1. Akbas Aliyev ES, Günal Okumuş H, Karakus Y, Ersoz Alan B, Cak HT. Letter to the Editor: Olanzapine Treatment and Polyuria-Polydipsia in Two Children with Autism Spectrum Disorder. Journal of child and adolescent psychopharmacology. 2021; 31(7): 513.

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2. Akter T, Ali MH, Khan MI, Satu MS, Uddin MJ, Alyami SA, Ali S, Azad A, Moni MA. Improved Transfer-Learning-Based Facial Recognition Framework to Detect Autistic Children at an Early Stage. Brain sciences. 2021; 11(6).

Autism spectrum disorder (ASD) is a complex neuro-developmental disorder that affects social skills, language, speech and communication. Early detection of ASD individuals, especially children, could help to devise and strategize right therapeutic plan at right time. Human faces encode important markers that can be used to identify ASD by analyzing facial features, eye contact, and so on. In this work, an improved transfer-learning-based autism face recognition framework is proposed to identify kids with ASD in the early stages more precisely. Therefore, we have collected face images of children with ASD from the Kaggle data repository, and various machine learning and deep learning classifiers and other transfer-learning-based pre-trained models were applied. We observed that our improved MobileNet-V1 model demonstrates the best accuracy of 90.67% and the lowest 9.33% value of both fall-out and miss rate compared to the other classifiers and pre-trained models. Furthermore, this classifier is used to identify different ASD groups investigating only autism image data using k-means clustering technique. Thus, the improved MobileNet-V1 model showed the highest accuracy (92.10%) for k = 2 autism sub-types. We hope this model will be useful for physicians to detect autistic children more explicitly at the early stage.

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3. Al-Sarraj Y, Al-Dous E, Taha RZ, Ahram D, Alshaban F, Tolfat M, El-Shanti H, Albagha OME. Family-Based Genome-Wide Association Study of Autism Spectrum Disorder in Middle Eastern Families. Genes. 2021; 12(5).

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by abnormalities in language and social communication with substantial clinical heterogeneity. Genetic factors play an important role in ASD with heritability estimated between 70% to 80%. Genome-wide association studies (GWAS) have identified multiple loci associated with ASD. However, most studies were performed on European populations and little is known about the genetic architecture of ASD in Middle Eastern populations. Here, we report the first GWAS of ASD in the Middle eastern population of Qatar. We analyzed 171 families with ASD, using linear mixed models adjusting for relatedness and other confounders. Results showed that common single nucleotide polymorphisms (SNP) in seven loci are associated with ASD (p < 1 × 10(-5)). Although the identified loci did not reach genome-wide significance, many of the top associated SNPs are located within or near genes that have been implicated in ASD or related neurodevelopmental disorders. These include GORASP2, GABBR2, ANKS6, THSD4, ERCC6L, ARHGEF6, and HDAC8. Additionally, three of the top associated SNPs were significantly associated with gene expression. We also found evidence of association signals in two previously reported ASD-susceptibility loci (rs10099100 and rs4299400). Our results warrant further functional studies and replication to provide further insights into the genetic architecture of ASD.

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4. Amaral DG. Introduction to commentary by Laurent Mottron and responses. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2212.

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5. Bennett HJ, Haegele JA. Running Biomechanics of Adolescents With Autism Spectrum Disorder. Journal of biomechanical engineering. 2021; 143(11).

Research examining gait biomechanics of persons with autism spectrum disorder (ASD) has grown significantly in recent years and has demonstrated that persons with ASD walk at slower self-selected speeds and with shorter strides, wider step widths, and reduced lower extremity range of motion and moments compared to neurotypical controls. In contrast to walking, running has yet to be examined in persons with ASD. The purpose of this study was to examine lower extremity running biomechanics in adolescents (13-18-year-olds) with ASD and matched (age, sex, and body mass index (BMI)) neurotypical controls. Three-dimensional kinematics and ground reaction forces (GRFs) were recorded while participants ran at two matched speeds: self-selected speed of adolescents with ASD and at 3.0 m/s. Sagittal and frontal plane lower extremity biomechanics and vertical GRF waveforms were compared using two-way analyses of variances (ANOVAs) via statistical parametric mapping (SPM). Adolescents with ASD ran with reduced stride length at self-selected speed (0.29 m) and reduced vertical displacement (2.1 cm), loading-propulsion GRFs (by 14.5%), propulsion plantarflexion moments (18.5%), loading-propulsion hip abduction moments (44.4%), and loading knee abduction moments (69.4%) at both speeds. Running at 3.0 m/s increased sagittal plane hip and knee moments surrounding initial contact (both 10.4%) and frontal plane knee angles during midstance (2.9 deg) and propulsion (2.8 deg) compared to self-selected speeds. Reduced contributions from primarily the ankle plantarflexion but also knee abduction and hip abduction moments likely reduced the vertical GRF and displacement. As differences favored reduced loading, youth with ASD can safely be encouraged to engage in running as a physical activity.

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6. Biosca-Brull J, Pérez-Fernández C, Mora S, Carrillo B, Pinos H, Conejo NM, Collado P, Arias JL, Martín-Sánchez F, Sánchez-Santed F, Colomina MT. Relationship between Autism Spectrum Disorder and Pesticides: A Systematic Review of Human and Preclinical Models. International journal of environmental research and public health. 2021; 18(10).

Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped behaviors. Although its genetic basis is unquestionable, the involvement of environmental factors such as exposure to pesticides has also been proposed. Despite the systematic analyses of this relationship in humans, there are no specific reviews including both human and preclinical models. The present systematic review summarizes, analyzes, and discusses recent advances in preclinical and epidemiological studies. We included 45 human and 16 preclinical studies. These studies focused on Organophosphates (OP), Organochlorine (OC), Pyrethroid (PT), Neonicotinoid (NN), Carbamate (CM), and mixed exposures. Preclinical studies, where the OP Chlorpyrifos (CPF) compound is the one most studied, pointed to an association between gestational exposure and increased ASD-like behaviors, although the data are inconclusive with regard to other ages or pesticides. Studies in humans focused on prenatal exposure to OP and OC agents, and report cognitive and behavioral alterations related to ASD symptomatology. The results of both suggest that gestational exposure to certain OP agents could be linked to the clinical signs of ASD. Future experimental studies should focus on extending the analysis of ASD-like behaviors in preclinical models and include exposure patterns similar to those observed in human studies.

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7. Bitsika V, Sharpley CF. Direct and Inverse Correlates of Post-Traumatic Stress Disorder among School-Age Autistic Boys. International journal of environmental research and public health. 2021; 18(10).

Young people with autism are often bullied at school, a potential direct correlate of Post-Traumatic Stress Disorder (PTSD). This may be compounded by their difficulties in social interaction. Alternately, some of these young people may develop ‘coping strategies’ against bullying that may have an inverse association with PTSD. As a vulnerable population for PTSD, a sample of 71 young males with autism were surveyed for their self-reported experiences of being bullied at school, their coping strategies for dealing with this bullying, and their own evaluations of the severity of two of the key diagnostic criteria for PTSD. Their mothers also provided a rating of the severity of the three major diagnostic criteria for autism for these boys. Over 80% of this sample had been bullied, and there was a significant direct correlation between this and PTSD score, and between their mother-rated severity of the boys’ social interaction difficulties, but also a significant inverse correlation between their coping strategies and PTSD score. There were differences in these relationships according to whether the boys attended elementary or secondary school. These findings hold implications for the identification, assessment and support of autistic youth at risk of PTSD.

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8. Block G, Jannati A, Maynard TR, Pascual-Leone A, O’Connor MG. Personality in Autism Spectrum Disorder: Associations With Face Memory Deficit and Theory of Mind. Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology. 2021; 34(2): 117-28.

OBJECTIVE: To examine the personality profiles of adults with autism spectrum disorder (ASD) using a standard personality assessment and to investigate the association between personality, ASD-related face memory deficit (FMD), and theory of mind (ToM). In a broader context, to examine whether there are distinct clinical phenotypes in the ASD population that have implications for personality development and treatment. METHOD: Fifty-five adults with ASD and 22 neurotypical (NT) adults underwent a battery of neuropsychological tests, including measures of personality, face memory, and ToM. We compared ASD and NT groups in terms of their Personality Assessment Inventory (PAI) profiles. Additional analyses focused on the association between specific PAI scales and FMD. Performance on the Eyes Test was compared across groups and was examined in relation to FMD. RESULTS: Adults with ASD demonstrated significant elevations on several PAI scales compared with NT adults. The presence of FMD was associated with differing PAI profiles among the ASD adults. The ASD adults with FMD scored significantly higher on scales that are sensitive to positive impression management and treatment rejection and significantly lower on scales that are sensitive to borderline personality, anxiety, depression, schizophrenia, and stress. There was a significant association between performance on the Eyes Test and FMD in the ASD group. CONCLUSION: Adults with ASD have a unique personality profile. Further, ASD adults with FMD have reduced insight into their difficulties with emotional processing and may not be as sensitive as ASD adults without FMD to the emotions of others.

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9. Constantino JN. Response to « A Radical Change in Our Autism Research Strategy is Needed: Back to Prototypes » by Mottron et al. (2021). Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2221-3.

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10. Contalbrigo L, Borgi M, De Santis M, Collacchi B, Tuozzi A, Toson M, Redaelli V, Odore R, Vercelli C, Stefani A, Luzi F, Valle E, Cirulli F. Equine-Assisted Interventions (EAIs) for Children with Autism Spectrum Disorders (ASD): Behavioural and Physiological Indices of Stress in Domestic Horses (Equus caballus) during Riding Sessions. Animals : an open access journal from MDPI. 2021; 11(6).

