1. Almutairi MM, Nadeem A, Ansari MA, Bakheet SA, Attia SM, Albekairi TH, Alhosaini K, Algahtani M, Alsaad AMS, Al-Mazroua HA, Ahmad SF. Lead (Pb) exposure exacerbates behavioral and immune abnormalities by upregulating Th17 and NF-κB-related signaling in BTBR T(+) Itpr3(tf)/J autistic mouse model. Neurotoxicology;2022 (Jun 26);91:340-348.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that are characterized by abnormal social interaction impairments in communication and repetitive and restricted activities or interests. Even though the exact etiology of ASD remains unknown. Lead (Pb) is a toxin known to harm many organs in the body, it is one of the most ubiquitous metal exposures which is associated with neurological deficits. Previous studies have shown that the exposure to Pb may play a role in ASD. BTBR T(+) Itpr3(tf)/J (BTBR) mouse model is commonly used as a preclinical model for ASD. In this study, we investigated the effects of Pb exposure on sociability, self-grooming and marble burying behaviors tests in BTBR mice. We further examined the effects of Pb on IL-17A- RORγT-, STAT3-, NF-κB p65-, iNOS-, TLR-2- and TLR-4-producing CD45(+) cells in spleen using flow cytometry. We also explored the effects of Pb on IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA expression in the brain tissue using RT-PCR analysis. Our results demonstrated that Pb exposure substantially increased repetitive behavior, marble burying and decrease social interactions in BTBR mice. In addition, in spleen cells, Pb exposure exaggerated CD45(+)IL-17A(+), CD45(+)RORγT(+), CD45(+)STAT3(+), CD45(+)NF-κB p65(+), CD45(+)iNOS(+), CD45(+)TLR-2(+) and CD45(+)TLR-4(+) in BTBR mice. We also found that Pb significantly increased IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA in the brain tissue. Therefore, Pb exposure exacerbates behavioral and neuroimmune function in BTBR mice, suggesting a potentially strong role for Pb in ASD.

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2. Andonovski ME, Antonarakis GS. Autism spectrum disorder and dentoalveolar trauma: a systematic review and meta-analysis. J Stomatol Oral Maxillofac Surg;2022 (Jun 28)

OBJECTIVES: Patients with autism spectrum disorder (ASD) may be more predisposed to oral pathology, including dentoalveolar trauma. Our aim was to assess the risk of dentoalveolar trauma in patients with ASD. MATERIALS AND METHODS: Meta-analysis methodology was used to compared the prevalence of dentoalveolar trauma in individuals with ASD compared to children without ASD. A literature search was carried out, with predefined inclusion and exclusion criteria, to identify controlled studies evaluating dentoalveolar trauma in individuals with ASD. Data were combined using the random-effects meta-analysis model. RESULTS: Out of an initial 154 studies, 14 were selected for inclusion in the meta-analysis, resulting in a total of 1488 individuals with ASD. Meta-analysis results showed significant difference in the overall risk of dentoalveolar trauma between individuals with ASD versus a control group (RR = 1.45). Looking at specific types of dentoalveolar trauma, individuals with ASD were found to be more at risk for partial or total luxation injuries (RR = 3.02) than healthy individuals. CONCLUSIONS: Children with ASD are more at risk for dentoalveolar trauma than children without ASD, especially for more severe dentoalveolar trauma such as luxation and avulsion injuries.

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3. Armingol E, Baghdassarian HM, Martino C, Perez-Lopez A, Aamodt C, Knight R, Lewis NE. Context-aware deconvolution of cell-cell communication with Tensor-cell2cell. Nat Commun;2022 (Jun 27);13(1):3665.

Cell interactions determine phenotypes, and intercellular communication is shaped by cellular contexts such as disease state, organismal life stage, and tissue microenvironment. Single-cell technologies measure the molecules mediating cell-cell communication, and emerging computational tools can exploit these data to decipher intercellular communication. However, current methods either disregard cellular context or rely on simple pairwise comparisons between samples, thus limiting the ability to decipher complex cell-cell communication across multiple time points, levels of disease severity, or spatial contexts. Here we present Tensor-cell2cell, an unsupervised method using tensor decomposition, which deciphers context-driven intercellular communication by simultaneously accounting for multiple stages, states, or locations of the cells. To do so, Tensor-cell2cell uncovers context-driven patterns of communication associated with different phenotypic states and determined by unique combinations of cell types and ligand-receptor pairs. As such, Tensor-cell2cell robustly improves upon and extends the analytical capabilities of existing tools. We show Tensor-cell2cell can identify multiple modules associated with distinct communication processes (e.g., participating cell-cell and ligand-receptor pairs) linked to severities of Coronavirus Disease 2019 and to Autism Spectrum Disorder. Thus, we introduce an effective and easy-to-use strategy for understanding complex communication patterns across diverse conditions.

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4. Bain JM, Snyder LG, Helbig KL, Cooper DD, Chung WK, Goodspeed K. Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications. J Neurodev Disord;2022 (Jun 28);14(1):40.

BACKGROUND: SLC6A1-related disorder is a recently identified, rare, genetic neurodevelopmental disorder that is associated with loss-of-function variants in SLC6A1. This gene encodes GABA transporter type I that is responsible for re-uptake of GABA from the synapse into the pre-synaptic terminal or circulating neuroglia. Based upon retrospective review of published cases and available research databases including Epi25 collective and SLC6A1 Connect patient database, the phenotypic spectrum is broad and includes developmental delay, epilepsy, and autism or autistic traits. SLC6A1 is one of the genes included in the Simons Searchlight registry, which includes standardized data collection across genetically identified neurodevelopmental conditions. METHODS: In this study, we compare parent-report measures of phenotypic features in the Simons Searchlight registry to previously published, provider-reported cases to assess if parent-report measures are consistent with what has been reported in the literature. RESULTS: There were 116 participants in the provider-reported dataset compared to 43 individuals in the caregiver-reported dataset. Carriers in Searchlight had 83 unique pathogenic or likely pathogenic variants in SLC6A1, which were predominantly missense or nonsense variants. There was no significant difference between groups for the prevalence of developmental delay, ASD, or ADHD. Caregivers more often reported hypotonia, while epilepsy was slightly more frequently reported by providers. CONCLUSIONS: We propose that standardized parent-report data collection methods are consistent with provider reports on many core features of SLC6A1-related disorder. The availability of patient registries and standardized natural history studies may fill an important need in clinical trial readiness programs, with larger sample sizes than smaller published case series.

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5. Brefort E, Saint-Georges-Chaumet Y, Cohen D, Saint-Georges C. Two-year follow-up of 90 children with autism spectrum disorder receiving intensive developmental play therapy (3i method). BMC Pediatr;2022 (Jun 28);22(1):373.

