BACKGROUND:Acute seizures may evolve into status epilepticus (SE), prolonged and self-sustaining seizures that may result in brain injury or death. Rapid treatment with a benzodiazepine (BZD) is most effective. However, SE treatment remains delayed in many cases. We previously performed a single-center quality improvement study which resulted in more rapid treatment, decreased intensive care utilization, and decreased cost. Now, we are conducting a multicenter trial to test the hypothesis that pragmatic changes in treating acute inpatient seizures reduce time and are implementable across diverse hospital settings. METHODS/DESIGN:We designed a multicenter stepped wedge cluster randomized trial with three unidirectional 12-month steps following one baseline step. After dissemination visits, sites will attempt to implement a standardized bundle consisting of: (1) standardize default BZD to non-IV; (2) target treatment time within 10 min; (3) relocate and bundle items for BZD administration to a single location; (4) prioritize basic seizure first aid as initial assessment; (5) implement SE-specific documentation templates; (6) implement multidisciplinary site QI teams. Our primary outcome is median time from seizure diagnosis to BZD administration. Secondary outcomes are median changes in Pediatric Cerebral Performance Category score, ICU transfer rate, and cost of hospitalization. We will study implementation outcomes using mixed methods based on the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework. DISCUSSION:QuITT-SE is designed to test the effect and implementation of a pragmatic set of interventions on treatment times in SE. If successful, results will provide a generalizable roadmap for broad implementation through healthcare systems that should improve outcomes in SE. TRIAL REGISTRATION:Clinicaltrials.gov (NCT06194747). Funded by the National Institutes of Health (R01NS133037).

Background Elexacaftor-tezacaftor-ivacaftor (ETI) therapy has shown improvement in lung function, BMI and reduction in pulmonary exacerbations but the impact of genotype and severity of lung disease on heterogeneity of ETI efficacy in real life is not known. Methods This is a prospective observational study. Clinical data at baseline and at one-year of therapy were compared for the total cohort and for two subgroups; genotype [homozygous vs. heterozygous for F508del], and severity of lung disease at ETI initiation (ppFEV1 <80 % vs. ≥80 %). Results Among the total cohort of 115 pwCF, median age of 23 (17, 32) years, 66 (58 %) were homozygous, 76 (66 %) had ppFEV1 <80 %. Significant increases in mean ppFEV1 and mean BMI and decrease in MRSA and Pa culture positivity on sputum/throat swab were observed at one year of ETI therapy in the total cohort, and in groups based on either genotype or disease severity (p < 0.05 in all). Comparing one-year prior to one-year on ETI therapy, significant improvements were noted in pulmonary exacerbations, hospital admissions, antibiotic courses, number of pwCF receiving daily chest therapy, dornase alfa and hypertonic saline in the total cohort and in all four subgroups (p < 0.05 for all). Though improvements were not dependent on genotype, we noted larger mean differences in ppFEV1, BMI, pulmonary exacerbations and antibiotic use in the group with more severe lung disease (ppFEV1 <80 %) after one year of ETI therapy. Conclusion ETI therapy improved clinical outcomes in pwCF which were impacted by severity of underlying lung disease.

