Seattle Children’s Research Institute

Background Risk factors for severe respiratory syncytial virus (RSV) illness include early infancy, premature birth, and underlying medical conditions. However, the clinical significance of respiratory viral co-detection is unclear. We compared the clinical outcomes of young children with RSV-only detection and those with RSV viral co-detection. Methods We conducted active, population-based surveillance of children with medically attended fever or respiratory symptoms at 7 US medical centers (1 December 2016–31 March 2020). Demographic and clinical data were collected through parental interviews and chart abstractions. Nasal swabs, with or without throat swabs, were systematically tested for RSV and 6 other common respiratory virus groups. We compared clinical outcomes, including hospitalization, and among those hospitalized, length of stay, intensive care unit admission, supplemental oxygen use, and intubation, between children aged <2 years with RSV-only detection and those with RSV co-detection. Results We enrolled 18 008 children aged <2 years. Of 17 841 (99.1%) tested for RSV, 5099 (28.6%) were positive. RSV was singly detected in 3927 children (77.0%) and co-detected in 1172 (23.0%). RSV co-detection with parainfluenza virus or adenovirus was associated with significantly lower odds of hospitalization (adjusted odds ratio, 0.56; 95% confidence interval [CI]: .33–.95; P = .031) and supplemental oxygen use (adjusted odds ratio, 0.66; 95% CI: .46–.95; P = .026), respectively, than RSV-only detection. For all other comparisons, we did not identify a significant association between RSV co-detection and worse clinical outcomes. Conclusions Co-detection of RSV with another respiratory virus was not significantly associated with worse clinical outcomes compared with RSV-only detection.

The aminoacyl-tRNA synthetases (AaRSs) are an ancient family of structurally diverse enzymes that are divided into two major classes. The functionalities of most AaRSs are inextricably linked to their oligomeric states. While GluRSs were previously classified as monomers, the current investigation reveals that the form expressed in Pseudomonas aeruginosa is a rotationally pseudosymmetrical homodimer featuring intersubunit tRNA binding sites. Both subunits display a highly bent, “pipe strap” conformation, with the anticodon binding domain directed toward the active site. The tRNA binding sites are similar in shape to those of the monomeric GluRSs, but are formed through an approximately 180-degree rotation of the anticodon binding domains and dimerization via the anticodon and D-arm binding domains. As a result, each anticodon binding domain is poised to recognize the anticodon loop of a tRNA bound to the adjacent protomer. Additionally, the anticodon binding domain has an α-helical C -terminal extension containing a conserved lysine-rich consensus motif positioned near the predicted location of the acceptor arm, suggesting dual functions in tRNA recognition. The unique architecture of Pa GluRS broadens the structural diversity of the GluRS family, and member synthetases of all bacterial AaRS subclasses have now been identified that exhibit oligomerization.

Somatic mosaicism produces genetic differences between cells in an individual and is an underrecognized contributor to phenotypic variability. Precise understanding of the natural history of genetic diseases, therefore, requires detection and recognition of low-level mosaicism, which remains technically challenging, particularly for X-linked genes. Here, we identify six males with mosaic X-linked adrenoleukodystrophy (X-ALD), a neurometabolic peroxisomal disorder caused by pathogenic variants in ABCD1 that is currently included in 44 state newborn screening (NBS) programs, and estimate the incidence of somatic mosaicism. Of 227 males from 2 laboratories performing ABCD1 next-generation sequencing, 1.8% (4/227) had pathogenic or likely pathogenic ABCD1 variants that were mosaic. In one mosaic male individual, allele-specific measurements across multiple tissues demonstrated ABCD1 variant allele fractions ranging from 66 to 82%. Our findings have implications for the identification of X-ALD through NBS, and additional studies could provide insight into the pathogenesis and natural history of X-ALD.

