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PurposeModels to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes.Experimental designMatched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model.ResultsPDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden.ConclusionsThe variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

ImportanceRepeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions.ObjectiveTo evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention.Design, setting, and participantsThis cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities.InterventionsCommunities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023.Main outcomes and measuresThe primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census.ResultsA total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months.Conclusions and relevanceMortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference.Trial registrationClinicalTrials.gov Identifier: NCT03676764.

PurposeThe aims of this study were (a) to evaluate the convergent validity of the Language Use Inventory (LUI) with measures of autism spectrum disorder (ASD) symptoms, language, and social skills and (b) to assess discriminant validity of the LUI with measures of nonlanguage skills, including daily living skills and motor development.MethodThis study sample included participants from a longitudinal study (n = 239) of infant siblings with elevated familial likelihood of ASD and lower familial likelihood. Assessment measures completed at 36 months included the LUI, the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), the Mullen Scales of Early Learning, and the Vineland Adaptive Behavior Scales-Second Edition. Bivariate Pearson correlations were estimated between ADOS-2 comparison scores and four language and social skills measures. Additional correlations were estimated between LUI total scores and standard scores from nonlanguage measures. A series of Fisher's Z transformations were applied to evaluate whether bivariate correlations were significantly different.ResultsAll four language and social skill measures were moderately to strongly associated with each other and ASD symptom severity scores. The correlation between ADOS-2 comparison scores and LUI total scores was significantly stronger than ADOS-2 correlations with all other measures.ConclusionsOur findings provide support for the LUI as a feasible, pragmatic language-targeted instrument for inclusion in early developmental evaluations prompted by language concerns. Administration of the LUI may accelerate earlier referral for a comprehensive assessment of ASD symptoms. Given the high correlation with ADOS-2 scores, an LUI total score in a clinical range of concern may encourage a clinician to refer families for a full diagnostic evaluation of ASD.

Mollusc and crustacean consumption in the first 1000 d may improve maternal and child health by providing essential nutrients. However, in some contexts, molluscs and crustaceans have been associated with allergies and environmental contamination, potentially leading to adverse health and development outcomes. It is unclear whether the health benefits of consuming molluscs and crustaceans, collectively classified as shellfish in nutrition, are outweighed by the potential risks to pregnant women and children. We conducted a scoping review (PROSPERO: CRD42022320454) in PubMed, Scopus and EBSCO Global Health of articles published between January 2000 and March 2022 that assessed shellfish consumption during pregnancy, lactation or childhood (0-2 years) in relation to maternal health, child health or child development. A total of forty-six articles were included in this review. Overall, shellfish consumption was associated with higher biomarkers of environmental contaminants, with mercury being the most studied and having the strongest evidence base. The limited research on nutritional biomarker status shows an association between shellfish consumption and iodine status. Preterm birth was not associated with shellfish consumption, but newborn anthropometry showed mixed results, with several studies reporting lower birth weight with higher shellfish consumption. The few studies that examined child development and maternal health outcomes reported no significant associations. This review revealed trade-off health risks and benefits with inclusion of molluscs and crustaceans in the dietary patterns of mothers and young children. More research is needed to understand how these aquatic animal-source foods may be safely consumed and leveraged for improving human nutrition.

Young children may experience higher per- and polyfluoroalkyl substances (PFAS) exposure than adults due to breastfeeding, higher dust ingestion rates, and frequent hand-to-mouth activities. We explored temporal trends and determinants of child serum PFAS concentrations and their correlations with paired maternal PFAS concentrations. From 2009 to 2017, we collected one blood sample from each of 541 children aged 2-5 years participating in the Childhood Autism Risks from Genetics and Environment (CHARGE) study and quantified 14 PFAS in serum. For nine frequently detected PFAS (>65% of samples), we performed multiple regression adjusting for potential determinants to estimate mean percent concentration changes. For a subset of 327 children, we also quantified nine PFAS in their mother's serum collected at the same visit and computed Spearman correlation coefficients (rsp) between maternal and child PFAS concentrations. During 2009-2017, child serum concentrations of all nine PFAS decreased by 6-25% annually. Several PFAS concentrations were higher among non-Hispanic white children and those with highly educated parents. Most maternal and child PFAS concentrations were moderately correlated (rsp = 0.13-0.39), with a strong correlation for N-methyl perfluorooctane sulfonamido acetic acid (rsp = 0.68). Breastfeeding duration appeared to contribute to higher child and lower maternal PFAS concentrations, resulting in relatively weak correlations between maternal and child PFAS concentrations for samples collected in early childhood. Considering that more than half of our study children had neurodevelopmental concerns, the generalizability of our findings might be limited.

Introduction: Pediatric patients account for 6–10% of emergency medical services (EMS) activations in the United States. Approximately 30% of these children are not transported to an emergency department (ED). Adult data in the literature reports higher hospitalization and complications following non-transport. Few studies discuss epidemiology and characteristics of pediatric non-transport; however, data on outcome is limited. Our primary aim was to determine outcomes of non-transported children within our urban EMS system before and during the COVID-19 pandemic. Our secondary objective was to explore reasons for non-transport.Methods: This was a prospective, descriptive pilot study. We compared EMS data for September 2019 (pre-COVID-19) to September 2020 (pandemic). Included were children aged 0–17 years who activated EMS and did not receive transport to the primary hospital for the EMS capture area. We defined outcomes as repeat EMS activation, ED visits, and hospital admissions, all within 72 hours. Data was obtained via electronic capture. We used descriptive statistics to analyze our data, chi square for categorical data, stepwise logistic regression, and univariate logistic regression to test for association of covariates with non-transport.Results: There were 1,089 pediatric EMS activations in September 2019 and 780 in September 2020. Non-transport occurred in 633 (58%) in September 2019 and 412 (53%) in September 2020. Emergency medical services was reactivated within 72 hours in the following: 9/633 (1.4%) in 2019; and 5/412 (1.2%) in 2020 (P = 0.77). Visits to the ED occurred in 57/633 (9%) in 2019 and 42/412 (10%) in 2020 (P = 0.53). Hospital admissions occurred in 10/633 (1.5%) in 2019 and 4/412 (0.97%) in 2020 (P = 0.19). One non-transported patient was admitted to the intensive care unit in September 2020 (12 years, and fever were associated with repeat EMS activation. The most common reason for non-transport in both study periods was that the parent felt an ambulancewas not necessary (47%).Conclusion: In our system, non-transport of pediatric patients occurred in >50% of EMS activations with no significant adverse outcome. Age >12 years, fever, and Hispanic ethnicity were more common in repeated EMS activations. The most common reason for non-transport was parents feeling it was not necessary. Future studies are needed to develop reliable EMS guidelines for pediatric non-transport.

