods We conducted a four-center randomized controlled pilot and feasibility trial evaluating TXA in children with severe hemorrhagic brain and/or torso injuries. We initiated the trial enrolling patients without EFIC. After 3 months of enrollment, we met our a priori futility threshold and paused the trial to incorporate EFIC procedures and obtain regulatory approval. We then restarted the trial allowing EFIC if the guardian was unable to provide timely written consent. We used descriptive statistics to compare characteristics of eligible patients approached with and without EFIC procedures. We also calculated the time delay to restart the trial using EFIC. Results We enrolled 1 of 15 (6.7%) eligible patients (0.17 per site per month) prior to using EFIC procedures. Of the 14 missed eligible patients, 7 (50%) were not enrolled because guardians were not present or were injured and unable to provide written consent. After obtaining approval for EFIC, we enrolled 30 of 48 (62.5%) eligible patients (1.34 per site per month). Of these 30 patients, 22 (73.3%) were enrolled with EFIC. Of the 22, no guardians refused written consent after randomization. There were no significant differences in the eligibility rate and patient characteristics enrolled with and without EFIC procedures. Across all sites, the mean delay to restart the trial using EFIC procedures was 12 months. Conclusions In a multicenter trial of severely injured children, the use of EFIC procedures greatly increased the enrollment rate and was well accepted by guardians. Initiating the trial without EFIC procedures led to a significant delay in enrollment.

Background Concerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings. Methods A total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics. Results A few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84–0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85–0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52–0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55–0.79). Conclusions In pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT.

Background The incidence of adolescent suicide is rising in the United States, yet we have limited information regarding short-term prediction of suicide attempts. Our aim was to identify predictors of suicide attempts within 3-months of an emergency department (ED) visit. Methods Adolescents, ages 12-17, seeking health care at 13 pediatric EDs (Pediatric Emergency Care Applied Research Network) and one Indian Health Service Hospital in the United States were consecutively recruited. Among 10,664 approached patients, 6,448 (60%) were enrolled and completed a suicide risk survey. A subset of participants (n = 2,897) was assigned to a 3-month telephone follow-up, and 2,104 participants completed this follow-up (73% retention). Our primary outcome was a suicide attempt between the ED visit and 3-month follow-up. Results One hundred four adolescents (4.9%) made a suicide attempt between enrollment and 3-month follow-up. A large number of baseline predictors of suicide attempt were identified in bivariate analyses. The final multivariable model for the full sample included the presence of suicidal ideation during the past week, lifetime severity of suicidal ideation, lifetime history of suicidal behavior, and school connectedness. For the subgroup of adolescents who did not report recent suicidal ideation at baseline, the final model included only lifetime severity of suicidal ideation and social connectedness. Among males, the final model included only lifetime severity of suicidal ideation and past week suicidal ideation. For females, the final model included past week suicidal ideation, lifetime severity of suicidal ideation, number of past-year nonsuicidal self-injury (NSSI) incidents, and social connectedness. Conclusions Results indicate that the key risk factors for adolescent suicide attempts differ for subgroups of adolescents defined by sex and whether or not they report recent suicidal thoughts. Results also point to the importance of school and social connectedness as protective factors against suicide attempts.

BACKGROUND: Resuscitation with crystalloid fluid is a cornerstone of pediatric septic shock treatment. However, the optimal type of crystalloid fluid is unknown. We aimed to determine the feasibility of conducting a pragmatic randomized trial to compare balanced (lactated Ringer’s [LR]) with 0.9% normal saline (NS) fluid resuscitation in children with suspected septic shock. METHODS: Open-label pragmatic randomized controlled trial at a single academic children’s hospital from January to August 2018. Eligible patients were >6 months to

