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Introduction: Individuals on the autism spectrum (ASD) often experience poor mental health and coping strategies compared to their peers due to social exclusion and co-occurring conditions. Resiliency has been identified as a key factor in preventing adverse outcomes and promoting mental health. Therefore, it is important to determine what strategies can be used to build resiliency among autistic individuals. The current paper is one of the first studies that aims to collect information from autistic individuals and their caregivers on potential strategies to enhance resiliency. Methods: We interviewed 18 participants from various provinces in Canada, comprising of 13 autistic individuals and 5 parents. We used thematic analysis to identify patterns in the data. Results: Thematic analysis revealed three themes to indicate strategies that could be used to enhance resiliency, including: (a) self-reliant strategies, (b) using community-based facilities, and (c) contextual and individual characteristics. Conclusion: Although the body of literature on resiliency is evolving, this paper provides a unique perspective as it is one of the few studies that considers the experiences of individuals on the spectrum. In addition, this study focuses on identifying and describing specific strategies that can be used to enhance resiliency and mental health, which consequently can help address the existing gaps in knowledge and practice. [ABSTRACT FROM AUTHOR]

Autism is a neurodevelopmental condition, behaviourally identified, which is generally characterised by social communication differences, and restrictive and repetitive patterns of behaviour and interests. It has long been claimed that it is more common in males. This observed preponderance of males in autistic populations has served as a focussing framework in all spheres of autism-related issues, from recognition and diagnosis through to theoretical models and research agendas. One related issue is the near total absence of females in key research areas. For example, this paper reports a review of over 120 brain-imaging studies of social brain processes in autism that reveals that nearly 70% only included male participants or minimal numbers (just one or two) of females. Authors of such studies very rarely report that their cohorts are virtually female-free and discuss their findings as though applicable to all autistic individuals. The absence of females can be linked to exclusionary consequences of autism diagnostic procedures, which have mainly been developed on male-only cohorts. There is clear evidence that disproportionately large numbers of females do not meet diagnostic criteria and are then excluded from ongoing autism research. Another issue is a long-standing assumption that the female autism phenotype is broadly equivalent to that of the male autism phenotype. Thus, models derived from male-based studies could be applicable to females. However, it is now emerging that certain patterns of social behaviour may be very different in females. This includes a specific type of social behaviour called camouflaging or masking, linked to attempts to disguise autistic characteristics. With respect to research in the field of sex/gender cognitive neuroscience, there is emerging evidence of female differences in patterns of connectivity and/or activation in the social brain that are at odds with those reported in previous, male-only studies. Decades of research have excluded or overlooked females on the autistic spectrum, resulting in the construction of inaccurate and misleading cognitive neuroscience models, and missed opportunities to explore the brain bases of this highly complex condition. A note of warning needs to be sounded about inferences drawn from past research, but if future research addresses this problem of male bias, then a deeper understanding of autism as a whole, as well as in previously overlooked females, will start to emerge. Plain Language Summary: Autism is a neurodevelopmental condition, behaviourally identified, which is generally characterised by social communication differences, and restrictive and repetitive patterns of behaviour and interests. It has long been claimed that it is more common in males, with oft-quoted ratios of 4M: 1F. This has been reflected in the development of diagnostic criteria for autism and, consequently, of measures of eligibility for autism research programmes, with females being (as is now emerging) disproportionately excluded. As outlined in this review, this issue has been particularly problematic in brain-based studies of autism. Many studies have only tested male autistic participants, or minimal numbers of autistic females. By default, sex differences were not examined. But the impression given by such research reports has commonly been that the findings would be applicable to all autistic individuals. Recent psychological and clinical research has shown that there are a significant number of autistic females who have been missed by traditional diagnostic practices. Their inclusion has increased their eligibility for autism research studies. With respect to brain research, it has become possible to devise studies with matched numbers of autistic females and males, and to replicate studies that have previously only tested males. Newly emerging findings from such studies are demonstrating that the 'robust' autism-related differences previously observed in autistic male-only cohorts do not fully generalise to autistic females. It will be necessary to exercise caution in drawing inferences from previous male-biased studies of the autistic brain. However, the identification and inclusion of previously excluded female autistic participants hopefully offers more accurate insights into this highly complex and heterogeneous condition. Highlights: Several decades of neuroimaging research into autism has been based almost entirely on males; even big data sets show strong evidence of male bias. There is clear evidence that autistic females are being excluded from the research process by failures in diagnostic practices that have been developed on male-biased cohorts. Models of autism which inform research protocols are based on male autism phenotypes; it appears to have been assumed that the substantially fewer females that are diagnosed will present with equivalent, if milder, patterns of autistic differences. Newly emerging findings from social cognitive neuroscience research studies investigating sex/gender differences in autistic behaviour and associated biological correlates are demonstrating that the 'robust' autism-related differences previously observed in autistic male-only cohorts do not fully generalise to autistic females. Autism research programmes should prioritise the exploration of sex/gender effects. [ABSTRACT FROM AUTHOR]

Background: A rise in the reported numbers of children with Autism Spectrum Disorder (ASD) highlights the need for dental practitioners to be more familiar with the treatment approaches for these special needs children to ensure comfortable, well-accepted and efficient management while in dental office. Aim: This paper aimed to acquire a deeper understanding of some of the innovative and best approaches to managing children with ASD in dental settings. Design: A systematic literature search was performed in PubMed, Scopus, Web of Science, Cochrane databases, and grey literature based on the PRISMA 2020 statement, using main keywords such as: 'management', 'dental', 'children', and 'Autism Spectrum Disorder'. Original full-text papers including randomised controlled trials (RCT) and all other designs of non-randomised controlled studies (NRS) reporting relevant intervention studies in English were included without any publication time limit. The quality of the evidence found eligible for the review were then assessed using the ROB-2 and ROBINS-I tools. Subsequently, the details of management interventions and impact of treatment approaches were compared and discussed. Results: Out of the 204 articles found, 109 unrelated articles were excluded during the initial screening. The full papers of remaining 28 were retrieved and only 15 (7%) articles were eligible to be reviewed; eight RCTs with 'some concerns' and 'high risk' categories particularly concerning their randomisation design, and seven NSRs with 'serious' to 'critical' bias largely due to confounding factors. Conclusion: Our review found inconclusive evidence on the strength of recent psychological and non-pharmacological approaches used to manage children with ASD in dental settings. Small sample size and lack of a control group in certain studies affected the strength of evidence and credibility of the findings. Nevertheless, this review shared informative details on some innovative approaches for better understanding of the management of children with ASD for dental professionals. [ABSTRACT FROM AUTHOR]

