Exome sequencing in every pregnancy? Results of trio exome sequencing in structurally normal fetuses.

OBJECTIVE: This study aimed to assess the detection rate of clinically significant results of prenatal exome sequencing (pES) in low-risk pregnancies and apparently normal fetuses in non-consanguineous couples. METHODS: A retrospective analysis of pES conducted at a single center from January 2020 to September 2023 was performed. Genetic counseling was provided, and detailed medical histories were obtained. High-risk pregnancies were excluded due to major ultrasound anomalies, sonographic soft markers, abnormal maternal biochemical screening, or family history suggestive of monogenic diseases as well as cases with pathogenic and likely pathogenic (P/LP) chromosomal microarray results. Exome analysis focused on ∼2100 genes associated with Mendelian genetic disorders. Variant analysis and classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Among 1825 pES conducted, 1020 low-risk cases revealed 28 fetuses (2.7%) with potentially clinically significant variants indicating known monogenic diseases, primarily de novo dominant variants (64%). Among these 28 cases, 9 fetuses (0.9%) had the potential for severe phenotypes, including shortened lifespan and intellectual disability, and another 12 had the potential for milder phenotypes. Seven cases were reported with variants of uncertain significance (VUS) that, according to the ACMG criteria, leaned toward LP, constituting 0.7% of the entire cohort. Termination of pregnancy was elected in 13 out of 1020 cases (1.2%) in the cohort, including 7/9 in the severe phenotypes group, 2/12 in the milder phenotype group, and 4/7 in the VUS group. CONCLUSION: The 2.7% detection rate highlights the significant contribution of pES in low-risk pregnancies. However, it necessitates rigorous analysis, and comprehensive genetic counseling before and after testing.

Identifying infants at risk of sudden unexpected death with an automated predictive risk model.

BACKGROUND/OBJECTIVE: Sudden unexpected infant death (SUID) is a common cause of infant death. We evaluated whether a predictive risk model (PRM) - Hello Baby - which was developed to stratify children by risk of entry into foster care could also identify infants at highest risk of SUID and non-fatal unsafe sleep events. PARTICIPANTS AND SETTING: Cases: Infants with SUID or an unsafe sleep event over 5½ years in a single county. CONTROLS: All births in the same county. METHODS: Retrospective case-control study. Demographic and clinical data were collected and a Hello Baby PRM score was assigned. Descriptive statistics and the predictive value of a PRM score of 20 were calculated. RESULTS: Infants with SUID (n = 62) or an unsafe sleep event (n = 37) (cases) were compared with 23,366 births (controls). Cases and controls were similar for all demographic and clinical data except that infants with unsafe sleep events were older. Median PRM score for cases was higher than controls (17.5 vs. 10, p < 0.001); 50 % of cases had a PRM score 17-20 vs. 16 % of controls (p < 0.001). CONCLUSIONS: The Hello Baby PRM can identify newborns at high risk of SUID and non-fatal unsafe sleep events. The ability to identify high-risk newborns prior to a negative outcome allows for individualized evaluation of high-risk families for modifiable risk factors which are potentially amenable to intervention. This approach is limited by the fact that not all counties can calculate a PRM or similar score automatically.

AST and ALT Elevation in Suspected Physical Abuse: Can the Threshold to Obtain an Abdominal CT be Raised?

