BACKGROUND:Secretory phospholipase A2 (sPLA2) is an inflammatory mediator linked to acute chest syndrome (ACS) in sickle cell disease (SCD), a serious complication that can develop during an acute vaso-occlusive pain episode (VOE). Plasma sPLA2 levels have been proposed as a potential biomarker for predicting ACS onset. OBJECTIVE:To assess serial plasma sPLA2 levels in 105 pediatric patients hospitalized for SCD-VOE and determine the effects of arginine therapy compared to placebo. PROCEDURES:This is a pharmacokinetics/pharmacodynamics and randomized controlled trial of intravenous arginine therapy. Statistical methods included t-tests, chi-square, and correlation analyses. RESULTS:Mean age was 12.7 ± 3.7 years, 48% were male, 67% had Hb-SS, and 70% were prescribed hydroxyurea. Using a previously established SCD-specific cutoff of 48 ng/mL, presenting sPLA2 levels were elevated in 33% of patients (mean sPLA2 level 85.7 ± 32.9 ng/mL). SPLA2 elevation in the emergency department was more common in patients with ACS compared to those without ACS (64% vs. 30%; p = 0.02; negative predictive value of 94%). Peak sPLA2 levels were significantly higher in febrile (n = 34) versus afebrile patients (n = 71;101.0 ± 45.3 vs. 48.7 ± 35.4 ng/mL; p < 0.0001). Among subjects with elevated baseline sPLA2, arginine therapy resulted in a significant reduction in sPLA2 levels by discharge compared to placebo (-27.8 ± 38.1 ng/mL; p = 0.002; n = 23 vs. -15.0 ± 41.2 ng/mL; p = 0.23; n = 12). CONCLUSIONS:SPLA2 is an underutilized biomarker of ACS given accumulating evidence of its role. In particular, low levels may identify patients at low risk for ACS. Arginine therapy may modulate inflammation in patients with SCD during VOE and/or ACS. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT02447874; NCT02536170.

BACKGROUND AND OBJECTIVE:In 2023, our emergency department, serving a region with one of the highest rates of new HIV infection, implemented Centers for Disease Control and Prevention-recommended universal, opt-out HIV screening for adolescents. However, few patients admitted to the pediatric hospital medicine service (PHM) were tested. To address this gap, we aimed to expand universal, opt-out HIV testing to PHM and evaluate screening implementation. METHODS:In this pre-postintervention study, we compared HIV testing rates for patients admitted to PHM aged 13 years or older during 5 months preimplementation and postimplementation (February to June 2024 and July to November 2024). Clinicians received regular education on HIV screening guidelines and opt-out language and were encouraged to incorporate screening in confidential psychosocial assessments. If the inpatient team did not offer testing, HIV navigators counseled adolescents, regardless of parental presence. Testing rates were compared with chi-square and Welch's t-test. RESULTS:There was a 38% increase in HIV screening from the preimplementation to postimplementation periods (preimplementation, 12.4%; postimplementation, 17.1%; P = .04). Postimplementation, 533 adolescents were eligible for HIV screening; 148 were approached, and 91 HIV tests were ordered (17.1% of eligible; 64% girls; mean age 16 ± 1.8 years), identifying one adolescent with HIV (>1% seroprevalence; 3% for boys). Adolescents were significantly more likely to be tested when approached by an HIV navigator than during a confidential interview (P = .004). Parental presence did not negatively impact adolescent participation. CONCLUSIONS:Adopting universal, opt-out HIV screening with HIV navigators in the inpatient setting significantly increased testing rates. Further studies on the most effective and sustainable approach to screening are needed.

Sickle cell disease attenuates nitric oxide signaling, limiting soluble guanylyl cyclase (sGC) stimulation needed for hemo-vascular function. Cytochrome b5 reductase 3 (CYB5R3) regulates sGC activity and expression. We show CYB5R3 T117S associates with reduced efficacy of the sGC stimulator riociguat. (NCT02633397).

