1. Alzrayer NM, Aldabas R, Alhossein A, Alharthi H. Naturalistic teaching approach to develop spontaneous vocalizations and augmented communication in children with autism spectrum disorder. Augmentative and alternative communication (Baltimore, Md : 1985). 2021; 37(1): 14-24.

Naturalistic developmental behavioral interventions (NDBI) have been shown to facilitate the development of spontaneous language in individuals with speech and language impairment. Several meta-analyses have reported a small number of studies that utilized naturalistic teaching approaches combined with augmentative and alternative communication (AAC) interventions to develop requesting skills in individuals with autism spectrum disorder (ASD). Therefore, the main purpose of this study was to determine whether a natural language paradigm (NLP) and time delay is effective in expanding vocal and augmented requesting skills in three children with ASD between the ages of 4 and 6 years. A concurrent multiple baseline design across participants was used to evaluate the effectiveness of the intervention. The results of the study demonstrated that the participants were successful in emitting vocal requests when both modalities were available and NLP combined with time delay was effective in increasing spontaneous vocal requests in all participants.

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2. Bourinaris T, Athanasiou A, Efthymiou S, Wiethoff S, Salpietro V, Houlden H. Allelic and phenotypic heterogeneity in Junctophillin-3 related neurodevelopmental and movement disorders. European journal of human genetics : EJHG. 2021; 29(6): 1027-31.

Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3 homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.

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3. Constable PA, Lee IO, Marmolejo-Ramos F, Skuse DH, Thompson DA. The photopic negative response in autism spectrum disorder. Clinical & experimental optometry. 2021; 104(8): 841-7.

CLINICAL RELEVANCE: To ascertain if the photopic negative response of the electroretinogram is different in autism spectrum disorder as a potential clinical marker. BACKGROUND: Visual function can be atypical in autism spectrum disorder and structural imaging of the ganglion cell layers has been reported to differ in these individuals. Therefore, we sought to investigate if the photopic negative response of the full field electroretinograms, a measure of ganglion cell function, could help explain the visual perceptual differences in autism spectrum disorder and support the structural changes observed. METHODS: Participants (n = 55 autism spectrum disorder, aged 5.4-26.7 years) and control (n = 87, aged 5.4-27.3 years) were recruited for the study. Full-field light-adapted electroretinograms using a Troland protocol with 10 flash strengths from -0.367 to 1.204 log photopic cd.s.m(-2) were recorded in each eye. The photopic negative response amplitudes at Tmin and at t = 72 ms were compared between groups along with the a- and b-wave values. RESULTS: There were no significant interactions between groups for the Photopic Negative Response measures of amplitude or time (p > 0.30). There was a group interaction between groups and flash strengths for the b-wave amplitude as previously reported (p < 0.001). CONCLUSION: The photopic negative response results suggest that there are no significant differences in the summed retinal ganglion cell responses produced by a full-field stimulus.

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4. Darki F, Nyström P, McAlonan G, Bölte S, Falck-Ytter T. T1-Weighted/T2-Weighted Ratio Mapping at 5 Months Captures Individual Differences in Behavioral Development and Differentiates Infants at Familial Risk for Autism from Controls. Cerebral cortex (New York, NY : 1991). 2021; 31(9): 4068-77.

Identifying structural measures that capture early brain development and are sensitive to individual differences in behavior is a priority in developmental neuroscience, with potential implications for our understanding of both typical and atypical populations. T1-weighted/T2-weighted (T1w/T2w) ratio mapping, which previously has been linked to myelination, represents an interesting candidate measure in this respect, as an accessible measure from standard magnetic resonance imaging (MRI) sequences. Yet, its value as an early infancy measure remains largely unexplored. Here, we compared T1w/T2w ratio in 5-month-old infants at familial risk (n = 27) for autism spectrum disorder (ASD) to those without elevated autism risk (n = 16). We found lower T1w/T2w ratio in infants at high risk for ASD within widely distributed regions, spanning both white and gray matter. In regions differing between groups, higher T1w/T2w ratio was robustly associated with higher age at scan (range: ~ 4-6.5 months), implying sensitivity to maturation at short developmental timescales. Further, higher T1w/T2w ratio within these regions was associated with higher scores on measures of concurrent developmental level. These findings suggest that T1w/T2w ratio is a developmentally sensitive measure that should be explored further in future studies of both typical and atypical infant populations.

