1. Castejon AM, Spaw JA, Rozenfeld I, Sheinberg N, Kabot S, Shaw A, Hardigan P, Faillace R, Packer EE. Improving Antioxidant Capacity in Children With Autism: A Randomized, Double-Blind Controlled Study With Cysteine-Rich Whey Protein. Frontiers in psychiatry. 2021; 12: 669089.

Previous studies indicate that children with autism spectrum disorder (ASD) have lower levels of glutathione. Nutritional interventions aim to increase glutathione levels suggest a positive effect on ASD behaviors, but findings are mixed or non-significant. A commercially available nutritional supplement comprising a cysteine-rich whey protein isolate (CRWP), a potent precursor of glutathione, was previously found to be safe and effective at raising glutathione in several conditions associated with low antioxidant capacity. Therefore, we investigated the effectiveness of a 90-day CRWP intervention in children with ASD and examined whether intracellular reduced and oxidized glutathione improvements correlated with behavioral changes. We enrolled 46 (of 81 screened) 3-5-year-old preschool children with confirmed ASD. Using a double-blind, randomized, placebo-controlled design, we evaluated the effectiveness of daily CRWP (powder form: 0.5 g/kg for children <20 kg or a 10-g dose for those >20 kg), compared with placebo (rice protein mimicking the protein load in the intervention group), on glutathione levels and ASD behaviors assessed using different behavioral scales such as Childhood Autism Rated Scale, Preschool Language Scale, Social Communication Questionnaire, Childhood Behavioral Checklist and the parent-rated Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). Forty children (CRWP, 21; placebo, 19) completed the 90-day treatment period. Improvements observed in some behavioral scales were comparable. However, the VABS-II behavioral assessment, demonstrated significant changes only in children receiving CRWP compared to those observed in the placebo group in the composite score (effect size 0.98; 95% confidence intervals 1.42-4.02; p = 0.03). Further, several VABS-II domain scores such as adaptive behavior (p = 0.03), socialization (p = 0.03), maladaptive behavior (p = 0.04) and internalizing behavior (p = 0.02) also indicated significant changes. Children assigned to the CRWP group showed significant increases in glutathione levels (p = 0.04) compared to those in the placebo group. A subanalysis of the VABS-II scale results comparing responders (>1 SD change from baseline to follow up) and non-responders in the CRWP group identified older age and higher levels of total and reduced glutathione as factors associated with a response. CRWP nutritional intervention in children with ASD significantly improved both glutathione levels and some behaviors associated with ASD. Further studies are needed to confirm these results. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/study/NCT01366859, identifier: NCT01366859.

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2. Dong H, Wang B, Feng J, Yue X, Jia F. Correlation Between Serum Concentrations of Menaquinone-4 and Developmental Quotients in Children With Autism Spectrum Disorder. Frontiers in nutrition. 2021; 8: 748513.

Objective: The vitamin K family has a wide range of effects in the body, including the central nervous system. Menaquinone-4 (MK-4), a form of vitamin K2, is converted from phylloquinone (PK), which is the main source of dietary vitamin K and is the main form of vitamin K in the brain. We conducted this study to investigate the serum concentration of MK-4 and the correlations between MK-4 and developmental quotients in children with autism spectrum disorder (ASD). Methods: We selected 731 children with ASD who were diagnosed for the first time. During the same period, 332 neurotypical children who underwent regular physical examinations in our outpatient department were selected as the TD group. We investigated the general situation of children, including gender and age. Children in ASD group were assessed for autistic symptoms and development quotients, including Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), ADOS-2, and Griffiths Development Scales-Chinese Language Edition (GDS-C). Both groups of children were tested for serum menaquinone-4. We compared serum menaquinone-4 levels of ASD group and TD group. We then conducted a correlation analysis between the level of menaquinone-4 and the developmental quotient of children with ASD. Results: The results of this study indicate that the serum concentration of MK-4 in children with ASD is lower than that in children with typical development (t = -2.702, P = 0.007). The serum concentration of MK-4 is related to the developmental quotients of several subscales in ASD children, and this correlation is more obvious in males. Conclusion: we conclude that MK-4 is present in lower concentrations in children with ASD, which may affect cognition and developmental quotients. The role of MK-4 in ASD needs to be further explored.