BACKGROUND: The Intensive, Interactive, and Individual (3i) intervention approach aims to decrease the severity of autism spectrum disorder (ASD) using intensive developmental play therapy (3i). We performed a retrospective study of 90 children who were enrolled for 2 years in the 3i approach to assess changes and predictors of changes in ASD severity at follow-up (FU). METHODS: The ASD severity of all patients (N = 119) who began 3i intervention between 2013 and 2018 was systematically measured using the childhood autism rating scale (CARS) and autism diagnosis interview-revised (ADI-R). Among them, 90 patients (mean age 5.6 ± 3.7 years) had a second assessment at the 2 year FU. CARS and ADI-R scores after 2 years of 3i intervention were compared to baseline scores using paired student’s t-tests. We used multiple linear regression models to assess the weight of baseline variables (e.g., age, oral language, sex, treatment intensity) on changes at the 2 year FU. RESULTS: Mean CARS and ADI-R subscores (interaction, communication, repetitive behaviour) decreased significantly by 20, 41, 27.5 and 25%, respectively (effect sizes: d > 0.8). Moreover, 55 and 46.7% of participants switched to a lower category of ASD severity based on the CARS scale and ADI-R interview, respectively. Multiple linear models showed that (i) a higher treatment intensity (more than 30 h per week) was significantly associated with a greater decrease (improvement) in the ADI-R interaction score; (ii) patients categorized as verbal subjects at baseline were associated with a better outcome, as ascertained by the CARS, ADI-R interaction and ADI-R communication scores; and (iii) older patients were significantly associated with a greater decrease in the ADI-R interaction score. However, we found no impact of sex, severity of ASD or comorbidities at baseline. CONCLUSION: This study performed on 90 children suggests that 3i therapy may allow for a significant reduction in ASD severity with improvements in interaction, communication, and repetitive behaviours. A study using a control group is required to assess the efficacy of 3i play therapy compared to other interventions.

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6. Calton S, Hall G. Autistic adults and their experiences with police personnel: a qualitative inquiry. Psychiatr Psychol Law;2022;29(2):274-289.

This study uses a qualitative methodological approach to investigate the experiences that autistic adults have when encountering police personnel. An anonymous, online, semi-structured survey asking open-ended questions about individual experience was used, and the data were analysed thematically. Although only five participants comprised the final sample, the findings illustrate how – despite differences in types of interaction and police contact – similar experiences were reported. Almost all participants reported experiencing a negative interaction with police, coupled with a limited understanding of the events surrounding their encounter. Four participants experienced some form of being stopped and questioned. This study aims to examine alternative perspectives, as previous research has focused on criminal justice personnel perspectives rather than autistic perspectives. This is one of a few qualitative Australian studies to seek individualised experiences from a community-based sample. Sampling and recruitment strategies need revision to attain a larger number of surveys in future research.

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7. Charidza CA, Gillmeister H. Differential beta desynchronisation responses to dynamic emotional facial expressions are attenuated in higher trait anxiety and autism. Cogn Affect Behav Neurosci;2022 (Jun 27)

Daily life demands that we differentiate between a multitude of emotional facial expressions (EFEs). The mirror neuron system (MNS) is becoming increasingly implicated as a neural network involved with understanding emotional body expressions. However, the specificity of the MNS’s involvement in emotion recognition has remained largely unexplored. This study investigated whether six basic dynamic EFEs (anger, disgust, fear, happiness, sadness, and surprise) would be differentiated through event-related desynchronisation (ERD) of sensorimotor alpha and beta oscillatory activity, which indexes sensorimotor MNS activity. We found that beta ERD differentiated happy, fearful, and sad dynamic EFEs at the central region of interest, but not at occipital regions. Happy EFEs elicited significantly greater central beta ERD relative to fearful and sad EFEs within 800 – 2,000 ms after EFE onset. These differences were source-localised to the primary somatosensory cortex, which suggests they are likely to reflect differential sensorimotor simulation rather than differential attentional engagement. Furthermore, individuals with higher trait anxiety showed less beta ERD differentiation between happy and sad faces. Similarly, individuals with higher trait autism showed less beta ERD differentiation between happy and fearful faces. These findings suggest that the differential simulation of specific affective states is attenuated in individuals with higher trait anxiety and autism. In summary, the MNS appears to support the skills needed for emotion processing in daily life, which may be influenced by certain individual differences. This provides novel evidence for the notion that simulation-based emotional skills may underlie the emotional difficulties that accompany affective disorders, such as anxiety.

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8. Chua B, Neoh M, Jeon M, Joyce A, Iandolo G, Hayton J, Esposito G, Dimitriou D. Impact of sleep on attention in primary school-aged autistic children: Exploratory cross-cultural comparison between Singapore and UK children. Res Dev Disabil;2022 (Jun 24);128:104271.

BACKGROUND: There is a growing body of research studying the impact sleep has on attention among typically developing (TD) children, but research is lacking among autistic children. AIMS: The present study aimed to explore, for the first time, differences in (1) attention, (2) sleep parameters among primary school-aged Singaporean autistic children (N = 26) and Singaporean TD children (N = 20), and with UK autistic (N = 11) and UK TD children (N = 16), and (3) the impact of sleep on attention. METHODS AND PROCEDURES: Actigraphy was used to objectively assess sleep, and a Continuous Performance Task was used to measure attentional domains. OUTCOMES AND RESULTS: There were inconclusive findings indicating that autistic children had poorer sustained attention than TD children. Although autistic children did not display more sleep difficulties than TD children, they showed shorter actual sleep duration (Singapore ASD = 7:00 h, UK ASD = 7:35 h, p < .01) and longer sleep latency (Singapore ASD = 30:15 min, UK ASD = 60:00 min, p < .01) than clinical recommendations. Sleep difficulties were also present among Singaporean and UK TD children. Both TD groups had less actual sleep duration than recommended (Singapore TD = 6:32 h, UK TD = 8:07 h). Singaporean TD children had sleep efficiency below recommended criterion (78.15%). Sleep impacted attention across all groups, but effects were different for autistic and TD groups. CONCLUSIONS AND IMPLICATIONS: The study highlighted the importance for practitioners and carers to adopt a child-centred approach to assessing sleep and attentional difficulties, especially among autistic children due to the high variability in performance within the group. The impact of cultural and school-setting differences on sleep was also raised.

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9. Connor A, Fabrizi SE, Nasamran A, Sung C. Near-Peer Facilitation of a Soft Skills Program for Young Adults With Autism. Am J Occup Ther;2022 (Jul 1);76(4)

IMPORTANCE: Young adults with autism spectrum disorder (ASD) experience poor employment outcomes. Teaching soft skills and using peer-based interventions improve outcomes for people with ASD. OBJECTIVE: To evaluate the preliminary efficacy of a soft skills intervention and the feasibility of delivery to a group of young adults with ASD by near-peer occupational therapy master’s-level students. DESIGN: Pretest-posttest single-group design. SETTING: College campus. PARTICIPANTS: Convenience sample of 14 young adults (M age = 21.57 yr) with ASD. INTERVENTION: The Assistive Soft Skills and Employment Training (ASSET) program is a 12-session, manualized, soft skills group intervention previously validated with the ASD population. Topics include communication, attitude and enthusiasm, teamwork, networking, professionalism, and stress management. OUTCOMES AND MEASURES: Social functioning, self-efficacy, and adaptive behavior were measured preintervention and immediately postintervention using standardized self-report rating scales. Participant satisfaction and experience were assessed using program-specific measures. RESULTS: Participants made statistically significant improvements, with medium to large effect sizes in social functioning, self-efficacy, and adaptive behavior. They reported high levels of satisfaction and a positive experience with the program content and delivery. CONCLUSIONS AND RELEVANCE: This study provides evidence of participant satisfaction and perceived soft skills improvement and confidence, in addition to the preliminary efficacy of master’s-level students as near-peer facilitators of the ASSET program with an ASD population. What This Article Adds: The results suggest that trained and supervised master’s-level students can effectively deliver a manualized intervention as near-peer facilitators, elicit positive feedback and high levels of participant satisfaction, and replicate and extend previously reported participant gains.