BACKGROUND: Identification of abdominal injury (AI) in children with concern for physical abuse is important as it can provide important medical and forensic information. Current recommendations are to obtain screening liver function tests (LFTs) in all children with suspected physical abuse and an abdominal computed tomography (CT) when the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is >80 IU/L. This threshold to obtain an abdominal CT is lower than general trauma guidelines which use a cutoff of AST > 200 or ALT >125 IU/L. METHODS: This was a retrospective review of children ages 0-60 months at a single pediatric tertiary care center who were evaluated for physical abuse and had AST or ALT >80 IU/L. Subjects were then stratified into two groups: mid-range (AST < 200 and ALT <125 IU/L) and high-range (AST > 200 and/or ALT >125 IU/L) LFTs. RESULTS: Abdominal CTs were performed in 55% (131/237) of subjects, 38% (50/131) with mid-range LFTs and 62% (81/131) with high-range LFTs. AI was identified in 19.8% (26/131) of subjects. Subjects with AI were older than those without AI [mean age (SD) 18.7 (12.5) vs. 11.6 (12.2) months, p = 0.009]. The highest yield of abdominal CTs positive for AI was in the group with high-range LFTs with signs or symptoms of AI at 52.0% (13/25; 95% CI: 31.3-72.2%). The negative predictive value of having mid-range LFTs and no signs or symptoms of AI was 100% (95% CI: 97.0-100%). CONCLUSIONS: Our data suggest that abdominal CT may not be necessary in children being evaluated for physical abuse who have AST < 200 and ALT <125 IU/L and do not have signs or symptoms of AI. This could limit the number of abdominal CTs performed. LEVEL OF EVIDENCE: Level IV, Diagnostic Test/Criteria.

New Functional Impairment After Hospital Discharge by Traumatic Brain Injury Mechanism in Younger Than 3 Years Old Admitted to the PICU in a Single Center Retrospective Study.

OBJECTIVES: Children who suffer traumatic brain injury (TBI) are at high risk of morbidity and mortality. We hypothesized that in patients with TBI, the abusive head trauma (AHT) mechanism vs. accidental TBI (aTBI) would be associated with higher frequency of new functional impairment between baseline and later follow-up. DESIGN: Retrospective single center cohort study. SETTING AND PATIENTS: Children younger than 3 years old admitted with TBI to the PICU at a level 1 trauma center between 2014 and 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, TBI mechanism, and Functional Status Scale (FSS) scores at baseline, hospital discharge, short-term (median, 10 mo [interquartile range 3-12 mo]), and long-term (median, 4 yr [3-6 yr]) postdischarge were abstracted from the electronic health record. New impairment was defined as an increase in FSS greater than 1 from baseline. Patients who died were assigned the highest score (30). Multivariable logistic regression was performed to determine the association between TBI mechanism with new impairment. Over 6 years, there were 460 TBI children (170 AHT, 290 aTBI), of which 13 with AHT and four with aTBI died. Frequency of new impairment by follow-up interval, in AHT vs. aTBI patients, were as follows: hospital discharge (42/157 [27%] vs. 27/286 [9%]; p < 0.001), short-term (42/153 [27%] vs. 26/259 [10%]; p < 0.001), and long-term (32/114 [28%] vs. 18/178 [10%]; p < 0.001). Sensory, communication, and motor domains were worse in AHT patients at the short- and long-term timepoint. On multivariable analysis, AHT mechanism was associated with greater odds (odds ratio [95% CI]) of poor outcome (death and new impairment) at hospital discharge (4.4 [2.2-8.9]), short-term (2.7 [1.5-4.9]), and long-term timepoints (2.4 [1.2-4.8]; p < 0.05). CONCLUSIONS: In patients younger than 3 years old admitted to the PICU after TBI, the AHT mechanism-vs. aTBI-is associated with greater odds of poor outcome in the follow-up period through to ~5 years postdischarge. New impairment occurred in multiple domains and only AHT patients further declined in FSS over time.

Predictors of Making a Referral to Child Protective Services Prior to Expert Consultation.

