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Purpose: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype., Methods: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy., Results: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family., Conclusion: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings., Competing Interests: Conflict of Interest Rebecca Ganetzky is a paid consultant for Minovia Therapeutics and Nurture Genomics. Neal Sondheimer is employed by Synlogic, Inc. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Neonatal hypoxic-ischemic encephalopathy is a clinical phenomenon that often results from perinatal asphyxia. To mitigate secondary neurologic injury, prompt initial assessment and diagnosis is needed to identify patients eligible for therapeutic hypothermia. However, occasionally neonates present with a clinical picture of hypoxic-ischemic encephalopathy without significant risk factors for perinatal asphyxia. We hypothesized that in patients with genetic abnormalities, the clinical manifestation of those abnormalities may overlap with hypoxic-ischemic encephalopathy criteria, potentially contributing to a causal misattribution. We reviewed 210 charts of infants meeting local protocol criteria for moderate to severe hypoxic-ischemic encephalopathy in neonatal intensive care units in Calgary, Alberta. All patients that met criteria for therapeutic hypothermia were eligible for the study. Data were collected surrounding pregnancy and birth histories, as well as any available genetic or metabolic testing including microarray, gene panels, whole-exome sequencing, and newborn metabolic screens. Twenty-eight patients had genetic testing such as microarray, whole-exome sequencing, or a gene panel, because of clinical suspicion. Ten of 28 patients had genetic mutations, including CDKL5 , pyruvate dehydrogenase, CFTR , CYP21A2 , ISY1 , KIF1A , KCNQ2 , SCN9A , MTFMT , and NPHP1 . All patients lacked significant risk factors to support a moderate to severe hypoxic-ischemic encephalopathy diagnosis. Treatment was changed in 2 patients because of confirmed genetic etiology. This study demonstrates the importance of identifying genetic comorbidities as potential contributors to a hypoxic-ischemic encephalopathy phenotype in neonates. Early identification of clinical factors that support an alternate diagnosis should be considered when the patient's clinical picture is not typical of hypoxic-ischemic encephalopathy and could aid in both treatment decisions and outcome prognostication.

Introduction: Pain and complications related to pediatric sickle cell disease (SCD) are associated with higher health care utilization. In other pediatric chronic conditions, psychosocial screening can help identify children and families at risk of increased health care utilization to guide resource allocation, address treatment needs, and improve care. This study aimed to investigate the utility of psychosocial screening in predicting increased health care utilization among youth with SCD., Methods: Youth with SCD (n = 74, 8-18 years) and their parents were recruited from comprehensive SCD clinics. Parents completed the Psychosocial Assessment Tool (PAT), which categorized family psychosocial risk into one of three categories: Universal (minimal distress), Targeted (elevated distress), and Clinical (persistent distress). Youth reported on their pain characteristics, and health care utilization was extracted from medical chart review. Differences in health care utilization were evaluated using analysis of variance (ANOVA) and moderation analyses., Results: Based on PAT risk, families were categorized into Universal (56.8%), Targeted (29.7%), and Clinical (13.5%) risk groups, with no significant group differences across demographic variables. Patients in the Targeted group reported significantly higher pain frequency than those in the Universal group (F[2, 66] = 3.7, p < .05). The association between pain frequency and health care utilization significantly varied on the basis of psychosocial risk, such that Clinical psychosocial risk strengthened the connection between pain frequency and health care utilization (β = .2, t = 2.1, p < .05)., Conclusions: Integrating the PAT into routine clinical care may help health care providers identify families in need of greater psychosocial or medical support to further optimize SCD management., (© 2021 Wiley Periodicals LLC.)

Background: Pediatric sickle cell disease (SCD) management can result in considerable caregiver distress. Parents of youth with chronic SCD pain may face the additional challenge of managing children's chronic pain and chronic illness. This study examined associations between parent psychological distress and child functioning and the moderating role of chronic pain among youth with SCD., Methods: Youth presenting to pediatric outpatient comprehensive SCD clinics and their primary caregivers completed a battery of questionnaires. Parents reported on parenting stress, parent mental and physical health, and family functioning. Children completed measures of pain characteristics, depressive symptoms, catastrophic thinking, functional disability, and quality of life., Results: Patients (N = 73, Mage = 14.2 years, 57% female) and their caregivers (Mage = 41.1 years, 88% mothers, 88% Black) participated. Worse parent functioning was associated with worse child pain, functioning, quality of life, and depressive symptoms. Beyond the effects of SCD, chronic SCD pain magnified the negative associations between parenting stress frequency and child quality of life, parent physical health and child quality of life, and parent depressive symptoms and child depressive symptoms., Conclusions: Chronic pain may exacerbate the relations between parent and child functioning beyond the effects of SCD alone. The management of both SCD and chronic pain may present additional challenges for parents that limit their psychosocial functioning. Family-focused interventions to support parents and youth with chronic SCD pain are warranted to optimize health outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The understanding of molecular biology in neurocritical care (NCC) is expanding rapidly and recognizing the important contribution of neuroinflammation, specifically changes in immunometabolism, towards pathological disease processes encountered across all illnesses in the NCC. Additionally, the importance of individualized inflammatory responses has been emphasized, acknowledging that not all individuals have the same mechanisms contributing towards their presentation. By understanding cellular processes that drive disease, we can make better personalized therapy decisions to improve patient outcomes. While the understanding of these cellular processes is evolving, the ability to measure such cellular responses at bedside to make acute care decisions is lacking. In this overview, we review cellular mechanisms involved in pathological neuroinflammation with a focus on immunometabolic dysfunction and review non-invasive bedside tools that have the potential to measure indirect and direct markers of shifts in cellular metabolism related to neuroinflammation. These tools include near-infrared spectroscopy, transcranial doppler, elastography, electroencephalography, magnetic resonance imaging and spectroscopy, and cytokine analysis. Additionally, we review the importance of genetic testing in providing information about unique metabolic profiles to guide individualized interpretation of bedside data. Together in tandem, these modalities have the potential to provide real time information and guide more informed treatment decisions.

