Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive brain tumors affecting early childhood and are characterized by bi-allelic inactivation of the SMARCB1 gene. Though patients benefit from multimodal therapy, there is no improvement in overall survival necessitating exploration of alternative approaches including innate-based immune therapy and epigenetic therapy, which have shown promise in treating adult brain tumors and other cancers. Though reconstitution of SMARCB1 in SMARCB1-deficient cells leads to activation of interferon-stimulated genes, the role of innate immune signaling has not been investigated in AT/RTs. METHODS Our data from a panel of AT/RT cell lines indicates loss of expression of key innate signaling components, like RIG-I, MDA-5, cGAS and STING that are required for sensing extracellular dsRNA and dsDNA. These cell lines also do not respond to dsDNA-based or dsRNA-based innate agonists. However, co-treatment of the BT-16 cell line with two epigenetic drugs, panobinostat and 5-azacytidine leads to re-expression of STING and RIG-I. Panobinostat/5-azacytidine co-treatment followed by either genomic DNA (dsDNA agonist) or poly(I:C) (dsRNA agonist) treatment results in induction of innate responses, measured by STAT1 phosphorylation and production of ISG-15 and IFIT-1. CONCLUSION Our data suggests that AT/RT cell lines are unresponsive to innate agonists possibly due to the loss of expression of key innate immune components. However, these pathways can be reactivated by epigenetic drugs and further potentiated by dsDNA/dsRNA-based innate agonists. Combined epigenetic reprogramming and innate pathway stimulation may serve as a potential therapy option for treating AT/RT.
Background The proposal to involve patients and the public (Patient and Public Involvement; PPI) in research is increasingly recognised as important in research concerning speech, language, and hearing and communication difficulties. Whilst there is extensive guidance about PPI involvement by national agencies such as the National Institute of Health Research in the UK, little information is currently available concerning whether these expectations are met in any area of healthcare provision. Aims This systematic review aimed to identify, describe and evaluate how PPI has been implemented and reported in research concerning childhood speech, language, hearing and communication difficulties. Methods Six electronic databases were systematically searched for eligible studies reporting PPI in these fields. Records were screened against predefined eligibility criteria. Data were extracted on study characteristics, PPI contributors, stages and methods of involvement, reported impacts, and quality of PPI reporting. The methodological and PPI quality were assessed using MMAT and GRIPP2 Short Form, and findings were synthesised narratively. Results Twenty-one studies were included. PPI was reported variously across speech, language, hearing and communication topics, the implementations varied considerably. Parents, carers and professionals were more commonly involved than children and young people themselves. Most studies used consultation-based approaches, often during early stages (e.g., study design or material development), while fewer reported involvement in later stages (e.g., dissemination, implementation or evaluation). Reporting was inconsistent, particularly regarding contributor characteristics, accessibility adaptations, decision-making influence, and the impact of PPI. Conclusions The systematic review showed that PPI in childhood speech, language, and hearing difficulties has advanced significantly, with the growing interest and number of publications, particularly in the past five years. The review also highlighted challenges such as confusion and heterogeneity of PPI concepts, representativeness issues, tokenistic practices, lack of support given to lay contributors, and limited impact evaluation. Future research should distinguish PPI from research participation, involve children and young people more directly where appropriate, report contributors' roles and influence more transparently, and consider accessibility and communication support throughout the involvement process. What this paper adds What is already known on the subject Health service providers and research funders now require attention to Patients and Public Involvement (PPI) in healthcare research. PPI highlights the need to work jointly with stakeholders at all steps involved in research to allow them to take governance over their health conditions. Whilst emphasis on PPI applies to health issues in general, there is no specific review of PPI considerations in research on health factors that affect hearing and communication difficulties. This omission is particularly noteworthy when considering issues that arise in early development. What this study adds to existing knowledge A systematic review was conducted to assess current progress with respect to PPI for hearing and communication research in childhood and adolescence. The review identified research involving PPI that met quality requirements. Challenges related to PPI were highlighted in further analyses that revealed confusion and heterogeneity in PPI concepts, representativeness issues, tokenistic practices, a lack of support given to lay contributors, and a limited evaluation of the impacts of PPI. What are the clinical implications of this work? PPI involvement in clinical research for communication and hearing difficulties should have a positive impact on the well-being of children and adolescents. Four challenges were highlighted when considering the current state of research on PPI in this domain: shallow involvement of the public and patients, conflicting expectations between groups participating in research, lack of clarity of research outcomes as they relate to PPI and variable standards of reporting PPI findings across studies. Tentative recommendations concerning how each of these matters could be addressed are offered.
