1. Al-Ayadhi L, Abualnaja A, AlZarroug A, Alharbi T, Alhowikan AM, Halepoto DM, Al-Mazidi S. A Disintegrin and Metalloproteinase Protein 8 (ADAM 8) in Autism Spectrum Disorder: Links to Neuroinflammation. Neuropsychiatr Dis Treat;2023;19:1771-1780.

BACKGROUND: Converging lines of evidence confirmed neuroinflammation’s role in autism spectrum disorder (ASD) etiological pathway. A disintegrin and metalloproteinase 8 (ADAM8) play major roles in inflammatory and allergic processes in various diseases. AIM: This study aimed to investigate ADAM8 plasma levels in autistic children compared to healthy controls. Also, to discover the association between ADAM8, disease severity, and neuroinflammation in ASD. METHODOLOGY: This case-control study included children with ASD (n=40) and aged-matched healthy controls (n=40). The plasma levels of the ADAM 8 were determined using enzyme-linked immunosorbent assay (ELISA). The assessment of ASD severity and social and sensory behaviors were categorized as mild, moderate and severe. Correlations among ADAM8 plasma levels and ASD severity scores [Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS) and Short Sensory Profile (SSP)] were obtained by Spearman correlation coefficient (r). RESULTS: ASD children (n=40), including severe autism (n=21) and mild-to-moderate autism (n=19), showed significantly (p ≤ 0.05) lower plasma levels of ADAM8 [4683 (2885-5229); 4663 (4060-5000); 4632 (2885-5229)], respectively, than those of healthy controls [5000 (4047-5000)] [median (IQR) pg/mL]. However, there was no significant difference between the ADAM8 levels of children with severe and mild-to-moderate autism (p = 0.71). Moreover, ADAM8 plasma levels were not significantly correlated with the severity of ASD measured by behavioral scales [CARS (r= -0.11, p=0.55), SRS (r=0.11, p= 0.95), SSP (r=-0.23, p=0.23)]. CONCLUSION: The low ADAM8 plasma levels in children with ASD possibly indicated that ADAM8 might be implicated in the pathogenesis of ASD but not in the severity of the disease. These results should be interpreted with caution until additional studies are carried out with larger populations to decide whether the reduction in plasma ADAM8 levels is a mere consequence of ASD or if it plays a pathogenic role in the disease.

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2. Belica I, Janšáková K, Celušáková H, Kopčíková M, Polónyiová K, Rašková B, Vidošovičová M, Ostatníková D, Babinská K. Plasma cytokine concentrations of children with autism spectrum disorder and neurotypical siblings. Cytokine;2023 (Aug 18);170:156333.

Several studies of autism spectrum disorder (ASD) have shown cytokine dysregulation in children with ASD, leading to a consideration of the immune theory of the ASD etiopathogenesis and a debate about cytokines as potential biomarkers of ASD. However, the results of these studies are still inconsistent. Overall, studies comparing the cytokine levels of children with ASD and neurotypical siblings achieved relatively different results than studies with control groups of non-siblings. The studies suggest that the immune profile of siblings of individuals with ASD serving as control is more similar to children with ASD than the profile of non-siblings. However, there are still only a few studies with control groups including neurotypical siblings of children with ASD. The aim of our study was to determine whether the concentration of plasma cytokine levels may differentiate children with ASD from their neurotypical siblings. The sample consisted of 40 children with ASD (mean age 7.11 years, SD 2.9) and 21 neurotypical siblings (mean age 7.38, SD 3.3). Levels of 20 cytokines were included into the statistical analysis. A multiple logistic regression model using multiple corrections showed that an increase in log-transformed plasma G-CSF (granulocyte colony stimulating factor) concentration is associated with an increased risk of the child being diagnosed as an ASD case (OR = 4.35, 95% CI 1.77, 10.73). Although the significantly increased concentration of G-CSF suggests a slightly different activity of the immune system of children with ASD, the overall cytokine profile of their siblings appeared to be very similar.

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3. Bobos D, Soufla G, Angouras DC, Lekakis I, Georgopoulos S, Melissari E. Investigation of the Role of BMP2 and -4 in ASD, VSD and Complex Congenital Heart Disease. Diagnostics (Basel);2023 (Aug 21);13(16)

Congenital heart malformations (CHMs) make up between 2 and 3% of annual human births. Bone morphogenetic proteins (BMPs) signalling is required for chamber myocardium development. We examined for possible molecular defects in the bone morphogenetic protein 2 and 4 (BMP2, -4) genes by sequencing analysis of all coding exons, as well as possible transcription or protein expression deregulation by real-time PCR and ELISA, respectively, in 52 heart biopsies with congenital malformations (atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy ofFallot (ToF) and complex cases) compared to 10 non-congenital heart disease (CHD) hearts. No loss of function mutations was found; only synonymous single nucleotide polymorphisms (SNPs) in the BMP2 and BMP4 genes were found. Deregulation of the mRNA expression and co-expression profile of the two genes (BMP2/BMP4) was observed in the affected compared to the normal hearts. BMP2 and -4 protein expression levels were similar in normal and affected hearts. This is the first study assessing the role of BMP-2 and 4 in congenital heart malformations. Our analysis did not reveal molecular defects in the BMP2 and -4 genes that could support a causal relationship with the congenital defects present in our patients. Importantly, sustained mRNA and protein expression of BMP2 and -4 in CHD cases compared to controls indicates possible temporal epigenetic, microRNA or post-transcriptional regulation mechanisms governing the initial stages of cardiac malformation.

