Corewell Health Children's

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

In July 2004, the Subcommittee on Hyperbilirubinemia of the American Academy of Pediatrics (AAP) published its clinical practice guideline on the management of hyperbilirubinemia in the newborn infant ≥35 weeks of gestation,1 and a similar guideline was published in 2007 by the Canadian Paediatric Society.2 Experience with implementation of the AAP guideline suggests that some areas require clarification. The 2004 AAP guideline also expressed hope that its implementation would "reduce the incidence of severe hyperbilirubinemia and bilirubin encephalopathy… ." We do not know how many practitioners are following the guideline, nor do we know the current incidence of bilirubin encephalopathy in the United States. We do know, however, that kernicterus is still occurring in the United States, Canada, and Western Europe.3–7 In 2002, the National Quality Forum suggested that kernicterus should be classified as a "serious reportable event,"8 sometimes termed a "never event,"9 implying that with appropriate monitoring, surveillance, and intervention, this devastating condition can, or should, be eliminated. Although this is certainly a desirable objective, it is highly unlikely that it can be achieved given our current state of knowledge and practice.10 In certain circumstances (notably, glucose-6-phosphate dehydrogenase [G6PD] deficiency, sepsis, genetic predisposition, or other unknown stressors), acute, severe hyperbilirubinemia can occur and can produce brain damage despite appropriate monitoring and intervention.In addition to clarifying certain items in the 2004 AAP guideline, we recommend universal predischarge bilirubin screening using total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) measurements, which help to assess the risk of subsequent severe hyperbilirubinemia. We also recommend a more structured approach to management and follow-up according to the predischarge TSB/TcB, gestational age, and other risk factors for hyperbilirubinemia. These recommendations represent a consensus of expert opinion based on the available evidence, and they are supported by several independent reviewers. Nevertheless, their efficacy in preventing kernicterus and their cost-effectiveness are unknown.We reviewed the report on screening for neonatal hyperbilirubinemia published by the Agency for Healthcare Research and Quality and prepared by the Tufts-New England Medical Center Evidence-Based Practice Center,11 the current report by the US Preventive Services Task Force,12 and other relevant literature.1,3–10,13–26The 2004 AAP guideline includes 2 categories of risk factors, but the distinction between these 2 categories has not been clear to all users of the guideline.These "risk factors for hyperbilirubinemia" are listed in Table 1. Understanding the predisposition to subsequent hyperbilirubinemia provides guidance for timely follow-up as well as the need for additional clinical and laboratory evaluation.These risk factors for bilirubin neurotoxicity are listed in the figures of the 2004 AAP guideline that provide recommendations for the use of phototherapy and exchange transfusion. These "neurotoxicity risk factors" encompass those that might increase the risk of brain damage in an infant who has severe hyperbilirubinemia1 (see Fig 1 and Table 2). The neurotoxicity risk factors are used in making the decision to initiate phototherapy or perform an exchange transfusion. These interventions are recommended at a lower bilirubin level when any of the neurotoxicity risk factors is present. Some conditions are found in both risk-factor categories. For example, lower gestational age and isoimmune hemolytic disease increase the likelihood of subsequent severe hyperbilirubinemia as well as the risk of brain damage by bilirubin.The 2004 AAP guideline recommends a predischarge bilirubin measurement and/or assessment of clinical risk factors to evaluate the risk of subsequent severe hyperbilirubinemia.1 New evidence suggests that combining a predischarge measurement of TSB or TcB with clinical risk factors might improve the prediction of the risk of subsequent hyperbilirubinemia.13,14,23 In addition, when interpreted by using the hour-specific nomogram (Fig 2), measurement of TSB or TcB also provides a quantitative assessment of the degree of hyperbilirubinemia. This provides guidance regarding the need (or lack of need) for additional testing to identify a cause of the hyperbilirubinemia and for additional TSB measurements.1The TSB can be measured from the same sample that is drawn for the metabolic screen. The risk zone (Fig 2) and the other clinical risk factors (Table 3) are then combined to assess the risk of subsequent hyperbilirubinemia and to formulate a plan for management and follow-up (Fig 3). When combined with the risk zone, the factors that are most predictive of hyperbilirubinemia risk are lower gestational age and exclusive breastfeeding.13,14,23 The lower the gestational age, the greater the risk of developing hyperbilirubinemia.13,14,23 For those infants from whom ≥2 successive TSB or TcB measurements are obtained, it is helpful to plot the data on the nomogram15 to assess the rate of rise. Hemolysis is likely if the TSB/TcB is crossing percentiles on the nomogram and suggests the need for further testing and follow-up (see Table 1 in the 2004 AAP guideline).Therefore, we recommend that a predischarge measurement of TSB or TcB be performed and the risk zone for hyperbilirubinemia determined15 on the basis of the infant's age in hours and the TSB or TcB measurement.It should be noted that, even with a low predischarge TSB or TcB level, the risk of subsequent hyperbilirubinemia is not zero,13,17 so appropriate follow-up should always be provided (Fig 3).Figure 3 provides our recommendations for management and follow-up, according to predischarge screening. Note that this algorithm represents a consensus of the authors and is based on interpretation of