Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States and vaso-occlusive pain episodes (VOE) are the leading cause of hospitalizations and emergency department (ED) visits1. There are limited therapies for acute management of VOE that directly target the underlying etiology for sickle-related pain therefore treatment is largely symptomatic. Moderate-to-severe pain is typically treated with parenteral hydration, opioids, and hospitalization to achieve adequate pain control.

Background: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. Methods: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. Discussion: Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. Trial registration: The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).

Introduction/Objective:Acute pain episodes are a major cause of health care utilization (HCU) in sickle cell disease (SCD), and adolescence is associated with increased pain frequency. We sought to determine whether there were differences in acute pain trajectories by sex and frequency of pain episodes among adolescents with SCD who presented to the emergency department (ED).Methods:Retrospective review of electronic health records from a large, multicampus, pediatric SCD program.Results:Of the 113 adolescents included, the mean age was 16.6 (SD 0.9), 41.6% (n = 47) were female, 77.9% (n = 88) had HbSS or a similarly severe genotype, and 43.4% (n = 49) had ≥3 episodes of HCU for pain, which we defined as having history of high HCU for pain. Those with a history of high HCU for pain had higher mean pain intensity scores at presentation, were more likely to receive either intravenous or intranasal opioids, and were more likely to be hospitalized. In a model considering the 3-way interaction between sex, history of high HCU for pain, and follow-up time from the initial pain intensity score, adjusted for opioid per kilogram body weight, and prescription of hydroxyurea, adolescent female patients with high HCU for pain had the slowest decline in pain intensity during treatment for acute pain in the ED.Conclusion:Sex and history of high HCU for pain are associated with acute pain trajectories in adolescents with SCD presenting to the ED. These novel findings should be confirmed in future prospective studies.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality. Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society–sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus. Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation. Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

BACKGROUND: There are no validated clinical decision aids to identify neonates and young children at risk of hospital readmission or postdischarge mortality in sub-Saharan Africa, leaving the decision to discharge a child to a clinician's impression. Our objective was to determine the precision of clinician impression to identify neonates and young children at risk for readmission and postdischarge mortality. METHODS: We conducted a survey study nested in a prospective observational cohort of neonates and children aged 1-59 months followed 60 days after hospital discharge from Muhimbili National Hospital in Dar es Salaam, Tanzania or John F. Kennedy Medical Center in Monrovia, Liberia. Clinicians who discharged each enrolled patient were surveyed to determine their perceived probability of the patient's risk of 60-day hospital readmission or postdischarge mortality. We calculated the area under the precision-recall curve (AUPRC) to determine the precision of clinician impression for both outcomes. RESULTS: Of 4247 discharged patients, 3896 (91.7%) had available clinician surveys and 3847 (98.7%) had 60-day outcomes available: 187 (4.8%) were readmitted and 120 (3.1%) died within 60 days of hospital discharge. Clinician impression had poor precision in identifying neonates and young children at risk of hospital readmission (AUPRC: 0.06, 95% CI: 0.04 to 0.08) and postdischarge mortality (AUPRC: 0.05, 95% CI: 0.03 to 0.08). Patients for whom clinicians attributed inability to pay for future medical treatment as the reason for risk for unplanned hospital readmission had 4.76 times the odds hospital readmission (95% CI: 1.31 to 17.25, p=0.02). CONCLUSIONS: Given the poor precision of clinician impression alone to identify neonates and young children at risk of hospital readmission and postdischarge mortality, validated clinical decision aids are needed to aid in the identification of young children at risk for these outcomes.

The mechanism by which T lymphocytes are tolerized to self or foreign antigens is still controversial. Clonal deletion is the major mechanism of tolerance for immature thymocytes; for mature T cells, tolerance is considered to reflect anergy rather than deletion, and to be a consequence of defective presentation of antigen. This paper documents a novel form of tolerance resulting when mature T cells encounter antigen in immunogenic form. Evidence is presented that exposure of mature T cells to Mlsa antigens in vivo leads to specific tolerance and disappearance of Mlsa-reactive Vβ6+ T cells. Surprisingly, the clonal elimination of Vβ6+ cells is preceded by marked expansion of these cells. Thus, tolerance induction can be the end result of a powerful immune response. These data raise important questions concerning the relationship of tolerance and memory.

