1. Alotaibi N, Maharatna K. Classification of Autism Spectrum Disorder From EEG-Based Functional Brain Connectivity Analysis. Neural computation. 2021; 33(7): 1914-41.

Autism is a psychiatric condition that is typically diagnosed with behavioral assessment methods. Recent years have seen a rise in the number of children with autism. Since this could have serious health and socioeconomic consequences, it is imperative to investigate how to develop strategies for an early diagnosis that might pave the way to an adequate intervention. In this study, the phase-based functional brain connectivity derived from electroencephalogram (EEG) in a machine learning framework was used to classify the children with autism and typical children in an experimentally obtained data set of 12 autism spectrum disorder (ASD) and 12 typical children. Specifically, the functional brain connectivity networks have quantitatively been characterized by graph-theoretic parameters computed from three proposed approaches based on a standard phase-locking value, which were used as the features in a machine learning environment. Our study was successfully classified between two groups with approximately 95.8% accuracy, 100% sensitivity, and 92% specificity through the trial-averaged phase-locking value (PLV) approach and cubic support vector machine (SVM). This work has also shown that significant changes in functional brain connectivity in ASD children have been revealed at theta band using the aggregated graph-theoretic features. Therefore, the findings from this study offer insight into the potential use of functional brain connectivity as a tool for classifying ASD children.

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2. Asaoka H, Baba C, Fujimoto N, Kobayashi C, Noro F. Improving the Use of Deictic Verbs in Children with Autism Spectrum Disorder. Developmental neurorehabilitation. 2021; 24(8): 525-39.

Background: Children with autism spectrum disorder (ASD) show difficulty in comprehension and production of the deictic verbs « come/go. » Objective: To examine whether introducing conditions related to daily conversations into training would improve the use of deictic verbs. Methods: Six Japanese children with ASD participated. We set up multiple scenes where the questioner presented the sentence using « come/go » with/without deictic gestures, and children with ASD replied with « come/go. » The conditions such as spatial relations between the two parties (face-to-face or side-by-side) and presentations of the gestures (moving one’s arm toward or away from the body or moving one’s upper body forward/backward) were introduced. Results: The appropriate use of deictic verbs during training and in daily life situations among children with ASD increased. Conclusions: Training children with ASD to look in the direction indicated by the questioner and to synchronize their bodies with the questioner’s movements promotes their acquisition of deictic verbs.

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3. Batteux C, Azarine A, Karsenty C, Petit J, Ciobotaru V, Brenot P, Hascoet S. Sinus Venosus ASDs: Imaging and Percutaneous Closure. Current cardiology reports. 2021; 23(10): 138.

PURPOSE OF THE REVIEW: Percutaneous closure of sinus venosus atrial septal defects (ASD) using covered stent implantation is a new and promising minimally invasive technique. New imaging tools are used to ensure preoperative anatomical characterization and preoperative guidance, which are key procedural success factors. Here we will describe and analyze these recent developments. RECENT FINDINGS: Sinus venosus ASDs present a wide variety of anatomical features which must be described and analyzed using various imaging tools, including 3D technology. Percutaneous closure is challenging, but can hasten clinical recovery compared to the gold-standard conventional open-heart surgery. The feasibility of percutaneous closure relies on precise preoperative anatomical study and on real-time guidance using a multimodal fusion imaging process. Three-dimensional modeling of sinus venosus ASD is essential to understand the large anatomical panel encountered in this pathology. Multimodal fusion imaging guidance is very useful for performing sinus venosus ASD percutaneous closure in selected patients.

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4. Bauleo A, Montesanto A, Pace V, Brando R, De Stefano L, Puntorieri D, Cento L, Loddo S, Calacci C, Novelli A, Falcone E. Rare copy number variants in ASTN2 gene in patients with neurodevelopmental disorders. Psychiatric genetics. 2021; 31(6): 239-45.

INTRODUCTION: In humans the normal development of cortical regions depends on the complex interactions between a number of proteins that promote the migrations of neuronal precursors from germinal zones and assembly into neuronal laminae. ASTN2 is one of the proteins implicated in such a complex process. Recently it has been observed that ASTN2 also regulates the surface expression of multiple synaptic proteins resulting in a modulation of synaptic activity. Several rare copy number variants (CNVs) in ASTN2 gene were identified in patients with neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), attention deficit-hyperactivity disorders and intellectual disability. METHODS: By using comparative genomic hybridization array technology, we analyzed the genomic profiles of five patients of three unrelated families with NDDs. Clinical diagnosis of ASD was established according to the Statistical Manual of Mental Disorders, Fifth Edition (APA 2013) criteria. RESULTS: We identified new rare CNVs encompassing ASTN2 gene in three unrelated families with different clinical phenotypes of NDDs. In particular, we identified a deletion of about 70 Kb encompassing intron 19, a 186 Kb duplication encompassing the sequence between the 5′-end and the first intron of the gene and a 205 Kb deletion encompassing exons 6-11. CONCLUSION: The CNVs reported here involve regions not usually disrupted in patients with NDDs with two of them affecting only the expression of the long isoforms. Further studies will be needed to analyze the impact of these CNVs on gene expression regulation and to better understand their impact on the protein function.