BACKGROUND:Wheezing illnesses are a leading cause of hospitalization for preschool-age children and are frequently treated with antibiotics. Observational studies have shown more frequent isolation of three pathogenic bacteria (Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae) from nasopharyngeal samples from children with recurrent episodes of wheezing than from those without such illnesses. METHODS:In this multicenter trial, we randomly assigned patients 18 to 59 months of age who presented to an emergency department with a moderate-to-severe episode of wheezing to receive azithromycin once daily at a dose of 12 mg per kilogram of body weight or matching placebo for 5 days. The primary outcome was the sum of scores on the Asthma Flare-up Diary for Young Children (ADYC) over 5 days. Primary-outcome scores could range from 5 to 35, with higher scores indicating more severe wheezing-related symptoms. Efficacy was assessed separately in patients who tested positive for pathogenic bacteria (the positive cohort) and in those who tested negative (the negative cohort). Secondary outcomes were length of stay in the emergency department, length of hospital stay, and return emergency department visits or hospitalizations within 72 hours. Bacterial clearance and antimicrobial resistance were measured at follow-up visits 1 to 3 weeks after randomization. RESULTS:Among 840 patients who underwent randomization, 521 tested positive for pathogenic bacteria. The trial was stopped for futility by the data and safety monitoring board after a planned interim analysis. ADYC scores did not differ significantly between the azithromycin and placebo groups in either the positive cohort (median, 9.59 [interquartile range, 7.29 to 12.60] vs. 9.72 [interquartile range, 7.66 to 12.17]; P = 0.70) or the negative cohort (median, 9.30 [interquartile range, 6.97 to 11.62] vs. 9.10 [interquartile range, 7.19 to 11.45]; P = 0.69). In the positive cohort, bacterial clearance was 58.7% in the azithromycin group and 11.4% in the placebo group. Secondary outcomes appeared to be similar in the two groups for both cohorts, as did the development of bacterial resistance and the incidence of adverse events. CONCLUSIONS:Azithromycin did not lead to a greater reduction in the severity of wheezing-related symptoms than placebo in preschool-age children who presented to the emergency department with moderate-to-severe acute wheezing. (Funded by the National Heart, Lung, and Blood Institute and others; AZ-SWED ClinicalTrials.gov number, NCT04669288.).

Sickle cell disease remains a major cause of childhood morbidity and mortality, particularly in sub-Saharan Africa. In September, 2025, WHO convened the Paediatric Drug Optimization for Sickle Cell Disease process to review approved therapies, pipeline candidates, and potentially curative approaches, and define priorities for children and adolescents. Hydroxyurea (hydroxycarbamide) was confirmed as the leading near-term priority, with age-appropriate soluble or dispersible formulations identified as essential to improve equitable paediatric access; preferred and minimum characteristics were defined through a formal target product profile. Among investigational agents, pyruvate kinase activators and decitabine plus tetrahydrouridine (NDec) emerged as promising candidates for paediatric investigation on the basis of emerging efficacy data and programmatic potential. Intersecting research priorities included identifying appropriate clinical trial endpoints, strengthening early and inclusive paediatric investigation, and proactively ensuring that the promise of potential cure through gene therapy does not delay investment in scalable disease-modifying treatments.

Post-discharge mortality (PDM), defined as deaths that occur in the weeks and months after hospital discharge, remains a critical, yet under-recognized, contributor to high childhood mortality rates in sub-Saharan Africa. However, a comprehensive understanding of effective interventions to prevent PDM is lacking. The aim for the present study was to evaluate the efficacy of published interventions to prevent PDM among neonates and children aged 0-18 years in sub-Saharan Africa. A systematic review was conducted to assess the efficacy of interventions for preventing PDM. The CABI Global Health, Cochrane Reviews, Cochrane Trials, ProQuest Dissertations and Theses, Embase, PubMed, and Web of Science databases were searched without language restriction. Publications that involved interventions for preventing PDM, included children, and were conducted in sub-Saharan Africa were included in the present study. Of 4,893 publications screened, 17 were included, with 12,938 participants in total (10.6% experienced PDM). The most common interventions included supplemental feeding programs, kangaroo mother care, antibiotic use, and micronutrient supplementation. Effectiveness varied within and between intervention types. Only two interventions resulted in statistically significant reductions in PDM: vitamin A supplementation for children with pneumonia (hazard ratio: 0.51; 95% CI: 0.29-0.90; low quality of evidence) and linkage to services for children with sickle cell disease (adjusted hazard ratio: 0.26; 95% CI: 0.08-0.83; low quality of evidence). No single intervention type provided consistent benefits across studies. Most interventions targeted children with specific diagnoses; however, some strategies addressed social determinants of health. Future research must prioritize cost-effective, scalable strategies across diverse sub-Saharan African settings to accelerate the prevention of PDM among children.

