1. Aishworiya R, Protic D, Hagerman R. Autism spectrum disorder in the fragile X premutation state: possible mechanisms and implications. J Neurol;2022 (Jun 20)

There is increasing recognition of the heterogeneity of origin of cases of autism spectrum disorder (ASD) with multiple forms of ASD having been identified over the decades. Among these, a genetic etiology can be identified in 20-40% of cases when a full genetic work-up is completed. The Fragile X premutation state (characterized by the presence of 55-200 CGG repeats in the FMR1 gene) is a relatively newly identified disease state that has since been associated with several disorders including fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI) and most recently, fragile X-associated neurodevelopmental disorders (FXAND) which commonly includes anxiety and depression. In addition to these associated disorders, extant literature and clinical observations have suggested an association between the premutation state and ASD. In this paper, we review the literature pertinent to this and discuss possible molecular mechanisms that may explain this association. This includes lowered levels of the FMR1 Protein (FMRP), GABA deficits, mitochondrial dysfunction and secondary genetic abnormalities that is seen in premutation carriers as well as their increased vulnerability to environmental stressors. Understanding these mechanisms can facilitate development of targeted treatment for specific sub-groups of ASD and premutation disorders in future.

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2. Alkire D, McNaughton KA, Yarger HA, Shariq D, Redcay E. Theory of mind in naturalistic conversations between autistic and typically developing children and adolescents. Autism;2022 (Jun 20):13623613221103699.

Conversation is a key part of everyday social interactions. Previous studies have suggested that conversational skills are related to theory of mind, the ability to think about other people’s mental states, such as beliefs, knowledge, and emotions. Both theory of mind and conversation are common areas of difficulty for autistic people, yet few studies have investigated how people, including autistic people, use theory of mind during conversation. We developed a new way of measuring cToM using two rating scales: cToM Positive captures behaviors that show consideration of a conversation partner’s mental states, such as referring to their thoughts or feelings, whereas cToM Negative captures behaviors that show a lack of theory of mind through violations of neurotypical conversational norms, such as providing too much, too little, or irrelevant information. We measured cToM in 50 pairs of autistic and typically developing children (ages 8-16 years) during 5-min « getting to know you » conversations. Compared to typically developing children, autistic children displayed more frequent cToM Negative behaviors but very similar rates of cToM Positive behaviors. Across both groups, cToM Negative (but not Positive) ratings were related to difficulties in recognizing emotions from facial expressions and a lower tendency to talk about others’ mental states spontaneously (i.e., without being instructed to do so), which suggests that both abilities are important for theory of mind in conversation. Altogether, this study highlights both strengths and difficulties among autistic individuals, and it suggests possible avenues for further research and for improving conversational skills.

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3. Almås IK, Smith DP, Eldevik S, Eikeseth S. Emergent Intraverbal and Reverse Intraverbal Behavior Following Listener Training in Children with Autism Spectrum Disorder. Anal Verbal Behav;2022 (Jun);38(1):1-23.

We evaluated whether intraverbal and reverse intraverbal behavior emerged following listener training in children with autism spectrum disorder (ASD). Six participants were each taught three sets of three « when? » questions in listener training. A multiple baseline design across behaviors (stimulus sets) was used to assess the effects of listener training. Results showed that intraverbal behavior emerged following listener training for five out of six participants. One participant received additional listener training and intraverbal training before intraverbal behavior emerged. Furthermore, reverse intraverbal responding occurred across all three sets of questions for three of the six participants. Establishing listener behavior may be a pathway for emergent intraverbal and reverse intraverbal responding in children with ASD. Future research could examine what skill repertoire may facilitate such transfer.

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4. Alves ALC, de Paula JJ, de Miranda DM, Romano-Silva MA. The Autism Spectrum Quotient in a sample of Brazilian adults: analyses of normative data and performance. Dement Neuropsychol;2022 (Apr-Jun);16(2):244-248.

Autism spectrum disorder (ASD) is characterized by difficulties in social interaction and inflexible behaviors/interests. To quantify ASD traits in adults with preserved intelligence, the Autism Spectrum Quotient (AQ) was developed, which is a self-report instrument and one of the most used and recommended tools. OBJECTIVES: We aimed to present a descriptive analysis of the AQ in a sample of Brazilian adults with neurotypical development (n=385) and investigate how the scale performs in a clinical subsample (n=33). METHODS: We recruited 1,024 participants. They answered the Self-Reporting Questionnaire-20 (SRQ-20), AQ, and about their psychiatric record. Then, we selected 385 participants without any psychiatric diagnosis to describe the distribution of the ASD traits. To investigate the AQ performance, we evaluated 33 adults with ASD and 19 adults with neurotypical development from the total sample (n=1,024). RESULTS: ASD traits were normally distributed in the population, with high internal consistency. Of a total of 91 men, volunteers with 32 points (clinical cutoff point) or more scored higher than 93% of the control sample. Of a total of 294 women, those who got a clinical score on the scale scored higher than 97%. In the clinical subsample (n=33), the positive predictive value (PPV) of the AQ was 0.84, and the negative predictive value (NPV) was 0.7. CONCLUSIONS: The study population has a different profile compared to the original study regarding the AQ scale. ASD traits were normally distributed in the neurotypical sample, and the scale seems to have a satisfactory performance to predict ASD. Future studies are required to adequate the use of the scale in the Brazilian population.

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5. Arija V, Esteban-Figuerola P, Morales-Hidalgo P, Jardí C, Canals-Sans J. Nutrient intake and adequacy in children with autism spectrum disorder: EPINED epidemiological study. Autism;2022 (Jun 20):13623613221098237.

Children with autism spectrum disorder (ASD) have a fivefold elevated risk of developing eating problems, which predisposes them to nutritional deficiencies. This study assesses nutritional intake and adequacy in children with ASD, subdiagnostic autistic symptoms and typically developing (TD) children. Preschool children with ASD and subdiagnostic symptoms had slightly lower intake of monounsaturated fatty acids (MUFA), vitamin D and vitamin B12. Primary school children with ASD and subdiagnostic symptoms had slightly higher intake of protein, cholesterol, thiamine and niacin, and a higher percentage of obesity than children with TD. All children had a high intake in sugars, fats and saturated fatty acids; a very highly inadequate intake of vitamins (vitamins D and E), fibre, b-carotene, calcium and magnesium; and a moderately inadequate intake of vitamin C, folate and iron. However, although all children need nutrition advice, children with ASD and subdiagnostic autistic symptoms had a poorer quality diet than those with TD.

