1. Allen EG, Charen K, Hipp HS, Shubeck L, Amin A, He W, Nolin SL, Glicksman A, Tortora N, McKinnon B, Shelly KE, Sherman SL. Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size. Genetics in medicine : official journal of the American College of Medical Genetics. 2021; 23(9): 1648-55.

PURPOSE: Approximately 20-30% of women with an FMR1 premutation experience fragile X-associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. METHODS: To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. RESULTS: As previously reported, women with 70-100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85-89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats. CONCLUSION: Using a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.

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2. Alsayouf HA, Talo H, Biddappa ML, De Los Reyes E. Risperidone or Aripiprazole Can Resolve Autism Core Signs and Symptoms in Young Children: Case Study. Children (Basel, Switzerland). 2021; 8(5).

Risperidone and aripiprazole are approved by the USA Food and Drug Administration for the treatment of irritability and aggression in children from the ages of 5 and 6 years, respectively. However, there are no approved medications for the treatment of autism spectrum disorder (ASD) core signs and symptoms. Nevertheless, early intervention is recognized as key to improving long-term outcomes. This retrospective case study included 10 children (mean age, 2 years 10 months) with ASD who presented with persistent irritability and aggression before 4 years of age that was unresponsive to behavioral interventions and sufficiently severe to consider pharmacological intervention with risperidone or aripiprazole combined with standard supportive therapies. Besides ameliorating comorbid behaviors, improvement was observed in ASD core signs and symptoms for all patients, with minimal-to-no symptoms observed in 60% of patients according to the Childhood Autism Rating Scale 2-Standard Test and Clinical Global Impression scales. Excessive weight gain in two patients was the only adverse effect observed that required intervention. This is the first study to suggest that ASD can potentially be treated in very young children (<4 years). Clinical trials are urgently required to validate these findings among this pediatric population.

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3. Alvari G, Furlanello C, Venuti P. Is Smiling the Key? Machine Learning Analytics Detect Subtle Patterns in Micro-Expressions of Infants with ASD. Journal of clinical medicine. 2021; 10(8).

Time is a key factor to consider in Autism Spectrum Disorder. Detecting the condition as early as possible is crucial in terms of treatment success. Despite advances in the literature, it is still difficult to identify early markers able to effectively forecast the manifestation of symptoms. Artificial intelligence (AI) provides effective alternatives for behavior screening. To this end, we investigated facial expressions in 18 autistic and 15 typical infants during their first ecological interactions, between 6 and 12 months of age. We employed Openface, an AI-based software designed to systematically analyze facial micro-movements in images in order to extract the subtle dynamics of Social Smiles in unconstrained Home Videos. Reduced frequency and activation intensity of Social Smiles was computed for children with autism. Machine Learning models enabled us to map facial behavior consistently, exposing early differences hardly detectable by non-expert naked eye. This outcome contributes to enhancing the potential of AI as a supportive tool for the clinical framework.

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4. Annesley SJ, Fisher PR. Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders. International journal of molecular sciences. 2021; 22(9).

Neurological disorders, including neurodegenerative diseases, are collectively a major cause of death and disability worldwide. Whilst the underlying disease mechanisms remain elusive, altered mitochondrial function has been clearly implicated and is a key area of study in these disorders. Studying mitochondrial function in these disorders is difficult due to the inaccessibility of brain tissue, which is the key tissue affected in these diseases. To overcome this issue, numerous cell models have been used, each providing unique benefits and limitations. Here, we focussed on the use of lymphoblastoid cell lines (LCLs) to study mitochondrial function in neurological disorders. LCLs have long been used as tools for genomic analyses, but here we described their use in functional studies specifically in regard to mitochondrial function. These models have enabled characterisation of the underlying mitochondrial defect, identification of altered signalling pathways and proteins, differences in mitochondrial function between subsets of particular disorders and identification of biomarkers of the disease. The examples provided here suggest that these cells will be useful for development of diagnostic tests (which in most cases do not exist), identification of drug targets and testing of pharmacological agents, and are a worthwhile model for studying mitochondrial function in neurological disorders.

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5. Arteche-López A, Gómez Rodríguez MJ, Sánchez Calvin MT, Quesada-Espinosa JF, Lezana Rosales JM, Palma Milla C, Gómez-Manjón I, Hidalgo Mayoral I, Pérez de la Fuente R, Díaz de Bustamante A, Darnaude MT, Gil-Fournier B, Ramiro León S, Ramos Gómez P, Sierra Tomillo O, Juárez Rufián A, Arranz Cano MI, Villares Alonso R, Morales-Pérez P, Segura-Tudela A, Camacho A, Nuñez N, Simón R, Moreno-García M, Alvarez-Mora MI. Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test. Genes. 2021; 12(4).

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.