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4. do Nascimento P, Oliveira Silva DF, de Morais T, de Rezende AA. Zinc Status and Autism Spectrum Disorder in Children and Adolescents: A Systematic Review. Nutrients;2023 (Aug 21);15(16)

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, the prevalence of which has increased in children and adolescents over the years. Studies point to deficiency of trace elements as one of the factors involved in the etiology of the disorder, with zinc being one of the main trace elements investigated in individuals with ASD. The aim of this review is to summarize scientific evidence about the relationship between zinc status and ASD in children and adolescents. This review has been registered in the International Prospective Register of Systematic Reviews (registration number CRD42020157907). The methodological guidelines adopted were in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were selected from an active investigation of the PubMed, Scopus, LILACS, and Google databases to search for observational studies. Fifty-two studies from twenty-two countries were included. The sample sizes ranged from 20 to 2635, and the participants ranged from 2 to 18 years old. Nine types of biological matrices were used, with hair, serum, and plasma being the most frequently used in the evaluation of zinc concentrations. Significant differences in zinc concentrations between the ASD and control groups were observed in 23 studies, of which 19 (36%) showed lower zinc concentrations in the ASD group. The classification of studies according to methodological quality resulted in high, moderate, and low quality in 10, 21, and 21 studies, respectively. In general, we did not observe a significant difference between zinc concentrations of children and adolescents with ASD compared to controls; however, studies point to an occurrence of lower concentrations of Zn in individuals with ASD. This review reveals that more prospective studies with greater methodological rigor should be conducted in order to further characterize this relation.

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5. Fang Y, Cui Y, Yin Z, Hou M, Guo P, Wang H, Liu N, Cai C, Wang M. Comprehensive systematic review and meta-analysis of the association between common genetic variants and autism spectrum disorder. Gene;2023 (Aug 18):147723.

BACKGROUND: Autism spectrum disorder (ASD) is neurodevelopmental disorder characterized by stereotyped behavior and deficits in communication and social interactions. To date, numerous studies have investigated the associations between genetic variants and ASD risk. However, the results of these published studies lack a clear consensus. In the present study, we performed a systematic review on the association between genetic variants and ASD risk. Meanwhile, we conducted a meta-analysis on available data to identify the association between the single nucleotide polymorphisms (SNPs) of candidate genes and ASD risk. METHODS: We systematically searched public databases including English and Chinese from their inception to August 1, 2022. Two independent reviewers extracted data and assessed study quality. Odds ratio and 95% confidence interval were used as effect indexes to evaluate the association between the SNPs of candidate genes and the risk of ASD. Heterogeneity was explored through subgroup, sensitivity, and meta-regression analyses. Publication bias was assessed by using Egger’s and Begg’s tests for funnel plot asymmetry. In addition, TSA analysis were performed to confirm the study findings. RESULTS: We summarized 84 SNPs of 32 candidate genes from 81 articles included in the study. Subsequently, we analyzed 16 SNPs of eight genes by calculating pooled ORs, and identified eight significant SNPs of contactin associated protein 2 (CNTNAP2), methylentetrahydrofolate reductase (MTHFR), oxytocin receptor (OXTR), and vitamin D receptor (VDR). Results showed that seven SNPs, including the CNTNAP2 rs2710102 (homozygote, heterozygote, dominant and allelic models) and rs7794745 (heterozygote and dominant models), MTHFR C677T (homozygote, heterozygote, dominant, recessive and allelic models) and A1298C (dominant and allelic models), OXTR rs2254298 (homozygote and recessive models), VDR rs731236 (homozygote, dominant, recessive and allelic models) and rs2228570 (homozygote and recessive models), were showed to be correlated with an increased ASD risk. By contrast, the VDR rs7975232 was correlated with a decreased the risk of ASD under the homozygote and allelic models. CONCLUSION: Our study summarized research evidence on the genetic variants of ASD and provides a broad and detailed overview of ASD risk genes. The C677T and A1298C polymorphisms of MTHFR, rs2710102 and rs7794745 polymorphisms of CNTNAP2, rs2254298 polymorphism of OXTR, and rs731236 and rs2228570 polymorphisms of VDR were genetic risk factors. The rs7975232 polymorphism of VDR was a genetic protective factor for ASD. Our study provides novel clues to clinicians and healthcare decision-makers to predict ASD susceptibility.