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6. Azimi S, Wong K, Lai YYL, Bourke J, Junaid M, Jones J, Pritchard D, Calache H, Winters J, Slack-Smith L, Leonard H. Dental procedures in children with or without intellectual disability and autism spectrum disorder in a hospital setting. Aust Dent J;2022 (Jun 19)

BACKGROUND: This population-based cohort study investigated dental procedures in the hospital setting in Western Australian children with or without intellectual disability and/or autism spectrum disorder aged up to 18 years. Considering previously reported disparities in dental disease between Indigenous and non-Indigenous Australian children, this study also investigated the effect of Indigenous status on dental procedures. METHODS: Data on Western Australian live births from 1983 to 2010 from the Midwives Notification System were linked to the Intellectual Disability Exploring Answers database and the Hospital Morbidity Data collection. Primary admissions for relevant dental diagnoses were identified, and treatment procedures for dental hospitalisation were investigated. Descriptive statistics and Pearson’s chi-squared test of independence were used for analysis. RESULTS: Overall, 76,065 episodes of dental hospitalisation were recorded. Among children with intellectual disability and/or autism spectrum disorder, Indigenous children experienced more extractions and fewer restorations (68.7% and 16.2%) compared to non-Indigenous children (51.5% and 25.9%). After six years, extraction occurred less often in children with intellectual disability and/or autism spectrum disorder than in those without, where most surgical dental extractions were in the 13-18 years age group. CONCLUSIONS: This study indicates a need for further improvements in access to dental services and the quality of care provided in hospitals for children with ID/ASD. There is also concern that more vulnerable Indigenous and all disadvantaged children are receiving an inadequate level of dental services resulting in more emergency dental hospitalisation and invasive treatment. © 2022 Australian Dental Association.

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7. Bagatell N, Chan DV, Syu YC, Lamarche EM, Klinger LG. Sensory Processing and Community Participation in Autistic Adults. Front Psychol;2022;13:876127.

BACKGROUND: Sensory processing differences have been shown to impact involvement in community activities. However, relatively little is known about how these differences affect community participation in autistic adults. OBJECTIVE: The objective of this study was to explore how sensory processing patterns of autistic adults impact community participation, including where people go, what they do, the amount of time in the community, and preferred locations. METHODS: We used data gathered from six autistic adults and their caregivers who participated in two studies. From Study 1, we reviewed results of the Adolescent and Adult Sensory Profile (AASP) and transcripts from interviews with caregivers. From Study 2, we reviewed GPS tracking data and transcripts from structured interviews with autistic adults focused on community participation. We read transcript data, identified quotes related to sensory processing and community participation and constructed individual participant narratives which linked findings from interviews, AASP, and GPS tracking. RESULTS: Participants included three males and three females ranging in age from 29 to 51. Each participant had a unique sensory processing profile that influenced where they went, the activities in which they engaged, how much time they spent in the community, and their preferred locations. Those whose sensory processing patterns indicated sensory sensitivity and sensory avoiding described the experience of certain environments as overwhelming and fatiguing and thus spent less time in the community and visited fewer places than those with other sensory processing patterns. CONCLUSION: Results highlight the importance of sensory processing, especially as it impacts participation in the community. Sensory processing patterns should be considered along with other personal and contextual factors when assessing community participation and personal sensory processing patterns should be matched with activities and environmental demands.

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8. Bergmann S, Van Den Elzen G, Kodak T, Niland H, Dawson D. Comparing Matrix-Training Procedures with Children with Autism Spectrum Disorder. Anal Verbal Behav;2022 (Jun);38(1):24-53.

Recombinative generalization is the production of responses in the presence of novel combinations of known components. For example, after learning « red triangle » and « blue square, » recombinative generalization is observed when a child can tact « red square » and « blue triangle. » Recombinative generalization can emerge from a history of matrix training, which involves carefully selecting and arranging stimuli and responses along at least two axes and training a subset of responses. With three children with autism spectrum disorder, we compared recombinative generalization of object-action or feature-object tacts when the component stimuli were trained before combination stimuli, trained along with combination stimuli, or untrained (i.e., combination only). For two participants, training the components along with some combinations led to the most untrained targets acquired without direct teaching. For the other participant, training the combinations only led to the greatest proportion of untrained targets acquired without direct teaching. We discuss stimulus control promoted by each teaching arrangement and suggestions for future research on recombinative generalization.

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9. Bertrams A. From autistic pragmatic language problems to a negative attitude toward human nature-a serial multiple mediation model. J Psychiatr Res;2022 (Jun 15);152:139-143.

It has recently been found that individuals high in autistic traits tend to believe that they are usually not treated fairly. In the present study, it is assumed that such a lowered personal belief in a just world is based on cumulative humiliation experiences that stem from autistic pragmatic language problems (e.g., communicating in a monotonous voice, not being « in tune » with others during conversations). Furthermore, the less individuals believe that they receive fair treatment, the more they may develop a negative attitude toward human nature (i.e., believing that humans are generally untrustworthy, unfair, and unhelpful). The serial multiple mediation model reflecting these assumptions received initial empirical support in a nonclinical sample (N = 344). Implications for professional health care are addressed.

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10. Bogenschutz M, Dinora P, Lineberry S, Prohn S, Broda M, West A. Promising Practices in the Frontiers of Quality Outcome Measurement for Intellectual and Developmental Disability Services. Front Rehabilit Sci;2022;3

Medicaid Home and Community-Based Services (HCBS) for people with intellectual and developmental disabilities (IDD) are vital for supporting people with IDD to live well in their communities, but there are not set standards for monitoring quality outcomes related to HCBS. In this paper, we propose promising practices for improving the quality of HCBS outcome measurement, based both in the literature and our own experience conducting an extensive U.S. state-level study. Specifically, we discuss: (1) using merged administrative datasets, (2) developing high-quality psychometrics that attend to ecological issues in measurement, (3) using advanced statistical analyses, and (4) creating immersive, user-friendly translational dissemination products. We conclude by suggesting what we see as important new frontiers for researchers to consider in order to enhance the quality of HCBS outcome measurement for people with IDD in the future.

