1. Arora A, Becker M, Marques C, Oksanen M, Li D, Mastropasqua F, Watts ME, Arora M, Falk A, Daub CO, Lanekoff I, Tammimies K. Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Scientific reports. 2023; 13(1): 10519.

Research continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.

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2. Assi A, Rebeyrat G, El Rachkidi R, Semaan K, Saad E, Mekhael E, Nassim N, Massaad A, Lafage V, Ghanem I, Pillet H, Skalli W. ASD with high pelvic retroversion develop changes in their acetabular orientation during walking. Brain & spine. 2023; 3: 101752.

INTRODUCTION: It was hypothesized that pelvic retroversion in Adult Spinal Deformity (ASD) can be related to an increased hip loading explaining the occurrence of hip-spine syndrome. RESEARCH QUESTION: How pelvic retroversion can modify acetabular orientation in ASD during walking? METHODS: 89 primary ASD and 37 controls underwent 3D gait analysis and full-body biplanar X-rays. Classic spinopelvic parameters were calculated from 3D skeletal reconstructions in addition to acetabular anteversion, abduction, tilt, and coverage. Then, 3D bones were registered on each gait frame to compute the dynamic value of the radiographic parameters during walking. ASD patients having a high PT were grouped as ASD-highPT, otherwise as ASD-normPT. Control group was divided in: C-aged and C-young, age matched to ASD-hightPT and ASD-normPT respectively. RESULTS: 25/89 patients were classified as ASD-highPT having a radiographic PT of 31° (vs 12° in other groups, p < 0.001). On static radiograph, ASD-highPT showed more severe postural malalignment than the other groups: ODHA = 5°, L1L5 = 17°, SVA = 57.4 mm (vs 2°, 48° and 5 mm resp. in other groups,all p < 0.001). During gait, ASD-highPT presented a higher dynamic pelvic retroversion of 30° (vs 15° in C-aged), along with a higher acetabular anteversion of 24° (vs 20°), external coverage of 38° (vs 29°) and a lower anterior coverage of 52° (vs 58°,all p < 0.05). CONCLUSION: ASD patients with severe pelvic retroversion showed an increased acetabular anteversion, external coverage and lower anterior coverage during gait. These changes in acetabular orientation, computed during walking, were shown to be related to hip osteoarthritis.

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3. Ball LE, Zhu X. Brief Report Prevalence of Bullying Among Autistic Adolescents in the United States: Impact of Disability Severity Status. Journal of autism and developmental disorders. 2023.

PURPOSE: The purpose of this study was to examine the prevalence of bullying behaviors among autistic and non-autistic adolescents between the ages of 12-17 years in the U.S. and the extent to which the severity of such disability impacts bullying behaviors, based on the 2019-2020 National Survey of Children’s Health. METHODS: Parental reports of bullying perpetration and victimization were used to compare bullying behaviors among a weighted sample of 1011 autistic and 28,016 non-autistic adolescents. RESULTS: Adjusting for participant sex, household income level, highest parent education, and race/ethnicity, autistic adolescents were significantly more likely to engage in bullying perpetration and experience bullying victimization than non-Autistic adolescents. Compared to non-autistic peers, autistic adolescents with moderate/severe autism were most likely to bully others (adjusted odds ratio [aOR] = 1.80, p < 0.05) and experience bullying victimization (aOR = 5.13, p < 0.01). CONCLUSION: This study provides an update on the prevalence of bullying perpetration and victimization among autistic adolescents, however, the influence of factors such as socialization and mental health on bullying behaviors needs exploration.

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4. Betz CL. Health care transition planning for adolescents and emerging adults with intellectual disabilities and developmental disabilities: Distinctions and challenges. Journal for specialists in pediatric nursing : JSPN. 2023: e12415.

PURPOSE: The purpose of this article is to provide the reader with insight and enhanced understanding of the health care transition planning process for adolescents and emerging adults with intellectual disabilities and developmental disabilities. There are distinctly different programmatic considerations that need to be addressed in advancing their transfer of care to adult providers and promoting their transition to adulthood. These differences are due in part to the federal and state legislative initiatives that were established in the education, rehabilitation, employment, and developmental disabilities service systems. In contrast, no comparable federal and state mandates exist in the system of health care. The legislative mandates in education, rehabilitation, and employment are presented and discussed as well as the federal legislation on rights and protections for individuals with intellectual disabilities and developmental disabilities. Consequently, health care transition (HCT) planning involves application of a framework of care that is characteristically different than the planning efforts undertaken for adolescents and emerging adults (AEA) with special health care needs (SHCN)/disabilities and for typically developing AEA. The best practice HCT recommendations are discussed in the context of this intellectual disabilities and developmental disabilities framework of care. CONCLUSIONS: Health care transition planning for adolescents and emerging adults with intellectual disabilities and developmental disabilities involves additional and distinctly clinical and programmatic models of care. PRACTICE IMPLICATIONS: Health care transition planning guidance for adolescents and emerging adults with intellectual disabilities and developmental disabilities are provided based upon best practice recommendations.