limited evidence (see below).Most infants discharged at <72 hours should be seen within 2 days of discharge.Earlier follow-up might be necessary for infants who have risk factors for severe hyperbilirubinemia,1,13,14,23 whereas those in the lower risk zones with few or no risk factors can be seen later (Fig 3). Figure 3 also provides additional suggestions for evaluation and management at the first follow-up visit.TcB measurements are being used with increasing frequency in hospital nurseries and in some outpatient settings. They have the advantage of providing instantaneous information and probably reduce the likelihood of missing a clinically significant TSB, making them particularly useful in outpatient practice. TcB measurements can significantly reduce the number of TSB measurements that are required, but as with any point-of-care test, regular monitoring for appropriate quality assurance by comparison with TSB measurements is necessary. Significant variation can occur among instruments, and the use of a new instrument should be compared with hospital laboratory measurements to ensure that the instrument is working properly; such checks should be performed periodically. TcB is a measurement of the yellow color of the blanched skin and subcutaneous tissue, not the serum, and should be used as a screening tool to help determine whether the TSB should be measured. Although TcB measurements provide a good estimate of the TSB level, they are not a substitute for TSB values, and a TSB level should always be obtained when therapeutic intervention is being considered.Most studies in term and late-preterm infants have indicated that the TcB tends to underestimate the TSB, particularly at higher TSB levels.18 Thus, investigators have adopted various techniques to avoid missing a high TSB level (ie, a false-negative TcB measurement). These techniques include measuring the TSB if The introduction of universal predischarge bilirubin screening, follow-up visits, and TSB/TcB measurements might increase costs. Ideally, a cost/benefit analysis should include the cost to prevent 1 case of kernicterus. The cost per case, however, highly depends on the incidence of kernicterus as well as its potential reduction resulting from the intervention. By using a strategy similar to that suggested in this guideline, and assuming an incidence of kernicterus of 1 in 100 000 live births and a relative risk reduction of 70%, the cost to prevent 1 case of kernicterus has been estimated as approximately $5.7 million.22 Because we do not know the current incidence of kernicterus in the United States or the actual relative risk reduction (if these guidelines were implemented universally), we cannot calculate the true cost/benefit ratio. Taking into account the lifetime cost of an infant with kernicterus, it is possible that there could be savings.22While endeavoring to clarify some areas addressed in the 2004 AAP guideline, we have also introduced new recommendations, both for the predischarge assessment of the risk of subsequent hyperbilirubinemia and for follow-up testing. We recognize that the quality of evidence for recommending universal predischarge screening and for the suggested management and follow-up (Fig 3) is limited and, in the absence of higher levels of evidence, our recommendations must, therefore, be based on expert opinion. As indicated in the reviews by the US Preventive Services Task Force12 and Trikalinos et al11 in this issue of Pediatrics, there are currently no good data to indicate that the implementation of these recommendations will reduce the risk of kernicterus, although published data suggest that predischarge screening can reduce the incidence of a TSB level of ≥25 mg/dL,24,25 perhaps by increasing the use of phototherapy.24 Nevertheless, because kernicterus is a devastating condition that leads to serious and permanent neurologic damage, and because published reports and our own review of cases in the medicolegal setting suggest that many of these cases could have been prevented, a reasonable argument can be made for implementing the suggested recommendations in the absence of better evidence. Because kernicterus is a rare condition, it is unlikely that we will be able to obtain adequate evidence in the short-term to support our recommendations. In their elegant polemic, Auerbach et al26 discussed "the tension between needing to improve care and knowing how to do it." They noted that, in the absence of appropriate evidence, "bold efforts at improvement can consume tremendous resources yet confer only a small benefit."26 We also recognize that although predischarge testing is relatively inexpensive and convenient, measuring the TSB after discharge is more difficult. TcB measurement is quite easy but is not currently available in most primary care settings. In addition, more evidence is needed to support the cost and efficacy of these recommendations. There is certainly a risk that these recommendations could lead to additional testing and an increase in both appropriate and inappropriate use of phototherapy.1,24 Nevertheless, it is our opinion that universal screening, when combined with the clinical risk factors (of which gestational age and exclusive breastfeeding are most important) and targeted follow-up, is a systems approach that is easy to implement and understand, and it provides a method of identifying infants who are at high or low risk for the development of severe hyperbilirubinemia. In addition to risk assessment, the measurement of TSB or TcB when interpreted by using the hour-specific nomogram provides the caregiver with an immediate and quantitative mechanism for assessing the degree of hyperbilirubinemia and the need for additional surveillance and testing. As such, it could play an important role in preventing acute bilirubin encephalopathy, although this has yet to be demonstrated.We are grateful for reviews and critiques of this commentary by neonatologists, bilirubinologists, pediatricians, and pediatric residents.