Background: We evaluated the clinical and cost-effectiveness of manualised sensory integration therapy (SIT) for autistic children with sensory processing difficulties in a two-arm randomised controlled trial. Trial processes and contextual factors which may have affected intervention outcomes were explored within a nested process evaluation. This paper details the process evaluation methods and results. We also discuss implications for evaluation of individual level, tailored interventions in similar populations. Methods: The process evaluation was conducted in line with Medical Research Council guidance. Recruitment, demographics, retention, adherence, and adverse effects are reported using descriptive statistics. Fidelity of intervention delivery is reported according to the intervention scoring manual. Qualitative interviews with therapists and carers were undertaken to explore the acceptability of the intervention and trial processes. Qualitative interviews with carers explored potential contamination. Results: Recruitment, reach and retention within the trial met expected thresholds. One hundred thirty-eight children and carers were recruited (92% of those screened and 53.5% of those who expressed an interest) with 77.5% retained at 6 months and 69.9% at 12 months post-randomisation. The intervention was delivered with structural and process fidelity with the majority (78.3%) receiving a 'sufficient dose' of intervention. However, there was considerable individual variability in the receipt of sessions. Carers and therapists reported that trial processes were generally acceptable though logistical challenges such as appointment times, travel and COVID restrictions were frequent barriers to receiving the intervention. No adverse effects were reported. Conclusions: The process evaluation was highly valuable in identifying contextual factors that could impact the effectiveness of this individualised intervention. Rigorous evaluations of interventions for autistic children are important, especially given the limitations such as limited sample sizes and short-term follow-up as faced by previous research. One of the challenges lies in the variability of outcomes considered important by caregivers, as each autistic child faces unique challenges. It is crucial to consider the role of parents or other caregivers in facilitating access to these interventions and how this may impact effectiveness. Trial registration: This trial is registered as ISRCTN14716440. August 11, 2016. [ABSTRACT FROM AUTHOR]

Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. Methods: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1–2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. Discussion: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. Trial registration: ISRCTN, ISRCTN15984604. Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021. [ABSTRACT FROM AUTHOR]

Background: Recent systematic reviews have indicated that cognitive behavioral therapy (CBT) is effective in reducing anxiety symptoms for autistic and non-autistic children. However, the vast majority of CBT research for autistic youth has been implemented within university settings and primarily by mental health providers. Schools hold great promise to equitably manage the mental health symptoms of autistic youth. Although preliminary research evaluating CBT within schools has been promising, CBT has not yet been compared to another readily available school mental health program. The goal of this protocol paper is to describe a multi-site study comparing two school-based interventions, Facing Your Fears-School Based (FYF-SB) and Zones of Regulation (ZOR) via a cluster randomized controlled type 1 hybrid effectiveness-implementation trial to determine which of the two interventions will best support autistic youth with anxiety in schools. Methods: Up to 100 elementary and middle schools will be randomized into FYF-SB or ZOR. Once schools are randomized, a minimum of two interdisciplinary school providers at each school will be trained to deliver either FYF-SB or ZOR over the course of 12 weeks to groups of 2–5 autistic students ages 8–14 years. Over the course of two years, a total of 200 autistic students will receive either ZOR or FYF-SB. The primary outcome of this trial is child anxiety, as rated by masked evaluators and via caregiver- and student-report, which will be measured at baseline, post-treatment, and 6-month follow-up. Semi-structured interviews will also be conducted with a purposive sample of students, caregivers, and school providers to understand the acceptability, appropriateness, and feasibility of either ZOR or FYF-SB. Stakeholder engagement is a central component of this project via two stakeholder advisory boards that will directly inform and oversee the project. Discussion: Results of this study will provide evidence about the relative impact of two school-based mental health interventions on outcomes reported as meaningful by caregivers and school providers. The additional focus on evaluating factors that support the implementation of FYF-SB and ZOR will allow future studies to test targeted implementation strategies that support mental health programming uptake and implementation within public schools. Trial registration: This trial is registered with clinicaltrials.gov (NCT05863520). [ABSTRACT FROM AUTHOR]

Background: Individuals with autism spectrum disorder (ASD) are more likely to use healthcare than their counterparts without disabilities, which imposes high medical costs to families and health systems. This study aimed to investigate healthcare costs and its determinants among individuals with ASD.Methods: In this systematic review, we searched online databases (Web of Science, Medline through PubMed and Scopus) for observational and experimental studies that included data on service use and costs associated with ASD and published between January 2000 and May 2021. Exclusion criteria included non-English language articles, duplicates, abstracts, qualitative studies, gray literature, and non-original papers (e.g., letters to editors, editorials, reviews, etc.).Results: Our searches yielded 4015 articles screened according to PRISMA guidelines. Of 4015 studies identified, 37 articles from 10 countries were eligible for final inclusion. Therapeutic interventions, outpatient visits and medications constituted the largest proportion of direct medical expenditure on individuals with ASD. Included studies suggest lack of health insurance, having associated morbidities, more severe symptoms, younger age groups and lower socioeconomic status (SES) are associated with higher medical expenditure in individuals with ASD.Conclusions: This systematic review identified a range of factors, including lower SES and lack of health insurance, which are associated with higher healthcare costs in people with ASD. Our study supports the formulation of policy options to reduce financial risks in families of individuals with ASD in countries which do not have a tax-based or universal health coverage system. [ABSTRACT FROM AUTHOR]

Background: Various parent training interventions have been shown to have some effect on the symptoms of children with autism. We carried out a systematic review and meta-analyses to assess effectiveness of parental training for children with autism on their symptoms and parental stress. Methods: Four electronic databases, CINAHL, EMBASE, MEDLINE and PsycINFO were searched until March 2020 for relevant literature. Two reviewers independently screened bibliographies using an eligibility checklist and extracted data using a structured proforma. We have also carried out meta-analyses when data were available for pooling. Results: Seventeen papers from 15 studies were included for data analysis. Fifteen papers showed a positive treatment effect when compared with the control group, although not always significant. Meta-analysis based on pooled data from only two studies in each respective intervention, showed small to moderate treatment effects for three interventions, DIR/Floortime, Pivotal Response and Parent focused training respectively. Conclusions: As in previous systematic reviews there was a mild to moderate treatment effects of three specific types of interventions respectively. However, it was difficult to draw any definitive conclusion about the effectiveness and generalisability of any intervention because of the wide variation in the interventions, control groups, outcome measures, small sample size, small number of studies in meta-analysis, overlap between the intervention and control procedures used in the included studies. There is an urgent need for experts in various international centres to jointly standardise a parent training intervention for children with autism and carry out a large scale RCT to assess its clinical and economic effectiveness. Research Registry Unique Identifying Number: reviewregistry915. [ABSTRACT FROM AUTHOR]