Objectives In 2020, firearm injuries surpassed automobile collisions as the leading cause of death in US children. Annual automobile fatalities have decreased during 40 years through a multipronged approach. To develop similarly targeted public health interventions to reduce firearm fatalities, there is a critical need to first characterize firearm injuries and their outcomes at a granular level. We sought to compare firearm injuries, outcomes, and types of shooters at trauma centers in four pediatric health systems across the USA. Methods We retrospectively extracted data from each institution's trauma registry, paper and electronic health records. Study included all patients less than 19 years of age with a firearm injury between 2003 and 2018. Variables collected included demographics, intent, resources used, and emergency department and hospital disposition. Descriptive statistics were reported using medians and IQRs for continuous data and counts with percentages for categorical data. χ 2 test or Fisher's exact test was conducted for categorical comparisons. Results Our cohort (n=1008, median age 14 years) was predominantly black and male. During the study period, there was an overall increase in firearm injuries, driven primarily by increases in the South (S) site (β=0.11 (SE 0.02), p=<0.001) in the setting of stable rates in the West and decreasing rates in the Northeast and Mid-Atlantic sites (β=-0.15 (SE 0.04), p=0.002; β=-0.19 (SE0.04), p=0.001). Child age, race, insurance type, resource use, injury type, and shooter type all varied by regional site. Conclusion The incidence of firearm-related injuries seen at four sites during 15 years varied by site and region. The overall increase in firearm injuries was predominantly driven by the S site, where injuries were more often unintentional. This highlights the need for region-specific data to allow for the development of targeted interventions to impact the burden of injury. Level of Evidence: II, retrospective study

Importance: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. Objectives: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. Design, Setting, and Participants: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. Exposure: SARS-CoV-2 detected via nucleic acid testing. Main Outcomes and Measures: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. Results: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). Conclusions and Relevance: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD). Arginine, the endogenous precursor for nitric oxide synthesis, is produced in the kidneys. Arginine bioavailability contributes to endothelial and myocardial dysfunction in CKD. Plasma from 129X1/SvJ mice with and without CKD (5/6th nephrectomy), and banked plasma from children with and without CKD were analyzed for amino acids involved in arginine metabolism, ADMA, and arginase activity. Echocardiographic measures of myocardial function were compared with plasma analytes. In a separate experiment, a non-specific arginase inhibitor was administered to mice with and without CKD. Plasma citrulline and glutamine concentrations correlated with multiple measures of myocardial dysfunction. Plasma arginase activity was significantly increased in CKD mice at 16 weeks vs. 8 weeks (p = 0.002) and ventricular strain improved after arginase inhibition in mice with CKD (p = 0.03). In children on dialysis, arginase activity was significantly increased vs. healthy controls (p = 0.04). Increasing ADMA correlated with increasing RWT in children with CKD (r = 0.54; p = 0.003). In a mouse model, and children, with CKD, arginine dysregulation correlates with myocardial dysfunction.

Introduction: Sickle cell disease (SCD) is a complex, chronic disease caused by abnormal polymerization of hemoglobin, which leads to severe pain episodes, fatigue, and end-organ damage. Patient reported outcomes (PROs) have emerged as a critical tool for measuring SCD disease severity and response to treatment. Areas covered: Authors review the key issues involved when deciding to use a PRO in a clinical trial. We describe the most highly recommended generic and disease-specific PRO tools in SCD and discuss the challenges of incorporating them in clinical practice. Expert opinion: PRO measures are essential to incorporate into SCD clinical trials either as primary or secondary outcomes. The use of PRO measures in SCD facilitates a patient-centered approach, which is likely to lead to improved outcomes. Significant challenges remain in adapting PRO tools to routine clinical use and in developing countries.