PURPOSE: To evaluate the DSM-5 diagnosis of Avoidant/Restrictive Food Intake Disorder (ARFID) in children and adolescents with poor eating not associated with body image concerns. METHODS: A retrospective case-control study of 8-18-year-olds, using a diagnostic algorithm, compared all cases with ARFID presenting to seven adolescent-medicine eating disorder programs in 2010 to a randomly selected sample with anorexia nervosa (AN) and bulimia nervosa (BN). Demographic and clinical information were recorded. RESULTS: Of 712 individuals studied, 98 (13.8%) met ARFID criteria. Patients with ARFID were younger than those with AN (n = 98) or BN (n = 66), (12.9 vs. 15.6 vs. 16.5 years), had longer durations of illness (33.3 vs. 14.5 vs. 23.5 months), were more likely to be male (29% vs. 15% vs. 6%), and had a percent median body weight intermediate between those with AN or BN (86.5 vs. 81.0 and 107.5). Patients with ARFID included those with selective (picky) eating since early childhood (28.7%); generalized anxiety (21.4%); gastrointestinal symptoms (19.4%); a history of vomiting/choking (13.2%); and food allergies (4.1%). Patients with ARFID were more likely to have a comorbid medical condition (55% vs. 10% vs. 11%) or anxiety disorder (58% vs. 35% vs. 33%) and were less likely to have a mood disorder (19% vs. 31% vs. 58%). CONCLUSIONS: Patients with ARFID were demographically and clinically distinct from those with AN or BN. They were significantly underweight with a longer duration of illness and had a greater likelihood of comorbid medical and/or psychiatric symptoms.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