OBJECTIVE: Suspicion for child abuse is influenced by implicit biases. Evaluation by a Child Abuse Pediatrician (CAP) may reduce avoidable child protective services (CPS) referrals. Our objective was to investigate the association of patient demographic, social and clinical characteristics with CPS referral before consultation by a CAP (preconsultation referral). METHODS: Children<5years-old undergoing in-person CAP consultation for suspected physical abuse from February 2021 through April 2022 were identified in CAPNET, a multicenter child abuse research network. Marginal standardization implemented with logistic regression analysis examined hospital-level variation and identified demographic, social, and clinical factors associated with preconsultation referral adjusting for CAP's final assessment of abuse likelihood. RESULTS: Among the 61% (1005/1657) of cases with preconsultation referral, the CAP consultant had low concern for abuse in 38% (384/1005). Preconsultation referrals ranged from 25% to 78% of cases across 10 hospitals (P < .001). In multivariable analyses, preconsultation referral was associated with public insurance, caregiver history of CPS involvement, history of intimate partner violence, higher CAP level of concern for abuse, hospital transfer, and near-fatality (all P < .05). The difference in preconsultation referral prevalence for children with public versus private insurance was significant for children with low CAP concern for abuse (52% vs 38%) but not those with higher concern for abuse (73% vs 73%), (P = .023 for interaction of insurance and abuse likelihood category). There were no differences in preconsultation referral based on race or ethnicity. CONCLUSIONS: Biases based on socioeconomic status and social factors may impact decisions to refer to CPS before CAP consultation.

Multiorgan Dysfunction Syndrome in Abusive and Accidental Pediatric Traumatic Brain Injury.

BACKGROUND: Abusive head trauma (AHT) is a mechanism of pediatric traumatic brain injury (TBI) with high morbidity and mortality. Multiorgan dysfunction syndrome (MODS), defined as organ dysfunction in two or more organ systems, is also associated with morbidity and mortality in critically ill children. Our objective was to compare the frequency of MODS and evaluate its association with outcome between AHT and accidental TBI (aTBI). METHODS: This was a single center, retrospective cohort study including children under 3 years old admitted to the pediatric intensive care unit with nonpenetrating TBI between 2014 and 2021. Presence or absence of MODS on days 1, 3, and 7 using the Pediatric Logistic Organ Dysfunction-2 score and new impairment status (Functional Status Scale score change > 1 compared with preinjury) at hospital discharge (HD), short-term timepoint, and long-term timepoint were abstracted from the electronic health record. Multiple logistic regression was performed to examine the association between MODS and TBI mechanism with new impairment status. RESULTS: Among 576 children, 215 (37%) had AHT and 361 (63%) had aTBI. More children with AHT had MODS on days 1 (34% vs. 23%, p = 0.003), 3 (28% vs. 6%, p < 0.001), and 7 (17% vs. 3%, p < 0.001) compared with those with aTBI. The most common organ failures were cardiovascular ([AHT] 66% vs. [aTBI] 66%, p = 0.997), neurologic (33% vs. 16%, p < 0.001), and respiratory (34% vs. 15%, p < 0.001). MODS was associated with new impairment in multivariable logistic regression at HD (odds ratio 19.1 [95% confidence interval 9.8-38.6, p < 0.001]), short-term discharge (7.4 [3.7-15.2, p < 0.001]), and long-term discharge (4.3 [2.0-9.4, p < 0.001])]. AHT was also associated with new impairment at HD (3.4 [1.6-7.3, p = 0.001]), short-term discharge (2.5 [1.3-4.7, p = 0.005]), and long-term discharge (2.1 [1.1-4.1, p = 0.036]). CONCLUSIONS: Abusive head trauma as a mechanism was associated with MODS following TBI. Both AHT mechanism and MODS were associated with new impairment at all time points.

Characterization of Circulating Cold Shock Proteins FGF21 and RBM3 in a Multi-Center Study of Pediatric Cardiac Arrest.