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6. Honaker MG, Weitlauf AS, Swanson AR, Hooper M, Sarkar N, Wade J, Warren ZE. Paisley: Preliminary validation of a novel app-based e-Screener for ASD in children 18-36 months. Autism Res;2023 (Aug 21)

The purpose of this study was to assess the validity of an autism e-screener, Paisley, when utilized in a clinical research setting via a tablet application. The Paisley application used a series of play-based activities, all of which incorporated varying aspects of the ASD-PEDS. Participants included children (18-36 months; n = 198) referred for evaluation of autism spectrum disorder (ASD) and community providers (n = 66) with differing levels of familiarity with ASD. Community providers administered the Paisley application to children who then completed a comprehensive psychological evaluation. Based on comprehensive evaluation, 75% of children met diagnostic criteria for ASD. Paisley scores were significantly higher for children diagnosed with ASD (15.06) versus those not diagnosed (9.34). The newly determined cutoff ASD-PEDS cutoff score of 13 had significantly higher specificity and positive predictive value than the originally proposed cutoff of 11. Results support the use of Paisley by community providers to identify autism risk in toddlers. Limitations and strengths of the work, as well as opportunities for future clinical validation, are described.

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7. Jacinto M, Monteiro D, Antunes R, Ferreira JP, Matos R, Campos MJ. Effects of exercise on body mass index and waist circumference of individuals with intellectual and developmental disabilities: a systematic review with meta-analysis. Front Physiol;2023;14:1236379.

Introduction/Methods: This systematic review with meta-analysis aims to assess the magnitude of the effects of physical exercise programs on body mass index (BMI) and waist circumference (WC) of individuals with Intellectual and Developmental Disabilities (IDD), metabolic and cardiovascular health markers. Results: Considering the eligibility criteria, a final sample of nine articles was obtained. For BMI, the Z-value obtained to test the null hypothesis (difference between means is zero), showed a Z = -2.176 and p = 0.03. The highest magnitude of the effect was from the intervention with combined training (difference in means: -0.399), with a value of Z = -1.815 and p = 0.07. For WC, the Z-value is zero, showing a Z = -3.306 and p = 0.001. The highest magnitude of the effect was from the intervention with continuous cardiorespiratory training of -0.786, with a value of Z = -2.793 and p = 0.005. Discussion: Physical exercise prevents increases in BMI and WC in individuals with IDD. Aerobic training seems to be more effective in promoting WC and combined training in BMI. Systematic Review Registration: [PROSPERO], identifier [CRD42021255316].

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8. Jiang M, Yan W, Zhang Y, Lu Z, Lu T, Zhang D, Li J, Wang L. Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study. J Transl Med;2023 (Aug 21);21(1):560.

BACKGROUND: Phosphodiesterases (PDEs) have been associated with psychiatric disorders in observational studies; however, the causality of associations remains unestablished. METHODS: Specifically, cyclic nucleotide PDEs were collected from genome-wide association studies (GWASs), including PDEs obtained by hydrolyzing both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (PDE1A, PDE2A, and PDE3A), specific to cGMP (PDE5A, PDE6D, and PDE9A) and cAMP (PDE4D and PDE7A). We performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the relationship between PDEs and nine psychiatric disorders. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran’s Q test, MR-Egger intercept test, MR Steiger test, leave-one-out analyses, funnel plot, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analyses. RESULTS: The PDEs specific to cAMP were associated with higher-odds psychiatric disorders. For example, PDE4D and schizophrenia (SCZ) (odds ratios (OR) = 1.0531, P(IVW) = 0.0414), as well as major depressive disorder (MDD) (OR = 1.0329, P(IVW) = 0.0011). Similarly, PDE7A was associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.0861, P(IVW) = 0.0038). Exploring specific PDE subtypes and increase intracellular cAMP levels can inform the development of targeted interventions. We also observed PDEs (which hydrolyzes both cAMP and cGMP) was associated with psychiatric disorders [OR of PDE1A was 1.0836 for autism spectrum disorder; OR of PDE2A was 0.8968 for Tourette syndrome (TS) and 0.9449 for SCZ; and OR of PDE3A was 0.9796 for MDD; P < 0.05]. Furthermore, psychiatric disorders also had some causal effects on PDEs [obsessive-compulsive disorder on increased PDE6D and decreased PDE2A and PDE4D; anorexia nervosa on decreased PDE9A]. The results of MR were found to be robust using multiple sensitivity analysis. CONCLUSIONS: In this study, potential causal relationships between plasma PDE proteins and psychiatric disorders were established. Exploring other PDE subtypes not included in this study could provide a more comprehensive understanding of the role of PDEs in psychiatric disorders. The development of specific medications targeting PDE subtypes may be a promising therapeutic approach for treating psychiatric disorders.

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9. Langley K, Del Pozo-Banos M, Daalsgard S, Paranjothy S, Riglin L, John A, Thapar A. Can a nation-wide e-cohort of ADHD and ASD in childhood be established using Welsh routinely available datasets?. BMJ Open;2023 (Aug 21);13(8):e071851.