Equine-assisted interventions (EAIs) are well-known complementary practices combining physical activity with emotional/cognitive stimulation. They are especially suited for children with autism spectrum disorders (ASD) who need a high degree of physical and psychological enrichment. Even though EAIs have become a common practice, stress responses in horses interacting with individuals that can manifest inappropriate behaviours, such as ASD children, have not been thoroughly investigated. Our multicentre study aimed to investigate behavioural and physiological indices of stress in horses involved in EAI standardised sessions with children with ASD compared to typically developing (TD) children. A controlled within-subject design with repeated measurements involving 19 horses and 38 children was adopted. Stress-related behaviours, heart rate, heart rate variability, and eye temperature were recorded during the riding sessions. Moreover, blood samples were collected from horses before and after each session to monitor changes in blood adrenocorticotropic hormone (ACTH), cortisol, and catecholamines. Results indicate that, in general, stress responses in horses involved in EAIs did not differ as a function of the horse being ridden by children with ASD or TD. A lower sympathetic tone in horses involved in ASD sessions was found, while in the mounting and dismounting phases, horses displayed behavioural signs of stress, independently from children’s behaviour. We conclude that professionals working in EAI should increase their awareness of animal welfare and refine riding practices, taking into account horse’s needs.

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11. Couderc S, Cousson-Gélie F, Pernon E, Porro B, Miot S, Baghdadli A. Burnout among direct support workers of adults with autism spectrum disorder and intellectual disability. Scandinavian journal of caring sciences. 2021.

BACKGROUND: Direct support workers (DSWs) accompany adults with autism spectrum disorder (ASD) and intellectual disability (ID) in residential care homes. Such DSWs, without specialised ASD training, are exposed to chronic stress linked to supporting ASD-ID clients and must adjust by coping strategies adapted to the needs of the residents. Nevertheless, difficulties adjusting constitute a burnout risk for DSWs, characterised by high levels of emotional exhaustion, depersonalisation and loss of a sense of personal accomplishment. We aimed to describe the burnout of DSWs who support adults with ASD-ID and to identify personal variables (experience and specialised training for ASD) and transactional variables (perceived stress and coping strategies) that could predict and mediate burnout. METHOD: In total, 125 DSWs accompanying ASD-ID adults on a daily basis were included. Each participant answered four questionnaires measuring burnout, sociodemographic and professional variables, coping strategies and perceived stress. RESULTS: Five per cent of DSWs were in a state of burnout. Eighteen, six and fifty-nine per cent showed high average scores of emotional exhaustion, depersonalisation and loss of a sense of personal accomplishment, respectively. Being older, specialised training in ASD, stress perceived as a challenge and problem-focused coping strategies were associated with low levels of depersonalisation and loss of a sense of personal accomplishment. CONCLUSIONS: Understanding the burnout process of ASD-ID DSWs may require the assessment of the organisational characteristics linked to the quality of life of the DSWs and the recognition of their specific needs when facing difficulties. The necessary ASD-focused training and support depends on an appraisal that would be individualised to adult ASD-ID DSWs.

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12. Damiani S, Guiot C, Nola M, Donadeo A, Bassetti N, Brondino N, Politi P. Two Faces of a Coin? A Systematic Review of Source Monitoring and Its Relationship with Memory in Autism. Brain sciences. 2021; 11(5).

The ability to discriminate the origin of stimuli, known as source monitoring, is crucial for self-other distinction and the integration of internally generated and externally generated experiences. Despite its valence, evidence on source monitoring in autism is yet scarce and unclear. We systematically reviewed literature concerning source monitoring in autism and its relationship with other constructs, such as memory type, encoding effects, social cognition, general intelligence, and clinical factors. Source-monitoring performance (operationalized as error or accuracy) was reduced in autistic participants in 9 of the 15 studies that met the inclusion criteria. When explicitly investigated, free-recall memory impairments in autism were shown to influence source monitoring deficits. General intelligence was another important factor linked to source-monitoring performance. Conversely, other memory types or encoding effects were not impaired in autism, and no univocal association could be found with source monitoring. Social cognition and clinical symptoms were rarely assessed in spite of their possible involvement in source monitoring. The heterogeneity of the task design, outcome measures and demographical factors limited study comparability. As a research framework on source monitoring as a construct of primary interest in autism is still lacking, we propose preliminary indications for future investigations based on the collected findings.

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13. Della Vecchia S, Milone R, Cagiano R, Calderoni S, Santocchi E, Pasquariello R, Battini R, Muratori F. Focusing on Autism Spectrum Disorder in Xia-Gibbs Syndrome: Description of a Female with High Functioning Autism and Literature Review. Children (Basel, Switzerland). 2021; 8(6).

BACKGROUND: Xia-Gibbs syndrome (XGS) is a rare disorder caused by de novo mutations in the AT-Hook DNA binding motif Containing 1 (AHDC1) gene, which is characterised by a wide spectrum of clinical manifestations, including global developmental delay, intellectual disability, structural abnormalities of the brain, global hypotonia, feeding problems, sleep difficulties and apnoea, facial dysmorphisms, and short stature. METHODS: Here, we report on a girl patient who shows a peculiar cognitive and behavioural profile including high-functioning autism spectrum disorder (ASD) without intellectual disability and provide information on her developmental trajectory with the aim of expanding knowledge of the XGS clinical spectrum. On the basis of the current clinical case and the literature review, we also attempt to deepen understanding of behavioural and psychiatric manifestations associated with XGS. RESULTS: In addition to the patient we described, a considerable rate of individuals with XGS display autistic symptoms or have been diagnosed with an autistic spectrum disorder. Moreover, the analysis of the few psychopathological profiles of patients with XGS described in the literature shows a frequent presence of aggressive and self-injurious behaviours that could be either an expression of autistic functioning or an additional symptom of the ASD evolution. A careful investigation of the abovementioned symptoms is therefore required, since they could represent a « red flag » for ASD.

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14. Dell’Osso L, Cremone IM, Amatori G, Cappelli A, Cuomo A, Barlati S, Massimetti G, Vita A, Fagiolini A, Carmassi C, Carpita B. Investigating the Relationship between Autistic Traits, Ruminative Thinking, and Suicidality in a Clinical Sample of Subjects with Bipolar Disorder and Borderline Personality Disorder. Brain sciences. 2021; 11(5).

(1) Background: Previous literature reported in both subjects with Borderline personality disorder (BPD) and Bipolar disorder (BD) higher levels of autistic traits, linked to a greater suicidality risk. The aim of this study was to evaluate and compare the presence of autistic traits in a sample of individuals with BD or BPD, with a specific focus on suicidality. (2) Methods: We recruited two clinical samples of subjects (BPD and BD) and a control group without a diagnosis according to DSM-5 (CTL). Subjects were assessed with the AdAS Spectrum, the RRS and, for evaluating suicidality, the MOODS-SR. (3) Results: The CTL group showed significantly lower scores of both BD and BPD on AdAS Spectrum, RRS, and suicidality scores. BPD subjects showed significantly lower scores than BD ones in most of AdAS Spectrum domain scores. Correlation and regression analyses highlighted specific patterns of association among AdAS Spectrum domains, RRS, and suicidality in each clinical group. (4) Conclusions: Both BPD and BD individuals show greater levels of autistic traits, which seem to be distributed in a continuum featuring the highest levels among BD subjects. In both disorders, higher autistic traits were linked to suicidal tendencies, although with different patterns of association between BD and BPD subjects.

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15. Di Giorgio E, Polli R, Lunghi M, Murgia A. Impact of the COVID-19 Italian Lockdown on the Physiological and Psychological Well-Being of Children with Fragile X Syndrome and Their Families. International journal of environmental research and public health. 2021; 18(11).

On 10 March 2020, in Italy, a total lockdown was put in place to limit viral transmission of COVID-19 infection as much as possible. Research on the psychological impact of the COVID-19 pandemic highlighted detrimental effects in children and their parents. However, little is known about such effects in children with neurodevelopment disorders and their caregivers. The present study investigated how the lockdown has impacted the physiological and psychological well-being of children with Fragile X-Syndrome (FXS), aged from 2 to 16 years, and their mothers. In an online survey, 48 mothers of FXS children reported their perception of self-efficacy as caregivers and, at the same time, their children’s sleep habits, behavioral and emotional difficulties during, and retrospectively, before the lockdown. Results showed a general worsening of sleep quality, and increasing behavioral problems. Although mothers reported a reduction in external support, their perception of self-efficacy as caregivers did not change during the home confinement compared to the period before. Overall, the present study suggested that specific interventions to manage sleep problems, as well as specific therapeutic and social support for increasing children and mother psychological well-being, need to be in place to mitigate the long-term effects of a lockdown.

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16. Dionne O, Corbin F. An « Omic » Overview of Fragile X Syndrome. Biology. 2021; 10(5).

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

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17. Frolli A, Bosco A, Di Carmine F, Cavallaro A, Lombardi A, Sergi L, Corrivetti G, Ricci MC. Parent Training and Therapy in Children with Autism. Pediatric reports. 2021; 13(2): 216-26.

