1. Alam MS, Rashid MM, Roy R, Faizabadi AR, Gupta KD, Ahsan MM. Empirical Study of Autism Spectrum Disorder Diagnosis Using Facial Images by Improved Transfer Learning Approach. Bioengineering (Basel, Switzerland). 2022; 9(11).

Autism spectrum disorder (ASD) is a neurological illness characterized by deficits in cognition, physical activities, and social skills. There is no specific medication to treat this illness; only early intervention can improve brain functionality. Since there is no medical test to identify ASD, a diagnosis might be challenging. In order to determine a diagnosis, doctors consider the child’s behavior and developmental history. The human face can be used as a biomarker as it is one of the potential reflections of the brain and thus can be used as a simple and handy tool for early diagnosis. This study uses several deep convolutional neural network (CNN)-based transfer learning approaches to detect autistic children using the facial image. An empirical study is conducted to select the best optimizer and set of hyperparameters to achieve better prediction accuracy using the CNN model. After training and validating with the optimized setting, the modified Xception model demonstrates the best performance by achieving an accuracy of 95% on the test set, whereas the VGG19, ResNet50V2, MobileNetV2, and EfficientNetB0 achieved 86.5%, 94%, 92%, and 85.8%, accuracy, respectively. Our preliminary computational results demonstrate that our transfer learning approaches outperformed existing methods. Our modified model can be employed to assist doctors and practitioners in validating their initial screening to detect children with ASD disease.

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2. Alhazmi S, Aljahdli B, Farsi R, Alharbi M, Algothmi K, Alburae N, Ganash M, Azhari S, Basingab F, Almuhammadi A, Alqosaibi A, Alkhatabi H, Elaimi A, Jan M, Aldhalaan H, Alyoubi R, Alrafiah A, Alrofaidi A. The correlation between copy number variation in Chromosome 14 and DNA methylation in Saudi autistic children. European review for medical and pharmacological sciences. 2022; 26(21): 7866-82.

OBJECTIVE: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that represents a range of aberrant behaviour symptoms such as repetitive behaviours and defects in social communication. The prevalence of ASD has been increasing worldwide and many studies have reported that both genetic and epigenetic factors play an important role in the etiology of this disorder. The aim of this study was to investigate the implementation of DNA methylation and Copy number variation (CNV) in the diagnosis of ASD. PATIENTS AND METHODS: This study was carried out on 14 Saudi autistic children and four of their healthy siblings. Comparative genomic hybridization array was used to identify CNV in chromosome 14 and MethyLight qPCR was used to estimate levels of DNA methylation. RESULTS: The results identified CNVs in six cytobands in chromosome 14 for 13 out of 14 autistic samples: 14q11.1-q11.2, 14q11.2, 14q12, 14q21.1, 14q32.2, and 14q32.33. However, some of these cytobands were also found in normal samples with different sizes. Interestingly, chromosomal abnormalities in 14q11.1-q11.2 was only found in ASD samples. The result also showed an increase in methylation ratio of ASD samples in those CNV regions compared with their siblings. CONCLUSIONS: The findings suggest that CNV in 14q11.1-q11.2 might be a potential target in ASD diagnosis and further work is required to detect which biological pathways are affected.

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3. Arteaga-Henríquez G, Lugo-Marín J, Gisbert L, Setién-Ramos I, Martínez-Gallo M, Pujol-Borrell R, Ramos-Quiroga JA. Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. International journal of molecular sciences. 2022; 23(22).

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I(2) = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I(2) = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I(2) = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I(2) = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I(2) = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = -0.42, p = 0.008, I(2) = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I(2) = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I(2) = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings.

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4. Artık A, Çengel Kültür SE, Portakal O, Karaboncuk AY. The association between autistic traits and serum testosterone, oxytocin, and androstenedione levels in prepubertal male drug naive children with attention-deficit/hyperactivity disorder. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2022.

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) might have similar problems as in autism spectrum disorder (ASD) and show impairment in social behaviour. Also, there is a relationship between social relationship skills and ToM (theory of mind) skills of children with ADHD. Besides, ASD is associated with prenatal exposure to high levels of androgens, and oxytocin plays a role in the modulation of emotions, coping with stress, and social behaviour like ASD. In this study, the relationship between autistic traits and serum oxytocin, testosterone, and androstenedione levels in prepubertal male drug naive children with ADHD has been investigated. METHOD: Eighty-three prepubertal children, who were diagnosed with ADHD between the ages of 6-10 years old, are included in the study. For the study, intelligence levels were evaluated by using WISC-4, and autistic traits were measured by using both social responsiveness scale and theory of mind tests. In addition, serum oxytocin, testosterone, and androstenedione levels were measured by using ELISA. RESULTS: It has been found that serum testosterone levels of patients with lower autistic traits are significantly lower than those with moderate and severe autistic traits, while the serum oxytocin levels are significantly higher. Also, patients with severe autistic traits have had significantly higher serum androstenedione levels than those with lower and moderate autistic traits. CONCLUSION: This study suggests that patients who have higher autistic traits have elevated testosterone and androstenedione levels and lower serum oxytocin levels. Further studies are needed to clarify this relationship.

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5. Auvichayapat P, Intayot K, Udomchat C, Suphakunpinyo C, Patjanasoontorn N, Keeratitanont K, Tunkamnerdthai O, Jensen MP, Humbert AT, Auvichayapat N. Long-term effects of transcranial direct current stimulation in the treatment of autism spectrum disorder: A randomized controlled trial. Developmental medicine and child neurology. 2022.

AIM: To compare the efficacy of 0, 5, and 20 sessions of transcranial direct current stimulation (tDCS) for reducing symptoms of autism spectrum disorder (ASD). METHOD: Thirty-six male children with ASD (mean age 2 years 3 months, SD 4 months, age range 1 years 6 months-2 years 11 months) were balanced and stratified by age, sex, and baseline severity of ASD, to: (1) a control group that received 20 sessions of sham tDCS; (2) a 5-session tDCS group (5-tDCS) that received 5 sessions of active tDCS followed by 15 sessions of sham tDCS; and (3) a 20-session tDCS group (20-tDCS) that received 20 sessions of active tDCS. All groups participated in the special school activity of Khon Kaen Special Education Center, Thailand. The primary outcome was autism severity as measured by the Childhood Autism Severity Scale. RESULTS: The 5-tDCS and 20-tDCS groups evidenced greater reductions in autism severity than the control group at days 5 and 14, and months 6 and 12. There were no significant differences in the outcome between the 5- and 20-tDCS groups at any time point. Within-group analysis showed clinically meaningful improvements starting at month 6 for the participants in the control group, and clinically meaningful improvements starting on day 5 in both active tDCS groups, all of which were maintained to month 12. INTERPRETATION: The 5- and 20-session tDCS seems to reduce autism severity faster than sham tDCS. These effects maintained at least for 1 year.

