Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors.

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

How Cancer Harms the Developing Brain: Long-Term Outcomes in Pediatric Cancer Survivors.

Survival rates for pediatric cancer are improving, resulting in a rising need to understand and address long-term sequelae. In this narrative review, we summarize the effects of cancer and its treatment on the developing brain, with a focus on neurocognitive function in leukemia and pediatric brain tumor survivors. We then discuss possible mechanisms of brain injury and management considerations.

Academic clinician educators: Confronting the challenges to successful retirement.

Background: The academic clinician-educator (CE) often has a career spanning 40 or more years. Retirement represents the last stage of one's professional identity. Planning for retirement can be both exciting and challenging. Although it would seem reasonable that there would be research addressing the transition to retirement that incorporates guidance on important decisions or pathways to retirement with outcomes related to satisfaction, adjustment, or fulfillment in retirement, in fact, there is minimal such research. As CEs, the recently retired authors have drawn on our experiences in pediatrics as the foundation for our inquiry. The authors suggest that retirement decisions and needs differ in academic health center (AHC) faculty from those in health-care private practice. As an example, we suggest that CEs in all specialties, and likely other senior faculty in the health sciences, may have unique opportunities in retirement to enrich their institutions and their specialty organizations. The gaps we have encountered and our experiences in the retirement process have resulted in this paper, in which we encourage research that will inform more substantial, timely, and practical advice going forward. Methods: Our exploration of retirement from AHC careers includes two foci: (1) A review of relevant literature on retirement issues the CE, AHC, and national educator organizations might consider important in this transition process; and (2) the description of a theoretical framework known as Conservation of Resources Theory simply to help organize perspectives on the losses, gains, or conservation of tangible and intangible resources to weigh in the planning and transition process. Results: Several considerations relevant to retirement planning, both specific to academic faculty retirement in the health sciences and to retirement planning more broadly, emerged from our literature exploration. However, there were virtually no studies addressing these considerations, both personal and professional, accompanied by tracking their impact on satisfaction or well-being once in retirement. Discussion: Emerging from our examination of literature and our experiences in transitioning to retirement are a number of questions deserving of further study, likely in longitudinal, comparative or more broadly in global inquiries, in the effort to develop models to guide the retiring academic CE. Over the next decade, there will be so many faculty members considering or negotiating retirement that there is an urgent need to develop and study models that both inform this process and monitor outcomes in terms of satisfaction with the retirement years.

Visual outcomes after bevacizumab-based therapy for optic pathway glioma.

In optic pathway glioma (OPG), bevacizumab-based therapy (BBT) has promising effects on radiographic tumor burden, but the impact on vision is less clear. This single-institution study characterized visual acuity (VA) and visual field (VF) outcomes in 17 pediatric OPG patients treated with BBT. VA was stable or improved in 14 patients. Nine patients had evaluable VF data, six of whom experienced stability or improvement. Among six patients with vision deterioration as a treatment indication, stable or improved was observed for both VA and VF in five patients. In summary, BBT was associated with favorable visual outcomes in this cohort of patients with OPG.

Review of Machine Learning and Artificial Intelligence (ML/AI) for the Pediatric Neurologist.

Artificial intelligence (AI) and a popular branch of AI known as machine learning (ML) are increasingly being utilized in medicine and to inform medical research. This review provides an overview of AI and ML (AI/ML), including definitions of common terms. We discuss the history of AI and provide instances of how AI/ML can be applied to pediatric neurology. Examples include imaging in neuro-oncology, autism diagnosis, diagnosis from charts, epilepsy, cerebral palsy, and neonatal neurology. Topics such as supervised learning, unsupervised learning, and reinforcement learning are discussed.

Successful Endovascular Therapy in COVID-19 Associated Pediatric Ischemic Stroke.