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6. Bast N, Boxhoorn S, Supér H, Helfer B, Polzer L, Klein C, Cholemkery H, Freitag CM. Atypical Arousal Regulation in Children With Autism but Not With Attention-Deficit/Hyperactivity Disorder as Indicated by Pupillometric Measures of Locus Coeruleus Activity. Biological psychiatry Cognitive neuroscience and neuroimaging. 2021.

BACKGROUND: Atypical arousal regulation may explain slower mean reaction time (MRT) in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder compared with typical development. The locus coeruleus-norepinephrine system (LC-NE) underlies arousal regulation and adapts its activity to the utility of a task. LC-NE tonic and phasic activity are indexed by baseline pupil size (BPS) and stimulus-evoked pupillary response (SEPR). METHODS: The study assessed pupillometry in ASD (n = 31, 3 female/28 male), attention-deficit/hyperactivity disorder (n = 28, 3 female/25 male), and typically developing control subjects (n = 31, 16 female/15 male) during a visuospatial reaction-time task that manipulates arousal by conditions with low and high task utility. We estimated linear mixed models of BPS, SEPR, and MRT in a per-trial analysis to investigate arousal regulation of task performance. RESULTS: Slower MRT occurred in the ASD group compared with the typically developing control group during low-utility conditions while controlling for dimensional ASD and attention-deficit/hyperactivity disorder symptoms. In low-utility conditions, BPS and SEPR were inversely related and both were associated with faster MRT. Increased ASD symptoms across groups were associated with higher BPS during low-utility conditions. Changes in BPS and SEPR between task-utility conditions were smaller in the ASD group. CONCLUSIONS: Slower visuospatial task performance in ASD is specific to low task utility. Arousal was associated with task performance and showed altered activity in ASD. Increased BPS during low-utility conditions suggested increased LC-NE tonic activity as an ASD symptom marker in children. Smaller changes in BPS and SEPR in ASD indicated attenuated LC-NE activity adaptation in response to high-utility conditions. Slower performance and atypical arousal regulation are probably associated with attenuated LC-NE activity adaptation.

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7. Berry-Kravis EM, Harnett MD, Reines SA, Reese MA, Ethridge LE, Outterson AH, Michalak C, Furman J, Gurney ME. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nature medicine. 2021; 27(5): 862-70.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

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8. Boretti A. Reviewing the association between aluminum adjuvants in the vaccines and autism spectrum disorder. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2021; 66: 126764.

The manuscript reviews the association between aluminum adjuvants (AlAd) in vaccines and autism spectrum disorder (ASD). Aluminum (Al) is neurotoxic. Infants who have received AlAd in vaccines show a higher rate of ASD. The behavior of mice changes with Al injection. Patients suffering from ASD have higher concentrations of Al in their brains. Thus, AlAd is an etiologic factor in ASD. Immune efficacy led to the use of the AlAd in vaccines; however, the safety of those who are vaccinated with such vaccines has not been considered. The mechanisms of action of AlAd and the pharmacodynamics of injected AlAd used in vaccines are not well-characterized. The association between aluminum adjuvants in the vaccines and autism spectrum disorder is suggested by multiple lines of evidence.

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9. Burak Gürbüz M, Rekik I. MGN-Net: A multi-view graph normalizer for integrating heterogeneous biological network populations. Medical image analysis. 2021; 71: 102059.

With the recent technological advances, biological datasets, often represented by networks (i.e., graphs) of interacting entities, proliferate with unprecedented complexity and heterogeneity. Although modern network science opens new frontiers of analyzing connectivity patterns in such datasets, we still lack data-driven methods for extracting an integral connectional fingerprint of a multi-view graph population, let alone disentangling the typical from the atypical variations across the population samples. We present the multi-view graph normalizer network (MGN-Net(2)), a graph neural network based method to normalize and integrate a set of multi-view biological networks into a single connectional template that is centered, representative, and topologically sound. We demonstrate the use of MGN-Net by discovering the connectional fingerprints of healthy and neurologically disordered brain network populations including Alzheimer’s disease and Autism spectrum disorder patients. Additionally, by comparing the learned templates of healthy and disordered populations, we show that MGN-Net significantly outperforms conventional network integration methods across extensive experiments in terms of producing the most centered templates, recapitulating unique traits of populations, and preserving the complex topology of biological networks. Our evaluations showed that MGN-Net is powerfully generic and easily adaptable in design to different graph-based problems such as identification of relevant connections, normalization and integration.

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10. Catusi I, Garzo M, Capra AP, Briuglia S, Baldo C, Canevini MP, Cantone R, Elia F, Forzano F, Galesi O, Grosso E, Malacarne M, Peron A, Romano C, Saccani M, Larizza L, Recalcati MP. 8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature. Genes. 2021; 12(5).