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10. Dai YG, Carter AS. Characterizing Accommodations by Parents of Young Children with Autism: A Mixed Methods Analysis. J Autism Dev Disord;2022 (Jun 28)

Symptoms of autism influence families’ participation in daily activities, but few studies have broadly explored the types of accommodations caregivers make to their family’s routines after their child is diagnosed with autism. The current study used a mixed-methods approach to characterize the rate and types of accommodations made by 171 families and the child and family characteristics that predicted accommodations. Most families (91%) endorsed making accommodations in the past year. Lower income, older child age, marginalized racial/ethnic identity, and higher levels of child problem behavior predicted accommodations in a greater number of domains. Thematic analysis illuminated the types of accommodations caregivers made and their motivation for making these lifestyle adjustments. Findings have important implications for parent-mediated interventions and policy.

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11. Davy G, Unwin KL, Barbaro J, Dissanayake C. Leisure, employment, community participation and quality of life in caregivers of autistic children: A scoping review. Autism;2022 (Jun 28):13623613221105836.

We searched a wide range of academic journals for published information on the participation levels of caregivers of autistic children in activities relating to leisure, social, community and employment contexts, and the impact that participation may have on caregiver quality of life. Overall, we found that the impact of parenting an autistic child is broad with caregivers often prioritising their child’s needs over their own, particularly in occupational participation, which impacts their quality of life. Findings also highlighted a need for further research to investigate the experience of caregivers, and the relationship between participation and quality of life in caregivers of autistic children, as the results can inform the development of better supports for them.

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12. Dellapiazza F, Michelon C, Picot MC, Baghdadli A. Early risk factors for anxiety disorders in children with autism spectrum disorders: results from the ELENA Cohort. Sci Rep;2022 (Jun 28);12(1):10914.

Anxiety in children with autism spectrum disorder (ASD) negatively affects their social interactions, and quality of life. It is necessary to identify early risk factors for anxiety to tailor prevention and interventions. We aimed to examine the clinical level of anxiety in children with ASD from 5 to 10 years of age and identify potential early risk factors 3 years earlier. Participants were ASD children included in ELENA, a French prospective cohort. In this study, we used the collection of data at Time 1-T1 (at baseline) and Time 2-T2 (3 years after T1). Two groups were identified at T2 according to the threshold for anxiety on the CBCL: ASD-only group and ASD + anxiety group. Our results showed that half of the children in our sample had a clinical level of anxiety at T2. Regression analysis showed that greater ASD severity and lower sensory processing difficulties predicted lower anxiety, whereas higher levels of restricted and repetitive behaviours tended to predict higher levels of anxiety. The high prevalence of clinical-level anxiety in our sample suggests the need for specific assessment and targeted treatment of anxiety on a routine basis.

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13. Deng J, Wang Y, Hu M, Lin J, Li Q, Liu C, Xu X. Deleterious Variation in BR Serine/Threonine Kinase 2 Classified a Subtype of Autism. Front Mol Neurosci;2022;15:904935.

Recently, deleterious variants in the BR serine/threonine kinase 2 (BRSK2) gene have been reported in patients with autism spectrum disorder (ASD), suggesting that BRSK2 is a new high-confidence ASD risk gene, which presents an opportunity to understand the underlying neuropathological mechanisms of ASD. In this study, we performed clinical and neurobehavioral evaluations of a proband with a de novo non-sense variant in BRSK2 (p.R222X) with other reported BRSK2 mutant patients. To validate BRSK2 as an ASD risk gene, we generated a novel brsk2b-deficient zebrafish line through CRISPR/Cas9 and characterized its morphological and neurobehavioral features as well as performed molecular analysis of neurogenesis-related markers. The proband displayed typical ASD behaviors and language and motor delay, which were similar to other published BRSK2 mutant patients. Morphologically, brsk2b (-/-) larvae exhibited a higher embryonic mortality and rate of pericardium edema, severe developmental delay, and depigmentation as well as growth retardation in the early developmental stage. Behaviorally, brsk2b(-/-) zebrafish displayed significantly decreased activity in open field tests and enhanced anxiety levels in light/dark tests and thigmotaxis analysis. Specifically, brsk2b(-/-) zebrafish showed a prominent reduction of social interaction with peers and disrupted social cohesion among homogeneous groups. Molecularly, the mRNA expression levels of homer1b (a postsynaptic density scaffolding protein), and mbpa, mpz, and plp1b (molecular markers of oligodendrocytes and myelination) were increased in the brain tissues of adult brsk2b(-/-) zebrafish, while the expression level of isl1a, a marker of motor neurons, was decreased. Taken together, for the first time, we established a novel brsk2b-deficient zebrafish model that showed prominent ASD-like behaviors. In addition, the disturbed mRNA expression levels of neurogenesis-related markers implied that the processes of postsynaptic signaling as well as oligodendrocytes and myelination may be involved. This discovery may suggest a path for further research to identify the underlying neuropathological mechanisms between BRSK2 and ASD.

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14. Doğan S, Çolak A. Social robots in the instruction of social skills in autism: a comprehensive descriptive analysis of single-case experimental designs. Disabil Rehabil Assist Technol;2022 (Jun 26):1-20.

PURPOSE: The rapid technological advances, the traits of individuals with ASD and their interest in technology are promising for the instruction of social skills to individuals with autism spectrum disorder (ASD) using various technological interventions. Robotic interventions are among these. However, although robotics is frequently used with individuals with ASD, there is a limited number of reviews on social skills instruction and methods. The present study aimed to conduct a comprehensive descriptive analysis on single-case experimental designs where social skills were instructed to individuals with ASD and social robots were included as independent variables. MATERIALS AND METHODS: Thirteen single-case experimental designs published in peer-reviewed journals in which social skills were taught to individuals with ASD using social robots were reviewed with a comprehensive descriptive analysis based on five categories: (a) key characteristics, (b) methodological characteristics, (c) findings, (d) data analysis, and (e) key parameters in single-case experimental designs. RESULTS: Social robots are generally effective in the instruction of social skills. Several social skills (e.g., making eye contact, social interaction, simple greetings) were instructed in the studies. Humanoid robots and NAO were used generally. The study data were predominantly analyzed statistically. There were several problems in research based on the basic parameters in single-case experimental designs. CONCLUSIONS: The researches in this study differ in several respects (e.g., results, data analysis, and dependent variable). Thus, there is still a need for several robotics studies in the instruction of social skills. IMPLICATIONS FOR REHABILITATIONThis study will be a guide for teachers who currently use robots in their classrooms but do not know which skills to use in teaching and how to use them functionally, as it shows applied research with robots.The findings of this research will show implementers working with children with ASD that technological tools can be used in rehabilitation environments, and that teachers can take a place in their robots in interventions for children with ASD, giving them a different perspective.It will be seen that the education of children with ASD is not only 1:1 and with humans, but robots can also provide education. In this way, the power of technology in teaching will become clearer. Especially in rehabilitation.Finally, this research will offer new options in teaching especially for teachers who aim at teaching social skills and will give them the opportunity to comprehensively examine the processes of different studies on these subjects.

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15. Ellis Weismer S, Saffran JR. Differences in Prediction May Underlie Language Disorder in Autism. Front Psychol;2022;13:897187.

Language delay is often one of the first concerns of parents of toddlers with autism spectrum disorder (ASD), and early language abilities predict broader outcomes for children on the autism spectrum. Yet, mechanisms underlying language deficits in autistic children remain underspecified. One prominent component of linguistic behavior is the use of predictions or expectations during learning and processing. Several researcher teams have posited prediction deficit accounts of ASD. The basic assumption of the prediction accounts is that information is processed by making predictions and testing violations against expectations (prediction errors). Flexible (neurotypical) brains attribute differential weights to prediction errors to determine when new learning is appropriate, while autistic individuals are thought to assign disproportionate weight to prediction errors. According to some views, these prediction deficits are hypothesized to lead to higher levels of perceived novelty, resulting in « hyperplasticity » of learning based on the most recent input. In this article, we adopt the perspective that it would be useful to investigate whether language deficits in children with ASD can be attributed to atypical domain-general prediction processes.

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16. Hoekstra RA. Serving the underserved: How can we reach autism families who systemically miss out on support?. Autism;2022 (Jun 25):13623613221105389.

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17. Horgan F, Kenny N, Flynn P. A systematic review of the experiences of autistic young people enrolled in mainstream second-level (post-primary) schools. Autism;2022 (Jun 25):13623613221105089.

Internationally, more autistic pupils are being educated in mainstream schools. Some people have voiced concerns that this policy roll-out is happening before examining the effective outcomes for autistic students. Concerns have also been expressed regarding a lack of the voices of autistic pupils themselves within research and policy. This study was undertaken in order to gather literature that explores the views and experiences of autistic young people in relation to their mainstream school placement at the secondary level. This study aims to summarise the existing literature and provide a new, more complete account of the school experiences of this cohort. After an extensive search, 33 studies were identified by the authors as meeting a set of inclusion criteria. All of the studies included in this review elicited the views and perspectives of at least one autistic young person regarding their mainstream secondary school placement. Upon carefully analysing these studies, the authors developed three key themes as follows: ‘Demands of mainstream placements’, ‘Social participation’ and ‘Impacts on the student’. Our analysis revealed that for many autistic young people, mainstream school is a complex and demanding social environment. Further research that prioritises the voices and perspectives of this cohort is essential as inclusive policy and practice continues to develop.

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18. Jensen AR, Lane AL, Werner BA, McLees SE, Fletcher TS, Frye RE. Modern Biomarkers for Autism Spectrum Disorder: Future Directions. Mol Diagn Ther;2022 (Jun 27)

Autism spectrum disorder is an increasingly prevalent neurodevelopmental disorder in the world today, with an estimated 2% of the population being affected in the USA. A major complicating factor in diagnosing, treating, and understanding autism spectrum disorder is that defining the disorder is solely based on the observation of behavior. Thus, recent research has focused on identifying specific biological abnormalities in autism spectrum disorder that can provide clues to diagnosis and treatment. Biomarkers are an objective way to identify and measure biological abnormalities for diagnostic purposes as well as to measure changes resulting from treatment. This current opinion paper discusses the state of research of various biomarkers currently in development for autism spectrum disorder. The types of biomarkers identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, and visual attention, metabolic including abnormalities in mitochondrial, folate, trans-methylation, and trans-sulfuration pathways, immune including autoantibodies and cytokine dysregulation, autonomic nervous system, and nutritional. Many of these biomarkers have promising preliminary evidence for prenatal and post-natal pre-symptomatic risk assessment, confirmation of diagnosis, subtyping, and treatment response. However, most biomarkers have not undergone validation studies and most studies do not investigate biomarkers with clinically relevant comparison groups. Although the field of biomarker research in autism spectrum disorder is promising, it appears that it is currently in the early stages of development.

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19. Kong XJ, Wei Z, Sun B, Tu Y, Huang Y, Cheng M, Yu S, Wilson G, Park J, Feng Z, Vangel M, Kong J, Wan G. Different Eye Tracking Patterns in Autism Spectrum Disorder in Toddler and Preschool Children. Front Psychiatry;2022;13:899521.

BACKGROUND: Children with autism spectrum disorder (ASD) have been observed to be associated with fixation abnormality as measured eye tracking, but the dynamics behind fixation patterns across age remain unclear. MATERIALS AND METHODS: In this study, we investigated gaze patterns between toddlers and preschoolers with and without ASD while they viewed video clips and still images (i.e., mouth-moving face, biological motion, mouthing face vs. moving object, still face picture vs. objects, and moving toys). RESULTS: We found that the fixation time percentage of children with ASD showed significant decrease compared with that of TD children in almost all areas of interest (AOI) except for moving toy (helicopter). We also observed a diagnostic group (ASD vs. TD) and chronological age (Toddlers vs. preschooler) interaction for the eye AOI during the mouth-moving video clip. Support vector machine analysis showed that the classifier could discriminate ASD from TD in toddlers with an accuracy of 80% and could discriminate ASD from TD in preschoolers with an accuracy of 71%. CONCLUSION: Our results suggest that toddlers and preschoolers may be associated with both common and distinct fixation patterns. A combination of eye tracking and machine learning methods has the potential to shed light on the development of new early screening/diagnosis methods for ASD.

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20. Lee JK, Andrews DS, Ozturk A, Solomon M, Rogers S, Amaral DG, Nordahl CW. Altered Development of Amygdala-Connected Brain Regions in Males and Females with Autism. J Neurosci;2022 (Jun 27)

Altered amygdala development is implicated in the neurobiology of autism, but little is known about the coordinated development of the brain regions directly connected with the amygdala. Here we investigated the volumetric development of an amygdala-connected network, defined as the set of brain regions with monosynaptic connections with the amygdala, in autism from early to middle childhood. Nine-hundred and fifty longitudinal structural MRI scans were acquired from 282 children (93 female) with autism and 128 children with typical development (61 female) at up to four timepoints (mean ages: 39, 52, 64, 137 months, respectively). Volumes from 32 amygdala-connected brain regions were examined using mixed effects multivariate distance matrix regression. The Social Responsiveness Scale-2 was administered to assess degree of autistic traits and social impairments. The amygdala-connected network exhibited persistent diagnostic differences (ps ≤ 0.03) that increased over time (ps ≤ 0.02). These differences were most prominent in autistics with more impacted social functioning at baseline. This pattern was not observed across regions without monosynaptic amygdala connection. We observed qualitative sex-differences. In males, the bilateral subgenual anterior cingulate cortices were most affected, while in females the left fusiform and superior temporal gyri were most affected. In conclusion, (a) autism is associated with widespread alterations to the development of brain-regions connected with the amygdala, which were associated with autistic social behaviors, and (b) autistic males and females exhibited different patterns of alterations, adding to a growing body of evidence of sex differences in the neurobiology of autism.SIGNIFICANCE STATEMENTGlobal patterns of development across brain regions with monosynaptic connection to the amygdala differentiate autism from typical development, and is modulated by social functioning in early childhood. Alterations to brain regions within the amygdala-connected network differed in males and females with autism. Results also indicate larger volumetric differences in regions having monosynaptic connection with the amygdala than in regions without monosynaptic connection.

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21. Lee Y, Keown LJ, Sanders MR. The effectiveness of the Stepping Stones Triple P seminars for Korean families of a child with a developmental disability. Heliyon;2022 (Jun);8(6):e09686.

BACKGROUND: Children with a developmental disability (DD) are more likely to develop behavioral problems. The Stepping Stones Triple P Positive Parenting Program (SSTP) for parents of children with a DD has demonstrated effectiveness for improving parenting practices and reducing child behavior problems. However, there is scant research in Asian countries and with less intensive SSTP interventions. AIM: This study examined the effectiveness of the SSTP seminars for Korean parents of a child with a DD. METHODS: Parents were randomly assigned to an intervention group (n = 21) or a delayed intervention group (n = 17). Data was collected on child adjustment problems, parenting practices, parental adjustment, and family relationships from both groups at pre- and post-intervention, and from the intervention group at 4-month follow-up. Twelve parents provided post-intervention interview data. RESULTS: A series of one-way Analysis of Covariance (ANCOVA) were used to examine differences between the intervention and delayed intervention groups at post-intervention. Significant short-term intervention effects were found for reductions in child behavior and emotional difficulties, and dysfunctional parenting practices. These improvements were maintained 4-months later by the intervention group. At post-intervention, inter-parental child-rearing conflict was reduced as a trend, with a moderate effect size. Interviews provided additional insights into the benefits gained from program participation. CONCLUSIONS: Findings, for parents within this study, contribute to the evidence base for the effectiveness of the SSTP seminars.

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22. Massrali A, Adhya D, Srivastava DP, Baron-Cohen S, Kotter MR. Corrigendum: Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia. Front Neurosci;2022;16:943903.

[This corrects the article DOI: 10.3389/fnins.2022.834058.].

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23. Melo C, Ribeiro TP, Prior C, Gesta C, Martins V, Oliveira G, Temudo T. Motor stereotypies in autism spectrum disorder: Clinical randomized study and classification proposal. Autism;2022 (Jun 28):13623613221105479.

Motor stereotypies are one of the most frequent features in children with a diagnosis of autism spectrum disorder. They may disrupt children’s functioning and development and be a potential source of stress for families. Several factors, including sex, age, cognitive ability, and severity of autism spectrum disorder, may influence the presence and intensity of stereotypies. The present study aimed to identify the prevalence of motor stereotypies in a group of children with autism spectrum disorder. In addition, it sought to investigate whether sex, age, cognitive ability, verbal language, neurological comorbidities, and severity of autism spectrum disorder were associated with an increased probability and higher number, duration, and variability of stereotypies. A total of 134 participants aged 2.3-17.6 years underwent a clinical protocol with standardized video-recorded sessions. Stereotypies were identified and classified by two independent evaluators. The prevalence of stereotypies was 56.7%, and a total of 1198 motor stereotypies were captured. Children who were younger, nonverbal, and had higher severity of autism spectrum disorder had an increased probability of presenting stereotypies. Being nonverbal or having higher severity of autism spectrum disorder was also associated with presenting a higher number of stereotypies. Children with developmental delay, intellectual disability, or epilepsy displayed longer stereotypies, and children with developmental delay or intellectual disability additionally presented more diverse stereotypies. As part of the study, the authors present a clinical classification model, a glossary, and video samples of motor stereotypies. The findings of this study suggest that children who are younger, nonverbal, have lower cognitive ability, and have higher severity of autism spectrum disorder may have a higher burden of stereotypies. Earlier intervention and monitoring of these children have the potential to improve their long-term outcomes.

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24. Micai M, Fulceri F, Salvitti T, Romano G, Poustka L, Diehm R, Iskrov G, Stefanov R, Guillon Q, Rogé B, Staines A, Sweeney MR, Boilson AM, Leósdóttir T, Saemundsen E, Moilanen I, Ebeling H, Yliherva A, Gissler M, Parviainen T, Tani P, Kawa R, Pisula E, Vicente A, Rasga C, Budişteanu M, Dale I, Povey C, Flores N, Jenaro C, Monroy ML, Primo PG, Charman T, Cramer S, Warberg CK, Canal-Bedia R, Posada M, Schendel D, Scattoni ML. Autistic Adult Services Availability, Preferences, and User Experiences: Results From the Autism Spectrum Disorder in the European Union Survey. Front Psychiatry;2022;13:919234.

There is very little knowledge regarding autistic adult services, practices, and delivery. The study objective was to improve understanding of current services and practices for autistic adults and opportunities for improvement as part of the Autism Spectrum Disorder in the European Union (ASDEU) project. Separate survey versions were created for autistic adults, carers of autistic adults, and professionals in adult services. 2,009 persons responded to the survey and 1,085 (54%) of them completed at least one of the services sections: 469 autistic adults (65% female; 55% <35 years old), 441 carers of autistic adults (27% female; 6% <35 years old), 175 professionals in adult services (76% female; 67% in non-medical services). Top choices by autistic adults, carers or professionals for services best suiting their current needs were: residential services: "help in own home" (adults, carers of high independent adults, professionals), "fulltime residential facility" (carers of low independent adults); employment services: "job mentors" (adults, carers of high independent adults, professionals), "Sheltered employment" (carers of low independent adults); education services: "support in regular education setting" (all groups); financial services: financial support in lieu of employment ("Supplementary income for persons unable to have full employment" for adults, "full pension" for carers of low independent adults) or to supplement employment earnings for carers of high independent adults and professionals; social services: "behavior training" (adults) and "life skills training" (carers and professionals). Waiting times for specific services were generally < 1 month or 1-3 months, except for residential services which could be up to 6 months; most professionals were uninformed of waiting times (>50% responded « don’t know »). Five of seven residential services features recommended for autistic adults were experienced by <50% of adults. The knowledge of good local services models that work well for autistic adults was generally low across all services areas. The variation in services experiences and perceptions reported by autistic adults, carers, or professionals underscore the need to query all groups for a complete picture of community services availability and needs. The results showed areas for potential improvement in autistic adult services delivery in the EU to achieve recommended standards.

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25. Nemet S, Asher I, Yoles I, Baevsky T, Sthoeger Z. Early childhood allergy linked with development of attention deficit hyperactivity disorder and autism spectrum disorder. Pediatr Allergy Immunol;2022 (Jun);33(6)

BACKGROUND: Previous studies reported controversial results regarding the association between allergic disorders and attention deficit hyperactivity disorder (ADHD)/autism spectrum disorder (ASD). The aim of this article was to investigate whether allergic disorders are associated with ADHD/ASD in a large cohort of pediatric patients. METHODS: A retrospective study using the pediatric (0-18 year) database (ICD-9-CM codes) of Clalit Health Services during the years (2000-2018). Diagnosis of all disorders was made by specialist physicians. RESULTS: A total of 117 022 consecutive non-selective allergic children diagnosed with one or more allergic disorder (asthma, rhinitis, conjunctivitis, skin, food, or drug allergy) and 116 968 non-allergic children were enrolled to our study. The mean follow-up period was 11 ± 6 years. The presence of allergic disorders in early childhood (mean age of allergic diagnosis 4.5 ± 4.3 years) in boys as well as in girls significantly increased the risk to develop ADHD (O.R 2.45, CI 2.39-2.51; p < .0001), ASD (O.R 1.17, CI 1.08-1.27; p < .0001), or both ADHD + ASD (O.R 1.5, CI 1.35-1.79; p < .0001). Children with more than one allergic comorbidity revealed a much higher risk. In a multivariable analysis (adjusted for age at study entry, number of yearly visits, and gender), the risk of allergic children to develop ADHD and ADHD + ASD, but not ASD alone, remained significantly higher. CONCLUSION: Allergic disorder in early childhood significantly increased the risk to develop ADHD, and to a less extend ASD, in later life.

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26. Okay K, Varış P, Miral S, Pavlopoulou A, Oktay Y, Karakülah G. Whole Genome Analysis of Dizygotic Twins With Autism Reveals Prevalent Transposon Insertion Within Neuronal Regulatory Elements: Potential Implications for Disease Etiology and Clinical Assessment. J Autism Dev Disord;2022 (Jun 27)

Transposable elements (TEs) have been implicated in autism spectrum disorder (ASD). However, our understanding of their roles is far from complete. Herein, we explored de novo TE insertions (dnTEIs) and de novo variants (DNVs) across the genomes of dizygotic twins with ASD and their parents. The neuronal regulatory elements had a tendency to harbor dnTEIs that were shared between twins, but ASD-risk genes had dnTEIs that were unique to each twin. The dnTEIs were 4.6-fold enriched in enhancers that are active in embryonic stem cell (ESC)-neurons (p < 0.001), but DNVs were 1.5-fold enriched in active enhancers of astrocytes (p = 0.0051). Our findings suggest that dnTEIs and DNVs play a role in ASD etiology by disrupting enhancers of neurons and astrocytes.

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27. Pino MC, Donne IL, Vagnetti R, Tiberti S, Valenti M, Mazza M. Using the Griffiths Mental Development Scales to Evaluate a Developmental Profile of Children with Autism Spectrum Disorder and Their Symptomatologic Severity. Child Psychiatry Hum Dev;2022 (Jun 28)

Early diagnosis is crucial for Autism spectrum disorder (ASD) and is achieved through a screening of developmental indicators to recognise children who are at risk of autism. One of the most widely used instruments in clinical practice for assessing child development is the Griffiths Mental Development Scale (GMDS). We sought (a) to assess longitudinally whether children diagnosed with ASD, with a mean age of 33.50 months (SD 7.69 months), show a developmental delay of abilities measured by the GMDS over time and (b) to analyse which skills of the GMDS could be associate to the symptomatologic severity of ASD. Our results showed lower scores of General Quotient and all sub-quotients of GMDS from first (T0) to second assessment (T1), except for the Performance sub-quotient. Three sub-quotients (Personal-Social, Hearing and Language and Practical Reasoning) also associate symptom severity at the time when the diagnosis of ASD is made.

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28. Préfontaine I, Lanovaz MJ, Rivard M. Brief Report: Machine Learning for Estimating Prognosis of Children with Autism Receiving Early Behavioral Intervention-A Proof of Concept. J Autism Dev Disord;2022 (Jun 28)

Although early behavioral intervention is considered as empirically-supported for children with autism, estimating treatment prognosis is a challenge for practitioners. One potential solution is to use machine learning to guide the prediction of the response to intervention. Thus, our study compared five machine algorithms in estimating treatment prognosis on two outcomes (i.e., adaptive functioning and autistic symptoms) in children with autism receiving early behavioral intervention in a community setting. Each machine learning algorithm produced better predictions than random sampling on both outcomes. Those results indicate that machine learning is a promising approach to estimating prognosis in children with autism, but studies comparing these predictions with those produced by qualified practitioners remain necessary.

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29. Rao S, Baranova A, Yao Y, Wang J, Zhang F. Genetic Relationships between Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and Intelligence. Neuropsychobiology;2022 (Jun 28):1-13.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) commonly co-occur; both traits exert an influence on intelligence scores. Genetic relationships between these three traits are far from being clear. METHODS: The summary results of genome-wide association studies of ADHD (20,183 cases and 35,191 controls), ASD (18,381 cases and 27,969 controls), and intelligence (269,867 participants) were used for the analyses. Local genetic correlation analysis and polygenic overlap analysis were used to explore the shared genetic components between ADHD, ASD, and intelligence. Mendelian randomization (MR) analysis was used to examine the causal associations between ADHD, ASD, and intelligence. A cross-trait meta-analysis was performed to identify pleiotropic genetic variants across the three traits. RESULTS: Our results showed that intelligence has a positive and negative genetic correlation with ASD and ADHD, respectively, including three hub genomic regions showing correlated genetic effects across the three traits. Polygenic overlap analysis indicated that all the risk variants contributing to ADHD are overlapped with half of those for intelligence, and the majority of the shared variants have opposite effect directions between them. The majority of risk variants (80%) of ASD are overlapped with almost all the risk variants of intelligence (97%). Notably, some ASD/intelligence overlapping variants displayed opposing effects on these two conditions. MR analysis showed that the genetic liability to higher intelligence was associated with an increased risk for ASD (OR = 1.12) and a decreased risk for ADHD (OR = 0.78). Cross-trait meta-analyses identified 170 pleiotropic genomic loci across the three traits, including 12 novel loci. Functional analyses of the novel genes support their potential involvement in neurodevelopment. CONCLUSION: Our results suggest that ADHD is associated with inheriting a reduced set of low-intelligence alleles, whereas ASD results from incongruous effects from a mixture of high-intelligence and low-intelligence contributing alleles summed up with additional, ASD-specific risk variants not associated with intelligence.

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30. Rauter A, Schneider H, Prinz W. Effectivity of ILF Neurofeedback on Autism Spectrum Disorder-A Case Study. Front Hum Neurosci;2022;16:892296.

Autism spectrum disorder (ASD) is a neural and mental developmental disorder that impacts brain connectivity and information processing. Although application of the infra-low frequency (ILF) neurofeedback procedure has been shown to lead to significant changes in functional connectivity in multiple areas and neuronal networks of the brain, rather limited data are available in the literature for the efficacy of this technique in a therapeutic context to treat ASD. Here we present the case study of a 5-year-old boy with ASD, who received a treatment of 26 sessions of ILF neurofeedback over a 6-month period. A systematic and quantitative tracking of core ASD symptoms in several categories was used to document behavioral changes over time. The ILF neurofeedback intervention decreased the average symptom severity of every category to a remarkable degree, with the strongest effect (80 and 77% mean severity reduction) for physical and sleep symptoms and the lowest influence on behavioral symptoms (15% mean severity reduction). This case study is representative of clinical experience, and thus shows that ILF neurofeedback is a practical and effective therapeutic instrument to treat ASD in children.

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31. Stone B, Cameron A, Dowling S. The autistic experience of homelessness: Implications from a narrative enquiry. Autism;2022 (Jun 25):13623613221105091.

Recent research suggests many autistic people experience homelessness. However, little is known about the types of homelessness autistic people experience and what barriers autistic people face when trying to exit homelessness. This study involved gathering life stories of autistic people who had experienced homelessness. Ten autistic participants talked about their pathways through homelessness and the difficulties they had in accessing support. After first becoming homeless, participants tended to experience rough sleeping and sofa surfing. When participants approached housing and homelessness services, they were often told they were not eligible for support. This could happen when support workers were not aware of autism, or when autism was not considered ‘severe’ enough. Overcrowding, confrontation and lack of control over routine and environment were particular issues for participants when they entered homelessness hostels. Some participants chose to sleep on the streets rather than stay in environments which increased social anxiety and sensory difficulties. This study discusses ways in which homelessness and housing services can increase accessibility and improve engagement for autistic people. It is important to increase awareness of autism while understanding that autistic people who experience homelessness may have complex needs. In addition, services need to listen to autistic people with lived experience of homelessness to decide what changes will have the most impact.

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32. Tekola B, Kinfe M, Girma Bayouh F, Hanlon C, Hoekstra RA. The experiences of parents raising children with developmental disabilities in Ethiopia. Autism;2022 (Jun 25):13623613221105085.

The experiences of parents raising children with developmental disabilities have been widely researched, although most of this research comes from Western, high-income countries. In comparison, little is known about the lived experiences of parents of children with developmental disabilities in low- and middle-income countries and in Africa in particular. We interviewed 14 mothers and 4 fathers in Addis Ababa and the rural town of Butajira to explore what life is like for parents caring for children with developmental disabilities in Ethiopia. Cultural and religious beliefs played a role in the types of delays or differences in their child’s development that parents noticed early and the kinds of support they sought. Parents experienced stigma and lack of understanding from others. Their experiences regarding some of the challenges they faced such as lack of appropriate services varied based on where they lived (urban or rural). Single mothers especially were faced with multiple struggles including poverty, stigma, and lack of social support. Implications for future research and interventions that aim to increase knowledge about developmental disabilities, tackle stigma and improve the lives of children and their families are discussed.

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33. Thawley AJ, Veneziani LP, Rabelo-da-Ponte FD, Riederer I, Mendes-da-Cruz DA, Bambini-Junior V. Aberrant IL-17 Levels in Rodent Models of Autism Spectrum Disorder: A Systematic Review. Front Immunol;2022;13:874064.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterised by stereotyped behaviours, specific interests, and impaired communication skills. Elevated levels of pro-inflammatory cytokines, such as interleukin-17A (IL-17A or IL-17), have been implicated as part of immune alterations that may contribute to this outcome. In this context, rodent models have helped elucidate the role of T-cell activation and IL-17 secretion in the pathogenesis of ASD. Regarding the preclinical findings, the data available is contradictory in offspring but not in the pregnant dams, pointing to IL-17 as one of the main drivers of altered behaviour in some models ASD, whilst there are no alterations described in IL-17 levels in others. To address this gap in the literature, a systematic review of altered IL-17 levels in rodent models of ASD was conducted. In total, 28 studies that explored IL-17 levels were included and observed that this cytokine was generally increased among the different models of ASD. The data compiled in this review can help the choice of animal models to study the role of cytokines in the development of ASD, seeking a parallel with immune alterations observed in individuals with this condition. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42022306558.

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34. Vernocchi P, Ristori MV, Guerrera S, Guarrasi V, Conte F, Russo A, Lupi E, Albitar-Nehme S, Gardini S, Paci P, Ianiro G, Vicari S, Gasbarrini A, Putignani L. Gut Microbiota Ecology and Inferred Functions in Children With ASD Compared to Neurotypical Subjects. Front Microbiol;2022;13:871086.

Autism spectrum disorders (ASDs) is a multifactorial neurodevelopmental disorder. The communication between the gastrointestinal (GI) tract and the central nervous system seems driven by gut microbiota (GM). Herein, we provide GM profiling, considering GI functional symptoms, neurological impairment, and dietary habits. Forty-one and 35 fecal samples collected from ASD and neurotypical children (CTRLs), respectively, (age range, 3-15 years) were analyzed by 16S targeted-metagenomics (the V3-V4 region) and inflammation and permeability markers (i.e., sIgA, zonulin lysozyme), and then correlated with subjects’ metadata. Our ASD cohort was characterized as follows: 30/41 (73%) with GI functional symptoms; 24/41 (58%) picky eaters (PEs), with one or more dietary needs, including 10/41 (24%) with food selectivity (FS); 36/41 (88%) presenting high and medium autism severity symptoms (HMASSs). Among the cohort with GI symptoms, 28/30 (93%) showed HMASSs, 17/30 (57%) were picky eaters and only 8/30 (27%) with food selectivity. The remaining 11/41 (27%) ASDs without GI symptoms that were characterized by HMASS for 8/11 (72%) and 7/11 (63%) were picky eaters. GM ecology was investigated for the overall ASD cohort versus CTRLs; ASDs with GI and without GI, respectively, versus CTRLs; ASD with GI versus ASD without GI; ASDs with HMASS versus low ASSs; PEs versus no-PEs; and FS versus absence of FS. In particular, the GM of ASDs, compared to CTRLs, was characterized by the increase of Proteobacteria, Bacteroidetes, Rikenellaceae, Pasteurellaceae, Klebsiella, Bacteroides, Roseburia, Lactobacillus, Prevotella, Sutterella, Staphylococcus, and Haemophilus. Moreover, Sutterella, Roseburia and Fusobacterium were associated to ASD with GI symptoms compared to CTRLs. Interestingly, ASD with GI symptoms showed higher value of zonulin and lower levels of lysozyme, which were also characterized by differentially expressed predicted functional pathways. Multiple machine learning models classified correctly 80% overall ASDs, compared with CTRLs, based on Bacteroides, Lactobacillus, Prevotella, Staphylococcus, Sutterella, and Haemophilus features. In conclusion, in our patient cohort, regardless of the evaluation of many factors potentially modulating the GM profile, the major phenotypic determinant affecting the GM was represented by GI hallmarks and patients’ age.

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35. Weng Z, Yue Z, Zhu Y, Chen JY. DEMA: a distance-bounded energy-field minimization algorithm to model and layout biomolecular networks with quantitative features. Bioinformatics;2022 (Jun 24);38(Suppl 1):i359-i368.

SUMMARY: In biology, graph layout algorithms can reveal comprehensive biological contexts by visually positioning graph nodes in their relevant neighborhoods. A layout software algorithm/engine commonly takes a set of nodes and edges and produces layout coordinates of nodes according to edge constraints. However, current layout engines normally do not consider node, edge or node-set properties during layout and only curate these properties after the layout is created. Here, we propose a new layout algorithm, distance-bounded energy-field minimization algorithm (DEMA), to natively consider various biological factors, i.e., the strength of gene-to-gene association, the gene’s relative contribution weight and the functional groups of genes, to enhance the interpretation of complex network graphs. In DEMA, we introduce a parameterized energy model where nodes are repelled by the network topology and attracted by a few biological factors, i.e., interaction coefficient, effect coefficient and fold change of gene expression. We generalize these factors as gene weights, protein-protein interaction weights, gene-to-gene correlations and the gene set annotations-four parameterized functional properties used in DEMA. Moreover, DEMA considers further attraction/repulsion/grouping coefficient to enable different preferences in generating network views. Applying DEMA, we performed two case studies using genetic data in autism spectrum disorder and Alzheimer’s disease, respectively, for gene candidate discovery. Furthermore, we implement our algorithm as a plugin to Cytoscape, an open-source software platform for visualizing networks; hence, it is convenient. Our software and demo can be freely accessed at http://discovery.informatics.uab.edu/dema. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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36. Xu Y, Wang Y, Xu J, Song Y, Liu B, Xiong Z. Leveraging Existing 16SrRNA Microbial Data to Define a Composite Biomarker for Autism Spectrum Disorder. Microbiol Spectr;2022 (Jun 28):e0033122.