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5. Byres LP, Mufteev M, Yuki KE, Wei W, Piekna A, Wilson MD, Rodrigues DC, Ellis J. Identification of TIA1 mRNA targets during human neuronal development. Molecular biology reports. 2021; 48(9): 6349-61.

BACKGROUND: Neuronal development is a tightly controlled process involving multi-layered regulatory mechanisms. While transcriptional pathways regulating neurodevelopment are well characterized, post-transcriptional programs are still poorly understood. TIA1 is an RNA-binding protein that can regulate splicing, stability, or translation of target mRNAs, and has been shown to play critical roles in stress response and neurodevelopment. However, the identity of mRNAs regulated by TIA1 during neurodevelopment under unstressed conditions is still unknown. METHODS AND RESULTS: To identify the mRNAs targeted by TIA1 during the first stages of human neurodevelopment, we performed RNA immunoprecipitation-sequencing (RIP-seq) on human embryonic stem cells (hESCs) and derived neural progenitor cells (NPCs), and cortical neurons under unstressed conditions. While there was no change in TIA1 protein levels, the number of TIA1 targeted mRNAs decreased from pluripotent cells to neurons. We identified 2400, 845, and 330 TIA1 mRNA targets in hESCs, NPC, and neurons, respectively. The vast majority of mRNA targets in hESC were genes associated with neurodevelopment and included autism spectrum disorder-risk genes that were not bound in neurons. Additionally, we found that most TIA1 mRNA targets have reduced ribosomal engagement levels. CONCLUSION: Our results reveal TIA1 mRNA targets in hESCs and during human neurodevelopment, indicate that translation repression is a key process targeted by TIA1 binding and implicate TIA1 function in neuronal differentiation.

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6. Giles AE, Almuzayyen A, Buduhan G. Ingested removable partial denture causing esophageal perforation in a patient with autism: Management and prevention. The Journal of prosthetic dentistry. 2021.

A 60-year-old woman with autism and a repetitive swallowing behavior ingested a removable partial denture that impacted in the proximal esophagus. Attempts at endoscopic removal were unsuccessful. Esophageal perforation was recognized, necessitating emergency transcervical surgical exploration, esophagotomy with foreign body removal, and repair of the esophageal perforation. She had a prolonged postoperative stay involving mechanical ventilatory support and gastric tube feeds. This situation was predictable and preventable, and application of key principles may help avoid such catastrophic incidents in similar patients.

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7. Lee K, Schertz HH. Association of turn-taking functions with joint attention in toddlers with autism. Autism : the international journal of research and practice. 2021: 13623613211039945.

Back-and-forth interaction, or turn taking, may support later joint attention, a more complex form of interaction, when promoted in interventions for young children with autism, especially depending on the child’s intent when interacting. In the present study, we observed videos of 20 toddlers with autism engaging in turn taking with their caregivers during an intervention designed to support children’s joint attention. We sought to identify when the children displayed turn taking socially and when they were using it for nonsocial purposes in the intervention videos. We also observed videos after the intervention was complete to identify when children used joint attention when interacting with their caregivers. After these observations, we used these video data to explore the relationship of social turn taking to joint attention, and the relationship of nonsocial turn taking to joint attention. We found a significant relationship between social turn taking and joint attention, but not between nonsocial turn taking and joint attention. These findings support the importance of considering social turn taking in interactions between young children with autism and their caregivers.

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8. Motta M, Stecula D. Quantifying the effect of Wakefield et al. (1998) on skepticism about MMR vaccine safety in the U.S. PloS one. 2021; 16(8): e0256395.

BACKGROUND: Efforts to trace the rise of childhood vaccine safety concerns in the US often suggest Andrew Wakefield and colleagues’ retracted 1998 Lancet study (AW98)-which alleged that the MMR vaccine can cause children to develop autism-as a primary cause of US vaccine skepticism. However, a lack of public opinion data on MMR safety collected before/after AW98’s publication obscures whether anecdotal accounts are indicative of a potentially-causal effect. METHODS: We address this problem using a regression discontinuity framework to study change in monthly MMR injury claims (N = 74,850; from 1990-2019) from the Vaccine Adverse Events Reporting System (VAERS) to proxy concern about vaccine safety. Additionally, we suggest a potential mechanism for the effect of AW98 on vaccine skepticism, via automated sentiment analyses of MMR-related news stories (N = 674; from 1996-2000) in major television and newspaper outlets. RESULTS: AW98 led to an immediate increase of about 70 MMR injury claims cases per month, averaging across six estimation strategies (meta-analytic effect = 70.44 [52.19, 88.75], p < 0.01). Preliminary evidence suggests that the volume of negative media attention to MMR increased in the weeks following AW98's publication, across four estimation strategies (meta-analytic effect = 9.59% [3.66, 15.51], p < 0.01). CONCLUSIONS: Vaccine skepticism increased following the publication of AW98, which was potentially made possible by increased negative media coverage of MMR. SIGNIFICANCE: Childhood vaccine skepticism presents an important challenge to widespread vaccine uptake, and undermines support for pro-vaccine health policies. In addition to advancing our understanding of the previously-obscured origins of US vaccine skepticism, our work cautions that high-profile media attention to inaccurate scientific studies can undermine public confidence in vaccines. We conclude by offering several recommendations that researchers and health communicators might consider to detect and address future threats to vaccine confidence.