Abstract Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that allow targeted genetic testing; in others, elucidating genetic or environmental background is more challenging. Aim: To decipher genetic etiologies among a large single-center cohort of SGA-SS children and to stratify them according to molecular mechanisms leading to pre- and postnatal growth failure. Patients/Methods: In our center 447 children (223 females) fulfilled the criteria of SGA-SS. Of these 182 families agreed to take part and offered the child’s and both parents’ DNA for genetic testing by a panel of 399 growth-related genes, or by Whole Exome Sequencing (WES). The results were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Pathogenic or likely pathogenic variants (according to ACMG standards and guidelines) were confirmed by Sanger sequencing. Results: The genetic etiology was elucidated in 73/182 (40%) children so far. We confirmed (likely) pathogenic gene variants affecting pituitary development and/or the GH-IGF-1 axis in 10/73 (14%) patients (PTCH1, HGMA2 [in two], OTX2, LHX4, GHSR, STAT3, IGFALS, IGF1R [in two]), abnormal components of cartilaginous matrix in 17/73 (23%) (ACAN [in two], FLNB [in three], FBLN5, COL11A1[in four], COL1A2, COL2A1[in five], MATN3), impaired paracrine regulation of chondrocytes in 4/73 (6%) (NPR2 [in three], FGFR3), SHOX gene defects in 12/73 (16%), gene variants affecting other components of intracellular regulation and signaling in 9/73 (12%) (CDC42, KMT2A, KMT2D, NSD1, SRCAP, PRG4, PTPN11, SON, LMNA), Silver-Russell syndrome (11p15 [in seven] or UPD7) in 11/73 (15%), and miscellaneous single-gene or chromosomal conditions (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in an additional ten (14%) children. Conclusions: In our study we showed that by using current genetic techniques we were able to elucidate the genetic cause in a significant number of patients born SGA-SS. The genetic etiology spectrum of SGA-SS reflects the complex system of growth regulation, with a significant role of growth plate genes that are causative in 33/73 (45%) cases clarified thus far. Acknowledgements: The study was co-funded by grants AZV NV18-07-00283 and GAUK 408120.
Abstract Background Multi-system inflammatory syndrome in children (MIS-C) is a rare consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MIS-C shares features with common infectious and inflammatory syndromes and differentiation early in the course is difficult. Identification of early features specific to MIS-C may lead to faster diagnosis and treatment. We aimed to determine clinical, laboratory, and cardiac features distinguishing MIS-C patients within the first 24 hours of admission to the hospital from those who present with similar features but ultimately diagnosed with an alternative etiology. Methods We performed retrospective chart reviews of children (0-20 years) who were admitted to Vanderbilt Children’s Hospital and evaluated under our institutional MIS-C algorithm between June 10, 2020-April 8, 2021. Subjects were identified by review of infectious disease (ID) consults during the study period as all children with possible MIS-C require an ID consult per our institutional algorithm. Clinical, lab, and cardiac characteristics were compared between children with and without MIS-C. The diagnosis of MIS-C was determined by the treating team and available consultants. P-values were calculated using two-sample t-tests allowing unequal variances for continuous and Pearson’s chi-squared test for categorical variables, alpha set at < 0.05. Results There were 128 children admitted with concern for MIS-C. Of these, 45 (35.2%) were diagnosed with MIS-C and 83 (64.8%) were not. Patients with MIS-C had significantly higher rates of SARS-CoV-2 exposure, hypotension, conjunctival injection, abdominal pain, and abnormal cardiac exam (Table 1). Laboratory evaluation showed that patients with MIS-C had lower platelet count, lymphocyte count and sodium level, with higher c-reactive protein, fibrinogen, B-type natriuretic peptide, and neutrophil percentage (Table 2). Patients with MIS-C also had lower ejection fraction and were more likely to have abnormal electrocardiogram. Conclusion We identified early features that differed between patients with MIS-C from those without. Development of a diagnostic prediction model based on these early distinguishing features is currently in progress. Disclosures Natasha B. Halasa, MD, MPH, Genentech (Other Financial or Material Support, I receive an honorarium for lectures - it’s a education grant, supported by genetech)Quidel (Grant/Research Support, Other Financial or Material Support, Donation of supplies/kits)Sanofi (Grant/Research Support, Other Financial or Material Support, HAI/NAI testing) Natasha B. Halasa, MD, MPH, Genentech (Individual(s) Involved: Self): I receive an honorarium for lectures - it’s a education grant, supported by genetech, Other Financial or Material Support, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Grant/Research Support, Research Grant or Support James A. Connelly, MD, Horizon Therapeutics (Advisor or Review Panel member)X4 Pharmaceuticals (Advisor or Review Panel member)