OBJECTIVES: We investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) for future longitudinal research. DESIGN: Individuals with a childhood diagnosis of ADHD/ASD as recorded on routinely available healthcare datasets were compared with matched controls and a sample of directly assessed individuals with ADHD. SETTING: This study used data from the Welsh Secure Anonymised Information Linkage Databank in Wales, UK. Routinely collected data from primary care, emergency department and hospital admissions were linked at person level. PARTICIPANTS: All individuals in Wales, UK born between 1 January 1991 and 31 December 2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using International Classification of Diseases, 10th Revision and National Health Service (NHS) READ codes and matched to 3 controls each and 154 individuals with ADHD recruited from an established research study. OUTCOME MEASURES: Recorded service use for anxiety and depression, alcohol and drug use and self-harm including emergency department use in young adulthood (age 16-25 years). RESULTS: 7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); 1.4% and 0.9% of the population, respectively. Cox’s regression analyses showed ADHD was associated with increased risks of anxiety/depression (HR: 2.36, 95% CI: 2.20 to 2.53), self-harm (HR: 5.70, 95% CI: 5.07 to 6.40), alcohol (HR: 3.95, 95% CI: 3.42 to 4.56), drug use (HR: 5.88, 95% CI: 5.08 to 6.80) and emergency department service use (HR: 1.36, 95% CI: 1.31 to 1.41). Those with ASD were at increased risk of anxiety/depression (HR: 2.11, 95% CI: 1.91 to 2.34), self-harm (HR: 2.93, 95% CI: 2.45 to 3.50) and drug use (HR: 2.21, 95% CI: 1.66 to 2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort. CONCLUSIONS: Our identification strategy demonstrated the feasibility of establishing a large e-cohort of those with ADHD/ASD with expected patterns of poorer early adult outcomes, demonstrating a valid method of identifying large samples for future longitudinal studies without selective attrition.

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10. Lyall K, Rando J, Wang S, Hamra GB, Chavarro J, Weisskopf MG, Croen LA, Fallin MD, Hertz-Picciotto I, Volk HE, Schmidt RJ, Newschaffer CJ. Examining Prenatal Dietary Factors in Association with Child Autism-Related Traits Using a Bayesian Mixture Approach: Results from 2 United States Cohorts. Curr Dev Nutr;2023 (Aug);7(8):101978.

BACKGROUND: Prior work has suggested relationships between prenatal intake of certain nutrients and autism. OBJECTIVES: We examined a broad set of prenatal nutrients and foods using a Bayesian modeling approach. METHODS: Participants were drawn from the Early Autism Risks Longitudinal Investigation (n = 127), a cohort following women with a child with autism through a subsequent pregnancy. Participants were also drawn from the Nurses’ Health Study II (NHSII, n = 713), a cohort of United States female nurses, for comparison analyses. In both studies, information on prospectively reported prenatal diet was drawn from food frequency questionnaires, and child autism-related traits were measured by the Social Responsiveness Scale (SRS). Bayesian kernel machine regression was used to examine the combined effects of several nutrients with neurodevelopmental relevance, including polyunsaturated fatty acids (PUFAs), iron, zinc, vitamin D, folate, and other methyl donors, and separately, key food sources of these, in association with child SRS scores in crude and adjusted models. RESULTS: In adjusted analyses, the overall mixture effects of nutrients in Early Autism Risks Longitudinal Investigation and foods in both cohorts on SRS scores were not observed, though there was some suggestion of decreasing SRS scores with increasing overall nutrient mixture in NHSII. No associations were observed with folate within the context of this mixture, but holding other nutrients fixed, n-6 PUFAs were associated with lower SRS scores in NHSII. In both cohorts, lower SRS scores were observed with higher intake of some groupings of vegetables, though for differing types of vegetables across cohorts, and some vegetable groups were associated with higher SRS scores in NHSII. CONCLUSIONS: Our work extends prior research and suggests the need to further consider prenatal dietary factors from a combined effects perspective. In addition, findings here point to potential differences in nutrient associations based on a family history of autism, which suggests the need to consider gene interactions in future work.

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11. Milla LA, Corral L, Rivera J, Zuñiga N, Pino G, Nunez-Parra A, Cea-Del Rio CA. Neurodevelopment and early pharmacological interventions in Fragile X Syndrome. Front Neurosci;2023;17:1213410.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the leading monogenic cause of autism and intellectual disability. For years, several efforts have been made to develop an effective therapeutic approach to phenotypically rescue patients from the disorder, with some even advancing to late phases of clinical trials. Unfortunately, none of these attempts have completely succeeded, bringing urgency to further expand and refocus research on FXS therapeutics. FXS arises at early stages of postnatal development due to the mutation and transcriptional silencing of the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1) and consequent loss of the Fragile X Messenger Ribonucleoprotein (FMRP) expression. Importantly, FMRP expression is critical for the normal adult nervous system function, particularly during specific windows of embryogenic and early postnatal development. Cellular proliferation, migration, morphology, axonal guidance, synapse formation, and in general, neuronal network establishment and maturation are abnormally regulated in FXS, underlying the cognitive and behavioral phenotypes of the disorder. In this review, we highlight the relevance of therapeutically intervening during critical time points of development, such as early postnatal periods in infants and young children and discuss past and current clinical trials in FXS and their potential to specifically target those periods. We also discuss potential benefits, limitations, and disadvantages of these pharmacological tools based on preclinical and clinical research.