BACKGROUND Gastric cancer invades local tissue extensively and metastasizes through the circulation to remote organs. Patients with metastasized gastric cancer have poor clinical outcomes. The vasculature in the cancer niche is developed poorly, thus allowing cancer cells to be released into the circulation. However, it is poorly understood how cancer cells adhere to and transmigrate through the fully developed endothelium in remote organs and what key adhesive ligands are involved in the process. Here, we report results from a study designed to investigate the role of hyperadhesive VWF (von Willebrand factor) in promoting the pulmonary metastasis of gastric cancer. METHODS We used mouse models to investigate the roles of hyperadhesive VWF in the pulmonary metastasis of gastric cancer. The findings from these mouse models were validated through in vitro experiments that specifically examined how VWF promoted gastric cancer-derived extracellular vesicles to activate endothelial cells and analyzed established databases of patients with gastric cancer. RESULTS VWF in cancer-bearing mice became hyperadhesive and mediated the adhesion of gastric cancer-derived extracellular vesicles to the endothelium, where gastric cancer-derived extracellular vesicles caused endothelial permeability and promoted the transmigration of cancer cells to the interstitial tissue of the lungs. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type motifs, type 13) prevented the pulmonary metastasis of gastric cancer cells in mice. We further validated the findings in mice through targeted in vitro experiments and by associating VWF with the outcomes of patients with gastric cancer through established databases of patients with gastric cancer using bioinformatics tools. CONCLUSIONS We show how VWF becomes hyperadhesive to promote the pulmonary metastasis of gastric cancer through its interaction with gastric cancer-derived extracellular vesicles and that the hyperadhesive activity of VWF is reduced by ADAMTS-13 to prevent the metastasis.

Objectives Restricting dietary fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can alleviate symptoms in children with disorders of gut-brain interaction (DGBI). Due to the restrictions of a low FODMAP diet (LFD), a less restrictive FODMAP Gentle diet (FGD) has been suggested. However, the types and amounts of high FODMAP foods and carbohydrates commonly consumed by children have not been studied. We aimed to identify the high FODMAP foods and proportions of FODMAP carbohydrates consumed by children with DGBI and healthy children (HC) and to determine which usually ingested FODMAPs would be restricted on the FGD. Methods Three-day diet records from both children with DGBI and HC were analyzed and compared to assess the type and amount of high FODMAP foods and carbohydrates ingested. Additionally, the ingested FODMAPs that would be restricted on the FGD were determined. Results Diet records from 77 children with DGBI and 64 HC were analyzed. The number of foods ingested daily was similar between children with DGBI and HC (12.3 ± 4.2 vs 12.9 ± 3.4, respectively); high FODMAP foods comprised most foods eaten in both groups. Children with DGBI (vs. HC) ate fewer high FODMAP foods per day (6.5 ± 2.3 vs 8.7 ± 2.4, P < 0.0001, respectively). Fructans were the most consumed FODMAP carbohydrate in both groups, and children with DGBI (vs. HC) consumed fewer fructans, lactose, fructose, and polyols (all P < 0.0001). The top 3 food categories consumed in both groups were wheat-containing foods, dairy, and fruits/ 100% fruit juices. In children with DGBI, 80.9% of the high FODMAP foods consumed would be limited on the FGD. Conclusions Children with DGBI consume fewer high FODMAP foods and carbohydrates than HC, with the top consumed FODMAP carbohydrates being fructans, lactose, and fructose. A FGD would restrict most high FODMAP foods consumed by children with DGBI.

As the primary source of noradrenaline in the brain, the locus coeruleus (LC) regulates arousal, avoidance and stress responses1,2. However, how local neuromodulatory inputs control LC function remains unresolved. Here we identify a population of transcriptionally, spatially and functionally diverse GABAergic (γ-aminobutyric acid-producing) neurons in the LC dendritic field that receive distant inputs and modulate modes of LC firing to control global arousal levels and arousal-related processing and behaviours. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing with spatial transcriptomics to molecularly define both LC noradrenaline-producing and peri-LC cell types. We identify several neuronal cell types that underlie peri-LC functional diversity using a series of complementary neural circuit approaches in behaving mice. Our findings indicate that LC and peri-LC neurons are transcriptionally, functionally and anatomically heterogenous neuronal populations that modulate arousal and avoidance states. Defining the molecular, cellular and functional diversity of the LC and peri-LC provides a roadmap for understanding the neurobiological basis of arousal, motivation and neuropsychiatric disorders.