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5. David MM. The Role of the Microbiome in Autism: All That We Know about All That We Don’t Know. mSystems. 2021; 6(2).

Autism spectrum disorder (ASD) is a remarkably complex disorder influenced by both genetic and environmental factors. Numerous microbial diversity surveys conducted over the past decade have attempted to link specific ASD biomarkers to gastrointestinal tract disturbances, but results generated across cohorts and studies remain inconsistent. This commentary discusses multidirectional interactions between the host, the microbiome, and external factors germane to autism. Recent studies posit the heritability of the gut microbiome itself, confounding attempts to discern heritable from nonheritable effectors in neurodevelopmental disorders. Elucidating the ever-evolving gut microbiome’s role in modulating the ASD phenotype will most certainly require new experimental methodologies and designs. In a recent paper published in mSystems (J. Fouquier, N. Moreno Huizar, J. Donnelly, C. Glickman, et al., mSystems e00848-20, 2021, https://doi.org/10.1128/mSystems.00848-20), the authors describe a web of interactions by collecting samples longitudinally, analyzing cross-sectional cohorts, and recording nonbinary phenotypic measurements.

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6. David MM, Tataru C, Daniels J, Schwartz J, Keating J, Hampton-Marcell J, Gottel N, Gilbert JA, Wall DP. Children with Autism and Their Typically Developing Siblings Differ in Amplicon Sequence Variants and Predicted Functions of Stool-Associated Microbes. mSystems. 2021; 6(2).

The existence of a link between the gut microbiome and autism spectrum disorder (ASD) is well established in mice, but in human populations, efforts to identify microbial biomarkers have been limited due to a lack of appropriately matched controls, stratification of participants within the autism spectrum, and sample size. To overcome these limitations, we crowdsourced the recruitment of families with age-matched sibling pairs between 2 and 7 years old (within 2 years of each other), where one child had a diagnosis of ASD and the other did not. Parents collected stool samples, provided a home video of their ASD child’s natural social behavior, and responded online to diet and behavioral questionnaires. 16S rRNA V4 amplicon sequencing of 117 samples (60 ASD and 57 controls) identified 21 amplicon sequence variants (ASVs) that differed significantly between the two cohorts: 11 were found to be enriched in neurotypical children (six ASVs belonging to the Lachnospiraceae family), while 10 were enriched in children with ASD (including Ruminococcaceae and Bacteroidaceae families). Summarizing the expected KEGG orthologs of each predicted genome, the taxonomic biomarkers associated with children with ASD can use amino acids as precursors for butyragenic pathways, potentially altering the availability of neurotransmitters like glutamate and gamma aminobutyric acid (GABA).IMPORTANCE Autism spectrum disorder (ASD), which now affects 1 in 54 children in the United States, is known to have comorbidity with gut disorders of a variety of types; however, the link to the microbiome remains poorly characterized. Recent work has provided compelling evidence to link the gut microbiome to the autism phenotype in mouse models, but identification of specific taxa associated with autism has suffered replicability issues in humans. This has been due in part to sample size that sufficiently covers the spectrum of phenotypes known to autism (which range from subtle to severe) and a lack of appropriately matched controls. Our original study proposes to overcome these limitations by collecting stool-associated microbiome on 60 sibling pairs of children, one with autism and one neurotypically developing, both 2 to 7 years old and no more than 2 years apart in age. We use exact sequence variant analysis and both permutation and differential abundance procedures to identify 21 taxa with significant enrichment or depletion in the autism cohort compared to their matched sibling controls. Several of these 21 biomarkers have been identified in previous smaller studies; however, some are new to autism and known to be important in gut-brain interactions and/or are associated with specific fatty acid biosynthesis pathways.

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7. Drimalla H, Baskow I, Behnia B, Roepke S, Dziobek I. Imitation and recognition of facial emotions in autism: a computer vision approach. Molecular autism. 2021; 12(1): 27.

BACKGROUND: Imitation of facial expressions plays an important role in social functioning. However, little is known about the quality of facial imitation in individuals with autism and its relationship with defining difficulties in emotion recognition. METHODS: We investigated imitation and recognition of facial expressions in 37 individuals with autism spectrum conditions and 43 neurotypical controls. Using a novel computer-based face analysis, we measured instructed imitation of facial emotional expressions and related it to emotion recognition abilities. RESULTS: Individuals with autism imitated facial expressions if instructed to do so, but their imitation was both slower and less precise than that of neurotypical individuals. In both groups, a more precise imitation scaled positively with participants’ accuracy of emotion recognition. LIMITATIONS: Given the study’s focus on adults with autism without intellectual impairment, it is unclear whether the results generalize to children with autism or individuals with intellectual disability. Further, the new automated facial analysis, despite being less intrusive than electromyography, might be less sensitive. CONCLUSIONS: Group differences in emotion recognition, imitation and their interrelationships highlight potential for treatment of social interaction problems in individuals with autism.