PURPOSE: Traumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video-EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS. METHODS: Eighty-seven consecutive, unselected (mild - severe), acute TBI patients requiring pediatric intensive care unit (PICU) admission at two academic centers were monitored prospectively with cEEG per established clinical TBI protocols. Clinical and subclinical seizures and status epilepticus (SE, clinical and subclinical) were assessed for their relation to clinical risk factors and short-term outcome measures. KEY FINDINGS: Of all patients, 42.5% (37/87) had seizures. Younger age (p = 0.002) and injury mechanism (abusive head trauma - AHT, p < 0.001) were significant risk factors. Subclinical seizures occurred in 16.1% (14/87), while 6.9% (6/87) had only subclinical seizures. Risk factors for subclinical seizures included younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p < 0.001). SE occurred in 18.4% (16/87) with risk factors including younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p = 0.002). Subclinical SE was detected in 13.8% (12/87) with significant risk factors including younger age (p < 0.001), AHT (p = 0.001), and intraaxial bleed (p = 0.004). Subclinical seizures were associated with lower discharge King's Outcome Scale for Childhood Head Injury (KOSCHI) score (p = 0.002). SE and subclinical SE were associated with increased hospital length of stay (p = 0.017 and p = 0.041, respectively) and lower hospital discharge KOSCHI (p = 0.007 and p = 0.040, respectively). SIGNIFICANCE: cEEG monitoring significantly improves detection of seizures/SE and is the only way to detect subclinical seizures/SE. cEEG may be indicated after pediatric TBI, particularly in younger children, AHT cases, and those with intraaxial blood on computerized tomography (CT).

Pediatricians and family physicians deal regularly with jaundiced newborn infants who emerge unscathed from their transient exposure to an elevated serum bilirubin level. Yet, despite published guidelines for the management of neonatal jaundice, there are rare infants in whom bilirubin

This is a report of 6 cases (one bilateral) of congenital irreducible, permanent lateral dislocation of the patella, ages 5 to 14; 2 patients were normal and 4 were mongoloid. The dislocation was reduced by means of a newly-devised surgical reconstruction of anterior attachments of nearly all of the para-articular bone and ligamentous structures. The 2-year follow-up results are satisfactory.

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

BACKGROUND AND OBJECTIVES: Breastfed newborns are more likely to develop prolonged hyperbilirubinemia than those fed formula, but the prevalence of prolonged hyperbilirubinemia in a largely white, North American breastfed population is unknown. In this population, we documented the natural history of jaundice and the prevalence of prolonged hyperbilirubinemia, and we evaluated the utility of assessing the cephalocaudal progression of jaundice in office-based practices. METHODS: We measured transcutaneous bilirubin (TcB) levels during the first month in 1044 predominantly breastfed infants ≥35 weeks of gestation and assigned a cephalocaudal zone score to each infant at the time of the TcB measurement. RESULTS: TcB level was ≥5 mg/dL in 43% of infants at age 21 ± 3 days and 34% were clinically jaundiced. At 28 ± 3 days, the TcB was ≥5 mg/dL in 34% and 21% were jaundiced. There was a strong correlation between the TcB level and the jaundice zone score, but there was a wide range of TcB levels associated with each score. CONCLUSIONS: Practitioners can be reassured that it is normal for 20% to 30% of predominantly breastfed newborns to be jaundiced at age 3 to 4 weeks and for 30% to 40% of these infants to have bilirubin levels ≥5 mg/dL. The jaundice zone score does not provide an accurate assessment of the bilirubin level, but a score of zero (complete absence of jaundice) suggests that the level is unlikely to be >12.9 mg/dL, whereas a score of ≥4 usually predicts a level of ≥10 mg/dL.

OBJECTIVES: The main goal was to develop new z-score reference ranges for common fetal echocardiographic measurements from a large referral population. METHODS: A retrospective cross-sectional study of 2735 fetuses was performed for standard biometry (biparietal diameter (BPD) and femoral diaphysis length (FDL)) and an assessment of menstrual age (MA). Standardized fetal echocardiographic measurements included aortic valve annulus and pulmonary valve annulus diameters at end-systole, right and left ventricular diameters at end-diastole, and cardiac circumference from a four-chamber view of the heart during end-diastole. Normal z-score ranges were developed for these echocardiographic measurements using MA, BPD and FDL as independent variables. This was accomplished by using first standard regression analysis and then weighted regression of absolute residual values for each parameter in order to adjust for inconstant variance. RESULTS: A simple, linear regression model was the best description of the data in each case and correlations between fetal cardiac measurements and the independent variables were excellent. There was significant heteroscedasticity of standard deviation with increasing gestational age, which also could be modeled with simple linear regression. After this adjustment, the residuals conformed to a normal distribution, validating the calculation and interpretation of z-scores. CONCLUSION: Development of reliable z-scores is possible for common fetal echocardiographic parameters by applying statistical methods that are based on a large sample size and weighted regression of absolute residuals in order to minimize the effect of heteroscedasticity. These normative ranges should be especially useful for the detection and monitoring of suspected fetal cardiac size and growth abnormalities.