Importance:Acute pain episodes are the leading cause of emergency department visits and hospitalizations for patients with sickle cell disease (SCD), yet US Food and Drug Administration-approved drugs for acute pain episodes are lacking. During acute pain episodes, patients develop acute arginine deficiency associated with longer time to crisis resolution and greater total parenteral opioid use. Multiple single-center, phase 2 randomized clinical trials have shown that arginine is safe, is opioid sparing, improves cardiopulmonary function, and reduces length of hospital stay. Objective:To determine the efficacy and safety of intravenous arginine for SCD acute pain episodes. Design, Setting, and Participants:Prospective, phase 3, double-blind randomized clinical trial conducted between June 21, 2021, and June 13, 2024, in 10 US children's hospitals enrolling patients aged 3 to 21 years presenting to the emergency department with SCD acute pain episodes requiring parenteral opioids. Interventions:Patients were randomized to receive intravenous arginine (200 mg/kg followed by 100 mg/kg every 8 hours until discharge; n = 129) or saline placebo (n = 142). Main Outcomes and Measures:The primary outcome was time to crisis resolution, defined as hours from initial study drug delivery to last intravenous opioid dose. Secondary outcomes included total parenteral opioid use (intravenous morphine equivalents in milligrams per kilogram from first study drug dose to last intravenous opioid dose), pain scores, and patient-reported outcomes. Results:Of 274 randomized participants, 271 received study drug; the mean age was 14.3 years (SD, 4.3 years), 51% were male, and 92% were Black. The trial was halted early for futility, as time to crisis resolution was similar in those receiving arginine vs placebo (median, 60.8 hours [IQR, 34.8-109.0 hours] vs 65.8 hours [IQR, 31.1-111.1 hours], respectively; absolute difference, 7.2 hours; 95% CI, -21.6 to 35.9 hours). No significant differences were seen in total parenteral opioid use, pain scores, patient-reported outcomes, or safety events. Conclusions and Relevance:Arginine therapy did not shorten time to crisis resolution compared with placebo among children and young adults with SCD acute pain episodes. Trial Registration:ClinicalTrials.gov Identifier: NCT04839354.

Importance Acute pain episodes are the leading cause of emergency department visits and hospitalizations for patients with sickle cell disease (SCD), yet US Food and Drug Administration–approved drugs for acute pain episodes are lacking. During acute pain episodes, patients develop acute arginine deficiency associated with longer time to crisis resolution and greater total parenteral opioid use. Multiple single-center, phase 2 randomized clinical trials have shown that arginine is safe, is opioid sparing, improves cardiopulmonary function, and reduces length of hospital stay. Objective To determine the efficacy and safety of intravenous arginine for SCD acute pain episodes. Design, Setting, and Participants Prospective, phase 3, double-blind randomized clinical trial conducted between June 21, 2021, and June 13, 2024, in 10 US children’s hospitals enrolling patients aged 3 to 21 years presenting to the emergency department with SCD acute pain episodes requiring parenteral opioids. Interventions Patients were randomized to receive intravenous arginine (200 mg/kg followed by 100 mg/kg every 8 hours until discharge; n = 129) or saline placebo (n = 142). Main Outcomes and Measures The primary outcome was time to crisis resolution, defined as hours from initial study drug delivery to last intravenous opioid dose. Secondary outcomes included total parenteral opioid use (intravenous morphine equivalents in milligrams per kilogram from first study drug dose to last intravenous opioid dose), pain scores, and patient-reported outcomes. Results Of 274 randomized participants, 271 received study drug; the mean age was 14.3 years (SD, 4.3 years), 51% were male, and 92% were Black. The trial was halted early for futility, as time to crisis resolution was similar in those receiving arginine vs placebo (median, 60.8 hours [IQR, 34.8-109.0 hours] vs 65.8 hours [IQR, 31.1-111.1 hours], respectively; absolute difference, 7.2 hours; 95% CI, −21.6 to 35.9 hours). No significant differences were seen in total parenteral opioid use, pain scores, patient-reported outcomes, or safety events. Conclusions and Relevance Arginine therapy did not shorten time to crisis resolution compared with placebo among children and young adults with SCD acute pain episodes. Trial Registration ClinicalTrials.gov Identifier: NCT04839354