Abstract This study examines whether employment security influences fertility decisions across countries by introducing a multidimensional Employment Security Index that captures broader labor market conditions underlying the growing one-and-done family phenomenon. The study employs an unbalanced panel of 176 countries covering the period 2000–2024. The Employment Security Index is constructed from unemployment, youth unemployment, vulnerable employment, and female labor force participation using World Bank data. The relationship is estimated using a two-way fixed-effects model with Driscoll–Kraay standard errors, complemented by robustness tests and heterogeneity analyses across income groups and geographical regions. Stronger employment security is positively and significantly associated with higher fertility after controlling for macroeconomic and demographic characteristics. The findings remain robust across lagged specifications, alternative samples, exclusion of the COVID-19 period, and alternative employment security measures. The positive association is particularly evident in upper-middle- and high-income countries and varies across geographical regions, highlighting substantial institutional heterogeneity. This study extends population economics by conceptualizing employment security as a multidimensional construct rather than relying on individual labor market indicators. It also provides one of the largest global longitudinal assessments of the employment–fertility relationship, offering new evidence that labor market stability constitutes an important economic foundation of contemporary fertility decline and the increasing prevalence of one-child family formation. JEL Classification: J13; J21; J64
Abstract Despite custodial grandparents’ significant contributions to their grandchildren’s healthy development, unique needs of older adults often remain unmet with a limited cultural understanding of intergenerational caregiving. Using a phenomenological approach, interviews and focus groups were conducted with 75 custodial grandparents in Malawi (n=29), South Korea (n=23), and the U.S. (n=23). Malawian grandparents presented financial and physical hardships; however, they experienced strong support from community. Korean grandparents reported similar needs as Malawian grandparents while additionally experiencing cultural biases toward grandparent-headed families (maternal grandparenting and adult child’s divorce). The U.S. grandparents disclosed increased needs for social support as well as family trauma with intergenerational impacts. The increase in custodial grandparent population across the world and findings from this comparative transnational research highlight the need for development of a model for culturally responsive practice with grandparent-headed families in a global context. Part of a symposium sponsored by the Grandparents as Caregivers Interest Group.
Background/Objectives: Cerebral palsy (CP) is the most prevalent physical disability in the pediatric population, resulting in functional limitations and restrictions in participation, with higher prevalence rates in low- and middle-income countries. Caregivers of children and adolescents with CP face both physical and emotional challenges, and their perceptions of the body may act as contextual and cultural indicators shaping children's participation, care practices, and well-being within the family environment. This study aimed to understand the perceptions, values, and cultural beliefs of family caregivers about the bodies of children and adolescents with CP. Methods: A qualitative study was conducted using six focus groups with 22 mothers and grandmothers of children and adolescents with CP. Participants were recruited from rehabilitation services. Discussions were audio-recorded, transcribed verbatim, and analyzed using content analysis. The analytical process involved systematic coding, categorization, and thematic interpretation to identify recurring meanings and patterns across narratives. Results: Three thematic categories emerged: (1) perceptions of the body within social interactions; (2) viewing the body as capable of performing activities independently when stimulated/taught; and (3) viewing the body as dependent, requiring constant supervision and support. Conclusions: The findings highlight the need to expand family caregivers' knowledge about CP to promote children's participation and mitigate beliefs related to limitations, dependence, fragility, and vulnerability.