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

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11. Cavus N, Lawan AA, Ibrahim Z, Dahiru A, Tahir S, Abdulrazak UI, Hussaini A. A Systematic Literature Review on the Application of Machine-Learning Models in Behavioral Assessment of Autism Spectrum Disorder. Journal of personalized medicine. 2021; 11(4).

Autism spectrum disorder (ASD) is associated with significant social, communication, and behavioral challenges. The insufficient number of trained clinicians coupled with limited accessibility to quick and accurate diagnostic tools resulted in overlooking early symptoms of ASD in children around the world. Several studies have utilized behavioral data in developing and evaluating the performance of machine learning (ML) models toward quick and intelligent ASD assessment systems. However, despite the good evaluation metrics achieved by the ML models, there is not enough evidence on the readiness of the models for clinical use. Specifically, none of the existing studies reported the real-life application of the ML-based models. This might be related to numerous challenges associated with the data-centric techniques utilized and their misalignment with the conceptual basis upon which professionals diagnose ASD. The present work systematically reviewed recent articles on the application of ML in the behavioral assessment of ASD, and highlighted common challenges in the studies, and proposed vital considerations for real-life implementation of ML-based ASD screening and diagnostic systems. This review will serve as a guide for researchers, neuropsychiatrists, psychologists, and relevant stakeholders on the advances in ASD screening and diagnosis using ML.

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12. Chang CL, Liu TL, Hsiao RC, Yang P, Chen YL, Yen CF. Callous-Unemotional Traits among Adolescents with Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, or Typical Development: Differences between Adolescents’ and Parents’ Views. International journal of environmental research and public health. 2021; 18(8).

This study examined parent-adolescent agreement on the callous, uncaring, and unemotional dimensions of callous-unemotional (CU) traits and the differences in adolescent-reported and parent-reported CU traits among 126 adolescents with autism spectrum disorder (ASD), 207 adolescents with attention-deficit/hyperactivity disorder (ADHD), and 203 typically developing (TD) adolescents. Adolescent-reported and parent-reported CU traits on the three dimensions of the Inventory of Callous and Unemotional Traits were obtained. The strength of CU traits and the differences between adolescent-reported and parent-reported traits were compared among the three groups using analysis of covariance. Parent-adolescent agreement was examined using intraclass correlation. The results reveal that both adolescent-reported and parent-reported callousness and uncaring traits in the ASD and ADHD groups were significantly stronger than those in the TD group. Parent-adolescent agreement on the uncaring trait was fair across the three groups, whereas that on callousness was poor across all three groups. Parent-adolescent agreement on unemotionality was fair in the TD group but poor in the ADHD and ASD groups. ASD and ADHD groups had significantly greater differences in scores reported by parents and adolescents on the callousness trait than the TD group. The parent-adolescent score differences in the uncaring trait were also larger in the ASD group than in the TD group. Thus, these results support the application of a multi-informant approach in CU trait assessment, especially for adolescents with ASD or ADHD.

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13. Chen K, Liu C, Liu X, Wang Z, Luo R, Li S, Yu Y, Alderman H. Nutrition, Cognition, and Social Emotion among Preschoolers in Poor, Rural Areas of South Central China: Status and Correlates. Nutrients. 2021; 13(4).

Existing empirical evidence suggests that the prevalence of undernutrition in remote and poor, rural areas is still high among Chinese children. While evidence reveals that undernutrition may detrimentally affect child development, studies focusing on rural Chinese preschoolers are sparse. Using the baseline survey of a preschool’s free nutritious lunch pilot program, this study examined the relationship between child undernutrition and developmental outcomes among a preschool-aged sample in poor, rural areas of China. We conducted the baseline survey in Hunan province in south central China in September 2018. A total of 1293 preschoolers living in two (then) nationally designated poverty counties in rural Hunan served as our study sample. Children’s nutritional statuses were measured using height-for-age z-score, weight-for-age z-score, and anemia, while their cognitive and socio-emotional skills were assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) and Strengths and Difficulties Questionnaire (SDQ), respectively. We find that 33% of sample preschoolers were anemic, whereas the incidences of stunting and wasting were 11% and 2%, respectively. About 54% of the sample children had delay in at least one of the developmental domains measured in this study. Our findings provide suggestive evidence supporting that children from certain backgrounds tend to experience worse nutritional and developmental outcomes than their counterparts. After controlling for socioeconomic status, we observed that both anemia and stunting were negatively associated with children’s cognitive performance; however, they were not associated with socio-emotional performance. As such, this study suggests that free lunch programs have the potential to change children’s developmental trajectory in preschool. We believe that our results will contribute to the debate surrounding whether the nutritious lunch program in China should be expanded to the preschool education level.

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14. Colizzi M, Bortoletto R, Costa R, Zoccante L. Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence. Nutrients. 2021; 13(4).

Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation.

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15. Colombini G, Duradoni M, Carpi F, Vagnoli L, Guazzini A. LEAP Motion Technology and Psychology: A Mini-Review on Hand Movements Sensing for Neurodevelopmental and Neurocognitive Disorders. International journal of environmental research and public health. 2021; 18(8).