OBJECTIVE:Assess the clinical value of routine laboratory testing in the emergency department (ED) during behavioral disturbance evaluations in children with autism spectrum disorder (ASD). METHODS:A retrospective chart review of patients ages 3 to 21 years with ASD presenting to 3 pediatric EDs with behavioral disturbance from January 2019 to January 2020. Local laboratory standards were used to determine abnormal ranges in ED screening labs. Patients with abnormal findings were reviewed for medical significance, defined as the need for a medical intervention, inpatient observation, or the inclusion of a nonbehavioral diagnostic code due to an abnormal laboratory test result. RESULTS:A total of 209 eligible ED encounters were reviewed. Mean age was 14.5±3.1 years, and 84% were male. Of those, 84% (176/209) received venipuncture for screening labs per protocol, of which 97% (170/176) featured abnormal test results. Only 2 abnormal labs (1%) revealed clinically significant findings. Compared with whites, more patients of non-White race received venipuncture (90% vs. 73%, P =0.001) but less non-whites receiving venipuncture were admitted to psychiatric facilities (44% vs. 62%, P =0.01). CONCLUSION:This study demonstrates that routine screening labs in asymptomatic children with ASD presenting to the ED with behavioral disturbances are often outside the range of normal, but without clinical relevance. This practice may lead to unnecessary and painful venipuncture. Children with ASD are a uniquely vulnerable population for whom we should choose wisely.

INTRODUCTION:Childhood mortality rates following hospital discharge may outpace inpatient mortality rates in some sub-Saharan African settings. Broadly validated risk assessment tools and biomarkers to identify children at risk for post-discharge mortality (PDM) are lacking. Moreover, clinical diagnoses (eg, pneumonia, sepsis, etc.) that confer high risk of PDM share a common pathobiology that culminates in endothelial dysfunction. The objectives of this study are to (1) externally validate existing risk assessment tools for PDM at 60 days and (2) test the association between a marker of endothelial dysfunction (ie, the global arginine bioavailability ratio [GABR]) and 60-day PDM among young children. METHODS AND ANALYSIS:This is a prospective, observational cohort study of neonates (aged 0-28 days, n=1000) and infants and children (aged 1-59 months, n=1000) consecutively discharged from two hospitals in Western Kenya (ie, Jaramogi Oginga Odinga Teaching and Referral Hospital [JOOTRH] and Siaya County Referral Hospital). Candidate variables for previously developed risk assessment tools identified through a systematic review and plasma samples will be collected on the day of hospital discharge. Caregivers of participants will receive telephone calls 30 days and 60 days following discharge to ascertain participants' vital status. Test characteristics and area under the receiver operating characteristic curves will be calculated for each risk tool to determine their discriminatory value. Risk predictiveness and calibration of each tool will also be determined. Mean and median levels of GABR will be compared between cases and matched controls, and conditional logistic regression will be used to test the association between GABR and PDM. ETHICS AND DISSEMINATION:This protocol has received clearance from the Kenya Medical Research Institute Scientific Ethics Review Unit, the JOOTRH Ethics Research Committee, and the Emory University institutional review board. Our results will be disseminated through scientific presentations at national and international conferences and peer-reviewed publications.