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6. Ben Hassen N, Molins F, Garrote-Petisco D, Serrano M. Emotional regulation deficits in autism spectrum disorder: The role of alexithymia and interoception. Research in developmental disabilities. 2022; 132: 104378.

The aim of this study was to analyze emotional regulation, alexithymia and interoception in a group of people diagnosed with ASD (n = 27), a normative population with a technical academic training (n = 30), and another group with a humanities/health training (n = 20). Results showed significantly higher scores in alexithymia and emotional regulation problems, and lower scores in interoception in the ASD group. Also, alexithymia was found to correlate with emotional regulation, which was found to be significant in all three groups. In addition, interoception correlated negatively with alexithymia in the ASD group. Finally, the scores of the group with the technical training were closer to those of the ASD group compared to the humanities/health group.

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7. Browning H, Veit W. Autism and the preference for imaginary worlds. The Behavioral and brain sciences. 2022; 45: e279.

Dubourg and Baumard mention a potential role for the human drive to systemise as a factor motivating interest in imaginary worlds. Given that hyperexpression of this trait has been linked with autism (Baron-Cohen, , ), we think this raises interesting implications for how those on the autism spectrum may differ from the neurotypical population in their engagement with imaginary worlds.

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8. Chaxiong P, Dimian AF, Wolff JJ. Restricted and repetitive behavior in children with autism during the first three years of life: A systematic review. Frontiers in psychology. 2022; 13: 986876.

Restricted and repetitive behavior (RRB) is a core diagnostic feature of autism spectrum disorder (ASD). Previous research shows that RRB is prevalent early in life and observed in neurotypical development as well. Less is known, however, about early RRB patterns, developmental trajectories, and the relation to outcomes for autistic children. The purpose of this systematic review was to synthesize findings from studies examining RRB in autistic children from birth through age 3. A detailed protocol was designed a priori based on PRISMA guidelines for systematic reviews. From the published literature, 41 peer reviewed journal articles were identified and included in this review. Our synthesis of the literature suggests that differences in RRB are evident prior to age 2 in children with or who go onto be diagnosed with autism. These differences were evident for both frequency and intensity of RRB across multiple topographies. There were mixed results regarding functional outcomes associated with early RRB, such as cognitive and adaptive behavior, though relations appeared to become stronger as children aged beyond toddlerhood. Notably, level of RRB appears unrelated to autism severity in young autistic children. A wide range of RRB have been reported to be elevated in autistic children during the first years of life, including repetitive motor behaviors, atypical sensory behaviors, insistence on sameness (IS), and self-injurious behaviors (SIBs). In contrast to studies of older children, RRB in very young autistic children do not appear to be associated with functional outcomes but may be valuable to include in early screening efforts. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/huzf3, unique identifier: doi: 10.17605/OSF.IO/HUZF3.

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9. Cohen AL, Kroeck MR, Wall J, McManus P, Ovchinnikova A, Sahin M, Krueger DA, Bebin EM, Northrup H, Wu JY, Warfield SK, Peters JM, Fox MD. Tubers Affecting the Fusiform Face Area Are Associated with Autism Diagnosis. Annals of neurology. 2022.

OBJECTIVE: Tuberous sclerosis complex (TSC) is associated with focal brain « tubers » and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms. METHODS: We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network. We tested for associations between ASD diagnosis and tuber burden within the whole brain, specific lobes, and at 8 regions of interest derived from the ASD neuroimaging literature, including the anterior cingulate, orbitofrontal and posterior parietal cortices, inferior frontal and fusiform gyri, superior temporal sulcus, amygdala, and supplemental motor area. Next, we performed an unbiased data-driven voxelwise lesion symptom mapping (VLSM) analysis. Finally, we calculated the risk of ASD associated with positive findings from the above analyses. RESULTS: There were no significant ASD-related differences in tuber burden across the whole brain, within specific lobes, or within a priori regions derived from the ASD literature. However, using VLSM analysis, we found that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD. INTERPRETATION: Although TSC is a rare cause of ASD, there is a strong association between tuber involvement of the right FFA and ASD diagnosis. This highlights a potentially causative mechanism for developing autism in TSC that may guide research into ASD symptoms more generally. ANN NEUROL 2022.

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10. Csillag A, Ádám Á, Zachar G. Avian models for brain mechanisms underlying altered social behavior in autism. Frontiers in physiology. 2022; 13: 1032046.

The current review is an update on experimental approaches in which birds serve as model species for the investigation of typical failure symptoms associated with autism spectrum disorder (ASD). The discussion is focused on deficiencies of social behavior, from social interactions of domestic chicks, based on visual and auditory cues, to vocal communication in songbirds. Two groups of pathogenetic/risk factors are discussed: 1) non-genetic (environmental/epigenetic) factors, exemplified by embryonic exposure to valproic acid (VPA), and 2) genetic factors, represented by a list of candidate genes and signaling pathways of diagnostic or predictive value in ASD patients. Given the similarities of birds as experimental models to humans (visual orientation, vocal learning, social cohesions), avian models usefully contribute toward the elucidation of the neural systems and developmental factors underlying ASD, improving the applicability of preclinical results obtained on laboratory rodents. Furthermore, they may predict potential susceptibility factors worthy of investigation (both by animal studies and by monitoring human babies at risk), with potential therapeutic consequence.

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11. Daly G, Jackson J, Lynch H. Family life and autistic children with sensory processing differences: A qualitative evidence synthesis of occupational participation. Frontiers in psychology. 2022; 13: 940478.