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11. Boterberg S, Zanatta A, Moerman F, Schaubroeck S, Siew J, De Schryver M, Roeyers H. The impact of COVID-19 measures on parent-reported restricted and repetitive behaviours in pre-school children with autism. Heliyon;2022 (Jun);8(6):e09727.

BACKGROUND: COVID-19 restrictive measures have had a considerable impact on daily life routines, which may be especially challenging for families of children with autism. In pre-schoolers with autism, it is likely that the disruption of routines mainly impacts the presence of restrictive and repetitive behaviours (RRBs). Furthermore, influence of comorbid conditions, secondary behavioural difficulties and home environment characteristics on RRBs was explored. METHOD: A cross-sectional online survey design was used to collect parent-report data on 254 children with autism (2.5-6 years) during lockdown in the early months of the pandemic. RRBs were assessed using the Repetitive Behaviour Scale-Revised (RBS-R). RESULTS: Parents reported a significant increase in stereotypic, self-injurious, compulsive and ritualistic behaviour, and restricted interests after implementation of COVID-19 restrictions. The presence of a co-occurring condition, such as language impairments or intellectual disability, was associated with more self-injurious and stereotypic behaviour. However, there was no effect of home environment on RRBs. Further, most children showed increases in internalising and/or externalising behaviour. Increased inattentive behaviour was associated with more ritualistic and stereotypic behaviour, and restricted interests. Decreases in hyperactivity were related to more restricted interests. Importantly, in a subset of children, parents reported less behavioural difficulties during the lockdown. CONCLUSIONS: Findings highlight the importance of flexible implementation and continuity of care for pre-schoolers with autism and support for parents. Further follow-up of children with autism and RRBs, and co-occurring behavioural difficulties is needed and could enhance our understanding of the long-term effects associated with sudden restrictive measures to daily routines.

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12. Coccurello R, Marrone MC, Maccarrone M. The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders. Front Pharmacol;2022;13:869606.

The latest years have witnessed a growing interest towards the relationship between neuropsychiatric disease in children with autism spectrum disorders (ASD) and severe alterations in gut microbiota composition. In parallel, an increasing literature has focused the attention towards the association between derangement of the endocannabinoids machinery and some mechanisms and symptoms identified in ASD pathophysiology, such as alteration of neural development, immune system dysfunction, defective social interaction and stereotypic behavior. In this narrative review, we put together the vast ground of endocannabinoids and their partnership with gut microbiota, pursuing the hypothesis that the crosstalk between these two complex homeostatic systems (bioactive lipid mediators, receptors, biosynthetic and hydrolytic enzymes and the entire bacterial gut ecosystem, signaling molecules, metabolites and short chain fatty acids) may disclose new ideas and functional connections for the development of synergic treatments combining « gut-therapy, » nutritional intervention and pharmacological approaches. The two separate domains of the literature have been examined looking for all the plausible (and so far known) overlapping points, describing the mutual changes induced by acting either on the endocannabinoid system or on gut bacteria population and their relevance for the understanding of ASD pathophysiology. Both human pathology and symptoms relief in ASD subjects, as well as multiple ASD-like animal models, have been taken into consideration in order to provide evidence of the relevance of the endocannabinoids-microbiota crosstalk in this major neurodevelopmental disorder.

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13. Cooper CM, Rosen T, Kim H, Eaton NR, Cohn E, Drahota A, Moskowitz LJ, Lerner MD, Kerns CM. Predictors of expert providers’ familiarity with intervention practices for school- and transition-age youth with autism spectrum disorder. Autism;2022 (Jun 20):13623613221100787.

School-age children, adolescents, and young adults with autism spectrum disorder encounter many different types of providers in their pursuit of treatment for anxiety, behavior problems, and social difficulties. These providers may all be familiar with different types of intervention practices. However, research has not yet investigated patterns in expert providers’ familiarity with different practices nor how these patterns are related to the characteristics of providers (years in practice, academic discipline, setting) and the youth (age and intellectual disability) they typically support. A panel of 53 expert transdisciplinary providers rated their familiarity with 55 intervention practices (derived from research and expert nominations) via an online Delphi poll. Advanced statistical methods were used to identify types of intervention practices with which providers were familiar, which included two approaches (cognitive and behavioral) and two strategies (engagement and accessibility). Providers who practiced outside a school setting or treated clients without intellectual disability were more familiar with cognitive approaches. Clinical psychologists, behavior analysts, and school-based providers were more familiar with behavioral approaches. Providers practicing outside school settings were also more familiar with engagement strategies, and providers with more years in practice were more familiar with accessibility strategies. These results may help families and researchers to better anticipate how services may vary depending on the types of autism spectrum disorder providers seen and work to reduce disparities in care that may result.

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14. Edwards M, Huang M, Joseph S. The Fragile X Protein Disordered Regions Bind a Novel RNA Target. Biochemistry;2022 (Jun 21);61(12):1199-1212.

The fragile X proteins (FXPs) are a family of RNA-binding proteins that regulate mRNA translation to promote proper neural development and cognition in mammals. Of particular interest to researchers is the fragile X mental retardation protein (FMRP), as its absence leads to a neurodevelopmental disorder: fragile X syndrome (FXS), the leading monogenetic cause of autism spectrum disorders. A primary focus of research has been to determine mRNA targets of the FXPs in vivo through pull-down techniques, and to validate them through in vitro binding studies; another approach has been to perform in vitro selection experiments to identify RNA sequence and structural targets. These mRNA targets can be further investigated as potential targets for FXS therapeutics. The most established RNA structural target of this family of proteins is the G-quadruplex. In this article, we report a 99 nucleotide RNA target that is bound by all three FXPs with nanomolar equilibrium constants. Furthermore, we determined that the last 102 amino acids of FMRP, which includes the RGG motif, were necessary and sufficient to bind this RNA target. To the best of our knowledge, this is one of only a few examples of non-G-quadruplex, non-homopolymer RNAs bound by the RGG motif/C-termini of FMRP.