Background: To estimate the prevalence of malocclusion in individuals with autism spectrum disorders (ASD) and to assess the relationship between ASD and malocclusion. Methods: We searched electronic databases including PubMed, Scopus, Web of Science, Cochrane, Embase, SciELO LILACS, Proquest, OpenGrey and Google Scholar. There were no language or publication dates restrictions. Two researchers independently performed selection, data extraction and quality assessment. Quality assessment and risk of bias were evaluated through the Newcastle–Ottawa scale and ROBINS-E tool. Meta-analyses using random effect models were used to estimate pooled measures of prevalence of malocclusion characteristics in individuals with ASD and pooled odds ratio (OR) on the relationship between ASD and malocclusion characteristics. Subgroup meta-analyses were conducted according to children and adolescents, history of orthodontic treatment, and occurrence of other syndromes and medical conditions. Results: Searching identified 5549 papers with 238 were selected for full assessment. Eighteen cross-sectional studies were included according to inclusion criteria. Of them, eleven studies were considered of moderate quality. A judgement of critical risk of bias occurred for thirteen studies. The most prevalent malocclusion characteristics in individuals with ASD were crowding (33%; 95% CI 22 to 44%) and increased maxillary overjet (39%; 95% CI 23 to 54%). Individuals with ASD had higher odds of Angle's Class II (OR 1.92; 95% CI 1.36 to 2.72), Angle's Class III (OR 2.33; 95% CI 1.29 to 4.23), open bite (OR 1.96; 95% CI 1.21 to 3.16), and increased maxillary overjet (OR 1.53; 95% CI 1.06 to 2.21) than individuals without ASD. Conclusions: Angle's Class II, Angle's Class III, anterior open bite and increased maxillary overjet were more prevalent in individuals with ASD than those without ASD. Further high-quality studies are needed. [ABSTRACT FROM AUTHOR]

Background: There are a growing number of evidence-based interventions (EBIs) for autistic individuals, but few are successfully implemented with fidelity in under-resourced communities and with families from traditionally disenfranchised groups. Implementation science offers tools to increase EBI use in communities, but most implementation strategies are designed specific to a single EBI. It is not feasible to develop a new implementation strategy each time a new EBI is introduced in the community. Therefore, to test the effectiveness and generalizability of implementation strategies we are developing and testing a multifaceted implementation strategy with three EBIs concurrently. The goal of this protocol paper is to describe the randomized field trial of an implementation strategy for use across autism EBIs, diverse settings and participants, with the goal of increasing rapid uptake of effective practices to reach our most vulnerable children. Methods: We developed a multifaceted implementation strategy called Using Novel Implementation Tools for Evidence-based intervention Delivery (UNITED) to facilitate the implementation and sustainment of three EBIs in under-resourced settings. We will compare fidelity to, and effectiveness of, each intervention [Mind the Gap (MTG), Remaking Recess (RR), Self-Determined Learning Model of Instruction (SDLMI)] with and without UNITED in a randomized field trial. Randomization will be stratified using a minimization allocation method. We will train community practitioners using remote delivery of modules specific to the intervention, and active coaching via Zoom for at least 6 sessions and up to 12 as dictated by each EBI. Our primary outcome is fidelity to each EBI, and our secondary outcome is at the child or family level (family empowerment for MTG, child peer social engagement for RR, and adolescent self-determination for SDLMI, respectively). We will measure progress through the implementation phases using the Stages of Implementation Completion and cost-effectiveness of UNITED. Discussion: The results of this study will provide rigorous data on the effectiveness and generalizability of one relatively light-touch implementation strategy in increasing use of autism EBIs and associated outcomes in diverse under resourced public service settings for underrepresented autistic youth. Trial registration: Mind the Gap: Clinicaltrials.gov Identifier: NCT04972825 (Date registered July 22, 2021); Remaking Recess: Clinicaltrials.gov Identifier: NCT04972838 (Date registered July 22, 2021); Self-Determined Learning Model of Instruction: Clinicaltrials.gov Identifier: NCT04972851 (Date registered July 22, 2021). [ABSTRACT FROM AUTHOR]

Background: This paper aimed to describe the diagnostic service trajectory of families of children with autism or intellectual disability in the province of Québec and identify predictors of parents' perceptions of its quality.Methods: The Evaluation of the services Trajectory in Autism by Parents instrument was completed by 259 parents at an assessment clinic. Children's clinical records were also examined.Results: On average 26 months elapsed between their first concerns and their child's diagnosis, a period during which few (25%) received support. Parents' evaluations were generally positive but were lower for the accessibility of the pre-assessment phase and the flexibility of the assessment process. Longer delays and a greater number of professionals consulted were associated with lower quality ratings. Some language-, immigration status-, and income-related differences in families' appraisals were noted.Conclusion: The diagnostic trajectory for neurodevelopmental disorders within public services in Québec presents some efficiency and accessibility challenges. Possible improvements are proposed to facilitate screening and to support families throughout this phase of their trajectory. [ABSTRACT FROM AUTHOR]

Background: Individuals on the autism spectrum face significant disparities in health and physicians often report difficulties in providing care to autistic patients. In order to improve the quality of care autistic individuals receive, it is important to identify the barriers that physicians experience in providing care so that these may be addressed. This paper reports the initial development and preliminary evaluation of a physician-report 'Barriers to Providing Healthcare' measurement tool.Method: An established taxonomy of healthcare barriers for autistic individuals informed the initial draft of a 22-item measurement tool. This measurement tool was distributed to physicians working in various healthcare specialties and settings. Exploratory factor analysis (EFA) was conducted to determine the construct validity of the tool; discriminant validity between, and internal consistency of, the resultant factors were assessed. Multiple regressions were used to explore variables potentially associated with barriers endorsed by physicians.Results: A total of 203 physicians were included in the analyses. The EFA resulted in a 17-item tool with three distinct factors which explained 37.6% of the variance: 1) Patient-related barriers (Cronbach's α = 0.83; e.g., the patient's reactivity to the healthcare environment); 2) Healthcare provider (HCP)/family-related barriers (Cronbach's α = 0.81; e.g., a lack of providers willing to work with autistic patients); and 3) System-related barriers (Cronbach's α = 0.84; e.g., there is a lack of support for patients and families). Discriminant validity between the factors was adequate (r < .8). The barriers that were most frequently endorsed as occurring 'often' or 'very often' included a lack of support for patients and families (endorsed by 79.9% of physicians); communication difficulties (73.4%); and a lack of coordination between services (69.9%). The regression analyses identified no significant associated variables.Conclusion: A preliminary version of a novel physician-report tool to assess barriers to providing care to autistic patients has been developed although further validation work is required. The use of this tool will help physicians to identify issues specific to different medical specialities and healthcare settings. This information may help identify the supports physicians require to recognise and implement the required accommodations. Future research which elucidates barriers to healthcare provision for autistic patients is required to support systemic change in healthcare so as to improve care experiences and health outcomes for people on the autism spectrum. [ABSTRACT FROM AUTHOR]