Fibroblast Growth Factor 21 (FGF21) is a neuroprotective hormone induced by cold exposure that targets the ß-klotho co-receptor. ß-klotho is abundant in the newborn brain but decreases rapidly with age. RNA-Binding Motif 3 (RBM3) is a potent neuroprotectant upregulated by FGF21 in hypothermic conditions. We characterized serum FGF21 and RBM3 levels in patients enrolled in a prospective multi-center study of pediatric cardiac arrest (CA) via a secondary analysis of samples collected to evaluate brain injury biomarkers. Patients (n = 111) with remnant serum samples available from at least two of three available timepoints (0-24, 24-48 or 48-72 hours post-resuscitation) were included. Serum samples from 20 healthy controls were used for comparison. FGF21 was measured by Luminex and internally validated enzyme-linked immunoassay (ELISA). RBM3 was measured by internally validated ELISA. Of postarrest patients, 98 were managed with normothermia, while 13 were treated with therapeutic hypothermia (TH). FGF21 increased >20-fold in the first 24 hours postarrest versus controls (681 pg/mL [200-1864] vs. 29 pg/mL [15-51], n = 99 vs. 19, respectively, p < 0.0001, median [interquartile range]) with no difference in RBM3. FGF21 did not differ by sex, while RBM3 was increased in females versus males at 48-72 hours postarrest (1866 pg/mL [873-5176] vs. 1045 pg/mL [535-2728], n = 40 vs. 54, respectively, p < 0.05). Patients requiring extracorporeal membrane oxygenation (ECMO) postresuscitation had increased FGF21 versus those who did not at 48-72 hours (6550 pg/mL [1455-66,781] vs. 1213 pg/mL [480-3117], n = 7 vs 74, respectively, p < 0.05). FGF21 and RBM3 did not correlate (Spearman's rho = 0.004, p = 0.97). We conclude that in a multi-center study of pediatric CA patients where normothermic targeted temperature management was largely used, FGF21 was markedly increased postarrest versus control and highest in patients requiring ECMO postresuscitation. RBM3 was sex-dependent. We provide a framework for future studies examining the effect of TH on FGF21 or use of FGF21 therapy after pediatric CA.

Recommendations on Social Determinants of Health in Neurologic Disease.

Social determinants of health (SDOH) are increasingly recognized as important drivers of inequities in neurologic disease and outcomes. However, our understanding of the biopsychosocial mechanisms by which SDOH affect neurologic disease remains in its infancy. The most robust epidemiologic research has been on the associations between education, schooling, and place-based social determinants on cognition, dementia, and cerebrovascular disease later in life. Further research is needed to more deeply understand the complex interplay of SDOH on neurologic disease. Few SDOH screening tools have been validated in populations with neurologic disease. In addition, comparison across studies and populations is hampered by lack of standardized common data elements. Experiences of populations historically underrepresented in research should be centered in future research studies, and changes should be made in recruitment expectations and measurement choices. For research on inequities, it is critical to support and incentivize institutional infrastructure to foster meaningful engagement with populations affected by research. Finally, it remains to be seen whether individual-level health or behavioral interventions or place-level, systemic or policy interventions to reduce population burden will be most effective in reducing inequities in neurologic disease and outcomes. Although numerous clinical trials have focused on addressing downstream SDOH such as health literacy and health behaviors (e.g., medication adherence, physical activity, diet), few have addressed upstream, structural determinants which may have a more profound impact on addressing inequities in neurologic disease. Ultimately, further research is needed to determine which specific SDOH should be targeted and how, when, and by whom they should be addressed to improve neurologic outcomes.

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. Exposure: Brain MRI or MRS. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.

Disseminating child abuse clinical decision support among commercial electronic health records: Effects on clinical practice.

