The CPT1A Arctic variant: perspectives of community members and providers in two Alaska tribal health settings.

Newborn screening in Alaska includes screening for carnitine palmitoyltransferase 1A (CPT1A) deficiency. The CPT1A Arctic variant is a variant highly prevalent among Indigenous peoples in the Arctic. In this study, we sought to elicit Alaska Native (AN) community member and AN-serving healthcare providers' knowledge and perspectives on the CPT1A Arctic variant. Focus groups with community members and healthcare providers were held in two regions of Alaska between October 2018 and January 2019. Thematic analysis was used to identify recurring constructs. Knowledge and understanding about the CPT1A Arctic variant and its health impact varied, and participants were interested in learning more about it. Additional education for healthcare professionals was recommended to improve providers' ability to communicate with family caregivers about the Arctic variant. Engagement with AN community members identified opportunities to improve educational outreach via multiple modalities for providers and caregivers on the Arctic variant, which could help to increase culturally relevant guidance and avoid stigmatization, undue worry, and unnecessary intervention. Education and guidance on the care of infants and children homozygous for the CPT1A Arctic variant could improve care and reduce negative psychosocial effects.

HIV Transmission Through Premastication.

Premastication is a potential route of transmission of HIV from caregiver to child. We report the case of a 13-month-old Alaska Native child from rural Alaska who presented with failure to thrive, recurrent pneumonias, severe dental decay, and dysphagia. The mother was HIV-uninfected. Respiratory failure prompted transfer to a children's hospital outside of Alaska where the child received a diagnosis of HIV infection. A grandparent who had been acting as primary caregiver was discovered to be HIV-infected with detectable viral load resulting from intermittent nonadherence to her medication regimen. This grandparent reported feeding the child premasticated food. Sequencing of the hypervariable C2V5 region of the HIV envelope gene in both patients demonstrated less than 0.05% variation, consistent with transmission from grandparent to child. Health care providers should be aware that transmission of HIV can occur via premastication, educate parents and caregivers regarding this risk, and rigorously pursue HIV testing when indicated even in children with HIV-uninfected mothers.

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic.

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

Assessing the Impact of Prenatal Medication for Opioid Use Disorder on Discharge Home With Parents Among Infants With Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: The number of women with opioid-related diagnoses in the United States has significantly increased in recent decades, resulting in concomitantly higher rates of infants born with neonatal opioid withdrawal syndrome (NOWS). Addressing prenatal opioid exposure is a priority for Alaska health systems. The objectives of this study were to: (1) identify maternal and neonatal factors associated with receipt of Medication for opioid use disorder (MOUD) and (2) determine the impact of prenatal MOUD on discharge to parents among infants with NOWS in 3 Alaska hospitals. METHODS: A retrospective chart review using a standard abstraction form was conducted to collect data on neonatal and maternal characteristics, neonatal treatment, and infant discharge disposition for infants with NOWS born at the 3 hospitals between July 2016 and December 2019. A multivariable logistic regression model was used to determine factors associated with discharge to parents. RESULTS: There were 10,719 births at the 3 hospitals during the study period, including 193 infants (1.8%) with NOWS. Among the 193 mothers, 91 (47.2%) received MOUD during pregnancy. Among infants with NOWS, 136 (70.5%) were discharged to parents, 51 (26.4%) were discharged to a relative or foster care. Infants were significantly (odds ratio 3.9) more likely to be discharged to parents if the mother had received prenatal MOUD. CONCLUSIONS: MOUD among pregnant women with opioid use disorder furthers the goal of keeping families together and is a critical step towards reducing the impact of the ongoing opioid epidemic on Alaska families, communities, and the child welfare system.

Best Practices for Conducting Clinical Trials With Indigenous Children in the United States.

We provide guidance for conducting clinical trials with Indigenous children in the United States. We drew on extant literature and our experience to describe 3 best practices for the ethical and effective conduct of clinical trials with Indigenous children. Case examples of pediatric research conducted with American Indian, Alaska Native, and Native Hawaiian communities are provided to illustrate these practices. Ethical and effective clinical trials with Indigenous children require early and sustained community engagement, building capacity for Indigenous research, and supporting community oversight and ownership of research. Effective engagement requires equity, trust, shared interests, and mutual benefit among partners over time. Capacity building should prioritize developing Indigenous researchers. Supporting community oversight and ownership of research means that investigators should plan for data-sharing agreements, return or destruction of data, and multiple regulatory approvals. Indigenous children must be included in clinical trials to reduce health disparities and improve health outcomes in these pediatric populations. Establishment of the Environmental Influences on Child Health Outcomes Institutional Development Award States Pediatric Clinical Trials Network (ECHO ISPCTN) in 2016 creates a unique and timely opportunity to increase Indigenous children's participation in state-of-the-art clinical trials.

Environmental Health Consults in Children Hospitalized with Respiratory Infections.

