1. Arslanoglu E, Cine N, Kara KA, Yılmaz AA, Tomrukcu F, Bicer M, Tuncer E, Yavuz Y, Ceyran H. Temperate approach to ASD closure in pulmonary arterial hypertension: the fenestrated patch technique. Cardiology in the young. 2021; 31(12): 1953-7.

The most common CHD in the adult patient population is an atrial septal defect due to its asymptomatic nature in early life. However, when diagnosis and treatment are delayed, pulmonary arterial hypertension may develop as a long-term complication, sometimes before adulthood. The presence of PAH adversely affects the results of surgical treatment and may even eliminate the feasibility of surgery in some patients. In such patients who have high pulmonary artery pressure and pulmonary vascular resistance at the margin of inoperability, the response to the acute vasoreactivity test determines the treatment modality.In our retrospective study, a total of 906 patients who underwent ASD closure between January, 2011 and November, 2020, seven of which had undergone the fenestrated patch procedure after they were identified to have high PAP, but positive AVT test response were included. Short-term follow-up of patients with fenestrated ASD patches revealed decreased pulmonary pressure, regression in NYHA classification, and improvement in symptoms.The fenestrated patch technique should be kept in mind as an option to expand the surgical spectrum in the treatment of patients with high pulmonary pressures, where complete closure is risky. It appears that the fenestrated patch technique is a safe approach in the management of pulmonary hypertension in patients with ASD who have pulmonary hypertension, according to short- and midterm follow-up findings.

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2. Buddell T, Quinn CC. An autism-associated calcium channel variant causes defects in neuronal polarity in the ALM neuron of C. elegans. microPublication biology. 2021; 2021.

Variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including bipolar disorder, schizophrenia, and ADHD. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. In our previous work, we demonstrated that an egl-19(gof) mutation, which is equivalent to the Timothy syndrome mutation in CACNA1C, can disrupt termination of the PLM axon in C. elegans. Here, we report a novel phenotype for the egl-19(gof) mutation, whereby it causes the growth of an ectopic process from the ALM cell body. We also extend our previous results to show that the egl-19(gof) mutation causes axon termination defects not only in the PLM axon, but also in the ALM axon. These results suggest that the Timothy syndrome mutation can disrupt multiple steps of axon development. Further work exploring the molecular mechanisms that underlie these perturbations in neuronal polarity and axon termination will give us better understanding of how variants in CACNA1C contribute to the axonal defects that underlie autism.

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3. Deng PY, Klyachko VA. Channelopathies in fragile X syndrome. Nature reviews Neuroscience. 2021; 22(5): 275-89.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein-protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP-channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.

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4. E AC, Dounavi K, Ferguson J. Telehealth to train interventionists teaching functional living skills to children with autism spectrum disorder. Journal of applied behavior analysis. 2021; 54(2): 511-29.

The number of Board Certified Behavior Analysts® (BCBA®s) available outside of the United States is significantly lower than the number of individuals with a diagnosis of autism spectrum disorder (ASD) requiring services. Research on alternative delivery platforms, such as telehealth, to disseminate interventions to those in need is of paramount importance. The current study evaluated the effectiveness of training professionals working with individuals with ASD in behavior-analytic procedures through telehealth. Four professional-child dyads took part. Data were collected on the professionals’ treatment fidelity and number of independent steps performed by the children for 3 functional daily living skills. The study employed a multiple probe design across participants and included a cost analysis. All 4 professionals met the mastery criterion and all 4 children demonstrated increases in independence.

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5. Jurek L, Occelli P, Denis A, Amestoy A, Maffre T, Dauchez T, Oreve MJ, Baghdadli A, Schroder C, Jay A, Zelmar A, Revah-Levy A, Gallifet N, Aldred C, Garg S, Green J, Touzet S, Geoffray MM. Efficacy of parent-mediated communication-focused treatment in toddlers with autism (PACT) delivered via videoconferencing: a randomised controlled trial study protocol. BMJ open. 2021; 11(4): e044669.

INTRODUCTION: Intervention in the preschool period is currently recommended for autism spectrum disorder. Therapies delivered by parents are particularly suitable for young children. Preschool Autism Communication Trial (PACT) is a parent-mediated therapy that has shown a significant and sustained impact on autism symptom reduction. However, access to such evidence-based therapies for families is limited due to autism centres located in large urban areas. Using videoconferencing to deliver PACT training to parents may improve accessibility for families living in underserved areas. METHODS AND ANALYSIS: This single-blind randomised controlled trial, involving six sites in France, will investigate the efficacy of a telehealth, videoconferencing-based, parent-mediated PACT therapy on autism symptoms, over a 12-month period. It will compare PACT plus treatment as usual (TAU) against TAU only in a cohort of 238 toddlers (119 per group) aged 18-36 months at inclusion and living with their families more than 40 min away from the specialist centres for autism. Primary outcome will include change of overall autism score on the Autism Diagnostic Observation Scale (ADOS) at 12 months. Secondary outcomes will measure change in child skills, child functioning, impact on parents (stress, health, priorities) and implementation characteristics. Repeated measures analyses will be used to test the effect of PACT intervention on the overall ADOS module 1 score over the 12-month study period. Linear mixed models will be used with time, treatment allocation and the interaction between treatment and time as fixed effects and individual variation as random effect. ETHICS AND DISSEMINATION: This protocol (V.5, date: 25 October 2019) is approved by the French National Review Board (reference no 2018-A02516-49). The results will be disseminated via peer-reviewed journals TRIAL REGISTRATION NUMBER: NCT04244721.

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6. Kisbu-Sakarya Y, Doenyas C. Can school teachers’ willingness to teach ASD-inclusion classes be increased via special education training? Uncovering mediating mechanisms. Research in developmental disabilities. 2021; 113: 103941.

Changing teacher willingness to teach inclusive classes is critical in achieving optimal outcomes for students with autism spectrum disorder (ASD). The present study investigated the mechanisms underlying the effects of a teacher training in special education strategies for students with ASD on mainstream school teachers’ behavioral intentions toward inclusive education. Specifically, the role of attitudes and autism self-efficacy were explored as mediators in this process. The sample comprised 763 mainstream school teachers from eleven cities in Northeastern Turkey who participated in an intensive training that included special education strategies for students with ASD, evidence-based special education applications, and inclusive education practices. Statistical mediation analyses revealed that the training increased teachers’ willingness to teach inclusive classes and intention to implement special education techniques in the regular education classroom through increasing their autism self-efficacy. However, though attitudes toward inclusive education was a significant predictor of both willingness to teach inclusive classes and intent to use special education techniques, the training did not improve attitudes. Based on these findings, additional strategies or components to change attitudes toward inclusive education were recommended to be integrated into the teacher training programs on special education strategies for inclusive education.

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7. Lan Z, Xu S, Wu Y, Xia L, Hua K, Li M, Liu M, Yin Y, Li C, Huang S, Feng Y, Jiang G, Wang T. Alterations of Regional Homogeneity in Preschool Boys With Autism Spectrum Disorders. Frontiers in neuroscience. 2021; 15: 644543.

OBJECTIVES: The study was aimed at investigating the alterations of local spontaneous brain activity in preschool boys with autism spectrum disorders (ASD). METHODS: Based on regional homogeneity (ReHo), the acquired resting state functional magnetic resonance imaging (fMRI) data sets, which included 86 boys with ASD and 54 typically developing (TD) boys, were used to detect regional brain activity. Pearson correlation analysis was used to study the relationship between abnormal ReHo value and the Childhood Autism Rating Scale (CARS), Autism Behavior Checklist (ABC), developmental quotient, and age. RESULTS: In the ASD group, we found increased ReHo in the right calcarine as well as decreased ReHo in the opercular part of the left inferior frontal gyrus, the left middle temporal gyrus, the left angular gyrus, and the right medial orbital frontal cortex (p < 0.05, false discovery rate correction). We did not find a correlation between the results of brain regions and the CARS, ABC, and age. CONCLUSIONS: Our study found spontaneous activity changes in multiple brain regions, especially the visual and language-related areas of ASD, that may help to further understand the clinical characteristics of boys with ASD.

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8. Larner O, Roberts J, Twiss J, Freeman L. A Need for Consistency in Behavioral Phenotyping for ASD: Analysis of the Valproic Acid Model. Autism research and treatment. 2021; 2021: 8863256.

Autism spectrum disorder (ASD) is a highly prevalent and impairing neurodevelopmental disorder that affects 1 : 54 persons. Over the last several decades, the reported incidence of ASD in the US has increased potentially due to increased awareness and improved diagnostic measurement. Although ASD prevalence is increasing, the etiology of ASD remains relatively unknown. To better understand the neurological basis of ASD, rodent models of ASD have been developed for research. Currently, there is not a standardized set of behavioral tests to quantify ASD-like behavior in rodents. The goal of this review is to present an overview of the methodologies used to analyze ASD-like behaviors in rodents, focusing on the valproic acid (VPA) model, and illustrate inconsistencies between different approaches. Despite that the in utero VPA rodent model for ASD is widely used and extensively characterized, behaviors vary substantially between different researchers. Moving forward, consistency in behavioral method analytics would benefit progress in evaluating interventions for all models of ASD and help to uncover unique qualities underlying mechanisms causing ASD signs and symptoms.

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9. Lung FW, Shu BC. Two-stage window screening and development trajectories in early identification of autism spectrum disorder among Han Chinese children. BMC research notes. 2021; 14(1): 130.

OBJECTIVE: An understanding of the trajectory and norm of development in children is needed in order to understand the concept of the spectrum in the diagnosis of autism spectrum disorder (ASD). Children’s developmental growth trajectory was measured from six to 66 months in the Taiwan Birth Cohort Study dataset (N = 11,145). Additionally, over 4 years of follow-up, the negative predictive value of using the Parental Concern Checklist and Taiwan Birth Cohort Study Developmental Instrument was also investigated as the first stage of screening in a two-stage window screening method for ASD diagnosis. RESULTS: The growth trajectory showed that children’s language development began to increase at 18 months, and peaked at 36 months. On the other hand, social development showed steady growth from 18 to 66 months. The increase in the trajectory of children’s language development prior to age three, when compared with other developmental dimensions, may increase the difficulty of diagnosing ASD. The two-stage window screening method can be used in settings where the screening sample is large, such as in community or primary care settings, and has been found to be time- and cost-efficient. Better understanding of children’s developmental trajectory can enhance detection and intervention for ASD.

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10. McKinney A, Weisblatt EJ, Hotson KL, Bilal Ahmed Z, Dias C, BenShalom D, Foster J, Murphy S, Villar SS, Belmonte MK. Overcoming hurdles to intervention studies with autistic children with profound communication difficulties and their families. Autism : the international journal of research and practice. 2021; 25(6): 1627-39.

Autistic children who speak few or no words or who have an intellectual disability are the most in need of new understandings and treatments, but the most often left out of the research that can bring these benefits. Researchers perceive difficulties around compliance with instructions, testing, challenging behaviours and family stress. Although research with these children can indeed be difficult, their continuing exclusion is unethical and unacceptable. Drawing on our experiences testing a possible treatment for children with profound autism, we provide 10 practical guidelines related to (1) interacting physically, (2) combining play and testing, (3) responding to challenging behaviour, (4) finding suitable tests, (5) relationships with parents, (6) relationships with siblings, (7) involving stakeholders, (8) planning the testing times, (9) the role of the clinical supervisor and (10) recruiting and retaining participants. We hope that these guidelines will prepare and embolden other research teams to work with profoundly autistic children, ending their historical exclusion from research. These guidelines also could be useful for conducting research with children with intellectual disabilities.

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11. Meinke C, Quinlan MA, Paffenroth KC, Harrison FE, Fenollar-Ferrer C, Katamish RM, Stillman I, Ramamoorthy S, Blakely RD. Serotonin Transporter Ala276 Mouse: Novel Model to Assess the Neurochemical and Behavioral Impact of Thr276 Phosphorylation In Vivo. Neurochemical research. 2022; 47(1): 37-60.

The serotonin (5-HT) transporter (SERT) is a key regulator of 5-HT signaling and is a major target for antidepressants and psychostimulants. Human SERT coding variants have been identified in subjects with obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) that impact transporter phosphorylation, cell surface trafficking and/or conformational dynamics. Prior to an initial description of a novel mouse line expressing the non-phosphorylatable SERT substitution Thr276Ala, we review efforts made to elucidate the structure and conformational dynamics of SERT with a focus on research implicating phosphorylation at Thr276 as a determinant of SERT conformational dynamics. Using the high-resolution structure of human SERT in inward- and outward-open conformations, we explore the conformation dependence of SERT Thr276 exposure, with results suggesting that phosphorylation is likely restricted to an inward-open conformation, consistent with prior biochemical studies. Assessment of genotypes from SERT/Ala276 heterozygous matings revealed a deviation from Mendelian expectations, with reduced numbers of Ala276 offspring, though no genotype differences were seen in growth or physical appearance. Similarly, no genotype differences were evident in midbrain or hippocampal 5-HT levels, midbrain and hippocampal SERT mRNA or midbrain protein levels, nor in midbrain synaptosomal 5-HT uptake kinetics. Behaviorally, SERT Ala276 homozygotes appeared normal in measures of anxiety and antidepressant-sensitive stress coping behavior. However, these mice displayed sex-dependent alterations in repetitive and social interactions, consistent with circuit-dependent requirements for Thr276 phosphorylation underlying these behaviors. Our findings indicate the utility of SERT Ala276 mice in evaluation of developmental, functional and behavioral consequences of regulatory SERT phosphorylation in vivo.

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12. Mouga S, Castelhano J, Café C, Sousa D, Duque F, Oliveira G, Castelo-Branco M. Social Attention Deficits in Children With Autism Spectrum Disorder: Task Dependence of Objects vs. Faces Observation Bias. Frontiers in psychiatry. 2021; 12: 640599.

Social attention deficits represent a central impairment of patients suffering from autism spectrum disorder (ASD), but the nature of such deficits remains controversial. We compared visual attention regarding social (faces) vs. non-social stimuli (objects), in an ecological diagnostic context, in 46 children and adolescents divided in two groups: ASD (N = 23) and typical neurodevelopment (TD) (N = 23), matched for chronological age and intellectual performance. Eye-tracking measures of visual scanning, while exploring and describing scenes from three different tasks from the Autism Diagnostic Observation Schedule (ADOS), were analyzed: « Description of a Picture, » « Cartoons, » and « Telling a Story from a Book. » Our analyses revealed a three-way interaction between Group, Task, and Social vs. Object Stimuli. We found a striking main effect of group and a task dependence of attentional allocation: while the TD attended first and longer to faces, ASD participants became similar to TD when they were asked to look at pictures while telling a story. Our results suggest that social attention allocation is task dependent, raising the question whether spontaneous attention deficits can be rescued by guiding goal-directed actions.

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13. Norcia AM, Lee A, Meredith WJ, Kohler PJ, Pei F, Ghassan SA, Libove RA, Phillips JM, Hardan AY. A case-control study of visual, auditory and audio-visual sensory interactions in children with autism spectrum disorder. Journal of vision. 2021; 21(4): 5.

To assess the relative integrity of early visual and auditory processes in autism spectrum disorder (ASD), we used frequency-tagged visual and auditory stimulation and high-density electroencephalogram recordings of unimodal and dual-modality responses in a case-control design. To test for the specificity of effects on ASD, we recorded from a smaller group of children with attention-deficit hyperactivity disorder (ADHD). Horizontal 3 cycle per degree (cpd) gratings were presented at 5 Hz, and a random stream of /ba/, /da/, /ga/ syllables was presented at 6 Hz. Grating contrast response functions were measured unimodally and in the presence of a 64-dB auditory input. Auditory response functions were measured unimodally and in the presence of a 40% contrast grating. Children with ASD (n = 34) and ADHD (n = 13) showed a common lack of audio-visual interaction compared to typically developing children (n = 40) when measured at the first harmonic of the visual stimulus frequency. Both patient groups also showed depressed first harmonic responses at low contrast, but the ADHD group had consistently higher first-harmonic responses at high contrast. Children with ASD had a preferential loss of second-harmonic (transient) responses. The alteredtransient responses in ASD are likely to arise very early in the visual pathway and could thus have downstream consequences for many other visual mechanisms and processes. The alteration in audio-visual interaction could be a signature of a comorbid phenotype shared by ASD and ADHD, possibly due to alterations in attentional selection systems.

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14. Taylor MJ, Ronald A, Martin J, Lundström S, Hosang GM, Lichtenstein P. Examining the association between childhood autistic traits and adolescent hypomania: a longitudinal twin study. Psychological medicine. 2021: 1-10.

BACKGROUND: There is evidence that autism spectrum disorders (ASDs) co-occur with bipolar disorder (BD) relatively frequently. Individuals with BD often report symptoms of mania and hypomania during adolescence, prior to the age of onset for BD. It is unknown whether these symptoms are associated with ASDs. We examined whether diagnoses of ASDs and autistic traits were associated with hypomania in a large, population-based Swedish twin sample. METHODS: Parental structured interviews assessed autistic traits, and were used to assign screening diagnoses of ASDs, when twins were aged 9 or 12 (N = 13 533 pairs). Parents then completed questionnaires assessing hypomania when the twins were aged 15 and 18 (N = 3852 pairs at age 15, and 3013 pairs at age 18). After investigating the phenotypic associations between these measures, we used the classical twin design to test whether genetic and environmental influences on autistic traits influence variation in adolescent hypomania. RESULTS: Autistic traits and ASD diagnoses in childhood were associated with elevated scores on the measures of adolescent hypomania. Twin analyses indicated that 6-9% of the variance in hypomania was explained by genetic influences that were shared with autistic traits in childhood. When repeating these analyses for specific autistic trait domains, we found a stronger association between social interaction difficulties and hypomania than for other autistic trait domains. CONCLUSIONS: These results indicate a genetic link between autistic traits and hypomania in adolescence. This adds to the growing evidence base of genetic factors associated with ASDs showing links with psychiatric outcomes across childhood and into adulthood.

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15. Washington P, Tariq Q, Leblanc E, Chrisman B, Dunlap K, Kline A, Kalantarian H, Penev Y, Paskov K, Voss C, Stockham N, Varma M, Husic A, Kent J, Haber N, Winograd T, Wall DP. Crowdsourced privacy-preserved feature tagging of short home videos for machine learning ASD detection. Scientific reports. 2021; 11(1): 7620.

Standard medical diagnosis of mental health conditions requires licensed experts who are increasingly outnumbered by those at risk, limiting reach. We test the hypothesis that a trustworthy crowd of non-experts can efficiently annotate behavioral features needed for accurate machine learning detection of the common childhood developmental disorder Autism Spectrum Disorder (ASD) for children under 8 years old. We implement a novel process for identifying and certifying a trustworthy distributed workforce for video feature extraction, selecting a workforce of 102 workers from a pool of 1,107. Two previously validated ASD logistic regression classifiers, evaluated against parent-reported diagnoses, were used to assess the accuracy of the trusted crowd’s ratings of unstructured home videos. A representative balanced sample (N = 50 videos) of videos were evaluated with and without face box and pitch shift privacy alterations, with AUROC and AUPRC scores > 0.98. With both privacy-preserving modifications, sensitivity is preserved (96.0%) while maintaining specificity (80.0%) and accuracy (88.0%) at levels comparable to prior classification methods without alterations. We find that machine learning classification from features extracted by a certified nonexpert crowd achieves high performance for ASD detection from natural home videos of the child at risk and maintains high sensitivity when privacy-preserving mechanisms are applied. These results suggest that privacy-safeguarded crowdsourced analysis of short home videos can help enable rapid and mobile machine-learning detection of developmental delays in children.

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16. Watson L, Hanna P, Jones CJ. A systematic review of the experience of being a sibling of a child with an autism spectrum disorder. Clinical child psychology and psychiatry. 2021; 26(3): 734-49.

Difficulties associated with Autism Spectrum Disorders can cause considerable impact on personal, familial, social, educational and occupational functioning. Living with a child who has an Autism Spectrum Disorder can therefore pose a challenge to family members, including typically developing siblings. However, it is only in recent years that the experience of typically developing siblings has become a focal point. A systematic review using keywords across six databases was undertaken to summarise qualitative studies that focused on the experience of being a sibling of a child with an Autism Spectrum Disorder. Fifteen studies met inclusion criteria and a thematic synthesis was completed. The synthesis found that having a sibling who has an Autism Spectrum Disorder can impact typically developing sibling’s self-identity and personal development in a number of ways. Similarly, interactions with the sibling who has Autism Spectrum Disorders and with other individuals can evoke a myriad of experiences that can both benefit and challenge typically developing siblings. The ability of typically developing siblings to cope with adverse experiences needs to remain a focus. This synthesis concludes that further research is needed to identify which methods are the most effective in supporting typically developing siblings of children with Autism Spectrum Disorders.

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17. Zhao X, Shi W, Li X, Li W, Li C. Autistic traits and negative emotions in the general population during COVID-19: Mediating roles of the behavioural immune system and COVID-19 risk perception. Psychiatry research. 2021; 300: 113918.

Identifying the susceptibility factors of the emotional response to COVID-19 is highly significant for the psychological epidemic-crisis intervention, and autistic-related traits (ATs) is likely to be one of the candidate factors. The current study explored the relationships between ATs, emotional response to COVID-19, and the behavioural immune system (BIS) measured by trait pathogen avoidance and COVID-19 risk perception in the general population. The results showed that ATs predicted increased negative emotions directly and indirectly by enhancing the activation tendency of BIS and COVID-19 risk perception. The findings provide a candidate hypothesis for the reaction characteristics to pathogen threats in individuals with ASD and expand the understanding of individual differences in response to COVID-19.

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