Importance: The COVID-19 pandemic has affected youth mental health. Increases in site-specific eating disorder (ED) care have been documented; however, multisite studies demonstrating national trends are lacking. Objective: To compare the number of adolescent/young adult patients seeking inpatient and outpatient ED care before and after onset of the COVID-19 pandemic. Design, Setting, and Participants: Using an observational case series design, changes in volume in inpatient and outpatient ED-related care across 15 member sites (14 geographically diverse hospital-based adolescent medicine programs and 1 nonhospital-based ED program) of the US National Eating Disorder Quality Improvement Collaborative was examined. Sites reported monthly volumes of patients seeking inpatient and outpatient ED care between January 2018 and December 2021. Patient volumes pre- and postpandemic onset were compared separately for inpatient and outpatient settings. Demographic data such as race and ethnicity were not collected because this study used monthly summary data. Exposures: Onset of the COVID-19 pandemic. Main Outcomes and Measures: Monthly number of patients seeking inpatient/outpatient ED-related care. Results: Aggregate total inpatient ED admissions were 81 in January 2018 and 109 in February 2020. Aggregate total new outpatient assessments were 195 in January 2018 and 254 in February 2020. Before the COVID-19 pandemic, the relative number of pooled inpatient ED admissions were increasing over time by 0.7% per month (95% CI, 0.2%-1.3%). After onset of the pandemic, there was a significant increase in admissions over time of 7.2% per month (95% CI, 4.8%-9.7%) through April 2021, then a decrease of 3.6% per month (95% CI, -6.0% to -1.1%) through December 2021. Prepandemic, pooled data showed relative outpatient ED assessment volume was stable over time, with an immediate 39.7% decline (95% CI, -50.4% to -26.7%) in April 2020. Subsequently, new assessments increased by 8.1% (95% CI, 5.3%-11.1%) per month through April 2021, then decreased by 1.5% per month (95% CI, -3.6% to 0.7%) through December 2021. The nonhospital-based ED program did not demonstrate a significant increase in the absolute number of admissions after onset of the pandemic but did see a significant increase of 8.2 (95% CI, 6.2-10.2) additional inquiries for care per month in the first year after onset of the pandemic. Conclusions and Relevance: In this study, there was a significant COVID-19 pandemic-related increase in both inpatient and outpatient volume of patients with EDs across sites, particularly in the first year of the pandemic. Given inadequate ED care availability prior to the pandemic, the increased postpandemic demand will likely outstrip available resources. Results highlight the need to address ED workforce and program capacity issues as well as improve ED prevention strategies.

Objectives: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. Design: Retrospective study. Setting: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. Patients: Children (&lt; 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. Interventions: None. Measurements and Main Results: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25–14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index ( n = 817) was 19.4 kg/m 2 (16–25.8 kg/m 2 ), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU ( n = 379) and hospital ( n = 857) stay were 3.9 days (2–7.7 d) and 4 days (1.9–7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. Conclusions: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