Background: Studies have shown a correlation between language abilities and alcohol use; however, results are inconsistent. A recent study using a discordant twin design showed an association between early child language development and later alcohol use behaviors; i.e., the twin with more advanced language abilities was more likely to try alcohol earlier in adolescence (Latvala et al., 2014). The authors suggested that this could result from better socialization of individuals with greater language abilities, which could lead to more opportunities for alcohol experimentation. The findings by Latvala et al. raise interesting questions, but the study has limitations, and replication is needed., Method: We aimed to replicate and build upon these results utilizing 488 same sex twin pairs from the Colorado Longitudinal Twin Study, a longitudinal sample with quantitative measures of language abilities starting when the twins were 14 months old., Results: We found no significant correlations between a latent measure of child language abilities or measures of general cognitive ability at ages 14, 20, and 24 months and a latent alcohol use variable at ages 17 and 22 years., Conclusion: Our results did not replicate the association between early language ability and later alcohol use reported by Latvala et al. Possible reasons for differing results across samples, including varying cultural norms as well as differences in educational attainment, peer influences, and novelty seeking, were discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Perinatal stroke is the most common cause of unilateral cerebral palsy. Mechanisms of post-stroke developmental plasticity in children are poorly understood. To better understand the relationship between functional connectivity and disability, we used resting-state fMRI to compare sensorimotor connectivity with clinical dysfunction., Methods: School-aged children with periventricular venous infarction (PVI) and unilateral cerebral palsy were compared to controls. Resting-state BOLD signal was acquired on 3 T MRI and analyzed using CONN in SPM12. Functional connectivity was computed between S1, M1, supplementary motor area (SMA), and thalamus of the left/non-lesioned and right/lesioned hemisphere. Primary outcome was connectivity expressed as a Fisher-transformed correlation coefficient. Motor function was measured using the Assisting Hand Assessment (AHA), and Melbourne Assessment (MA). Proprioceptive function was measured using a robotic position matching task (VarXY)., Results: Participants included 15 PVI and 21 controls. AHA and MA in stroke patients were negatively correlated with connectivity (increased connectivity = poorer performance). Position sense was inversely correlated with connectivity (increased connectivity = improved performance) between the non-lesioned S1 and thalamus/SMA. In controls, VarXY was positively correlated with connectivity between the thalamus and bilateral sensorimotor regions., Conclusions: Resting state fMRI measures of sensorimotor connectivity are associated with clinical sensorimotor function in children with unilateral cerebral palsy secondary to PVI. Greater insight into understanding reorganization of brain networks following perinatal stroke may facilitate personalized rehabilitation., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: Adolescents with conduct and substance use problems are at increased risk for premature mortality, but the extent to which these risk factors reflect family- or individual-level differences and account for shared or unique variance is unknown. This study examined common and independent contributions to mortality hazard in adolescents ascertained for conduct disorder (CD) and substance use disorder (SUD), their siblings and community controls, hypothesizing that individual differences in CD and SUD severity would explain unique variation in mortality risk beyond that due to clinical/control status and demographic factors., Design: Mortality analysis in a prospective study (Genetics of Antisocial Drug Dependence Study) that began in 1993., Setting: Multi-site sample recruited in San Diego, California and Denver, Colorado, USA., Participants: A total of 1463 clinical probands were recruited through the juvenile correctional system, court-mandated substance abuse treatment programs and correctional schools, along with 1399 of their siblings, and 904 controls., Measurements: Mortality and cause-of-death were assessed via National Death Index search (released October, 2017)., Findings: There were 104 deaths documented among 3766 (1168 female) adolescents and young adults (average age 16.79 years at assessment, 32.69 years at death/censoring). Mortality hazard for clinical probands and their siblings was 4.99 times greater than that of controls (95% confidence interval = 2.40-10.40; P < 0.001). After accounting for demographic characteristics, site, clinical status, familial dependence and shared contributions of CD and SUD, CD independently predicted mortality hazard, whereas SUD severity did not., Conclusions: In the United States, youth with conduct and substance use disorders and their siblings face far greater risk of premature death than demographically similar community controls. In contrast to substance use disorder severity, conduct disorder is a robust predictor of unique variance in all-cause mortality hazard beyond other risk factors., (© 2018 Society for the Study of Addiction.)

The present study examined the influence of maternal and child characteristics on parenting behaviors in a genetically informative study. The participants were 976 twins and their mothers from the Colorado Longitudinal Twin Study and the Twin Infant Project. Indicators of positive parenting were coded during parent-child interactions when twins were 7-36 months old. Child cognitive abilities and affection were independent correlates of positive parenting. There were significant gender differences in the magnitude of genetic and environmental influences on positive parenting, with shared environmental influences on parenting of girls and additive genetic influences on parenting of boys. Girls received significantly more positive parenting than boys. Differences in etiology of positive parenting may be explained by developmental gender differences in child cognitive abilities and affection, such that girls may have more rewarding interactions with parents, evoking more positive parenting.