Background: The Early Markers for Autism (EMA) study is a population-based case–control study designed to learn more about early biologic processes involved in ASD. Methods: Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD (n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions. Results: EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels. Limitations: Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced. Conclusions: Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) and schizotypal disorder (SD) both have a heterogenous presentation, with significant overlaps in symptoms and behaviour. Due to elevated recognition and knowledge of ASD worldwide, there is a growing rate of referrals from primary health professionals to specialised units. At all levels of assessment, the differential diagnostic considerations between ASD and SD exert major challenges for clinicians. Although several validated screening questionnaires exist for ASD and SD, none have differential diagnostic properties. Accordingly, in this study, we aim to develop a new screening questionnaire, the schiZotypy Autism Questionnaire (ZAQ), which provides a combined screening for both conditions, while also indicating the relative likelihood of each. Methods: We aim to test 200 autistic patients and 100 schizotypy patients recruited from specialised psychiatric clinics and 200 controls from the general population (Phase 1). The results from ZAQ will be compared to the clinical diagnoses from interdisciplinary teams at specialised psychiatric clinics. After this initial testing phase, the ZAQ will be validated in an independent sample (Phase 2). Conclusions: The aim of the study is to investigate the discriminative properties (ASD vs. SD), diagnostic accuracy, and validity of the schiZotypy Autism Questionnaire (ZAQ). Funding: Funding was provided by Psychiatric Centre Glostrup, Copenhagen Denmark, Sofiefonden (Grant number: FID4107425), Trygfonden (Grant number:153588), Takeda Pharma. Trial registration: Clinical Trials, NCT05213286, Registered 28 January 2022, clinicaltrials.gov/ct2/show/NCT05213286?cond = RAADS&draw = 2&rank = 1. [ABSTRACT FROM AUTHOR]

Background: Machine learning (ML) algorithms and methods offer great tools to analyze large complex genomic datasets. Our goal was to compare the genomic architecture of schizophrenia (SCZ) and autism spectrum disorder (ASD) using ML. Methods: In this paper, we used regularized gradient boosted machines to analyze whole-exome sequencing (WES) data from individuals SCZ and ASD in order to identify important distinguishing genetic features. We further demonstrated a method of gene clustering to highlight which subsets of genes identified by the ML algorithm are mutated concurrently in affected individuals and are central to each disease (i.e., ASD vs. SCZ "hub" genes). Results: In summary, after correcting for population structure, we found that SCZ and ASD cases could be successfully separated based on genetic information, with 86–88% accuracy on the testing dataset. Through bioinformatic analysis, we explored if combinations of genes concurrently mutated in patients with the same condition ("hub" genes) belong to specific pathways. Several themes were found to be associated with ASD, including calcium ion transmembrane transport, immune system/inflammation, synapse organization, and retinoid metabolic process. Moreover, ion transmembrane transport, neurotransmitter transport, and microtubule/cytoskeleton processes were highlighted for SCZ. Conclusions: Our manuscript introduces a novel comparative approach for studying the genetic architecture of genetically related diseases with complex inheritance and highlights genetic similarities and differences between ASD and SCZ. [ABSTRACT FROM AUTHOR]

Lyvin Tat and Noemi Cannizzaro contributed equally to this paper B Correction: Molecular Autism (2022) 13:27 b . https://doi.org/10.1186/s13229-022-00508-3 Following publication of the original article [[1]], the authors reported that the 4th author (Alexios A. Panoutsopoulos) was omitted from the author group. WDFY3 mutation alters laminar position and morphology of cortical neurons. [Extracted from the article]

Microglial abnormality and heterogeneity are observed in autism spectrum disorder (ASD) patients and animal models of ASD. Microglial depletion by colony stimulating factor 1-receptor (CSF1R) inhibition has been proved to improve autism-like behaviors in maternal immune activation mouse offspring. However, it is unclear whether CSF1R inhibition has extensive effectiveness and pharmacological heterogeneity in treating autism models caused by genetic and environmental risk factors. Here, we report pharmacological functions and cellular mechanisms of PLX5622, a small-molecule CSF1R inhibitor, in treating Cntnap2 knockout and valproic acid (VPA)-exposed autism model mice. For the Cntnap2 knockout mice, PLX5622 can improve their social ability and reciprocal social behavior, slow down their hyperactivity in open field and repetitive grooming behavior, and enhance their nesting ability. For the VPA model mice, PLX5622 can enhance their social ability and social novelty, and alleviate their anxiety behavior, repetitive and stereotyped autism-like behaviors such as grooming and marble burying. At the cellular level, PLX5622 restores the morphology and/or number of microglia in the somatosensory cortex, striatum, and hippocampal CA1 regions of the two models. Specially, PLX5622 corrects neurophysiological abnormalities in the striatum of the Cntnap2 knockout mice, and in the somatosensory cortex, striatum, and hippocampal CA1 regions of the VPA model mice. Incidentally, microglial dynamic changes in the VPA model mice are also reported. Our study demonstrates that microglial depletion and repopulation by transient CSF1R inhibition is effective, and however, has differential pharmacological functions and cellular mechanisms in rescuing behavioral deficits in the two autism models. [ABSTRACT FROM AUTHOR]

Background: Children with Neurofibromatosis 1 (NF1) show cognitive, behavioural and social differences compared to their peers. However, the age and sequence at which these differences begin to emerge is not fully understood. This prospective cohort study examines the cognitive, behavioural, ADHD trait and autism symptom development in infant and pre-school children with NF1 compared with typically developing (TD) children without a family history of neurodevelopmental conditions. Methods: Data from standardised tests was gathered at 5, 10, 14, 24 and 36 months of age (NF1 n = 35, TD n = 29). Developmental trajectories of cognitive (Mullen Scales of Early Learning, MSEL) and adaptive behavioural (Vineland Adaptive Behavior Scales, VABS) development from 5 to 36 months were analysed using linear mixed modelling. Measures of ADHD (Child Behavior Checklist) and autism traits (ADOS-2, BOSA-MV and ADI-R) were assessed at 24 and 36 months. Results: The developmental trajectory of cognitive skills (all domains of the MSEL) and behavioural skills (four domains of the VABS) differed significantly between NF1 and TD groups. Post-hoc tests demonstrated that the NF1 participants scored significantly lower than TD participants at 24 months on all MSEL and VABS domains. The NF1 cohort demonstrated higher mean autism and ADHD traits at 24 months and 14% of the NF1 cohort met a research diagnostic classification for autism at 36 months. Limitations: The study has a relatively small sample size due to variable retention and rolling recruitment. Due to limitations imposed by the COVID-19 pandemic, we utilised the Brief Observation of Symptoms of Autism for Minimally Verbal children (BOSA-MV) for some participants, which was administered online and may not gather as accurate a picture of traits as ADOS-2. The BOSA-MV was utilised for 41% of participants with NF1 at 36 months compared to 11% at 24 months. This may explain the reduction in the percentage of children with NF1 that met autism criteria at 36 months. Conclusions: By 24 months of age, the NF1 cohort show lower cognitive skills and adaptive behaviour and higher levels of autism and ADHD traits as compared to TD children. This has implications for developmental monitoring and referral for early interventions. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Background: Phenotypic heterogeneity in early language, intellectual, motor, and adaptive functioning (LIMA) features are amongst the most striking features that distinguish different types of autistic individuals. Yet the current diagnostic criteria uses a single label of autism and implicitly emphasizes what individuals have in common as core social-communicative and restricted repetitive behavior difficulties. Subtype labels based on the non-core LIMA features may help to more meaningfully distinguish types of autisms with differing developmental paths and differential underlying biology. Methods: Unsupervised data-driven subtypes were identified using stability-based relative clustering validation on publicly available Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS) data (n = 615; age = 24–68 months) from the National Institute of Mental Health Data Archive (NDA). Differential developmental trajectories between subtypes were tested on longitudinal data from NDA and from an independent in-house dataset from UCSD. A subset of the UCSD dataset was also tested for subtype differences in functional and structural neuroimaging phenotypes and relationships with blood gene expression. The current subtyping model was also compared to early language outcome subtypes derived from past work. Results: Two autism subtypes can be identified based on early phenotypic LIMA features. These data-driven subtypes are robust in the population and can be identified in independent data with 98% accuracy. The subtypes can be described as Type I versus Type II autisms differentiated by relatively high versus low scores on LIMA features. These two types of autisms are also distinguished by different developmental trajectories over the first decade of life. Finally, these two types of autisms reveal striking differences in functional and structural neuroimaging phenotypes and their relationships with gene expression and may highlight unique biological mechanisms. Limitations: Sample sizes for the neuroimaging and gene expression dataset are relatively small and require further independent replication. The current work is also limited to subtyping based on MSEL and VABS phenotypic measures. Conclusions: This work emphasizes the potential importance of stratifying autism by a Type I versus Type II distinction focused on LIMA features and which may be of high prognostic and biological significance. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism. Methods: On gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed. Results: Male offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group. Conclusions: The research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD. [ABSTRACT FROM AUTHOR]