Indoor air pollutants contribute to respiratory infections and asthma exacerbations in children. Rural Alaska Native children experience some of the highest U.S. rates of respiratory hospitalizations, which are associated with lack of in-home running water, household crowding, and woodstove use. In our previous study, in-home education and modifications reduced respiratory symptoms, and medical visits. In this study, we evaluated the feasibility of providing in-hospital environmental health consults for parents/guardians of children < 5 years old hospitalized at the Alaska Native Medical Center with respiratory infections or asthma. Environmental health specialists conducted 92 in-hospital consults and mailed Healthy Homes Toolkits to households. Local housing authorities completed low-cost home modifications in 47 eligible households. Participants reported changes in household behaviors that were specifically addressed in the consult or included in the Toolkit (e.g. allergen-impermeable pillow covers). Reported respiratory symptoms were decreased at the 6-month follow-up. Over a 2 year period the median overall medical costs for respiratory illness in study children were $70,500. Children with in-home piped water had half the daily overall medical costs than children without in-home piped water ($74 compared to $144). In this study, we demonstrate that it is feasible to provide environmental consults, mail Toolkits, and arrange home modifications to the homes of children hospitalized with respiratory illness. These findings, along with the high costs of medical care for these children, suggest in-hospital environmental health consults are a cost-effective intervention.

IDeA States Pediatric Clinical Trials Network for Underserved and Rural Communities.

The National Institutes of Health's Environmental Influences on Child Health Outcomes (ECHO) program aims to study high-priority and high-impact pediatric conditions. This broad-based health initiative is unique in the National Institutes of Health research portfolio and involves 2 research components: (1) a large group of established centers with pediatric cohorts combining data to support longitudinal studies (ECHO cohorts) and (2) pediatric trials program for institutions within Institutional Development Awards states, known as the ECHO Institutional Development Awards States Pediatric Clinical Trials Network (ISPCTN). In the current presentation, we provide a broad overview of the ISPCTN and, particularly, its importance in enhancing clinical trials capabilities of pediatrician scientists through the support of research infrastructure, while at the same time implementing clinical trials that inform future health care for children. The ISPCTN research mission is aligned with the health priority conditions emphasized in the ECHO program, with a commitment to bringing state-of-the-science trials to children residing in underserved and rural communities. ISPCTN site infrastructure is critical to successful trial implementation and includes research training for pediatric faculty and coordinators. Network sites exist in settings that have historically had limited National Institutes of Health funding success and lacked pediatric research infrastructure, with the initial funding directed to considerable efforts in professional development, implementation of regulatory procedures, and engagement of communities and families. The Network has made considerable headway with these objectives, opening two large research studies during its initial 18 months as well as producing findings that serve as markers of success that will optimize sustainability.

Pediatric Cancers among Alaska Native People.

OBJECTIVE: To evaluate the descriptive epidemiology of pediatric cancers among Alaska Native people. STUDY DESIGN: We used data from the Alaska Native Tumor Registry, a population-based registry capturing cancer information among Alaska Native people 1969-present. Specifically, we examined all cases of cancer diagnosed among individuals ages 0-19 years. Cases were classified according to the International Classification of Childhood Cancers, 3rd edition (ICCC-3). We estimated incidence and distribution of cases by ICCC-3 cancer site, comparing between the time periods 1969-1996 and 1997-2016. We assessed 12-month and 5-year cause-specific survival, and examined differences over the time period, adjusted for age, sex, and ICCC-3 site. RESULTS: Incidence rates of pediatric cancers increased between 1969 and 1996 (n = 134) and 1997 and 2016 (n = 186) among Alaska Native people, from 139.8 in 1 000 000 (95% CI, 116.99-165.7) to 197.54 in 1 000 000 (95% CI, 170.1-228.1). Distribution of ICCC-3 sites differed between time periods (P < .0001). Finally, cancer survival was high; the 12-month survival probability from all ICCC-3 sites combined was 0.88 (95% CI, 0.84-0.92) and the 5-year survival probability was 0.76 (95% CI, 0.70-0.81) for 1969-2016. After adjusting for age, sex, and ICCC-3 site, we observed a 57% decrease in the risk of death when comparing Alaska Native pediatric cancer cases diagnosed in 1997-2016 with those diagnosed in 1969-1996. CONCLUSIONS: This information will be of value for our understanding of pediatric cancers among Indigenous peoples of the US, and will also be informative for clinicians providing care to this population.

Research and policy priorities for addressing prenatal exposure to opioids in Alaska.