INTRODUCTION:Sickle cell disease (SCD) is an inherited blood disorder affecting approximately 100,000 individuals in the United States and millions worldwide, characterized by acute vaso-occlusive pain episodes (VOEs) and other complications that frequently necessitate emergency department (ED) visits. AREAS COVERED:Despite therapeutic advancements, ED care remains a major concern, often cited by patients as the area of healthcare most in need of improvement. National guidelines have been established to ensure ideal emergency SCD care and management, however, these guidelines do not address barriers or facilitators that affect implementation in the complex ED setting. This review examines current diagnostic and management approaches for common SCD complications requiring ED utilization, particularly fever and pain in pediatric patients. It highlights the challenges children with SCD face in emergency care and the existing knowledge gaps. Despite guidelines recommending timely, individualized pain treatment, implementation remains inconsistent, resulting in prolonged suffering and increased hospitalizations. EXPERT OPINION:Future research should focus on enhancing guideline adherence, reducing disparities, and developing targeted therapies. Novel biomarkers could improve early diagnosis, while standardized severity scoring systems may optimize triage and treatment decisions. Advancing biomarker research and investigational therapies beyond traditional supportive care holds promise for improving SCD management and patient outcomes.

Background/Objective: Cobalamin (B12) deficiency is reported in 18% of adults with sickle cell disease (SCD) and only 10% without SCD; limited data are available on children. Diagnosing B12 deficiency is challenging given the lack of an established gold standard method of assessment and the unique renal features of SCD. B12 metabolism can be impacted by the clinical use of nitrous oxide gas (N2O), which is a standard therapy for SCD pain in some European countries. In response to emerging reports of neurologic sequalae in patients with SCD receiving N2O, we evaluated the prevalence of B12 deficiency in children with SCD pain. Methods: Secondary analysis of prospective blood and urine samples in children aged 3–21 hospitalized with SCD pain. B12 deficiency was defined as plasma methylmalonic acid (MMA) > 592 nmol/L or urine MMA/creatinine ≥ 2.2 mmol/mol. Results: Ninety-four children (13 ± 4 years, 54% female, 68% hemoglobin-SS, and 72% on hydroxyurea) were assessed. Further, 53% (50/94) had B12 deficiency diagnosed by either urine, plasma, or both; 27% (25/94) were deficient based on urine; 39% (37/94) were deficient by plasma; and 13% (12/94) were deficient by both plasma and urine. Plasma MMA and urine MMA/creatinine did not correlate with hemoglobin or mean corpuscular volume. Conclusions: B12 deficiency was common in children with SCD. The absence of a gold standard for diagnosing B12 deficiency compounded with the reliability issues of testing modalities make it impractical to determine whether this is an over- or under-estimation of the true prevalence. Future studies to better understand the dynamics of B12 metabolism during acute and steady states in SCD are warranted and could elucidate the influence of acute SCD pain on these biomarkers.

We present a prospective randomized, placebo-controlled trial of intravenous arginine in patients 3-21 years hospitalized with sickle cell disease vaso-occlusive pain episodes (SCD-VOE) at two tertiary-care children's hospitals. Participants were randomized into 1 of 3 arms: Standard-dose (SD; 100 mg/kg/dose) every 8 h, Loading-dose (200 mg/kg followed by SD), or Placebo. The primary outcome was total parenteral opioid use (TPO). Secondary outcomes included time-to-crisis-resolution, pain scores, patient-reported outcomes (PROs), arginine bioavailability, and biomarkers of oxidative stress/mitochondrial function. Of 1548 patients screened, 108 were randomized (36 per study-arm; mean 12.6 ± 3.8 years, 52% female, and 65% hemoglobin-SS). This study did not meet its primary endpoint. TPO, time-to-crisis-resolution, pain scores, and PROs at discharge were similar across arms. Post hoc sensitivity analyses of children 5-16 years old demonstrated nearly double TPO utilization in those receiving placebo versus arginine (n = 87, p = 0.056), achieving significance in patients with plasma arginine < 60 μM. Arginine was low at presentation in 79% of patients (mean 50 ± 28 μM), and increased with arginine therapy (p < 0.001). Arginine bioavailability at VOE presentation inversely correlated with time-to-crisis-resolution (r = -0.39, p = 0.01) after placebo, an association eliminated by arginine supplementation (r = -0.04, p = 0.70). A dose-dependent increase in platelet-mitochondrial activity occurred after arginine versus no change after placebo (p < 0.001); plasma protein-carbonyl levels, a measure of oxidative stress, decreased after arginine therapy (p < 0.001) but increased in the placebo group (p = 0.02). SCD-VOE is associated with an acquired arginine deficiency that correlates with worse clinical outcomes. Arginine improved mitochondrial function and decreased oxidative stress compared to placebo, with clinically relevant opioid-sparing becoming significant in children with the lowest arginine concentration. TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT02536170) in August 2015.