Objectives: The use of electronic health record (EHR)-embedded child abuse clinical decision support (CA-CDS) may help decrease morbidity from child maltreatment. We previously reported on the development of CA-CDS in Epic and Allscripts. The objective of this study was to implement CA-CDS into Epic and Allscripts and determine its effects on identification, evaluation, and reporting of suspected child maltreatment. Materials and Methods: After a preimplementation period, CA-CDS was implemented at University of Wisconsin (Epic) and Northwell Health (Allscripts). Providers were surveyed before the go-live and 4 months later. Outcomes included the proportion of children who triggered the CA-CDS system, had a positive Child Abuse Screen (CAS) and/or were reported to Child Protective Services (CPS). Results: At University of Wisconsin (UW), 3.5% of children in the implementation period triggered the system. The CAS was positive in 1.8% of children. The proportion of children reported to CPS increased from 0.6% to 0.9%. There was rapid uptake of the abuse order set.At Northwell Health (NW), 1.9% of children in the implementation period triggered the system. The CAS was positive in 1% of children. The child abuse order set was rarely used. Preimplementation, providers at both sites were similar in desire to have CA-CDS system and perception of CDS in general. After implementation, UW providers had a positive perception of the CA-CDS system, while NW providers had a negative perception. Discussion: CA-CDS was able to be implemented in 2 different EHRs with differing effects on clinical care and provider feedback. At UW, the site with higher uptake of the CA-CDS system, the proportion of children who triggered the system and the rate of positive CAS was similar to previous studies and there was an increase in the proportion of cases of suspected abuse identified as measured by reports to CPS. Our data demonstrate how local environment, end-users' opinions, and limitations in the EHR platform can impact the success of implementation. Conclusions: When disseminating CA-CDS into different hospital systems and different EHRs, it is critical to recognize how limitations in the functionality of the EHR can impact the success of implementation. The importance of collecting, interpreting, and responding to provider feedback is of critical importance particularly with CDS related to child maltreatment.

International Consensus Statement on the Radiological Screening of Contact Children in the Context of Suspected Child Physical Abuse.

Importance: Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. Objective: To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. Evidence Review: This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. Findings: Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. Conclusions and Relevance: This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Increased severity of abusive head trauma during the first year of the COVID-19 pandemic.

BACKGROUND: Abusive head trauma (AHT) is the leading cause of death from physical abuse in children. Reports regarding the impact of the COVID-19 pandemic on rates and severity of AHT are limited and with conflicting results. OBJECTIVE: To determine the number and clinical characteristics of AHT cases presenting to a pediatric tertiary care center during the first year of the COVID-19 pandemic compared to the two prior years. PARTICIPANTS AND SETTING: We performed a retrospective cohort study of patients <5 years old diagnosed with AHT at a single pediatric tertiary care center over a three-year period. METHODS: Data were obtained for the pandemic year and two years before, including demographics, length of stay, physical and retinal examination findings, radiologic studies, electroencephalogram results, and mortality. RESULTS: There were 27 cases of AHT during the first year of the pandemic and 55 during the two pre-pandemic years. Length of stay was similar for the two cohorts. The mortality rate was higher during the pandemic (29.6 % vs. 3.6 %; p < .01), as were the proportion of patients with retinal hemorrhages (84.6 % vs. 41.5 %; p < .01) and abnormal cervical spine imaging (52.6 % vs. 21.2 %; p = .02). There were no differences in age, sex, race, abnormalities on dermatological exam, skeletal surveys, and electroencephalograms. CONCLUSIONS: We did not observe an increase in the number of patients with AHT during the pandemic but did see an increase in mortality, patients with retinal hemorrhages, and patients with abnormalities on cervical spine imaging. These data suggest a higher severity of AHT presenting to a pediatric tertiary care center during the pandemic.

Child Abuse Pediatrics Research Network: The CAPNET Core Data Project.

OBJECTIVE: Examine the epidemiology of subspecialty physical abuse evaluations within CAPNET, a multicenter child abuse pediatrics research network. METHODS: We conducted a cross-sectional study of children <10 years old who underwent an evaluation (in-person or remote) by a child abuse pediatrician (CAP) due to concerns for physical abuse at ten CAPNET hospital systems from February 2021 through December 2021. RESULTS: Among 3667 patients with 3721 encounters, 69.4% were <3 years old; 44.3% <1 year old, 59.1% male; 27.1% Black; 57.8% White, 17.0% Hispanic; and 71.0 % had public insurance. The highest level of care was outpatient/emergency department in 60.7%, inpatient unit in 28.0% and intensive care in 11.4%. CAPs performed 79.1% in-person consultations and 20.9% remote consultations. Overall, the most frequent injuries were bruises (35.2%), fractures (29.0%), and traumatic brain injuries (TBI) (16.2%). Abdominal (1.2%) and spine injuries (1.6%) were uncommon. TBI was diagnosed in 30.6% of infants but only 8.4% of 1-year old children. In 68.2% of cases a report to child protective services (CPS) was made prior to CAP consultation; in 12.4% a report was made after CAP consultation. CAPs reported no concern for abuse in 43.0% of cases and mild/intermediate concern in 22.3%. Only 14.2% were categorized as definite abuse. CONCLUSION: Most children in CAPNET were <3 years old with bruises, fractures, or intracranial injuries. CPS reports were frequently made prior to CAP consultation. CAPs had a low level of concern for abuse in majority of cases.