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12. Möde L, Borgolte A, Ghaneirad E, Roy M, Sinke C, Szycik GR, Bleich S, Wiswede D. Cognitive control in adults with high-functioning autism spectrum disorder: a study with event-related potentials. Front Psychiatry;2023;14:1180827.

INTRODUCTION: Little is known about cognitive control in adults with high-functioning forms of autism spectrum disorder because previous research focused on children and adolescents. Cognitive control is crucial to monitor and readjust behavior after errors to select contextually appropriate reactions. The congruency effect and conflict adaptation are measures of cognitive control. Post-error slowing, error-related negativity and error positivity provide insight into behavioral and electrophysiological correlates of error processing. In children and adolescent with autism spectrum disorder deficits in cognitive control and error processing have been shown by changes in post-error slowing, error-related negativity and error positivity in the flanker task. METHODS: We performed a modified Eriksen flanker task in 17 adults with high-functioning autism spectrum disorder and 17 healthy controls. As behavioral measures of cognitive control and error processing, we included reaction times and error rates to calculate congruency effects, conflict adaptation, and post-error slowing. Event-related potentials namely error-related negativity and error positivity were measured to assess error-related brain activity. RESULTS: Both groups of participants showed the expected congruency effects demonstrated by faster and more accurate responses in congruent compared to incongruent trials. Healthy controls exhibited conflict adaptation as they obtained performance benefits after incongruent trials whereas patients with autism spectrum disorder did not. The expected slowing in reaction times after errors was observed in both groups of participants. Individuals with autism spectrum disorder demonstrated enhanced electrophysiological error-processing compared to healthy controls indicated by increased error-related negativity and error positivity difference amplitudes. DISCUSSION: Our findings show that adults with high-functioning autism spectrum disorder do not show the expected upregulation of cognitive control in response to conflicts. This finding implies that previous experiences may have a reduced influence on current behavior in these patients which possibly contributes to less flexible behavior. Nevertheless, we observed intact behavioral reactions after errors indicating that adults with high-functioning autism spectrum disorder can flexibly adjust behavior in response to changed environmental demands when necessary. The enhancement of electrophysiological error-processing indicates that adults with high-functioning autism spectrum disorder demonstrate an extraordinary reactivity toward errors reflecting increased performance monitoring in this subpopulation of autism spectrum disorder patients.

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13. Mohammad S, de Ruijter MJT, Rukh G, Rask-Andersen M, Mwinyi J, Schiöth HB. Well-being spectrum traits are associated with polygenic scores for autism. Autism Res;2023 (Aug 21)

Individuals with autism spectrum disorder (ASD) tend to experience lower well-being as demonstrated mostly for children and adolescents in epidemiological studies. A further investigation of inclusive well-being, in terms of five well-being spectrum (5-WBS) traits including neuroticism, depression, loneliness, life satisfaction, and positive affect, among adults with ASD may deepen our understanding of their well-being, and lead to the possibility to further modify societal supportive mechanisms for individuals with ASD. This study aims to investigate if a genetic predisposition for ASD is associated with 5-WBS traits using polygenic risk score (PRS) analysis. PRS for ASD were calculated based on the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and were created in the independent cohort UK Biobank. Regression analyses were performed to investigate the association between ASD PRS and 5-WBS traits in the UK Biobank population including 337,423 individuals. ASD PRS were significantly associated with all 5-WBS traits, showing a positive association with the negative WBS traits, neuroticism (max R(2)  = 0.04%, p < 1 × 10(-4) ), depression (max R(2)  = 0.06%, p < 1 × 10(-4) ), loneliness (max R(2)  = 0.04%, p < 1 × 10(-4) ), and a negative association with the positive WBS traits, life satisfaction (max R(2)  = 0.08%, p < 1 × 10(-4) ), positive affect (max R(2)  = 0.10%, p < 1 × 10(-4) ). The findings suggest that adults carrying a high load of risk single nucleotide peptides (SNPs) for ASD are more likely to report decreased well-being. The study demonstrates a considerable connection between susceptibility to ASD, its underlying genetic etiology and well-being.

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14. Mohammadi K, Samavi A, Mehdiabadi FZ, Samavi SA. Psychometric validation of concerning behavior scale in Iranian children and young people with autism spectrum disorder. Front Psychiatry;2023;14:1153112.

INTRODUCTION: Assessment of Concerning Behavior (ACB) was introduced by Tarver et al. (2021) to evaluate mental health and problematic/risky behaviors in children and young people with autism spectrum disorder (ASD). METHODS: This study examined the psychometric validation of the Assessment of Concerning Behavior (ACB) in an Iranian sample of parents of children and young people with ASD. Confirmatory factor analysis was conducted to examine the structure of ACB in a sample of 303 parents. RESULTS: The data supported the two factor structure, all factor loadings were significant and scale structure was confirmed similar to the original scale. The results supported the two-factor structure for ACB that included internalizing and externalizing problems scales. The two factors of ACB are positively correlated with Aberrant Behavior Checklist scores which showed that the validity of two factors is satisfactory. The reliability of the two subscales was reasonable as well. CONCLUSION: The study suggests that the ACB could be an operational tool to assess the mental health and problematic/risky behaviors in Iranian children and young people with ASD.