Background: Vaccines against COVID-19 target the spike protein. There is minimal information on longitudinal COVID-19 immune profiling in recovered versus naïve and vaccinated versus non-vaccinated healthcare workers (HCWs). Methods: This is a prospective longitudinal observational cohort of pediatric HCWs (pHCWs) conducted during 2020-2022 at an academic center, exploring the impact of COVID-19 vaccination on immunoglobulin G (IgG) antibody titers over time and cross-reactivity with other coronaviruses, including SARS-CoV-1, MERS-CoV, and seasonal coronaviruses (HCoV-HKU1 and HCoV-OC43). Results: A total of 642 pHCWs initially enrolled, and 337 participants had repeat IgG titers measured post-vaccine and post-booster. Most participants were female, median age range of 31-40 years. Anti-spike was higher in all vaccinated individuals versus non-vaccinated (p < 0.0001) and naïve versus infected (p < 0.0001). A single dose of vaccine was sufficient to attain maximum titers in recovered participants versus naïve who received both doses of vaccine. Anti-spike titers dropped significantly at 9 months after the primary series, whereas sustained anti-spike titers were observed at 9 months post-booster. Conclusions: All vaccinated pHCWs developed antibodies to spike. COVID-19 infection and/or vaccination yielded antibodies that cross-reacted to SARS-CoV-1, MERS-CoV, HCoV-HKU1, and HCoV-OC43. Anti-spike titers were more durable post-booster compared to the primary series. Longitudinal immune profiling of COVID-19 responses provides vital data to shape public health policies, optimize vaccine strategies, and strengthen pandemic preparedness.

Rapid treatment and frequent reassessment of pain are key components of treatment guidelines for acute sickle cell disease (SCD) pain. Few studies, however, report the associations between emergency department (ED) pain scores, number of ED opioid doses, receipt of an opioid prescription, ED visit disposition, or ED return visits. This seven-site retrospective cohort study analyzed 4983 ED visits by children with SCD pain using electronic health record data from the Pediatric Emergency Care Applied Research Network Registry. ED pain scores included initial, last, and change in scores (initial minus last), measured on a 0-10 scale. Dispositions of discharge and hospital admission were included. Modified Poisson regression and the Cochran-Armitage test of trend were used for analysis. The median (IQR) initial pain score was 8.0 (6-10); last pain score was 5.0 (2-8); and median decrease was 2.0 (0-5). In multivariable analysis, last pain score was the best predictor of disposition. For the return visit analyses, of the 2377 visits discharged at index ED visit, 29% returned within 14 days. Higher initial and last ED pain scores were associated with increased return visits. Children with no opioid discharge prescription and ≥3 ED opioid doses had a return visit rate of 36% compared to 22% if the child received an opioid prescription and only one ED opioid. Increasing discharge opioid prescriptions and targeting interventions for those who receive multiple ED opioid doses could decrease return visits.