Association of Blood-Based Brain Injury Biomarker Concentrations With Outcomes After Pediatric Cardiac Arrest.

Importance: Families and clinicians have limited validated tools available to assist in estimating long-term outcomes early after pediatric cardiac arrest. Blood-based brain-specific biomarkers may be helpful tools to aid in outcome assessment. Objective: To analyze the association of blood-based brain injury biomarker concentrations with outcomes 1 year after pediatric cardiac arrest. Design, Setting, and Participants: The Personalizing Outcomes After Child Cardiac Arrest multicenter prospective cohort study was conducted in pediatric intensive care units at 14 academic referral centers in the US between May 16, 2017, and August 19, 2020, with the primary investigators blinded to 1-year outcomes. The study included 120 children aged 48 hours to 17 years who were resuscitated after cardiac arrest, had pre-cardiac arrest Pediatric Cerebral Performance Category scores of 1 to 3 points, and were admitted to an intensive care unit after cardiac arrest. Exposure: Cardiac arrest. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (death or survival with a Vineland Adaptive Behavior Scales, third edition, score of <70 points) at 1 year after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCH-L1), neurofilament light (NfL), and tau concentrations were measured in blood samples from days 1 to 3 after cardiac arrest. Multivariate logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were performed to examine the association of each biomarker with outcomes on days 1 to 3. Results: Among 120 children with primary outcome data available, the median (IQR) age was 1.0 (0-8.5) year; 71 children (59.2%) were male. A total of 5 children (4.2%) were Asian, 19 (15.8%) were Black, 81 (67.5%) were White, and 15 (12.5%) were of unknown race; among 110 children with data on ethnicity, 11 (10.0%) were Hispanic, and 99 (90.0%) were non-Hispanic. Overall, 70 children (58.3%) had a favorable outcome, and 50 children (41.7%) had an unfavorable outcome, including 43 deaths. On days 1 to 3 after cardiac arrest, concentrations of all 4 measured biomarkers were higher in children with an unfavorable vs a favorable outcome at 1 year. After covariate adjustment, NfL concentrations on day 1 (adjusted odds ratio [aOR], 5.91; 95% CI, 1.82-19.19), day 2 (aOR, 11.88; 95% CI, 3.82-36.92), and day 3 (aOR, 10.22; 95% CI, 3.14-33.33); UCH-L1 concentrations on day 2 (aOR, 11.27; 95% CI, 3.00-42.36) and day 3 (aOR, 7.56; 95% CI, 2.11-27.09); GFAP concentrations on day 2 (aOR, 2.31; 95% CI, 1.19-4.48) and day 3 (aOR, 2.19; 95% CI, 1.19-4.03); and tau concentrations on day 1 (aOR, 2.44; 95% CI, 1.14-5.25), day 2 (aOR, 2.28; 95% CI, 1.31-3.97), and day 3 (aOR, 2.04; 95% CI, 1.16-3.57) were associated with an unfavorable outcome. The AUROC models were significantly higher with vs without the addition of NfL on day 2 (AUROC, 0.932 [95% CI, 0.877-0.987] vs 0.871 [95% CI, 0.793-0.949]; P = .02) and day 3 (AUROC, 0.921 [95% CI, 0.857-0.986] vs 0.870 [95% CI, 0.786-0.953]; P = .03). Conclusions and Relevance: In this cohort study, blood-based brain injury biomarkers, especially NfL, were associated with an unfavorable outcome at 1 year after pediatric cardiac arrest. Additional evaluation of the accuracy of the association between biomarkers and neurodevelopmental outcomes beyond 1 year is needed.