RATIONALE: Children dependent on mechanical ventilation are a vulnerable population by virtue of their chronic disability and are therefore at increased risk for health disparities and access barriers. The present study is the first, to our knowledge, to conduct a large-scale survey of caregivers of ventilator-dependent children to develop a comprehensive socio-demographic profile. OBJECTIVES: To describe the demographic and health status profile of ventilator-dependent children, to identify the types of unmet needs families caring for a child on a ventilator face, and to determine the correlates of access to care coordination. METHODS: A survey was administered to 122 parents whose children attended a pediatric home ventilator clinic at a large tertiary Midwestern medical center (84% of the clinic population). MEASUREMENTS AND MAIN RESULTS: Half of the patient population had severe functional limitations, and 70% had one or more comorbidities. One quarter of caregivers reported current financial struggles, and 16% screened positive for a probable depressive disorder. More than half of families reported unmet needs for care, most frequently therapeutic services and skilled nursing care. Of those reporting an unmet need for skilled nursing care, lack of adequate staffing was the main barrier (71.1%). Financial struggles and a probable caregiver depressive disorder were significantly associated with an unmet need for care coordination. CONCLUSIONS: This is the first large-scale quantitative study to investigate the themes of unmet need and care coordination within this vulnerable population. The results suggest these families face barriers accessing therapeutic and skilled nursing services, and caregiver mental health and financial struggles may be important points of intervention for service providers through the inclusion of multidisciplinary care teams and the strengthening of social services referral networks.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

BACKGROUND: Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens. CASE PRESENTATION: A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. Tracheal aspirate samples for mycobacterial DNA and culture from days 22 and 27 of illness were negative by PCR but grew Mycobacterium tuberculosis after 8 weeks, long after the child's passing. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread. CONCLUSION: The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.

INTRODUCTION: Laparoscopic inguinal hernia repair in children is in evolution. Multiple methods of passing the suture around the peritoneum at the level of the internal inguinal ring exist. Cauterization of the peritoneum at the internal ring is thought to increase scarring and decrease recurrence. We have employed a sutureless, cautery only, laparoscopic single port repair of inguinal hernias and patent processus vaginalis (PPV) in girls. METHODS: After institutional ethical review was obtained, a retrospective review of sutureless laparoscopic inguinal hernia repairs in girls by 4 surgeons at separate institutions was performed. Patient demographics, intraoperative findings, and postoperative outcomes were recorded and analyzed. The technique involves an umbilical 30° camera and either a separate 3 mm stab incision in the midclavicular line or a 3 mm Maryland grasper placed next to the camera, and the distal most portion of the hernia sac is grasped and pulled into the abdomen and cauterized obliterating the sac. RESULTS: Eighty inguinal hernias were repaired using this technique in 67 girls between July 2009 and September 2015. The ages and weights ranged from 1 month to 16 years and from 2 to 69 kg, respectively. There was one conversion to open approach because an incarcerated ovary was too close to the ring. A single umbilical incision was utilized in 85%. Fifty-seven percent patients had hernias on the right whereas 42% had hernias on the left. Of the patients with presumed unilateral hernias, 22 patients were found to have PPV and were treated through the same incisions, 17/22 were found during a contralateral hernia surgery and 5/22 were found incidentally during appendectomy. Average operative time for unilateral and bilateral hernias was 22 minutes (5-38 minutes) and 31 minutes (11-65 minutes), respectively. No patient required a hospital stay because of the hernia repair. At an average of 25 months follow-up (1.6-75 months), there were no recurrences. The only complication was a single lateral port site hernia on a 2 kg, former 24 week postmenstrual age girl before adapting the technique to single-site surgery for all. CONCLUSIONS: Laparoscopic sutureless inguinal hernia repair is safe and effective in girls of all ages. The single-site modification allows for superior cosmetic result and lower complication profile. The Burnia allows for adequate treatment of unilateral and bilateral inguinal hernias with a single incision in the umbilicus.