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15. Elgen SKF, Røiseland MA, Bircow EI, Vollsæter M, Hysing M. Correction to: Symptoms and antecedents of autism in children born extremely premature: a national population-based study. Eur Child Adolesc Psychiatry;2022 (Jun 21)

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16. Engal E, Baker M, Salton M. The chromatin roots of abnormal splicing in autism. Trends Genet;2022 (Jun 21)

Spatiotemporal gene expression drives neurodevelopment. Therefore, abnormal expression during development results in atypical brain function. Alterations in gene expression have been described in autism spectrum disorder (ASD). Here, we focus on one aspect of gene expression, pre-mRNA splicing, specifically, the mechanism of its regulation by chromatin and how this is altered in ASD.

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17. Glumbic N, Grujicic R, Stupar S, Petrovic S, Pejovic-Milovancevic M. Positive Effects of the Caregiver Skill Training Program on Children With Developmental Disabilities: Experiences From Serbia. Front Psychiatry;2022;13:913142.

BACKGROUND: Intervention programs for children with developmental disabilities increasingly target caregiver training to implement effective strategies for child development. Research conducted in different countries shows that the Caregiver Skills Training Program (CST) developed by the World Health Organization and Autism Speaks could also be a recommended intervention. METHODS: The pre-pilot phase included seven, and the pilot phase included 29 families of children with developmental disabilities trained to implement the intervention program. The caregivers were asked to complete the Autism Treatment Evaluation Checklist at the beginning and at the end of the program. RESULTS: In the pre-pilot phase, the Wilcoxon signed-rank test determined a statistically significant improvement in Speech, Language and Communication (z = -2.99, p < 0.05) and Health/Physical/Behavior (z = -2.375, p < 0.05) after caregiver participation in the training program. In the pilot phase, the paired t-test also determined a statistically significant improvement in Speech, Language and Communication between the first (M = 24.52, SD = 5.57) and the second testing (M = 25.66, SD = 6.11), t((28)) = -2.29, p < 0.05, as well as a significant improvement between the first (M = 36.62; SD = 7.15) and the second testing (M = 35.38; SD = 5.91), t((28)) = 2.11, p < 0.05 in Health/Physical/Behavior. Eta squared values (0.16 and 0.14) indicate that the intervention effect was significant. No differences were determined in Sociability and Sensory/Cognitive Awareness between the first and the second testing. CONCLUSION: The initial results of the Caregiver Skills Training Program are encouraging. For this program to be recommended as an evidence-based intervention, further research should be conducted on larger samples, controlling possible intervening variables.

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18. Han Y, Jin S, Liu L, Qu Z, Gao L, Li P, Xiong W, Zhang X. Exploring associations between urine levels of phthalates and autism spectrum disorder symptoms: a case-control study in Tianjin, China. Environ Sci Pollut Res Int;2022 (Jun 21)

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders. The etiology of autism remains unclear, but a growing body of evidence indicates that phthalates play a role in its pathogenesis. The aim of this study was to compare the urine levels of phthalates in children with ASD and healthy children. We also explored whether phthalates have an effect on ASD symptoms. The participants in this study included 101 children with ASD (79 boys and 22 girls) and 101 sex- and age-matched controls. The levels of phthalates were analyzed by gas chromatography-mass spectrometry (GC-MS). We detected significant differences in monoethyl phthalate (MEP) levels between the severe ASD and control groups (p < 0.05). Mono-n-butyl phthalate (MBP) concentration was positively correlated with language skill impairment in ASD (β: 0.387, p = 0.041). MEP levels were associated with the CARS "Imitation" score in all children (OR: 1.470). MBP levels were associated with the "Nonverbal Communication" score among boys (OR: 1.233), and MEP levels were associated with the "Nonverbal Communication" score among girls (OR: 2.648). MEP levels were related to the CARS total score after adjustment for sex (β: 1.524, p = 0.047). Compared with the reference mono(2-ethylhexyl) phthalate (MEHP) group, children with ASD in the medium-exposure group had an OR of 3.370 for aggravating ASD severity. These results suggested that increased exposure to phthalates contributes to more ASD symptoms and that there are potentially sex-specific associations. These findings warrant further confirmation.

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19. He X, Yu Y, Ouyang Y. Evaluation and Analysis of the Intervention Effect of Systematic Parent Training Based on Computational Intelligence on Child Autism. Comput Math Methods Med;2022;2022:7746374.

Autism, also known as pervasive developmental disorder or autism spectrum disorder, is a group of clinical syndromes of developmental delay or impairment. Social impairment, verbal communication impairment, and behavioral impairment are the three conditions for the diagnosis of autism spectrum disorder, according to the American Psychiatric Association’s Diagnostic and Statistical Manual. According to relevant statistics, about 1 in 100 children is now diagnosed with autism, and their rehabilitation treatment is also valued by people from all walks of life. In the rehabilitation training of autistic children, it is found that the rehabilitation training of autistic children should pay attention to the role of parents and family environment. It is crucial that parents receive systematic training and act as partners in the development of the intervention plan. Research shows that a specific structured education and skills training program for parents of children with autism can be beneficial in improving behavioral problems, functional communication, and symptoms of autism in children with autism. To this end, this paper has completed the following work: Secondly, a portion of the systematic training of CA parents is discussed, followed by an explanation of the structure and principles of BPNN. Finally, the BPNN is utilized to create a model for assessing the impact of systematic parent instruction on CA. The experimental findings suggest that the proposed BPNN outperforms the competition.

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20. Hwang YH, Hayward BE, Zafarullah M, Kumar J, Durbin Johnson B, Holmans P, Usdin K, Tassone F. Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation. Sci Rep;2022 (Jun 21);12(1):10419.

