1. Albizua I, Charen K, Shubeck L, Talboy A, Berry-Kravis E, Kaufmann WE, Stallworth JL, Drazba KT, Erickson CA, Sweeney JA, Tartaglia N, Warren SF, Hagerman R, Sherman SL, Warren ST, Jin P, Allen EG. Descriptive analysis of seizures and comorbidities associated with fragile X syndrome. Mol Genet Genomic Med;2022 (Jul 18):e2001.

BACKGROUND: Fragile X syndrome is characterized by a myriad of physical features, behavioral features, and medical problems. Commonly found behavioral features are hyperactivity, anxiety, socialization difficulties, and ASD. There is also a higher incidence than in the general population of strabismus, otitis media, and mitral valve prolapse. In addition, one of the most common medical problems associated with FXS is an increased risk of seizures. A subset of individuals carrying the full mutation of the FMR1 gene and diagnosed with fragile X syndrome (FXS) are reported to experience seizures, mostly during the first 10 years of their life span. METHODS: As part of a larger project to identify genetic variants that modify the risk of seizures, we collected clinical information from 49 carriers with FXS who experienced seizures and 46 without seizures. We compared seizure type and comorbid conditions based on the source of data as well as family history of seizures. RESULTS: We found that the concordance of seizure types observed by parents and medical specialists varied by type of seizure. The most common comorbid condition among those with seizures was autism spectrum disorder (47% per medical records vs. 33% per parent report compared with 19% among those without seizures per parent report); the frequency of other comorbid conditions did not differ among groups. We found a slightly higher frequency of family members who experienced seizures among the seizure group compared with the nonseizure group. CONCLUSION: This study confirms previously reported features of seizures in FXS, supports additional genetic factors, and highlights the importance of information sources, altogether contributing to a better understanding of seizures in FXS.

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2. Alhazmi S, Alzahrani M, Farsi R, Alharbi M, Algothmi K, Alburae N, Ganash M, Azhari S, Basingab F, Almuhammadi A, Alqosaibi A, Alkhatabi H, Elaimi A, Jan M, Aldhalaan HM, Alrafiah A, Alrofaidi A. Multiple Recurrent Copy Number Variations (CNVs) in Chromosome 22 Including 22q11.2 Associated with Autism Spectrum Disorder. Pharmgenomics Pers Med;2022;15:705-720.

INTRODUCTION: Autism spectrum disorder (ASD) is a developmental disorder that can cause substantial social, communication, and behavioral challenges. Genetic factors play a significant role in ASD, where the risk of ASD has been increased for unclear reasons. Twin studies have shown important evidence of both genetic and environmental contributions in ASD, where the level of contribution of these factors has not been proven yet. It has been suggested that copy number variation (CNV) duplication and the deletion of many genes in chromosome 22 (Ch22) may have a strong association with ASD. This study screened the CNVs in Ch22 in autistic Saudi children and assessed the candidate gene in the CNVs region of Ch22 that is most associated with ASD. METHODS: This study included 15 autistic Saudi children as well as 4 healthy children as controls; DNA was extracted from samples and analyzed using array comparative genomic hybridization (aCGH) and DNA sequencing. RESULTS: The aCGH detected (in only 6 autistic samples) deletion and duplication in many regions of Ch22, including some critical genes. Moreover, DNA sequencing determined a genetic mutation in the TBX1 gene sequence in autistic samples. This study, carried out using aCGH, found that six autistic patients had CNVs in Ch22, and DNA sequencing revealed mutations in the TBX1 gene in autistic samples but none in the control. CONCLUSION: CNV deletion and the duplication of the TBX1 gene could be related to ASD; therefore, this gene needs more analysis in terms of expression levels.

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3. Anstey NJ, Kapgal V, Tiwari S, Watson TC, Toft AKH, Dando OR, Inkpen FH, Baxter PS, Kozić Z, Jackson AD, He X, Nawaz MS, Kayenaat A, Bhattacharya A, Wyllie DJA, Chattarji S, Wood ER, Hardt O, Kind PC. Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3(-/y) rat model of autism. Mol Autism;2022 (Jul 18);13(1):34.