Haploinsufficiency of AUTS2 is associated with a neurodevelopmental disorder characterized by intellectual disability, autistic features, and spasticity. AUTS2 protein interacts with p300, encoded by EP300 , through the HX repeat domain of AUTS2, thereby activating transcription. We previously reported two de novo variants in the HX repeat domain of AUTS2 . These variants disrupt the AUTS2‐P300 interaction, resulting in a phenotype resembling Rubinstein‐Taybi Syndrome (RSTS) associated with variants in EP300/CREBBP . Here, we expand beyond the initial clinical description to delineate the HX domain‐associated phenotype and compare it to the AUTS2‐haploinsufficient phenotype. We reviewed clinical data, photographs, and neuroimaging studies to examine genotype–phenotype relationships. Our review of 80 individuals included 14 individuals we present here and 66 individuals with AUTS2 variants presented in the literature. The clinical features for individuals with variants in the HX repeat domain include severe intellectual disability, severe language disability, distinct craniofacial and skeletal dysmorphic features, and neuroimaging findings. Facial dysmorphisms include wide and prominent nasal bridges with complex nasal shapes and dysmorphic eyebrows. Dysmorphisms include digit anomalies: Symphalangism and hypoplasia of distal phalanges, exclusive to the HX domain variant group. Cerebellar anomalies not seen with other AUTS2 variants are seen within this group. Our report delineates a distinct and severe clinical phenotype associated with variants in the AUTS2 HX domain, including an in‐depth comparison with the AUTS2 haploinsufficiency phenotype features.

Importance Enterovirus D68 (EV-D68) typically causes mild to severe acute respiratory illness (ARI). Testing and surveillance for EV-D68 in the US are limited, and important epidemiologic gaps remain. Objective To characterize the epidemiology and clinical severity of EV-D68 among US children seeking care for ARI from 2017 to 2022, using a multisite, active, systematic surveillance network. Design, Setting, and Participants This cross-sectional study collected data from the New Vaccine Surveillance Network, an active, prospective, population-based surveillance system of emergency departments (EDs) and hospitals at 7 US academic medical centers. Children with ARI and EV-D68–positive results were enrolled during platform-wide EV-D68 testing periods (July to October 2017, July to November 2018, July to November 2020, and July 2021 to December 2022). Included children were aged younger than 18 years, reported 1 or more qualifying ARI symptoms, with a symptom duration less than 14 days at enrollment. Data were analyzed from in October 2024. Exposures Laboratory-confirmed EV-D68 infection, including overall infections or those without viral codetection. Main Outcomes and Measures Trends and characteristics of EV-D68, including demographics, underlying conditions, and clinical severity by health care setting, were explored. Among hospitalized children with EV-D68–positive results without viral codetection, multivariable logistic regression was used to examine factors associated with receipt of (1) supplemental oxygen or (2) intensive care. Results From 2017 to 2022, 976 children with EV-D68–positive results were identified (median [IQR] age, 47 [18-63] months; 391 [40.1%] female); most were enrolled in 2018 (382 children) and 2022 (533 children). Among these, 856 had no viral codetection, of which 320 were discharged home from the ED (median [IQR] age, 33 [16-59] months; 180 male [56.3%]; 237 [74.1%] with no reported underlying conditions) and 536 were hospitalized (median [IQR] age, 40 [19-69] months; 330 male [61.6%]; 268 [50.0%] with no reported underlying conditions). Among those hospitalized, 199 (37.1%) reported a history of asthma or reactive airway disease (RAD) and 77 (14.4%) reported a condition other than asthma or RAD. Having an underlying condition other than asthma or RAD was associated with increased odds of receiving supplemental oxygen (adjusted odds ratio, 2.72; 95% CI, 1.43-5.18) or intensive care admission (adjusted odds ratio, 3.09; 95% CI, 1.72-5.56); neither age group nor history of asthma or RAD were associated with oxygen receipt or intensive care admission. Conclusions and Relevance In this cross-sectional study of children with medically attended EV-D68 infections, EV-D68 was associated with severe disease in otherwise healthy children of all ages, and children with nonasthma or RAD comorbidities were at higher risk for severe outcomes when hospitalized.