Objective: With the rapid growth in the population of Asian and Asian American college students in the United States, there is a need for research examining their participation in potentially risky sexual behaviors in order to expand understanding of this group's needs. This study focused on attachment orientation and hookup motives as predictors of hookup behaviors, which involve engaging in sexual behaviors without expectation of a long-term relationship.Methods: Participants included 169 Asian or Asian American college students ranging in age from 18 to 27 years who completed an online survey.Results: Results indicated that over half of participants reported engaging in hookup behaviors. The strongest predictors of hookup behaviors were increased age, liberal sexual attitudes, motivations to achieve excitement/sexual enhancement, and motivations to find a long-term partner. However, attachment orientations did not predict hookup behaviors. Results provide insight into a profile of Asian American college students increasingly exploring sexuality throughout young adulthood.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Unaccompanied immigrant children continue to arrive at the US-Mexico border and are at high risk for ongoing abuse, neglect, and poor mental and physical health. We are medical and legal experts in the fields of immigrant and refugee health, child abuse, and the legal rights of international refugee and migrant children. We provide an overview of US federal agencies with custody of unaccompanied immigrant children, a summary of medical care provided while in custody, and recent findings from the independent Juvenile Care Monitor Report mandating new custodial conditions for immigrant children while in federal custody. We provide recommendations to improve the health and well-being of unaccompanied immigrant children while in custody and once released to US sponsors. (Am J Public Health. Published online ahead of print February 8, 2024:e1-e7. https://doi.org/10.2105/AJPH.2023.307570).

Pharmacokinetic (PK) studies in children are usually small and have ethical constraints due to the medical complexities of drawing blood in this special population. Often, population PK models for the drug(s) of interest are available in adults, and these models can be extended to incorporate the expected deviations seen in children. As a consequence, there is increasing interest in the use of optimal design methodology to design PK sampling schemes in children that maximize information using a small sample size and limited number of sampling times per dosing period. As a case study, we use the novel tuberculosis drug delamanid, and show how applications of optimal design methodology can result in highly efficient and model-robust designs in children for estimating PK parameters using a limited number of sampling measurements. Using developed population PK models based on available data from adults living with and without HIV, and limited data on children without HIV, competing designs for children living with HIV were derived and assessed based on robustness to model uncertainty.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

ObjectiveTo evaluate associations between neighborhood income and burden of hospitalizations for children with short bowel syndrome (SBS).Study designWe used the Pediatric Health Information System (PHIS) database to evaluate associations between neighborhood income and hospital readmissions, readmissions for central line-associated bloodstream infections (CLABSI), and hospital length of stay (LOS) for patients

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

ObjectivesWe characterize occult lesion diagnosis rates after initial Bell's palsy diagnoses.MethodsA de-identified database of all facial palsy patients who presented to an extensive health care system across 22 years was created using Epic SlicerDicer. Among patients with Bell's palsy diagnoses, we extracted demographic and any subsequent occult lesion diagnosis data across various clinical sites. Descriptive and multivariable regression analyses comparing patients with occult lesion diagnoses made at different time points were included.ResultsAmong the total 3912 facial palsy patients, 2240 had Bell's palsy diagnoses, of which 217 (9.7%) had subsequent lesion diagnoses at a median (IQR) of 12.3 (4.2, 23.8) months, consisting of cranial nerve neoplasms (62.2%), parotid gland neoplasms (34.1%), and cholesteatomas (3.7%). Although a large proportion of total lesions were diagnosed within the first 3 months (19.8%), 69.5% were diagnosed after 6 months. There were no demographic differences among patients diagnosed with different lesion types, but Asian patients were more likely to be diagnosed with occult lesions after 12 months after Bell's palsy diagnosis compared with white patients (odds ratio = 6.2, p = 0.001).ConclusionsIn one of the largest Bell's palsy cohorts to date, we identified a 9.7% occult lesion diagnosis rate at a median of 12.3 months after Bell's palsy diagnosis. These data underscore the importance of timely workup for occult lesions in cases of facial palsy with no signs of recovery after 3-4 months.Level of evidence4 Laryngoscope, 134:911-918, 2024.

Abstract: People with schizophrenia are at increased risk for contracting HIV and face higher mortality rates compared with the general population. Viral suppression is key to HIV care, yet little is known about this metric among people with HIV and schizophrenia. A chart review was conducted among people with HIV/AIDS and schizophrenia living in San Francisco who had received inpatient mental health services between 2010 and 2016. Demographic, laboratory, medication, encounter, and discharge data were collected, and were compared with all people living with HIV in San Francisco (PLWH-SF). Among 153 people living with HIV and comorbid schizophrenia, 77% were virally suppressed, compared to 67% for all PLWH-SF. Viral suppression for people with comorbid HIV and schizophrenia living in San Francisco appears higher than PLWH-SF. Further research is needed to confirm the association and mechanisms behind better treatment outcomes for people living with HIV and comorbid schizophrenia.