BACKGROUND: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. METHODS: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3(-/y) rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3(-/y) rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). RESULTS: We observed that, unlike the wildtype, Nlgn3(-/y) rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3(-/y) rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3(-/y) than wildtype rats, indicating the functional impact of the increased cellular excitability. LIMITATIONS: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. CONCLUSIONS: We describe altered fear responses in Nlgn3(-/y) rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD.

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4. Arora V, Takkar A, Mehta A, Malleda N, Kumar P. Fragile X Syndrome Due to a Frameshift Deletion: A Rare Mechanism. Indian J Pediatr;2022 (Jul 20)

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5. Baroncelli L, Auel S, Rinne L, Schuster AK, Brand V, Kempkes B, Dietrich K, Müller M. Oral Feeding of an Antioxidant Cocktail as a Therapeutic Strategy in a Mouse Model of Rett Syndrome: Merits and Limitations of Long-Term Treatment. Antioxidants (Basel);2022 (Jul 20);11(7)

Rett syndrome (RTT) is a severe neurodevelopmental disorder that typically arises from spontaneous germline mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. For the first 6-18 months of life, the development of the mostly female patients appears normal. Subsequently, cognitive impairment, motor disturbances, hand stereotypies, epilepsy, and irregular breathing manifest, with previously learned skills being lost. Early mitochondrial impairment and a systemic oxidative burden are part of the complex pathogenesis, and contribute to disease progression. Accordingly, partial therapeutic merits of redox-stabilizing and antioxidant (AO) treatments were reported in RTT patients and Mecp2-mutant mice. Pursuing these findings, we conducted a full preclinical trial on male and female mice to define the therapeutic value of an orally administered AO cocktail composed of vitamin E, N-acetylcysteine, and α-lipoic acid. AO treatment ameliorated some of the microcephaly-related aspects. Moreover, the reduced growth, lowered blood glucose levels, and the hippocampal synaptic plasticity of Mecp2(-/y) mice improved. However, the first-time detected intensified oxidative DNA damage in Mecp2-mutant cortex persisted. The behavioral performance, breathing regularity, and life expectancy of Mecp2-mutant mice did not improve upon AO treatment. Long-term-treated Mecp2(+/-) mice eventually became obese. In conclusion, the AO cocktail ameliorated a subset of symptoms of the complex RTT-related phenotype, thereby further confirming the potential merits of AO-based pharmacotherapies. Yet, it also became evident that long-term AO treatment may lose efficacy and even aggravate the metabolic disturbances in RTT. This emphasizes the importance of a constantly well-balanced redox balance for systemic well-being.

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6. Cross L, Piovesan A, Atherton G. Autistic people outperform neurotypicals in a cartoon version of the Reading the Mind in the Eyes. Autism Res;2022 (Jul 20)

Prior research suggests that while autistic people may demonstrate poorer facial emotion recognition when stimuli are human, these differences lessen when stimuli are anthropomorphic. To investigate this further, this work explores emotion recognition in autistic and neurotypical adults (n = 196). Groups were compared on a standard and a cartoon version of the Reading the Mind in the Eyes test. Results indicated that autistic individuals were not significantly different from neurotypicals on the standard version. However, autistic people outperformed neurotypicals on the cartoon version. The implications for these findings regarding emotion recognition deficits and the social motivation account of autism are discussed and support the view of socio-cognitive differences rather than deficits in this population.

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7. da Hora CL, Sella AC. Evaluation parameters for evidence-based practices for people with autism spectrum disorder: a narrative review of group and single-subject design studies. Psicol Reflex Crit;2022 (Jul 20);35(1):23.

Recommendations for using evidence-based practices have become increasingly common in services for individuals diagnosed with autistic spectrum disorder (ASD). The aim of this study was to conduct a narrative literature review to identify differences and similarities in evidence-evaluation criteria for group and single-subject designs that empirically support interventions for people with ASD. Data sources used in this analysis were reports and articles elaborated by different clearinghouses (i.e., National Autism Center, National Professional Development Center, and the National Clearinghouse on Autism Evidence and Practice). The criteria for evaluating evidence, as defined by these documents, contained specific components or quality indicators for each type of study design. The different criteria for evaluating evidence and for classifying the interventions (once evidence was evaluated) were identified and described. This manuscript discusses the need for (a) expanding the analysis beyond the evidence identified by different researchers and organizations such as the clearinghouses, (b) proposing interventions that are based not only on scientific evidence but also on social validity – which is directed by client idiosyncrasies, and (c) attention to the fact that EBPs should not be seen as static information regarding interventions with empirical support: evidence-based practices are the result of constant analysis of the intervention implementation data added to professional training and client values and context. Some additional issues and the study limitations are also presented.

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8. Del Casale A, Ferracuti S, Alcibiade A, Simone S, Modesti MN, Pompili M. Neuroanatomical correlates of autism spectrum disorders: A meta-analysis of structural magnetic resonance imaging (MRI) studies. Psychiatry Res Neuroimaging;2022 (Jul 20);325:111516.

Autism spectrum disorders (ASD) are neurodevelopmental disorders correlated to various neuroanatomical modifications. We aimed to identify neuroanatomical changes assessed in magnetic resonance imaging (MRI) studies of autism spectrum disorder (ASD) through Activation Likelihood Estimate (ALE) meta-analysis. We included 19 peer-reviewed magnetic resonance imaging (MRI) studies that analyzed cortical volume in patients with ASD compared to healthy control subjects (HCs). The between-group analyses comparing subjects with ASD to HCs showed a volumetric reduction of a large cluster in the right brain, including the uncus/amygdala, parahippocampal gyrus, and entorhinal cortex, and putamen. The anomalies are primarily found in the right hemisphere, involved in social cognitive function, particularly impaired in ASD. These results correlate with several clinical aspects of ASD. These volumetric alterations can be considered a major correlate of disease in the context of multifactorial etiology. Further studies on brain lateralization in ASD are needed, considering the clinical phenotype variability of these disorders.

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9. Dougherty JD, Marrus N, Maloney SE, Yip B, Sandin S, Turner TN, Selmanovic D, Kroll KL, Gutmann DH, Constantino JN, Weiss LA. Can the « female protective effect » liability threshold model explain sex differences in autism spectrum disorder?. Neuron;2022 (Jul 20)

Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a « female protective effect » (FPE) envisions males and females have « differing thresholds » under a « liability threshold model » (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical features, the stability of the sex ratio across diagnostic changes, and highlight other key prerequisites. Our findings reveal that several key predictions of the DT-LTM are not supported by current data, requiring us to establish a different conceptual framework for evaluating alternate models that explain sex differences in ASD.

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10. Esnafoglu E, Subaşı B. Association of low 25-OH-vitamin D levels and peripheral inflammatory markers in patients with autism spectrum disorder: Vitamin D and inflammation in Autism. Psychiatry Res;2022 (Jul 20);316:114735.

Inflammatory mechanisms and Vitamin D are reported to play important roles in the pathophysiology of Autism Spectrum Disorders (ASD). There are ample evidences that vitamin D has an anti-inflammatory effect. In this study, we aimed, for the first time, to investigate the 25-OH-vitamin D with inflammation markers in ASD patients. The study included 154 patients with ASD and 98 healthy subjects. 25-OH-Vitamin D levels and simple peripheral inflammatory markers such as Neutrophil-Lymphocyte ratio (NLR), C-reactive protein (CRP) and, sedimentation were measured in all subjects. K-SADS-PL-DSM 5 were administered to all subjects to evaluate the psychiatric diagnosis. Childhood Autism Rating Scale was used to asses severity of autism. In the patient group, high CRP rate, leukocyte, neutrophil and NLR were significantly high compared to the healthy control group. 25-OH-Vitamin D levels were found to be statistically significantly lower in the ASD group. While a significant negative correlation was found between 25-OH-Vitamin D and CRP, NLR, neutrophil counts in ASD patients, a positive correlation was found between lymphocyte counts. Especially in male ASD patients, the relationship between 25-OH-Vitamin D and inflammation markers was more pronounced. Our findings support the association of vitamin D and inflammation in ASD.

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11. Han J, Jiang G, Ouyang G, Li X. A Multimodal Approach for Identifying Autism Spectrum Disorders in Children. IEEE Trans Neural Syst Rehabil Eng;2022;30:2003-2011.

Identification of autism spectrum disorder (ASD) in children is challenging due to the complexity and heterogeneity of ASD. Currently, most existing methods mainly rely on a single modality with limited information and often cannot achieve satisfactory performance. To address this issue, this paper investigates from internal neurophysiological and external behavior perspectives simultaneously and proposes a new multimodal diagnosis framework for identifying ASD in children with fusion of electroencephalogram (EEG) and eye-tracking (ET) data. Specifically, we designed a two-step multimodal feature learning and fusion model based on a typical deep learning algorithm, stacked denoising autoencoder (SDAE). In the first step, two SDAE models are designed for feature learning for EEG and ET modality, respectively. Then, a third SDAE model in the second step is designed to perform multimodal fusion with learned EEG and ET features in a concatenated way. Our designed multimodal identification model can automatically capture correlations and complementarity from behavior modality and neurophysiological modality in a latent feature space, and generate informative feature representations with better discriminability and generalization for enhanced identification performance. We collected a multimodal dataset containing 40 ASD children and 50 typically developing (TD) children to evaluate our proposed method. Experimental results showed that our proposed method achieved superior performance compared with two unimodal methods and a simple feature-level fusion method, which has promising potential to provide an objective and accurate diagnosis to assist clinicians.

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12. Horvath PM, Piazza MK, Kavalali ET, Monteggia LM. MeCP2 loss-of-function dysregulates microRNAs regionally and disrupts excitatory/inhibitory synaptic transmission balance. Hippocampus;2022 (Aug);32(8):610-623.

Rett syndrome is a leading cause of intellectual disability in females primarily caused by loss of function mutations in the transcriptional regulator MeCP2. Loss of MeCP2 leads to a host of synaptic phenotypes that are believed to underlie Rett syndrome pathophysiology. Synaptic deficits vary by brain region upon MeCP2 loss, suggesting distinct molecular alterations leading to disparate synaptic outcomes. In this study, we examined the contribution of MeCP2’s newly described role in miRNA regulation to regional molecular and synaptic impairments. Two miRNAs, miR-101a and miR-203, were identified and confirmed as upregulated in MeCP2 KO mice in the hippocampus and cortex, respectively. miR-101a overexpression in hippocampal cultures led to opposing effects at excitatory and inhibitory synapses and in spontaneous and evoked neurotransmission, revealing the potential for a single miRNA to broadly regulate synapse function in the hippocampus. These results highlight the importance of regional alterations in miRNA expression and the specific impact on synaptic function with potential implications for Rett syndrome.

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13. Knight EJ, Krakowski AI, Freedman EG, Butler JS, Molholm S, Foxe JJ. Attentional influences on neural processing of biological motion in typically developing children and those on the autism spectrum. Mol Autism;2022 (Jul 18);13(1):33.

BACKGROUND: Biological motion imparts rich information related to the movement, actions, intentions and affective state of others, which can provide foundational support for various aspects of social cognition and behavior. Given that atypical social communication and cognition are hallmark symptoms of autism spectrum disorder (ASD), many have theorized that a potential source of this deficit may lie in dysfunctional neural mechanisms of biological motion processing. Synthesis of existing literature provides some support for biological motion processing deficits in autism spectrum disorder, although high study heterogeneity and inconsistent findings complicate interpretation. Here, we attempted to reconcile some of this residual controversy by investigating a possible modulating role for attention in biological motion processing in ASD. METHODS: We employed high-density electroencephalographic recordings while participants observed point-light displays of upright, inverted and scrambled biological motion under two task conditions to explore spatiotemporal dynamics of intentional and unintentional biological motion processing in children and adolescents with ASD (n = 27), comparing them to a control cohort of neurotypical (NT) participants (n = 35). RESULTS: Behaviorally, ASD participants were able to discriminate biological motion with similar accuracy to NT controls. However, electrophysiologic investigation revealed reduced automatic selective processing of upright biologic versus scrambled motion stimuli in ASD relative to NT individuals, which was ameliorated when task demands required explicit attention to biological motion. Additionally, we observed distinctive patterns of covariance between visual potentials evoked by biological motion and functional social ability, such that Vineland Adaptive Behavior Scale-Socialization domain scores were differentially associated with biological motion processing in the N1 period in the ASD but not the NT group. LIMITATIONS: The cross-sectional design of this study does not allow us to definitively answer the question of whether developmental differences in attention to biological motion cause disruption in social communication, and the sample was limited to children with average or above cognitive ability. CONCLUSIONS: Together, these data suggest that individuals with ASD are able to discriminate, with explicit attention, biological from non-biological motion but demonstrate diminished automatic neural specificity for biological motion processing, which may have cascading implications for the development of higher-order social cognition.

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14. Miller HL, Thomi M, Patterson RM, Nandy K. Correction: Effects of Intersectionality Along the Pathway to Diagnosis for Autistic Children With and Without Co-occurring Attention Deficit Hyperactivity Disorder in a Nationally-Representative Sample. J Autism Dev Disord;2022 (Jul 19)

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15. Pourtavakoli A, Ghafouri-Fard S. Calcium signaling in neurodevelopment and pathophysiology of autism spectrum disorders. Mol Biol Rep;2022 (Jul 20)

BACKGROUND: Autism spectrum disorder (ASD) covers a group of neurodevelopmental disorders with complex genetic background. Several genetic mutations, epigenetic alterations, copy number variations and single nucleotide polymorphisms have been reported that cause ASD or modify its phenotype. Among signaling pathways that influence pathogenesis of ASD, calcium signaling has a prominent effect. METHODS: We searched PubMed and Google Scholar databases with key words « Calcium signaling » and « Autism spectrum disorder ». CONCLUSION: This type of signaling has essential roles in the cell physiology. Endoplasmic reticulum and mitochondria are the key organelles involved in this signaling. It is vastly accepted that organellar disorders intensely influence the central nervous system (CNS). Several lines of evidence indicate alterations in the function of calcium channels in polygenic disorders affecting CNS. In the current review, we describe the role of calcium signaling in normal function of CNS and pathophysiology of ASD.

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16. Sohl K, Kilian R, Brewer Curran A, Mahurin M, Nanclares-Nogués V, Liu-Mayo S, Salomon C, Shannon J, Taraman S. Feasibility and Impact of Integrating an Artificial Intelligence-Based Diagnosis Aid for Autism Into the Extension for Community Health Outcomes Autism Primary Care Model: Protocol for a Prospective Observational Study. JMIR Res Protoc;2022 (Jul 19);11(7):e37576.

BACKGROUND: The Extension for Community Health Outcomes (ECHO) Autism Program trains clinicians to screen, diagnose, and care for children with autism spectrum disorder (ASD) in primary care settings. This study will assess the feasibility and impact of integrating an artificial intelligence (AI)-based ASD diagnosis aid (the device) into the existing ECHO Autism Screening Tool for Autism in Toddlers and Young Children (STAT) diagnosis model. The prescription-only Software as a Medical Device, designed for use in children aged 18 to 72 months at risk for developmental delay, produces ASD diagnostic recommendations after analyzing behavioral features from 3 distinct inputs: a caregiver questionnaire, 2 short home videos analyzed by trained video analysts, and a health care provider questionnaire. The device is not a stand-alone diagnostic and should be used in conjunction with clinical judgment. OBJECTIVE: This study aims to assess the feasibility and impact of integrating an AI-based ASD diagnosis aid into the ECHO Autism STAT diagnosis model. The time from initial ECHO Autism clinician concern to ASD diagnosis is the primary end point. Secondary end points include the time from initial caregiver concern to ASD diagnosis, time from diagnosis to treatment initiation, and clinician and caregiver experience of device use as part of the ASD diagnostic journey. METHODS: Research participants for this prospective observational study will be patients suspected of having ASD (aged 18-72 months) and their caregivers and up to 15 trained ECHO Autism clinicians recruited by the ECHO Autism Communities research team from across rural and suburban areas of the United States. Clinicians will provide routine clinical care and conduct best practice ECHO Autism diagnostic evaluations in addition to prescribing the device. Outcome data will be collected via a combination of electronic questionnaires, reviews of standard clinical care records, and analysis of device outputs. The expected study duration is no more than 12 months. The study was approved by the institutional review board of the University of Missouri-Columbia (institutional review board-assigned project number 2075722). RESULTS: Participant recruitment began in April 2022. As of June 2022, a total of 41 participants have been enrolled. CONCLUSIONS: This prospective observational study will be the first to evaluate the use of a novel AI-based ASD diagnosis aid as part of a real-world primary care diagnostic pathway. If device integration into primary care proves feasible and efficacious, prolonged delays between the first ASD concern and eventual diagnosis may be reduced. Streamlining primary care ASD diagnosis could potentially reduce the strain on specialty services and allow a greater proportion of children to commence early intervention during a critical neurodevelopmental window. TRIAL REGISTRATION: ClinicalTrials.gov NCT05223374; https://clinicaltrials.gov/ct2/show/NCT05223374. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37576.

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17. Spain D, Stewart GR, Mason D, Milner V, Fairhurst B, Robinson J, Gillan N, Ensum I, Stark E, Happe F. Telehealth Autism Diagnostic Assessments With Children, Young People, and Adults: Qualitative Interview Study With England-Wide Multidisciplinary Health Professionals. JMIR Ment Health;2022 (Jul 20);9(7):e37901.

BACKGROUND: Autism spectrum disorder (hereafter, autism) is a common neurodevelopmental condition. Core traits can range from subtle to severe and fluctuate depending on context. Individuals can present for diagnostic assessments during childhood or adulthood. However, waiting times for assessment are typically lengthy, and many individuals wait months or even years to be seen. Traditionally, there has been a lack of standardization between services regarding how many and which multidisciplinary health professionals are involved in the assessment and the methods (diagnostic tools) that are used. The COVID-19 pandemic has affected routine service provision because of stay-at-home mandates and social distancing guidelines. Autism diagnostic services have had to adapt, such as by switching from conducting assessments in person to doing these fully via telehealth (defined as the use of remote technologies for the provision of health care) or using blended in-person or telehealth methods. OBJECTIVE: This study explored health professionals’ experiences of and perspectives about conducting telehealth autism diagnostic assessments, including barriers and facilitators to this, during the COVID-19 pandemic; potential telehealth training and supervision needs of health professionals; how the quality and effectiveness of telehealth autism diagnostic services can be enhanced; and experiences of delivering postdiagnostic support remotely. METHODS: A total of 45 health professionals, working in varied settings across England, participated in one-off, in-depth semistructured qualitative interviews. These were conducted via videoconferencing or telephone. Altogether, participants represented 7 professional disciplines (psychiatry, medicine, psychology, speech and language therapy, occupational therapy, nursing, and social work). The data were then analyzed thematically. RESULTS: Thematic analysis indicated the following 7 themes: practicalities of telehealth, telehealth autism diagnostic assessments, diagnostic conclusions, clinical considerations, postdiagnostic support, future ways of working, and health professionals’ experiences and needs. Overall, telehealth autism diagnostic assessments were deemed by many participants to be convenient, flexible, and efficient for some patients, families, and health professionals. However, not all patients could be assessed in this way, for example, because of digital poverty, complex clinical presentation, or concerns about risk and safeguarding. Working remotely encouraged innovation, including the development of novel assessment measures. However, some participants expressed significant concerns about the validity and reliability of remotely assessing social communication conditions. CONCLUSIONS: A shift to telehealth meant that autism diagnostic services remained operational during the COVID-19 pandemic. However, this method of working has potentially affected the parity of service, with people presenting with clinical complexity having to potentially wait longer to be seen or given a diagnostic opinion. There is also a lack of standardization in the provision of services. Further research should identify evidence-based ways of enhancing the timeliness, accessibility, and robustness of the autism diagnostic pathway, as well as the validity and reliability of telehealth methods.

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18. Stoyanova M, Hachmeriyan M, Levkova M, Bichev S, Georgieva M, Mladenov V, Angelova L. Molecular screening for fragile X syndrome in children with unexplained intellectual disability and/or autistic behaviour. Folia Med (Plovdiv);2022 (Feb 28);64(1):27-32.

Fragile X syndrome (FXS, OMIM #300624) is the most common inherited form of intellectual disability and the leading monogenic cause of autism.

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19. Su L, Zhang M, Ji F, Zhao J, Wang Y, Wang W, Zhang S, Ma H, Jiao J. Microglia homeostasis mediated by epigenetic ARID1A regulates neural progenitor cells response and leads to autism-like behaviors. Mol Psychiatry;2022 (Jul 20)

Microglia are resident macrophages of the central nervous system that selectively emerge in embryonic cortical proliferative zones and regulate neurogenesis by altering molecular and phenotypic states. Despite their important roles in inflammatory phagocytosis and neurodegenerative diseases, microglial homeostasis during early brain development has not been fully elucidated. Here, we demonstrate a notable interplay between microglial homeostasis and neural progenitor cell signal transduction during embryonic neurogenesis. ARID1A, an epigenetic subunit of the SWI/SNF chromatin-remodeling complex, disrupts genome-wide H3K9me3 occupancy in microglia and changes the epigenetic chromatin landscape of regulatory elements that influence the switching of microglial states. Perturbation of microglial homeostasis impairs the release of PRG3, which regulates neural progenitor cell self-renewal and differentiation during embryonic development. Furthermore, the loss of microglia-driven PRG3 alters the downstream cascade of the Wnt/β-catenin signaling pathway through its interaction with the neural progenitor receptor LRP6, which leads to misplaced regulation in neuronal development and causes autism-like behaviors at later stages. Thus, during early fetal brain development, microglia progress toward a more homeostatic competent phenotype, which might render neural progenitor cells respond to environmental cross-talk perturbations.

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20. Zhao L, Li Y, Kou X, Chen B, Cao J, Li J, Zhang J, Wang H, Zhao J, Shi S. Stem Cells from Human Exfoliated Deciduous Teeth Ameliorate Autistic-Like Behaviors of SHANK3 Mutant Beagle Dogs. Stem Cells Transl Med;2022 (Jul 20);11(7):778-789.

Mesenchymal stem cell-based therapy has emerged as a great potential approach to treat individuals with autism spectrum disorders (ASD), a group of developmental disabilities characterized by impairments in social interaction and communication. Stem cells from human exfoliated deciduous teeth (SHED), holding earlier developing characteristics, have immune-modulatory and anti-inflammatory properties. To investigate whether SHED transplantation can rescue autistic-like symptoms in SHANK3 mutant beagle dogs, 12 SHANK3 mutant beagle dogs were randomly assigned into 2 groups according to their behavior evaluated by social interaction tests. Six mutant dogs received 6 intravenous infusions of SHED and were followed up for 3 months by testing social interaction and inflammatory cytokine levels. We found that infusion of SHED significantly improved impaired social novel preference of SHANK3 mutant beagle dogs at 1- and 3-month follow-ups. Social intimacies (following, sniffing, and licking) between mutant beagle dogs and human experimenters were partly improved. Stressed tail posture, indicating social stress, was also significantly alleviated. In addition, we showed that the levels of serum interferon-γ and interleukin-10 were notably increased and decreased, respectively, in SHANK3 mutant beagle dogs. Infusion of SHED was able to rescue altered interferon-γ and interleukin-10 levels. We failed to observe any serious adverse events after infusion of SHED. In summary, SHED transplantation may be a safe and effective therapy for ASD. The correction in the levels of serum interferon-γ and interleukin-10 may serve as an index to predict autistic severity and therapeutic outcomes.

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