With the introduction of the Diagnostic and Statistical Manual of Mental Disorders-5th ed. (DSM-5) autism spectrum disorders (ASD) fall into the category of neurodevelopmental disorders. ASD is characterized by the inhibitory mechanisms responsible for social adaptation and emotional expression being underdeveloped, causing a child’s recognition and understanding of emotions to be impaired. Our study hypothesizes that early intervention using behavioral interventions such as Applied Behavior Analysis (ABA) and reflexive functions (RF) training on parents can improve the development of joint attention (JA), a cognitive precursor to the theory of mind (ToM) and mentalization processes. We considered a sample of 84 children aged between 20 and 30 months who had received a diagnosis of risk of autism spectrum disorder (level 1). The sample was divided into two groups of 42 subjects, in the first group we carried out a weekly behavioral parent training (PT) based only on ABA principles, while in the second group we carried out a weekly PT aimed at improving reflective functions and parental awareness according to a model inspired by the model based on emotional mirroring and mentalization of Fonagy. Our study shows that parents who are able to make sense of both their own mental state and that of their child can serve as a protective factor for the child’s development even in atypical developmental situations such as in ASD.

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18. Gardner-Hoag J, Novack M, Parlett-Pelleriti C, Stevens E, Dixon D, Linstead E. Unsupervised Machine Learning for Identifying Challenging Behavior Profiles to Explore Cluster-Based Treatment Efficacy in Children With Autism Spectrum Disorder: Retrospective Data Analysis Study. JMIR medical informatics. 2021; 9(6): e27793.

BACKGROUND: Challenging behaviors are prevalent among individuals with autism spectrum disorder; however, research exploring the impact of challenging behaviors on treatment response is lacking. OBJECTIVE: The purpose of this study was to identify types of autism spectrum disorder based on engagement in different challenging behaviors and evaluate differences in treatment response between groups. METHODS: Retrospective data on challenging behaviors and treatment progress for 854 children with autism spectrum disorder were analyzed. Participants were clustered based on 8 observed challenging behaviors using k means, and multiple linear regression was performed to test interactions between skill mastery and treatment hours, cluster assignment, and gender. RESULTS: Seven clusters were identified, which demonstrated a single dominant challenging behavior. For some clusters, significant differences in treatment response were found. Specifically, a cluster characterized by low levels of stereotypy was found to have significantly higher levels of skill mastery than clusters characterized by self-injurious behavior and aggression (P<.003). CONCLUSIONS: These findings have implications on the treatment of individuals with autism spectrum disorder. Self-injurious behavior and aggression were prevalent among participants with the worst treatment response, thus interventions targeting these challenging behaviors may be worth prioritizing. Furthermore, the use of unsupervised machine learning models to identify types of autism spectrum disorder shows promise.

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19. Gillberg C. Response to Mottron. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2228-9.

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20. Grossi E, Caminada E, Goffredo M, Vescovo B, Castrignano T, Piscitelli D, Valagussa G, Franceschini M, Vanzulli F. Patterns of Restricted and Repetitive Behaviors in Autism Spectrum Disorders: A Cross-Sectional Video Recording Study. Preliminary Report. Brain sciences. 2021; 11(6).

BACKGROUND: Several instruments have been proposed to investigate restricted, repetitive behaviors (RRBs) in individuals with Autism Spectrum Disorder (ASD). Systematic video observations may overcome questionnaire and interview limitations to investigate RRBs. This study aimed to analyze stereotypic patterns through video recordings and to determine the correlation between the number and appearance of RRBs to ASD severity. METHODS: Twenty health professionals wearing a body cam recorded 780 specific RRBs during everyday activities of 67 individuals with ASD (mean age: 14.2 ± 3.72 years) for three months. Each stereotypy was classified according to its complexity pattern (i.e., simple or complex) based on body parts and sensory channels involved. RESULTS: The RRBs spectrum for each subject ranged from one to 33 different patterns (mean: 11.6 ± 6.82). Individuals with a lower number of stereotypies shown a lower ASD severity compared to subjects with a higher number of stereotypies (p = 0.044). No significant differences were observed between individuals exhibiting simple (n = 40) and complex patterns (n = 27) of stereotypies on ASD severity, age, sex, and the number of stereotypes. CONCLUSIONS: This study represents the first attempt to systematically document expression patterns of RRBs with a data-driven approach. This may provide a better understanding of the pathophysiology and management of RRBs.

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21. Haegele JA, Maher AJ. Male autistic youth experiences of belonging in integrated physical education. Autism : the international journal of research and practice. 2022; 26(1): 51-61.

Recent years have seen calls to amplify the voices of autistic people in research about their subjective experiences. Despite this, we know little about how autistic youth experience integrated physical education, particularly in the United States. The term integrated is used to describe a setting in which all students, regardless of educational needs, are educated in the same physical space. In this study, we sought to explore the perspectives of autistic youth toward their experiences in integrated physical education, and the roles of social interactions and relationships with peers in those experiences. Findings noted that several factors influenced the ways and extent to which our participants interacted with their peers during physical education. Unfortunately, most of our participants recalled experiencing bullying, and that physical education offered an environment where bullying was most frequent and comparatively unique compared to other contexts throughout the school day. The locker room, a space linked to physical education, was of particular concern because of a lack of teacher presence. Despite the negative views of and experiences in physical education, there was evidence of participants actively pursuing to connect with peers in this context. However, most instances where participants recalled pursuing friendship were not welcomed from others, which stunted their sense of belonging in this space. Given the role that belonging plays in what it means « to be included, » our research supports emerging ideas that even though autistic students were educated in the same physical spaces as their non-autistic peers, feelings of inclusion were largely absent.

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22. Haify SN, Buijsen RAM, Verwegen L, Severijnen L, de Boer H, Boumeester V, Monshouwer R, Yang WY, Cameron MD, Willemsen R, Disney MD, Hukema RK. Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation. Human molecular genetics. 2021; 30(17): 1632-48.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected. FXTAS is caused by a CGG-repeat expansion (CGGexp) in the fragile X mental retardation 1 (FMR1) gene. CGGexp RNA is translated into the FMRpolyG protein by a mechanism called RAN translation. Although both gene and pathogenic trigger are known, no therapeutic interventions are available at this moment. Here, we present, for the first time, primary hippocampal neurons derived from the ubiquitous inducible mouse model which is used as a screening tool for targeted interventions. A promising candidate is the repeat binding, RAN translation blocking, small molecule 1a. Small molecule 1a shields the disease-causing CGGexp from being translated into the toxic FMRpolyG protein. Primary hippocampal neurons formed FMRpolyG-positive inclusions, and upon treatment with 1a, the numbers of FMRpolyG-positive inclusions are reduced. We also describe for the first time the formation of FMRpolyG-positive inclusions in the liver of this mouse model. Treatment with 1a reduced the insoluble FMRpolyG protein fraction in the liver but not the number of inclusions. Moreover, 1a treatment had a reducing effect on the number of Rad23b-positive inclusions and insoluble Rad23b protein levels. These data suggest that targeted small molecule therapy is effective in an FXTAS mouse model and has the potential to treat CGGexp-mediated diseases, including FXTAS.

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23. Hollocks MJ, Meiser-Stedman R, Kent R, Lukito S, Briskman J, Stringer D, Lord C, Pickles A, Baird G, Charman T, Simonoff E. The association of adverse life events and parental mental health with emotional and behavioral outcomes in young adults with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1724-35.

People with autism spectrum disorder (ASD) are at increased risk of developing co-occurring mental health difficulties across the lifespan. Exposure to adverse life events and parental mental health difficulties are known risk factors for developing a range of mental health difficulties. This study investigates the association of adverse life events, parental stress and mental health with emotional and behavioral problems in young adults with ASD. One hundred and fifteen young adults with ASD derived from a population-based longitudinal study were assessed at three time-points (12-, 16-, and 23-year) on questionnaire measures of emotional and behavioral problems. Parent-reported exposure to adverse life events and parental stress/mental health were measured at age 23. We used structural equation modeling to investigate the stability of emotional and behavioral problems over time, and the association between adverse life events and parental stress and mental health and emotional and behavioral outcomes at 23-year. Our results indicate that exposure to adverse life events was significantly associated with increased emotional and behavioral problems in young adults with ASD, while controlling for symptoms in childhood and adolescence. Higher reported parental stress and mental health difficulties were associated with a higher frequency of behavioral, but not emotional problems, and did not mediate the impact of adverse life events. These results suggest that child and adolescent emotional and behavioral problems, exposure to life events and parent stress and mental health are independently associated, to differing degrees, with emotional or behavioral outcomes in early adulthood. LAY SUMMARY: People with autism experience high rates of mental health difficulties throughout childhood and into adult life. Adverse life events and parental stress and mental health may contribute to poor mental health in adulthood. We used data at three time points (12-, 16-, and 23-year) to understand how these factors relate to symptoms at 23-year. We found that emotional and behavioral problems in childhood, adverse life events and parent mental health were all associated with increased emotional and behavioral problems in adulthood.

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24. Huang CC, Kang LJ. Participation in Play and Leisure Activities of Young Children with Autism Spectrum Disorder and Typically Developing Children in Taiwan: A Preliminary Study. International journal of environmental research and public health. 2021; 18(11).

Participation in enjoyable activities is essential for the health and development of young children with and without disabilities. For preschool children with autism spectrum disorder (ASD), there is limited knowledge regarding their participation in play, learning, recreation, and social activities. This was a preliminary study that compares the participation between children 2-6 years of age with ASD (n = 25) and age- and sex-matched typically developing (TD) (n = 25) children. The Chinese version of the Assessment of Preschool Children’s Participation (APCP-C) measures participation in play, skill development, active physical recreation, and social activities. Parents of the children in this study completed the APCP-C by structured interview. The results showed that children with ASD had lower participation diversity and intensity than TD children in play activities. A lower percentage of children participating in individual activity was found for children with ASD than TD children in most APCP-C activities. Professionals that serve young children with special needs are encouraged to partner with parents to provide playful and socially enhancing activities for preschool children with ASD.