Cumulative studies have utilized high-throughput sequencing of the 16SrRNA gene to characterize the composition and structure of the microbiota in autism spectrum disorder (ASD). However, they do not always obtain consistent results; thus, conducting cross-study comparisons is necessary. This study sought to analyze the alteration of fecal microbiota and the diagnostic capabilities of gut microbiota biomarkers in individuals with ASD using the existing 16SrRNA microbial data and explore heterogeneity among studies. The raw sequence and metadata from 10 studies, including 1,019 samples, were reanalyzed. Results showed no significant difference in alpha diversity of fecal microbiota between ASD and the control group. However, a significant difference in the composition structure of fecal microbiota was observed. Given the large differences in sample selection and technical differences, the separation of fecal microbiota between ASD and controls was not observed. Subgroup analysis was performed on the basis of different country of origin, hypervariable regions, and sequencing platforms, and the dominant genera in ASD and healthy control groups were determined by linear discriminant analysis (LDA) of the effect size (LEfSe) algorithm and Wilcoxon rank-sum test. Machine learning analyses were carried out to determine the diagnostic capabilities of potential microbial biomarkers. A total of 12 genera were identified to distinguish ASD from control, and the AUC of the training set and verification set was 0.757 and 0.761, respectively. Despite cohort heterogeneity, gut microbial dysbiosis of ASD has been proven to be a widespread phenomenon. Therefore, fecal microbial markers are of great significance in diagnosing ASD diseases and possible candidates for further mechanistic study of the role of intestinal microbiota in ASD. IMPORTANCE This study provides an updated analysis to characterize the gut microbiota in ASD using 16SrRNA gene high-throughput sequencing data from 10 publicly available studies. Our analysis suggests an association between the fecal microbiota and ASD. Sample selection and technical differences between studies may interfere with the species composition analysis of the ASD group and control group. By summarizing the results of 16SrRNA gene sequencing from multiple fecal samples, we can provide evidence to support the use of microbial biomarkers to diagnose the occurrence of ASD. Our study provides a new perspective for further revealing the correlation between gut microbiota and ASD from the perspective of 16SrRNA sequencing in larger samples.

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37. Yankowitz LD, Petrulla V, Plate S, Tunc B, Guthrie W, Meera SS, Tena K, Pandey J, Swanson MR, Pruett JR, Jr., Cola M, Russell A, Marrus N, Hazlett HC, Botteron K, Constantino JN, Dager SR, Estes A, Zwaigenbaum L, Piven J, Schultz RT, Parish-Morris J. Infants later diagnosed with autism have lower canonical babbling ratios in the first year of life. Mol Autism;2022 (Jun 27);13(1):28.

BACKGROUND: Canonical babbling-producing syllables with a mature consonant, full vowel, and smooth transition-is an important developmental milestone that typically occurs in the first year of life. Some studies indicate delayed or reduced canonical babbling in infants at high familial likelihood for autism spectrum disorder (ASD) or who later receive an ASD diagnosis, but evidence is mixed. More refined characterization of babbling in the first year of life in infants with high likelihood for ASD is needed. METHODS: Vocalizations produced at 6 and 12 months by infants (n = 267) taking part in a longitudinal study were coded for canonical and non-canonical syllables. Infants were categorized as low familial likelihood (LL), high familial likelihood diagnosed with ASD at 24 months (HL-ASD) or not diagnosed (HL-Neg). Language delay was assessed based on 24-month expressive and receptive language scores. Canonical babble ratio (CBR) was calculated by dividing the number of canonical syllables by the number of total syllables. Generalized linear (mixed) models were used to assess the relationship between group membership and CBR, controlling for site, sex, and maternal education. Logistic regression was used to assess whether canonical babbling ratios at 6 and 12 months predict 24-month diagnostic outcome. RESULTS: No diagnostic group differences in CBR were detected at 6 months, but HL-ASD infants produced significantly lower CBR than both the HL-Neg and LL groups at 12 months. HL-Neg infants with language delay also showed reduced CBR at 12 months. Neither 6- nor 12-month CBR was significant predictors of 24-month diagnostic outcome (ASD versus no ASD) in logistic regression. LIMITATIONS: Small numbers of vocalizations produced by infants at 6 months may limit the reliability of CBR estimates. It is not known if results generalize to infants who are not at high familial likelihood, or infants from more diverse racial and socioeconomic backgrounds. CONCLUSIONS: Lower canonical babbling ratios are apparent by the end of the first year of life in ASD regardless of later language delay, but are also observed for infants with later language delay without ASD. Canonical babbling may lack specificity as an early marker when used on its own.

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38. Zappella M. [Autism: a diagnostic dilemma]. Zh Nevrol Psikhiatr Im S S Korsakova;2022;122(6):71-76.

In the last decades autism diagnosis has shown great differences in prevalence studies, apparently related to methods applied in the evaluation of children with relational and\or communicative difficulties. In the present study a literature evaluation is conducted, suggesting the advantages of an extensive and accurate clinical evaluation of the child with his family, possibly supported by tests like CARS, convergent with this approach and, in contrast, risks related to the use of semi-structured tests. Some of the last-mentioned tests have been considered, decades ago, as `golden standard’ for diagnosis, but this was probably an unfortunate illusion, which may have favoured many inappropriate diagnoses. The history of the concept of autism is described, split between the suggestion of dealing with `one’ condition and, alternatively, with a behaviour related to different syndromes and disorders. Various examples on positive evolution of this condition are reported, supporting the view of autism as an abnormal behaviour, usually comorbid with other conditions, in some cases curable and amenable to correction up to the removal of the diagnosis.

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39. Zhang H, Gu Y, He W, Kuo F, Zhang Y, Wang D, He L, Yang Y, Wang H, Chen Y. Correlation Between Sialidase NEU1 mRNA Expression Changes in Autism Spectrum Disorder. Front Psychiatry;2022;13:870374.

Abnormal alterations in enzymes functioned in sialic acid modifications may be associated with ASD. In order to study the differences in peripheral blood sialidase (neuraminidase 1; NEU1) mRNA expression between autism spectrum disorder (ASD) children and healthy control, and to examine the correlation between NEU1 mRNA expression and the main behavioral phenotypes in children with ASD, we performed RT-qPCR to measure NEU1 mRNA expression in peripheral blood of 42 children with ASD and 42 healthy controls. In addition, we used the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) to measure and evaluate the behavioral phenotypes of children with ASD. Our results showed that NEU1 mRNA in the ASD group was significantly higher than in the control group (P < 0.0001). In addition, the ADOS-2 diagnostic scores of 42 children with ASD were correlated with their NEU1 mRNA expression results (R = 0.344, P = 0.0257). Moreover, in general, NEU1 mRNA expression was also positively correlated with the Social Affect (SA) of ADOS-2 (R = 0.3598, P = 0.0193) but not with the Restricted and Repetitive Behavior (RRB) (R = 0.15, P = 0.3432). Our results indicated that sialidase NEU1 mRNA was significantly increased in children with ASD, and its expression was correlated with the SA of children with ASD, which suggested that sialidase NEU1 may affect the SA of ASD. Our data highlighted the potential of NEU1 expression change may play an important role in ASD disease and lay the foundation for further studies on the relationship between NEU1 and ASD.

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40. Zhang R. Oxytocin – A key to aetiology and treatment for Autism Spectrum Disorder. EBioMedicine;2022 (Jun 24);81:104126.

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41. Zhong C, Shah R, Rando J, Park B, Girardi T, Walker CK, Croen LA, Fallin MD, Hertz-Picciotto I, Lee BK, Schmidt RJ, Volk HE, Newschaffer CJ, Salafia CM, Lyall K. Placental morphology in association with autism-related traits in the EARLI study. BMC Pregnancy Childbirth;2022 (Jun 28);22(1):525.

BACKGROUND: In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. METHODS: Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). RESULTS: In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. CONCLUSIONS: Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

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