Cerebrovascular diseases attributed to coronavirus disease 2019 (COVID-19) are uncommon but can result in devastating outcomes. Pediatric acute ischemic strokes are themselves rare and with very few large vessel occlusion related acute ischemic strokes attributed to COVID-19 described in the literature as of date. COVID-19 pandemic has contributed to acute stroke care delays across the world and with pediatric endovascular therapy still in its infancy, it poses a great challenge in facilitating good outcomes in children presenting with acute ischemic strokes in the setting of COVID-19. We present a pediatric patient who underwent endovascular therapy for an internal carotid artery occlusion related acute ischemic stroke in the setting of active COVID-19 and had an excellent outcome thanks to a streamlined stroke pathway involving the vascular neurology, neuro-interventional, neurocritical care, and anesthesiology teams.

Cerebrospinal fluid cytokine, chemokine, and SARS-CoV-2 antibody profiles in children with neuropsychiatric symptoms associated with COVID-19.

BACKGROUND: Neuropsychiatric symptoms and CSF cytokine, chemokine, and SARS-COV-2 antibody profiles are unknown in pediatric patients with COVID-19 or multisystem inflammatory syndrome (MIS-C), (NP-COVID-19). METHODS: Children at a single pediatric institution quaternary referral center with laboratory-confirmed COVID-19 or MIS-C and neuropsychiatric symptoms were included in this retrospective case series. Clinical symptoms, ancillary testing data, treatments and outcomes are described. Multiplexed electrochemiluminescence assays for cytokines, chemokines and SARS-CoV-2 antibodies were tested in the CSF NP-COVID-19 patients compared to five controls and were analyzed using the Student's t-test. RESULTS: Three of five NP-COVID-19 patients had psychiatric symptoms, and two patients had encephalopathy and seizures. All patients had full or near resolution of neuropsychiatric symptoms by discharge. One patient received intravenous steroids for treatment for psychiatric symptoms; 3/5 other patients received immunotherapy for MIS-C, including IVIG, high-dose steroids, anakinra, and tocilizumab. Pro-inflammatory chemokines, including MIG, MPC, MIP-1ß, and TARC were significantly elevated in NP-COVID-19 patients compared to controls. Two of five patients had elevated CSF neurofilament light chain. CSF SARS-CoV-2 antibody titers to the full-length spike, receptor binding domain and N-terminal domain were significantly elevated. SARS-CoV-2 antibody titers strongly correlated with pro-inflammatory chemokines/cytokines, including IL-1ß, IL-2, IL-8, TNF-α, and IFN-γ (P≤0.05 for all). CONCLUSIONS: A spectrum of neuropsychiatric clinical manifestations can occur in children with SARS-CoV-2 infection. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV-2 mediated NP-COVID-19. Additional study is required to understand the pathophysiologic mechanisms of neuroinflammation in children with COVID-19 and MIS-C.

Reducing Prescribing Errors in Hospitalized Children on the Ketogenic Diet.

BACKGROUND: Children on the ketogenic diet must limit carbohydrate intake to maintain ketosis and reduce seizure burden. Patients on ketogenic diet are vulnerable to harm in the hospital setting where carbohydrate-containing medications are commonly prescribed. We developed clinical decision support to reduce inappropriate prescription of carbohydrate-containing medications in hospitalized children on ketogenic diet. METHODS: A clinical decision support alert was developed through formative and summative usability testing. The alert warned prescribers when they entered an order for a carbohydrate-containing medication in patients on ketogenic diet. The alert was implemented using a quasi-experimental design with sequential crossover from control to intervention at two tertiary care pediatric hospitals within a single health system. The primary outcome was carbohydrate-containing medication orders per patient-day. RESULTS: During the study period, there were 280 ketogenic diet patient admissions totaling 1219 patient-days. The carbohydrate-containing medication order rate declined from 0.69 to 0.35 orders per patient-day (absolute rate reduction 0.34, 95% confidence interval 0.25-0.43), corresponding to 256 inappropriate orders prevented. The alert fired 398 times and was accepted (i.e., the order was removed) 227 times for an overall acceptance rate of 57%. CONCLUSIONS: Implementation of a clinical decision support alert at order-entry resulted in a sustained reduction in carbohydrate-containing medication orders for hospitalized patients on ketogenic diet without an increase in alert burden. Clinical decision support developed with user-centered design principles can improve patient safety for children on ketogenic diet by influencing prescriber behavior.