Early post-traumatic seizures (PTS) are associated with worse outcomes in children with traumatic brain injury (TBI). Our aim was to identify the association between continuous electroencephalogram (cEEG) characteristics and early PTS risk following pediatric severe TBI. We also evaluated the relationship between cEEG background features and outcomes. A single-center retrospective cohort study was performed on children between 0 and 18 years of age admitted to the pediatric intensive care unit from 2016 to 2019 with severe TBI and cEEG monitoring within 7 days of injury. Raw cEEG tracings were reviewed by an epileptologist in accordance with American Clinical Neurophysiology Society (ACNS) Critical Care EEG terminology. Univariate comparisons were made between children with and without early PTS, as well as between those with and without varying cEEG background features. Eighteen children (31%) of the 59 included had early PTS. Interictal abnormalities, inclusive of sporadic spikes and sharp waves, rhythmic delta activity, or lateralized periodic discharges (LPDs) were more common among children with seizures (100 vs. 22%; p < 0.01). LPDs were also more common in the seizure group (44 vs. 2%; p < 0.01). Background discontinuity was associated with worse Glasgow Outcome Scale-Extended Pediatric Version (GOS-E Peds) scores at discharge and 3-, 6-, and 12-month post-discharge ( p < 0.01). Lack of reactivity was also associated with worse GOS-E Peds scores at 3-, 6-, and 12-month post-discharge ( p < 0.01). Interictal abnormalities and LPDs were each associated with early PTS following pediatric severe TBI. Larger studies should evaluate if high-risk patients would benefit from prolonged cEEG monitoring and/or more aggressive anti-seizure prophylaxis. Discontinuity and lack of variability were associated with worse outcomes. Future studies should attempt to clarify their role as potential early markers of prognosis.

INTRODUCTION:The diagnosis of cystic fibrosis (CF) can impact the mental health of caregivers. This study aimed to explore prevalence of postpartum depression (PPD) symptoms in caregivers of infants with CF or CFTR-related metabolic syndrome (CRMS). METHODS:This prospective, observational study was conducted in a CF clinic at a tertiary hospital over 4 years. Caregivers of infants with CF/CRMS completed serial surveys over the first year of life. Surveys included the Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire-9 (PHQ-9) and the General Anxiety Disorder-7 (GAD-7). A control group of healthy infant caregivers was used for comparative analysis of EPDS scores. RESULTS:Analyses were conducted on 55 caregivers of 42 infants with CF/CRMS and 915 caregivers of healthy infants. Caregivers of infants with CF/CRMS had a significantly higher prevalence of elevated EPDS scores and higher mean EPDS scores for visit 1 (age 1-2mo) and visit 3 (age 6-9mo) compared to healthy controls (p < 0.001 for both). There was a higher prevalence of caregivers identifying thoughts of self-harm in the CF/CRMS cohort (8.3%) compared to caregivers of healthy controls (1.2%) at visit 1 (p = 0.015) and at visit 3 (CF/CRMS 8.8%; control 1.7%; p = 0.030). EPDS scores correlated with PHQ-9 and GAD-7 scores, particularly earlier in the infant's life. CONCLUSIONS:Caregivers of infants with CF/CRMS may be at higher risk of PPD and thoughts of self-harm when compared to healthy controls. Given what is known about the impact of PPD on mental and physical health of children, early identification is vital for this population.

BACKGROUND:Many conditions, including autoimmune disease and idiopathic pulmonary hemosiderosis (IPH), can cause diffuse alveolar hemorrhage (DAH). Little is known about the epidemiology and outcomes in children. OBJECTIVES:This retrospective cohort study sought to describe the etiologies and outcomes of DAH in pediatric patients at a tertiary care center. METHODS:This study involved review of patient records with diagnostic codes or bronchoscopy reports suggestive of pulmonary hemorrhage at a large children's hospital over 11 years (2010-2020). Patients were included if they met criteria for DAH, defined as bilateral pulmonary infiltrates and at least one of the following: (1) hemoptysis, (2) blood visible on bronchoscopic exam without apparent airway source, or (3) DAH noted on biopsy or autopsy. Infants less than 10 days corrected gestational age were excluded. RESULTS:Seventy-one children with DAH were included in the analysis. Cardiovascular disease was the most common etiology. Bleeding diathesis was common, but all patients had other causes of DAH. Patients with IPH were younger than those with autoimmune disease (p < .001). Most (77%) patients required mechanical ventilation, though this was less common among patients with autoimmune disease. Overall mortality was high (37%) but varied based on underlying etiology; mortality was higher in patients with cardiovascular disease (65%) while no deaths were seen in patients with autoimmune disease or IPH (p = .002). Survivors of DAH who performed pulmonary function tests had normal lung function. CONCLUSIONS:DAH frequently causes respiratory failure in children. In our cohort, mortality was highest in patients with cardiovascular disease.