Introduction Brain heterotopia represent a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to severe clinical picture (resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors. Objectives In this paper we present our experience regarding behavior problems in patients with heterotopia. Methods A cohort of 16 pediatric patients with brain heterotopia, six females and ten males, with age at last follow-up ranging from 2 months to 24 years were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Specific psychological tests and psychiatric evaluation were performed in all children for behavior problems assessment. Results Six individuals presented behavioral problems: autism (three patients) and hyperkinesia with attention deficit (three patients). All of them had intellectual disability or learning problems; five patients had epilepsy, with drug-resistant seizures in four cases. In two cases the behavioral problems occurred before the onset of epileptic seizures. Conclusions Behavior problems are important features in patients with brain heterotopia, making the management of these patients more difficult, especially when they occur in association with drug-resistant epilepsy. Acknowledgements: This work was supported partially by grants of the Romanian National Authority for Scientific Research and Innovation CCCDI – UEFISCDI, Projects COFUND-ERANET E-RARE 3-HETER-OMICS-2 Number 87/2019 and 88/2019 within PNCDI III. Disclosure No significant relationships.
Purpose This study examined associations among concussion history, multidimensional sleep health, physical activity, and serious cognitive difficulty in a nationally representative sample of US adolescents. Methods Cross-sectional data from adolescents aged 12-17 years participating in the 2022-2024 National Survey of Children's Health were analyzed. Sequential multivariable models accounting for complex sampling examined associations among concussion history, short sleep duration, bedtime inconsistency, sports participation, physical activity, and serious cognitive difficulty. Sensitivity analyses evaluated alternative bedtime consistency operationalizations and interaction effects. Results In fully adjusted models, concussion history (aOR = 2.07, 95% CI = 1.72-2.48), short sleep duration (aOR = 1.27, 95% CI = 1.11-1.46), bedtime inconsistency (aOR = 1.42, 95% CI = 1.22-1.65), no sports participation (aOR = 2.05, 95% CI = 1.81-2.33), insufficient physical activity (aOR = 1.32, 95% CI = 1.09-1.58), greater ACE burden, and lower caregiver capacity (aOR = 2.04, 95% CI = 1.80-2.31) were associated with greater odds of serious cognitive difficulty. Exploratory analyses identified a statistically significant short sleep × bedtime inconsistency interaction (Wald F = 4.35, p = .037), whereas concussion-related interaction terms were not statistically significant. Adjusted predicted probabilities demonstrated substantial cumulative neurobehavioral vulnerability across multidimensional sleep health and concussion-risk profiles. Conclusion Insufficient sleep duration and bedtime inconsistency were independently associated with serious cognitive difficulty among US adolescents. Findings support consideration of both sleep duration and sleep regularity in adolescent neurobehavioral health promotion efforts. Current knowledge/study rationale Concussion history and insufficient sleep have independently been associated with poorer neurobehavioral functioning among adolescents. However, fewer nationally representative studies have examined multidimensional sleep health constructs, including bedtime consistency, in relation to serious cognitive difficulty. Study impact Short sleep duration and bedtime inconsistency were associated with greater odds of serious cognitive difficulty among US adolescents. Findings support multidimensional sleep health frameworks emphasizing the combined importance of sleep duration and bedtime consistency for adolescent cognitive functioning.
Abstract This symposium identifies risk and protective factors in childhood and adolescence that continue to influence the physical and cognitive health of older adults. Dimensions of early life inequality include geographic location, educational opportunities, and total amount of adversity faced. Papers in the symposium use data from three major U.S. longitudinal studies: the Health and Retirement Study (HRS), the MacArthur Study of Midlife in the U.S. (MIDUS), and the Wisconsin Longitudinal Study (WLS). Each paper focuses on the mechanisms (i.e., mediators and moderators) linking well-being in childhood and adolescence to health in older adulthood. Greenfield, Akincigil, and Moorman find that net of IQ, college education boosts later life cognition, especially for men who had a low probability of college attendance. Kemp and Montez further find that state economic policy and adult health behavior explain later life disparities in health by educational attainment. Herd, Sicinski, and Asthana continue the theme of geographic place, finding that rural children who were raised on farms are at a cognitive disadvantage in later life. Both Ferraro and Sauerteig and Homan and Kong generate indices of total childhood misfortune. Ferraro and Sauerteig conclude that childhood misfortune affects obesity by way of adult health behavior, specifically, physical activity. Homan and Kong find that childhood misfortune affects subjective and functional health by way of the psychological mechanism of purpose in life. Together, these five papers begin to identify the ways in which experiences in childhood and adolescence have long-lasting consequences for a variety of health outcomes in later life.