OBJECTIVES/HYPOTHESIS: To examine the effect of and predict the success of type 1 laryngeal cleft (LC-1) augmentation through swallowing evaluations. STUDY DESIGN: Retrospective chart analysis. METHODS: Sixty-eight patients with LC-1s underwent interarytenoid injection laryngoplasty (IL) and were examined. The median age at IL was 9 months. Swallowing evaluations were performed pre- and postoperatively using fiberoptic endoscopic examination of swallowing or modified barium swallow. The presence of aspiration or penetrations at various consistencies was recorded. McNemar's tests were used to detect changes in swallowing pre- and postoperatively. Logistic regression was used to assess factors affecting the odds of postoperative success. RESULTS: Preoperatively, 89.7% of patients demonstrated penetration or aspiration. Post-IL, 69.1% were safe for thins, and 75% showed improvement in swallowing. Postoperatively, there was a significant reduction in patients experiencing problems with thin liquids (P < 0.001) and in those with frank or silent aspiration (P < 0.001). Patients with penetrations on thin liquids had higher likelihood of a successful IL (odds ratio [OR] = 3.68, P = 0.021). The probability of success with silent aspiration at any consistency was significantly decreased (OR = 0.26, P = 0.015). Fifteen patients underwent formal endoscopic surgical repair, and 90.0% were safe with thin consistencies postoperatively. CONCLUSION: A large proportion of patients with LC-1 and associated swallowing dysfunctions respond favorably to IL and formal repair. Children who demonstrated penetration with thin liquids had a higher rate of swallowing dysfunction resolution post-IL; whereas patients demonstrating silent aspiration had poorer responses to IL. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2838-2843, 2016.

AIM: To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. METHODS: Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated. RESULTS: For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.79 ± 1.84 vs 9.14 ± 2.25 mg/dL) and ETCOc (1.61 ± 0.45 vs 2.02 ± 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB ≥75th percentile had ETCOc ≥ 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.28 ± 1.97 vs 9.53 ± 2.78 mg/dL), ETCOc (1.72 ± 0.48 vs 2.38 ± 1.89 ppm, p = 0.05) and TB ROR (0.011 ± 0.440 vs 0.172 ± 0.471 mg/dL/h) were different between the groups. CONCLUSION: The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders.

BACKGROUND: Even relatively low serum bilirubin concentrations can cause neurodevelopmental impairment in extremely low birth weight (EBWL) infants, while sequelae from hyperbilirubinemia in late preterm and term infants are rare and occur only at very high serum bilirubin levels. Phototherapy is the current treatment of choice. OBJECTIVE: To present an update on the most important issues involved in phototherapy for jaundiced infants. RESULTS: Light absorption by bilirubin in the skin transforms the native Z,Z-bilirubin to conformational photoisomers Z,E-bilirubin and E,Z-bilirubin and structural photoisomers E,Z-lumirubin and E,E-lumirubin. Formation and excretion of Z,E-bilirubin and E,Z-lumirubin are both important routes of elimination of bilirubin through bile and urine, although the precise contributions of the various photoisomers to the overall elimination of bilirubin are unknown. It appears that the photoisomers of bilirubin are predominantly formed in the plasma, and the rate of formation is affected by the hemoglobin concentration. Phototherapy lights with an emission spectrum of 460-490 nm provide the most efficient bilirubin-reducing light. LEDs should replace fluorescent tubes and halogen spotlights as the preferred light sources. Recent data raise concerns that sick ELBW infants under prolonged phototherapy may have an increased risk of death, though survivors may benefit from reduced rates of neurodevelopmental impairment. Comparison of the efficacy of cycled vs. continuous phototherapy has given divergent results. Changing the infant's position does not increase the efficacy of phototherapy. CONCLUSION: During the last decade, we have made progress in our understanding of how and where phototherapy works and in its practical applications.

Intracranial arteriovenous malformations (AVM) are a rare feature of Bannayan-Riley-Ruvalcaba syndrome (BRRS). Palencia et al reported a case of intracranial arteriovenous malformation in a child with BRRS in a Spanish journal in 1986. However, the occurrence of dural AVM in a patient with BRRS has not since been addressed in the literature. Advancements in imaging and therapeutic embolization, and the ability now to screen for phosphatase and tensin homologue (PTEN) mutations allow us to detect and manage these patients sooner. Early detection of intracranial AVMs is necessary because of the risk for progression to venous ischemia and resultant neurologic damage. We present the case of a child with headaches and periorbital venous congestion due to a dural AVM with bilateral venous outflow occlusion who was treated with multiple embolizations, now with interval remission of headache symptoms.