BOUT++ turbulence simulations were performed to investigate the impact of turbulence spreading on the edge localized mode (ELM) size and divertor heat flux width $({\lambda _q})$ broadening in small ELM regimes. This study is motivated by EAST experiments. BOUT++ linear simulations of a pedestal radial electric field (Er) scan show that the dominant toroidal number mode (n) shifts from high-n to low-n, with a narrow mode spectrum, and the maximum linear growth rate increases as the pedestal Er well deepens. The nonlinear simulations show that as the net E × B pedestal flow increases, the pressure fluctuation level and its inward penetration beyond the top of the pedestal both increase. This leads to a transition from small ELMs to large ELMs. Both inward and outward turbulence spreading are sensitive to the scrape-off-layer (SOL) plasma profiles. The inward turbulence spreading increases for the steep SOL profiles, leading to increasing pedestal energy loss in the small ELM regime. The SOL width $({\lambda _q})$ is significantly broadened progressing from the ELM-free to small ELM regime, due to the onset of strong radial turbulent transport. The extent of the SOL width $({\lambda _q})$ broadening depends strongly on outward turbulence spreading. The fluctuation energy intensity flux ${\varGamma _\varepsilon }$ at the separatrix can be enhanced by increasing either pedestal Er flow shear or local SOL pressure gradient. The ${\lambda _q}$ is broadened as the fluctuation energy intensity flux ${\varGamma _\varepsilon }$ at the last close flux surface (LCFS) increases. Local SOL E × B flow shear will restrain outward turbulence spreading and the associated heat flux width broadening. Operating in H-mode with small ELMs has the potential to solve two critical problems: reducing the ELM size and broadening the SOL width.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

BackgroundFamilies experience financial burden and household material hardship (HMH) after a pediatric cancer diagnosis. This study investigates types of financial assistance and other financial coping strategies (FCS) adopted by families during the first year after diagnosis.MethodsRetrospective survey of caregivers of pediatric patients diagnosed with cancer from 2015 to 2019. The survey collected data on demographics, diagnosis, income, HMH, and private, hospital, and government assistance received and other FCS adopted after diagnosis. Bivariate and multivariable logistic regressions were used to analyze FCS by income. Subgroup analysis of families experiencing HMH was used to identify predictors of receiving government assistance.ResultsOf 156 respondents, 52% were low-to-middle income, 29% had public insurance, and 22% had non-English language preference. Low-to-middle-income families were more likely to incur debt (odds ratio [OR] 6.24, p

Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show that the RNA-editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing is a common attribute of relapsed T cell acute lymphoblastic leukemia (T-ALL) regardless of molecular subtype. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL patient-derived xenograft models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor melanoma differentiation-associated protein 5 (MDA5). Moreover, we uncover that the cell-intrinsic level of MDA5 dictates the dependency on the ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.

Elevated "neural noise" has been advanced as an explanation of autism and autistic sensory experiences. However, functional neuroimaging measures of neural noise may be vulnerable to contamination by recording noise. This study explored variability of electrophysiological responses to tones of different intensities in 127 autistic and 79 typically-developing children aged 2-5 years old. A rigorous data processing pipeline, including advanced visualizations of different signal sources that were maximally independent across different time lags, was used to identify and eliminate putative recording noise. Inter-trial variability was measured using median absolute deviations (MADs) of EEG amplitudes across trials and inter-trial phase coherence (ITPC). ITPC was elevated in autism in the 50 and 60 dB intensity conditions, suggesting diminished (rather than elevated) neural noise in autism, although reduced ITPC to soft 50 dB sounds was associated with increased loudness discomfort. Autistic and non-autistic participants did not differ in MADs, and indeed, the vast majority of the statistical tests examined in this study yielded no significant effects. These results appear inconsistent with the neural noise account.

Purpose of reviewSleep health is a commonly overlooked component of pediatric cardiometabolic risk. Disparities in sleep duration and meeting of pediatric sleep guidelines have been well documented among at-risk populations in the United States, including Latinos. However, sleep research often fails to describe or account for contextual and cultural factors impacting the ability for Latino families to meet guidelines. The current review focuses on recent findings related to measurement of sleep duration, understanding of contextual factors that impact sleep hygiene, and interventions designed to increase sleep duration and quality among U.S. Latino families with infants, young children, and adolescents.Recent findingsTen studies focusing on sleep health in U.S. Latino children, using different study designs were identified. Overall, cross-sectional studies confirmed inadequate sleep among Latino children, intervention studies demonstrated promise of culturally-sensitive health behavior education for improving sleep in early childhood, and qualitative studies highlighted neighborhood and cultural factors that impact sleep quality.Implications for clinical practice and researchRather than new prevalence studies on adherence to sleep recommendations among Latino families, research focusing on adapting clinical guidelines to accommodate the realities of many Latino families (e.g., co-sleeping and bedsharing) will advance our knowledge. A shift towards objective measurement of the 24-h period as well as evaluating specific contextual barriers that make It challenging to meet sleep guidelines for Latino children is needed.

Nicotine and tobacco product (NTP) use remains prevalent in adolescence/young adulthood. The effects of NTPs on markers of brain health during this vulnerable neurodevelopmental period remain largely unknown. This report investigates associations between NTP use and gray matter cerebral blood flow (CBF) in adolescents/young adults. Adolescent/young adult (16-22 years-old) nicotine users (NTP; N = 99; 40 women) and non-users (non-NTP; N = 95; 56 women) underwent neuroimaging sessions including anatomical and optimized pseudo-continuous arterial spin labeling scans. Groups were compared on whole-brain gray matter CBF estimates and their relation to age and sex at birth. Follow-up analyses assessed correlations between identified CBF clusters and NTP recency and dependence measures. Controlling for age and sex, the NTP vs. non-NTP contrast revealed a single cluster that survived thresholding which included portions of bilateral precuneus (voxel-wise alpha

With the widespread adoption of intranasal radiofrequency (RF) devices, our objective was to report national adverse events (AEs) associated with their use. The Food and Drug Administration's Manufacturer and User Facility Device Experience was queried. A total of 24 device-related AEs were reported, 11 (45.8%) for Celon® (Olympus), 3 (12.5%) for Vivaer® (Aerin), 2 (8.3%) for Neuromark® (Neurent), and 8 (33.3%) for Rhinaer® (Aerin). Seven (63.6%) of the Celon®-related complications were related to tissue necrosis (largely user error-related), but 1 (9.1%) episode of pediatric ocular palsy was also reported. Vivaer® complications included synechiae formation, a mucosal perforation, and a case of empty nose syndrome. Of the posterior nasal nerve ablating devices, 9 of 10 AEs were epistaxes, of which 7 (77.8%) required operative intervention. Surgeons should exercise vigilance and tissue-appropriate device settings when utilizing RF devices. Epistaxis and tissue necrosis may occur, as well as more rare, but devastating, complications.

BackgroundSystematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates.ObjectiveTo develop a prediction model for maternal tobacco smoking in late pregnancy based on birth certificate information using a combination of self- or provider-reported smoking and biomarkers (smoking metabolites) in neonatal blood spots as the alloyed gold standard.MethodsWe designed a case-control study where childhood cancer cases were identified from the California Cancer Registry and controls were from the California birth rolls between 1983 and 2011 who were cancer-free by the age of six. In this analysis, we included 894 control participants and performed high-resolution metabolomics analyses in their neonatal dried blood spots, where we extracted cotinine [mass-to-charge ratio (m/z) = 177.1023] and hydroxycotinine (m/z = 193.0973). Potential predictors of smoking were selected from California birth certificates. Logistic regression with stepwise backward selection was used to build a prediction model. Model performance was evaluated in a training sample, a bootstrapped sample, and an external validation sample.ResultsOut of seven predictor variables entered into the logistic model, five were selected by the stepwise procedure: maternal race/ethnicity, maternal education, child's birth year, parity, and child's birth weight. We calculated an overall discrimination accuracy of 0.72 and an area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval [CI] 0.77, 0.84) in the training set. Similar accuracies were achieved in the internal (AUC 0.81, 95% CI 0.77, 0.84) and external (AUC 0.69, 95% CI 0.64, 0.74) validation sets.ConclusionsThis easy-to-apply model may benefit future birth registry-based studies when there is missing maternal smoking information; however, some smoking status misclassification remains a concern when only variables from the birth certificate are used to predict maternal smoking.

BackgroundDespite being disproportionately impacted by COVID-19 due to a lack of structural support, marginalized communities have been largely ignored in the politically polarized debate over school masking. In response to this, we sought to explore masking attitudes by centering the voices of parents and children at historically marginalized, predominantly Hispanic schools in southern California.MethodsWe conducted a mixed-methods study with parents and children attending 26 low-income predominantly Hispanic-serving elementary schools. A random sample of parents was asked to provide a freelist of words they associate with masking. A subset of parents with children aged 4-6 was recruited from these surveys to participate in parent-child interviews (PCI). We calculated Smith's salience index for all unique items, stratifying by language (English/Spanish). Item salience guided PCI thematic analysis for additional context and meaning.Results648 participants provided 1118 unique freelist items in English and Spanish. 19 parent-child pairs were interviewed, 11 in Spanish and 8 in English. The most salient words were "safety"(0.37), "protection"(0.12), "prevention"(0.05), "health"(0.04), "good"(0.03), "can't breathe"(0.03), "necessary"(0.02), "care"(0.02), "precaution"(0.02), and "unnecessary"(0.02). Spanish speakers had a more favorable view of masking than English speakers, particularly regarding "protection" (0.20 vs 0.08) and "prevention" (0.10 vs 0.02).DiscussionMasking is an affordable individual-level risk mitigation that protects the communities that have inequitably shouldered the burdens of the COVID-19 pandemic. We recommend that policymakers prioritize the views of those most impacted when deciding on risk mitigation policies like school masking.

A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying mechanisms are unclear. We identified loss-of-function sequence variants in the epigenomic regulator gene SIN3A in two patients with complex CDH. Tissue-specific deletion of Sin3a in mice resulted in defects in diaphragm development, lung hypoplasia, and pulmonary hypertension, the cardinal features of CDH and major causes of CDH-associated mortality. Loss of SIN3A in the lung mesenchyme resulted in reduced cellular differentiation, impaired cell proliferation, and increased DNA damage. Treatment of embryonic Sin3a mutant mice with anacardic acid, an inhibitor of histone acetyltransferase, reduced DNA damage, increased cell proliferation and differentiation, improved lung and pulmonary vascular development, and reduced pulmonary hypertension. These findings demonstrate that restoring the balance of histone acetylation can improve lung development in the Sin3a mouse model of CDH.

AbstractRNA-binding proteins (RBPs) are emerging as a novel class of therapeutic targets in cancer, including in leukemia, given their important role in posttranscriptional gene regulation, and have the unexplored potential to be combined with existing therapies. The RBP insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3) has been found to be a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. Here, we study the combined effects of targeting IGF2BP3 and menin-MLL interaction in MLL-AF4-driven leukemia in vitro and in vivo, using genetic inhibition with CRISPR-Cas9-mediated deletion of Igf2bp3 and pharmacologic inhibition of the menin-MLL interaction with multiple commercially available inhibitors. Depletion of Igf2bp3 sensitized MLL-AF4 leukemia to the effects of menin-MLL inhibition on cell growth and leukemic initiating cells in vitro. Mechanistically, we found that both Igf2bp3 depletion and menin-MLL inhibition led to increased differentiation in vitro and in vivo, seen in functional readouts and by gene expression analyses. IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with small molecule MI-503 alone and showed enhanced antileukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4-mediated leukemogenesis and a potent therapeutic target, providing a paradigm for targeting leukemia at both the transcriptional and posttranscriptional level.