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8. Erden S, Akbaş İleri B, Sadıç Çelikkol Ç, Nalbant K, Kılınç İ, Yazar A. Serum B12, homocysteine, and anti-parietal cell antibody levels in children with autism. International journal of psychiatry in clinical practice. 2022; 26(1): 8-13.

AIMS: To compare vitamin B12, homocysteine, and anti-parietal cell antibody (APCA) levels between children with ASD and controls, paired in terms of age, sex, and socioeconomic level. METHODS: The research group consisted of 69 children, 36 with ASD and 33 controls. The severity of ASD was determined using the Childhood Autism Rating Scale (CARS). Serum vitamin B12, homocysteine and human anti-parietal cell levels were analysed using enzyme-linked immunosorbent assay. RESULTS: The serum vitamin B12 and homocysteine levels in children with ASD were lower than in the control group, but there was no significant difference in terms of APCA levels. CONCLUSIONS: Deficiencies in micronutrients, such as B12, may play a role in the pathogenesis and clinical symptoms of autism. However, it is believed that these parameters should be analysed in a wider population to clarify their effect on the aetiology of ASD.KEY POINTWe hypothesised that low levels of vitamin B12 and homocysteine levels reported in previous studies might be associated with APCA levels.The homocysteine and B12 levels were found to be significantly lower in children with ASD. There was no significant difference in serum APCA levels.No significant relationship was found between B12 levels and APCA.Given all these findings, it can be stated that vitamin B12 deficiency is not associated with an absorption-related mechanism due to the presence of APCA.Deficiencies in micronutrients, such as B12, may play a role in the pathogenesis and clinical symptoms of autism.In future studies, it will be beneficial to investigate other mechanisms that may cause vitamin B12 deficiency.

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9. Etchecopar-Etchart D, Da Fonseca D, Lançon C, Boyer L, Fond G. Psychonutritional intervention for autism spectrum disorders. L’Encephale. 2021; 47(4): 289-90.

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10. Fouquier J, Moreno Huizar N, Donnelly J, Glickman C, Kang DW, Maldonado J, Jones RA, Johnson K, Adams JB, Krajmalnik-Brown R, Lozupone C. The Gut Microbiome in Autism: Study-Site Effects and Longitudinal Analysis of Behavior Change. mSystems. 2021; 6(2).

Research relating gut microbiome composition to autism spectrum disorders (ASD) has produced inconsistent results, indicative of the disorder’s complexity and the need for more sophisticated experimental designs. We address this need by (i) comparing gut microbiome composition between individuals with ASD and neurotypical controls in Arizona and Colorado using standardized DNA extraction and sequencing methods at both locations and (ii) longitudinally evaluating the gut microbiome’s relationship to autism behavioral severity, diet, and gastrointestinal symptoms. Gut microbiome composition differed between individuals in Arizona and individuals in Colorado, and gastrointestinal symptoms were significantly higher in ASD individuals than in neurotypical individuals in Arizona but not in Colorado. Gut microbiome composition was significantly associated with ASD while controlling for study-site location but not when controlling for gastrointestinal symptoms. This suggests that non-ASD-related study site differences in gut microbiome composition and different degrees of gastrointestinal symptoms involvement with ASD between sites may contribute to inconsistent results in the literature regarding the association between gut microbiome composition and ASD. In the longitudinal analysis, we found that difference in levels of lethargy/social withdrawal measured in individuals at different time points correlated with the degree of change in gut microbiome composition and that a worsening of inappropriate speech between time points was associated with decreased gut microbiome diversity. This relationship between changes in the gut microbiome composition within individuals and ASD behavioral severity metrics indicates that longitudinal study designs may be useful for exploring microbial drivers of ASD severity when substantial variability exists in baseline microbiome compositions across individuals and geographical regions.IMPORTANCE Autism spectrum disorder (ASD) is a brain developmental disorder with varying behavioral symptom severity both across individuals and within individuals over time. There have been promising but also inconsistent literature results regarding how the gut microbiota (microbiome) may be involved. We found that the gut microbiome in individuals with ASD is affected by study-site location as well as gastrointestinal symptom severity. When we sampled some individuals with ASD at several different time points, we found that some behaviors, such as lethargy/social withdrawal and inappropriate speech, changed along with changes in the gut microbiota composition. This is the first study to relate severity of behavior symptoms to gut microbiome composition within individuals over time and suggests a dynamic relationship between ASD-associated symptoms and gut microbes. Longitudinal study designs as well as collaborative efforts across multiple centers are needed to fully characterize the relationship between ASD and gut microbes.