Autistic children with sensory processing differences successfully navigate and engage in meaningful family daily occupations within home and community environments through the support of their family. To date however, much of the research on autistic children with sensory processing differences, has primarily been deficit focused, while much of the caregiver research has focused on issues of distress, burden, effort, and emotional trauma in coping with their child’s diagnosis. This study aimed to conduct a qualitative evidence synthesis, using a meta-ethnographic approach to explore the gap identified in understanding successful occupational experiences of family participation and daily family routines when supporting an autistic child with sensory processing differences and to offer an alternative strengths-based perspective. Inclusion criteria were studies which were peer-reviewed qualitative design, published from 2000 to 2021, and that concerned parents/caregivers’ perspectives of family occupations of children diagnosed with autism spectrum disorder. Studies were electronically searched in eight databases from October to December 2021 and 23 studies were identified which met the inclusion criteria. Noblit and Hare’s seven step approach for conducting analysis in meta-ethnography was used, and three themes identified: (1) sensory processing differences in daily life, (2) what is hard about hard, and (3) orchestrating family life. Results identified the centrality of sensory experiences in understanding family life. Living with unpredictability while orchestrating certainty through routines was core to successful participation. This review provides insights into how parents negotiate the complexities of constructing family life when living with an autistic child. The results can inform the design of future interventions that specifically address the relationship between meaningful participation in family occupations and daily routines and sensory processing in autistic children. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022298938, identifier: CRD42022298938.

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12. Drosos E, Maye H, Youshani AS, Ehsan S, Burnand C, D’Urso PI. Awake brain surgery for autistic patients: Is it possible?. Surgical neurology international. 2022; 13: 543.

BACKGROUND: Awake neurosurgery is currently the mainstay for eloquent brain lesions. Opting for an awake operation is affected by a number of patient-related factors. We present a case of a patient with autistic spectrum disorder (ASD) that was successfully operated for a brain tumor through awake craniotomy. To the best of our knowledge, this is the first reported case in the literature. CASE DESCRIPTION: A 42-year-old patient, with known ASD since his childhood, underwent awake craniotomy for a left supplementary motor area tumor. Detailed preoperative preparation of the patient was done to identify special requirements and establish a good patient-team relationship. Intraoperatively, continuous language and motor testing were performed. Conversation and music were the main distractors used. Throughout the operation, the patient remained calm and cooperative, even during a focal seizure. Mapping allowed for >80% resection of the tumor. Postoperatively, the patient recovered without any deficits. CONCLUSION: This case shows that with growing experience and meticulous preparation, the limits of awake craniotomy can be expanded to include more patients that were previously considered unfit.

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13. Elkin TD, Zhang Y, Reneker JC. Gaze Fixation and Visual Searching Behaviors during an Immersive Virtual Reality Social Skills Training Experience for Children and Youth with Autism Spectrum Disorder: A Pilot Study. Brain sciences. 2022; 12(11).

Children and youth with Autism Spectrum Disorder (ASD) display difficulties recognizing and interacting with behavioral expressions of emotion, a deficit that makes social interaction problematic. Social skills training is foundational to the treatment of ASD, yet this intervention is costly, time-consuming, lacks objectivity, and is difficult to deliver in real-world settings. This pilot project investigated the use of an immersive virtual reality (IVR) headset to simulate real-world social interactions for children/youth with ASD. The primary objective was to describe gaze fixation and visual search behaviors during the simulated activity. Ten participants were enrolled and completed one social-skills training session in the IVR. The results demonstrate differential patterns between participants with mild, moderate, and severe ASD in the location and duration of gaze fixation as well as the patterns of visual searching. Although the results are preliminary, these differences may shed light on phenotypes within the continuum of ASD. Additionally, there may be value in quantifying gaze and visual search behaviors as an objective metric of interventional effectiveness for social-skills training therapy.

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14. Enav Y, Hardan AY, Gross JJ. Cognitive reappraisal training for parents of children with autism spectrum disorder. Frontiers in psychiatry. 2022; 13: 995669.

Parents of children with autism spectrum disorder (ASD) experience higher stress levels than those of typically developing children. The goal of the current study was to examine whether a mentalization-based intervention would enhance parental cognitive reappraisal, an adaptive form of emotion regulation associated with lower levels of stress. Findings from 27 parents who completed a short training indicated an improvement in cognitive reappraisal. In exploratory analyses, two different types of reappraisal were examined. The intervention-related improvement was found mainly with one type of reappraisal, namely reflective reappraisal that consist of cognitive reappraisal with mentalization characteristics. In light of the evidence indicating that high cognitive reappraisal and high reflective functioning are associated with quality caregiving, findings from the current study suggesting that a brief mentalization-based intervention supports ASD parents’ cognitive reappraisal with mentalization characteristics are promising and warrant further investigation.

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15. Feng S, Wang Q, Hu Y, Lu H, Li T, Song C, Fang J, Chen L, Yi L. Increasing Audiovisual Speech Integration in Autism Through Enhanced Attention to Mouth. Developmental science. 2022: e13348.

Autistic children show less audiovisual speech integration in the McGurk task, which correlates with their reduced mouth-looking time. The present study examined whether autistic children’s less audiovisual speech integration in the McGurk task could be increased by increasing their mouth-looking time. We recruited 4- to 8-year-old autistic children and nonautistic children. In two experiments, we manipulated children’s mouth-looking time, measured their audiovisual speech integration by employing the McGurk effect paradigm, and tracked their eye movements. In Experiment 1, we blurred the eyes in McGurk stimuli and compared children’s performances in blurred-eyes and clear-eyes conditions. In Experiment 2, we cued children’s attention to either the mouth or eyes of McGurk stimuli or asked them to view the McGurk stimuli freely. We found that both blurring the speaker’s eyes and cuing to the speaker’s mouth increased mouth-looking time and increased audiovisual speech integration in the McGurk task in autistic children. In addition, we found that blurring the speaker’s eyes and cuing to the speaker’s mouth also increased mouth-looking time in nonautistic children, but neither blurring the speaker’s eyes nor cuing to the speaker’s mouth increased their audiovisual speech integration in the McGurk task. Our findings suggest that audiovisual speech integration in the McGurk task in autistic children could be increased by increasing their attention to the mouth. Our findings contribute to a deeper understanding of relations between face attention and audiovisual speech integration, and provide insights for the development of professional supports to increase audiovisual speech integration in autistic children. This article is protected by copyright. All rights reserved.

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16. Gai J, Xing J, Wang Y, Lei J, Zhang C, Zhang J, Tang J. Exploration of potential targets and mechanisms of Naringenin in treating autism spectrum disorder via network pharmacology and molecular docking. Medicine. 2022; 101(46): e31787.