The optimal timing for diagnostic skin prick testing (SPT) after food-induced anaphylaxis is unknown. This is largely related to the concern for potential transient skin nonreactivity after a systemic reaction (SR) related to the theoretical risk of "empty mast cell syndrome" or postanaphylaxis mast cell anergy (PAMA),1 which may render degranulated mast cells unable to respond until its mediators can regenerate, leading to a false-negative (FN) result. This concern stems from historical observations of temporarily nonreactive SPT to whole bee extract.

Background: Respiratory syncytial virus (RSV) infection is associated with significant morbidity in infants. Risk factors for severe disease beyond the first 2 years of life have not been fully defined. Methods: Children <5 years hospitalized with virologically confirmed RSV infection were identified over six respiratory seasons (10/2012-4/2018) and their medical records manually reviewed. Multivariable analyses were performed to define the age-specific (<6, 6-24, and >24-59 months) risk factors associated with oxygen administration, PICU admission, mechanical ventilation, and duration of hospitalization. Results: We identified 5143 children hospitalized with RSV infection: 53.5% (n = 2749) <6 months; 31.7% (n = 1631) 6-24 months; and 14.8% (n = 763) >24-59 months. Rates of ICU admission were high (35%-36%) and comparable across age groups, while children >24-59 and 6-24 versus those <6 months required supplemental oxygen more frequently (73%; 71%; 68%, respectively; p = .003). The presence of comorbidities increased with age (25%, <6 months; 46%, 6-24 months; 70%, >24-59 months; p < .001). Specifically, neuromuscular disorders, chronic lung disease, and reactive airway disease/asthma were predictive of worse clinical outcomes in children aged 6-24 and >24-59 months, while RSV-viral codetections increased the risk of severe outcomes in children aged <6 and 6-24 months of age. Conclusions: Almost half of children hospitalized with RSV infection were >6 months. Underlying comorbidities increased with age and remained associated with severe disease in older children, while RSV-viral codetections were predictive of worse clinical outcomes in the youngest age groups. These data suggest the importance of defining the clinical phenotype associated with severe RSV according to age, and the persistent burden associated with RSV beyond infancy.

Objective: Mitigation of household allergens is associated with the reduction of asthma exacerbations in those with allergic asthma and is recommended in recent asthma guidelines. However, we need to better understand patient knowledge of aeroallergens in their homes prior to integrating direct allergen measurement methods into standard asthma care. Methods: We conducted a mixed-methods sequential pilot study consisting of a survey and virtual interview with caregivers of children aged 3 to 15 with asthma diagnosis (any severity) about asthma control, household environment, mitigation knowledge and strategies, and knowledge of allergens and asthma. Results: A total of 21 participants responded and 13 completed the virtual interview. Less than half identified mice (43%), rats (29%), and cockroaches (43%) as sources of allergens on the online survey, and no individuals mentioned these in discussions. Only 23% were able to define the term "allergen," but 69% could list examples. There was a poor correlation between perceived asthma control (57% stated asthma control was good or excellent) compared to asthma that was classified as well controlled per Expert Panel Report 3 (EPR-3) guidelines (33% based on albuterol use and asthma symptoms). Finally, visual identification of mouse infestation was associated with active steps taken to mitigate mouse exposure (P = 0.007). Conclusion: Implementation of new Asthma Management Guidelines: Focused Updates 2020 by the National Institutes of Health will require additional aeroallergen education for individuals with asthma who do not recognize that cockroaches, rats, and mice can cause asthma symptoms, do not know the definition of an allergen, and do not correctly perceive asthma control status. Environmental assessment with education addressing these could hopefully decrease additional pharmaceutical needs.