The fragile X mental retardation (FMR1) gene contains an expansion-prone CGG repeat within its 5′ UTR. Alleles with 55-200 repeats are known as premutation (PM) alleles and confer risk for one or more of the FMR1 premutation (PM) disorders that include Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-Associated Neuropsychiatric Disorders (FXAND). PM alleles expand on intergenerational transmission, with the children of PM mothers being at risk of inheriting alleles with > 200 CGG repeats (full mutation FM) alleles) and thus developing Fragile X Syndrome (FXS). PM alleles can be somatically unstable. This can lead to individuals being mosaic for multiple size alleles. Here, we describe a detailed evaluation of somatic mosaicism in a large cohort of female PM carriers and show that 94% display some evidence of somatic instability with the presence of a series of expanded alleles that differ from the next allele by a single repeat unit. Using two different metrics for instability that we have developed, we show that, as with intergenerational instability, there is a direct relationship between the extent of somatic expansion and the number of CGG repeats in the originally inherited allele and an inverse relationship with the number of AGG interruptions. Expansions are progressive as evidenced by a positive correlation with age and by examination of blood samples from the same individual taken at different time points. Our data also suggests the existence of other genetic or environmental factors that affect the extent of somatic expansion. Importantly, the analysis of candidate single nucleotide polymorphisms (SNPs) suggests that two DNA repair factors, FAN1 and MSH3, may be modifiers of somatic expansion risk in the PM population as observed in other repeat expansion disorders.

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21. Jian J, Li LG, Zhao PJ, Zheng RJ, Dong XW, Zhao YH, Yin BQ, Cheng H, Li HL, Li EY. TCHis mitigate oxidative stress and improve abnormal behavior in a prenatal valproic acid-exposed rat model of autism. Physiol Genomics;2022 (Jun 20)

Objective Troxerutin is known for its anti-inflammatory and antioxidative effects in nerve impairment. The purpose of this study is to investigate the effect of troxerutin and cerebroprotein hydrolysate injections (TCHis) on prenatal valproic acid (VPA)-exposed rats. Methods The VPA was administered to pregnant rats on gestational day 12.5 to induce a model of autism. The offsprings were given the treatment of TCHis on postnatal day (PND) 21-50. On PND 43-50, the behavioral analysis of offsprings was performed after the treatment of TCHis for 1 h. On PND 50, the offsprings were harvested and the brains were collected. The hippocampus and prefrontal cortex were isolated for relevant biochemical detections. Results The administration of TCHis increased the pain sensitivity and improved abnormal social behaviors in prenatal VPA-exposed rats. Prenatal expose of VPA induced neuronal loss and apoptosis, enhanced reactive oxygen species (ROS) production, and promoted oxidative stress in hippocampus and prefrontal cortex, while these effects were reversed by the postnatal treatment of TCHis. In addition, postnatal administration of TCHis ameliorated mitochondrial function in hippocampus and prefrontal cortex of prenatal VPA-exposed rats. Conclusion This study concluded that postnatal treatment of TCHis reduced oxidative stress and ameliorated abnormal behavior in a prenatal VPA-induced rat model of autism.

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22. Kumazaki H, Muramatsu T, Yoshikawa Y, Matsumoto Y, Kuwata M, Takata K, Ishiguro H, Mimura M. Differences in the Optimal Motion of Android Robots for the Ease of Communications Among Individuals With Autism Spectrum Disorders. Front Psychiatry;2022;13:883371.

Android robots are employed in various fields. Many individuals with autism spectrum disorders (ASD) have the motivation and aptitude for using such robots. Interactions with these robots are structured to resemble social situations in which certain social behaviors can occur and to simulate daily life. Considering that individuals with ASD have strong likes and dislikes, ensuring not only the optimal appearance but also the optimal motion of robots is important to achieve smooth interaction and to draw out the potential of robotic interventions. We investigated whether individuals with ASD found it easier to talk to an android robot with little motion (i.e., only opening and closing its mouth during speech) or an android robot with much motion (i.e., in addition to opening and closing its mouth during speech, moving its eyes from side to side and up and down, blinking, deeply breathing, and turning or moving its head or body at random). This was a crossover study in which a total of 25 participants with ASD experienced mock interviews conducted by an android robot with much spontaneous facial and bodily motion and an android robot with little motion. We compared demographic data between participants who answered that the android robot with much motion was easier to talk to than android robot with little motion and those who answered the opposite. In addition, we investigated how each type of demographic data was related to participants’ feeling of comfort in an interview setting with an android robot. Fourteen participants indicated that the android robot with little motion was easier to talk to than the robot with much motion, whereas 11 participants answered the opposite. There were significant differences between these two groups in the sensory sensitivity score, which reflects the tendency to show a low neurological threshold. In addition, we found correlations between the sensation seeking score, which reflects the tendency to show a high neurological threshold, and self-report ratings of comfort in each condition. These results provide preliminary support for the importance of setting the motion of an android robot considering the sensory traits of ASD.

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23. Li Y, Xu S, Lee GT. The Effects of Tact Training on Echolalia in Children with Autism Spectrum Disorder in China. Anal Verbal Behav;2022 (Jun);38(1):74-83.

Echolalia can negatively impact multiple skill areas in children diagnosed with autism spectrum disorder (ASD), including skills related to academic and social performance. The purpose of this study was to employ a multiple probe across participants design to evaluate the effects of tact training on delayed echolalia in three children in China diagnosed with ASD. The results of this study indicated that tact training was effective in decreasing echolalia and increasing appropriate tacts for all three children. The effects were maintained 7 weeks following the completion of training.

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24. Lombardo MV, Mandelli V. Rethinking Our Concepts and Assumptions About Autism. Front Psychiatry;2022;13:903489.

Autism is a clinical consensus diagnosis made based on behavioral symptoms of early developmental difficulties in domains of social-communication (SC) and restricted repetitive behaviors (RRB). Many readily assume that alongside being optimal for separating individuals based on SC and RRB behavioral domains, that the label should also be highly useful for explaining differential biology, outcomes, and treatment (BOT) responses. However, we also now take for granted the fact that the autism population is vastly heterogeneous at multiple scales, from genome to phenome. In the face of such multi-scale heterogeneity, here we argue that the concept of autism along with the assumptions that surround it require some rethinking. While we should retain the diagnosis for all the good it can do in real-world circumstances, we also call for the allowance of multiple other possible definitions that are better tailored to be highly useful for other translational end goals, such as explaining differential BOT responses.