Naringenin (NR) is a kind of flavonoid which plays a great role in the treatment of autism spectrum disorder (ASD). However, the underlying mechanism of NR in treating ASD still remains unclear. This study used network pharmacology and molecular docking to examine the potential targets and pharmacological mechanism of NR on ASD. Targets related to NR were screened from Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), Encyclopedia of Traditional Chinese Medicine Database (ETCM), Traditional Chinese Medicine Integrated Database (TCMID), PharmaMapper database, and targets related to ASD were screened from Online Mendelian Inheritance In Man (OMIM), Disgenet, GeneCards, Therapeutic Target Database (TTD), Drugbank, and ETCM. Screened of the intersected gene targets. Then, we used the protein-protein interaction (PPI) networks to construct a PPI network and used Network Analyzer plug-in to perform topological analysis to screen out the core target. We used Metascape platform to perform gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and used Chem draw, Pymol, AutoDock 1.5.6 software for molecular docking verification with core targets. A total of 149 targets of NR and 1594 potential targets of ASD were screened, and 43 intersected targets and 8 key targets were obtained and screened. A total of 176 GO items were obtained by GO enrichment analysis (P < .05), 153 entries on biological process (BP), 12 entries on BP and 11entries on cell composition (CC) were included. A total of 100 signaling pathways were obtained by KEGG pathway enrichment screening (P < .05).The pathways that are closely related to the pathogenesis of ASD are estrogen signaling, thyroid hormone signaling pathway, prolactin signaling pathway, and endocrine resistance pathway. Molecular docking results showed that NR had the best docking activity with the core target CASP3, and had good binding ability with AKT1, ESR1, ACTB and MAPK3. Taken together, our findings support that NR exerts therapeutic effects on ASD with multi-target, and multi-pathway characteristics, which provides a preliminary theoretical basis for clinical trials. The mechanism of anti-oxidative stress response, anti-apoptosis, regulation of cell growth and metabolism, anti-inflammatory, balance hormone levels may be important for the therapeutic effect.

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17. Guo C, Chen F, Yan J, Gao X, Zhu M. Atypical prosodic realization by Mandarin-speaking autistic children: Evidence from tone sandhi and neutral tone. Journal of communication disorders. 2022; 100: 106280.

Introduction Atypical prosodic features have been widely reported in autism spectrum disorder (ASD), primarily in non-tonal language speakers. Nevertheless, the prosodic realizations in autistic people who speak tonal languages were relatively understudied. This study aimed to investigate the acoustic and phonetic patterns at the word-level speech in Mandarin-speaking autistic and typically developing (TD) children at different age ranges. Methods Thirty Mandarin-speaking autistic children (15 three- to five-year-olds and 15 six- to eight-year-olds) were recruited into the ASD group. The TD group consisted of 30 age- and gender-matched children. We employed a picture-naming task to elicit the spontaneous speech production of Mandarin disyllabic words in which tone change processes occur, namely Tone 3 (T3) sandhi and neutral tone (T0). Results The phonetic analysis showed that the ASD group generally could produce typical-like T3 sandhi and T0 in terms of pitch height. However, relative to the TD group, they exhibited flatter pitch contours during T3 sandhi production. Moreover, the acoustic pitch mean of citation tones in the ASD group was also significantly higher, accompanied by more rigid pitch curves in contour tones. In addition, the atypical temporal realization in the ASD group was manifested by the longer duration of T0 and the earlier inflection position of T3. Conclusions Mandarin-speaking autistic children under eight had the phonological ability to produce context-dependent tones based on connected tonal information at the word level. Nevertheless, their phonetic prosodic realization of tone change processes was atypical. Our findings provide evidence of atypical prosody in autistic children who speak tone languages. Clinically, these findings may be attributable to underlying neural differences in autistic children.

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18. Hernandez MH, Bote V, Serra LA, Cendros M, Salazar J, Mestres C, Guijarro S, Alvarez A, Lamborena C, Mendez I, Sanchez B, Hervas A, Arranz MJ. CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders. Pharmacogenomics and personalized medicine. 2022; 15: 951-7.

PURPOSE: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety. PATIENTS AND METHODS: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype. RESULTS: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05). CONCLUSION: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

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19. Ifrim MF, Janusz-Kaminska A, Bassell GJ. Development of single-molecule ubiquitination mediated fluorescence complementation to visualize protein ubiquitination dynamics in dendrites. Cell reports. 2022; 41(7): 111658.

The ubiquitination/proteasome system is important for the spatiotemporal control of protein synthesis and degradation at synapses, while dysregulation may underlie autism spectrum disorders (ASDs). However, methods allowing direct visualization of the subcellular localization and temporal dynamics of protein ubiquitination are lacking. Here we report the development of Single-Molecule Ubiquitin Mediated Fluorescence Complementation (SM-UbFC) as a method to visualize and quantify the dynamics of protein ubiquitination in dendrites of live neurons in culture. Using SM-UbFC, we demonstrate that the rate of PSD-95 ubiquitination is elevated in dendrites of FMR1 KO neurons compared with wild-type controls. We further demonstrate the rapid ubiquitination of the fragile X messenger ribonucleoprotein, FMRP, and the AMPA receptor subunit, GluA1, which are known to be key events in the regulation of synaptic protein synthesis and plasticity. SM-UbFC will be useful for future studies on the regulation of synaptic protein homeostasis.

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20. Jeon M, Esposito G, Halstead E, Haghighatfard A, Dimitriou D, Neoh MJY. Cross-country comparison of parental reports and objective measures of sleep patterns of typically developing children and autistic children between the UK and South Korea. Sleep medicine. 2022; 101: 162-77.

Sleep duration and disturbances in typically developing (TD) children have been found to vary across countries. Given the impact of culture on sleep patterns in TD children, it is also necessary to examine the impact of culture on sleep patterns in children with atypical development. However, previous studies have often relied only on parent reports of children’s sleep. Hence, the present study conducted a cross-cultural comparison of sleep duration and disturbances of school-aged TD children and autistic children in the UK and South Korea (hereafter Korea) using both subjective and objective sleep measurements. Cultural differences were observed in both actigraphy measures and parent reports of children’s sleep duration and disturbances. Both TD children and autistic children in Korea had a later bedtime, later getting up time and shorter nocturnal sleep duration than their peers in the UK (p < .05). Furthermore, greater parent-reported sleep disturbances were reported in TD children in Korea compared to TD children in the UK and in autistic children in the UK compared to autistic children in Korea. Correlational analyses indicated that most parent-reported measures of children's sleep did not significantly correlate with objective measures and child reports, suggesting that studies on children's sleep can benefit by collecting data from multiple sources. Taken together, these findings suggest a cultural influence on sleep duration and disturbances of both TD children and autistic children. This study raises questions for further research to identify factors underlying cultural differences in children's sleep duration and disturbances.