The current opioid crisis in Alaska and the USA will negatively affect the health and wellbeing of future generations. The increasing number of infants born with neonatal opioid withdrawal syndrome (NOWS) has had a profound impact on families, health care providers and the child welfare system. This manuscript summarises the main themes of a Symposium held in Anchorage, Alaska with health care providers, researchers, elders and public health officials that focused on identifying emerging challenges, trends and potential solutions to address the increasing number of infants and children affected by maternal opioid use. Five areas of importance for research and policy development that would direct improvement in the care of infants with NOWS in Alaska are outlined with the goal of supporting a research agenda on opioid misuse and child health across the circumpolar north. Abbreviations: NOWS - neonatal opioid withdrawal syndrome; NAS - neonatal abstinence syndrome; MAT - medication-assisted treatment; NICU - neonatal intensive care unit; OATs - opioid agonist treatments; OCS - office of children's services; ANTHC - Alaska Native Tribal Health Consortium; OUD - opioid use disorder; SBIRT - screening, brief intervention and referral to treatment; ISPCTN - IDeA States Pediatric Clinical Trials Network; NIH - National Institutes of Health; ANMC - Alaska Native Medical Center; DHSS - Department of Health and Social Services; AAPP - All Alaska Pediatric Partnership.

Invasive Haemophilus influenzae Serotype a Infection in Children: Clinical Description of an Emerging Pathogen-Alaska, 2002-2014.

BACKGROUND: Invasive infections from Haemophilus influenzae serotype a (Hia) have been reported with increasing frequency, especially among indigenous populations. However, there are limited population-based studies of clinical severity. We studied invasive Hia infections in Alaska to determine clinical characteristics, mortality and sequelae. METHODS: We defined an invasive Hia infection as the first detection of Hia from a usually sterile site in a child <10 years of age from Alaska. We identified cases using the Alaska Invasive Bacterial Diseases Surveillance System and reviewed medical charts up to 2 years after reported illness. RESULTS: We identified invasive Hia infections in 36 children, 28 (78%) <1 year old, 34 (94%) living in an Alaskan village and 25 (69%) without documented underlying illness. Overlapping clinical presentations included meningitis in 15 children (42%); bacteremia and pneumonia in 10 children (28%); and bone, joint or soft tissue infections in 10 children (22%). In 4 other children, no source of invasive infection was identified. Intensive care was provided for 11 children (31%); 12 children (33%) required surgical intervention. One year after infection, 4 children (11%) had died from Hia, and 5 children (14%) had ongoing neurologic sequelae. CONCLUSIONS: Invasive Hia infections in Alaska occurred predominantly in Alaska Native infants in rural communities. Although one-third of children had preexisting conditions, most cases occurred without known comorbidity. Clinical syndromes were frequently severe. One year after infection, 1 in 4 children had either died or had neurologic sequelae. An effective vaccine would prevent significant morbidity and mortality in affected populations.

A randomized multi-institutional crossover comparison of the GlideScope® Cobalt Video laryngoscope to the flexible fiberoptic bronchoscope in a Pierre Robin manikin.

BACKGROUND: The GlideScope Cobalt Video laryngoscope is being used more often in children with challenging laryngoscopy. There are, however, no pediatric trials comparing it to flexible fiberoptic bronchoscopy, the current accepted gold standard. This preliminary manikin study compares the first-attempt intubation success of the GlideScope Cobalt video laryngoscope to the flexible fiberoptic bronchoscope when performed by attending pediatric anesthesiologists at two major pediatric centers. METHODS: This prospective randomized, crossover study evaluated 120 attempts (60 with each study device) to intubate the AirSim Pierre Robin manikin (PRM) with fiberoptic bronchoscopy and video laryngoscopy (VL). Attending pediatric anesthesiologists from two quaternary pediatric centers were eligible to participate. Each attending anesthesiologist randomly performed a single tracheal intubation attempt with one of the study devices followed by the alternate method. The primary outcome was the first-attempt success rate of tracheal intubation. Blinding was not feasible. We hypothesized that first-attempt success would be higher with fiberoptic bronchoscopy. RESULTS: Thirty anesthesiologists from each center were randomized to use one of the study devices followed by the alternate method. We analyzed all participants' data. There was no overall difference in first-attempt success between VL and fiberoptic bronchoscopy (88.3% vs 85% respectively, P = 0.59). There were significant institutional differences in first-attempt success using VL (76.7% vs 100%). CONCLUSIONS: There was no difference in first-attempt success of tracheal intubation using VL vs fiberoptic bronchoscopy when performed by attending anesthesiologists at two large pediatric centers. However, institutional differences exist in success rates with VL across the two centers. Results from single-center device evaluations should be verified by multi-center evaluations. A significant proportion of attending anesthesiologists lack experience with advanced airway devices; targeted education may enhance intubation success and patient safety.

Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant.

A high prevalence of the sequence variant c.1436C→T in the CPT1A gene has been identified among Alaska Native newborns but the clinical implications of this variant are unknown. We conducted medically supervised fasts in 5 children homozygous for the c.1436C→T variant. Plasma free fatty acids increased normally in these children but their long-chain acylcarnitine and ketone production was significantly blunted. The fast was terminated early in two subjects due to symptoms of hypoglycemia. Homozygosity for the c.1436C→T sequence variant of CPT1A impairs fasting ketogenesis, and can cause hypoketotic hypoglycemia in young children. Trial registration www.clinical trials.gov NCT00653666 "Metabolic Consequences of CPT1A Deficiency"