Technological advancement is constantly evolving, and it is also developing in the mental health field. Various applications, often based on virtual reality, have been implemented to carry out psychological assessments and interventions, using innovative human-machine interaction systems. In this context, the LEAP Motion sensing technology has raised interest, since it allows for more natural interactions with digital contents, via an optical tracking of hand and finger movements. Recent research has considered LEAP Motion features in virtual-reality-based systems, to meet specific needs of different clinical populations, varying in age and type of disorder. The present paper carried out a systematic mini-review of the available literature using Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The inclusion criteria were (i) publication date between 2013 and 2020, (ii) being an empirical study or project report, (iii) written in English or Italian languages, (iv) published in a scholarly peer-reviewed journal and/or conference proceedings, and (v) assessing LEAP Motion intervention for four specific psychological domains (i.e., autism spectrum disorder, attention-deficit/hyperactivity disorder, dementia, and mild cognitive impairment), objectively. Nineteen eligible empirical studies were included. Overall, results show that protocols for attention-deficit hyperactivity disorder and autism spectrum disorder can promote psychomotor and psychosocial rehabilitation in contexts that stimulate learning. Moreover, virtual reality and LEAP Motion seem promising for the assessment and screening of functional abilities in dementia and mild cognitive impairment. As evidence is, however, still limited, deeper investigations are needed to assess the full potential of the LEAP Motion technology, possibly extending its applications. This is relevant, considering the role that virtual reality could have in overcoming barriers to access assessment, therapies, and smart monitoring.

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16. Diefenbach GJ, Stevens KT, Dunlap A, Nicholson AM, Grella ON, Pearlson G, Assaf M. Autistic Traits Moderate Reappraisal Success for Depression and Anxiety Symptoms. Journal of autism and developmental disorders. 2022; 52(4): 1435-43.

Cognitive reappraisal is associated with reduced emotional distress; however, little is known about the nature of this relationship in autism. This study tested whether autistic traits moderate reappraisal success (i.e., the negative correlation between reappraisal use and emotional symptom severity). Emotional symptoms were assessed using measures of depression, anxiety, and stress. It was hypothesized that more severe autistic traits would be associated with weaker reappraisal success across all scales. Data were collected from 377 adults using an on-line survey. Structural equation models found moderation effects for depression and anxiety, but not stress. Contrary to hypotheses, more severe autistic traits were associated with stronger reappraisal success. These preliminary results support including reappraisal in emotion regulation treatments for individuals with autistic traits.

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17. Ehinger Y, Matagne V, Cunin V, Borloz E, Seve M, Bourgoin-Voillard S, Borges-Correia A, Villard L, Roux JC. Analysis of Astroglial Secretomic Profile in the Mecp2-Deficient Male Mouse Model of Rett Syndrome. International journal of molecular sciences. 2021; 22(9).

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2-deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome.

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18. Fetta A, Carati E, Moneti L, Pignataro V, Angotti M, Bardasi MC, Cordelli DM, Franzoni E, Parmeggiani A. Relationship between Sensory Alterations and Repetitive Behaviours in Children with Autism Spectrum Disorders: A Parents’ Questionnaire Based Study. Brain sciences. 2021; 11(4).

The relationship between sensory profile and repetitive behaviours in autism spectrum disorder (ASD) has long been known. However, there is no consensus on the type of relationship that exists between them. This monocentric retrospective-prospective observational study aimed (a) to detect a clinical correlation between the severity of repetitive behaviours and the alterations of sensory profile in a sample of 50 children diagnosed with ASD; (b) to evaluate how different patterns of stereotypies and sensory alterations correlate with each other and with the main clinical-instrumental variables in the same sample. We enrolled 29 children in the retrospective phase of the study and 21 in the prospective phase. The Repetitive Behaviour Scale-Revised (RBS-R) and the Short Sensory Profile (SSP) were administered to the caregivers, and clinical-instrumental data were collected. SSP and RBS-R total scores directly correlated with a high significance rate. Among the subscales, the strongest correlations involved « Visual/Auditory Sensitivity », related to « Stereotyped Behaviour » and « Sameness Behaviour ». « Under-Responsive/Seeks Sensation » related to « Stereotyped Behaviour ». Sex and intellectual disability significantly influenced both the stereotypies and the sensory alterations of the examined population. In conclusion, this study provides new insights into the relationship between sensory alterations and repetitive behaviours in ASD children by using direct medical observation and parent observation.

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19. Floríndez LI, Floríndez DC, Price ME, Floríndez FM, Como DH, Polido JC, Baezconde-Garbanati L, Pyatak E, Cermak SA. Exploring Eating Challenges and Food Selectivity for Latinx Children with and without Autism Spectrum Disorder Using Qualitative Visual Methodology: Implications for Oral Health. International journal of environmental research and public health. 2021; 18(7).