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15. Nicoli G, Pavon G, Grayson A, Emerson A, Mitra S. Touch may reduce cognitive load during assisted typing by individuals with developmental disabilities. Front Integr Neurosci;2023;17:1181025.

Many techniques have attempted to provide physical support to ease the execution of a typing task by individuals with developmental disabilities (DD). These techniques have been controversial due to concerns that the support provider’s touch can influence the typed content. The most common interpretation of assisted typing as an ideomotor phenomenon has been qualified recently by studies showing that users with DD make identifiable contributions to the process. This paper suggests a neurophysiological pathway by which touch could lower the cognitive load of seated typing by people with DD. The required sensorimotor processes (stabilizing posture and planning and executing manual reaching movements) and cognitive operations (generating and transcribing linguistic material) place concurrent demands on cognitive resources, particularly executive function (EF). A range of developmental disabilities are characterized by deficits in sensorimotor and EF capacity. As light touch has been shown to facilitate postural coordination, it is proposed that a facilitator’s touch could assist the seated typist with sensorimotor and EF deficits by reducing their sensorimotor workload and thereby freeing up shared cognitive resources for the linguistic elements of the task. This is the first theoretical framework for understanding how a facilitator’s touch may assist individuals with DD to contribute linguistic content during touch-assisted typing.

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16. Prasitwut P, Wantanakorn P, Chuchottaworn K, Reangkanjanaseart S, Chuthapisith J. Effectiveness of Fabric Weaving Therapy for Children with Autism Spectrum Disorder: A Randomized Waitlist-Controlled Trial. J Integr Complement Med;2023 (Aug 21)

Objectives: To evaluate the effectiveness of weaving therapy on clinical outcomes and quality of life of autistic children. Design: Randomized waitlist-controlled trial. Setting/Location: Developmental and Behavioral Pediatrics Clinic, Faculty of Medicine Ramathibodi Hospital. Subjects: Twenty-three autistic children. Interventions: Weaving therapy was performed weekly for 6 months (3 months for hospital-based intervention and 3 months for home-based intervention). Outcome measures: Childhood Autism Rating Scale-second edition (CARS-2) and Pediatric Quality of Life Inventory (PedsQL) were measured at preintervention, 3 and 6 months postintervention. Methods: Twenty-three autistic children, aged 7.8-16.6 years, were randomized into an intervention group (N = 11) and a 3-month waitlist period group (N = 12). Ten weaving sessions were performed by the children, along with their parents, weekly for 3 months in hospital, and continued at home for an additional 3 months. The weaving therapy was delayed for 3 months in the waitlist group, followed by a 6-month intervention as the intervention group. Results: There was significant improvement on CARS-2 (p < 0.01) and PedsQL scores (p < 0.01) in the intervention group after the first 3-month weaving therapy. Meanwhile, in the waitlist group, no significant difference was found on CARS-2 (p = 0.09) and PedsQL scores (p = 0.26) during no weaving period. After the waitlist group began weaving therapy for 3 months, the authors found a significant improvement on both CARS-2 and PedsQL scores (p < 0.01both). Between-group comparisons showed that the intervention group had significant improvement on CARS-2 (p = 0.002) and PedsQL (p < 0.001) after 3-month weaving comparing with the waitlist group. After all the 23 participants finished a 6-month weaving therapy, there was significant difference in CARS-2 (p < 0.001) and PedsQL scores (p < 0.001) between pre- and postintervention. Conclusions: These findings suggest that traditional Thai fabric weaving therapy, as an alternative and complementary intervention, appears to be an effective therapy in improving the clinical symptoms and quality of life among autistic children. Clinical Trial Registration number: TCTR20200420002.

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17. Querzani A, Sirchia F, Rustioni G, Rossi A, Orsini A, Marseglia GL, Savasta S, Chiapparini L, Foiadelli T. KIRREL3-related disorders: a case report confirming the radiological features and expanding the clinical spectrum to a less severe phenotype. Ital J Pediatr;2023 (Aug 21);49(1):99.

BACKGROUND: Neurodevelopmental disorders have a multifactorial etiology, since biological, genetic, psychosocial and environmental risk factors are involved. Recent studies have been linking neurodevelopmental disorders and intellectual disability with a variety of genes, some of which encoding neuronal cell-adhesion molecules. Among these, KIRREL3 is known to play a role in CNS development, and his variants have recently been related to intellectual disability, autism spectrum disorder, childhood apraxia of speech, cerebellar hypoplasia and mild dysmorphic features. CASE PRESENTATION: In this study, we describe a young Caucasian boy with mild intellectual disability, cerebellar anomalies (cerebellar hypoplasia and mega cisterna magna) and minor dysmorphic features associated to a novel KIRREL3 variant. CONCLUSIONS: Aim of the present case report is to expand the clinical spectrum of KIRREL3-related diseases towards a milder phenotype than what is already described in the literature. We speculate that the interaction between KIRREL3 and CASK might play a major role in promoting cognitive and cerebellar development, contributing to a variety of clinical manifestations.