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3. El-Tellawy MM, Ahmad AR, Saad K, Alruwaili TAM, AbdelMoneim IM, Shaaban I, Alinad AKM, Albulayhid SBH, Khalaf SM. Effect of hyperbaric oxygen therapy and Tomatis sound therapy in children with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry. 2022; 113: 110457.

Many therapeutic and dietary regimens have been studied for children with autism spectrum disorder (ASD) in the last three decades. We aimed to evaluate the efficacy of hyperbaric oxygen therapy (HBOT) and Tomatis sound therapy (TST) in an Egyptian cohort of children with ASD. This study was a prospective, open label, randomized interventional clinical trial. One hundred forty-six children with ASD with no previous rehabilitation therapy were enrolled in our study. Patients were randomly divided into four groups: the first group received hyperbaric oxygen therapy, the second group received Tomatis sound therapy, the third group received a combination of both modalities, and the fourth group, the control group, received no intervention. We found that the combination of Tomatis sound therapy with hyperbaric oxygen therapy had a superior effect in improving autism symptoms than each intervention alone (CARS after therapy 35.04 ± 13.38 versus 49.34 ± 17.54 before the intervention, p < 0.001). The combination of both modalities may be helpful for children with ASD. The most distinctive evidence that supports the use of combination therapy for ASD is still controversial; however, our study provides some evidence of the benefit of combination therapy for children with ASD. Future studies should use a more sophisticated research design and begin by finding a consistent baseline measure that can be used to evaluate the effects of these therapies for ASD.

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4. Honarmand Tamizkar K, Badrlou E, Aslani T, Brand S, Arsang-Jang S, Ghafouri-Fard S, Taheri M. Dysregulation of NF-κB-Associated LncRNAs in Autism Spectrum Disorder. Frontiers in molecular neuroscience. 2021; 14: 747785.

Autism spectrum disorder (ASD) is a long-standing neurodevelopmental condition with prominent effects on social behavior of affected children. This disorder has been linked with neuroinflammatory responses. NF-κB has been shown to affect these responses in the orbitofrontal cortex of patients with ASD, thus being implicated in the pathogenesis of ASD. We measured expression of some NF-κB-associated lncRNAs and mRNAs (DILC, ANRIL, PACER, CHAST, ADINR, DICER1-AS1, HNF1A-AS1, NKILA, ATG5 and CEBPA) in the peripheral blood of ASD kids vs. healthy children. Expression quantities of ADINR, ANRIL, DILC, NKILA and CHAST were meaningfully higher in ASD cases compared with healthy kids (Posterior Beta = 1.402, P value < 0.0001; Posterior Beta = 2.959, P value < 0.0001; Posterior Beta = 0.882, P value = 0.012; Posterior Beta = 1.461, P value < 0.0001; Posterior Beta = 0.541, P value = 0.043, respectively). The Bonferroni corrected P values for these lncRNAs remained significant except for CHAST and DILC. Expression levels of other genes were not considerably different between cases and controls. Expressions of ATG5, DICER-AS1 and DILC were correlated with age of ASD patients (P < 0.0001). Among ASD cases, the most robust correlation has been detected between ADINR and NKILA (r = 0.87, P < 0.0001). Expression of none of genes has been correlated with age of healthy children. Among this group of children, expression levels of ADINR and CHAST were robustly correlated (r = 0.83, P < 0.0001). ANRIL had the greatest AUC value (AUC = 0.857), thus the best diagnostic power among the assessed genes. NKILA ranked the second position in this regard (AUC = 0.757). Thus, NF-κB-associated lncRNAs might partake in the pathogenesis of ASD.

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5. Huang M, Liu K, Wei Z, Feng Z, Chen J, Yang J, Zhong Q, Wan G, Kong XJ. Serum Oxytocin Level Correlates With Gut Microbiome Dysbiosis in Children With Autism Spectrum Disorder. Frontiers in neuroscience. 2021; 15: 721884.