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9. Rosenheck M, Sheeler C, Saré RM, Gurney ME, Smith CB. Effects of chronic inhibition of phosphodiesterase-4D on behavior and regional rates of cerebral protein synthesis in a mouse model of fragile X syndrome. Neurobiology of disease. 2021; 159: 105485.

Fragile X Syndrome (FXS) is caused by silencing the FMR1 gene which results in intellectual disability, hyperactivity, sensory hypersensitivity, autistic-like behavior, and susceptibility to seizures. This X-linked disorder is also associated with reduced cAMP levels in humans as well as animal models. We assessed the therapeutic and neurochemical effects of chronic administration of the phosphodiesterase-4D negative allosteric modulator, BPN14770, in a mouse model of FXS (Fmr1 KO). Groups of male Fmr1 KO mice and control littermates were treated with dietary BPN14770 commencing postnatal day 21. A dose-response effect was investigated. At 90 days of age, mice underwent behavior tests including open field, novel object recognition, three chambered sociability and social novelty tests, passive avoidance, and sleep duration analysis. These tests were followed by in vivo measurement of regional rates of cerebral protein synthesis (rCPS) with the autoradiographic L-[1-(14)C]leucine method. BPN14770 treatment had positive effects on the behavioral phenotype in Fmr1 KO mice. Some effects such as increased sleep duration and increased social behavior occurred in both genotypes. In the open field, the hyperactivity response in Fmr1 KO mice was ameliorated by BPN14770 treatment at low and intermediate doses. BPN14770 treatment tended to increase rCPS in a dose-dependent manner in WT mice, whereas in Fmr1 KO mice effects on rCPS were less apparent. Results indicate BPN14770 treatment improves some behavior in Fmr1 KO mice. Results also suggest a genotype difference in the regulation of translation via a cAMP-dependent pathway.

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10. Rosenthal SB, Willsey HR, Xu Y, Mei Y, Dea J, Wang S, Curtis C, Sempou E, Khokha MK, Chi NC, Willsey AJ, Fisch KM, Ideker T. A convergent molecular network underlying autism and congenital heart disease. Cell systems. 2021; 12(11): 1094-107.e6.

Patients with neurodevelopmental disorders, including autism, have an elevated incidence of congenital heart disease, but the extent to which these conditions share molecular mechanisms remains unknown. Here, we use network genetics to identify a convergent molecular network underlying autism and congenital heart disease. This network is impacted by damaging genetic variants from both disorders in multiple independent cohorts of patients, pinpointing 101 genes with shared genetic risk. Network analysis also implicates risk genes for each disorder separately, including 27 previously unidentified genes for autism and 46 for congenital heart disease. For 7 genes with shared risk, we create engineered disruptions in Xenopus tropicalis, confirming both heart and brain developmental abnormalities. The network includes a family of ion channels, such as the sodium transporter SCN2A, linking these functions to early heart and brain development. This study provides a road map for identifying risk genes and pathways involved in co-morbid conditions.

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11. Vuijk R, Deen M, Arntz A, Geurts HM. First Psychometric Properties of the Dutch Interview for Diagnostic Assessment of Autism Spectrum Disorder in Adult Males Without Intellectual Disability. Journal of autism and developmental disorders. 2021.

For autism spectrum disorder (ASD) in adults there are several diagnostic instruments available with a need for consideration of the psychometric properties. This study aimed to conduct a first psychometric evaluation of a new diagnostic ASD instrument, the NIDA (Dutch Interview for Diagnostic assessment of ASD in adults) in 90 adult males without intellectual disability (age 18-65 years) in the Netherlands: 30 with ASD, 30 with a Personality Disorder and 30 nonpatient controls. The interrater agreement ranged from 0.79 to 1.00, the convergent validity including sensitivity and specificity ranged from 0.76 to 1.00, and we observed an adequate concurrent criterion-related validity. These promising findings can serve as foundation for future psychometric NIDA studies in a more diverse population. TRIAL REGISTRATION: The Netherlands National Trial Register NTR6391. Registered 04 May 2017.

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