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11. Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Ross D, Stanley V, Sonmez FM, Topaloglu H, Zaki MS, Hosny H, Gad S, Gleeson JG. Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia. European journal of human genetics : EJHG. 2021; 29(6): 957-64.

HEAT repeats are 37-47 amino acid flexible tandem repeat structural motifs occurring in a wide variety of eukaryotic proteins with diverse functions. Due to their ability to undergo elastic conformational changes, they often serve as scaffolds at sites of protein interactions. Here, we describe four affected children from two families presenting with pontocerebellar hypoplasia manifest clinically with neonatal seizures, severe intellectual disability, and motor delay. Whole exome sequencing identified biallelic variants at predicted splice sites in intron 31 of HEATR5B, encoding the HEAT repeat-containing protein 5B segregating in a recessive fashion. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. HEATR5B is expressed during brain development in human, and we failed to recover live-born homozygous Heatr5b knockout mice. Taken together, our results implicate loss of HEATR5B in pontocerebellar hypoplasia.

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12. Janvier D, Choi YB, Klein C, Lord C, Kim SH. Brief Report: Examining Test-Retest Reliability of the Autism Diagnostic Observation Schedule (ADOS-2) Calibrated Severity Scores (CSS). Journal of autism and developmental disorders. 2022; 52(3): 1388-94.

Describing the relative severity and change in autism symptoms is crucial for the appropriate characterization of clinical and research populations. The calibrated severity score (CSS) of the Autism Diagnostic Observation Schedule-2 (ADOS-2; Lord et al., 2012) was created to better describe autism symptom severity consistently across different ages and language levels. The CSS has been widely used to quantify and compare symptom severity on a 10-point scale across Modules; however, its test re-test reliability has not been studied. With 608 ADOS observations, we showed strong test re-test reliability of the CSS across all ADOS Modules. The results support the use of the ADOS CSS as a reliable tool to quantify autism symptom severity across development.

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13. Jurek L, Baltazar M, Gulati S, Novakovic N, Núñez M, Oakley J, O’Hagan A. Response (minimum clinically relevant change) in ASD symptoms after an intervention according to CARS-2: consensus from an expert elicitation procedure. European child & adolescent psychiatry. 2021: 1-10.

The lack of consensual measures to monitor core change in Autism Spectrum Disorder (ASD) or response to interventions leads to difficulty to prove intervention efficacy on ASD core symptoms. There are no universally accepted outcome measures developed for measuring changes in core symptoms. However, the CARS (Childhood Autism Rating Scale) is one of the outcomes recommended in the EMA Guideline on the clinical development of medicinal products for the treatment of ASD. Unfortunately, there is currently no consensus on the response definition for CARS among individuals with ASD. The aim of this elicitation process was to determine an appropriate definition of a response on the CARS2 scale for interventions in patients with Autism Spectrum Disorder (ASD). An elicitation process was conducted following the Sheffield Elicitation Framework (SHELF). Five experts in the field of ASD and two experts in expert knowledge elicitation participated in an 1-day elicitation workshop. Experts in ASD were previously trained in the SHELF elicitation process and received a dossier of scientific evidence concerning the topic. The response definition was set as the mean clinically relevant improvement averaged over all patients, levels of functioning, age groups and clinicians. Based on the scientific evidence and expert judgment, a normal probability distribution was agreed to represent the state of knowledge of this response with expected value 4.03 and standard deviation 0.664. Considering the remaining uncertainty of the estimation and the available literature, a CARS-2 improvement of 4.5 points has been defined as a threshold to conclude to a response after an intervention. A CARS-2 improvement of 4.5 points could be used to evaluate interventions’ meaningfulness in indivudals. This initial finding represents an important new benchmark and may aid decision makers in evaluating the efficacy of interventions in ASD.