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5. Clarke EB, Lord C. Social competence as a predictor of adult outcomes in autism spectrum disorder. Development and psychopathology. 2023: 1-16.

There is a wealth of literature characterizing social difficulties in autism spectrum disorder (ASD). However, little work has replicated longitudinal findings from typical development that adolescent social competence predicts positive adult outcomes in ASD. The current study examined social competence trajectories from 2 to 26 and the utility of three social competence measures collected in adolescence in predicting work, residential status, friendship, and romantic outcomes in a longitudinal cohort (n = 253) of ASD. Using group-based trajectory modeling, we identified two patterns of social competence development: a low trajectory characterized by slow linear gains throughout childhood and plateauing in adulthood, and a high trajectory characterized by steeper linear gains in childhood followed by decline in adulthood. Regression models indicated one social competence measure, Vineland Social-AE scores, significantly predicted employment, residential status, and friendships in adulthood. One other social competence measure, SSQ total scores, also significantly predicted friendship in adulthood. Only nonverbal IQ at 9 predicted the likelihood of having ever had a romantic relationship. These findings highlight the role of social competence in both atypical and typical development and suggest the social impairments associated with ASD do not necessarily impact all realms of social functioning equally.

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6. Fan SJS, Chen SP. Does culture play a role? A pilot study on Western services for a Chinese-Canadian family with children with Autism spectrum disorder. Disability and rehabilitation. 2023: 1-9.

Purpose: Autism spectrum disorder (ASD) affects one in 66 children in Canada, and its symptoms may be particularly challenging for parents from a Chinese background. Further, when working with Chinese families, Western-educated service providers may experience difficulty in applying culturally relevant and family-centered care. This study examined the experiences of one Chinese-Canadian family as they receive intervention services for their two children with ASD.Materials and methods: This pilot, single-case design, qualitative case study included semi-structured interviews with the parents, grandparents, as well as three service providers’ views.Results: Three major themes emerged from the data in the form of tensions: (1) within the family members; (2) within the therapeutic relationships, and (3) in addressing culture in therapy.Conclusions: Results suggested that although the family identified key cultural differences, service providers did not sufficiently address these within the therapeutic relationship, and the need for culturally-relevant and family-centered care was not fulfilled. Chinese-Canadian parents for children with autism spectrum disorder adopt both Chinese and Western values that fit best for their circumstances.Service providers and family members can have conflicting priorities, making family-centered care, culturally-relevant care challenging.Culture plays an important role in family expectations, and should be incorporated with more intention in the rehabilitation process. eng.

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7. Hellings J. Pharmacotherapy in autism spectrum disorders, including promising older drugs warranting trials. World journal of psychiatry. 2023; 13(6): 262-77.

Available pharmacotherapies for autism spectrum disorders (ASD) are reviewed based on clinical and research experience, highlighting some older drugs with emerging evidence. Several medications show efficacy in ASD, though controlled studies in ASD are largely lacking. Only risperidone and aripiprazole have Federal Drug Administration approval in the United States. Methylphenidate (MPH) studies showed lower efficacy and tolerability for attention deficit hyperactivity disorder (ADHD) than in the typically developing (TD) population; atomoxetine demonstrated lower efficacy but comparable tolerability to TD outcomes. Guanfacine improved hyperactivity in ASD comparably to TD. Dex-troamphetamine promises greater efficacy than MPH in ASD. ADHD medications reduce impulsive aggression in youth, and may also be key for this in adults. Controlled trials of the selective serotonin reuptake inhibitors citalopram and fluoxetine demonstrated poor tolerability and lack of efficacy for repetitive behaviors. Trials of antiseizure medications in ASD remain inconclusive, however clinical trials may be warranted in severely disabled individuals showing bizarre behaviors. No identified drugs treat ASD core symptoms; oxytocin lacked efficacy. Amitriptyline and loxapine however, show promise. Loxapine at 5-10 mg daily resembled an atypical antipsychotic in positron emission tomography studies, but may be weight-sparing. Amitriptyline at approximately 1 mg/ kg/day used cautiously, shows efficacy for sleep, anxiety, impulsivity and ADHD, repetitive behaviors, and enuresis. Both drugs have promising neurotrophic properties.