Objective To assess patient characteristics and care factors that are associated with correct and incorrect predictions of future care locations (ICU vs. non-ICU) by the Criticality Index-Dynamic (CI-D), with the goal of enhancing the CI-D. Design Retrospective structured chart review Participants All pediatric inpatients admitted from January` 1st 2018 – February 29th 2020 through the emergency department. Main outcome(s) and measure(s) Patient characteristics and care factors associated with correct (true positives, true negatives) and incorrect predictions (false positives, false negatives) of future care locations (ICU vs. non-ICU) by the CI-D were assessed. Results Of the 3,018, patients, 139 transitioned from non-ICU locations to ICU care; 482 were transferred from the ICU to non-ICU care locations, and 2,400 remained in non-ICU care locations. For the ICU Prediction group, the false negative patients were older, more frequently male, and had longer hospital and ICU lengths of stay compared to the true positive patients. The significant differences in the ICU Prediction group for false negative compared to the true positive patients included a less frequent: primary diagnosis of respiratory failure, use of high flow nasal canula, hourly cardio-respiratory vital signs prior to transfer to the ICU, and neurologic vital signs after transfer from the ICU. For the ICU Discharge prediction group, false positive patients were more frequently: younger, had a primary diagnosis of respiratory failure, more frequently received respiratory support after discharge from the ICU, and received less frequent neurological vital signs prior to transfer from the ICU. For the Non-transfer prediction category, demographics and clinical variables did not differ between the true negative and false positive prediction groups. Conclusion and relevance We conducted the first comprehensive analysis via structured chart reviews of patient characteristics and care factors that are associated with correct and incorrect predictions of future care locations by the machine learning algorithm, the CI-D, gaining insights into potential new predictor variables for inclusion in the model to improve future model iterations.

Central nervous system (CNS) tumors are a leading cause of pediatric cancer-related death. Chimeric antigen receptor (CAR) T cells are an innovative approach for these affected children who are in desperate need of novel therapies, but CNS-directed cellular therapies have only recently advanced to the clinic. Although early-phase trials have begun to demonstrate the feasibility of manufacturing fractionated doses and the tolerability of repeated infusions for children with CNS tumors, major challenges remain. In this review, we will take an inventory of the current state of the pediatric CNS CAR T-cell field through the lens of translational obstacles to broader clinical success. Significance CNS tumors are the leading cause of cancer-related death in children, highlighting the dire need for new treatment strategies. CAR T cells represent a unique approach, distinct from the cytotoxic chemotherapies and small-molecule inhibitors that have dominated the clinical trial space for decades. Phase I CAR T-cell trials have shown feasibility and possible efficacy against pediatric CNS tumors; however, many challenges must be overcome if these therapeutics are going to be beneficial to most affected children. Although rapid translational development and early-phase trials have quickly evolved our understanding, the pediatric CNS CAR T-cell community now yearns for critical assessments and open dialogue about overcoming the remaining obstacles ahead.

The gamma‐tubulin ring complex (γ‐TuRC) plays a role in coordinating centrosome and spindle pole body formation during cell division. TUBG1 encodes a critical component of the γ‐TuRC. Pathogenic TUBG1 variants can cause a range of alterations in cortical gyral patterning, microcephaly, and other neurological manifestations. We describe two missense variants in TUBG1 and their associated clinical phenotypes. One individual has microcephaly, epilepsy, and a simplified gyral pattern with a TUBG1 variant interpreted as pathogenic. The other individual has a likely pathogenic TUBG1 variant that explains the milder presentation of autism spectrum disorder, intellectual disability, later‐onset well‐controlled epilepsy, a normocephalic head size, and no detectable structural abnormalities on neuroimaging.

Background Prophylactic azithromycin in pregnancy has been shown to lower infections in birthing parents and newborns, particularly skin and soft tissue infections (SSTIs) which are common in Fiji. We aimed to determine the safety and efficacy of 2 g of oral azithromycin administered during labour on infant SSTIs. Methods This blinded, randomised placebo-control trial included healthy, pregnant adults and their infants presenting for delivery at a tertiary hospital in Suva, Fiji. Participants in labour were randomly assigned a single dose of 2 g of oral azithromycin or placebo in a 1:1 ratio, stratified by ethnicity. Active and placebo drugs were identical to mask treatment allocation. The primary outcome was cumulative incidence of infant SSTIs by 3 months of age. Intention-to-treat analysis was used and included participants with SSTI data collected at all visits. Safety outcomes were described as percentages by arm at specified time points. Results From June 2019 to January 2022, 2110 pregnant persons were enrolled and randomised, with 1059 and 1063 births in the azithromycin and placebo groups, respectively. 1671 infants were included in the primary analysis (816 in azithromycin and 855 in placebo group). We found a 27% decrease in infant SSTIs in the azithromycin group (5.8%; 95% CI 4.4–7.6) compared to placebo (7.8%; 95% CI 6.2–9.8), but the 95% confidence interval crossed the null value (RR 0.73; 95% CI 0.51–1.06). We observed similar numbers of serious adverse events in both arms, and no cases of infant hypertrophic pyloric stenosis. Conclusions There was a modest relative reduction in infant SSTIs but this was small in absolute terms with no statistically discernible difference. Our findings do not support routine intrapartum azithromycin prophylaxis for this outcome alone. However, the rates of SSTIs highlight the importance of prevention and timely treatment in Fiji. Trial registration 2019–04-18, ClinicalTrials.gov identifier: NCT03925480