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14. Kawamura A, Katayama Y, Kakegawa W, Ino D, Nishiyama M, Yuzaki M, Nakayama KI. The autism-associated protein CHD8 is required for cerebellar development and motor function. Cell reports. 2021; 35(1): 108932.

Mutations in the gene encoding the chromatin remodeler chromodomain helicase DNA-binding protein 8 (CHD8) are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have long been thought to be related to ASD pathogenesis, it has remained largely unknown whether dysfunction of CHD8 in the cerebellum contributes to ASD phenotypes. We here show that cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 in mice impairs the proliferation and differentiation of these cells as well as gives rise to cerebellar hypoplasia and a motor coordination defect, but not to ASD-like behavioral abnormalities. CHD8 is found to regulate the expression of neuronal genes in GNPs. It also binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in these cells. Our results have thus uncovered a key role for CHD8 in cerebellar development, with important implications for understanding the contribution of this brain region to ASD pathogenesis.

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15. Luckhardt C, Schütz M, Mühlherr A, Mössinger H, Boxhoorn S, Dempfle A, Salvador R, Ruffini G, Pereira HC, Castelo-Branco M, Latinus M, Bonnet-Brilhault F, Siemann J, Siniatchkin M, Ecker C, Freitag CM. Phase-IIa randomized, double-blind, sham-controlled, parallel group trial on anodal transcranial direct current stimulation (tDCS) over the left and right tempo-parietal junction in autism spectrum disorder-StimAT: study protocol for a clinical trial. Trials. 2021; 22(1): 248.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction, and stereotyped, repetitive behaviour and sensory interests. To date, there is no effective medication that can improve social communication and interaction in ASD, and effect sizes of behaviour-based psychotherapy remain in the low to medium range. Consequently, there is a clear need for new treatment options. ASD is associated with altered activation and connectivity patterns in brain areas which process social information. Transcranial direct current stimulation (tDCS) is a technique that applies a weak electrical current to the brain in order to modulate neural excitability and alter connectivity. Combined with specific cognitive tasks, it allows to facilitate and consolidate the respective training effects. Therefore, application of tDCS in brain areas relevant to social cognition in combination with a specific cognitive training is a promising treatment approach for ASD. METHODS: A phase-IIa pilot randomized, double-blind, sham-controlled, parallel-group clinical study is presented, which aims at investigating if 10 days of 20-min multi-channel tDCS stimulation of the bilateral tempo-parietal junction (TPJ) at 2.0 mA in combination with a computer-based cognitive training on perspective taking, intention and emotion understanding, can improve social cognitive abilities in children and adolescents with ASD. The main objectives are to describe the change in parent-rated social responsiveness from baseline (within 1 week before first stimulation) to post-intervention (within 7 days after last stimulation) and to monitor safety and tolerability of the intervention. Secondary objectives include the evaluation of change in parent-rated social responsiveness at follow-up (4 weeks after end of intervention), change in other ASD core symptoms and psychopathology, social cognitive abilities and neural functioning post-intervention and at follow-up in order to explore underlying neural and cognitive mechanisms. DISCUSSION: If shown, positive results regarding change in parent-rated social cognition and favourable safety and tolerability of the intervention will confirm tDCS as a promising treatment for ASD core-symptoms. This may be a first step in establishing a new and cost-efficient intervention for individuals with ASD. TRIAL REGISTRATION: The trial is registered with the German Clinical Trials Register (DRKS), DRKS00014732 . Registered on 15 August 2018. PROTOCOL VERSION: This study protocol refers to protocol version 1.2 from 24 May 2019.

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16. Morson S, Yang Y, Price DJ, Pratt T. Expression of Genes in the 16p11.2 Locus during Development of the Human Fetal Cerebral Cortex. Cerebral cortex (New York, NY : 1991). 2021; 31(9): 4038-52.

The 593 kbp 16p11.2 copy number variation (CNV) affects the gene dosage of 29 protein coding genes, with heterozygous 16p11.2 microduplication or microdeletion implicated in about 1% of autism spectrum disorder (ASD) cases. The 16p11.2 CNV is frequently associated with macrocephaly or microcephaly indicating early defects of neurogenesis may contribute to subsequent ASD symptoms, but it is unknown which 16p11.2 transcripts are expressed in progenitors and whose levels are likely, therefore, to influence neurogenesis. Analysis of human fetal gene expression data revealed that KIF22, ALDOA, HIRIP3, PAGR1, and MAZ transcripts are expressed in neural progenitors with ALDOA and KIF22 significantly enriched compared to post-mitotic cells. To investigate the possible roles of ALDOA and KIF22 proteins in human cerebral cortex development we used immunohistochemical staining to describe their expression in late first and early second trimester human cerebral cortex. KIF22 protein is restricted to proliferating cells with its levels increasing during the cell cycle and peaking at mitosis. ALDOA protein is expressed in all cell types and does not vary with cell-cycle phase. Our expression analysis suggests the hypothesis that altered neurogenesis in the cerebral cortex contributes to ASD in 16p11.2 CNV patients.