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8. Ji C, Tang Y, Zhang Y, Huang X, Li C, Yang Y, Wu Q, Xia X, Cai Q, Qi XR, Zheng JC. Glutaminase 1 deficiency confined in forebrain neurons causes autism spectrum disorder-like behaviors. Cell reports. 2023; 42(7): 112712.

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD.

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9. Lu H, Zuo L, Roddick KM, Zhang P, Oku S, Garden J, Ge Y, Bellefontaine M, Delhaye M, Brown RE, Craig AM. Alternative splicing and heparan sulfation converge on neurexin-1 to control glutamatergic transmission and autism-related behaviors. Cell reports. 2023; 42(7): 112714.

Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain, with over a thousand alternatively spliced forms and further structural heterogeneity contributed by heparan sulfate glycan modification. Yet, interactions between these modes of post-transcriptional and post-translational modification have not been studied. We reveal that these regulatory modes converge on neurexin-1 splice site 5 (S5): the S5 insert increases the number of heparan sulfate chains. This is associated with reduced neurexin-1 protein level and reduced glutamatergic neurotransmitter release. Exclusion of neurexin-1 S5 in mice boosts neurotransmission without altering the AMPA/NMDA ratio and shifts communication and repetitive behavior away from phenotypes associated with autism spectrum disorders. Thus, neurexin-1 S5 acts as a synaptic rheostat to impact behavior through the intersection of RNA processing and glycobiology. These findings position NRXN1 S5 as a potential therapeutic target to restore function in neuropsychiatric disorders.

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10. Metwally AM, Helmy MA, Salah El-Din EM, Saleh RM, Abdel Raouf ER, Abdallah AM, Khadr Z, Elsaied A, El-Saied MM, Bassiouni RI, Nagi DA, Shehata MA, El-Alameey IR, El-Hariri HM, Salama SI, Rabah TM, Abdel-Latif GA, El Etreby LA, Elmosalami DM, Sami SM, Eltahlawy E, Ibrahim NA, Elghareeb NA, Badawy HY, Dewdar EM, Ashaat EA. National screening for Egyptian children aged 1 year up to 12 years at high risk of Autism and its determinants: a step for determining what ASD surveillance needs. BMC psychiatry. 2023; 23(1): 471.

This study aimed to provide a national estimate of the prevalence of the high risk of autism spectrum disorder (ASD) and their determinants. A national screening survey was conducted for 41,640 Egyptian children aged 1 to 12 years in two phases. Tools used were Vineland’s Adaptive Behavior Scales, Modified Checklist for Autism in Toddlers, Gilliam Autism Rating scale, and Denver II Developmental screening test. The overall prevalence of children at high risk of ASD was 3.3% (95% CI:3.1%-3.5%). Children living without mothers in homes, suffered from convulsions (AOR = 3.67; 95%CI:2.8-4.8), a history of cyanosis after birth (AOR = 1.87; 95% CI:1.35-2.59) or history of LBW babies (AOR = 1.53; 95% CI:1.23-1.89) carried higher odds of being at high risk of ASD.

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11. Nitschke AS, Oberlander TF, Hanley GE. Response: Maternal infection, prenatal antibiotics and risk of autism in the offspring. Paediatric and perinatal epidemiology. 2023.

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12. Nordahl CW. Why do we need sex-balanced studies of autism?. Autism research : official journal of the International Society for Autism Research. 2023.

Males are diagnosed with autism much more frequently than females, and most research study samples reflect this male predominance. The result is that autistic females are understudied. There is a critical need to increase our understanding of autistic females, both biologically and clinically. The only way to do this is to recruit sex-balanced cohorts in studies so that similarities and differences between males and females can be evaluated in all autism research studies. The purpose of this commentary is to (1) provide historical context about how females came to be under-represented in all research, not just in the field of autism and (2) learn from other areas of health and medicine about the potentially dire consequences of not studying both sexes, and (3) draw attention to the need to recruit sex-balanced cohorts in autism research, particularly in neuroimaging studies.