BACKGROUND:Seizures are one of the most common reasons for emergency medical services (EMS) activation for children, and current EMS practice results in underdosing and delayed delivery of anti-seizure medication. A prehospital evidence-based guideline recommends using intranasal or intramuscular midazolam as first-line treatment for pediatric seizures. Despite attempts to implement these guidelines, one-third of children having a paramedic-witnessed seizure have ongoing seizures on emergency department (ED) arrival; this may be due to inadequate or delayed midazolam dosing. Replacing the error-prone, sequential calculations with age-based midazolam dosing may be simpler, faster, and more effective without compromising safety. The objective of this manuscript is to describe the methodology of the Pediatric Dose Optimization for Seizures in EMS (PediDOSE) study, a clinical trial designed to compare the effectiveness and safety of an EMS protocol with four age-based categories for midazolam dosing relative to the current weight-based dosing. METHODS:We are conducting a large EMS-based stepped wedge trial in the Pediatric Emergency Care Applied Research Network (PECARN) by implementing midazolam dosing based on four age categories in seizure protocols in EMS systems in 20 cities. We believe that this implementation will stop more seizures before ED arrival without increasing respiratory failure rates. The primary aim of this study is to compare the effectiveness of age-based EMS midazolam dosing compared to the current weight-based dosing on seizure cessation upon ED arrival. The secondary aim is to determine the frequency of respiratory failure in children after the implementation of EMS midazolam dosing based on these age categories. CONCLUSION:If this study demonstrates that an EMS patient care protocol with age-based midazolam dosing is safe and more effective than current practice, the potential impact of this study is a paradigm shift in the treatment of pediatric seizures that can be easily implemented in EMS systems across the country. Beyond seizures, the concept of age-based dosing may also be applicable to other commonly encountered pediatric prehospital conditions for which medication may be indicated.

Post-discharge mortality is increasingly recognized as a major contributor to the high burden of childhood mortality in sub-Saharan Africa. Accurate identification of children at risk for post-discharge mortality is critically important to inform interventions to reduce deaths following hospital discharge. Our objective was to describe the current state of development, validation, or implementation for risk assessment tools for post-hospital discharge mortality (PDM) in sub-Saharan Africa. We conducted a systematic review of publications on risk assessment tools for PDM among children aged 0-18 years in sub-Saharan Africa. We searched CABI Global Health, Cochrane Reviews, Cochrane Trials, ProQuest Dissertations and Theses, Embase, PubMed, and Web of Science with no date or language restriction. We included publications if they described a tool/model with weights assigned to variables to quantify risk of PDM, included children, and were conducted in sub-Saharan Africa. We determined the level of evidence for tools using the Evidence-Based-Medicine Working Group hierarchy. Of 4,893 publications screened, 289 full texts were reviewed, and seven publications that reported 23 risk assessment tools for PDM among children in sub-Saharan Africa were identified. These studies enrolled 49,669 total participants (3.6%, n = 1,795 experienced PDM). There was substantial heterogeneity in identified risk factors, although all identified malnutrition as a risk factor for PDM. All risk assessment tools had fair (i.e., area under the receiver operating characteristic curve [AUC] ≥0.70) or good (AUC ≥ 0.80) discriminatory value in internal validation. Only two risk assessment tools had been externally validated, and none were implemented. Existing risk assessment tools to identify children at risk for PDM in sub-Saharan Africa lack broad validation and implementation. Malnutrition is a common risk factor for PDM. Further studies are needed to validate and implement such tools to reduce PDM among children.

INTRODUCTION:Community-acquired pneumonia (CAP) is a frequent and costly cause of pediatric emergency department (ED) visits and hospitalizations. Previous prognostic tools for CAP are limited by small samples, single-center or retrospective designs, lack of generalizability to ED settings, lack of biomarkers, or limited objective data. To overcome these limitations, we will derive and externally validate a prediction rule for pediatric CAP severity in a large, multicenter prospective cohort. METHODS:This is a prospective cohort study of children 3 months to 18 years old with CAP who present to EDs within the Pediatric Emergency Care Applied Research Network. Enrollment began 8/2023 and will end 7/2027. We exclude children with recent hospitalizations and chronic conditions (e.g., immunosuppression). A follow-up survey and record review is completed 8-15 days after the visit. Blood and nasal specimens are obtained to evaluate the role of C-reactive protein, procalcitonin, proadrenomedullin, and viral detection in severity prediction. The primary outcome is severity (three-tiered outcome of mild, moderate, or severe CAP) within 7 days of ED presentation. Model derivation will occur in ~4000 children from 7 EDs over 2 years. External validation will occur in a distinct cohort of at least 2000 children from 7 different EDs. Penalized regression, recursive partitioning, and machine learning will be used in model development. DISCUSSION:At study completion, we will have a validated CAP severity prediction rule well-positioned for implementation and further evaluation. We will also understand the role of specific biomarkers in predicting outcomes in children with CAP.