Diet and food choices significantly impact teeth, including enamel quality and development of dental caries. However, studies focusing on diet and its relation to oral care in Latinx children with and without Autism Spectrum Disorders (ASD) have been minimally addressed in research. This qualitative study used an inclusive visual methodology to explore what Latinx caregivers learned about their child’s diet preferences and food routines in relation to their oral health. As a secondary aim, the study sought to explore whether notable differences in diet emerged between Latinx children with and without ASD. Participants were 32 Latinx caregivers from 18 families with children with and without Autism (n = 8 with a typically developing child and n = 10 with a child with ASD) who completed a food journal activity and photo elicitation interview. Interviews were thematically coded for themes pertaining to parents’ perceptions of their child’s diet and oral health. Findings of this study indicate that the process of taking photos helped Latinx caregivers to better situate the barriers and behaviors influencing everyday food routines in their children within the context of relating to their overall oral health. Via their active participation in the research process, parents were empowered to note strategies they could employ that would directly impact their child’s oral health outcomes, such as reducing juice intake and monitoring sugar consumption. Therefore, visual research methodologies are an important strategy for researchers to consider in order to empower participants to be part of the research process and part of the outcomes, and to offer better understanding of the lived experience of populations underrepresented in the literature, such as Latinx children with and without ASD and their families.

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20. Fridberg E, Khokhlovich E, Vyshedskiy A. Watching Videos and Television Is Related to a Lower Development of Complex Language Comprehension in Young Children with Autism. Healthcare (Basel, Switzerland). 2021; 9(4).

The effect of passive video and television watching duration on 2- to 5-year-old children with autism was investigated in the largest and the longest observational study to date. Parents assessed the development of 3227 children quarterly for three years. Longer video and television watching were associated with better development of expressive language but significantly impeded development of complex language comprehension. On an annualized basis, low TV users (low quartile: 40 min or less of videos and television per day) improved their language comprehension 1.4 times faster than high TV users (high quartile: 2 h or more of videos and television per day). This difference was statistically significant. At the same time, high TV users improved their expressive language 1.3 times faster than low TV users. This difference was not statistically significant. No effect of video and television watching duration on sociability, cognition, or health was detected.

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21. Furnary T, Garcia-Milian R, Liew Z, Whirledge S, Vasiliou V. In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder. Toxics. 2021; 9(5).

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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22. Gomes AR, Fernandes TG, Cabral JMS, Diogo MM. Modeling Rett Syndrome with Human Pluripotent Stem Cells: Mechanistic Outcomes and Future Clinical Perspectives. International journal of molecular sciences. 2021; 22(7).

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Among many different roles, MeCP2 has a high phenotypic impact during the different stages of brain development. Thus, it is essential to intensively investigate the function of MeCP2, and its regulated targets, to better understand the mechanisms of the disease and inspire the development of possible therapeutic strategies. Several animal models have greatly contributed to these studies, but more recently human pluripotent stem cells (hPSCs) have been providing a promising alternative for the study of RTT. The rapid evolution in the field of hPSC culture allowed first the development of 2D-based neuronal differentiation protocols, and more recently the generation of 3D human brain organoid models, a more complex approach that better recapitulates human neurodevelopment in vitro. Modeling RTT using these culture platforms, either with patient-specific human induced pluripotent stem cells (hiPSCs) or genetically-modified hPSCs, has certainly contributed to a better understanding of the onset of RTT and the disease phenotype, ultimately allowing the development of high throughput drugs screening tests for potential clinical translation. In this review, we first provide a brief summary of the main neurological features of RTT and the impact of MeCP2 mutations in the neuropathophysiology of this disease. Then, we provide a thorough revision of the more recent advances and future prospects of RTT modeling with human neural cells derived from hPSCs, obtained using both 2D and organoids culture systems, and its contribution for the current and future clinical trials for RTT.

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23. Groba B, Nieto-Riveiro L, Canosa N, Concheiro-Moscoso P, Miranda-Duro MDC, Pereira J. Stakeholder Perspectives to Support Graphical User Interface Design for Children with Autism Spectrum Disorder: A Qualitative Study. International journal of environmental research and public health. 2021; 18(9).

The development of digital supports for people with autism has increased considerably in recent years. Technology designers and developers have interpreted the needs and learning styles of people with autism in different ways. As a result, there are generic, non-specific or heterogeneous guidelines for the design and development of technology for people with autism. This study aims to identify and describe the recommended elements to support graphical user interface design for children with Autism Spectrum Disorder (ASD), considering the stakeholders’ perspective, engaged in a computer application development. A qualitative, longitudinal, multicentre study was carried out. A sample of 39 participants belonging to four groups of stakeholders participated: children with autism, family members, professionals with experience in the intervention with children with autism, and professionals with expertise in the design and development of assistive technology. The techniques used to formalise the collection of information from participants were semi-structured interviews and observation. MAXQDA 2020 software (Verbi Software, Berlin, Germany) was used to analyse the data. The result is a guide with suggestions to support an interface design that emerges from the stakeholder perspectives. This study provides useful information to offer alternatives for children with ASD and facilitate the understanding of daily life.

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24. Ji G, Li S, Ye L, Guan J. Gene Module Analysis Reveals Cell-Type Specificity and Potential Target Genes in Autism’s Pathogenesis. Biomedicines. 2021; 9(4).

Multiple genetic factors contribute to the pathogenesis of autism spectrum disorder (ASD), a kind of neurodevelopmental disorder. Genes were usually studied separately for their associations with ASD. However, genes associated with ASD do not act alone but interact with each other in a network module. The identification of these modules is the basis for the systematic understanding of the pathogenesis of ASD. Moreover, ASD is characterized by highly pathogenic heterogeneity, and gene modules associated with ASD are cell-type-specific. In this study, based on the single-nucleus RNA sequencing data of 41 post-mortem tissue samples from the prefrontal cortex and anterior cingulate cortex of 19 ASD patients and 16 control individuals, we applied sparse module activity factorization, a matrix decomposition method consistent with the multi-factor and heterogeneous characteristics of ASD pathogenesis, to identify cell-type-specific gene modules. Then, statistical procedures were performed to detect highly reproducible cell-type-specific ASD-associated gene modules. Through the enrichment analysis of cell markers, 31 cell-type-specific gene modules related to ASD were further screened out. These 31 gene modules are all enriched with curated ASD risk genes. Finally, we utilized the expression patterns of these cell-type-specific ASD-associated gene modules to build predictive models for ASD. The excellent predictive performance also proved the associations between these gene modules and ASD. Our study confirmed the multifactorial and cell-type-specific characteristics of ASD pathogeneses. The results showed that excitatory neurons such as L2/3, L4, and L5/6-CC play essential roles in ASD’s pathogenic processes. We identified the potential ASD target genes that act together in cell-type-specific modules, such as NRG3, KCNIP4, BAI3, PTPRD, LRRTM4, and LINGO2 in the L2/3 gene modules. Our study offers new potential genomic targets for ASD and provides a novel method to study gene modules involved in the pathogenesis of ASD.

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25. Kunze MG, Machalicek W, Wei Q, St Joseph S. Coaching via Telehealth: Caregiver-Mediated Interventions for Young Children on the Waitlist for an Autism Diagnosis Using Single-Case Design. Journal of clinical medicine. 2021; 10(8).

Years can elapse between parental suspicion of a developmental delay and a diagnostic assessment, ultimately delaying access to medically necessary, autism-specific intervention. Using a single-case, concurrent multiple baseline design, autism spectrum disorder symptomology (i.e., higher-order restrictive and repetitive behaviors and interests; higher-order RRBIs) was targeted in toddlers (21-35 months) waiting for a diagnostic appointment. Caregivers were coached via telehealth to mediate early intervention to decrease interfering, inflexible higher-order RRBIs during play using four evidence-based applied behavior analytic strategies: modeling, prompting, differential reinforcement of appropriate behaviors, and response interruption and redirection. Six mother-child dyads were recruited from pediatrician offices and early intervention service districts in the United States. All families were considered under-served, under-resourced, or living in rural locations. A visual analysis of the data combined with Tau-U revealed a strong basic effect between the intervention package and parent strategy use and child flexible and inflexible behavior. Findings were consistent across participants with one exception demonstrating a moderate effect for flexible behaviors yet a strong effect for inflexible behaviors. Standardized mean difference was beyond zero for all participants. Implications for science and practice include support for early intervention of higher-order RRBIs for young children with and at risk for ASD.

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26. Leung JH, Purdy SC, Corballis PM. Improving Emotion Perception in Children with Autism Spectrum Disorder with Computer-Based Training and Hearing Amplification. Brain sciences. 2021; 11(4).

Individuals with Autism Spectrum Disorder (ASD) experience challenges with social communication, often involving emotional elements of language. This may stem from underlying auditory processing difficulties, especially when incoming speech is nuanced or complex. This study explored the effects of auditory training on social perception abilities of children with ASD. The training combined use of a remote-microphone hearing system and computerized emotion perception training. At baseline, children with ASD had poorer social communication scores and delayed mismatch negativity (MMN) compared to typically developing children. Behavioral results, measured pre- and post-intervention, revealed increased social perception scores in children with ASD to the extent that they outperformed their typically developing peers post-intervention. Electrophysiology results revealed changes in neural responses to emotional speech stimuli. Post-intervention, mismatch responses of children with ASD more closely resembled their neurotypical peers, with shorter MMN latencies, a significantly heightened P2 wave, and greater differentiation of emotional stimuli, consistent with their improved behavioral results. This study sets the foundation for further investigation into connections between auditory processing difficulties and social perception and communication for individuals with ASD, and provides a promising indication that combining amplified hearing and computer-based targeted social perception training using emotional speech stimuli may have neuro-rehabilitative benefits.

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27. Manjeese W, Mvubu NE, Steyn AJC, Mpofana T. Mycobacterium tuberculosis-Induced Maternal Immune Activation Promotes Autism-Like Phenotype in Infected Mice Offspring. International journal of environmental research and public health. 2021; 18(9).

The maternal system’s exposure to pathogens during pregnancy influences fetal brain development causing a persistent inflammation characterized by elevated pro-inflammatory cytokine levels in offspring. Mycobacterium tuberculosis (Mtb) is a global pathogen that causes tuberculosis, a pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of autism spectrum disorder (ASD), it is not known whether Mtb infection is sufficient to induce ASD associated behaviors, immune dysregulation and altered expression of synaptic regulatory genes. The current study infected pregnant Balb/c mice with Mtb H37Rv and valproic acid (VPA) individually and in combination. Plasma cytokine profiles were measured in offspring using the Bio-plex Th17 pro mouse cytokine panel. Mtb infection increased plasma interleukin (IL)-6 and IL-17A, while tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ and IL-1β were reduced when compared with saline. Mtb-induced maternal immune activation (MIA) offspring displayed increased grooming behavior. The study also revealed dysregulation in gene expression of synaptic molecules in the cerebellum. MIA rescued the VPA-induced effects on self-grooming and social interaction behaviors. Our finding therefore highlights a potential role of Mtb as a MIA agent that can potentially contribute to ASD.

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28. McConkey R, Samadi SA, Mahmoodizadeh A, Taggart L. The Use of Psychotropic Medication in Iranian Children with Developmental Disabilities. International journal of environmental research and public health. 2021; 18(8).

The use of psychotropic medication in children is increasing worldwide. Children with developmental disabilities seem to be prescribed these medications at a higher rate compared to their non-disabled peers. Little is known about prescribing in non-Western, middle-income studies. In Iran, the file records of 1133 children, aged 2 to 17 years, assessed as having autism spectrum disorder (ASD) or an intellectual disability (ID) in Tehran City and Province from 2005 to 2019 were collated, and information from parental reports of medications was extracted. Upwards of 80% of children with ASD and 56% of those with ID were prescribed a psychotropic medication with around one quarter in each group taking two or more medications. The rates were higher among male children showing difficult-to-manage behaviors such as hyperactivity, but less so for children of fathers with higher levels of education. The lack of alternative management strategies may be a significant driver for the use of psychotropic medications in Iran and other Low and Middle Income countries, despite their known side effects, and their failure to address the developmental needs of the children. Rather, multi-disciplinary, behavioral, therapeutic, and educational interventions are required, but these are not available widely in Iran, although a start has been made.

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29. Napoli SB, Vitale MP, Cafiero PJ, Micheletti MB, Bradichansky PP, Lejarraga C, Urinovsky MG, Escalante A, Rodriguez E, Schiariti V. Developing a Culturally Sensitive ICF-Based Tool to Describe Functioning of Children with Autism Spectrum Disorder: TEA-CIFunciona Version 1.0 Pilot Study. International journal of environmental research and public health. 2021; 18(7).

BACKGROUND: Autism spectrum disorder (ASD) affects the daily functioning of children and their families; however, in Argentina, there are no standardized tools to guide the description, evaluation, and follow-up of functioning and disability of children with ASD. To fill this gap, the overarching purpose of this study was to create a novel tool guided by the International Classification of Functioning, Disability, and Health (ICF) Core Sets for ASD for clinical practice. METHODS: A multistep methodology was used to identify the most relevant ICF categories for an Argentinian clinical setting. The content of this ICF-based shortlist was piloted and revised according to the results. Subsequently, a toolbox of measures was proposed to operationalize each ICF category. Finally, profiles of the functioning of 100 children with ASD were created. RESULTS: An ICF-based tool called TEA-CIFunciona was created, consisting of 32 ICF categories (10 body functions, 15 activities and participation, 7 environmental factors categories). The application of TEA-CIFunciona incorporated a family-centered approach in ASD evaluations and helped identify functional needs. CONCLUSIONS: TEA-CIFunciona is the first ICF-based instrument that guides the description of functioning of children with ASD in Argentina. TEA-CIFunciona standardizes collaborative assessments in pediatric ASD populations in Latin American contexts.

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30. Oblacińska A. Editorial. Journal of mother and child. 2021; 24(3): 1-2.

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31. Oerbeck B, Overgaard KR, Attwood T, Bjaastad JF. « Less stress »: a pilot study on a cognitive behavioral treatment program for anxiety in children with autism spectrum disorders. Scandinavian journal of child and adolescent psychiatry and psychology. 2021; 9: 30-40.

