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Abstract Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.

Abstract Magnetoelectrics with ultra-low symmetry and spin-orbit coupling are well known to display a number of remarkable properties including nonreciprocal directional dichroism. As a polar and chiral magnet, Ni3TeO6 is predicted to host this effect in three fundamentally different configurations, although only two have been experimentally verified. Inspired by the opportunity to unravel the structure-property relations of such a unique light-matter interaction, we combined magneto-optical spectroscopy and first-principles calculations to reveal nonreciprocity in the toroidal geometry and compared our findings with the chiral configurations. We find that formation of Ni toroidal moments is responsible for the largest effects near 1.1 eV—a tendency that is captured by our microscopic model and computational implementation. At the same time, we demonstrate deterministic control of nonreciprocal directional dichroism in Ni3TeO6 across the entire telecom wavelength range. This discovery will accelerate the development of photonics applications that take advantage of unusual symmetry characteristics.

Objective: The aim of this study is to identify characteristics of children for whom a developmental-behavioral pediatrician's (DBP) diagnostic impressions of autism spectrum disorder (ASD) or non-ASD were changed by Autism Diagnostic Observation Schedule (ADOS) results., Method: A prospective study of children 1½ to <6 years consecutively referred to 8 sites for possible ASD. Cognitive/developmental, language, and adaptive testing varied, as each site followed its usual clinical approach. DBPs documented diagnosis as ASD or non-ASD and their degree of diagnostic certainty (1-10) pre- and post-ADOS. Cases where DBP diagnostic impression did not change after ADOS administration ("Stable Group," n = 314) were compared with those for whom it did change ("Changed Group," n = 35), followed by matched random sample comparisons., Results: There were no significant differences in child characteristics (age, gender, race, ethnicity, insurance, caregiver education) between the Stable and Changed groups. DBPs' diagnostic certainty was significantly lower, both pre- and post-ADOS, in the Changed versus Stable group. Change was associated with milder symptoms of ASD and less impaired language. In an age- and gender-matched comparison, significant differences remained for diagnostic certainty and severity of social communication impairments. Cognitive scores were significantly higher in the Changed Group. Because of significantly higher caregiver education and a trend toward more privately insured children among the Changed Group, samples (n = 35 each) were then matched on those characteristics, revealing the same differences for diagnostic certainty, severity of ASD symptoms, and language skills., Conclusion: Young children with milder ASD symptoms and less impaired language may benefit most from the administration of the ADOS., Competing Interests: Disclosure: W. Barbaresi reported grants from the Health Resources and Services Administration/Maternal Child Health Bureau Developmental-Behavioral Pediatric Research Network and received a supplemental grant from Health Resources and Services Administration/Maternal Child Health Bureau to support this study. DBPNet itself is supported by a grant from Health Resources and Services Administration/Maternal Child Health Bureau, during the conduct of the study. The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

In single sheets of graphene, vacancy-induced states have been shown to host an effective spin-1/2 hole that can be Kondo screened at low temperatures. Here, we show how these vacancy-induced impurity states survive in twisted bilayer graphene (TBG), which thus provides a tunable system to probe the critical destruction of the Kondo effect in pseudogap hosts. Ab initio calculations and atomic-scale modeling are used to determine the nature of the vacancy states in the vicinity of the magic angle in TBG, demonstrating that the vacancy can be treated as a quantum impurity. Utilizing this insight, we construct an Anderson impurity model with a TBG host that we solve using the numerical renormalization group combined with the kernel polynomial method. We determine the phase diagram of the model and show how there is a strict dichotomy between vacancies in the AA/BB versus AB/BA tunneling regions. In AB/BA vacancies, the Kondo temperature at the magic angle develops a broad distribution with a tail to vanishing temperatures due to multifractal wave functions at the magic angle. We argue that scanning tunneling microscopy in the vicinity of the vacancy can act as a probe of both the critical single-particle states and the underlying many-body ground state in magic-angle TBG.

Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. No extramural funding was received in support of this session.

Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs, a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion, and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However, as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes, which secreted various pro-tumorigenic ligands including FGF1, as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype, the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon., (© 2024. The Author(s).)

Electric currents have the intriguing ability to induce magnetization in nonmagnetic crystals with sufficiently low crystallographic symmetry. Some associated phenomena include the non-linear anomalous Hall effect in polar crystals and the nonreciprocal directional dichroism in chiral crystals when magnetic fields are applied. In this work, we demonstrate that the same underlying physics is also manifested in the electronic tunneling process between the surface of a nonmagnetic chiral material and a magnetized scanning probe. In the paramagnetic but chiral metallic compound Co 1/3 NbS 2 , the magnetization induced by the tunneling current is shown to become detectable by its coupling to the magnetization of the tip itself. This results in a contrast across different chiral domains, achieving atomic-scale spatial resolution of structural chirality. To support the proposed mechanism, we used first-principles theory to compute the chirality-dependent current-induced magnetization and Berry curvature in the bulk of the material. Our demonstration of this magnetochiral tunneling effect opens up an avenue for investigating atomic-scale variations in the local crystallographic symmetry and electronic structure across the structural domain boundaries of low-symmetry nonmagnetic crystals., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Infants with prematurity, low birthweight, and medical comorbidities are at high risk for developmental delays and neurodevelopmental disabilities and require close monitoring. Due to the COVID-19 pandemic, high-risk infant follow-up (HRIF) programs have adapted to perform developmental assessments via telehealth., Objectives: Describe the referral rates to initiate, continue, or increase/add early intervention (EI) therapies based on in-person use of the Bayley Scales of Infant and Toddler Development, 4th Edition (BSID-IV) or telehealth use of the Developmental Assessment in Young Children, 2nd Edition (DAYC-2)., Methods: A retrospective chart review was conducted on 203 patients seen in the HRIF program at an academic medical center in Southern California. Patients were divided into in-person (BSID-IV) and telehealth (DAYC-2) assessment groups. Statistical analyses were performed to describe demographic characteristics, medical information, and referral rates for EI therapies by the types of visits., Results: The in-person and telehealth groups demonstrated similar demographic and clinical characteristics and comparable referral rates for initiating EI therapies. Telehealth patients already receiving therapies were recommended to increase/add EI therapies at a higher rate compared to in-person patients., Conclusions: The BSID-IV is widely used to assess for developmental delays in the high-risk infant population, but in-person administration of this tool poses limitations on its accessibility. Telehealth administration of an alternative tool, such as the DAYC-2, can lead to similar EI referral rates as in-person administration of the BSID-IV. Increased use of telehealth developmental assessments can promote timely detection of developmental delays and minimize gaps in healthcare access., Competing Interests: Declaration of competing interest The authors of this paper have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume; the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known., Research Question: Can a cluster-randomized trial design be used to assess whether the mode of mandatory ventilation affects the number of days alive and free of invasive mechanical ventilation among critically ill adults?, Study Design and Methods: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical ICU at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single-ventilator mode (volume control vs pressure control vs adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022, and will end on July 31, 2023., Results: This manuscript describes the protocol and statistical analysis plan for the MODE trial of ventilator modes comparing volume control, pressure control, and adaptive pressure control., Interpretation: Prespecifying the full statistical analysis plan prior to completion of enrollment increases rigor, reproducibility, and transparency of the trial results., Clinical Trial Registration: The trial was registered with clinicaltrials.gov on October 3, 2022, before initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

We combine synchrotron-based infrared absorption and Raman scattering spectroscopies with diamond anvil cell techniques and first-principles calculations to explore the properties of hafnia under compression. We find that pressure drives HfO[Formula: see text]:7%Y from the mixed monoclinic ([Formula: see text]) [Formula: see text] antipolar orthorhombic ([Formula: see text]) phase to pure antipolar orthorhombic ([Formula: see text]) phase at approximately 6.3 GPa. This transformation is irreversible, meaning that upon release, the material is kinetically trapped in the [Formula: see text] metastable state at 300 K. Compression also drives polar orthorhombic ([Formula: see text]) hafnia into the tetragonal ([Formula: see text]) phase, although the latter is not metastable upon release. These results are unified by an analysis of the energy landscape. The fact that pressure allows us to stabilize targeted metastable structures with less Y stabilizer is important to preserving the flat phonon band physics of pure HfO[Formula: see text]., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: Practice guidelines from the American Academy of Pediatrics and Society for Developmental and Behavioral Pediatrics recommend evidence-based behavioral therapy (BT) as first-line treatment for preschool-age children with ADHD, prior to medication initiation. Thus, this study's objective is to present the frequency of physician-documented receipt of BT in preschool-age children with ADHD prior to medication initiation and to determine factors associated with receipt BT receipt., Methods: This retrospective medical record review was conducted across 7 Developmental Behavioral Pediatrics Research Network (DBPNet) sites. Data were abstracted for children <72 months old seen by a DBP clinician and initiated on ADHD medication between 1/1/2013-7/1/2017. From narrative text of the medical records, BT receipt was coded as: parent training in behavior management (PTBM), Applied Behavior Analysis (ABA), other, or did not receive., Results: Of the 497 children in this study; 225 children (45%) had reported receipt of any BT prior to ADHD medication initiation, with 15.9% (n = 79) receiving PTBM. Children with co-existing diagnoses of ASD or disruptive behavior disorder were more likely to receive BT than children without co-existing conditions (59.3% vs 69.0% vs 30.6%). There was significant site variability in reported receipt of BT, ranging from 22.4% to 74.1%, and sex and insurance were not associated with BT rates., Conclusion: The percentage of children with documented receipt of any BT, and particularly PTBM, was low across all sites and co-existing conditions. These findings highlight the universal need to increase receipt of evidence-based BT for all young children with ADHD., Competing Interests: Conflicts of Interest and Source of Funding: All phases of this study were conducted by DBPNet, which is supported by cooperative agreement UT5MC42432 from the Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services. This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. The authors have no other conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The purpose of this study is to identify the sociocultural factors in the Black community that contribute to a delay in identification of Black children with autism spectrum disorder (ASD)., Methods: Four focus groups with parents of typically developing children were conducted at 2 Black Churches using a community-partnered participatory research approach and the socioecological model. Participants completed sociodemographic surveys, viewed CDC Autism Training Videos of Black children with ASD, and reported on their behavioral observations. Focus groups were audio recorded and transcribed. Thematic data analysis was conducted using NVivo software., Results: At the individual level, participants interpreted ASD-associated behaviors as a problem of timing of developmental milestones in the course of normative development rather than a sign of a disorder and positive and negative characteristics. At the interpersonal level, the role of grandparents and extended family was important for monitoring child development. At the organizational level, racial concordance with health care providers was seen as critical because of historical mistrust. At the community level, fear of racism and child protective services and inequitable care emerged. At the policy level, there were concerns about access to affordable, high-quality care., Conclusion: This study provides insight into the sociocultural factors in the faith-based Black community that may contribute to a delay in identification of Black children with ASD. Health care professionals need additional training to effectively serve Black children and families in the face of historical mistrust and health care inequity., Competing Interests: Disclosure: The authors certify that no party has a conflict of interest. The authors certify that all financial and material support for this research and work are clearly identified in the title page of the manuscript., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This study aimed to determine whether parent ratings of attention-deficit/hyperactivity disorder (ADHD) symptom severity or externalizing symptoms (EXT) or internalizing symptoms (INT) moderate response to stimulants (STIM) and alpha-2 adrenergic agonists (A2As) in preschool ADHD., Methods: Health records for children treated with medication for ADHD and with parent rating scale data available (N = 309; age <72 months) were reviewed at 7 Developmental-Behavioral Pediatric Research Network sites. Severity of ADHD was defined as the number of ADHD symptoms occurring often or very often on DSM-IV-based parent rating scales. EXT or INT from standardized rating scales were categorized as T score <60, 60 to <70, or ≥70. Ordinal logistic regression models predicting response to medication were calculated., Results: The median (interquartile range) age at ADHD diagnosis was 59 (54-65) months. One hundred eighty-three participants had ADHD symptom severity, and 195 had EXT or INT data. ADHD severity was not associated with medication response. Both EXT and INT were associated with medication response but with significant medication class by EXT/INT interactions. Children with higher EXT were less likely to respond to STIM, with percentage of nonresponders for T-score categories <60, 60 to <70, and ≥70 being 3.6%, 25.7%, and 33.3% (p = 0.016) and, for A2As, being 60%, 50%, and 33.3% (p = 0.55), respectively. A similar pattern was observed for INT categories: STIM 19.4%, 22.5%, and 50.0% (p = 0.002) and A2As 42.3%, 30%, and 42.3% (p = 0.48), respectively., Conclusion: For preschool ADHD, low ratings of EXT or INT are associated with a high likelihood of response to STIM. By contrast, response rates to STIM and A2As are more similar for children with high levels of EXT or INT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cardiopulmonary failure is the leading cause of death in Duchenne muscular dystrophy (DMD). Research into DMD-specific cardiovascular therapies is ongoing, but there are no Food and Drug Administration-approved cardiac end points. To adequately power a therapeutic trial, appropriate end points must be chosen and the rate of change for these end points reported. The objective of this study was to evaluate rate of change for cardiac magnetic resonance and blood biomarkers and to determine which measures associate with all-cause mortality in DMD., Methods: Seventy-eight DMD subjects underwent 211 cardiac magnetic resonance studies analyzed for left ventricular (LV) ejection fraction, indexed LV end diastolic and systolic volumes, circumferential strain, late gadolinium enhancement presence and severity (global severity score, and full width half maximum), native T1 mapping, T2 mapping, and extracellular volume. Blood samples were analyzed for BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and troponin I. Cox proportional hazard regression modeling was performed with all-cause mortality as the outcome., Results: Fifteen subjects (19%) died. LV ejection fraction, indexed end systolic volumes, global severity score, and full width half maximum worsened at 1 and 2 years while circumferential strain and indexed LV end diastolic volumes worsened at 2 years. LV ejection fraction, indexed LV end diastolic and systolic volumes, late gadolinium enhancement full width half maximum, and circumferential strain associated with all-cause mortality ( P <0.05). NT-proBNP was the only blood biomarker that associated with all-cause mortality ( P <0.05)., Conclusions: LV ejection fraction, indexed LV volumes, circumferential strain, late gadolinium enhancement full width half maximum, and NT-proBNP are associated with all-cause mortality in DMD and may be the best end points for use in cardiovascular therapeutic trials. We also report change over time of cardiac magnetic resonance and blood biomarkers., Competing Interests: Disclosures Dr Soslow is on the Advisory Board for PepGen. Drs Soslow and Hor are consultants for Sarepta. The other authors report no conflicts.

Objectives: To characterize and compare the type and frequency of a range of common and uncommon adverse effects (AEs) associated with α-2 adrenergic agonist (A2A) and stimulant treatment of attention-deficit/hyperactivity disorder at preschool-age as well as to evaluate the impact of age on common AEs., Study Design: This was a retrospective electronic medical record review of children <72 months of age (n = 497) evaluated at outpatient developmental-behavioral pediatric practices at 7 US academic medical centers within the Developmental-Behavioral Pediatrics Research Network. Data on AEs were abstracted for children who had treatment initiated by a developmental-behavioral pediatrician with an A2A or stimulant medication between January 2013 and July 2017; follow-up was complete by February 2019., Results: A2A and stimulants had distinctive AE profiles. A2A compared with stimulants had a greater proportion with daytime sleepiness and headaches; stimulants had significantly greater proportions for most other AE, including moodiness/irritability, difficulty with sleep, appetite suppression, stomachaches, skin picking/repetitive behaviors, withdrawn behavior, and weight loss. Younger age was associated with disruptive behavior and difficulty with sleep., Conclusions: Stimulants had a greater rate of most AEs compared with A2A. AE profiles, together with efficacy, should inform clinical decision-making. Prospective randomized clinical trials are needed to fully compare efficacy and AE profiles of A2A and stimulants., (Copyright © 2023 Elsevier Inc. All rights reserved.)