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25. Maurice V, Russet F, Scocco P, McNicholas F, Santosh P, Singh SP, Street C, Purper-Ouakil D. Transition from child and adolescent mental health care to adult services for young people with Attention-Deficit/Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder (ASD) in Europe: Barriers and recommendations. Encephale;2022 (Jun 17)

Transition in mental health care is the process ensuring continuity of care of a young patient arriving at the CAMHS (Child and Adolescent Mental Health Service) age boundary within mental health services. Transition refers to a transfer to an adult mental health service (AMHS), to private care or other mental health community services. A transition plan can also lead to a managed end of specialized care with involvement of a general practitioner or social services. For young people with a diagnosis of ADHD (Attention Deficit Hyperactivity Disorder) or ASD (Autism Spectrum Disorder), two disorders that persist into adulthood, an optimal transition would ensure continuity of care or facilitate access to specialized care in the case of a discharge. Transition typically occurs during adolescence, a known sensitive period when young people may experience major changes at several levels: physiological, psychological and social. Any barrier in the transition process resulting in discontinuity of care may worsen the symptoms of ADHD or ASD and can ultimately adversely affect the global mental health of young people with such neurodevelopmental disorders. The objectives of this narrative review are: 1/to identify the barriers in the transition process in mental health services often faced by young people with these two disorders; 2/to highlight specific recommendations for strengthening the CAMHS-AMHS interface that have been proposed by various countries in Europe.

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26. McLellan J, Kim DHJ, Bruce M, Ramirez-Celis A, Van de Water J. Maternal Immune Dysregulation and Autism-Understanding the Role of Cytokines, Chemokines and Autoantibodies. Front Psychiatry;2022;13:834910.

Autism spectrum disorder (ASD) is acknowledged as a highly heterogeneous, behaviorally defined neurodevelopmental disorder with multiple etiologies. In addition to its high heritability, we have come to recognize a role for maternal immune system dysregulation as a prominent risk factor for the development of ASD in the child. Examples of these risk factors include altered cytokine/chemokine activity and the presence of autoantibodies in mothers that are reactive to proteins in the developing brain. In addition to large clinical studies, the development of pre-clinical models enables the ability to evaluate the cellular and molecular underpinnings of immune-related pathology. For example, the novel animal models of maternal autoantibody-related (MAR) ASD described herein will serve as a preclinical platform for the future testing of targeted therapeutics for one ‘type’ of ASD. Identification of the cellular targets will advance precision medicine efforts toward tailored therapeutics and prevention. This minireview highlights emerging evidence for the role of maternal immune dysregulation as a potential biomarker, as well as a pathologically relevant mechanism for the development of ASD in offspring. Further, we will discuss the current limitations of these models as well as potential avenues for future research.

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27. Mitchell RA, Mitchell M, Williams K. The autism spectrum disorder phenotype in children with tuberous sclerosis complex: A systematic review and meta-analysis. Dev Med Child Neurol;2022 (Jun 20)

AIM: To investigate the phenotype in autistic children with tuberous sclerosis complex (TSC), specifically autism spectrum disorder (ASD) severity and characteristics, intellectual ability, adaptive and executive function, language skills, attention-deficit/hyperactivity disorder features, and internalizing and externalizing behaviours. METHOD: MEDLINE, Embase, and the Cochrane Library were searched up to March 2021. Studies that investigated predefined phenotypic factors in children with TSC-ASD were included according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) guidelines. Two authors independently reviewed titles, abstracts, full texts, and extracted the data. Risk of bias and GRADE assessments were completed. RESULTS: Thirty-four studies with 3160 children with TSC, 30% with ASD, were included. Meta-analysis found that 90% (95% confidence interval 86%-94%) of children with TSC-ASD have an intellectual disability. There was some evidence to suggest that young children with TSC-ASD and idiopathic ASD have a similar pattern of severity and behaviour. Overall, data about phenotypic characteristics were limited. INTERPRETATION: A greater proportion of children with TSC-ASD are reported to have an intellectual disability than children with idiopathic ASD. Early intervention should consider the needs of children with a high likelihood of intellectual disability. Research is needed to better understand the impacts of intellectual disability and other co-occurring difficulties on adaptive function, participation, and quality of life in TSC-ASD.

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28. Naguy A, Naguy C. Trichotieromania and Alopecia Areata Triggered by Aripiprazole-Methylphenidate Combo in an Autistic Child: The Nexus of Impulsivity-Compulsivity. Psychopharmacol Bull;2022 (May 31);52(2):157-160.

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29. Pan N, Auyeung B, Wang X, Lin LZ, Li HL, Zhan XL, Jin CK, Jing J, Li XH. Empathizing, systemizing, empathizing-systemizing difference and their association with autistic traits in children with autism spectrum disorder, with and without intellectual disability. Autism Res;2022 (Jul);15(7):1348-1357.

Empathizing, systemizing, and empathizing-systemizing difference can be linked to autistic traits in the general adult population and those with autism spectrum disorder (ASD), but these profiles and associations remain unclear in children with ASD, with and without intellectual disability (ASD + ID; ASD-noID). We recruited three groups including 160 boys with ASD (73 ASD + ID; 87 ASD-noID) and 99 typically developing (TD) boys (6-12 years). We measured empathizing, systemizing, and empathizing-systemizing difference using the parent-reported child Empathy and Systemizing Quotient (EQ-C/SQ-C). We measured autistic traits using the Social Responsiveness Scale (SRS). Among the three groups, children with ASD + ID and ASD-noID scored lower on the EQ-C and SQ-C than TD children (all p < 0.001). There was no difference in the EQ-C between children with ASD + ID and ASD-noID (16.59 ± 5.53 vs. 16.23 ± 5.85, p = 0.973), and the difference in the SQ-C attenuated to null when adjusting for intelligence between children with ASD-noID and TD children (18.89 ± 7.80 vs. 24.15 ± 6.73, p = 0.089). Children with ASD + ID scored higher on empathizing-systemizing difference than TD children but lower than children with ASD-noID (all p < 0.05). Negative associations between EQ-C and all autistic traits, null associations between SQ-C and all autistic traits, and positive associations between empathizing-systemizing difference and all autistic traits were found in all groups. We observed differences in empathizing, systemizing, and empathizing-systemizing difference and the consistency of their associations with autistic traits among the three groups. Our findings provide implication that behavioral interventions of ASD should consider the balance of empathizing and systemizing. LAY SUMMARY: We examined the profiles of empathizing, systemizing, and empathizing-systemizing difference in children with autism spectrum disorder, with and without intellectual disability (ASD + ID; ASD-noID), and typically developing (TD) children aged 6-12 years. We observed differences in these profiles and the consistency of their associations with autistic traits among the three groups. Empathizing and empathizing-systemizing difference, rather than systemizing, were associated with autistic traits within the three groups. Our findings provide implication that behavioral interventions of ASD should consider these imbalance profiles.