Frequent ventricular ectopy (VE) ≥ 10% in children with structurally normal hearts and the development of ventricular dysfunction is not well described. We aim to describe frequent VE ≥ 10% in children with structurally normal hearts and characterize the development of dysfunction. Patients with VE burden ≥ 10% on 24-h Holter performed between 2010 and 2019 were included in this retrospective review. Patients with structural heart disease and cardiomyopathy preceding the onset of VE were excluded. Medical records, electrocardiogram, Holter, and transthoracic echocardiogram data were analyzed. Patients were classified based on maximum VE burden on Holter ("frequent" 10-29% versus "very frequent" ≥ 30%), presence of runs of VE, VE morphology on ECG, coupling interval, and development of dysfunction. Two hundred thirty-four patients met inclusion criteria, 187 with frequent VE and 47 with very frequent VE. Seventeen (7%) patients developed ventricular dysfunction, the majority of whom had mild dysfunction. Very frequent VE > 30% and non-sustained ventricular tachycardia (NSVT) on Holter were associated with dysfunction. There was no association between coupling interval or prematurity index and dysfunction. Ventricular dysfunction is uncommon in children with structurally normal hearts and frequent VE burden > 10%, though VE burden > 30% and presence of NSVT were associated with dysfunction. Previously described characteristics to delineate higher risk VE based on coupling interval were not associated with dysfunction.

Objective Epilepsy surgery is vital in managing of children with drug-resistant epilepsy. Noninvasive and invasive testing modalities allow for evaluation and treatment of children with drug-resistant epilepsy. Evidence-based algorithms for this process do not exist. This study examines expert response to a vignette of pediatric nonlesional epilepsy to assess associations in evaluation and treatment choices. Methods We analyzed annual report data and an epilepsy practice survey reported in 2020 from 135 pediatric epilepsy center directors in the United States. Characteristics of centers along with noninvasive and invasive testing and surgical treatment strategies were collected. Multivariable logistic regression modeling was performed. Results The response rate was 100% with 135 responses included in the analyses. Most used noninvasive testing modalities included Neuropsychology evaluation (90%), interictal brain fluorodeoxyglucose-positron emission tomography (85%), and functional magnetic resonance imaging (MRI) (72%) with nearly half obtaining genetic testing. Choosing functional MRI was associated with stereo electroencephalography (EEG) ( P = .025) and selecting Wada with subdural grid/strips ( P = .038). Directors from pediatric-only centers were more likely to choose stereo EEG as opposed to combined centers ( P = .042). Laser interstitial thermal therapy was almost 7 times as likely to be chosen as a treatment modality compared with open resection in dedicated pediatric centers (OR 6.96, P = .002). Significance In a vignette of nonlesional childhood drug-resistant epilepsy, epilepsy center directors’ patterns of noninvasive testing, invasive testing, and treatment were examined. Management choices were associated with pediatric versus combined pediatric/adult center characteristics. Expert opinions demonstrated equipoise in evaluation and management of children with drug-resistant epilepsy and the need for evidence-based management strategies.

Frequent ventricular ectopy (VE) ≥ 10

BackgroundResearch studies are conflicting regarding new highly effective modulators and the association with mental health symptoms for adults and adolescents with cystic fibrosis (CF). For younger children, small studies and case reports indicate a wide range of effects, ranging from improvement in mood to the development of neuropsychiatric symptoms. However, a large placebo-controlled study indicated no causal connection. This study evaluates the frequency and severity of mental health symptoms in children and adolescents while taking elexacaftor/tezacaftor/ivacaftor (ETI).MethodsThe study includes 81 pediatric patients with CF followed at Nationwide Children's Hospital (NCH). Patient Reported Outcomes Measurement Information System (PROMIS)-Anxiety and Depression, Patient Health Questionnaire 8 (PHQ-8) and Generalized Anxiety Disorder Questionnaire (GAD-7) were used to screen for depression and anxiety. Age-appropriate questionnaires were completed over the first 18 months after initiating ETI.ResultsAt baseline, majority of participants reported mental health symptoms within normal limits (WNL). For participants with elevated baseline measures, depressive and anxiety symptoms significantly decreased throughout the study period. Depending on the metric, patients experiencing depressive and anxiety symptoms dropped to 2-3% (n = 1, on each depressive measure) and 0% (n = 0, on either anxiety measures) respectively by 18 months.ConclusionMost pediatric patients with CF did not endorse symptoms of depression or anxiety disorders at ETI initiation. Over the first 18 months of ETI usage, the percentage of patients with these symptoms decreased, suggesting that the percentage of patients experiencing severe symptoms of depression and anxiety may decrease with ongoing use of ETI.