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25. Kadlaskar G, Bergmann S, McNally Keehn R, Seidl A, Keehn B. Equivalent Behavioral Facilitation to Tactile Cues in Children with Autism Spectrum Disorder. Brain sciences. 2021; 11(5).

The alerting network, a subcomponent of attention, enables humans to respond to novel information. Children with ASD have shown equivalent alerting in response to visual and/or auditory stimuli compared to typically developing (TD) children. However, it is unclear whether children with ASD and TD show equivalent alerting to tactile stimuli. We examined (1) whether tactile cues affect accuracy and reaction times in children with ASD and TD, (2) whether the duration between touch-cues and auditory targets impacts performance, and (3) whether behavioral responses in the tactile cueing task are associated with ASD symptomatology. Six- to 12-year-olds with ASD and TD participated in a tactile-cueing task and were instructed to respond with a button press to a target sound /a/. Tactile cues were presented at 200, 400, and 800 ms (25% each) prior to the auditory target. The remaining trials (25%) were presented without tactile cues. Findings suggested that both groups showed equivalent alerting responses to tactile cues. Additionally, all children were faster to respond to auditory targets at longer cue-target intervals. Finally, there was an association between rate of facilitation and RRB scores in all children, suggesting that patterns of responding to transient phasic cues may be related to ASD symptomatology.

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26. Karpur A, Vasudevan V, Lello A, Frazier TW, Shih A. Food insecurity in the households of children with autism spectrum disorders and intellectual disabilities in the United States: Analysis of the National Survey of Children’s Health Data 2016-2018. Autism : the international journal of research and practice. 2021; 25(8): 2400-11.

Families of children with autism spectrum disorder are more likely to experience financial strain and resulting food insecurity due to additional cost of care, disparate access to needed services, and loss of income resulting from parental job loss. Utilizing nationally representative data, this analysis indicates that the families of children with autism spectrum disorder and co-occurring intellectual disabilities are twice as likely to experience food insecurity than families of children without disabilities after adjusting for various factors. Several factors, ranging from state-level policies such as Medicaid expansion to individual-level factors such as higher utilization of emergency room services, were associated with the higher prevalence of food insecurity in families of children with autism spectrum disorder and co-occurring intellectual disabilities. Implications of these findings on programs and policies supporting families in the COVID-19 pandemic are discussed.

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27. Kartawy M, Khaliulin I, Amal H. Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder. Brain sciences. 2021; 11(6).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the ASD mouse model based on the Shank3 mutation. The energy supply to the brain mostly relies on oxidative phosphorylation in the mitochondria. Recent studies show that mitochondrial dysfunction and oxidative stress are involved in ASD pathology. In this work, we performed SNO proteomics analysis of cortical tissues of the Shank3 mouse model of ASD with the focus on mitochondrial proteins and processes. The study was based on the SNOTRAP technology followed by systems biology analysis. This work revealed that 63 mitochondrial proteins were S-nitrosylated and that several mitochondria-related processes, including those associated with oxidative phosphorylation, oxidative stress, and apoptosis, were enriched. This study implies that aberrant SNO signaling induced by the Shank3 mutation can target a wide range of mitochondria-related proteins and processes that may contribute to the ASD pathology. It is the first study to investigate the role of NO-dependent mitochondrial functions in ASD.

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28. Kong XJ, Liu J, Liu K, Koh M, Sherman H, Liu S, Tian R, Sukijthamapan P, Wang J, Fong M, Xu L, Clairmont C, Jeong MS, Li A, Lopes M, Hagan V, Dutton T, Chan SP, Lee H, Kendall A, Kwong K, Song Y. Probiotic and Oxytocin Combination Therapy in Patients with Autism Spectrum Disorder: A Randomized, Double-Blinded, Placebo-Controlled Pilot Trial. Nutrients. 2021; 13(5).

Autism spectrum disorder (ASD) is a rapidly growing neurodevelopmental disorder. Both probiotics and oxytocin were reported to have therapeutic potential; however, the combination therapy has not yet been studied. We conducted a randomized, double-blinded, placebo-controlled, 2-stage pilot trial in 35 individuals with ASD aged 3-20 years (median = 10.30 years). Subjects were randomly assigned to receive daily Lactobacillus plantarum PS128 probiotic (6 × 10(10) CFUs) or a placebo for 28 weeks; starting on week 16, both groups received oxytocin. The primary outcomes measure socio-behavioral severity using the Social Responsiveness Scale (SRS) and Aberrant Behavior Checklist (ABC). The secondary outcomes include measures of the Clinical Global Impression (CGI) scale, fecal microbiome, blood serum inflammatory markers, and oxytocin. All outcomes were compared between the two groups at baseline, 16 weeks, and 28 weeks into treatment. We observed improvements in ABC and SRS scores and significant improvements in CGI-improvement between those receiving probiotics and oxytocin combination therapy compared to those receiving placebo (p < 0.05). A significant number of favorable gut microbiome network hubs were also identified after combination therapy (p < 0.05). The favorable social cognition response of the combination regimen is highly correlated with the abundance of the Eubacterium hallii group. Our findings suggest synergic effects between probiotics PS128 and oxytocin in ASD patients, although further investigation is warranted.

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29. Kurokawa S, Nomura K, Miyaho K, Sanada K, Iwamoto C, Naraoka M, Yoneda S, Tomizawa Y, Sawae Y, Iwanaga R, Mimura M, Kishimoto T. Gastrointestinal symptoms and sensory abnormalities associated with behavioral problems in children with neurodevelopmental disorders. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1996-2001.

Behavioral problems directly affect the quality of life of caregivers and children with autism spectrum disorder (ASD) and/or attention-deficit/hyperactivity disorder (ADHD), and is known to be associated with clinical factors such as gastrointestinal (GI) symptoms, sensory abnormalities, intellectual abilities, and use of medication. However, previous studies have not considered these relationships comprehensively. We conducted a cross-sectional study of 6-12-year-old children with diagnoses of ASD and/or ADHD at two hospitals in Japan. Scores for the aberrant behavior checklist (ABC), autism-spectrum quotient (AQ), and Conners 3, as well as information on daily sleep and exercise, GI symptoms, and Short Sensory Profile, were collected. Each factor was subjected to a correlation analysis to investigate its effect on ABC scores. A stepwise multiple linear regression analysis for the factors with p < 0.05 was performed. Data were obtained from 60 patients with a mean age of 8.3 years; 21 had ASD alone, 18 had ADHD alone, and 21 had ASD + ADHD. The correlation analyses identified six factors associated with ABC severity: (a) methylphenidate use, (b) Conners hyperactivity score, (c) Conners inattention score, (d) AQ score, (e) SSP score, and (f) GI symptom score. The multiple regression showed that "GI symptoms" and "sensory abnormalities" were independently associated with ABC severity. Although further studies are needed to show a causal relationship, appropriate assessment of GI symptoms and sensory abnormalities may help alleviate some problematic behaviors and improve the quality of life of children with neurodevelopmental disorders and their families. LAY SUMMARY: Behavioral problems in children with neurodevelopmental disorders are known to be associated with many factors. This study aimed to comprehensively investigate the known factors. We have discovered that "gastrointestinal symptoms" and "sensory abnormalities" were independently associated with Behavioral problems. Our results suggest that it is important for clinicians and caregivers to pay more attention to children's GI symptoms and sensory abnormalities that may not present as obvious symptoms or complaints.

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30. Leyser M, Marques FJP, Nascimento O. POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2021; 40: e2020415.

OBJECTIVE: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. DATA: sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. DATA: synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. CONCLUSIONS: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains. Publisher: Abstract available from the publisher. por.

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31. Liu TL, Hsiao RC, Chou WJ, Yen CF. Social Anxiety in Victimization and Perpetration of Cyberbullying and Traditional Bullying in Adolescents with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. International journal of environmental research and public health. 2021; 18(11).

Victimization and perpetration of cyberbullying and traditional bullying are prevalent among adolescents with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The aims of this study were to examine the role of social anxiety in victimization and perpetration of cyberbullying and traditional bullying in adolescents with ASD and ADHD in Taiwan. A total of 219 adolescents with ASD and 287 adolescents with ADHD aged 11-18 years and their caregivers were recruited from the child psychiatry outpatient clinics into this study. The associations of social anxiety with victimization and perpetration of cyberbullying and traditional bullying were examined using logistic regression analysis. The results indicated that after the effects of sex, age, and autistic social impairment were controlled, social anxiety increased the risk of being a victim of cyberbullying (Odds Ratios (OR) = 1.048; 95% Confidence Interval (CI): 1.013-1.084), a victim of traditional bullying (OR = 1.066; 95% CI: 1.036-1.097), and a perpetrator of traditional bullying (OR = 1.061; 95% CI: 1.027-1.096) in adolescents with ASD. After the effects of sex, age, and ADHD symptoms were controlled for, social anxiety increased the risk of being a victim of traditional bullying in adolescents with ADHD (OR = 1.067; 95% CI: 1.039-1.096). Social anxiety was significantly associated with several forms of bullying involvement in adolescents with ASD and ADHD and warrants being considered into prevention and intervention programs for bullying involvement.