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21. Jose DS, Varma R, Sambasivan SL, Philip L, Sandhya P, Sundaram S. Autism Spectrum Disorders: Barriers to Implementing Parent-Based Home Programs. Indian journal of pediatrics. 2022.

An exploratory survey to identify the barriers experienced by caregivers of children with autism spectrum disorders (ASD) when implementing home programs (HP) was conducted with a newly developed questionnaire, ‘barriers in the parent-based home program for ASD (BHPQ-ASD)’ in English and Malayalam. The questionnaire has 25 items in Likert scale response format and underwent face validation and cognitive debriefing. It was administered to 50 caregivers of ASD children for factor extraction and reliability analysis. Seven questions under service provider-related barriers emerged to have good psychometric properties in the principal axis factoring method and were grouped to form the ‘service provider-related BHPQ-ASD’ scale, which has very good internal consistency (Cronbach alpha 0.903). In regression analysis, parents of children not receiving occupational therapy (OT) reported 6.6 times more barriers when compared to those undergoing OT (OR 6.6, CI 1.5-29.7, p = 0.014). BHPQ-ASD is a useful valid tool for detecting the barriers to implementing HPs.

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22. Kawai M, Buck C, Chick CF, Anker L, Talbot L, Schneider L, Linkovski O, Cotto I, Parker-Fong K, Phillips J, Hardan A, Hallmayer J, O’Hara R. Sleep architecture is associated with core symptom severity in autism spectrum disorder. Sleep. 2022.

OBJECTIVE: While caregiver-reported sleep disturbances are common in children and adolescents with autism spectrum disorder (ASD), few studies have measured objective sleep in ASD compared to controls, and their findings are mixed. We investigated 1) differences in sleep architecture, specifically slow-wave sleep (SWS) and rapid eye movement sleep (REM), between ASD and typically developing controls (TD); and 2) if any observed differences in sleep were associated with core ASD symptoms. METHODS: We used ambulatory polysomnography (PSG) in 53 participants with ASD (ages 6 to 18) and 66 age-matched TD in their home sleeping environment. The primary outcome measures were SWS and REM sleep. Core behavioral ASD symptoms were assessed using the Autism Diagnostic Interview-Revised (ADI-R). Spectral power bands during sleep, and additional behavioral measures, were examined in exploratory analyses. RESULTS: Compared to TD, participants with ASD exhibited a higher SWS ratio and lower REM ratio. Within the ASD group, higher SWS was associated with more severe symptoms on the Restricted, Repetitive, and Stereotyped Behaviors subscale of the ADI-R. No association was observed between REM ratio and any ASD symptom. CONCLUSIONS: Increased SWS and reduced REM sleep ratio differentiated ASD from TD. However, only increased SWS was associated with more severe core ASD symptoms. Increased SWS may reflect neuronal immaturity specific to ASD in this age group. These findings may inform the underlying mechanisms of clinical symptoms observed in children and adolescents with ASD.

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23. Klaiman C, White S, Richardson S, McQueen E, Walum H, Aoki C, Smith C, Minjarez M, Bernier R, Pedapati E, Bishop S, Ence W, Wainer A, Moriuchi J, Tay SW, Deng Y, Jones W, Gillespie S, Klin A. Expert Clinician Certainty in Diagnosing Autism Spectrum Disorder in 16-30-Month-Olds: A Multi-site Trial Secondary Analysis. Journal of autism and developmental disorders. 2022: 1-16.

Differential diagnosis of young children with suspected autism spectrum disorder (ASD) is challenging, and clinician uncertainty about a child’s diagnosis may contribute to misdiagnosis and subsequent delays in access to early treatment. The current study was designed to replicate and expand a recent report in this Journal (McDonnell et al. in J Autism Dev Disord 49:1391-1401, https://doi.org/10.1080/15374416.2020.1823850 , 2019), in which only 60% of diagnoses were made with complete certainty by clinicians evaluating 478 toddlers and preschool children referred for possible ASD to specialized clinics. In this study, secondary analyses were performed on diagnostic, demographic and clinical data for 496 16-30-month-old children who were consecutive referrals to a 6-site clinical trial executed by specialized centers with experienced clinicians following best-practice procedures for the diagnosis of ASD. Overall, 70.2% of diagnoses were made with complete certainty. The most important factor associated with clinician uncertainty was mid-level autism-related symptomatology. Mid-level verbal age equivalents were also associated with clinician uncertainty, but measures of symptomatology were stronger predictors. None of the socio-demographic variables, including sex of the child, was significantly associated with clinician certainty. Close to one third of early diagnoses of ASD are made with a degree of uncertainty. The delineation of specific ranges on the ADOS-2 most likely to result in clinician uncertainty identified in this study may provide an opportunity to reduce random subjectivity in diagnostic decision-making via calibration of young-child diagnostic thresholds based on later-age longitudinal diagnostic outcome data, and via standardization of decision-making in regard to clinical scenarios frequently encountered by clinicians.

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24. Lee NR, McQuaid GA, Grosman HE, Jayaram S, Wallace GL. Vocational Outcomes in ASD: An Examination of Work Readiness Skills as well as Barriers and Facilitators to Employment Identified by Autistic Adults. Journal of autism and developmental disorders. 2022: 1-14.

Little is known about work readiness skills among autistic adults. This study sought to address this by examining work readiness skills and their relation to vocational outcomes among 281 autistic young adults. It also examined perceived barriers and facilitators to employment as articulated by a subset of autistic adults. Results revealed a variegated work readiness profile. Stronger work readiness skills (particularly work style/adaptability) were associated with more favorable vocational outcomes. Autistic participants articulated both barriers and facilitators to employment related to the autism phenotype, job search/work readiness, and workplace education. These findings indicate the need for research on phenotype-driven vocational rehabilitation strategies as well as workplace psychoeducation/accommodations to support vocational outcomes for autistic adults.

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25. Petroni V, Subashi E, Premoli M, Memo M, Lemaire V, Pietropaolo S. Long-term behavioral effects of prenatal stress in the Fmr1-knock-out mouse model for fragile X syndrome. Frontiers in cellular neuroscience. 2022; 16: 917183.

Fragile X syndrome (FXS) is a major neurodevelopmental disorder and the most common monogenic cause of autism spectrum disorder (ASD). FXS is caused by a mutation in the X-linked FMR1 gene leading to the absence of the FMRP protein, inducing several behavioral deficits, including motor, emotional, cognitive, and social abnormalities. Beside its clear genetic origins, FXS can be modulated by environmental factors, e.g., stress exposure: indeed the behavioral phenotype of FXS, as well as of ASD patients can be exacerbated by the repeated experience of stressful events, especially early in life. Here we investigated the long-term effects of prenatal exposure to unpredictable chronic stress on the behavioral phenotype of the Fmr1-knock-out (KO) mouse model for FXS and ASD. Mice were tested for FXS- and ASD-relevant behaviors first at adulthood (3 months) and then at aging (18 months), in order to assess the persistence and the potential time-related progression of the stress effects. Stress induced the selective emergence of behavioral deficits in Fmr1-KO mice that were evident in spatial memory only at aging. Stress also exerted several age-specific behavioral effects in mice of both genotypes: at adulthood it enhanced anxiety levels and reduced social interaction, while at aging it enhanced locomotor activity and reduced the complexity of ultrasonic calls. Our findings underline the relevance of gene-environment interactions in mouse models of neurodevelopmental syndromes and highlight the long-term behavioral impact of prenatal stress in laboratory mice.

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26. Pouyan Mehr D, Faraji N, Rezaei S, Keshavarz P. Single-locus and Haplotype Associations of GRIN2B Gene with Autism Spectrum Disorders and the Demographic and Clinical Characteristics of Patients in Guilan, Iran. Journal of autism and developmental disorders. 2022.

Autism spectrum disorders (ASDs) are described as generalized developmental disorders, with an average age of onset of 36 months. Genetic and environmental factors may contribute to this multifactorial disorder. The present study aimed to investigate the association of three GRIN2B polymorphisms, including rs1019385, rs1024893, and rs3764028, with ASDs. Based on the results, there was a significant difference regarding the genotype frequency of rs3764028 polymorphism between the control and case (ASD) groups (P = 0.027). According to the recessive model, this variant was associated with ASDs (P = 0.23). None of the eight haplotype models with frequencies above 0.5 showed significant differences between the case and control groups in terms of allelic frequency. The present results showed that the rs376028 variant was directly related to the phenotypic symptoms of ASDs.

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27. Quinn LA, Gilley SP, Ta AD, Frank BS, Foley CB, Moore JM. Case report: Pulmonary hypertensive crisis leading to cardiac arrest during endoscopic evaluation in a 6-year-old boy with autism, severe malnutrition, and undiagnosed scurvy. Frontiers in pediatrics. 2022; 10: 1008507.

Pediatric gastroenterologists are often responsible for the evaluation of malnutrition in the setting of selective eating. Endoscopic evaluation for conditions including eosinophilic esophagitis and celiac disease can help to identify and treat mucosal disease contributing to food selectivity. However, undiagnosed micronutrient deficiencies can cause cardiovascular derangements that significantly increase a patient’s anesthetic risk. Vitamin C deficiency in particular, alone or in combination with severe malnutrition, is associated with a severe but reversible form of pulmonary arterial hypertension that, while life threatening in the acute phase, may significantly improve within days of starting ascorbic acid replacement therapy. Here we present a case of a 6-year-old boy with autism spectrum disorder (ASD), severe malnutrition, and undiagnosed chronic vitamin C deficiency who developed a pulmonary hypertensive crisis after induction of general anesthesia leading to cardiac arrest during endoscopic evaluation. While the association between food selectivity among youth with neurodevelopmental differences and vitamin C deficiency is well-described, and pulmonary hypertension is a recognized rare complication of scurvy, extant literature has not addressed next steps to improve patient outcomes. Using this case report as a foundation, we discuss specific patient populations to screen and treat for micronutrient deficiencies prior to anesthesia and propose a novel clinical algorithm for pre-anesthesia risk stratification and mitigation in patients specifically at risk for scurvy and associated pulmonary hypertension.

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28. Randall KN, Bernard G, Durah L. Association between employment status and quality of life for individuals with intellectual or developmental disability. Journal of applied research in intellectual disabilities : JARID. 2022.

The current study examined how employment conditions (competitive employment, work center employment, unemployment) are associated with the quality of life (QoL) for individuals with intellectual or developmental disabilities. Using the Comprehensive Quality of Life Scale – Intellectual/Cognitive Disability (5th Edition; ComQoL-I5; Cummins, 1997a) to measure objective QoL factors, and the PWI-ID (Personal Wellbeing Index – Intellectual Disability, 3rd Edition; Cummins & Lau, 2005b) to measure subjective well-being, participants answered self-reporting questions regarding the seven QoL domains. Kruskal-Wallis H for Oneway Analysis of Variance was used to determine statistical significance between comparison work conditions. Results indicate significant findings in the objective QoL domains of Material Well-Being, Productivity, and Safety between the work conditions for individuals with intellectual and developmental disabilities, with participants in the competitive-employment group reporting the highest QoL objective scores in these areas. Implications of these findings for practice and research are discussed.

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29. Raz N, Heller I, Lombardi T, Marino G, Davidson EM, Eyal AM. Terpene-Enriched CBD oil for treating autism-derived symptoms unresponsive to pure CBD: Case report. Frontiers in pharmacology. 2022; 13: 979403.

Cannabidiol (CBD) rich products are successfully used in some countries for treating symptoms associated with autism spectrum disorder (ASD). Yet, CBD provides insufficient intervention in some individuals, or for some characterizing symptoms of ASD, raising the need for improved compositions. The current study presents a case wherein pure CBD was sufficient for treating ASD during childhood and early adolescence. However, it became insufficient during puberty accompanied by increased hyperactivity, agitation, and frequent severe aggressive behavior. Increasing the CBD dose did not result in significant improvement. Enriching the pure CBD with a carefully selected blend of anxiolytic and calming terpenes, resulted in gradual elimination of those aggressive events. Importantly, this was achieved with a significantly reduced CBD dose, being less than one-half the amount used when treating with pure CBD. This case demonstrates a strong improvement in efficacy due to terpene enrichment, where pure CBD was not sufficient. Combined with terpenes’ high safety index and the ease with which they can be incorporated into cannabinoid-containing products, terpene-enriched CBD products may provide a preferred approach for treating ASD and related conditions. The careful selection of terpenes to be added enables maximizing the efficacy and tailoring the composition to particular and changing needs of ASD subjects, e.g., at different times of the day (daytime vs nighttime products).

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30. Rosello R, Martinez-Raga J, Tomas JM, Rosello B, Berenguer C, Cortese S. Exploring developmental trajectories throughout adolescence of children with autism spectrum disorder without intellectual disability. Journal of neural transmission (Vienna, Austria : 1996). 2022.