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18. Rava J, Rosenau KA, Wilkie K, Curcio E, Kuo A. Implementation of a Minimal Sedation Protocol for Patients With Developmental Disabilities and Needle Phobia. Cureus;2023 (Jul);15(7):e42154.

Objective Patients with intellectual and developmental disabilities (IDD) experience needle phobia at greater rates than individuals in the general population. Needle phobia deters patients with IDD from receiving routine medical procedures, which impacts their physical health outcomes. The aim of this quality improvement study was to assess the feasibility of a minimal sedation protocol in an outpatient care setting for patients with IDD and needle phobia. Methods The sample included 18 patients characterized as having a diagnosis of IDD only or IDD and needle phobia compared to patients with only a diagnosis of needle phobia. Reasons for referral to intervention included routine lab work, therapeutic drug monitoring, and routine vaccination. The minimal sedation intervention involved intranasal administration of a benzodiazepine (midazolam) by a registered nurse. Outcomes of interest were administration of the sedation and administration of medical orders. Results Nearly a third of patients were children (33.3%, n=6), and 39% of patients were female (n=7). Individuals with IDD (including those both with and without needle phobias) comprised 72.2% of patients (n=13). Half of intervention encounters were successful in both administering the sedation and performing the medical orders (n=9). Among individuals with IDD, 38.4% successfully completed the intervention (n=5). Conclusion This pilot study assessed the feasibility of implementing a minimal sedation protocol in primary care outpatient care settings. The preliminary results suggest that the minimal sedation protocol may improve the uptake of needle-related medical procedures for patients with IDD and/or needle phobia. The minimal sedation protocol should be studied in a larger sample and among multiple outpatient settings to establish effectiveness of the intervention.

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19. Smits F, Houdmont J, Hill B, Pickles K. Mental wellbeing and psychosocial working conditions of autistic veterinary surgeons in the UK. Vet Rec;2023 (Aug 21):e3311.

BACKGROUND: Certain autistic characteristics (such as hyper-focus and attention to detail) are valued by veterinary surgeons and autistic adults may disproportionately self-select into the profession. Links between mental wellbeing and retention in the veterinary profession highlight an imperative to profile autistic veterinary surgeons’ mental wellbeing and identify protective factors. The psychosocial work environment may represent one such protective factor. We aimed to assess autistic veterinary surgeons’ mental wellbeing, the extent to which their psychosocial working conditions achieved UK government management standards and links between these. METHODS: Eighty-five autistic veterinary surgeons completed the Warwick-Edinburgh Mental Wellbeing Scale and the Health and Safety Executive’s Management Standards Indicator Tool. Descriptive comparisons were drawn with normative data; correlation and linear regression analyses examined relations between mental wellbeing and psychosocial working conditions. RESULTS: Mental wellbeing and psychosocial work environment quality were markedly below veterinary surgeon and general workforce norms. Psychosocial working conditions accounted for 44% of the unique variance in mental wellbeing, with ‘control’ and ‘role’ making a significant contribution. LIMITATION: This exploratory study involved a small self-selecting sample, raising the possibility of response bias. CONCLUSION: Work design centred on the enhancement of control and role clarity would likely support mental wellbeing in this population.

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20. Torres EB, Twerski G, Varkey H, Rai R, Elsayed M, Katz MT, Tarlowe J. The time is ripe for the renaissance of autism treatments: evidence from clinical practitioners. Front Integr Neurosci;2023;17:1229110.

INTRODUCTION: Recent changes in diagnostics criteria have contributed to the broadening of the autism spectrum disorders and left clinicians ill-equipped to treat the highly heterogeneous spectrum that now includes toddlers and children with sensory and motor issues. METHODS: To uncover the clinicians’ critical needs in the autism space, we conducted surveys designed collaboratively with the clinicians themselves. Board Certified Behavioral Analysts (BCBAs) and developmental model (DM) clinicians obtained permission from their accrediting boards and designed surveys to assess needs and preferences in their corresponding fields. RESULTS: 92.6% of BCBAs are open to diversified treatment combining aspects of multiple disciplines; 82.7% of DMs also favor this diversification with 21.8% valuing BCBA-input and 40.6% neurologists-input; 85.9% of BCBAs and 85.3% of DMs advocate the use of wearables to objectively track nuanced behaviors in social exchange; 76.9% of BCBAs and 57.0% DMs feel they would benefit from augmenting their knowledge about the nervous systems of Autism (neuroscience research) to enhance treatment and planning programs; 50.0% of BCBAs feel they can benefit for more training to teach parents. DISCUSSION: Two complementary philosophies are converging to a more collaborative, integrative approach favoring scalable digital technologies and neuroscience. Autism practitioners seem ready to embrace the Digital-Neuroscience Revolutions under a new cooperative model.

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21. Vicedo M. Autism’s heterogeneity in historical perspective: from challenge to opportunity. Front Psychol;2023;14:1188053.