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17. Osei-Kuffour D, Dheansa B. The prevalence of autism spectrum disorder in the paediatric burns population. Burns : journal of the International Society for Burn Injuries. 2021; 47(5): 1220-1.

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18. Storch EA, Wood JJ, Guzick AG, Small BJ, Kerns CM, Ordaz DL, Schneider SC, Kendall PC. Moderators of Response to Personalized and Standard Care Cognitive-Behavioral Therapy for Youth with Autism Spectrum Disorder and Comorbid Anxiety. Journal of autism and developmental disorders. 2022; 52(2): 950-8.

Anxiety/obsessive-compulsive disorders are common among youth with autism spectrum disorder (ASD). Two versions of cognitive behavior therapy (CBT) are effective, with some advantage for a personalized, adapted version. This study evaluated predictors and moderators of standard CBT and adapted CBT. Youth (N = 167) ages 7-13 were randomized to standard or adapted CBT, or treatment-as-usual. Age, IQ, ASD severity, and emotional-behavioral symptom severity were examined. More severe internalizing and emotional-behavioral problems predicted poorer treatment outcomes especially in standard versus personalized CBT. Elevated repetitive behaviors and restricted interests predicted poorer treatment outcomes across treatments, though youth with « moderate » repetitive behaviors and restricted interested experienced poorer outcomes only in standard but not personalized CBT. Externalizing symptoms directly predicted treatment outcomes. Older age predicted improved outcomes in adapted but not standard CBT. Findings highlight the need for further treatment refinements and the value in adapting treatment for youth with more complex presentations. Trial Registration Clinicialtrials.gov: NCT02028247; https://clinicaltrials.gov/ct2/show/NCT02028247 .

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19. Takeuchi J, Sakagami Y. Association between autistic tendency and mental health for studying abroad. Pediatrics international : official journal of the Japan Pediatric Society. 2021; 64(1): e14724.

BACKGROUND: To identify the association between autistic tendencies and mental health among university students who study abroad. METHODS: We conducted a historical cohort study at a Japanese university, targeting students who went overseas from 2012 to 2014 as part of study abroad program. We administered questionnaires to students before and after they completed the overseas study program. These questionnaires included items about sex, age, academic degrees, department affiliations, past experience of studying abroad, type of overseas program, and schedule of departures and returns. To determine students’ mental health problems, we considered cross-cultural maladaptation while studying abroad as the outcome by two reviewers. We also administered the Autism-Spectrum Quotient, Japanese version (AQ), and the General Health Questionnaire 60 Japanese version. We utilized the logistic regression model after adjusting for the General Health Questionnaire and country or region with programs to estimate odds ratios (OR) for considering outcomes. RESULTS: Of the 585 who participated in this study excluding two students for cancellations, 352 (60.2%) completed to following-up. The prevalence of mental health problems was 6.0% (21/406) and categorized when studying abroad. The mean AQ score was 19.3 (standard deviation = ±7.12). High AQ (a score of 33 and more) was prevalent among 3.7% (18/486). Students with high AQ had more mental health problems compared to those without high AQ (adjusted ORs 5.87; 95% confidence interval, 1.24-27.9, P = 0.03). CONCLUSIONS: We clarified the association between autistic tendencies and mental health for students studying abroad.

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20. Tunç B, Pandey J, St John T, Meera SS, Maldarelli JE, Zwaigenbaum L, Hazlett HC, Dager SR, Botteron KN, Girault JB, McKinstry RC, Verma R, Elison JT, Pruett JR, Jr., Piven J, Estes AM, Schultz RT. Diagnostic shifts in autism spectrum disorder can be linked to the fuzzy nature of the diagnostic boundary: a data-driven approach. Journal of child psychology and psychiatry, and allied disciplines. 2021; 62(10): 1236-45.