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32. Lombardo MV. Prototyping as subtyping strategy for studying heterogeneity in autism. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2224-7.

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33. López-Valverde P, Rico-Díaz J, Barcala-Furelos M, Martí-González M, Martín JL, López-García S. Instruments to Assess Physical Activity in Primary Education Students with Autism Spectrum Disorder: A Systematic Review. International journal of environmental research and public health. 2021; 18(9).

The scientific evidence supports that physical inactivity in childhood is a reality throughout the world which generates important consequences in the global development of children. Young people with Autism Spectrum Disorder (ASD), due to the characteristics of the disorder they suffer, constitute a group at risk. Therefore, assessing the levels of physical activity (PA) in this group is fundamental for subsequent decision making and implementation of PA promotion programmes. Consequently, the aim of this systematic review was to identify, summarise and analyse the main instruments used to assess the levels of PA (in terms of time and/or intensity) in primary school children diagnosed with ASD. Scientific articles in English and Spanish published in five databases were reviewed: PsycINFO, WOS, SPORTDiscus, Scopus and PubMed, following the guidelines of the PRISMA statement. Out of the 605 articles identified, 12 met the previously established inclusion criteria. The instruments used by the studies analysed were divided into two main groups: accelerometers and questionnaires. Both showed different strengths and limitations but agreed on the low levels registered of PA in children with ASD. For this reason, it is considered necessary that further research be carried out in this field, as well as the development and implementation of sports programmes adjusted and adapted to the needs and characteristics of the ASD group.

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34. Mammarella IC. Editorial: Time to Recognize Nonverbal Learning Disability to Foster Advances in Its Research. Journal of the American Academy of Child and Adolescent Psychiatry. 2022; 61(2): 120-1.

The definitions of most of the currently recognized neurodevelopmental disorders and the criteria used to identify them have seen important changes since their inclusion in diagnostic classification systems (see, for instance, how the definitions of specific learning disorders and autism spectrum disorder (ASD) have been revised in successive versions of DSM). As is the case with many other mental conditions, our understanding of neurodevelopmental disorders is continuously being updated in the light of new research findings. However, this has not been the case for nonverbal learning disability. More than 50 years since it was first described,(1) there is still no consensus on the merits of identifying it as a separate disorder or using a clear and acknowledged diagnostic label. Instead of trying to establish why nonverbal learning disability has yet to be included in the diagnostic manuals, this editorial examines why recognized criteria for the condition would improve research in this field and avoid the negative consequences of continuing to conduct research without adopting shared criteria.

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35. Matthews NL, Christenson K, Kiefer S, Smith CJ. A mixed-methods examination of the gap between intelligence and adaptive functioning in autistic young adults without intellectual disability. Autism : the international journal of research and practice. 2021; 25(8): 2317-30.

Adaptive functioning describes the age-appropriate skills necessary for independent living. Research suggests that autistic children, adolescents, and adults who do not have an intellectual disability demonstrate adaptive functioning challenges relative to their intellectual ability. Thus, even though many of these individuals have the intellectual capacity to excel in mainstream educational and vocational settings, their adaptive functioning challenges may serve as an obstacle to independence. The research on adaptive functioning in autistic adults is focused on statistical analysis of standardized assessments (e.g. parent-report on multiple choice questionnaires). Qualitative research that examines the narratives of young adults and their parents is needed to better understand adaptive functioning in young adults and their resulting service needs. This study combined statistical analysis of standardized assessments with qualitative analysis of interview responses from autistic young adults without intellectual disability and their parents. Findings replicated previous reports of adaptive functioning challenges and identified influences on adaptive functioning development, consequences of independence, and service needs. Taken together, findings indicate the need for interventions and services that facilitate adaptive functioning development in autistic adolescents and young adults and provide insight into potential intervention targets and strategies.

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36. Mottron L. A radical change in our autism research strategy is needed: Back to prototypes. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2213-20.

The evolution of autism diagnosis, from its discovery to its current delineation using standardized instruments, has been paralleled by a steady increase in its prevalence and heterogeneity. In clinical settings, the diagnosis of autism is now too vague to specify the type of support required by the concerned individuals. In research, the inclusion of individuals categorically defined by over-inclusive, polythetic criteria in autism cohorts results in a population whose heterogeneity runs contrary to the advancement of scientific progress. Investigating individuals sharing only a trivial resemblance produces a large-scale type-2 error (not finding differences between autistic and dominant population) rather than detecting mechanistic differences to explain their phenotypic divergences. The dimensional approach of autism proposed to cure the disease of its categorical diagnosis is plagued by the arbitrariness of the dimensions under study. Here, we argue that an emphasis on the reliability rather than specificity of diagnostic criteria and the misuse of diagnostic instruments, which ignore the recognition of a prototype, leads to confound autism with the entire range of neurodevelopmental conditions and personality variants. We propose centering research on cohorts in which individuals are selected based on their expert judged prototypicality to advance the theoretical and practical pervasive issues pertaining to autism diagnostic thresholds. Reversing the current research strategy by giving more weight to specificity than reliability should increase our ability to discover the mechanisms of autism. LAY SUMMARY: Scientific research into the causes of autism and its mechanisms is carried out on large cohorts of people who are less and less different from the general population. This historical trend may explain the poor harvest of results obtained. Services and intervention are provided according to a diagnosis that now encompasses extremely different individuals. Last, we accept as a biological reality the constant increase over the years in the proportion of autistic people among the general population. These drifts are made possible by the attribution of a diagnosis of autism to people who meet vague criteria, rather than to people who experienced clinicians recognize as autistic. We propose to change our research strategy by focusing on the study of the latter, fewer in number, but more representative of the « prototype » of autism. To do this, it is necessary to clearly distinguish the population on which the research is carried out from that to which we provide support. People must receive services according to their needs, and not according to the clarity of their diagnosis.

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37. Mottron L. Progress in autism research requires several recognition-definition-investigation cycles. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2230-4.

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38. Narzisi A, Sesso G, Berloffa S, Fantozzi P, Muccio R, Valente E, Viglione V, Villafranca A, Milone A, Masi G. Could You Give Me the Blue Brick? LEGO(®)-Based Therapy as a Social Development Program for Children with Autism Spectrum Disorder: A Systematic Review. Brain sciences. 2021; 11(6).

LEGO(®)-based therapy is a social skills development program aimed at children with autism spectrum disorder (ASD). A systematic review of the literature was conducted using PRISMA guidelines. PubMed, Scopus and Web of Science bibliographic databases were searched from their date of inception to August 2020. The review included 19 studies. Studies were classified according to experimental designs (e.g., Randomized Control Trial, Non-Randomized Studies of Interventions and case report and series) and a narrative synthesis of each was provided, along with a critical discussion of the strengths and weaknesses of the available literature on the topic. Although LEGO(®)-based therapy appears a promising treatment for social interaction in ASD, the findings of LEGO(®)-based therapy studies should be interpreted and generalized with caution, due to the low quality of the studies and the small sample sizes.

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39. Nolin SL, Napoli E, Flores A, Hagerman RJ, Giulivi C. Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene. International journal of molecular sciences. 2021; 22(11).

Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5′-UTR of the FMR1 gene are generally unstable, often expanding to a full mutation (>200) in one generation through maternal inheritance, leading to fragile X syndrome, a condition associated with autism and other intellectual disabilities. To uncover the early mechanisms of pathogenesis, we performed metabolomics and proteomics on amniotic fluids from PM carriers, pregnant with male fetuses, who had undergone amniocentesis for fragile X prenatal diagnosis. The prenatal metabolic footprint identified mitochondrial deficits, which were further validated by using internal and external cohorts. Deficits in the anaplerosis of the Krebs cycle were noted at the level of serine biosynthesis, which was confirmed by rescuing the mitochondrial dysfunction in the carriers’ umbilical cord fibroblasts using alpha-ketoglutarate precursors. Maternal administration of serine and its precursors has the potential to decrease the risk of developing energy shortages associated with mitochondrial dysfunction and linked comorbidities.

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40. Pandelache A, Francis D, Oertel R, Dickson R, Sachdev R, Ling L, Gamage D, Godler DE. Detection of Cryptic Fragile X Full Mutation Alleles by Southern Blot in a Female and Her Foetal DNA via Chorionic Villus Sampling, Complicated by Mosaicism for 45,X0/46,XX/47,XXX. Genes. 2021; 12(6).

We describe a female with a 72 CGG FMR1 premutation (PM) (CGG 55-199) and family history of fragile X syndrome (FXS), referred for prenatal testing. The proband had a high risk of having an affected pregnancy with a full mutation allele (FM) (CGG > 200), that causes FXS through hypermethylation of the FMR1 promoter. The CGG sizing analysis in this study used AmplideX triplet repeat primed polymerase chain reaction (TP-PCR) and long-range methylation sensitive PCR (mPCR). These methods detected a 73 CGG PM allele in the proband’s blood, and a 164 CGG PM allele in her male cultured chorionic villus sample (CVS). In contrast, the Southern blot analysis showed mosaicism for: (i) a PM (71 CGG) and an FM (285-768 CGG) in the proband’s blood, and (ii) a PM (165 CGG) and an FM (408-625 CGG) in the male CVS. The FMR1 methylation analysis, using an EpiTYPER system in the proband, showed levels in the range observed for mosaic Turner syndrome. This was confirmed by molecular and cytogenetic karyotyping, identifying 45,X0/46,XX/47,XXX lines. In conclusion, this case highlights the importance of Southern blot in pre- and postnatal testing for presence of an FM, which was not detected using AmplideX TP-PCR or mPCR in the proband and her CVS.