To investigate the levels of serum oxytocin (OT) in children with autism spectrum disorder (ASD) and explore the association between OT levels and gut microbiota relative abundances, we recruited 39 children with ASD children-mother dyads and 44 healthy controls. Serum OT levels were determined via enzyme-linked immunosorbent assay and gut microbiota abundances were determined by 16S rRNA sequencing. We found that the OT level of ASD was lower than the healthy control group overall (P < 0.05). Furthermore, we present preliminary evidence of gut microbiome dysbiosis observed among children with ASD to lower levels of OT based on correlational analysis between serum OT and specific gut microbiota abundances (P < 0.05). We also found sex-related differences in serum OT levels and GIS index (P < 0.05). However, the generalizability of findings relevant to females with ASD require further validation in future studies involving larger sample sizes and balanced sex distributions due to the small number of females involved in this study. Nonetheless, these new findings further our understanding of the effects of low serum OT levels among individuals with ASD, which provides preliminary evidence in hopes of guiding future study design or mechanistic studies. The findings of the present study may be suggestive of potential ASD subtypes based on ASD severity and gut microbiome composition that may facilitate the prediction of the therapeutic responses of OT among those with ASD.

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6. Jensen M, Tyryshkina A, Pizzo L, Smolen C, Das M, Huber E, Krishnan A, Girirajan S. Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion. Genome medicine. 2021; 13(1): 163.

BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional « second-hit » variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS: We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and « second-hit » variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS: We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of « second-hit » variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited « second-hits » in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying « second-hits » and genes with transcriptome alterations in deletion carriers. CONCLUSIONS: Our results suggest a potential mechanism for how « second-hit » variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

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7. Kong XJ, Sherman HT, Tian R, Koh M, Liu S, Li AC, Stone WS. Validation of Rapid Interactive Screening Test for Autism in Toddlers Using Autism Diagnostic Observation Schedule™ Second Edition in Children at High-Risk for Autism Spectrum Disorder. Frontiers in psychiatry. 2021; 12: 737890.

The Rapid Interactive screening Test for Autism in Toddlers (RITA-T) is a fast and inexpensive early screening measure for autism spectrum disorder (ASD) that was tested previously in children 18-36 months-old; the current validation study compared the RITA-T with the Autism Diagnostic Observation Schedule™ Second Edition (ADOS-2). The hypothesis is to validate the RITA-T with comparison to the ADOS-2. Thirty-five individuals (18-84 months-old) identified as at risk for ASD received the RITA-T and the ADOS-2 during a single visit. Participants were split into two age groups and both whole-group and sub-group data analysis were conducted. With all participants, RITA-T scores correlated significantly with ADOS-2 total scores (P < 0.001), social affect (SA) sub-scores (P < 0.001), and restrictive and repetitive behavior (RRB) sub-scores (P < 0.05). Similarly, ADOS-2 total and SA scores were significantly correlated in both age groups, while the RRB sub-score was only significant in females (P < 0.05). Lastly, correlations using subgroups based on ethnicity were only significant in the minority ("Other") group for ADOS-2 total scores and in the Asian group for SA sub-scores (P < 0.05). Our receiver operating characteristic analysis showed that the optimal cut-off score of the RITA-T was consistently at 14, with a sensitivity of 81% and a specificity of 89% in the combined age group with the ADOS-2 and with a sensitivity 74% and specificity 50% with the DSM-5; The area under the curve was 0.84 (95%CI: 0.69-0.99) for ASD classified by ADOS-2 and 0.89 (95%CI: 0.79-0.99) for ASD diagnosed by DSM-5. The RITA-T performed similarly to the ADOS-2 when both were administered in a single visit. Significant correlations between the measures help validate the potential usefulness of the RITA-T as a rapid early screening measure of ASD. This study helps to show that the RITA-T may be used in a larger age range than originally reported and in different ethnic groups. The study involves human participants and was reviewed and approved by the Institutional Review Board (IRB) of Massachusetts General Hospital (MGH, 2017P0000857).

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8. Lindly OJ, Shui AM, Stotts NM, Kuhlthau KA. Caregiver strain among North American parents of children from the Autism Treatment Network Registry Call-Back Study. Autism : the international journal of research and practice. 2021: 13623613211052108.

Caregiver strain is the adverse impact that parents of children with emotional and behavioral issues including autism often experience (e.g. negative consequences of caregiving such as financial strain and social isolation; negative feelings that are internal to the caregiver such as worry and guilt; and negative feelings directed toward the child such as anger or resentment). This study showed that on average caregiver strain did not significantly change in North American parents of children with autism during a 2-year period. Improved caregiver strain was linked to improved child functioning and behavior. Routine assessment of caregiver strain and referral to evidence-based programming and supports may help alleviate some of the burden that families of children with autism commonly experience.