Discovered >70 years ago by Ogden Bruton, X-linked agammaglobulinemia (XLA), characterized by recurrent bacterial infections, hypo/agammaglobulinemia, and peripheral blood B-cell deficiency, is among the best-established inborn errors of immunity (IEIs) and one of the most well-documented single types of IEIs, the incidence of which is estimated to be between 1:100,000 and 1:200,000. However, although the pathogenesis of XLA is well understood, several issues remain open for discussion. In this review, we describe several unresolved issues, including noncoding BTK variants, contiguous deletion syndrome, Helicobacter infection, noninfectious neurodegeneration, renal involvement, and malignancies. The primary treatment for XLA, immunoglobulin replacement therapy, administered either intravenously or subcutaneously, has remained unchanged since its discovery. Allogeneic hematopoietic cell transplantation has been successful in some XLA patients, but there are still few reports. However, it may be considered as a treatment option in the future. Given that XLA is one of the most common types of IEIs, resolving these issues is a priority.

PURPOSE Adolescents and young adults (AYAs) with advanced cancer (AC) report poor quality of life (QOL), high psychological distress, and minimal engagement in health care discussions. We assessed the effect of a novel resilience coaching program (Promoting Resilience in Stress Management [PRISM]-AC) on AYA outcomes. METHODS We conducted a multisite randomized trial of PRISM-AC versus usual care (UC) among AYAs age 12-24 years, diagnosed with AC within 2 weeks before enrollment. PRISM-AC consists of four sessions targeting AYA-endorsed resilience resources (stress management, goal-setting, cognitive reframing, and meaning-making) plus a session integrating elements of advance care planning. Participants completed surveys at baseline, and 3, 6, 9, and 12 months. The primary outcome was Pediatric QOL at 3 months; secondary/exploratory outcomes included 3-month changes in resilience (10-item Connor-Davidson Resilience Scale) and hope (Snyder Hope Scale), and trajectories of QOL, anxiety, and depression (Hospital Anxiety and Depression Scale) over 12 months. We examined associations with linear mixed effects regression models. We also explored PRISM-AC's impact on AYA participation in critical health care discussions, as documented in the electronic health record. RESULTS Between April 2019 and January 2024, we enrolled 239 AYAs (56% of 426 approached) and randomly assigned 195 (82% of enrolled; 96 UC, 99 PRISM). They were of mean age 16.5 years (standard deviation, 3.9), mostly White (63%), non-Hispanic (59%), and publicly insured (53%). At 3 months, we detected no significant differences between groups with respect to QOL, anxiety, or depression; PRISM-AYAs demonstrated greater improvements in resilience (+1.3 [5.9] v –1.4 (7.5); P = .038) and hope (+2.4 [10.4] v –2.8 [11.2]; P = .001) than UC-AYAs. Over the 12-month study period, PRISM-AYAs reported more improvements in QOL and anxiety, with significant differences at later time points (PRISM-QOL improvements, 6 months: +3.4 [95% CI, 0.1 to 6.6]; P = .043; 12 months: +6.8 [95% CI, 3.3 to 10.3]; P < .001). Although participation in key health care discussions was similar between groups from baseline to 6 months, 67% (95% CI, 35 to 88) and 50% (95% CI, 22 to 78) of PRISM-AYAs participated at 9 and 12 months, respectively, compared with 39% (95% CI, 20 to 61) and 38% (95% CI, 21 to 59) of UC-AYAs. CONCLUSION Among AYAs with AC, PRISM-AC did not immediately improve QOL. Rather, it improved resilience and hope, potentially enabling longer-term improvements in QOL.