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41. Pereira AS, Azhari A, Hong CA, Gaskin GE, Borelli JL, Esposito G. Savouring as an Intervention to Decrease Negative Affect in Anxious Mothers of Children with Autism and Neurotypical Children. Brain sciences. 2021; 11(5).

Savouring is an emotion regulation strategy and intervention that focuses on the process of attending, intensifying and prolonging positive experiences and positive affect associated with these memories. Personal savouring involves a reflection on positive memories that are specific to the individual and do not involve others. In contrast, relational savouring entails reflecting on instances when people were responsive to the needs of their significant others. Such interventions hold potential benefits in enhancing positive affect (PA) and reducing negative affect (NA) for both parents of children with autism spectrum disorder (ASD) and parents of neurotypical children. Adults with greater symptoms of generalised anxiety have been found to have less PA and more NA. However, no study has investigated the effects of a mother’s anxiety symptoms on the efficacy of savouring in enhancing PA and reducing NA. Thus, this paper combined personal and relational savouring to investigate whether savouring may enhance PA and reduce NA of a pooled sample of mothers of neurotypical children and mothers of children with ASD. 52 mothers of neurotypical children and 26 mothers of children with ASD aged 3-7 years old were given a series of questionnaires and randomly assigned to either relational savouring or personal savouring conditions. In relational savouring, mothers were asked to reflect upon a shared positive experience with their child while in the personal savouring condition, a personal positive experience was recalled. Across mothers of children with ASD and neurotypical children, findings suggest that savouring leads to a decrease in NA (p < 0.01) but not increases in PA. Similarly, mothers with higher levels of anxiety experience a greater decrease in NA (p < 0.001) compared to mothers with lower levels of anxiety post-savouring. This study proposes that a brief savouring intervention may be effective among mothers of preschoolers. As lower levels of negative affect is linked to healthier psychological well-being, mothers might be able to engage in more effective and warm parenting after savouring exercises, which would cultivate positive mother-child relationships that benefit their children in the long-term.

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42. Pushkarenko K, Causgrove Dunn J, Goodwin DL. Physical Literacy for Children Labeled With Autism Spectrum Disorder: Mothers’ Experiences of Ableism, Exclusion, and Trauma. Adapted physical activity quarterly : APAQ. 2021; 38(4): 525-45.

Countering the declining physical activity patterns of children labeled with autism spectrum disorder (ASD) has gained considerable research attention given its impact on health and quality of life. The purpose of this study was to explore how parents of children labeled with ASD understand the concept of physical literacy, based on their children’s participation in community-based physical activity programs. Using interpretive phenomenological analysis, six mothers of children labeled with ASD participated in one-on-one semistructured interviews. The conceptual framework of ecological systems theory supported the rationale for the study purpose, provided structure for the interview guide, and offered a reflexive context for interpretation. Four themes were generated from the thematic analysis: From embodied movement to normative skill expectations, Be flexible, not rigid, Systematic exclusion, and Valuable? . . . Absolutely! Despite experiences of marginalization, exclusion, and trauma within physical activity programs, mothers valued physical literacy development for their children given the positive outcomes of increasing family connections, engagement with peers, and enhanced wellness.

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43. Rosello R, Berenguer C, Martinez-Raga J, Miranda A, Cortese S. Subgroups of Children with Autism Spectrum Disorder without Intellectual Disability: A Longitudinal Examination of Executive and Socio-Adaptive Behaviors in Adolescence. Journal of clinical medicine. 2021; 10(10).

Within the autistic spectrum, there is remarkable variability in the etiology, presentation, and treatment response. This prospective study was designed to identify, through cluster analysis, subgroups of individuals with ASD without intellectual disability (ID) based on the severity of the core symptoms in childhood. The secondary aim was to explore whether these subgroups and a group with typical development (TD) differ in cognitive, adaptive, and social aspects measured in adolescence. The sample at baseline was comprised of 52 children with ASD without ID and 37 children with TD, aged 7-11. Among the ASD group, three clusters were identified. Cluster 1 (40%), ‘high severity’, presented high symptom severity on the DSM-5 criteria and the Social Communication Questionnaire. Cluster 2 (34%) showed ‘moderate severity’ on most of the scores. Cluster 3 (25%) corresponded to ‘low severity’, showing moderate social impairment and low restrictive, repetitive patterns of behavior, interests and activities. At 5-year follow-up, 45 adolescents with ASD without ID and 27 adolescents with TD were assessed. All clusters had significantly more difficulties in EF, ToM, socialization and adaptive behavior compared to TD. Social and adaptive trajectories between the ASD subgroups were relatively different; Cluster 3 showed poorer socialization and daily living skills than the other two subgroups. These findings highlight the importance of fully assessing social, cognitive, and adaptive profiles to develop care plans tailored to specific needs.

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44. Rossignol DA, Frye RE. A Systematic Review and Meta-Analysis of Immunoglobulin G Abnormalities and the Therapeutic Use of Intravenous Immunoglobulins (IVIG) in Autism Spectrum Disorder. Journal of personalized medicine. 2021; 11(6).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 2% of children in the United States. Growing evidence suggests that immune dysregulation is associated with ASD. One immunomodulatory treatment that has been studied in ASD is intravenous immunoglobulins (IVIG). This systematic review and meta-analysis examined the studies which assessed immunoglobulin G (IgG) concentrations and the therapeutic use of IVIG for individuals with ASD. Twelve studies that examined IgG levels suggested abnormalities in total IgG and IgG 4 subclass concentrations, with concentrations in these IgGs related to aberrant behavior and social impairments, respectively. Meta-analysis supported possible subsets of children with ASD with low total IgG and elevated IgG 4 subclass but also found significant variability among studies. A total of 27 publications reported treating individuals with ASD using IVIG, including four prospective, controlled studies (one was a double-blind, placebo-controlled study); six prospective, uncontrolled studies; 2 retrospective, controlled studies; and 15 retrospective, uncontrolled studies. In some studies, clinical improvements were observed in communication, irritability, hyperactivity, cognition, attention, social interaction, eye contact, echolalia, speech, response to commands, drowsiness, decreased activity and in some cases, the complete resolution of ASD symptoms. Several studies reported some loss of these improvements when IVIG was stopped. Meta-analysis combining the aberrant behavior checklist outcome from two studies demonstrated that IVIG treatment was significantly associated with improvements in total aberrant behavior and irritability (with large effect sizes), and hyperactivity and social withdrawal (with medium effect sizes). Several studies reported improvements in pro-inflammatory cytokines (including TNF-alpha). Six studies reported improvements in seizures with IVIG (including patients with refractory seizures), with one study reporting a worsening of seizures when IVIG was stopped. Other studies demonstrated improvements in recurrent infections, appetite, weight gain, neuropathy, dysautonomia, and gastrointestinal symptoms. Adverse events were generally limited but included headaches, vomiting, worsening behaviors, anxiety, fever, nausea, fatigue, and rash. Many studies were limited by the lack of standardized objective outcome measures. IVIG is a promising and potentially effective treatment for symptoms in individuals with ASD; further research is needed to provide solid evidence of efficacy and determine the subset of children with ASD who may best respond to this treatment as well as to investigate biomarkers which might help identify responsive candidates.

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45. Russell MJ, Michael Scott CW, Murias K, Ben Gibbard W, Cui X, Tough S, Zwicker JD. Cross-ministry data on service use and limitations faced by children in special education. Disability and health journal. 2021; 14(4): 101118.

BACKGROUND: Children with disabilities often face limitations that cross support sectors. OBJECTIVE: Our aim was to measure cross-ministry service use, outcomes, and functional limitations faced by children who qualified for special education. METHODS: We used longitudinal British Columbia ministry data linked to children (0-18y) registered in K-12 education. Children were grouped by special education funding (most to least; Level 1, Level 2, Level 3, Unfunded, and no special education), and related to 1) service use patterns, 2) the age they first used disability services, and 3) functional limitations reported in health visits. We also reported how length of special education use related to disability service use. RESULTS: Of 111,274 children, 154(0.1%) were Level 1, 4427(4.0%) Level 2, 2897(2.6%) Level 3, 13472(12.1%) Unfunded, and 90324(81.2%) not in special education. Children with higher funding levels, compared to lower levels of funding, generally were more likely to experience poorer outcomes, have functional limitations, have service needs, and receive early support. One exception was children with serious behavioral/mental health special education coding, which had poorer outcomes for their level of funding. Children received child disability supports early (about half of users started by 4y), but use was mostly limited to those with many years (9+years) of funded special education (70.7% of the all users) and biased to certain special education codes (i.e., Level 1, severe intellectual disability, and autism). CONCLUSIONS: This study provides evidence of the long-term, diverse needs of children in special education and may be used to inform decisions surrounding their support.

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46. Rynkiewicz A, Szura M, Bernaciak D, Kozak A, Karwowska M. Polish Adaptation of the Social Communication Questionnaire (SCQ) and Female Autism Phenotype: An Investigation of Potentially Sex-Biased Items in the Screening Assessment and Their Impact on Scores. Brain sciences. 2021; 11(6).