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13. Rakshe C, Kunneth S, Sundaram S, Agastinose Ronickom JF. Diagnostic Classification of ASD Using Fractal Functional Connectivity of fMRI and Logistic Regression. Studies in health technology and informatics. 2023; 305: 60-3.

Our study used functional magnetic resonance imaging and fractal functional connectivity (FC) methods to analyze the brain networks of Autism Spectrum Disorder (ASD) and typically developing participants using data available on ABIDE databases. Blood-Oxygen-Level-Dependent time series were extracted from 236 regions of interest of cortical, subcortical, and cerebellar regions using Gordon’s, Harvard Oxford, and Diedrichsen atlases respectively. We computed the fractal FC matrices which resulted in 27,730 features, ranked using XGBoost feature ranking. Logistic regression classifiers were used to analyze the performance of the top 0.1%, 0.3%, 0.5%, 0.7%, 1%, 2%, and 3% of FC metrics. Results showed that 0.5% percentile features performed better, with average 5-fold accuracy of 94%. The study identified significant contributions from dorsal attention (14.75%), cingulo-opercular task control (14.39%), and visual networks (12.59%). This study could be used as an essential brain FC method to diagnose ASD.

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14. Ratnaik R, Rakshe C, Kumar M, Agastinose Ronickom JF. Diagnostic Classification of ASD Improves with Structural Connectivity of DTI and Logistic Regression. Studies in health technology and informatics. 2023; 305: 64-7.

In this study, we examined the structural connectivity (SC) of autism spectrum disorder (ASD) and typical development using the distance correlation and machine learning algorithm. We preprocessed diffusion tensor images using a standard pipeline and parcellated the brain into 48 regions using atlas. We derived diffusion measures in white matter tracts, such as fractional anisotropy, radial diffusivity, axial diffusivity, mean diffusivity, and mode of anisotropy. Additionally, SC is determined by the Euclidean distance between these features. The SC were ranked using XGBoost and significant features were fed as the input to the logistic regression classifier. We obtained an average 10-fold cross-validation classification accuracy of 81% for the top 20 features. The SC computed from the anterior limb of internal capsule L to superior corona radiata R regions significantly contributed to the classification models. Our study shows the potential utility of adopting SC changes as the biomarker for the diagnosis of ASD.

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15. Spirito G, Filosi M, Domenici E, Mangoni D, Gustincich S, Sanges R. Exploratory analysis of L1 retrotransposons expression in autism. Molecular autism. 2023; 14(1): 22.

BACKGROUND: Autism spectrum disorder (ASD) is a set of highly heterogeneous neurodevelopmental diseases whose genetic etiology is not completely understood. Several investigations have relied on transcriptome analysis from peripheral tissues to dissect ASD into homogenous molecular phenotypes. Recently, analysis of changes in gene expression from postmortem brain tissues has identified sets of genes that are involved in pathways previously associated with ASD etiology. In addition to protein-coding transcripts, the human transcriptome is composed by a large set of non-coding RNAs and transposable elements (TEs). Advancements in sequencing technologies have proven that TEs can be transcribed in a regulated fashion, and their dysregulation might have a role in brain diseases. METHODS: We exploited published datasets comprising RNA-seq data from (1) postmortem brain of ASD subjects, (2) in vitro cell cultures where ten different ASD-relevant genes were knocked out and (3) blood of discordant siblings. We measured the expression levels of evolutionarily young full-length transposable L1 elements and characterized the genomic location of deregulated L1s assessing their potential impact on the transcription of ASD-relevant genes. We analyzed every sample independently, avoiding to pool together the disease subjects to unmask the heterogeneity of the molecular phenotypes. RESULTS: We detected a strong upregulation of intronic full-length L1s in a subset of postmortem brain samples and in in vitro differentiated neurons from iPSC knocked out for ATRX. L1 upregulation correlated with an high number of deregulated genes and retained introns. In the anterior cingulate cortex of one subject, a small number of significantly upregulated L1s overlapped with ASD-relevant genes that were significantly downregulated, suggesting the possible existence of a negative effect of L1 transcription on host transcripts. LIMITATIONS: Our analyses must be considered exploratory and will need to be validated in bigger cohorts. The main limitation is given by the small sample size and by the lack of replicates for postmortem brain samples. Measuring the transcription of locus-specific TEs is complicated by the repetitive nature of their sequence, which reduces the accuracy in mapping sequencing reads to the correct genomic locus. CONCLUSIONS: L1 upregulation in ASD appears to be limited to a subset of subjects that are also characterized by a general deregulation of the expression of canonical genes and an increase in intron retention. In some samples from the anterior cingulate cortex, L1s upregulation seems to directly impair the expression of some ASD-relevant genes by a still unknown mechanism. L1s upregulation may therefore identify a group of ASD subjects with common molecular features and helps stratifying individuals for novel strategies of therapeutic intervention.