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22. Wang J, Gao Y, Xiao L, Lin Y, Huang L, Chen J, Liang G, Li W, Yi W, Lao J, Zhang B, Gao TM, Zhong M, Yang X. Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1(-/-) mice. iScience;2023 (Aug 18);26(8):107476.

Mutations of the GABA-A receptor subunit β1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1(-/-) mouse model, which showed autistic-like behaviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABA(A)R-currents in the CA1 neurons were detected in Gabrb1(-/-) mice. NMDAR antagonist memantine or Glul inhibitor methionine sulfoximine could rescue the abnormal behaviors in Gabrb1(-/-) mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

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23. Xavier J, Johnson S, Cohen D. From child-peer similarity in imitative behavior to matched peer-mediated interventions in autism. Front Psychol;2023;14:1173627.

Self-consciousness develops through a long process, from pre-reflexive consciousness relying on body perception, to « meta » self-awareness. It emerges from the imitative experience between children and their peers. This experience linked to the capacity to test structural similarities between oneself and others, is addressed according to the concept of interpersonal affordance. We hypothesize that the opportunity for co-actors to engage in a process of interpersonal coordination is underlined by their similarity in terms of morphological, behavioral and motor features. This experience can sustain the emergence of new affordances for objects for each co-actor, as well as new affordances in terms of joint actions. We apply this idea in the context of peer-mediated interventions (PMI) in autism spectrum disorder (ASD). We argue that, in PMI, an encounter between children with autism and similar peers would foster the opportunity to engage in a spontaneous process of interpersonal coordination. This process would enable the development of self-consciousness and the emergence of perception of interpersonal, self and other’s affordances for children with autism. We conclude that metrics to assess morphological, behavioral and motor similarity should then be defined and used in future studies to test our hypothesis in children with autism versus TD children or between children with autism.

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24. Yamada M, Sugawara N, Kawamata Y, Yasui-Furukori N. Differences in self-reported psychotic symptoms between patients with autism spectrum disorder and those with schizophrenia. Neuropsychopharmacol Rep;2023 (Aug 21)

AIM: Patients with autism spectrum disorder (ASD) are prone to develop overt psychosis and share symptom presentations with those with schizophrenia (SZ). This study aimed to explore differences in the distributions of psychotic symptoms among first-visit patients with ASD, SZ, or a nonpsychiatric diagnosis (N-PD). METHODS: Data from first-visit patients were retrospectively collected from medical records from the Department of Psychiatry, Dokkyo Medical University Hospital between June 2019 and May 2021. A total of 254 patients with data on the PRIME Screen-Revised (PS-R) assessments were included in our analysis. In the hospital, all psychiatric diagnoses were based on the DSM-5 diagnostic criteria. RESULTS: In the ASD, SZ, and N-PD groups, endorsements of perplexity and delusional mood were 15.6% (7/45), 41.5% (44/106), and 1.1% (1/88), and those of perceptual abnormalities were 11.1% (5/45), 40.6% (43/106), and 2.3% (2/88), respectively. Trend analysis clarified that the endorsement of these psychotic symptoms increased from N-PD to ASD and SZ. In the multivariate-adjusted multinomial logistic regression analysis, the ASD and N-PD groups were compared with the SZ group. Higher age and the presence of perceptual abnormalities were associated with lack of an ASD diagnosis, whereas male sex, lack of perplexity and delusional mood, and lack of perceptual abnormalities were associated with N-PD. CONCLUSION: Our results are preliminary; however, a detailed assessment of positive symptoms might facilitate differentiation between ASD and SZ.

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25. Zajic MC, McCauley JB, McIntyre NS, Mundy PC. Writing Self-Concept, Text Engagement, and Writing Practices Across Contexts: Comparisons Between School-Age Children on the Autism Spectrum and Their Non-Autistic Peers. J Autism Dev Disord;2023 (Aug 21)

PURPOSE: Autistic children demonstrate highly variable written language skills. Existing research has focused on examining autistic children’s performance on direct assessments of written language. In contrast, few studies have sought to understand how autistic children conceptualize their writing abilities or engage with writing across different contexts compared to non-autistic peers. METHODS: This study used a researcher-designed questionnaire to examine writing self-concept, text engagement with different writing activities, and writing practices and beliefs across school and non-school contexts in school-age (10-18 years old) autistic children compared to their non-autistic peers. Data analysis approaches included « multiple indicators, multiple causes » (MIMIC) modeling; correlational and multiple regression analysis; non-parametric Mann-Whitney U tests; and principal components analysis. RESULTS: Groups did not differ in their writing self-concept ratings. Furthermore, both groups engaged with a variety of different writing activities to a similar extent except for text messages being lower for the autistic group. Five components were extracted via principal components analysis on items related to writing practices and beliefs across contexts; groups did not differ across the components. Overall, the non-autistic group showed more consistent relationships between writing self-concept as well as writing practices and beliefs with performance on a narrative writing task when compared to the autistic group. CONCLUSION: Results offer a preliminary understanding into how autistic children engage with writing across contexts for a variety of purposes when compared to their non-autistic peers and offer implications for continued research and educational practice.

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