Background: The 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. Methods: This 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. Discussion: This 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 registration: Clinicaltrials.gov identifier number NCT06005285. Registered on August 21, 2023. Protocol version: Issue date 6 August 2024; Protocol amendment number: 02. [ABSTRACT FROM AUTHOR]

Background : Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex. Methods: To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family. Results: We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females. Conclusions: Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism's genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is globally increasing in prevalence. The rise of ASD can be partially attributed to diagnostic expansion and advocacy efforts; however, the interplay between genetic predisposition and modern environmental exposures is likely driving a true increase in incidence. A range of evidence indicates that prenatal exposures are critical. Infection during pregnancy, gestational diabetes, and maternal obesity are established risk factors for ASD. Emerging areas of research include the effects of maternal use of selective serotonin reuptake inhibitors, antibiotics, and exposure to toxicants during pregnancy on brain development and subsequent ASD. The underlying pathways of these risk factors remain uncertain, with varying levels of evidence implicating immune dysregulation, mitochondrial dysfunction, oxidative stress, gut microbiome alterations, and hormonal disruptions. This narrative review assesses the evidence of contributing prenatal environmental factors for ASD and associated mechanisms as potential targets for novel prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Motor difficulties are common in many, but not all, autistic individuals. These difficulties can co-occur with other problems, such as delays in language, intellectual, and adaptive functioning. Biological mechanisms underpinning such difficulties are less well understood. Poor motor skills tend to be more common in individuals carrying highly penetrant rare genetic mutations. Such mechanisms may have downstream consequences of altering neurophysiological excitation-inhibition balance and lead to enhanced behavioral motor noise. Methods: This study combined publicly available and in-house datasets of autistic (n = 156), typically-developing (TD, n = 149), and developmental coordination disorder (DCD, n = 23) children (age 3–16 years). Autism motor subtypes were identified based on patterns of motor abilities measured from the Movement Assessment Battery for Children 2nd edition. Stability-based relative clustering validation was used to identify autism motor subtypes and evaluate generalization accuracy in held-out data. Autism motor subtypes were tested for differences in motor noise, operationalized as the degree of dissimilarity between repeated motor kinematic trajectories recorded during a simple reach-to-drop task. Results: Relatively 'high' (n = 87) versus 'low' (n = 69) autism motor subtypes could be detected and which generalize with 89% accuracy in held-out data. The relatively 'low' subtype was lower in general intellectual ability and older at age of independent walking, but did not differ in age at first words or autistic traits or symptomatology. Motor noise was considerably higher in the 'low' subtype compared to 'high' (Cohen's d = 0.77) or TD children (Cohen's d = 0.85), but similar between autism 'high' and TD children (Cohen's d = 0.08). Enhanced motor noise in the 'low' subtype was also most pronounced during the feedforward phase of reaching actions. Limitations: The sample size of this work is limited. Future work in larger samples along with independent replication is important. Motor noise was measured only on one specific motor task. Thus, a more comprehensive assessment of motor noise on many other motor tasks is needed. Conclusions: Autism can be split into at least two discrete motor subtypes that are characterized by differing levels of motor noise. This suggests that autism motor subtypes may be underpinned by different biological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Copy number variants (CNVs) have become increasingly instrumental in understanding the etiology of all diseases and phenotypes, including Neurocognitive Disorders (NDs). Among the well-established regions associated with ND are small parts of chromosome 16 deletions (16p11.2) and chromosome 15 duplications (15q3). Various methods have been developed to identify associations between CNVs and diseases of interest. The majority of methods are based on statistical inference techniques. However, due to the multi-dimensional nature of the features of the CNVs, these methods are still immature. The other aspect is that regions discovered by different methods are large, while the causative regions may be much smaller. Results: In this study, we propose a regularized deep learning model to select causal regions for the target disease. With the help of the proximal [20] gradient descent algorithm, the model utilizes the group LASSO concept and embraces a deep learning model in a sparsity framework. We perform the CNV analysis for 74,811 individuals with three types of brain disorders, autism spectrum disorder (ASD), schizophrenia (SCZ), and developmental delay (DD), and also perform cumulative analysis to discover the regions that are common among the NDs. The brain expression of genes associated with diseases has increased by an average of 20 percent, and genes with homologs in mice that cause nervous system phenotypes have increased by 18 percent (on average). The DECIPHER data source also seeks other phenotypes connected to the detected regions alongside gene ontology analysis. The target diseases are correlated with some unexplored regions, such as deletions on 1q21.1 and 1q21.2 (for ASD), deletions on 20q12 (for SCZ), and duplications on 8p23.3 (for DD). Furthermore, our method is compared with other machine learning algorithms. Conclusions: Our model effectively identifies regions associated with phenotypic traits using regularized deep learning. Rather than attempting to analyze the whole genome, CNVDeep allows us to focus only on the causative regions of disease. [ABSTRACT FROM AUTHOR]