BACKGROUND:Transverse aortic arch obstruction is a challenging lesion for which stent implantation provides a potentially important alternate therapy. The objectives were to evaluate the technical, procedural, and medium-to-long-term clinical outcomes of percutaneous stent implantation of transverse aortic arch obstruction. METHODS:This is a retrospective, multicenter study of transverse aortic arch stent implantation. Univariable and multivariable analyses were performed. RESULTS:Index catheterization included 187 stent implants in 146 patients. The median age is 14.3 years (interquartile range, 9.3-19), weight is 53 kg (30-69), and follow-up is 53 months (12-120). The most common stent design was open cell (n=90, 48%). Stents overlapped 142 arch vessels (37 carotid arteries) in 118 (81%) cases. Technical and procedural success rates were 100% and 88%, respectively. Lower weight (P=0.018), body surface area (P=0.013), and minimum-to-descending aortic diameter ratio (P<0.001) were associated with higher baseline aortic gradient. The residual gradient was inversely associated with implant and final dilation diameters (P<0.001). The combined incidence of aortic injury and stent-related complications was 14%. There were no reports of abnormal brain scans or stroke. Blood pressure cuff gradient, echocardiographic arch velocity, and hypertension rates improved within 1-year follow-up with increased antihypertensive medication use. Reintervention was reported in 60 (41%) patients at a median of 84 (22-148) months to first reintervention. On multivariable logistic regression, residual aortic gradient >10 mm Hg was associated with increased odds of reintervention at all time points when controlling for each final dilation diameter, weight, and minimum-to-descending aortic diameter ratio. CONCLUSIONS:Transverse aortic arch stent implantation has high rates of technical, procedural, and medium-to-long-term clinical success. Aortic gradient >10 mm Hg is associated with increased odds of reintervention at 1-year and most recent follow-ups. Open cell stent design was frequently used for its advantages in conformability, perfusion of arch vessels, low fracture rate, and the ability to perform effective angioplasty of side cells.

BACKGROUND:Little is known about the immune responses during acute asthma exacerbation. In this study, we examined immune responses in children following an acute asthma exacerbation. METHODS:We evaluated pro-inflammatory cytokine levels and gene expression profiles in blood samples from pediatric patients admitted for acute asthma exacerbation. Viral PCR was performed to differentiate between viral or non-viral-associated exacerbations. RESULTS:Following informed consent, clinical data were obtained from 20 children with asthma (median [interquartile range, IQR]: age 11.5 [8.0, 14.2]) years and 14 healthy age-matched controls (10.5 [7.0, 13.0]). Twelve had positive nasopharyngeal Polymerase chain reaction (PCR) for viral infection (11 rhinoviruses and 1 respiratory syncytial virus (RSV)). Nine were in the pediatric intensive care unit (PICU) and among them five required continuous positive airway pressure (CPAP). Mean (±SD) days on systemic steroids before drawing blood sample were 2.5 ± 1.6. Twelve had history of environmental allergies with 917 (274, 1396) IU/mL total IgE (median (IQR)). Compared with controls, IL-1RA and IL-10 levels were significantly increased and TNF-α significantly decreased in asthma subjects (p < .05 for all). RNA-seq analysis revealed 852 differentially expressed genes in subjects with asthma. Pathway analysis found upregulated genes and pathways involved in innate immune responses in subjects with asthma. Significantly reduced genes included pathways associated with T helper cell differentiation and activation. CONCLUSIONS:In acute asthma exacerbation, innate immune pathways remained increased while adaptive immune responses related to T helper cells are blunted and are independent of trigger or asthma severity. Our novel findings highlight the need to identify new therapies to target persistent innate immune responses to improve outcomes in acute asthma.