Use of a wearable device to assess sleep and motor function in Duchenne muscular dystrophy.

INTRODUCTION: Rest-activity disruption is an important feature of Duchenne muscular dystrophy (DMD). We sought to describe sleep impairment and its relationship to quality of life (QOL) and to evaluate associations between rest-activity, sleep quality, and 6-minute walk test (6MWT) in DMD. METHODS: Sleep impairment and its relationship to QOL was assessed by questionnaire in 54 children (33 ambulatory, 21 nonambulatory) with DMD. Rest-activity characteristics were calculated for 23 of these children (14 ambulatory, nine nonambulatory) by actigraphy. RESULTS: Pathologic sleep was reported in 11 (20%) participants and correlated with lower QOL but not with ambulatory status. In ambulatory participants who completed actigraphy, rest-activity rhythm fragmentation was associated with subjective sleep impairment. Habitual daytime activity level was associated with 6MWT performance. DISCUSSION: Children with DMD experience substantial sleep impairment that is related to QOL. Wrist actigraphy may be a parsimonious tool for monitoring both sleep and motor impairment in ambulatory children with DMD.

Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma.

Host genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology, are limited. Here, we evaluated variation in host genome of long-term survivors of medulloblastoma and its association with neurocognitive outcome. Whole-genome sequencing was conducted on peripheral blood of long-term survivors of pediatric medulloblastoma who also completed neuropsychological testing. Cognitively impaired and less impaired survivors did not differ in exposure to chemoradiation therapy or age at treatment. Unsupervised consensus clustering yielded two distinct variant clusters that were significantly associated with neurocognitive outcome. Interestingly, 34 of the 36 significant variants were found in noncoding DNA regions with unknown regulatory function. A separate unsupervised cluster analysis of variants within DNA repair genes identified discrete variant groups that were not associated with neurocognitive outcome, suggesting that variations in genes corresponding to a single functional group may be insufficient to predict long-term outcome alone. These findings are supportive of the presence of a genetic diathesis for treatment-related neurocognitive morbidity in medulloblastoma that may be driven by variation in noncoding regulatory elements.

Effective Discipline to Raise Healthy Children.

Pediatricians are a source of advice for parents and guardians concerning the management of child behavior, including discipline strategies that are used to teach appropriate behavior and protect their children and others from the adverse effects of challenging behavior. Aversive disciplinary strategies, including all forms of corporal punishment and yelling at or shaming children, are minimally effective in the short-term and not effective in the long-term. With new evidence, researchers link corporal punishment to an increased risk of negative behavioral, cognitive, psychosocial, and emotional outcomes for children. In this Policy Statement, the American Academy of Pediatrics provides guidance for pediatricians and other child health care providers on educating parents about positive and effective parenting strategies of discipline for children at each stage of development as well as references to educational materials. This statement supports the need for adults to avoid physical punishment and verbal abuse of children.

Impact of a Daily PICU Rounding Checklist on Urinary Catheter Utilization and Infection.

INTRODUCTION: In critically ill children, inappropriate urinary catheter (UC) utilization is associated with increased morbidity, including catheter-associated urinary tract infections (CAUTIs). Checklists are effective for reducing medical errors, but there is little data on their impact on device utilization in pediatric critical care. In this study, we evaluated UC utilization trends and CAUTI rate after implementing a daily rounding checklist. METHODS: A retrospective review of our checklist database from 2006 through 2016 was performed. The study setting was a 36-bed pediatric intensive care unit in a quaternary-care pediatric hospital. Interventions included the "Daily QI Checklist" in 2006, ongoing education regarding device necessity, and a CAUTI prevention bundle in 2013. UC utilization and duration were assessed via auto-correlated time series models and Cochran-Armitage tests for trend. Changes in CAUTI rate were assessed via Poisson regression. RESULTS: UC utilization decreased from 30% of patient-days in 2006 to 18% in 2016 (P < 0.0001, Cochran-Armitage trend test), while duration of UC use (median, 2.0 days; interquartile range, 1-4) did not change over time (P = 0.18). CAUTI rate declined from 9.49/1,000 UC-days in 2009 to 1.04 in 2016 (P = 0.0047). CONCLUSIONS: Implementation of the checklist coincided with a sustained 40% reduction in UC utilization. The trend may be explained by a combination of more appropriate selection of patients for catheterization and improved timeliness of UC discontinuation. We also observed an 89% decline in CAUTI rate that occurred after stabilization of UC utilization. These findings underscore the potential impact of a checklist on incorporating best practices into daily care of critically ill children.

A precise measurement of the magnetic field in the corona of the black hole binary V404 Cygni.

Observations of binary stars containing an accreting black hole or neutron star often show x-ray emission extending to high energies (>10 kilo--electron volts), which is ascribed to an accretion disk corona of energetic particles akin to those seen in the solar corona. Despite their ubiquity, the physical conditions in accretion disk coronae remain poorly constrained. Using simultaneous infrared, optical, x-ray, and radio observations of the Galactic black hole system V404 Cygni, showing a rapid synchrotron cooling event in its 2015 outburst, we present a precise 461 ± 12 gauss magnetic field measurement in the corona. This measurement is substantially lower than previous estimates for such systems, providing constraints on physical models of accretion physics in black hole and neutron star binary systems.

Redesigning Health Care Practices to Address Childhood Poverty.

Child poverty in the United States is widespread and has serious negative effects on the health and well-being of children throughout their life course. Child health providers are considering ways to redesign their practices in order to mitigate the negative effects of poverty on children and support the efforts of families to lift themselves out of poverty. To do so, practices need to adopt effective methods to identify poverty-related social determinants of health and provide effective interventions to address them. Identification of needs can be accomplished with a variety of established screening tools. Interventions may include resource directories, best maintained in collaboration with local/regional public health, community, and/or professional organizations; programs embedded in the practice (eg, Reach Out and Read, Healthy Steps for Young Children, Medical-Legal Partnership, Health Leads); and collaboration with home visiting programs. Changes to health care financing are needed to support the delivery of these enhanced services, and active advocacy by child health providers continues to be important in effecting change. We highlight the ongoing work of the Health Care Delivery Subcommittee of the Academic Pediatric Association Task Force on Child Poverty in defining the ways in which child health care practice can be adapted to improve the approach to addressing child poverty.

Screening for Social Determinants of Health Among Children and Families Living in Poverty: A Guide for Clinicians.

Approximately 20% of all children in the United States live in poverty, which exists in rural, urban, and suburban areas. Thus, all child health clinicians need to be familiar with the effects of poverty on health and to understand associated, preventable, and modifiable social factors that impact health. Social determinants of health are identifiable root causes of medical problems. For children living in poverty, social determinants of health for which clinicians may play a role include the following: child maltreatment, child care and education, family financial support, physical environment, family social support, intimate partner violence, maternal depression and family mental illness, household substance abuse, firearm exposure, and parental health literacy. Children, particularly those living in poverty, exposed to adverse childhood experiences are susceptible to toxic stress and a variety of child and adult health problems, including developmental delay, asthma and heart disease. Despite the detrimental effects of social determinants on health, few child health clinicians routinely address the unmet social and psychosocial factors impacting children and their families during routine primary care visits. Clinicians need tools to screen for social determinants of health and to be familiar with available local and national resources to address these issues. These guidelines provide an overview of social determinants of health impacting children living in poverty and provide clinicians with practical screening tools and resources.

Elevated viral restriction factor levels in cortical blood vessels in schizophrenia.

BACKGROUND: Higher tissue transcript levels of immune-related markers-including the recently discovered viral restriction factor interferon-induced transmembrane protein (IFITM), which inhibits viral entry and replication-have been reported in the prefrontal cortex in schizophrenia. Interestingly, mouse models of neuroinflammation have higher IFITM levels and deficits in γ-aminobutyric acid (GABA)-related markers that are similar to findings in schizophrenia, suggesting that a shared pathogenetic process might underlie diverse cortical pathology in the disorder. However, the cell types that overexpress IFITM messenger RNA (mRNA) in schizophrenia are unknown, and it is unclear whether higher IFITM mRNA levels are associated with lower GABA-related marker levels in the same schizophrenia subjects. METHODS: We used quantitative polymerase chain reaction and in situ hybridization with film and grain counting analyses to quantify IFITM mRNA levels in prefrontal cortex area 9 of 57 schizophrenia and 57 healthy comparison subjects and in antipsychotic-exposed monkeys. RESULTS: Quantitative polymerase chain reaction and in situ hybridization film analysis revealed markedly elevated IFITM mRNA levels (+114% and +117%, respectively) in prefrontal gray matter in schizophrenia. Interestingly, emulsion-dipped, Nissl-stained sections from schizophrenia and comparison subjects revealed IFITM mRNA expression in pia mater and blood vessels. The IFITM grain density over blood vessels was 71% higher in schizophrenia. The IFITM mRNA levels were negatively correlated with GABA-related mRNAs in the same schizophrenia subjects. CONCLUSIONS: The finding that schizophrenia subjects with higher IFITM mRNA levels in cortical blood vessels have greater disturbances in cortical GABA neurons suggests that these cell-type distinct pathological disturbances might be influenced by a shared upstream insult that involves immune activation.

Health and mental health needs of children in US military families.

The wars in Afghanistan and Iraq have been challenging for US uniformed service families and their children. Almost 60% of US service members have family responsibilities. Approximately 2.3 million active duty, National Guard, and Reserve service members have been deployed since the beginning of the wars in Afghanistan and Iraq (2001 and 2003, respectively), and almost half have deployed more than once, some for up to 18 months' duration. Up to 2 million US children have been exposed to a wartime deployment of a loved one in the past 10 years. Many service members have returned from combat deployments with symptoms of posttraumatic stress disorder, depression, anxiety, substance abuse, and traumatic brain injury. The mental health and well-being of spouses, significant others, children (and their friends), and extended family members of deployed service members continues to be significantly challenged by the experiences of wartime deployment as well as by combat mortality and morbidity. The medical system of the Department of Defense provides health and mental health services for active duty service members and their families as well as activated National Guard and Reserve service members and their families. In addition to military pediatricians and civilian pediatricians employed by military treatment facilities, nonmilitary general pediatricians care for >50% of children and family members before, during, and after wartime deployments. This clinical report is for all pediatricians, both active duty and civilian, to aid in caring for children whose loved ones have been, are, or will be deployed.

Endocannabinoid metabolism in the prefrontal cortex in schizophrenia.

Adolescent cannabis use is associated with greater relative risk, increased symptom severity, and earlier age of onset of schizophrenia. We investigated whether this interaction may be partly attributable to disease-related disturbances in metabolism of the major cortical endocannabinoid 2-arachidonoylglycerol (2-AG). Transcript levels for the recently discovered 2-AG metabolizing enzyme, α-ß-hydrolase domain 6 (ABHD6), were assessed using quantitative PCR in the prefrontal cortex of schizophrenia and healthy subjects (n=84) and antipsychotic- or tetrahydrocannabinol-exposed monkeys. ABHD6 mRNA levels were elevated in schizophrenia subjects who were younger and had a shorter illness duration but not in antipsychotic- or tetrahydrocannabinol-exposed monkeys. Higher ABHD6 mRNA levels may increase 2-AG metabolism which may influence susceptibility to cannabis in the earlier stages of schizophrenia.

Promoting the well-being of children whose parents are gay or lesbian.

Extensive data available from more than 30 years of research reveal that children raised by gay and lesbian parents have demonstrated resilience with regard to social, psychological, and sexual health despite economic and legal disparities and social stigma. Many studies have demonstrated that children's well-being is affected much more by their relationships with their parents, their parents' sense of competence and security, and the presence of social and economic support for the family than by the gender or the sexual orientation of their parents. Lack of opportunity for same-gender couples to marry adds to families' stress, which affects the health and welfare of all household members. Because marriage strengthens families and, in so doing, benefits children's development, children should not be deprived of the opportunity for their parents to be married. Paths to parenthood that include assisted reproductive techniques, adoption, and foster parenting should focus on competency of the parents rather than their sexual orientation.