Background Febrile infants commonly present to emergency departments for evaluation. Objective We describe the variation in diagnostic testing and hospitalization of febrile infants ≤60 days of age presenting to the emergency departments in the Pediatric Emergency Care Applied Research Network. Methods We enrolled a convenience sample of non-critically ill–appearing febrile infants (temperatures ≥38.0°C/100.4°F) ≤60 days of age who were being evaluated with blood cultures in 26 Pediatric Emergency Care Applied Research Network emergency departments between 2008 and 2013. Patients were divided into younger (0–28 days of age) and older (29–60 days of age) cohorts for analysis. We evaluated diagnostic testing and hospitalization rates by infant age group using chi-square tests and by site using analysis of variance. Results Four thousand seven hundred seventy-eight patients were eligible for analysis, of whom 1517 (32%) were 0–28 days of age. Rates of lumbar puncture and hospitalization were high (>90%) among infants ≤28 days of age, with chest radiography (35.5%) and viral testing (66.2%) less commonly obtained. Among infants 29–60 days of age, lumbar puncture (69.5%) and hospitalization (64.4%) rates were lower and declined with increasing age, with chest radiography (36.5%) use unchanged and viral testing (52.7%) slightly decreased. There was substantial variation between sites in the older cohort of infants, with lumbar puncture and hospitalization rates ranging from 40% to 90%. Conclusions The evaluation and disposition of febrile infants ≤60 days of age is highly variable, particularly among infants who are 29–60 days of age. This variation demonstrates an opportunity to modify diagnostic and management strategies based on current epidemiology to safely decrease invasive testing and hospitalization.

Study objective To determine the effect of providing risk estimates of clinically important traumatic brain injuries and management recommendations on emergency department (ED) outcomes for children with isolated intermediate Pediatric Emergency Care Applied Research Network clinically important traumatic brain injury risk factors. Methods This was a secondary analysis of a nonrandomized clinical trial with concurrent controls, conducted at 5 pediatric and 8 general EDs between November 2011 and June 2014, enrolling patients younger than 18 years who had minor blunt head trauma. After a baseline period, intervention sites received electronic clinical decision support providing patient-level clinically important traumatic brain injury risk estimates and management recommendations. The following primary outcomes in patients with one intermediate Pediatric Emergency Care Applied Research Network risk factor were compared before and after clinical decision support: proportion of ED computed tomography (CT) scans, adjusted for age, time trend, and site; and prevalence of clinically important traumatic brain injuries. Results The risk of clinically important traumatic brain injuries was known for 3,859 children with isolated findings (1,711 at intervention sites before clinical decision support, 1,702 at intervention sites after clinical decision support, and 446 at control sites). In this group, pooled CT proportion decreased from 24.2% to 21.6% after clinical decision support (odds ratio 0.86; 95% confidence interval 0.73 to 1.01). Decreases in CT use were noted across intervention EDs, but not in controls. The pooled adjusted odds ratio for CT use after clinical decision support was 0.73 (95% confidence interval 0.60 to 0.88). Among the entire cohort, clinically important traumatic brain injury was diagnosed at the index ED visit for 37 of 37 (100%) patients before clinical decision support and 32 of 33 patients (97.0%) after clinical decision support. Conclusion Providing specific risks of clinically important traumatic brain injury through electronic clinical decision support was associated with a modest and safe decrease in ED CT use for children at nonnegligible risk of clinically important traumatic brain injuries.

The pediatric emergency department (PED) represents an opportune time for alcohol and drug screening. The National Institute of Alcohol Abuse and Alcoholism (NIAAA) recommends a two-question alcohol screen for adolescents as a predictor of alcohol and drug misuse.A multi-site PED study was conducted to determine the association between the NIAAA two-question alcohol screen and adolescent cannabis use disorders (CUD), cigarette smoking, and lifetime use of other drugs.Participants included 12-17-year olds (n = 4834) treated in one of 16 participating PEDs. An assessment battery, including the NIAAA two-question screen and other measures of alcohol, tobacco and drug use, was self-administered on a tablet computer.A diagnosis of CUD, lifetime tobacco use or lifetime drug use was predicted by any self-reported alcohol use in the past year, which indicates a classification of moderate risk for middle school ages and low risk for high school ages on the NIAAA two-question screen. Drinking was most strongly predictive of a CUD, somewhat weaker for lifetime tobacco use, and weakest for lifetime drug use. This same pattern held for high school and middle school students and was stronger for high school students over middle school students for all three categories. This association was also found across gender, ethnicity and race. The association was strongest for CUD for high school students, sensitivity 81.7% (95% CI, 77.0, 86.5) and specificity 70.4% (95% CI, 68.6, 72.1). Conclusions/Importance: A single question about past year alcohol use can provide valuable information about other substance use, particularly marijuana.

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.