RationaleLimited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months postdrug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life. ObjectivesTo examine clinical outcomes 2 years post-ETI in patients with CF and advanced lung disease. MethodsThis single center institutional review board-approved, retrospective chart review assessed clinical markers (percent predicted forced expiratory volume in 1 s, weight, sweat chloride), quality of life and computed tomography scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within 2 years. ResultsEighteen identified patients (ages 15-49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants by the end of the study. ConclusionsThis study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV1, subjective reports of clinical status, level of activity, and a reduction in burden of treatment.

Persons with drug‐resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy.

Abstract Background Passive immunization via maternal antibodies (Ab) is a key mechanism for infant protection in early life. This study analyzed the landscape of passive immunization induced by SARS-CoV-2 infection and/or vaccination by comparing the magnitude and durability of the transferred Ab. Methods Prospective multicenter observational cohort study of SARS-CoV2-infected and/or vaccinated pregnant women and their infants. We collected maternal and cord blood samples at delivery and neonatal/infant samples at delivery, and at 1, 2, 6 and 12 months (mo) of age. RBD and Spike IgG Ab titers were measured by ELISA. Results 215 mothers (infected=106, vaccinated=67, infected and vaccinated=42) and 174 infants (n=87, n=54, n=33, respectively) were enrolled. At birth RBD Ab titers median [IQR] of infants from vaccinated mothers [4.28 (3.48-4.80)] log10 ng/ml and from infected and vaccinated mothers [4.61 (4.27-4.93)] log10 ng/ml were higher than those from infected mothers [2.20 (0.10-3.30)] log10 ng/ml, p< 0.001. These differences were observed until 6 mo of age, when only 1/13 (7.7%) infant from infected mothers had detectable maternal Ab compared to 14/15 (93.3%) and 8/8 (100%) from the vaccinated, and infected and vaccinated groups, respectively. At 12 mo none of the infants born to infected mothers had detectable maternal Ab, while in the vaccinated group (n=11), 3 (27.3%) had persistent Ab, and 4 (36.4%) suspected infection. At 12 mo in the infected and vaccinated group (n=6) 3 had no Ab, and 3 had suspected infection. The median [IQR] placental Ab transfer ratio was higher in the vaccinated only group (2.94 [1.34-3.74]) than the infected only group (1.19 [0.33-2.52]) p< 0.01. Linear regression analyses demonstrated that the mean RBD Ab transfer ratio for infants from vaccinated vs infected women was 1.76 (95% CI=1.07-2.88, p=0.025) higher after adjusting for trimester of infection or vaccination. Similar results were observed with Spike Ab. Demographic and clinical characteristics of the study population m; median. IQR; interquartile range. N/A; not applicable. Figure 1. Comparison of RBD antibody titers in infected, vaccinated and infected and vaccinated groups at the time of delivery (from maternal blood, cord blood and neonatal blood) and at months 1, 2, 6 and 12 from neonatal/infant blood. Figure 2. Correlation between maternal and neonatal RBD antibody titers in groups of infected, vaccinated and infected and vaccinated mothers. These correlations also represent the values of the antibody transfer ratios across the placenta. While the bisector (red line) represents the values for a transfer ratio (TR) = 1, all values above it would correspond with TR>1 and those below with TR < 1. Green dots represent the infected group, the blue dots the vaccinated group, and the orange dots the infected and vaccinated group. Conclusion Infants from vaccinated mothers demonstrated maternal Ab up to 6 mo with higher titers than infants born from infected mothers. Antibodies generated by vaccination were transferred more efficiently than those generated by infection regardless of the trimester in which occurred. Disclosures Asuncion Mejias, MD, PhD, MsCS, Astra-Zeneca: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant Octavio Ramilo, MD, AstraZeneca: Honoraria|Bill & Melinda Gates Foundation: Grant/Research Support|Janssen: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria