Headpulse measurement can reliably identify large-vessel occlusion stroke in prehospital suspected stroke patients: Results from the EPISODE-PS-COVID study.

BACKGROUND: Large-vessel occlusion (LVO) stroke represents one-third of acute ischemic stroke (AIS) in the United States but causes two-thirds of poststroke dependence and >90% of poststroke mortality. Prehospital LVO stroke detection permits efficient emergency medical systems (EMS) transport to an endovascular thrombectomy (EVT)-capable center. Our primary objective was to determine the feasibility of using a cranial accelerometry (CA) headset device for prehospital LVO stroke detection. Our secondary objective was development of an algorithm capable of distinguishing LVO stroke from other conditions. METHODS: We prospectively enrolled consecutive adult patients suspected of acute stroke from 11 study hospitals in four different U.S. geographical regions over a 21-month period. Patients received device placement by prehospital EMS personnel. Headset data were matched with clinical data following informed consent. LVO stroke diagnosis was determined by medical chart review. The device was trained using device data and Los Angeles Motor Scale (LAMS) examination components. A binary threshold was selected for comparison of device performance to LAMS scores. RESULTS: A total of 594 subjects were enrolled, including 183 subjects who received the second-generation device. Usable data were captured in 158 patients (86.3%). Study subjects were 53% female and 56% Black/African American, with median age 69 years. Twenty-six (16.4%) patients had LVO and 132 (83.6%) were not LVO (not-LVO AIS, 33; intracerebral hemorrhage, nine; stroke mimics, 90). COVID-19 testing and positivity rates (10.6%) were not different between groups. We found a sensitivity of 38.5% and specificity of 82.7% for LAMS ≥ 4 in detecting LVO stroke versus a sensitivity of 84.6% (p < 0.0015 for superiority) and specificity of 82.6% (p = 0.81 for superiority) for the device algorithm (CA + LAMS). CONCLUSIONS: Obtaining adequate recordings with a CA headset is highly feasible in the prehospital environment. Use of the device algorithm incorporating both CA and LAMS data for LVO detection resulted in significantly higher sensitivity without reduced specificity when compared to the use of LAMS alone.

Design and Implementation of a Didactic Curriculum in a Large Neonatal-Perinatal Medicine Fellowship Program: A Single-center Experience.

OBJECTIVE: Although the Accreditation Council for Graduate Medical Education and American Board of Pediatrics (ABP) provide regulations and guidance on fellowship didactic education, each program establishes their own didactic schedules to address these learning needs. Wide variation exists in content, educators, amount of protected educational time, and the format for didactic lectures. This inconsistency can contribute to fellow dissatisfaction, a perceived poor learning experience, and poor attendance. Our objective was to create a Neonatal-Perinatal Medicine (NPM) fellow curriculum based on adult learning theory utilizing fellow input to improve the perceived fellow experience. STUDY DESIGN: A needs assessment of current NPM fellows at Cincinnati Children's Hospital was conducted to guide the development of a new curriculum. Fellow perception of educational experience and board preparedness before and after introduction of the new curriculum was collected. Study period was from October 2018 to July 2021. RESULTS: One hundred percent of the fellows responded to the needs assessment survey. A response rate of 100 and 87.5% were noted on mid-curriculum survey and postcurriculum survey, respectively. Key themes identified and incorporated into the curriculum included schedule structure, content, and delivery mode. A new didactic curriculum implementing a consistent schedule of shorter lectures grouped by organ system targeting ABP core content was created. After curriculum implementation, fellows had higher self-perception of board preparedness, and overall improved satisfaction. CONCLUSION: Our positive experience in implementing this curriculum provides a framework for individual programs to implement similar curricula, and could be utilized to aid in development of national NPM curricula. KEY POINTS: · Fellowship didactic education varies significantly resulting in learner dissatisfaction and poor attendance.. · Widespread need to restructure didactic curricula exists.. · Our study provides a framework for future curricula..

Age at diagnosis and diagnostic delay across attention-deficit hyperactivity and autism spectrums.

BACKGROUND: Despite the known benefits of accurate and timely diagnosis for children with attention-deficit hyperactivity disorder and autism spectrum disorders (autism), for some children this goal is not always achieved. Existing research has explored diagnostic delay for autism and attention-deficit hyperactivity disorder only, and when attention-deficit hyperactivity disorder and autism co-occur, autism has been the focus. No study has directly compared age at diagnosis and diagnostic delay for males and females across attention-deficit hyperactivity disorder, autism and specifically, attention-deficit hyperactivity disorder + autism. METHODS: Australian caregivers (N = 677) of children with attention-deficit hyperactivity disorder, autism or attention-deficit hyperactivity disorder + autism were recruited via social media (n = 594) and the Monash Autism and ADHD Genetics and Neurodevelopment Project (n = 83). Caregivers reported on their child's diagnostic process. Diagnostic delay was the mean difference between general initial developmental concerns and the child's attention-deficit hyperactivity disorder and autism diagnosis. RESULTS: Children with autism were significantly younger at autism diagnosis than the attention-deficit hyperactivity disorder + autism group (ηp2 = 0.06), whereas children with attention-deficit hyperactivity disorder were significantly older at attention-deficit hyperactivity disorder diagnosis than the attention-deficit hyperactivity disorder + autism group (ηp2 = 0.01). Delay to attention-deficit hyperactivity disorder and autism diagnosis was significantly longer in the attention-deficit hyperactivity disorder + autism group compared to attention-deficit hyperactivity disorder (ηp2 = 0.02) and autism (η2 = 0.04) only. Delay to autism diagnosis for females with autism (η2 = 0.06) and attention-deficit hyperactivity disorder + autism (η2 = 0.04) was longer compared to males. CONCLUSIONS: Having attention-deficit hyperactivity disorder + autism and being female were associated with longer delays to diagnosis. The reasons for these delays and possible adverse effects on outcomes require further study.

Generation of induced pluripotent stem cell lines from three individuals with autism spectrum disorder.

Uncovering the molecular mechanisms of autism spectrum disorder (autism) necessitates development of relevant experimental models that are capable of recapitulating features of the clinical phenotype. Using non-integrative episomal vectors, peripheral blood mononuclear cells derived from three unrelated individuals diagnosed with autism were reprogrammed to induced pluripotent stem cells (iPSCs). The resultant lines exhibited the expected cellular morphology, karyotype, and evidence of pluripotency. These iPSCs constitute a valuable resource to support investigations of the underlying aetiology of autism.

Multicentre study protocol comparing standard NRP to deveLoped Educational Modules for Resuscitation of Neonates in the Delivery Room with Congenital Heart Disease (LEARN-CHD).

INTRODUCTION: Infants born with critical congenital heart defects (CCHDs) have unique transitional pathophysiology that often requires special resuscitation and management considerations in the delivery room (DR). While much is known about neonatal resuscitation of infants with CCHDs, current neonatal resuscitation guidelines such as the neonatal resuscitation programme (NRP) do not include algorithm modifications or education specific to CCHDs. The implementation of CCHD specific neonatal resuscitation education is further hampered by the large number of healthcare providers (HCPs) that need to be reached. Online learning modules (eLearning) may provide a solution but have not been designed or tested for this specific learning need. Our objective in this study is to design targeted eLearning modules for DR resuscitation of infants with specific CCHDs and compare HCP knowledge and team performance in simulated resuscitations among HCPs exposed to these modules compared with directed CCHD readings. METHODS AND ANALYSIS: In a prospective multicentre trial, HCP proficient in standard NRP education curriculum are randomised to either (a) directed CCHD readings or (b) CCHD eLearning modules developed by the study team. The efficacy of these modules will be evaluated using (a) individual preknowledge/postknowledge testing and (b) team-based resuscitation simulations. ETHICS AND DISSEMINATION: This study protocol is approved by nine participating sites: the Boston Children's Hospital Institutional Review Board (IRB-P00042003), University of Alberta Research Ethics Board (Pro00114424), the Children's Wisconsin IRB (1760009-1), Nationwide Children's Hospital IRB (STUDY00001518), Milwaukee Children's IRB (1760009-1) and University of Texas Southwestern IRB (STU-2021-0457) and is under review at following sites: University of Cincinnati, Children's Healthcare of Atlanta, Children's Hospital of Los Angeles and Children's Mercy-Kansas City. Study results will be disseminated to participating individuals in a lay format and presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals.

Dissecting Schizotypy and Its Association With Cognition and Polygenic Risk for Schizophrenia in a Nonclinical Sample.

Schizotypy is a multidimensional construct that captures a continuum of risk for developing schizophrenia-spectrum psychopathology. Existing 3-factor models of schizotypy, consisting of positive, negative, and disorganized dimensions have yielded mixed evidence of genetic continuity with schizophrenia using polygenic risk scores. Here, we propose an approach that involves splitting positive and negative schizotypy into more specific subdimensions that are phenotypically continuous with distinct positive symptoms and negative symptoms recognized in clinical schizophrenia. We used item response theory to derive high-precision estimates of psychometric schizotypy using 251 self-report items obtained from a non-clinical sample of 727 (424 females) adults. These subdimensions were organized hierarchically using structural equation modeling into 3 empirically independent higher-order dimensions enabling associations with polygenic risk for schizophrenia to be examined at different levels of phenotypic generality and specificity. Results revealed that polygenic risk for schizophrenia was associated with variance specific to delusional experiences (γ = 0.093, P = .001) and reduced social interest and engagement (γ = 0.076, P = .020), and these effects were not mediated via the higher-order general, positive, or negative schizotypy factors. We further fractionated general intellectual functioning into fluid and crystallized intelligence in 446 (246 females) participants that underwent onsite cognitive assessment. Polygenic risk scores explained 3.6% of the variance in crystallized intelligence. Our precision phenotyping approach could be used to enhance the etiologic signal in future genetic association studies and improve the detection and prevention of schizophrenia-spectrum psychopathology.

SARS-CoV-2 RNA positive pediatric organ donors: A case report.

BACKGROUND: Preliminary evidence suggests that non-lung organ donation from resolved, asymptomatic or mildly symptomatic SARS-CoV-2 infected adults may be safe. However, several biological aspects of SARS-CoV-2 infection differ in children and the risk for transmission and outcomes of recipients from pediatric donors with SARS-CoV-2 infection are not well described. METHODS: We report two unvaccinated asymptomatic pediatric non-lung organ deceased donors who tested positive for SARS-CoV-2 RNA by RT-PCR. Donor One unexpectedly had SARS-CoV-2 RNA detected in nasopharyngeal swab and plasma specimens at autopsy despite several negative tests (upper and lower respiratory tract) in the days prior to organ recovery. Donor Two had SARS-CoV- 2 RNA detected in multiple nasopharyngeal swabs but not lower respiratory tract specimens (endotracheal aspirate and bronchoalveolar lavage) during routine surveillance prior to organ recovery and was managed with remdesivir and monoclonal antibodies prior to organ recovery. RESULTS: Two hearts, two livers and four kidneys were successfully transplanted into seven recipients. No donor to recipient transmission of SARS-CoV-2 was observed and graft function of all organs has remained excellent for up to 7 months of followup. CONCLUSIONS: Due to the persistent gap between organ availability and the number of children waiting for transplants, deceased pediatric patients with non-disseminated SARS-CoV-2 infection, isolated to upper and/or lower respiratory tract, should be considered as potential non-lung organ donors.

Understanding the Diversity of Pharmacotherapeutic Management of ADHD With Co-occurring Autism: An Australian Cross-Sectional Survey.

Objectives: Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with other neurodevelopmental diagnoses, such as autism spectrum disorder (autism), which can make clinical decision making around symptom management challenging for clinicians. There is a paucity of research examining pharmacotherapeutic management of children who have ADHD with co-occurring diagnoses. We aimed to report on the co-occurring diagnoses and symptom profile of children, and report on medication use, stratified by ADHD, autism and ADHD + autism diagnoses. Methods and Materials: Caregivers of 505 children (2-18 years) with ADHD (n = 239), autism (n = 117), and co-occurring ADHD + autism (n = 149) completed a questionnaire on current medication use and clinical rating scales about their child's symptoms, as part of a broader project investigating diagnosis and management of symptoms in children with ADHD or autism. Results: The parents of the ADHD group reported a higher proportion of their children had learning disorders (17.15%) and speech and language disorders (4.60%) compared to the parents of the autism and ADHD + autism groups. Parents of the ADHD + autism group reported higher proportions of intellectual disability (5.37%), oppositional defiant disorder (20.13%), anxiety (38.93%), depression (6.71%) and genetic conditions (3.36%) in their children, in comparison to the parents of the ADHD and autism groups. Children with ADHD were reported to be taking a higher proportion of psychotropic medication (90%), followed by ADHD + autism (86%) and autism (39%). The parents of children with ADHD + autism reported a higher proportion of non-stimulant ADHD medication (25.5%), antipsychotic (18.79%), antidepressant (22.15%) and melatonin (31.54%) use by their children, compared to the parents of the ADHD and autism groups. Conclusions: A similar proportion of children with ADHD + autism and ADHD were reported to be taking medication. However, the types of medication taken were different, as expected with reported co-occurring diagnoses. The complexity of symptoms and diagnoses in ADHD + autism warrants targeted research to optimize management and therapeutic outcomes.

Can Neurocognitive Outcomes Assist Measurement-Based Care for Children with Attention-Deficit/Hyperactivity Disorder? A Systematic Review and Meta-Analyses of the Relationships Among the Changes in Neurocognitive Functions and Clinical Outcomes of Attention-Deficit/Hyperactivity Disorder in Pharmacological and Cognitive Training Interventions.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental conditions among school-age children. Early intervention and ongoing evaluation of treatment effectiveness are essential to minimize the life-long negative impact of ADHD. Neurocognitive functions have been reported to improve with pharmacological and cognitive training interventions for children with ADHD. We evaluated the value of measuring change in neurocognitive functions following ADHD interventions as a treatment outcome. We systematically reviewed randomized control trials of two distinctive types of ADHD interventions-pharmacological treatments and cognitive training-and summarized the changes in neurocognitive and clinical outcomes using a series of meta-analyses. Both pharmacological and cognitive training interventions showed positive effects on some aspects of neurocognitive functions. However, there were no significant correlations between changes in neurocognitive function (e.g., inhibition) and changes in ADHD behavioral symptoms (e.g., impulsive behavior). Although the associations between changes in neurocognitive function and clinical outcomes are not well studied, based on current findings, it is not suitable to use change in neurocognitive outcomes as a proxy for change in ADHD clinical symptom-based outcomes. There is, however, notable value in monitoring changes in neurocognitive function associated with ADHD interventions to achieve the following aims: (1) understanding full treatment effect on children with ADHD, (2) identifying ancillary indicators of subclinical changes, and (3) provision of objective and less biased measures of treatment effects. These findings are important evidence that changes in neurocognitive function could be a co-occurring objective indication that parallels the clinical effects of ADHD treatments.

Identifying Gaps in Resuscitation Practices Across Level-IV Neonatal Intensive Care Units.

OBJECTIVE: This study aimed to describe resuscitation practices in level-IV neonatal intensive care units (NICUs) and identify possible areas of improvement. STUDY DESIGN: This study was a cross-sectional cohort survey and conducted at the Level-IV NICUs of Children's Hospital Neonatal Consortium (CHNC). The survey was developed with consensus from resuscitation and education experts in the CHNC and pilot tested. An electronic survey was sent to individual site sponsors to determine unit demographics, resuscitation team composition, and resuscitation-related clinical practices. RESULTS: Of the sites surveyed, 33 of 34 sites responded. Unit average daily census ranged from less than 30 to greater than 100, with the majority (72%) of the sites between 30 and 75 patients. A designated code response team was utilized in 18% of NICUs, only 30% assigned roles before or during codes. The Neonatal Resuscitation Program (NRP) was the exclusive algorithm used during codes in 61% of NICUs, and 34% used a combination of NRP and the Pediatric Advanced Life Support (PALS). Most (81%) of the sites required neonatal attendings to maintain NRP training. A third of sites (36%) lacked protocols for high-acuity events. A code review process existed in 76% of participating NICUs, but only 9% of centers enter code data into a national database. CONCLUSION: There is variability among units regarding designated code team presence and composition, resuscitation algorithm, protocols for high-acuity events, and event review. These inconsistencies in resuscitation teams and practices provide an opportunity for standardization and, ultimately, improved resuscitation performance. Resources, education, and efforts could be directed to these areas to potentially impact future neonatal outcomes of the complex patients cared for in level-IV NICUs. KEY POINTS: · Resuscitation practice is variable in level-IV NICUs.. · Resuscitation algorithm training is not uniform. · Standardized protocols for high-acuity low-occurrence (HALO) events are lacking.

Examining the neural correlates of error awareness in a large fMRI study.

Goal-directed behavior is dependent upon the ability to detect errors and implement appropriate posterror adjustments. Accordingly, several studies have explored the neural activity underlying error-monitoring processes, identifying the insula cortex as crucial for error awareness and reporting mixed findings with respect to the anterior cingulate cortex (ACC). Variable patterns of activation have previously been attributed to insufficient statistical power. We therefore sought to clarify the neural correlates of error awareness in a large event-related functional magnetic resonance imaging (fMRI) study. Four hundred and two healthy participants undertook the error awareness task, a motor Go/No-Go response inhibition paradigm in which participants were required to indicate their awareness of commission errors. Compared to unaware errors, aware errors were accompanied by significantly greater activity in a network of regions, including the insula cortex, supramarginal gyrus (SMG), and midline structures, such as the ACC and supplementary motor area (SMA). Error awareness activity was related to indices of task performance and dimensional measures of psychopathology in selected regions, including the insula, SMG, and SMA. Taken together, we identified a robust and reliable neural network associated with error awareness.

Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits.

LAY ABSTRACT: Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients.

An Australian Cross-Sectional Survey of Parents' Experiences of Emergency Department Visits Among Children with Autism Spectrum Disorder.

Parents of children with ASD who had attended an Australian emergency department (ED; n = 421) completed a questionnaire relating to their experiences in the ED, including (1) child's reason for presentation and existing comorbidities, (2) quality of care during the visit (3) child's behaviour during visit, e.g. sensory responses to the ED environment, and disruptive behaviours. Children with comorbid ASD and intellectual disability were more likely to present with gastrointestinal issues and seizures, while those with comorbid ASD and oppositional defiant disorder were more likely to present with self-injury. ED staff awareness of ASD-related issues, including communication and expression of pain, were common difficulties for parents. The ED environment (e.g. lights, sounds, waiting areas), exacerbated child anxiety and led to disruptive behaviour.

Oculomotor deficits in attention deficit hyperactivity disorder (ADHD): A systematic review and comprehensive meta-analysis.

Atypical motor coordination and cognitive processes, such as response inhibition and working memory, have been extensively researched in individuals with attention deficit hyperactivity disorder (ADHD). Oculomotor neural circuits overlap extensively with regions involved in motor planning and cognition, therefore studies of oculomotor function may offer unique insights into motor and cognitive control in ADHD. We performed a series of pairwise meta-analyses based on data from 26 oculomotor studies in ADHD to examine whether there were differences in performance on visually-guided saccade, gap, antisaccade, memory-guided, pursuit eye movements and fixation tasks. These analyses revealed oculomotor disturbances in ADHD, particularly for difficulties relating to saccade inhibition, memorizing visual target locations and initiating antisaccades. There was no evidence for pursuit eye movement disturbances or saccade dysmetria. Investigating oculomotor abnormalities in ADHD may provide insight into top-down cognitive control processes and motor control, and may serve as a promising biomarker in ADHD research and clinical practice.

The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project design and methodologies: a dimensional approach to understanding neurobiological and genetic aetiology.

BACKGROUND: ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has hampered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters; and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters. METHODS: The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics. CONCLUSION: The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.

Genetic influences on hub connectivity of the human connectome.

Brain network hubs are both highly connected and highly inter-connected, forming a critical communication backbone for coherent neural dynamics. The mechanisms driving this organization are poorly understood. Using diffusion-weighted magnetic resonance imaging in twins, we identify a major role for genes, showing that they preferentially influence connectivity strength between network hubs of the human connectome. Using transcriptomic atlas data, we show that connected hubs demonstrate tight coupling of transcriptional activity related to metabolic and cytoarchitectonic similarity. Finally, comparing over thirteen generative models of network growth, we show that purely stochastic processes cannot explain the precise wiring patterns of hubs, and that model performance can be improved by incorporating genetic constraints. Our findings indicate that genes play a strong and preferential role in shaping the functionally valuable, metabolically costly connections between connectome hubs.