Abstract: Childhood conditions of inattention and disruptive behavior, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD), are prevalent but undertreated worldwide. One promising solution is harnessing digital technology to enhance school clinician training and ADHD/ODD intervention programs. We conducted a school-clustered randomized controlled trial of CLS-R-FUERTE: a program featuring training/consultation for school clinicians to deliver a six-week intervention comprised of weekly parent and student skills groups, as well as support teachers’ classroom management in the form of a Daily Report Card, all facilitated by electronic program manuals/materials and videoconferencing. A total of N = 163 (n = 6–8 students/school [ages 6–12] and their parents, teachers, and school clinicians) participated across eight public schools in Sinaloa, Mexico. We randomly assigned four schools to receive CLS-R-FUERTE immediately and four schools to receive school services as usual. We compared groups post-treatment on parent- and teacher-rated ADHD/ODD and impairment. We observed the program implementation in vivo, tracking trainer and school clinician program fidelity, as well as participant attendance and adherence, to evaluate feasibility. We also collected participant ratings of satisfaction and usability on the System Usability Scale to evaluate acceptability. Our CLS-R-FUERTE trial demonstrated high rates of program feasibility and acceptability comparable to prior in-person program trial findings. Students receiving CLS-R-FUERTE showed greater improvement in parent- and teacher-rated ADHD, as well as parent-rated ODD and impairment, compared to students receiving school services as usual. Results support the utility of global digital mental health programs training school clinicians to implement ADHD/ODD interventions, which have the potential to increase evidence-based treatment access and uptake across worldwide contexts.

BackgroundSchool-based health centers (SBHCs) are ideal settings to address social needs of youth and families. Case managers can play a vital role in social care interventions.MethodsWe piloted a program to incorporate a Case Manager into the care team of 1 SBHC serving 2 local schools with over 900 students and their surrounding communities. This project's purpose was to evaluate program feasibility, utilization, and acceptability. Our mixed-methods evaluation included analyses of data from electronic health records, client satisfaction surveys, and staff interviews.ResultsDuring the 6-month pilot, the Case Manager served 133 clients (about one third of all SBHC clients served) through 593 contacts. Most contacts included referrals to support services (90%) and 37% addressed newcomer immigrant adjustment. All 37 respondents to the satisfaction survey during the 3-month administration period (44% response rate) reported that the Case Manager made them feel comfortable asking for help; 95% reported getting the help they needed. The 7 SBHC staff interviewed shared many program benefits, including increased time for clinical services.Implications for school health policy, practice, and equityInequities in children's health and educational achievement are influenced by structural factors. Results from our pilot program demonstrate that SBHCs may be well-positioned to deliver social care interventions and that case managers enhance the ability to deliver quality care.ConclusionsSchool-based programs to address unmet social needs are critical to supporting learning and wellness for all youth. Robust studies are needed to further test the impacts of case management in SBHCs.

In 2019, the University of California at San Francisco (UCSF) launched the Child and Adolescent Psychiatry Portal (CAPP), a pediatric mental health care access (PMHCA) program providing remote mental health consultation services to pediatric primary care providers (PCPs) throughout Northern and Central California. The development and implementation of CAPP was guided by Human-Centered Design (HCD), an iterative, rapid-paced innovation process focusing on stakeholders’ needs and experiences, which shaped the development of CAPP’s programs. The resulting key programmatic elements are designed for pediatric workforce development: (1) PCP consultation with a child and adolescent psychiatrist via a telephone warmline; and (2) training and education for providers. CAPP has grown rapidly since its launch, having enrolled 1,714 providers from 257 practices spread across 36 counties and provided 3,288 consults on 2,703 unique lives as of August 2023. Preliminary evaluation findings indicate high PCP satisfaction with CAPP’s services, despite continued challenges of integrating behavioral health into primary care. Throughout the HCD and implementation process, multidisciplinary partnerships have proven critical in providing end-user input to inform and improve program design. This growing network of partnerships, developed through the cultivation of personal relationships and trust over time, has also proven essential for CAPP’s rapid growth and sustainability. Overall, this Community Case Study highlights the critical role of partnerships and the importance of taking a people-centered approach, as captured in CAPP’s motto, “Connecting for Care.”

BackgroundPrior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical "clusters" based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock).MethodsWe collected biomarker samples of children ages 0-17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors.ResultsOur final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging.ConclusionOur findings support prior work suggesting that social stress exposures contribute to increased inflammation in children.ImpactOur study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children.Clinical trial registrationNCT02746393.

Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that OS-derived exosomes can drive pro-tumorigenic or anti-tumorigenic phenotypes by transferring specific cargos, including proteins, nucleic acids, and metabolites, to neighboring cells, significantly impacting the regulation of cellular processes. This review discusses the advancement of exosomes and their cargos in OS. We examine how these exosomes contribute to the modulation of cellular phenotypes associated with tumor progression and metastasis. Furthermore, we explore the potential of exosomes as valuable biomarkers for diagnostics and prognostic purposes and their role in shaping innovative therapeutic strategies in OS treatment development.

Humans learn about the world through inductive reasoning, generalizing information about an individual to others in the category. Indeed, by infancy, monolingual children expect people who speak the same language (but not people who speak different languages) to be similar in their food preferences (Liberman et al., 2016). Here, we ask whether infants who are exposed to linguistic diversity are more willing to generalize information even across language-group lines. To test this, we ran an inductive inference task and collected data on exposure to linguistic diversity at the interpersonal and neighborhood levels. Infants with more linguistically diverse social networks were more likely to generalize a food preference across speakers of different languages. However, this relationship was not seen for neighborhood diversity. We discuss implications of this work on understanding the development of bias and its malleability based on early social experiences. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The ability to accurately decode others' facial expressions is essential for successful social interaction. Previous theories suggest that aspects of parental emotionality-the frequency, persistence and intensity of parents' own emotions-can influence children's emotion perception. Through a combination of mechanisms, parental emotionality may shape how children's brains specialize to respond to emotional expressions, but empirical data are lacking. The present study provides a direct empirical test of the relation between the intensity, persistence and frequency of parents' own emotions and children's neural responses to perceiving emotional expressions. Event-related potentials (ERPs) were recorded as typically developing 3- to 5-year-old children (final Ns = 59 and 50) passively viewed faces expressing different emotional valences (happy, angry and fearful) at full and reduced intensity (100% intense expression and 40% intense expression). We examined relations between parental emotionality and children's mean amplitude ERP N170 and negative central responses. The findings demonstrate a clear relation between parental emotionality and children's neural responses (in the N170 mean amplitude and latency) to emotional expressions and suggest that parents may influence children's emotion-processing neural circuitry.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children