Standardized screening assessments and sex differences in autism spectrum disorder (ASD) are still under-explored in Poland. This study investigated the differences between Polish ASD females and males based on the responses provided by parents/caregivers to a Polish adaptation of the Social Communication Questionnaire, SCQ Lifetime and SCQ Current. The study included 90 ASD participants from Mental Health Services and Autism Clinics in Poland with no intellectual disability and no profound communication difficulties. Parents provided information on the SCQ items which were compared under three domains of the Autism Diagnostic Interview-Revised (ADI-R). Four SCQ items with the examples were investigated. No significant differences were found between the two sexes in the three domains. The repetitive use of objects declined with age in ASD males. Although the findings of the present study did not reveal substantial gender biases in the Polish adaptation of the SCQ, it is necessary to take into account potential gender differences in the clinical presentation of ASD and in the adaptation of screening and diagnostic tools.

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47. Samadi SA. The Challenges of Bringing Up a Child with Autism Spectrum Disorders: Editorial for Brain Sciences Special Issue « Connections between Parental Involvement and Treatment of Children with Autism Spectrum Disorders (ASD) ». Brain sciences. 2021; 11(5).

There is no unique scientific method to guide parents in bringing up a child with autism spectrum disorders (ASD) […].

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48. Serrada-Tejeda S, Santos-Del-Riego S, May-Benson TA, Pérez-de-Heredia-Torres M. Influence of Ideational Praxis on the Development of Play and Adaptive Behavior of Children with Autism Spectrum Disorder: A Comparative Analysis. International journal of environmental research and public health. 2021; 18(11).

BACKGROUND: Traditionally, assessment of praxis skills in children with ASD has focused on the evaluation of aspects related to the planning and execution of actions. This study aimed to evaluate the ideational abilities of children with ASD and analyze possible relationships with the development of play and adaptive behaviors. METHODS: 40 children between 4 to 6 years (TD = 20; ASD = 20) were evaluated with the Test of Ideational Praxis, the Revised Knox Preschool Play Scale, and the Adaptive Behavior Assessment System II. RESULTS: Statistically significant relationships were obtained between ideational praxis and play skills development (r = 0.649; p = 0.01), adaptive leisure behavior (r = 0.338; p = 0.04) and social adaptive behavior (r = 0.319; p = 0.04). Results of multiple linear regression models found a linear relationship between ideational praxis and play development (p = 0.005) and adaptive leisure skills (p = 0.004), but not with social interaction skills (p > 0.05). CONCLUSIONS: Objective evaluation with a specific ideational praxis assessment facilitates understanding of the ideational abilities and widens understanding of praxis skills and their impact on play and adaptive behaviors in children with ASD.

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49. Shi C, Xin X, Zhang J. Domain Adaptation Using a Three-Way Decision Improves the Identification of Autism Patients from Multisite fMRI Data. Brain sciences. 2021; 11(5).

Machine learning methods are widely used in autism spectrum disorder (ASD) diagnosis. Due to the lack of labelled ASD data, multisite data are often pooled together to expand the sample size. However, the heterogeneity that exists among different sites leads to the degeneration of machine learning models. Herein, the three-way decision theory was introduced into unsupervised domain adaptation in the first time, and applied to optimize the pseudolabel of the target domain/site from functional magnetic resonance imaging (fMRI) features related to ASD patients. The experimental results using multisite fMRI data show that our method not only narrows the gap of the sample distribution among domains but is also superior to the state-of-the-art domain adaptation methods in ASD recognition. Specifically, the ASD recognition accuracy of the proposed method is improved on all the six tasks, by 70.80%, 75.41%, 69.91%, 72.13%, 71.01% and 68.85%, respectively, compared with the existing methods.

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50. Siddiqui UA, Ullah F, Iqbal A, Khan A, Ullah R, Paracha S, Shahzad H, Kwak KS. Wearable-Sensors-Based Platform for Gesture Recognition of Autism Spectrum Disorder Children Using Machine Learning Algorithms. Sensors (Basel, Switzerland). 2021; 21(10).

Autistic people face many challenges in various aspects of daily life such as social skills, repetitive behaviors, speech, and verbal communication. They feel hesitant to talk with others. The signs of autism vary from one individual to another, with a range from mild to severe. Autistic children use fewer communicative gestures compared with typically developing children (TD). With time, the parents may learn their gestures and understand what is occurring in their child’s mind. However, it is difficult for other people to understand their gestures. In this paper, we propose a wearable-sensors-based platform to recognize autistic gestures using various classification techniques. The proposed system defines, monitors, and classifies the gestures of the individuals. We propose using wearable sensors that transmit their data using a Bluetooth interface to a data acquisition and classification server. A dataset of 24 gestures is created by 10 autistic children performing each gesture about 10 times. Time- and frequency-domain features are extracted from the sensors’ data, which are classified using k-nearest neighbor (KNN), decision tree, neural network, and random forest models. The main objective of this work is to develop a wearable-sensor-based IoT platform for gesture recognition in children with autism spectrum disorder (ASD). We achieve an accuracy of about 91% with most of the classifiers using dataset cross-validation and leave-one-person-out cross-validation.

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51. Skafle I, Gabarron E, Dechsling A, Nordahl-Hansen A. Online Attitudes and Information-Seeking Behavior on Autism, Asperger Syndrome, and Greta Thunberg. International journal of environmental research and public health. 2021; 18(9).

The purpose of this study was to examine Internet trends data and sentiment in tweets mentioning autism, Asperger syndrome, and Greta Thunberg during 2019. We used mixed methods in analyzing sentiment and attitudes in viral tweets and collected 1074 viral tweets on autism that were published in 2019 (tweets that got more than 100 likes). The sample from Twitter was compared with search patterns on Google. In 2019, Asperger syndrome was closely connected to Greta Thunberg, as of the tweets specifically mentioning Asperger (from the total sample of viral tweets mentioning autism), 83% also mentioned Thunberg. In the sample of tweets about Thunberg, the positive sentiment expressed that Greta Thunberg was a role model, whereas the tweets that expressed the most negativity used her diagnosis against her and could be considered as cyberbullying. The Google Trends data also showed that Thunberg was closely connected to search patterns on Asperger syndrome in 2019. The study showed that being open about health information while being an active participant in controversial debates might be used against you but also help break stigmas and stereotypes.

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52. Smirnov K, Stroganova T, Molholm S, Sysoeva O. Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies. International journal of molecular sciences. 2021; 22(10).

Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.

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53. Solazzo S, Kojovic N, Robain F, Schaer M. Measuring the Emergence of Specific Abilities in Young Children with Autism Spectrum Disorders: The Example of Early Hyperlexic Traits. Brain sciences. 2021; 11(6).

The presence of a restricted interest in written materials, including an early ability to name and recognize letters and numbers, is regularly reported in preschoolers with autism spectrum disorders (ASDs). There is, however, scarce information on this early ability akin to emerging hyperlexic traits in preschoolers with ASD younger than 3 years old. Here, we defined a measure of early naming and recognition of letters and numbers in 155 preschoolers with ASD using a sliding window approach combined with a 90th percentile threshold criterion, and subsequently compared the profiles of children with ASD with and without early hyperlexic traits. Using this measure, we found that 9% of children with ASD showed early hyperlexic traits. The early ability to name and recognize letters and numbers was associated with a higher level of restricted and repetitive behaviors yet more social-oriented behaviors at baseline and with better expressive and written communication at baseline and one year later. This study contributes to a better definition of the profile of children with ASD with an early ability in letters and numbers akin to emerging hyperlexic traits, a skill that is associated with promising social strengths and language abilities in this subgroup of children.

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54. Sousa AF, Claro ML, Rondó PHC. SCREENING FOR NEUROPSYCHOMOTOR AND SOCIAL-EMOTIONAL DEVELOPMENT IN CHILDREN UNDER 24 MONTHS OF AGE IN THE BRAZILIAN SEMI-ARID REGION. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2021; 40: e2020172.

OBJECTIVE: To screen children under 24 months of age for neuropsychomotor and social-emotional development in a municipality of the Brazilian semi-arid region, using the Survey of Well-Being of Young Children (SWYC) scale. METHODS: This is a quantitative cross-sectional study with a non-probabilistic sample, involving children aged 1 to 24 months and their respective mothers, recruited from primary care services in the municipality of Picos, Piauí, Northeastern Brazil. The screening for neuropsychomotor and social-emotional development using the SWYC scale also provided information about the family context. In addition, we administered a questionnaire to assess the children’s demographic and socioeconomic factors. Descriptive data analysis was performed. RESULTS: The sample consisted mostly of adult mothers (84.0%), with more than 8 years of schooling (83.3%), belonging to the C, D, and E socioeconomic classes (75.3%). The prevalence of suspected cases of delayed neuropsychomotor development and social-emotional changes was 12.7 and 42.2%, respectively. CONCLUSIONS: The results point to the existence of children at risk of delayed development, particularly in the social-emotional domain, reaffirming the need to adopt child development screening as a health service routine, with the implementation of appropriate intervention programs. Publisher: Abstract available from the publisher. por.

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55. Szymona B, Maciejewski M, Karpiński R, Jonak K, Radzikowska-Büchner E, Niderla K, Prokopiak A. Robot-Assisted Autism Therapy (RAAT). Criteria and Types of Experiments Using Anthropomorphic and Zoomorphic Robots. Review of the Research. Sensors (Basel, Switzerland). 2021; 21(11).