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9. Mansour Y, Burchell A, Kulesza RJ. Central Auditory and Vestibular Dysfunction Are Key Features of Autism Spectrum Disorder. Frontiers in integrative neuroscience. 2021; 15: 743561.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, poor social skills, and difficulties with communication. Beyond these core signs and symptoms, the majority of subjects with ASD have some degree of auditory and vestibular dysfunction. Dysfunction in these sensory modalities is significant as normal cognitive development depends on an accurate representation of our environment. The hearing difficulties in ASD range from deafness to hypersensitivity and subjects with ASD have abnormal sound-evoked brainstem reflexes and brainstem auditory evoked potentials. Vestibular dysfunction in ASD includes postural instability, gait dysfunction, and impaired gaze. Untreated vestibular dysfunction in children can lead to delayed milestones such as sitting and walking and poor motor coordination later in life. Histopathological studies have revealed that subjects with ASD have significantly fewer neurons in the auditory hindbrain and surviving neurons are smaller and dysmorphic. These findings are consistent with auditory dysfunction. Further, the cerebellum was one of the first brain structures implicated in ASD and studies have revealed loss of Purkinje cells and the presence of ectopic neurons. Together, these studies suggest that normal auditory and vestibular function play major roles in the development of language and social abilities, and dysfunction in these systems may contribute to the core symptoms of ASD. Further, auditory and vestibular dysfunction in children may be overlooked or attributed to other neurodevelopmental disorders. Herein we review the literature on auditory and vestibular dysfunction in ASD. Based on these results we developed a brainstem model of central auditory and vestibular dysfunction in ASD and propose that simple, non-invasive but quantitative testing of hearing and vestibular function be added to newborn screening protocols.

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10. Mansour Y, Kulesza RJ. The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder. Frontiers in integrative neuroscience. 2021; 15: 730439.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by repetitive behaviors, poor social skills, and difficulties with communication and hearing. The hearing deficits in ASD range from deafness to extreme sensitivity to routine environmental sounds. Previous research from our lab has shown drastic hypoplasia in the superior olivary complex (SOC) in both human cases of ASD and in an animal model of autism. However, in our study of the human SOC, we failed to find any changes in the total number of neurons in the ventral nucleus of the trapezoid body (VNTB) or any changes in cell body size or shape. Similarly, in animals prenatally exposed to the antiepileptic valproic acid (VPA), we failed to find any changes in the total number, size or shape of VNTB neurons. Based on these findings, we hypothesized that the neurotransmitter profiles, ascending and descending axonal projections of the VNTB are also preserved in these neurodevelopmental conditions. We investigated this hypothesis using a combination of immunohistochemistry and retrograde tract tracing. We found no difference between control and VPA-exposed animals in the number of VNTB neurons immunoreactive for choline acetyltransferase (ChAT). Additionally, we investigated the ascending projections from the VNTB to both the central nucleus of the inferior colliculus (CNIC) and medial geniculate (MG) and descending projections to the cochlea. Our results indicate no significant differences in the ascending and descending projections from the VNTB between control and VPA-exposed animals despite drastic changes in these projections from surrounding nuclei. These findings provide evidence that certain neuronal populations and circuits may be protected against the effects of neurodevelopmental disorders.

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11. Mariggiò MA, Palumbi R, Vinella A, Laterza R, Petruzzelli MG, Peschechera A, Gabellone A, Gentile O, Vincenti A, Margari L. DRD1 and DRD2 Receptor Polymorphisms: Genetic Neuromodulation of the Dopaminergic System as a Risk Factor for ASD, ADHD and ASD/ADHD Overlap. Frontiers in neuroscience. 2021; 15: 705890.

The dopaminergic system (DS) is one of the most important neuromodulator systems involved in complex functions that are compromised in both autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), conditions that frequently occur in overlap. This evidence suggests that both disorders might have common neurobiological pathways involving the DS. Therefore, the aim of this study was to examine the DRD1 and DRD2 dopamine receptor single nucleotide polymorphisms (SNPs) as potential risk factors for ASD, ADHD, and ASD/ADHD overlap. Genetic data were obtained from four groups: 75 ASD patients, 75 ADHD patients, 30 patients with ASD/ADHD overlap, and 75 healthy controls. All participants were between 2 and 17 years old. We compared the genotypic and allelic frequency of 18 SNPs among all of the study groups. Moreover, in the case of statistically significant differences, odds ratios (OR) were obtained to evaluate if the presence of SNPs might be a risk factor of developing a specific clinical phenotype. This study found that DRD1 and DRD2 receptors SNPs might be considered as potential risk factors for ASD and ADHD. However, only DRD2-12 (rs7131465) was significantly associated with a higher risk for the ASD/ADHD overlap. These data support the hypothesis of the genetic neuromodulation of the DS in the neurobiology of these conditions.