Background: Chromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease. Results: The article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities - epilepsy, combined with moderate mental and motor developmental delay. Conclusions: Through detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Co-production is the collaboration between researchers and the lived experience community in designing, conducting and sharing research. The importance of co-production is increasingly advocated in both the autism and eating disorder fields. Despite this, there remains a lack of clarity at how to define, apply and conduct ethical co-production. Understanding common challenges and what we can do to overcome these challenges are integral to ensuring ethical and meaningful research with Autistic people with an eating disorder. The current study therefore explored: What are the barriers and facilitators to ethical co-production with Autistic people with an ED? Methods: Five workshops were conducted with 30 collaborators exploring barriers and facilitators to ethical co-production. Synchronous (online workshops) and asynchronous (offline discussion forum) data was analysed using thematic analysis. Themes were co-produced by a neurotypical and Autistic researcher with lived/living experience of an eating disorder. Results: Four themes were identified that explored barriers to ethical co-production: unequal partnerships, the inaccessibility of research, excluded by diagnoses and communication differences. Three themes were identified with regards to facilitators of ethical co-production: shared power (with sub-themes relationships, not roles and creative compensation), clarity and transparency and autism-affirming approaches. Discussion: Conducting ethical co-production with Autistic people with eating disorders has the potential to generate meaningful research that can be translated into improving the lives of the Autistic and eating disorder community. To achieve this, co-production teams should strive towards shared power and long-term relationships, adapting for communication differences and preferences and operating firmly within an autism-affirming framework. It is hoped that study findings will inspire collaboration, discussion and novel, translatable research. Plain English Summary: Co-production is the collaboration between researchers and the lived experience community in designing, conducting and sharing research. This study brought together Autistic people with lived/living experience of an eating disorder (ED), researchers, clinicians, third sector organisations and parents/carers to understand what the barriers (challenges) and facilitators (how to overcome these challenges) were to ethical co-production with Autistic people with an eating disorder. Common barriers were found to be unequal partnerships, difficulty accessing research, feeling or being excluded by a reliance on diagnoses and the impact of communication differences. Facilitators were felt to be a shared power dynamic, focusing on establishing relationships not just tokenistic roles and creating fair and person-centred compensation. Facilitators were also adapting for communication differences and moving away from harmful medicalised and ableists models, towards autism-affirming practice. It is hoped that the study will encourage discussion and positive co-production relationships between autism and ED researchers and the Autistic and ED community. It is also hoped that that this approach will lead to more meaningful research that will ultimately improve the lives of Autistic people with an ED. [ABSTRACT FROM AUTHOR]

Background: Interventions focused on cognitive function in neurodivergent children typically focus on single functions, e.g. working memory training. They are often focused on 'deficit' models and lack an emphasis on understanding areas of individual strengths and difficulties as a prerequisite to appropriate support. The multidimensional nature and phenotypic variability of cognitive profiles in these children indicate a need for a multicomponent-tailored intervention programme focused on understanding and supporting an individual child's cognitive functioning. Aims: The 'EPIC' intervention (Edinburgh Psychoeducation Intervention for Children and Young People) is focused on improving cognition, learning and behaviour in neurodivergent children such as those with attention deficit hyperactivity disorder (ADHD) or who are autistic. Building on our previous co-production work, this study aimed to use a participatory methods approach to develop EPIC practices and materials in relation to our key principles which include psychoeducation, multicomponent, individualised approach, strengths and difficulties profiling and pairing of a child's individual strengths and difficulties with internal and external strategies. We also set out to assess the feasibility and acceptability of EPIC, and pilot this novel tool-kit intervention with neurodivergent children and their parents and teachers. Methods: The intervention practices, materials and strategies of EPIC were co-produced with neurodivergent children, their parents, teachers and clinicians taking a strengths and difficulties approach. Identification of psychoeducation activities and strategy practices (e.g. mind-maps, chunking), testing of feasibility and collection of pilot data were conducted over a bi-weekly 8-week programme. Eleven neurodivergent children aged 7 to 12 completed the 16-session individualised programme. Acceptability and feasibility were ascertained via qualitative reports elicited within child and teacher interviews and child ratings of enjoyment. Pilot evaluation data was collected pre- and post-intervention participation, and across cognitive assessments (CANTAB, BRIEF), educational attainment (WIAT) and parent and teacher questionnaires measuring clinical symptoms and behaviour (Conners, AQ, SDQ, self-perception). Data was compared with a matched neurodivergent treatment-as-usual control group (N = 9). Results: The co-produced EPIC intervention was both feasible to deliver and acceptable to children, parents and their teachers. Pilot data identified that the 8-week intervention improved cognition (short-term and working memory) and literacy (receptive vocabulary, oral word fluency, listening comprehension). Improvements in the intervention group were also found for parent-reported child behavioural difficulties and aggression, and teacher-reported scholastic competence. Effect sizes generated (Cohen's d) ranged from 0.65 to 2.83. Parents reported continuing to use EPIC strategies when interviewed over a year after participating in the programme. Conclusion: The current study met our objectives fully. 'EPIC' (Edinburgh Psychoeducation Intervention for Children and Young People) is feasible in home and school contexts and improves a range of aspects of cognition, learning and behaviour in neurodivergent children. Our findings show EPIC is suitable to be assessed within a full-scale trial. [ABSTRACT FROM AUTHOR]

Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain. [ABSTRACT FROM AUTHOR]

Background: Individuals with Autism Spectrum Condition (ASC) are characterized by atypicalities in social interactions, compared to Typically Developing individuals (TD). The social motivation theory posits that these difficulties stem from diminished anticipation, reception, and/or learning from social rewards. Although learning from socioemotional outcomes is core to the theory, studies to date have been sparse and inconsistent. This possibly arises from a combination of theoretical, methodological and sample-related issues. Here, we assessed participants' ability to develop a spontaneous preference for actions that lead to desirable socioemotional outcomes (approaching/avoiding of happy/angry individuals, respectively), in an ecologically valid social scenario. We expected that learning abilities would be impaired in ASC individuals, particularly in response to affiliative social feedback. Method: We ran an online social reinforcement learning task, on two large online cohorts with (n = 274) and without (n = 290) ASC, matched for gender, age and education. Participants had to indicate where they would sit in a waiting room. Each seat was associated with different probabilities of approaching/avoiding emotional individuals. Importantly, the task was implicit, as participants were not instructed to learn, and emotional expressions were never mentioned. We applied both categorical analyses contrasting the ASC and TD groups and dimensional factor analysis on affective questionnaires. Results: Contrary to our hypothesis, participants showed spontaneous learning from socioemotional outcomes, regardless of their diagnostic group. Yet, when accounting for dimensional variations in autistic traits, as well as depression and anxiety, two main findings emerged among females who failed to develop explicit learning strategies: (1) autism severity in ASC correlated with reduced learning to approach happy individuals; (2) anxiety-depression severity across both ASC and TD participants correlated with reduced learning to approach/avoid happy/angry individuals, respectively. Conclusions: Implicit spontaneous learning from socioemotional outcomes is not generally impaired in autism but may be specifically associated with autism severity in females with ASC, when they do not have an explicit strategy for adapting to their social environment. Clinical diagnosis and intervention ought to take into account individual differences in their full complexity, including the presence of co-morbid anxiety and depression, when dealing with social atypicalities in autism. [ABSTRACT FROM AUTHOR]

Background: The nutritional status and growth of children with Autism spectrum disorders (ASD) is influenced significantly by two factors; food selectivity behaviors due to their consumption of a limited variety of food and the high incidence of gastrointestinal (GIT) disorders. Aim: This study aimed to assess the nutritional adequacy and growth pattern of ASD children aged three to twelve years compared to their healthy developing peers. Methods: A national comparative, facility-based cross-sectional study was conducted in eight Egyptian governorates on 285 Egyptian children diagnosed with ASD and 224 children who are their relatives as healthy developing peers. Anthropometric measurements were obtained, including weight, height, head circumference, and mid-upper arm circumference. Body Mass Index (BMI) was calculated and all numbers were plotted on WHO growth charts. Assessment of food preferences, and nutrient intake adequacy of children was done using the Food preference questionnaire, and the Dietary Reference Intakes (DRIs) of Egyptian children. Results: Calorie-dense food and sugar intake were higher among ASD children than their healthy developing peers. ASD children omit some important protein sources such as dairy (COR = 5.2, 95% CI:2.7–9.9), meat, and poultry (COR = 2.7, 95% CI: 1.6–4.7), and a lower intake of fruits and vegetables than their healthy developing peers. For children with ASD in all age groups, a deficiency in the range of 50–60% was detected for vitamins (C, D, B6, thiamine, riboflavin, niacin) and minerals (iron). A deficiency in the range of 60–70% was detected for folate and calcium. A deficiency of vitamin C calcium and iron was also detected for both children with ASD and their healthy developing relatives aged 6 to 12 years. GIT disorders were common among ASD children compared to healthy developing peers (COR = 2.8 to 10.3). Children with ASD had four-fold higher odds of stunting (COR = 4.1, CI: 1.7–10.1), threefold higher odds of being overweight (COR = 3.3, CI: 1.48–7.32), and nearly eleven-fold higher odds of obesity (COR = 11.4, CI: 4.05–32.17) compared to their healthy developing peers. Conclusion: ASD children are prone to overweight and protein malnutrition. Their intake of fruits and vegetables is inadequate and hence their intake of vitamins and minerals is insufficient, contributing to stunting. [ABSTRACT FROM AUTHOR]

Background: Given the recent evidence on gender differences in the presentation of autism, there is an increasing concern that current tools for autism do not adequately capture traits more often found in women. If tools for autism measure autistic traits differently based on gender alone, their validity may be compromised as they may not be measuring the same construct across genders. Measurement invariance investigations of autism measures can help assess the validity of autism constructs for different genders. The aim of this systematic review is to identify and critically appraise the psychometric properties of all self-report tools for autism in adults that meet two criteria: (a) they have been published since or included in the NICE (2014) recommendations, and (b) they have undergone gender-related measurement invariance investigations as part of their validation process. Methods: A search of electronic databases will be conducted from 2014 until the present using MEDLINE, Embase, and PsycINFO using predefined search terms to identify eligible studies. The search for grey literature will include sources such as OpenGrey, APA PsycEXTRA, and Scopus. Two reviewers will independently screen titles, abstracts, and full texts for eligibility. The references of included studies will be searched for additional records. The methodological quality of the studies will be evaluated using the COSMIN Risk of Bias checklist, while psychometric quality of findings will be assessed based on criteria for good measurement properties and ConPsy checklist. The quality of the total body of evidence will be appraised using the approach outlined in the modified GRADE guidelines. Discussion: This systematic review will be among the first to assess the psychometric properties and gender-related measurement invariance of self-reported measures for autism in adults that were published since (or included in) NICE (2014) guidelines. The review will provide recommendations for the most suitable tool to assess for autism without gender bias. If no such measure is found, it will identify existing tools with promising psychometric properties that require further testing, or suggest developing a new measure. Systematic review registration: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42023429350. [ABSTRACT FROM AUTHOR]

Background: For people with autism spectrum disorder (ASD), daily life can be highly stressful with many unpredictable events that can evoke emotion dysregulation (ED): a strong difficulty with appropriately negative affect regulation. For some of the patients with ASD, treatment as usual does not prove to be effective for ED. They may be at risk of life-long impairment, development of other disorders and loss of motivation for most regular forms of therapy. A highly promising method that may prove effective for therapy-resistant individuals with ASD is Psychotherapy incorporating horses (PIH). PIH uses the interactions of the horse and the patients on the ground and does not include horseriding. While often met with prejudgment and scepticism, reports from parents and therapists as well as a recent systematic review suggest that PIH may have beneficial effects on youths with ASD. Therefore, we examine clinical outcomes both in the short and in the long terms of PIH offered to adolescents with ASD and severe ED despite regular therapy. Methods: A total of 35 adolescents aged 11–18 years with ASD will receive PIH during 15 sessions once a week with randomization to five different groups differentiating in baseline phase from 2 to 6 weeks. PIH uses horses to promote social awareness and self-awareness as well as relationship management and self-management. The primary outcome is the response to treatment on the Emotion Dysregulation Index (EDI). The secondary outcome measures include ASD symptom severity, quality of life, self-esteem, global and family functioning, and goal attainment. Assessments take place at the baseline (T0), at the end of baseline phase A (T1), after completion of intervention phase B (T2), after the end of post-measurement phase C (T3) and after one year (T4). Qualitative interviews of participants, parents and therapists will be held to reveal facilitators and barriers of PIH and a cost-effectiveness study will be performed. Discussion: This study aims at contributing to clinical practice for adolescents with ASD and persistent emotion regulation problems despite 1.5 year of treatment by offering Psychotherapy incorporating horses in a study with series of randomised, baseline controlled n-of-1 trials. Trial registration: www.ClinicalTrials.gov NCT05200351, December 10th 2021. [ABSTRACT FROM AUTHOR]

Introduction: Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called "Adappt," aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences. Method: A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with "Adappt." Discussion: Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care. Trial registration: This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework (https://osf.io/5znqv). [ABSTRACT FROM AUTHOR]

Background: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. Methods: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. Results: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. Limitations: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic. Conclusions: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability. [ABSTRACT FROM AUTHOR]

Background: Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population. Methods: To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families). Results: We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3–4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D2 on the order of 1 × 10−5). Limitations: We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification. Conclusions: This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis. [ABSTRACT FROM AUTHOR]