Supporting the development of a child with autism is a multi-profile therapeutic work on disturbed areas, especially understanding and linguistic expression used in social communication and development of social contacts. Previous studies show that it is possible to perform some therapy using a robot. This article is a synthesis review of the literature on research with the use of robots in the therapy of children with the diagnosis of early childhood autism. The review includes scientific journals from 2005-2021. Using descriptors: ASD (Autism Spectrum Disorders), Social robots, and Robot-based interventions, an analysis of available research in PubMed, Scopus and Web of Science was done. The results showed that a robot seems to be a great tool that encourages contact and involvement in joint activities. The review of the literature indicates the potential value of the use of robots in the therapy of people with autism as a facilitator in social contacts. Robot-Assisted Autism Therapy (RAAT) can encourage child to talk or do exercises. In the second aspect (prompting during a conversation), a robot encourages eye contact and suggests possible answers, e.g., during free conversation with a peer. In the third aspect (teaching, entertainment), the robot could play with autistic children in games supporting the development of joint attention. These types of games stimulate the development of motor skills and orientation in the body schema. In future work, a validation test would be desirable to check whether children with ASD are able to do the same with a real person by learning distrust and cheating the robot.

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56. Tisato V, Silva JA, Longo G, Gallo I, Singh AV, Milani D, Gemmati D. Genetics and Epigenetics of One-Carbon Metabolism Pathway in Autism Spectrum Disorder: A Sex-Specific Brain Epigenome?. Genes. 2021; 12(5).

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. From a genetic and epigenetic side, several candidate genes have been reported as potentially linked to ASD, which can be detected in about 10-25% of patients. Folate gene polymorphisms have been previously associated with other psychiatric and neurodegenerative diseases, mainly focused on gene variants in the DHFR gene (5q14.1; rs70991108, 19bp ins/del), MTHFR gene (1p36.22; rs1801133, C677T and rs1801131, A1298C), and CBS gene (21q22.3; rs876657421, 844ins68). Of note, their roles have been scarcely investigated from a sex/gender viewpoint, though ASD is characterized by a strong sex gap in onset-risk and progression. The aim of the present review is to point out the molecular mechanisms related to intracellular folate recycling affecting in turn remethylation and transsulfuration pathways having potential effects on ASD. Brain epigenome during fetal life necessarily reflects the sex-dependent different imprint of the genome-environment interactions which effects are difficult to decrypt. We here will focus on the DHFR, MTHFR and CBS gene-triad by dissecting their roles in a sex-oriented view, primarily to bring new perspectives in ASD epigenetics.

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57. Töpf A, Pyle A, Griffin H, Matalonga L, Schon K, Sickmann A, Schara-Schmidt U, Hentschel A, Chinnery PF, Kölbel H, Roos A, Horvath R. Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1). European journal of human genetics : EJHG. 2021; 29(9): 1348-53.

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism.

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58. Trifonova EA, Klimenko AI, Mustafin ZS, Lashin SA, Kochetov AV. Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?. International journal of molecular sciences. 2021; 22(10).

Autism spectrum disorder (ASD) is characterized by uncommon genetic heterogeneity and a high heritability concurrently. Most autoimmune disorders (AID), similarly to ASD, are characterized by impressive genetic heterogeneity and heritability. We conducted gene-set analyses and revealed that 584 out of 992 genes (59%) included in a new release of the SFARI Gene database and 439 out of 871 AID-associated genes (50%) could be attributed to one of four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, and 4. vitamin D3-sensitive genes. With the exception of FMRP targets, which are obviously associated with the direct involvement of local translation disturbance in the pathological mechanisms of ASD, the remaining categories are represented among AID genes in a very similar percentage as among ASD predisposition genes. Thus, mTOR signaling pathway genes make up 4% of ASD and 3% of AID genes, mTOR-modulated genes-31% of both ASD and AID genes, and vitamin D-sensitive genes-20% of ASD and 23% of AID genes. The network analysis revealed 3124 interactions between 528 out of 729 AID genes for the 0.7 cutoff, so the great majority (up to 67%) of AID genes are related to the mTOR signaling pathway directly or indirectly. Our present research and available published data allow us to hypothesize that both a certain part of ASD and AID comprise a connected set of disorders sharing a common aberrant pathway (mTOR signaling) rather than a vast set of different disorders. Furthermore, an immune subtype of the autism spectrum might be a specific type of autoimmune disorder with an early manifestation of a unique set of predominantly behavioral symptoms.

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59. Valverde-Esteve T, Salvador-Garcia C, Gil-Gómez J, Maravé-Vivas M. Sustainable Service-Learning in Physical Education Teacher Education: Examining Postural Control to Promote ASD Children’s Well-Being. International journal of environmental research and public health. 2021; 18(10).

As classrooms become more and more diverse, it is imperative to provide physical education teacher education (PETE) students with opportunities to develop competencies that promote quality education for all students. In this study, PETE students applied a physical education service-learning (SL) program aimed at enhancing Autism Spectrum Disorder (ASD) children’s motor domain and general well-being-objectives that are connected to the third focus of the United Nations’ Sustainable Development Goals (SDGs). Traditionally, research on SL has focused on students’ outcomes, and there is a call to examine SL’s effects on service receivers, which is the gap this paper aspires to fill. The aim of this study was to measure the postural control of children with ASD who were involved in a 6-month SL program in comparison to ASD peers in a control group. A quasi-experimental design was used in which a total of 29 children with ASD participated. The results of the experimental group showed a significant improvement in the vestibular pathways, an improvement trend in the somatosensorial and visual pathways and improvements in the dynamic tests. This study provides valuable feedback about how SL programs can benefit ASD children to improve their postural control, thus contributing to the third SDG concerned with well-being promotion.

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60. Westmark CJ. Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome. Nutrients. 2021; 13(6).

Breastfeeding is associated with numerous health benefits, but early life nutrition has not been specifically studied in the neurodevelopmental disorder fragile X syndrome (FXS). Herein, I evaluate associations between the consumption of breast milk during infancy and the prevalence of autism, allergies, diabetes, gastrointestinal (GI) problems and seizures in FXS. The study design was a retrospective survey of families enrolled in the Fragile X Online Registry and Accessible Research Database (FORWARD). There was a 1.7-fold reduction in the prevalence of autism in FXS participants who were fed breast milk for 12 months or longer. There were strong negative correlations between increased time the infant was fed breast milk and the prevalence of autism and seizures and moderate negative correlations with the prevalence of GI problems and allergies. However, participants reporting GI problems or allergies commenced these comorbidities significantly earlier than those not fed breast milk. Parsing the data by sex indicated that males exclusively fed breast milk exhibited decreased prevalence of GI problems and allergies. These data suggest that long-term or exclusive use of breast milk is associated with reduced prevalence of key comorbidities in FXS, although breast milk is associated with the earlier development of GI problems and allergies.

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61. Wu Y, Cui N, Xing H, Zhong W, Arrowood C, Johnson CM, Jiang C. In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model. Journal of cellular physiology. 2021; 236(12): 8082-98.

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents.

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62. Yang S, Liu Z, Xiong X, Cai K, Zhu L, Dong X, Wang J, Zhu H, Shi Y, Chen A. Effects of Mini-Basketball Training Program on Social Communication Impairment and Executive Control Network in Preschool Children with Autism Spectrum Disorder. International journal of environmental research and public health. 2021; 18(10).

This study evaluated the effect of a 12-week mini-basketball training program (MBTP) on social communication (SC) and the executive control network (ECN) in preschool children with autism spectrum disorders (ASD). We finally assigned 30 preschool children with ASD to an experiment group (n = 15, 12 males, 3 females) or a control group (n = 15, 13 males, 2 females). The experiment group participated in a 12-week MBTP (40-min sessions per day, 5 days a week), while the control group only received the institutional routine behavioral rehabilitation intervention. The SC of preschool children with ASD was measured using the Social Responsiveness Scale, Second Edition (SRS-2), whereas functional connectivity (FC) of the ECN was assessed using resting-state functional magnetic resonance imaging (rs-fMRI) at pre-and post-test. Our results showed that SC exhibited significant improvement in the intervention group, especially in SRS-2 total score, social cognition, and social communication. We found significantly enhanced functional connectivity between the right cerebellum and left inferior frontal gyrus in the experimental group, while functional connectivity between the left middle temporal gyrus and right cerebellum were decreased in the control group. Furthermore, there were no significant correlations between the change in SC scores and FC of the ECN. Altogether, this study provides valuable insights that a 12-week MBTP improves SC and functional connectivity of the ECN in preschool children with ASD. We further inferred that neural mechanisms might be associated with changing the ECN of preschool ASD children caused by the 12-week MBTP.

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63. Ye J, Wang H, Cui L, Chu S, Chen N. The progress of chemokines and chemokine receptors in autism spectrum disorders. Brain research bulletin. 2021; 174: 268-80.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders and the main symptoms of ASD are impairments in social communication and abnormal behavioral patterns. Studies have shown that immune dysfunction and neuroinflammation play a key role in ASD patients and experimental models. Chemokines are groups of small proteins that regulate cell migration and mediate inflammation responses via binding to chemokine receptors. Thus, chemokines/chemokine receptors may be involved in neurodevelopmental disorders and associated with ASD. In this review, we summarize the research progress of chemokine aberrations in ASD and also review the recent progress of clinical treatment of ASD and pharmacological research related to chemokines/chemokine receptors. This review highlights the possible connection between chemokines/chemokine receptors and ASD, and provides novel potential targets for drug discovery of ASD.

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64. Yoon J, Mao Y. Dissecting Molecular Genetic Mechanisms of 1q21.1 CNV in Neuropsychiatric Disorders. International journal of molecular sciences. 2021; 22(11).

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.

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