Association of EEG and Blood-Based Brain Injury Biomarker Accuracy to Prognosticate Mortality After Pediatric Cardiac Arrest: An Exploratory Study.

BACKGROUND: Evaluate the accuracy of brain-based blood biomarkers neuron-specific enolase (NSE) and S100b and electroencephalography (EEG) features alone and in combination with prognosticate 6-month mortality after pediatric cardiac arrest. We hypothesized that the combination of blood brain-based biomarkers and EEG features would have superior classification accuracy of outcome versus either alone. METHODS: Children (n = 58) aged between 1 week and 17 years admitted to the ICU following cardiac arrest at a tertiary care children's hopital were eligible for this secondary study. Blood NSE and S100b were measured closest to 24 hours after return of spontaneous circulation (ROSC). EEGs closest to 24 hours (median 11, interquartile range [IQR] 6 to 16 h) post-ROSC were evaluated by two epileptologists. EEG grade was informed by background frequency, amplitude, and continuity. Sleep spindles were present or absent. Mortality was assessed at six months post-ROSC. Area under the receiver operator curve (AUC) was performed for individual and combined brain-based biomarkers and EEG features. RESULTS: Children were aged 2.6 (IQR 0.6 to 10.4) years, and 25 (43%) died. Children who died had increased blood NSE (49.7 [28.0 to 63.1] vs 18.2 [9.8 to 31.8] ng/mL) and S100b (0.118 [0.036 to 0.296] vs 0.012 [0.003 to 0.021] ng/mL) and poor (discontinuous or isoelectric) EEG grade (76% vs 33%) more frequently than survivors (P < 0.05). AUC for NSE to predict mortality was 0.789, and was 0.841 when combined with EEG grade and spindles. S100b AUC for mortality was 0.856 and was optimal alone. CONCLUSIONS: In this exploratory study, the combination of brain-based biomarkers and EEG features may provide more accurate prognostication than either test alone after pediatric cardiac arrest.

The CAPNET multi-center data set for child physical abuse: Rationale, methods and scope.

BACKGROUND: The pediatric subspecialty of Child Abuse Pediatrics (CAP) was certified by the American Board of Medical Subspecialties in 2006. Relative to its impact on pediatric health, CAP-focused research has been relatively under-funded. Multi-center networks related to CAP-focused research have made important advances, but have been limited in scope and duration. CAPNET is multi-center network whose mission is to support CAP-focused research. OBJECTIVE: To describe the rationale, development, and scope of the CAPNET research network infrastructure, the CAPNET data registry and associated data resources. METHODS: Based on existing priorities for CAP-focused research, we used consensus building and iterative testing to establish inclusion criteria, common data elements, data quality assurance, and data sharing processes for children with concerns of physical abuse. RESULTS: We describe the rationale, methods and intended scope for the development of the CAPNET research network and data registry. CAPNET is currently abstracting data for children <10 years (120 months) old who undergo sub-specialty evaluation for physical abuse at 10 US pediatric centers (approximately 4000 evaluations/year total) using an online data capture form. Data domains include: demographics; visit timing and providers, medical/social history, presentation, examination findings, laboratory and radiographic testing, diagnoses, outcomes, and data for contact children. We describe the methods and criteria for collecting and validating data which are broadly available to CAP investigators. CONCLUSIONS: CAPNET represents a new data resource for the CAP research community and will increase the quantity and quality of CAP-focused research.

Microdeletion of 16q24.1-q24.2-A unique etiology of Lymphedema-Distichiasis syndrome and neurodevelopmental disorder.

Interstitial deletions of 16q24.1-q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema-Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1-q24.2. This report extends the phenotype of both 16q24.1-q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3'-UTR part of FOXC2.