Background: An intense and precocious interest in written material, together with a discrepancy between decoding and reading comprehension skills are defining criteria for hyperlexia, which is found in up to 20% of autistic individuals. It may represent the extreme end of a broader interest in written material in autism. This study examines the magnitude and nature of the interest in written material in a large population of autistic and non-autistic children. Methods: All 701 children (391 autistic, 310 non-autistic) under the age of 7 referred to an autism assessment clinic over a span of 4 years were included. Ordinal logistic regressions assessed the association between diagnosis and the level of interest in letters and numbers. A nested sample of parents of 138 autistic, 99 non-autistic clinical, and 76 typically developing (TD) children completed a detailed questionnaire. Cox proportional hazards models analyzed the age of emergence of these interests. Linear regressions evaluated the association between diagnosis and interest level. The frequency of each behaviour showing interest and competence with letters and numbers were compared. Results: In the two studies, 22 to 37% of autistic children had an intense or exclusive interest in letters. The odds of having a greater interest in letters was 2.78 times higher for autistic children than for non-autistic clinical children of the same age, and 3.49 times higher for the interest in numbers, even if 76% of autistic children were minimally or non-verbal. The age of emergence of these interests did not differ between autistic and TD children and did not depend on their level of oral language. Non-autistic children showed more interest in letters within a social context. Limitations: The study holds limitations inherent to the use of a phone questionnaire with caregivers and missing sociodemographic information. Conclusions: The emergence of the interest of autistic children toward written language is contemporaneous to the moment in their development where they display a strong deficit in oral language. Together with recent demonstrations of non-social development of oral language in some autistic children, precocious and intense interest in written material suggests that language acquisition in autism may follow an alternative developmental pathway. [ABSTRACT FROM AUTHOR]

Background: Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions. Methods: In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks. Results: We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case–control gene expression studies suggests a female molecular predisposition towards Alzheimer's disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis. Conclusion: Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences. Highlights: Numerous but small autosomal sex differences in expression exist in all brain regions tested. Autosomal genes with enriched expression in males are enriched in neuronal pathways. Autosomal genes with enriched expression in females are enriched with immune system functions. Integration with single-nucleus datasets suggest these differences are more likely related to cell state differences than cell number differences. The female cortex shows an enrichment of genes expressed in Alzheimer's disease brains. Plain English Summary: We sought to understand why females have higher rates of Alzheimer's disease, and males have higher rates of autism. One idea was that the female brain at baseline may be more similar to an Alzheimer's brain, so it is easier for them to shift into that state (likewise, males may be more similar to autism). To test this, we examined gene expression differences between brains of biological males and biological females. While all people have the same ~ 25,000 genes, each gene can be on or off ('expressed') to different extents. Overall, we found that there were differences in gene expression between males and females in all brain regions tested but more differences in some brain regions than others. By looking at the role of these genes we estimate that female immune system processes might be more active in the brain. We also found female brain gene expression looked slightly more like people with Alzheimer's compared to people without Alzheimer's, which may explain why females get Alzheimer's disease more easily. However, the male brain gene expression did not look more like autism, suggesting that the reason males have higher rates of autism is complex and needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Brief questionnaires that comprehensively capture key restricted and repetitive behaviours (RRBs) across different informants have potential to support autism diagnostic services. We tested the psychometric properties of the 20-item Repetitive Behaviours Questionnaire-3 (RBQ-3), a questionnaire that includes self-report and informant-report versions enabling use across the lifespan. Method: In Study 1, adults referred to a specialised adult autism diagnostic service (N = 110) completed the RBQ-3 self-report version, and a relative or long-term friend completed the RBQ-3 informant-report version. Clinicians completed the abbreviated version of the Diagnostic Interview for Social and Communication Disorders (DISCO-Abbreviated) with the same adults as part of the diagnostic process. For half of the assessments, clinicians were blind to the RBQ-3 ratings. We tested internal consistency, cross-informant reliability and convergent validity of the RBQ-3. In Study 2, a follow-up online study with autistic (N = 151) and non-autistic (N = 151) adults, we further tested internal consistency of the RBQ-3 self-report version. We also tested group differences and response patterns in this sample. Results: Study 1 showed good to excellent internal consistency for both self- and informant-report versions of the RBQ-3 (total score, α = 0.90, ω = 0.90, subscales, α = 0.76-0.89, ω = 0.77-0.88). Study 1 also showed cross-informant reliability as the RBQ-3 self-report scores significantly correlated with RBQ-3 informant-report scores for the total score (rs = 0.71) and subscales (rs= 0.69-0.72). Convergent validity was found for both self and informant versions of the RBQ-3, which significantly correlated with DISCO-Abbreviated RRB domain scores (rs = 0.45-0.54). Moreover, the RBQ-3 scores showed significantly weaker association with DISCO -Abbreviated scores for the Social Communication domain, demonstrating divergent validity. Importantly, these patterns of validity were found even when clinicians were blind to RBQ-3 items. In Study 2, for both autistic and non-autistic groups, internal consistency was found for the total score (α = 0.82-0.89, ω = 0.81-0.81) and for subscales (α = 0.68-0.85, ω = 0.69-0.85). A group difference was found between groups. Limitations: Due to the characteristics and scope of the specialist autism diagnostic service, further testing is needed to include representative samples of age (including children) and intellectual ability, and those with a non-autistic diagnostic outcome. Conclusions: The RBQ-3 is a questionnaire of RRBs that can be used across the lifespan. The current study tested its psychometric properties with autistic adults without intellectual disability and supported its utility for both clinical diagnostic and research settings. [ABSTRACT FROM AUTHOR]

Background: Categorization and its influence on perceptual discrimination are essential processes to organize information efficiently. Individuals with Autism Spectrum Condition (ASC) are suggested to display enhanced discrimination on the one hand, but also to experience difficulties with generalization and ignoring irrelevant differences on the other, which underlie categorization. Studies on categorization and discrimination in ASC have mainly focused on one process at a time, however, and typically only used either behavioral or neural measures in isolation. Here, we aim to investigate the interrelationships between these perceptual processes using novel stimuli sampled from a well-controlled artificial stimulus space. In addition, we complement standard behavioral psychophysical tasks with frequency-tagging EEG (FT-EEG) to obtain a direct, non-task related neural index of discrimination and categorization. Methods: The study was completed by 38 adults with ASC and 38 matched neurotypical (NT) individuals. First, we assessed baseline discrimination sensitivity by administering FT-EEG measures and a complementary behavioral task. Second, participants were trained to categorize the stimuli into two groups. Finally, participants again completed the neural and behavioral discrimination sensitivity measures. Results: Before training, NT participants immediately revealed a categorical tuning of discrimination, unlike ASC participants who showed largely similar discrimination sensitivity across the stimuli. During training, both autistic and non-autistic participants were able to categorize the stimuli into two groups. However, in the initial training phase, ASC participants were less accurate and showed more variability, as compared to their non-autistic peers. After training, ASC participants showed significantly enhanced neural and behavioral discrimination sensitivity across the category boundary. Behavioral indices of a reduced categorical processing and perception were related to the presence of more severe autistic traits. Bayesian analyses confirmed overall results. Limitations: Data-collection occurred during the COVID-19 pandemic. Conclusions: Our behavioral and neural findings indicate that adults with and without ASC are able to categorize highly similar stimuli. However, while categorical tuning of discrimination sensitivity was spontaneously present in the NT group, it only emerged in the autistic group after explicit categorization training. Additionally, during training, adults with autism were slower at category learning. Finally, this multi-level approach sheds light on the mechanisms underlying sensory and information processing issues in ASC. [ABSTRACT FROM AUTHOR]