BACKGROUND: Diagnostic shifts at early ages may provide invaluable insights into the nature of separation between autism spectrum disorder (ASD) and typical development. Recent conceptualizations of ASD suggest the condition is only fuzzily separated from non-ASD, with intermediate cases between the two. These intermediate cases may shift along a transition region over time, leading to apparent instability of diagnosis. METHODS: We used a cohort of children with high ASD risk, by virtue of having an older sibling with ASD, assessed at 24 months (N = 212) and 36 months (N = 191). We applied machine learning to empirically characterize the classification boundary between ASD and non-ASD, using variables quantifying developmental and adaptive skills. We computed the distance of children to the classification boundary. RESULTS: Children who switched diagnostic labels from 24 to 36 months, in both directions, (dynamic group) had intermediate phenotypic profiles. They were closer to the classification boundary compared to children who had stable diagnoses, both at 24 months (Cohen’s d = .52) and at 36 months (d = .75). The magnitude of change in distance between the two time points was similar for the dynamic and stable groups (Cohen’s d = .06), and diagnostic shifts were not associated with a large change. At the individual level, a few children in the dynamic group showed substantial change. CONCLUSIONS: Our results suggested that a diagnostic shift was largely due to a slight movement within a transition region between ASD and non-ASD. This fact highlights the need for more vigilant surveillance and intervention strategies. Young children with intermediate phenotypes may have an increased susceptibility to gain or lose their diagnosis at later ages, calling attention to the inherently dynamic nature of early ASD diagnoses.

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21. Xiao L, Yan J, Yang T, Zhu J, Li T, Wei H, Chen J. Fecal Microbiome Transplantation from Children with Autism Spectrum Disorder Modulates Tryptophan and Serotonergic Synapse Metabolism and Induces Altered Behaviors in Germ-Free Mice. mSystems. 2021; 6(2).

To determine the relationship of the gut microbiota and its metabolites with autism spectrum disorder (ASD)-like behaviors and preliminarily explore the potential molecular mechanisms, the fecal microbiota from donors with ASD and typically developing (TD) donors were transferred into germ-free (GF) mice to obtain ASD-FMT mice and TD-FMT mice, respectively. Behavioral tests were conducted on these mice after 3 weeks. 16S rRNA gene sequencing of the cecal contents and untargeted metabolomic analysis of the cecum, serum, and prefrontal cortex were performed. Untargeted metabolomics was also used to analyze fecal samples of TD and ASD children. Western blotting detected the protein expression levels of tryptophan hydroxylase 1 (TPH1), serotonin transporter (SERT), and serotonin 1A receptor (5-HT1AR) in the colon and TPH2, SERT, and 5-HT1AR in the prefrontal cortex of mice. ASD-FMT mice showed ASD-like behavior and a microbial community structure different from that of TD-FMT mice. Tryptophan and serotonin metabolisms were altered in both ASD and TD children and ASD-FMT and TD-FMT mice. Some microbiota may be related to tryptophan and serotonin metabolism. Compared with TD-FMT mice, ASD-FMT mice showed low SERT and 5-HT1AR and high TPH1 expression levels in the colon. In the prefrontal cortex, the expression levels of TPH2 and SERT were increased in the ASD-FMT group relative to the TD-FMT group. Therefore, the fecal microbiome of ASD children can lead to ASD-like behaviors, different microbial community structures, and altered tryptophan and serotonin metabolism in GF mice. These changes may be related to changes in some key proteins involved in the synthesis and transport of serotonin.IMPORTANCE The relationship between the gut microbiota and ASD is not yet fully understood. Numerous studies have focused on the differences in intestinal microbial and metabolism profiles between TD and ASD children. However, it is still not clear if these microbes and metabolites cause the development of ASD symptoms. Here, we collected fecal samples from TD and ASD children, transplanted them into GF mice, and found that the fecal microbiome of ASD children can lead to ASD-like behaviors, different microbial community structures, and altered tryptophan and serotonin metabolism in GF mice. We also demonstrated that tryptophan and serotonin metabolism was also altered in ASD and TD children. Together, these findings confirm that the microbiome from children with ASD may lead to ASD-like behavior of GF mice through metabolites, especially tryptophan and serotonin metabolism.

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22. Zhou RY, Ma BX, Wang JJ. Difficulties in the Diagnosis and Treatment of Children with Autism Spectrum Disorder in China. Journal of autism and developmental disorders. 2022; 52(2): 959-61.

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