BackgroundTobacco smoke adversely affects the prognosis of adult cancers including myeloid leukemia, but less is known in children.MethodsWe evaluated whether pre- and postnatal exposures to tobacco smoke decrease 5-year survival of 1,235 childhood acute lymphoblastic leukemia (ALL) and 188 childhood acute myeloid leukemia (AML) cases derived from a population-based case-control study in California. Cases were diagnosed between 1995 and 2015 (median follow-up time of 13.2 years overall). We obtained data on tobacco smoking (before conception, during pregnancy, after birth), parental education and income, clinical features, and vital status through 2020. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with smoking, adjusting for sociodemographic characteristics and risk group (ALL only).ResultsAbout 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared with nonsmoking fathers [HR = 1.41; 95% confidence interval (CI), 0.95-3.44 and 3.47; 95% CI, 1.37-8.81, respectively for

Musical instrument training has been linked to improved academic and cognitive abilities in children, but it remains unclear why this occurs. Moreover, access to instrument training is not always feasible, thereby leaving less fortunate children without opportunity to benefit from such training. Although music-based video games may be more accessible to a broader population, research is lacking regarding their benefits on academic and cognitive performance. To address this gap, we assessed a custom-designed, digital rhythm training game as a proxy for instrument training to evaluate its ability to engender benefits in math and reading abilities. Furthermore, we tested for changes in core cognitive functions related to math and reading to inform how rhythm training may facilitate improved academic abilities. Classrooms of 8-9 year old children were randomized to receive either 6 weeks of rhythm training (N = 32) or classroom instruction as usual (control; N = 21). Compared to the control group, results showed that rhythm training improved reading, but not math, fluency. Assessments of cognition showed that rhythm training also led to improved rhythmic timing and language-based executive function (Stroop task), but not sustained attention, inhibitory control, or working memory. Interestingly, only the improvements in rhythmic timing correlated with improvements in reading ability. Together, these results provide novel evidence that a digital platform may serve as a proxy for musical instrument training to facilitate reading fluency in children, and that such reading improvements are related to enhanced rhythmic timing ability and not other cognitive functions associated with reading performance. RESEARCH HIGHLIGHTS: Digital rhythm training in the classroom can improve reading fluency in 8-9 year old children Improvements in reading fluency were positively correlated with enhanced rhythmic timing ability Alterations in reading fluency were not predicted by changes in other executive functions that support reading A digital platform may be a convenient and cost-effective means to provide musical rhythm training, which in turn, can facilitate academic skills.

The process by which infants learn verbs through daily social interactions is not well-understood. This study investigated caregivers' use of verbs, which have highly abstract meanings, during unscripted toy-play. We examined how verbs co-occurred with distributional and embodied factors including pronouns, caregivers' manual actions, and infants' locomotion, gaze, and object-touching. Object-action verbs were used significantly more often during caregiver-infant joint attention interactions. Movement and cognition verbs showed distinct co-occurrences with different contexts. Cognition and volition verbs were differentiated by pronouns. These findings provide evidence for how verb acquisition may be supported by the distributional and embodied contexts in caregiver-infant interactions.

Do children think of genetic inheritance as deterministic or probabilistic? In two novel tasks, children viewed the eye colors of animal parents and judged and selected possible phenotypes of offspring. Across three studies (N = 353, 162 girls, 172 boys, 2 non-binary; 17 did not report gender) with predominantly White U.S. participants collected in 2019-2021, 4- to 12-year-old children showed a probabilistic understanding of genetic inheritance, and they accepted and expected variability in the genetic inheritance of eye color. Children did not show a mother bias but they did show two novel biases: perceptual similarity and sex-matching. These results held for unfamiliar animals and several physical traits (e.g., eye color, ear size, and fin type), and persisted after a lesson.

We examined the relations of language skills (vocabulary, listening comprehension, and oral retell), transcription skills (spelling and handwriting fluency), and domain-general cognitions/executive functions (working memory and attentional control) to writing quality for English-Spanish emergent bilingual children in Grade 1. Data were from a convenience sample of 211 children (57% girls; 82% Hispanic, 9.5% White, 4% Asian American children) who were assessed on written composition, vocabulary, listening comprehension, oral retell, and spelling in English and Spanish; handwriting fluency and working memory in English; and attentional control rated by their teachers. Confirmatory factor analysis results showed that writing quality in English and Spanish in narrative and opinion genres was best described as a unidimensional skill. Structural equation model results showed that English oral language, English spelling, and Spanish spelling skills, but not Spanish oral language skill, were independently related to writing quality, after controlling for gender, English learner status, Hispanic status, and enrollment in dual immersion program. The relations of working memory and attentional control to writing quality were indirect, mediated by oral language and transcription skills. These results are discussed in light of theory and in the context of emergent bilingual children in primary grades.

BackgroundDespite the ubiquity of adolescent screen use, there are limited longitudinal studies that examine the prospective relationships between screen time and child behavioral problems in a large, diverse nationwide sample of adolescents in the United States, which was the objective of the current study.MethodsWe analyzed cohort data of 9,538 adolescents (9-10 years at baseline in 2016-2018) with two years of follow-up from the Adolescent Brain Cognitive Development (ABCD) Study. We used mixed-effects models to analyze associations between baseline self-reported screen time and parent-reported mental health symptoms using the Child Behavior Checklist, with random effects adjusted for age, sex, race/ethnicity, household income, parent education, and study site. We tested for effect modification by sex and race/ethnicity.ResultsThe sample was 48.8% female and racially/ethnically diverse (47.6% racial/ethnic minority). Higher total screen time was associated with all mental health symptoms in adjusted models, and the association was strongest for depressive (B = 0.10, 95% CI 0.06, 0.13, p

BackgroundA major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations.MethodsData from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight

The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in multiple generations of rodents and humans. These lipophilic pollutants accumulate in adipose tissue and appear to decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue (BAT). We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of BAT. To address this, we exposed C57BL/6 J mice to DDT or DDE from gestational day (GD) 11.5 to postnatal day (PND) 5, evaluated longitudinal body temperature, and performed reduced representation bisulfite sequencing and RNA sequencing of BAT from infant and adult offspring. Exposure to DDT or DDE reduced core body temperature in adult mice, and differential methylation at the pathway and gene level was persistent from infancy to adulthood. Furthermore, thermogenesis and biological pathways essential for thermogenic function, such as oxidative phosphorylation and mechanistic target of rapamycin kinase (mTOR) signaling, were enriched with differential methylation and RNA transcription in adult mice exposed to DDT or DDE. PAZ6 human brown preadipocytes were differentiated in the presence of DDT or DDE to understand the brown adipocyte-autonomous effect of these pollutants. In vitro exposure led to limited changes in RNA expression; however, mitochondrial membrane potential was decreased in vitro with 0.1 µM and 1 µM doses of DDT or DDE. These results demonstrate that concentrations of DDT and DDE relevant to human exposure have a significant effect on thermogenesis, the transcriptome, and DNA methylome of mouse BAT and the mitochondrial function of human brown adipocytes.

BackgroundHuman papillomavirus (HPV) infections can cause cancers of the cervix, vagina, vulva, penis, anus, and oropharynx. The most recently approved HPV vaccine, Gardasil-9, protects against HPV infection and can prevent HPV-associated invasive cancers. However, Gardasil-9 is one of the most underused vaccines in the US today. Young adults are at risk for HPV infection, but many are not vaccinated. This study uses a randomized controlled trial (RCT) to test an innovative multilevel intervention to increase HPV vaccination rates among young adults. In this paper, we describe the research protocol.MethodsThe study uses a two by three factorial design. A total of 1200 young adults in Texas, age 18-26 years, who have not been previously fully vaccinated against HPV will be randomly assigned to one of six conditions to receive: (1) standard CDC information about HPV vaccination (control); (2) video narratives about HPV vaccination; (3) written narratives about HPV vaccination; or (4-6) enhanced access to HPV vaccine combined with (4) standard CDC information, (5) video narratives, or (6) written narratives. The two primary outcomes are the rate of HPV vaccination initiation by 3-month follow-up and rate of HPV vaccination completion by 9-month follow-ups. We will determine the impact of the individual level intervention (i.e., persuasive narratives through video or written format), the systemic level intervention (i.e., enhanced access to HPV vaccines), and the combination of both levels, on HPV vaccination initiation and completion. We will also use purposive sampling to select participants to take part in semi-structured interviews/focus groups to better understand the mechanisms of the intervention.DiscussionRecruitment and data collection began in March 2022. We expect to complete data collection by March 2026. We expect that narratives, enhanced access, and the combination of both will improve HPV vaccination initiation and completion rates among young adults. If proven successful, these individual- and system-level interventions can be easily disseminated in regions with low HPV vaccination rates to improve HPV vaccination, and ultimately decrease HPV-related cancer burden.Trial registrationNCT05057312.

BackgroundThe rising number of children identified with autism has led to exponential growth in for-profit applied behavior analysis (ABA) agencies and the use of highly structured approaches that may not be developmentally appropriate for young children. Multiple clinical trials support naturalistic developmental behavior interventions (NDBIs) that integrate ABA and developmental science and are considered best practices for young autistic children. The Early Start Denver Model (ESDM) is a comprehensive NDBI shown to improve social communication outcomes for young autistic children in several controlled efficacy studies. However, effectiveness data regarding NDBI use in community-based agencies are limited.MethodsThis study uses a community-partnered approach to test the effectiveness of ESDM compared to usual early behavioral intervention (EBI) for improving social communication and language in autistic children served by community agencies. This is a hybrid type 1 cluster-randomized controlled trial with 2 conditions: ESDM and EBI. In the intervention group, supervising providers will receive training in ESDM; in the control group, they will continue EBI as usual. We will enroll and randomize 100 supervisors (50 ESDM, 50 EBI) by region. Each supervisor enrolls 3 families of autistic children under age 5 (n = 300) and accompanying behavior technicians (n = 200). The primary outcome is child language and social communication at 6 and 12 months. Secondary outcomes include child adaptive behavior, caregiver use of ESDM strategies, and provider intervention fidelity. Child social motivation and caregiver fidelity will be tested as mediating variables. ESDM implementation determinants will be explored using mixed methods.DiscussionThis study will contribute novel knowledge on ESDM effectiveness, the variables that mediate and moderate child outcomes, and engagement of its mechanisms in community use. We expect results from this trial to increase community availability of this model and access to high-quality intervention for young autistic children, especially those who depend on publicly funded intervention services. Understanding implementation determinants will aid scale-up of effective models within communities.Trail registrationClinicaltrials.gov identifier number NCT06005285. Registered on August 21, 2023.Protocol versionIssue date 6 August 2024; Protocol amendment number: 02.

Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45+ cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45+ cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain's innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants.

ImportanceEpidural analgesia is used by approximately 70% of birthing persons in the US to alleviate labor pain and is a common cause of elevated temperature in the birthing parent during labor, which, in turn, is associated with adverse neonatal outcomes such as hypoxic-ischemic encephalopathy (HIE).ObjectiveTo determine whether epidural analgesia is associated with increased risk of HIE after adjusting for the birthing person's maximal temperature before epidural placement and for the propensity to get an epidural.Design, setting, and participantsThis retrospective, population-based cohort study was conducted at 15 Kaiser Permanente Northern California hospitals. Participants included singleton neonates born at 35 weeks' or later gestational age between 2012 and 2019. Elective cesarean deliveries and deliveries within 2 hours of hospital admission were excluded. Data analysis was performed from November 2022 to June 2024.ExposureThe primary exposure was epidural analgesia during labor.Main outcomes and measuresThe primary outcome was HIE, defined as the presence of both neonatal acidosis (ie, pH

The cerebellum has been consistently shown to be atypical in autism spectrum disorder (ASD). However, despite its known role in sensorimotor function, there is limited research on its association with sensory over-responsivity (SOR), a common and impairing feature of ASD. Thus, this study sought to examine functional connectivity of the sensorimotor cerebellum in ASD compared to typically developing (TD) youth and investigate whether cerebellar connectivity is associated with SOR. Resting-state functional connectivity of the sensorimotor cerebellum was examined in 54 ASD and 43 TD youth aged 8-18 years. Using a seed-based approach, connectivity of each sensorimotor cerebellar region (defined as lobules I-IV, V-VI and VIIIA&B) with the whole brain was examined in ASD compared to TD youth, and correlated with parent-reported SOR severity. Across all participants, the sensorimotor cerebellum was functionally connected with sensorimotor and visual regions, though the three seed regions showed distinct connectivity with limbic and higher-order sensory regions. ASD youth showed differences in connectivity including atypical connectivity within the cerebellum and increased connectivity with hippocampus and thalamus compared to TD youth. More severe SOR was associated with stronger connectivity with cortical regions involved in sensory and motor processes and weaker connectivity with cognitive and socio-emotional regions, particularly prefrontal cortex. These results suggest that atypical cerebellum function in ASD may play a role in sensory challenges in autism.

PurposeEmerging research evidence suggests positive relationships between higher screen time and eating disorders. However, few studies have examined the prospective associations between screen use and eating disorder symptoms in early adolescents and how problematic screen use may contribute to symptom development.MethodsWe analyzed prospective cohort data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 10,246, 2016-2020, ages 9-14). Logistic regression analyses were used to estimate the longitudinal associations between baseline self-reported screen time and eating disorder symptoms in year two. Logistic regression analyses were also used to estimate cross-sectional associations between problematic screen use in year two (either problematic social media or mobile phone use) and eating disorder symptoms in year two. Eating disorder symptoms based on the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) included fear of weight gain, self-worth tied to weight, engaging in compensatory behaviors, binge eating, and distress with binge eating.ResultsEach additional hour of total screen time and social media use was associated with higher odds of fear of weight gain, self-worth tied to weight, compensatory behaviors to prevent weight gain, binge eating, and distress with binge eating two years later (odds ratio [OR] 1.05-1.55). Both problematic social media and mobile phone use were associated with higher odds of all eating disorder symptoms (OR 1.26-1.82).ConclusionsFindings suggest greater total screen time, social media use, and problematic screen use are associated with more eating disorder symptoms in early adolescence. Clinicians should consider assessing for problem screen use and, when high, screen for disordered eating.Level of evidenceLevel III: Evidence obtained from well-designed cohort or case-control analytic studies.

BackgroundFollowing a decline in perinatal HIV transmission from 20% to 10% between 2010 and 2017 in Kenya, rates have since plateaued with an estimated 8% transmission rate in 2021. Between October 2016 and September 2021, Family AIDS Care & Education Services (FACES) supported HIV care and treatment services across 61 facilities in Kisumu County, Kenya with an emphasis on service strengthening for pregnant and postpartum women living with HIV to reduce perinatal HIV transmission. This included rigorous implementation of national HIV guidelines and implementation of 3 locally adapted evidence-based interventions targeted to the unique needs of women and their infants. We examined whether these person-centered program enhancements were associated with changes in perinatal HIV transmission at FACES-supported sites over time.Methods and findingsWe conducted a repeated cross-sectional study of annually aggregated routinely collected documentation of perinatal HIV transmission risk through the end of breastfeeding at FACES-supported facilities between October 2016 and September 2021. Data included 12,599 women living with HIV with baseline antenatal care metrics, and, a separate data set of 11,879 mother-infant pairs who were followed from birth through the end of breastfeeding (overlapping with those in antenatal care 2 years prior). FACES implemented 3 interventions for pregnant and postpartum women living with HIV in 2019: (1) high-risk clinics; (2) case management; and (3) a mobile app to support treatment engagement. Our primary outcome was infant HIV acquisition by the end of breastfeeding (18 to 24 months). We compared infant HIV acquisition risk in the final year of the FACES program (2021) to the year before intervention scale-up and following implementation of the "Treat All" policy (2018). Mother-infant pair loss to follow-up was a secondary outcome. Program data were aggregated by year and site, thus in multivariable regression, we adjusted for site-level characteristics, including facility type, urban versus rural, number of women with HIV in antenatal care each year, and the proportion among them under 25 years of age. Between October 2016 and September 2021, 81,172 pregnant women received HIV testing at the initiation of antenatal care, among whom 12,599 (15.5%) were living with HIV, with little variation in HIV prevalence over time. The risk of infant HIV acquisition by 24 months of age declined from 4.9% (101/2,072) in 2018 to 2.2% (48/2,156) in 2021 (adjusted risk difference -2.6% [95% confidence interval (CI): -3.7, -1.6]; p < 0.001). Loss to follow-up declined from 9.9% (253/2,556) in 2018 to 2.5% (59/2,393) in 2021 (risk difference -7.5% [95% CI: -8.8, -6.2]; p < 0.001). During the same period, UNAIDS estimated rates of perinatal transmission in the broader Nyanza region and in Kenya as a whole did not decline. The main limitation of this study is that we lacked a comparable control group.ConclusionsThese findings suggest that implementation of person-centered interventions was associated with significant declines in perinatal HIV transmission and loss to follow-up of pregnant and postpartum women.