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12. Milovanovic M, Grujicic R. Electroencephalography in Assessment of Autism Spectrum Disorders: A Review. Frontiers in psychiatry. 2021; 12: 686021.

Electroencephalography (EEG) can further out our understanding of autistic spectrum disorders (ASD) neurophysiology. Epilepsy and ASD comorbidity range between 5 and 46%, but its temporal relationship, causal mechanisms and interplay with intellectual disability are still unknown. Epileptiform discharges with or without seizures go as high as 60%, and associate with epileptic encephalopathies, conceptual term suggesting that epileptic activity can lead to cognitive and behavioral impairment beyond the underlying pathology. Seizures and ASD may be the result of similar mechanisms, such as abnormalities in GABAergic fibers or GABA receptor function. Epilepsy and ASD are caused by a number of genetic disorders and variations that induce such dysregulation. Similarly, initial epilepsy may influence synaptic plasticity and cortical connection, predisposing a growing brain to cognitive delays and behavioral abnormalities. The quantitative EEG techniques could be a useful tool in detecting and possibly measuring dysfunctions in specific brain regions and neuronal regulation in ASD. Power spectra analysis reveals a U-shaped pattern of power abnormalities, with excess power in the low and high frequency bands. These might be the consequence of a complicated network of neurochemical changes affecting the inhibitory GABAergic interneurons and their regulation of excitatory activity in pyramidal cells. EEG coherence studies of functional connectivity found general local over-connectivity and long-range under-connectivity between different brain areas. GABAergic interneuron growth and connections are presumably impaired in the prefrontal and temporal cortices in ASD, which is important for excitatory/inhibitory balance. Recent advances in quantitative EEG data analysis and well-known epilepsy ASD co-morbidity consistently indicate a role of aberrant GABAergic transmission that has consequences on neuronal organization and connectivity especially in the frontal cortex.

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13. Oğuz S, Arslan UE, Kiper P, Alikaşifoğlu M, Boduroğlu K, Utine GE. Diagnostic yield of microarrays in individuals with non-syndromic developmental delay and intellectual disability. Journal of intellectual disability research : JIDR. 2021; 65(12): 1033-48.

BACKGROUND: Intellectual disability (ID), or developmental delay (DD) when the individual is yet under 5 years of age, is evident before 18 years of age and is characterised by significant limitations in both intellectual functioning and adaptive behaviour. ID/DD may be clinically classified as syndromic or non-syndromic. Genomic copy number variations (CNVs) constitute a well-established aetiological subgroup of ID/DD. Overall diagnostic yield of microarrays is estimated at 10-25% for ID/DD, especially higher when particular clinical features that render the condition syndromic accompany. METHODS: In this study, we aimed to investigate the diagnostic yield of microarrays in the subgroup of individuals with non-syndromic ID/DD (NSID/NSDD). A total of 302 NSID/NSDD individuals who have undergone microarray analysis between October 2013 and April 2020 were included. Accompanying clinical data, including head circumference, delayed developmental areas, seizures and behavioural problems were collected and analysed separately in NSID and NSDD subgroups. RESULTS: The diagnostic yield of microarray analyses in NSID/NSDD was determined as 10.9% in NSID (10.7%) and in NSDD (11.1%). Presence of behavioural and epileptic problems did not contribute to the diagnostic yield. However, in the presence of macrocephaly, the contribution to diagnostic yield was statistically significant particularly in NSDD group. The most common pathogenic CNVs involved chromosomes 16, 15 and X. Lastly, we propose a Xq21.32q22.1 deletion as likely pathogenic in a child with isolated language delay and accompanying seizures. CONCLUSIONS: Particularly in neurodevelopmental diseases, microarrays are useful for establishing the diagnosis and detecting novel susceptibility regions. Future studies would accurately classify the herein presented variants of uncertain significance CNVs as pathogenic or benign.

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14. Polónyiová K, Belica I, Celušáková H, Janšáková K, Kopčíková M, Szapuová Ž, Ostatníková D. Comparing the impact of the first and second wave of COVID-19 lockdown on Slovak families with typically developing children and children with autism spectrum disorder. Autism : the international journal of research and practice. 2021: 13623613211051480.

A global pandemic caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2) affected everyday lives of all people, including individuals with special needs, such as autism spectrum disorder. The aim of this research was to compare the mental health of families with children with autism spectrum disorder to families with typically developing children, and between the first and the second wave of COVID-19 outbreak in Slovakia. This mainly included symptoms of depression, anxiety, and stress of parents and problem behavior or sleeping difficulties of their children. The research sample consisted of 332 parents (155 of which have children with autism spectrum disorder), 179 surveyed during the first wave and 153 during the second wave. Online parent questionnaire was created, including demographic and specific topic questions, Depression Anxiety and Stress Scale-42 questionnaire, and internalizing and externalizing maladaptive behavior subscales from Vineland Adaptive Behavior Scales. Our results show that during the first wave, parents of autism spectrum disorder children suffered high levels of anxiety. During the second wave, both groups of parents suffered increased anxiety, stress, and depression, but especially severe for parents of children with autism spectrum disorder. Internalizing maladaptive behavior of autistic children grew significantly between the waves. Parental depression, anxiety, and stress were interconnected with maladaptive behavior of both autism spectrum disorder and typically developing children, suggesting the importance of the therapy options for whole families.

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15. Ronis ST, Byers ES, Brotto LA, Nichols S. Beyond the Label: Asexual Identity Among Individuals on the High-Functioning Autism Spectrum. Archives of sexual behavior. 2021; 50(8): 3831-42.

Researchers have suggested that asexuality, which has been conceptualized traditionally as a persistent lack of sexual attraction to others, may be more common among individuals with autism spectrum disorder than in the neurotypical population. However, no studies to date have considered how these individuals understand and conceptualize their sexual identity. The aim of this study was to provide a more nuanced understanding of asexuality among individuals with high-functioning autism spectrum disorder (HF-ASD) than has been done in the past. Individuals with ASD, 21-72 years old (M = 34.04 years, SD = 10.53), were recruited from online communities that serve adults with ASD and Amazon’s Mechanical Turk to complete an online survey of sexual and gender identity. Overall, 17 (5.1%) participants who met study criteria (N = 332) self-identified as asexual. However, 9 of the 17 people identifying as asexual expressed at least some sexual attraction to others. In addition, based on open-ended responses, some participants linked their asexual identity more with a lack of desire or perceived skill to engage in interpersonal relations than a lack of sexual attraction. Results suggest that researchers should be cautious in attributing higher rates of asexuality among individuals with ASD than in the general population to a narrow explanation and that both researchers and professionals working with individuals with ASD should consider multiple questions or approaches to accurately assess sexual identity.

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16. Ronkin E, Tully EC, Branum-Martin L, Cohen LL, Hall C, Dilly L, Tone EB. Sex differences in social communication behaviors in toddlers with suspected autism spectrum disorder as assessed by the ADOS-2 toddler module. Autism : the international journal of research and practice. 2021: 13623613211047070.

When toddlers are suspected of autism spectrum disorder (ASD), the gold-standard assessment technique is with the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) Toddler Module, a behavioral observation system. ASD is a neurodevelopmental condition more frequently diagnosed in toddler boys than in toddler girls. There is some evidence that the ADOS-2 assesses behaviors that are more characteristic of boys with ASD than girls. Thus, it is possible that focusing on these behaviors contributes at least in part to why more boys are diagnosed than girls. Specifically, girls may show more social skills than boys during the ADOS-2 assessment due to their socialization histories, which may lead to missed diagnoses of ASD in toddler girls. The current study examined eight social behaviors assessed by the ADOS-2 in a sample of toddlers with suspected ASD to see if they contributed differently to the total score of those items. Examination of those items suggested that those social communication behaviors work the same for boys and girls with suspected ASD, which was inconsistent with hypotheses. However, examination of particular items raises the possibility of examining creative/imaginative play as an area for future research.

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17. Shahamiri SR, Thabtah F, Abdelhamid N. A new classification system for autism based on machine learning of artificial intelligence. Technology and health care : official journal of the European Society for Engineering and Medicine. 2021.

BACKGROUND: Autistic Spectrum Disorder (ASD) is a neurodevelopment condition that is normally linked with substantial healthcare costs. Typical ASD screening techniques are time consuming, so the early detection of ASD could reduce such costs and help limit the development of the condition. OBJECTIVE: We propose an automated approach to detect autistic traits that replaces the scoring function used in current ASD screening with a more intelligent and less subjective approach. METHODS: The proposed approach employs deep neural networks (DNNs) to detect hidden patterns from previously labelled cases and controls, then applies the knowledge derived to classify the individual being screened. Specificity, sensitivity, and accuracy of the proposed approach are evaluated using ten-fold cross-validation. A comparative analysis has also been conducted to compare the DNNs’ performance with other prominent machine learning algorithms. RESULTS: Results indicate that deep learning technologies can be embedded within existing ASD screening to assist the stakeholders in the early identification of ASD traits. CONCLUSION: The proposed system will facilitate access to needed support for the social, physical, and educational well-being of the patient and family by making ASD screening more intelligent and accurate.

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18. Stoppel DC, McCamphill PK, Senter RK, Heynen AJ, Bear MF. mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence. Frontiers in psychiatry. 2021; 12: 718953.

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (« tolerance ») after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

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19. Verdura E, Pérez-Cano L, Sabido-Vera R, Guney E, Hyvelin JM, Durham L, Gomez-Mancilla B. Heterogeneity in Fragile X Syndrome Highlights the Need for Precision Medicine-Based Treatments. Frontiers in psychiatry. 2021; 12: 722378.

Fragile X syndrome (FXS) is the most frequent monogenic cause of autism or intellectual disability, and research on its pathogenetic mechanisms has provided important insights on this neurodevelopmental condition. Nevertheless, after 30 years of intense research, efforts to develop treatments have been mostly unsuccessful. The aim of this review is to compile evidence from existing research pointing to clinical, genetic, and therapeutic response heterogeneity in FXS and highlight the need of implementing precision medicine-based treatments. We comment on the high genetic and phenotypic heterogeneity present in FXS, as a contributing factor to the difficulties found during drug development. Given that several clinical trials have showed a non-negligeable fraction of positive responders to drugs targeting core FXS symptoms, we propose that success of clinical trials can be achieved by tackling the underlying heterogeneity in FXS by accurately stratifying patients into drug-responder subpopulations. These precision medicine-based approaches, which can be first applied to well-defined monogenic diseases such as FXS, can also serve to define drug responder profiles based on specific biomarkers or phenotypic features that can associate patients with different genetic backgrounds to a same candidate drug, thus repositioning a same drug for a larger number of patients with NDDs.

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20. Wang N, Zhao Y, Gao J. Association Between Peripheral Blood Levels of Vitamin A and Autism Spectrum Disorder in Children: A Meta-Analysis. Frontiers in psychiatry. 2021; 12: 742937.

Vitamin A is an essential fat-soluble micronutrient that plays important roles in a surprisingly wide variety of biological processes from early growth and development to brain maintenance. Numerous clinical studies have been conducted to explore the relationship between peripheral vitamin A levels and autism spectrum disorder (ASD), but the results of these studies are controversial. Therefore, we assessed the association between peripheral vitamin A levels and ASD in the present meta-analysis. Relevant records were retrieved through the Embase, Web of Knowledge and PubMed databases up to 13 November 2020. Reference lists were also searched and analyzed. Hedges’ g with its corresponding 95% confidence interval (CI) was used to assess the association between peripheral vitamin A levels and ASD. A fixed or random effects model was selected according to a heterogeneity test in overall and subgroup analyses. Five records (six studies) with 935 ASD children and 516 healthy children were included in the present study. Significantly decreased peripheral vitamin A concentrations were observed in ASD children compared with healthy children (Hedges’ g = -0.600, 95% CI -1.153 to -0.048, P = 0.033). A similar result was also obtained after removing the studies identified by Galbraith plots. In addition, no obvious publication bias was found in the meta-analysis. The findings of our meta-analysis suggested decreased peripheral vitamin A levels in ASD children compared with healthy children. Further investigations into the effects of vitamin A on the development of ASD are warranted.

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