Characterizing the developmental trajectories of children with autism spectrum disorder (ASD) throughout adolescence and across different domains of functioning offers opportunities to improve long-term outcomes. This prospective study explored, for the first time, the evolution of children with ASD-without intellectual disability (ID) in terms of socio-adaptative skills, learning behaviors, executive functioning (EF), and internalizing/externalizing problems, compared to typically developing (TD) peers. Forty-five children with ASD-without ID and 37 matched TD children (aged 7-11) were assessed at baseline and after 5 years. Parents and teachers completed measures on theory of mind (ToM), socialization, daily living skills, learning style, EF, and emotional/behavioural difficulties at both time points. On all the domains assessed, the ASD group performed significantly worse than the TD group, both in childhood and adolescence. Specific changes were noted between baseline and follow-up assessment on adaptive skills, prosocial behavior, emotional control, inhibit, working memory and monitoring. Group membership (ASD/TD) was influenced by peer relationships and inhibit EF variables. These findings have implications for clinical and school settings.

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31. Schlegel S, Eisenberg DB, Caneira L, Augustyn M. Challenging Case: Caregiver-Fabricated Illness Masquerading as Autism Spectrum Disorder. Journal of developmental and behavioral pediatrics : JDBP. 2022.

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32. Stogios N, Hahn MK, Lunsky Y, Desarkar P, Agarwal SM. Addressing Metabolic Comorbidity in Individuals With Intellectual and Developmental Disability on Antipsychotics: A Clinical Case Series. Journal of clinical psychopharmacology. 2022.

PURPOSE/BACKGROUND: Individuals with intellectual and developmental disabilities (IDDs) are at increased risk for serious metabolic comorbidities, which is further exacerbated by the high rate of antipsychotic use in this population. There is currently a lack of literature on effective treatment options for antipsychotic-induced weight gain and metabolic abnormalities in IDD. This case series reports on the clinical use of metformin in patients with IDD on antipsychotics. METHODS/PROCEDURES: We conducted a retrospective review of patients in a novel clinical service at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada for adults with IDD experiencing antipsychotic-related weight gain and other metabolic aberrations. Charts were reviewed for weight and other metabolic outcome measures before and after commencing metformin treatment. FINDINGS/RESULTS: In 11 patients referred to this clinic, the mean weight loss while on metformin treatment was 11.1 kg, with over 50% of the sample achieving clinically meaningful weight loss of >7%. Additional adaptive changes were observed for fasting glucose, glycated hemoglobin, triglyceride, and high-density lipoprotein cholesterol levels. IMPLICATIONS/CONCLUSIONS: In line with its use in severe mental illness, metformin may be a safe, effective, and accessible treatment option for patients with IDD experiencing metabolic adverse effects of antipsychotic medication. Further research and randomized controlled trials are needed to examine the efficacy of metformin in this population.

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33. Sun F, Chen Y, Gao Q, Zhao Z. Abnormal gray matter structure in children and adolescents with high-functioning autism spectrum disorder. Psychiatry research Neuroimaging. 2022; 327: 111564.

The present study aimed to explore the brain structural mechanisms underlying clinical dysfunction in patients with ASD using magnetic resonance imaging (MRI). After screening T1 structural images from the Autism Brain Imaging Data Exchange (ABIDE) database, 111 children and adolescents with high-functioning ASD and 151 typically developing (TD) subjects matched were included in this study. We first compared the differences in gray matter volume (GMV) and gray matter density (GMD) between the two groups. Then, the relationships between GMV/GMD and clinical assessments in ASD patients were evaluated. We found that compared with the TD group, the ASD group showed increased GMV/GMD in the precuneus, thalamus, hippocampus and cingulate gyrus. Moreover, in the ASD group, social interaction was negatively correlated with GMD in the bilateral superior temporal gyrus and limbic system; communication was positively correlated with GMD in the right middle temporal gyrus, inferior frontal gyrus, and anterior cingulate gyrus; and repetitive behavior was positively correlated with GMD in the cerebellum and negatively correlated with GMV in the prefrontal cortex. In conclusion, the gray matter structure in children and adolescents with ASD was abnormal, and different clinical dysfunctions in ASD patients were related to structural abnormalities in specific regions.

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34. Tong Z, Zhou X, Chu Y, Zhang T, Zhang J, Zhao X, Wang Z, Ding R, Meng Q, Yu J, Wang J, Kang Y. Implications of oral streptococcal bacteriophages in autism spectrum disorder. NPJ biofilms and microbiomes. 2022; 8(1): 91.

Growing evidence suggests altered oral and gut microbiota in autism spectrum disorder (ASD), but little is known about the alterations and roles of phages, especially within the oral microbiota in ASD subjects. We enrolled ASD (n = 26) and neurotypical subjects (n = 26) with their oral hygiene controlled, and the metagenomes of both oral and fecal samples (n = 104) are shotgun-sequenced and compared. We observe extensive and diverse oral phageome comparable to that of the gut, and clear signals of mouth-to-gut phage strain transfer within individuals. However, the overall phageomes of the two sites are widely different and show even less similarity in the oral communities between ASD and control subjects. The ASD oral phageome exhibits significantly reduced abundance and alpha diversity, but the Streptococcal phages there are atypically enriched, often dominating the community. The over-representation of Streptococcal phages is accompanied by enriched oral Streptococcal virulence factors and Streptococcus bacteria, all exhibiting a positive correlation with the severity of ASD clinical manifestations. These changes are not observed in the parallel sampling of the gut flora, suggesting a previously unknown oral-specific association between the excessive Streptococcal phage enrichment and ASD pathogenesis. The findings provide new evidence for the independent microbiome-mouth-brain connection, deepen our understanding of how the growth dynamics of bacteriophages and oral microbiota contribute to ASD, and point to novel effective therapeutics.

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35. Vakharia M, Pehlivan D, Hoyos-Martinez A, Glaze DG, Tosur M. New-Onset Diabetes Presenting With Hyperosmolar Hyperglycemic State in a Lean Adolescent With Atypical Rett Syndrome Using Antipsychotics. Clinical diabetes : a publication of the American Diabetes Association. 2022; 40(4): 503-7.

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36. Wilkinson S, Evans S, DeJong M. Assessing autism spectrum disorder in children with a background of maltreatment: challenges and guidance. Archives of disease in childhood. 2022.