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30. Prohn SM, Dinora P, Broda MD, Bogenschutz M, Lineberry S. Measuring Four Personal Opportunities for Adults With Intellectual and Developmental Disabilities. Inclusion (Wash);2022;10(1):19-34.

This study tests an empirically derived model for measuring personal opportunities for people with intellectual and developmental disabilities (IDD) using National Core Indicators In-Person Survey (NCI-IPS) state and national datasets. The four personal opportunities measured, (a) privacy rights, (b) everyday choice, (c) community participation, and (d) expanded friendships, were informed by existing conceptualizations of service as well as NCI-IPS measures. Analyses confirmed the fit of a four-factor model and demonstrated that factors were significantly and positively correlated. To demonstrate the relationships between personal opportunities and personal and environmental characteristics, we estimated a structural equation model that regressed personal opportunities on age, gender, place of residence, and level of intellectual disability. Implications for using personal opportunities for evaluating service quality of IDD systems are discussed.

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31. Ribeiro TC, Farhat LC, Casella E, Graeff-Martins AS, Baron-Cohen S, Allison C, Polanczyk GV. Brazilian Portuguese Childhood Autism Spectrum Test: an investigation of the factor structure of autistic traits in school-aged children from Brazil. Braz J Psychiatry;2022 (Jun 20)

OBJECTIVE: There is limited evidence about the cross-cultural validity of autistic symptoms in school-aged children in Brazil. METHODS: We translated the Childhood Autism Spectrum Test scale to Brazilian Portuguese and performed factor analyses to investigate the factor structure of parent-reported autistic symptoms in a large sample (N = 8571) of children/adolescents from a school survey in the metropolitan area of São Paulo. RESULTS: Autistic symptoms were best conceptualized under a correlated-factors model with two factors: one predominantly characterized by social-communication symptoms and the other by inflexible/restricted language, behaviours, and interests symptoms. CONCLUSIONS: These findings provide evidence that the structure of autistic symptoms in Brazil is similar to that described in other countries, indicating the cross-cultural validity of autism in Brazil.

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32. Rinaldi LJ, Simner J, Koursarou S, Ward J. Autistic traits, emotion regulation, and sensory sensitivities in children and adults with Misophonia. J Autism Dev Disord;2022 (Jun 21)

Misophonia is an unusually strong aversion to everyday sounds such as chewing, crunching, or breathing. Previous studies have suggested that rates of autism might be elevated in misophonia, and here we examine this claim in detail. We present a comprehensive review of the relevant literature, and two empirical studies examining children and adults with misophonia. We tested 142 children and 379 adults for traits associated with autism (i.e., attention-to-detail, attention-switching, social processing, communication, imagination, emotion regulation, and sensory sensitivity across multiple domains). Our data show that autistic traits are indeed elevated in misophonics compared to controls. We discuss our findings in relation to models of the interface between autism, sensory sensitivities, and the specific features of misophonia.

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33. Saré RM, Lemons A, Smith CB. Effects of Treatment With Hypnotics on Reduced Sleep Duration and Behavior Abnormalities in a Mouse Model of Fragile X Syndrome. Front Neurosci;2022;16:811528.

Many patients with fragile X syndrome (FXS) have sleep disturbances, and Fmr1 knockout (KO) mice (a model of FXS) have reduced sleep duration compared to wild type (WT). Sleep is important for brain development, and chronic sleep restriction during development has long-lasting behavioral effects in WT mice. We hypothesized that the sleep abnormalities in FXS may contribute to behavioral impairments and that increasing sleep duration might improve behavior. We treated adult male Fmr1 KO and WT mice subacutely with three different classes of hypnotics (DORA-22, ramelteon, and zolpidem) and caffeine, a methylxanthine stimulant, and we tested the effects of treatments on sleep duration and behavior. Behavior tests included activity response to a novel environment, anxiety-like behavior, and social behavior. As expected, all hypnotics increased, and caffeine decreased sleep duration in the circadian phase in which drugs were administered. Caffeine and DORA-22 treatment significantly reduced activity in the open field regardless of genotype. Other effects were not as apparent.

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34. Shekhawat DS, Gupta T, Singh P, Sharma P, Singh K. Monitoring tools for early identification of children with developmental delay in India: an update. Child Neuropsychol;2022 (Aug);28(6):814-830.

Developmental screening is challenging in both developed countries and developing countries. An estimated 10% of children experience developmental delay leading to disability in India. Unfortunately, the Indian literature is limited regarding early identification and intervention of developmental delays in youngsters, given multiple barriers in implementing screening. Quick screening tools can easily be integrated into the routine work-up of infants and young children in the primary health-care system and the literature has shown the efficiency of early identification and intervention for children born with high-risk profiles. Therefore, validated screening tools may improve the early identification of developmental delay in young children, further enhancing the clinical outcome of children with developmental delays. India introduced the first development screening tool in 1991, the Baroda Development Screening Test (BDST), followed by Developmental Assessment Scale for Indian Infants (DASII), Trivandrum Development Screening Chart (TDSC). Indian researchers have adapted few development screening tools from standardized tools available from Western countries. This review highlights the different screening tools adapted in India, psychometric properties and adapted items to the gold standard, critical appraisal of most commonly used screening tools and description on strengths and limitations. The goal is to help clinicians understand the rationale behind each tool and the different domains evaluated as per the child’s needs.

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35. Wang B, Dong H, Li H, Yue X, Xie L. A Probable Way Vitamin D Affects Autism Spectrum Disorder: The Nitric Oxide Signaling Pathway. Front Psychiatry;2022;13:908895.