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16. Wang LJ, Tsai CS, Chou WJ, Li CJ, Lee SY, Chen YC, Lin IC. Medical outcomes of children with neurodevelopmental disorders after SARS-CoV-2 vaccination: A six-month follow-up study. Vaccine. 2023; 41(29): 4267-73.

INTRODUCTION: The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines have been approved for children and adolescents for protecting against SARS-CoV-2 infection. This longitudinal study aimed to compare adverse outcomes after SARS-CoV-2 vaccination in children with neurodevelopmental disorders (ND) (e.g., attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], communication disorders, intellectual disability, and tic disorders) and healthy control children. METHODS: A total of 1335 children who received the SARS-CoV-2 vaccination (762 children with ND and 573 healthy controls) were recruited. All subjects were followed-up for 180 days, and outcome events were defined as outpatient department (OPD) or emergency department (ER) visits during follow-up. Multivariate Cox proportional hazards regression models were used to identify the potential differences in outcomes between the propensity score-matched ND group (n = 311) and the control group (n = 311), and to explore the factors associated with outcomes among all children with ND (n = 762). RESULTS: Compared with the control group, children with ND exhibited a higher likelihood of subsequent OPD or ER visits and paediatric neurology OPD visits after the first dose of vaccination. However, we found that only a small proportion of the children visited the OPD or ER because of adverse vaccination-related effects. Among all children with ND, those with communication disorders showed a higher likelihood of any OPD or ER visit. Paediatric neurology OPD visits were associated with communication disorders, intellectual disability, and methylphenidate and aripiprazole prescriptions. ADHD and ASD were not associated with adverse outcomes. CONCLUSIONS: No specific ND diagnosis or medication use clearly increased the risk of adverse effects of SARS-CoV-2 vaccination. Children with ND can be reassured that the SARS-CoV-2 vaccination is a safe regimen to protect themselves.

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17. Wright N, Courchesne V, Pickles A, Bedford R, Duku E, Kerns CM, Bennett T, Georgiades S, Hill J, Richard A, Sharp H, Smith IM, Vaillancourt T, Zaidman-Zait A, Zwaigenbaum L, Szatmari P, Elsabbagh M. A longitudinal comparison of emotional, behavioral and attention problems in autistic and typically developing children. Psychological medicine. 2023: 1-13.

BACKGROUND: Mental health problems are elevated in autistic individuals but there is limited evidence on the developmental course of problems across childhood. We compare the level and growth of anxious-depressed, behavioral and attention problems in an autistic and typically developing (TD) cohort. METHODS: Latent growth curve models were applied to repeated parent-report Child Behavior Checklist data from age 2-10 years in an inception cohort of autistic children (Pathways, N = 397; 84% boys) and a general population TD cohort (Wirral Child Health and Development Study; WCHADS; N = 884, 49% boys). Percentile plots were generated to quantify the differences between autistic and TD children. RESULTS: Autistic children showed elevated levels of mental health problems, but this was substantially reduced by accounting for IQ and sex differences between the autistic and TD samples. There was small differences in growth patterns; anxious-depressed problems were particularly elevated at preschool and attention problems at late childhood. Higher family income predicted lower base-level on all three dimensions, but steeper increase of anxious-depressed problems. Higher IQ predicted lower level of attention problems and faster decline over childhood. Female sex predicted higher level of anxious-depressed and faster decline in behavioral problems. Social-affect autism symptom severity predicted elevated level of attention problems. Autistic girls’ problems were particularly elevated relative to their same-sex non-autistic peers. CONCLUSIONS: Autistic children, and especially girls, show elevated mental health problems compared to TD children and there are some differences in predictors. Assessment of mental health should be integrated into clinical practice for autistic children.

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18. Yuan F, Chen H, Li F, Zhao W, Song S. Analysis on effect and influencing factors of precision rehabilitation therapy on scales of ABC, CARS, CHAT and CABS in children with autism spectrum disorder. Minerva medica. 2023.

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