There may be some similarities in the presentation of children who have autism spectrum disorder (ASD) and those exposed to maltreatment affecting assessment and diagnosis. Overlapping characteristics include difficulties understanding and maintaining relationships, sensitivity to routine and hyper-reactivity to sensory inputs. Children who have been maltreated are at increased risk of various developmental vulnerabilities with both environmental and genetic factors being relevant. The existing epidemiological evidence has found that looked-after children are more likely to screen positively for neurodevelopmental disorders and there are smaller scale studies in adoptive children finding higher rates of ASD than would be expected in the general population. Other research suggests a predominantly genetic basis for this increased risk in keeping with what is generally understood about the aetiology of autism. Children exposed to profound deprivation in Romanian orphanages were found to be at higher risk of a pattern of traits termed ‘quasi autistic’ which tended to reduce following adoption, but these findings have not been replicated in children experiencing maltreatment in birth families. Reactive attachment disorder (RAD) has some overlapping criteria with ASD, but its prevalence is unknown and children with RAD should be more socially reciprocal and not have the same repetitive and restricted behaviours and interests. We recommend experienced multidisciplinary assessment that considers both the possibility of maltreatment in children with ASD and neurodevelopmental vulnerabilities in children who have been maltreated and advise on assessment and management strategies.

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37. Yen TL, Huang TN, Lin MH, Hsu TT, Lu MH, Shih PY, Ellegood J, Lerch J, Hsueh YP. Sex bias in social deficits, neural circuits and nutrient demand in Cttnbp2 autism models. Brain : a journal of neurology. 2022.

Autism spectrum disorders caused by both genetic and environmental factors are strongly male-biased neuropsychiatric conditions. However, the mechanism underlying the sex bias of autism spectrum disorders remains elusive. Here, we use a mouse model in which the autism-linked gene Cttnbp2 is mutated to explore the potential mechanism underlying the autism sex bias. Autism-like features of Cttnbp2 mutant mice were assessed via behavioral assays. C-FOS staining identified sex-biased brain regions critical to social interaction, with their roles and connectivity then validated by chemogenetic manipulation. Proteomic and bioinformatic analyses established sex-biased molecular deficits at synapses, prompting our hypothesis that male-biased nutrient demand magnifies Cttnbp2 deficiency. Accordingly, intakes of branched-chain amino acids (BCAA) and zinc were experimentally altered to assess their effect on autism-like behaviors. Both deletion and autism-linked mutation of Cttnbp2 result in male-biased social deficits. Seven brain regions, including the infralimbic area of the medial prefrontal cortex (ILA), exhibit reduced neural activity in male mutant mice but not in females upon social stimulation. ILA activation by chemogenetic manipulation is sufficient to activate four of those brain regions susceptible to Cttnbp2 deficiency and consequently to ameliorate social deficits in male mice, implying an ILA-regulated neural circuit is critical to male-biased social deficits. Proteomics analysis reveals male-specific downregulated proteins (including SHANK2 and PSD-95, two synaptic zinc-binding proteins) and female-specific upregulated proteins (including RRAGC) linked to neuropsychiatric disorders, which are likely relevant to male-biased deficits and a female protective effect observed in Cttnbp2 mutant mice. Notably, RRAGC is an upstream regulator of mTOR that senses branched-chain amino acids (BCAA), suggesting that mTOR exerts a beneficial effect on females. Indeed, increased BCAA intake activates the mTOR pathway and rescues neuronal responses and social behaviors of male Cttnbp2 mutant mice. Moreover, mutant males exhibit greatly increased zinc demand to display normal social behaviors. Mice carrying an autism-linked Cttnbp2 mutation exhibit male-biased social deficits linked to specific brain regions, differential synaptic proteomes and higher demand for BCAA and zinc. We postulate that lower demand for zinc and BCAA are relevant to the female protective effect. Our study reveals a mechanism underlying sex-biased social defects and also suggests a potential therapeutic approach for autism spectrum disorders.

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38. Zylbersztejn A, Stilwell PA, Zhu H, Ainsworth V, Allister J, Horridge K, Stephenson T, Wijlaars L, Gilbert R, Heys M, Hardelid P. Trends in hospital admissions during transition from paediatric to adult services for young people with learning disabilities or autism: Population-based cohort study. The Lancet regional health Europe. 2023; 24: 100531.

BACKGROUND: Transition from paediatric to adult health care may disrupt continuity of care, and result in unmet health needs. We describe changes in planned and unplanned hospital admission rates before, during and after transition for young people with learning disability (LD), or autism spectrum disorders (ASD) indicated in hospital records, who are likely to have more complex health needs. METHODS: We developed two mutually exclusive cohorts of young people with LD, and with ASD without LD, born between 1990 and 2001 in England using national hospital admission data. We determined the annual rate of change in planned and unplanned hospital admission rates before (age 10-15 years), during (16-18 years) and after (19-24 years) transition to adult care using multilevel negative binomial regression models, accounting for area-level deprivation, sex, birth year and presence of comorbidities. FINDINGS: The cohorts included 51,291 young people with LD, and 46,270 autistic young people. Admission rates at ages 10-24 years old were higher for young people with LD (54 planned and 25 unplanned admissions per 100 person-years) than for autistic young people (17/100 and 16/100, respectively). For young people with LD, planned admission rates were highest and constant before transition (rate ratio [RR]: 0.99, 95% confidence interval [CI] 0.98-0.99), declined by 14% per year of age during (RR: 0.86, 95% CI: 0.85-0.88), and remained constant after transition (RR: 0.99, 95% CI: 0.99-1.00), mainly due to fewer admissions for non-surgical care, including respite care. Unplanned admission rates increased by 3% per year of age before (RR: 1.03, 95% CI: 1.02-1.03), remained constant during (RR: 1.01, 95% CI: 1.00-1.03) and increased by 3% per year after transition (RR: 1.03, 95% CI: 1.02-1.04). For autistic young people, planned admission rates increased before (RR: 1.06, 95% CI: 1.05-1.06), decreased during (RR: 0.95, 95% CI: 0.93-0.97), and increased after transition (RR: 1.05, 95%: 1.04-1.07). Unplanned admission rates increased most rapidly before (RR: 1.16, 95% CI: 1.15-1.17), remained constant during (RR: 1.01, 95% CI: 0.99-1.03), and increased moderately after transition (RR: 1.03, 95% CI: 1.02-1.04). INTERPRETATION: Decreases in planned admission rates during transition were paralleled by small but consistent increases in unplanned admission rates with age for young people with LD and autistic young people. Decreases in non-surgical planned care during transition could reflect disruptions to continuity of planned/respite care or a shift towards provision of healthcare in primary care and community settings and non-hospital arrangements for respite care. FUNDING: National Institute for Health Research Policy Research Programme.

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