Vitamin D (VD) deficiency during pregnancy and early brain development is an important environmental risk factor for autism spectrum disorder (ASD). Its specific mechanism of action is still unclear. However, one study on the correlation between metabolomics and VD levels in children with ASD has found that the whole-blood arginine (Arg) levels of children with ASD are significantly negatively correlated with serum VD levels, suggesting that the effect of VD on ASD may be related to the signaling pathway involving Arg. Arg is a precursor of nitric oxide (NO), and changes in its levels most directly affect NO levels and signal transduction pathways. NO, a biologically active free radical, is both a neurotransmitter and a neuromodulator in the central nervous system and is related to the pathogeneses of various neurological diseases. The NO signaling pathway is not only affected by VD levels but also closely related to ASD through a series of mechanisms, such as neurotransmitter imbalance, immune disorders, and oxidative stress. Therefore, the effect of VD on ASD may be achieved via regulation of the NO signaling pathway. The current review discusses the relationship among VD, NO, and ASD as suggested by a large body of evidence in the literature in an effort to provide clues for researchers on the pathogenesis of ASD and the mechanism of VD’s impact on ASD.

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36. Wolbert F, Nikoleit K, Steinbrink M, Luebbert C, Sadowski G. The Shelf Life of ASDs: 1. Measuring the Crystallization Kinetics at Humid Conditions. Mol Pharm;2022 (Jun 21)

Amorphous solid dispersions (ASDs), where an active pharmaceutical ingredient (API) is dissolved in a polymer, are a favored formulation technique to achieve sufficient bioavailability of poorly water-soluble APIs. The shelf life of such ASDs is often limited by API crystallization. Crystallization depends strongly on the storage conditions (relative humidity and temperature) and the polymer selected for generating the ASD. Determining the crystallization kinetics of ASDs under various conditions requires suitable analytical methods. In this work, two different analytical methods were compared and cross-validated: The first builds on water-sorption measurements combined with thermodynamic predictions ( Eur. J. Pharm. Biopharm. 2018, 127, 183-193, DOI: 10.1016/j.toxrep.2018.11.002), whereas the second applies Raman spectroscopy. Using the two independent methods, factors influencing the crystallization kinetics of ASDs containing the API griseofulvin were investigated quantitatively. It was found that crystallization kinetics increases with increasing temperature and relative humidity. Additionally, the influence of different polymers (poly(vinylpyrrolidone-co-vinyl acetate) and Soluplus) on crystallization kinetics were investigated. The experimentally obtained crystallization kinetics were described using the Johnson-Mehl-Avrami-Kolmogorov model and are the basis for future shelf life predictions at desired storage conditions.

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37. Wong WP, Chow SL. Evaluation on the effectiveness on the implementation of WHO caregiver skills training (CST) programme in Hong Kong: a randomised controlled trial protocol. BMJ Open;2022 (Jun 20);12(6):e054099.

INTRODUCTION: This protocol delineates the research design and analytical framework used to evaluate the effectiveness of the WHO-CST (CST, caregiver skills training) in Hong Kong. The WHO-CST aims to enhance the caregiver skills of parents of children with potential autism spectrum disorders (ASD) and/or developmental delays. METHODS AND ANALYSIS: In this study, 130 eligible caregiver-child dyads were recruited and randomly assigned to the experimental and wait-list-control groups. A randomised controlled trial design was adopted to compare the changes between the two groups regarding caregivers’ skills, knowledge and practices when interacting with their children with impairments due to ASD. Assessments were conducted before, immediately after and 1 month after the completion of the WHO-CST programme. The primary measurement tool was the joint engagement rating inventory developed by WHO experts to gauge how parents engage their children. A 10-min video recording of their dyadic interaction and behaviours in a defined play setting was used for the measurement. A set of other measurements of caregivers’ knowledge, confidence and experience of using the caregiving skills were also measured. ETHICS AND DISSEMINATION: Ethics approval was received from the Human Research Ethics Committee (EA1901033), The University of Hong Kong. The final findings of this study will be disseminated through public reports, peer-reviewed publication or at a conference launched for the WHO-CST programme. TRIAL REGISTRATION NUMBER: ChiCTR2000034585.

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38. Zhang Y, Zhang J, Pan Z, He X. Effects of Washed Fecal Bacteria Transplantation in Sleep Quality, Stool Features and Autism Symptomatology: A Chinese Preliminary Observational Study. Neuropsychiatr Dis Treat;2022;18:1165-1173.

PURPOSE: Autism spectrum disorder is a highly complex neurological and psychosocial disorder characterized by social dysfunction, severe reduction in speech, and a single stereotyped behavior. The treatment methods are currently limited, and children with autism generally suffer from constipation and sleep disorders. It is urgent to find an alternative psychotropic drug, given the drug dependence and adverse reactions that may occur with long-term medication. PATIENTS AND METHODS: This retrospective study included 49 children with autism at the first affiliated Hospital of Guangdong Pharmaceutical University, who received washed fecal microbiota transplantation (WMT) treatment between June 2019 and July 2021 and compared the sleep disorder scores between the constipation group, control group and blank group. RESULTS: Second WMT could significantly improve the sleep disorder scores in the constipation group (p=0.026) and the decrease in sleep disturbance scale for children (SDSC) score was synchronized with the increase in Bristol stool form scale (BSFS) score. However, there was no significant difference between patients without constipation (p=0.54), and the behavior of autism improved in both groups. CONCLUSION: WMT could relieve constipation and improve sleep disorders in children with autism, with no deterioration in stool morphology and sleep disorders in other children. Moreover, there were no obvious serious adverse clinical events after WMT.

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39. Zuniga-Kennedy M, Davoren M, Shuffrey LC, Luna RA, Savidge T, Prasad V, Anderson GM, Veenstra-VanderWeele J, Williams KC. Intestinal Predictors of Whole Blood Serotonin Levels in Children With or Without Autism. J Autism Dev Disord;2022 (Jun 21)

Hyperserotonemia, or elevated levels of whole blood serotonin (WB5-HT), was the first biomarker linked to autism spectrum disorder (ASD). Despite numerous studies investigating the etiology of hyperserotonemia, results have been inconsistent. Recent findings suggest a relationship between the immune system and hyperserotonemia. The current study investigated whether intestinal 5-HT levels, 5-HT gene expression, or intestinal cell types predict WB5-HT. Participants included thirty-one males aged 3-18 who were classified into one of three groups: ASD and functional GI issues, typically developing with GI issues, and typically developing without GI issues. Samples from a lower endoscopy were analyzed to examine the pathways in predicting WB-5HT. Results demonstrated an association between T-Lymphocytes and WB5-HT.

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