BACKGROUND: Comorbid anxiety disorders are prevalent in children with autism spectrum disorders (ASD), but only a minority receives adequate treatment for anxiety. Cognitive behavioral therapy (CBT) has been shown to be effective in treating anxiety disorders. The objectives of the present pilot study were to test the feasibility of the CBT program « Less stress » for comorbid anxiety disorders in children with ASD and explore whether an improvement in diagnostic outcomes for anxiety disorders and symptoms of anxiety was found after treatment. METHODS: Participants were ten children diagnosed with ASD and anxiety disorders (eight boys, mean age = 9.5 years, range 8 – 12 years). The « Less Stress » program includes three months of weekly treatment sessions followed by three monthly booster sessions. Five therapists participated. A standardized semi-structured diagnostic interview with the mothers was used to assess comorbid disorders. Child anxiety symptoms were measured with the Revised Child Anxiety and Depression Scale (RCADS). RESULTS: The therapists found the manual easy to use but adaptations were necessary, particularly shorter sessions due to frequent (n = 7) comorbid Attention-Deficit/Hyperactivity Disorder. The participants found the program useful and the parents noted that they had learned methods they could continue using after the end of the program.Eight of ten children completed the treatment. Seven of the eight completers benefited from the program. Five of those seven children were free from all anxiety disorders, while two had fewer anxiety disorders. On a group level, a significant mean reduction of anxiety symptoms (RCADS) was found after treatment. CONCLUSION: The therapists found the « Less stress » program to be a feasible intervention in a sample of children with ASD and comorbid anxiety. The significant reduction of anxiety after treatment is promising, but a replication in a larger and more rigorous study is needed to investigate the effectiveness of the intervention.

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32. Oshima F, Murata T, Ohtani T, Seto M, Shimizu E. A preliminary study of schema therapy for young adults with high-functioning autism spectrum disorder: a single-arm, uncontrolled trial. BMC research notes. 2021; 14(1): 158.

OBJECTIVE: Psychological problems associated with isolation and mistrust are common among young adults with autism spectrum disorder (ASD). Schema therapy (ST) has recently been shown to be effective against chronic personality problems of various mental disorders, including personality disorders. This pilot clinical trial aimed to explore the feasibility and acceptability of ST in young adults with high-functioning ASD. RESULTS: Following the intervention, a significant reduction in early maladaptive schemas and improvements in quality of life and social adjustment were observed. ST may be feasible and is applicable to young adults with HF-ASD. Trial registration UMIN000014535; registered on July 11, 2014.

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33. Pecor KW, Barbayannis G, Yang M, Johnson J, Materasso S, Borda M, Garcia D, Garla V, Ming X. Quality of Life Changes during the COVID-19 Pandemic for Caregivers of Children with ADHD and/or ASD. International journal of environmental research and public health. 2021; 18(7).

The COVID-19 pandemic has presented many challenges to caregivers of children. Families with children with attention-deficit/hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) are an understudied but potentially vulnerable population to changes during the outbreak. As such, the aim of this study was to contrast quality of life for caregivers of children with ADHD and/or ASD, before and during the pandemic, compared to caregivers of neurotypical (NT) children. Total, Parent Health-Related Quality of Life, and Family Functioning Summary Scores from the Family Impact Module of the Pediatric Quality of Life Inventory(TM) were contrasted among caregivers of children with ADHD, ASD, comorbid ADHD and ASD, and NT development. For all scores, caregivers of ADHD and/or ASD children reported lower quality of life, both before and during the pandemic, in comparison to caregivers of NT children. For all diagnoses, quality of life decreased during the pandemic, but caregivers of children with ADHD and/or ASD reported a greater decrease in quality of life than caregivers for NT children. There are limitations to this study in terms of the composition of the sample and the survey methodology, but we are able to conclude that caregivers of children with ADHD and/or ASD have been disproportionately affected by the pandemic, and it is imperative that these families receive additional resources and support to improve their quality of life.

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34. Piras IS, Manti F, Costa A, Carone V, Scalese B, Talboom JS, Veronesi C, Tabolacci C, Persico AM, Huentelman MJ, Sacco R, Lintas C. Molecular biomarkers to track clinical improvement following an integrative treatment model in autistic toddlers. Acta neuropsychiatrica. 2021; 33(5): 267-72.

OBJECTIVES: Identifying an objective, laboratory-based diagnostic tool (e.g. changes in gene expression), when used in conjunction with disease-specific clinical assessment, could increase the accuracy of the effectiveness of a therapeutic intervention. METHODS: We assessed the association between treatment outcome and blood RNA expression before the therapeutic intervention to post-treatment (after 1 year) of five autism spectrum disorder (ASD) toddlers who underwent an intensive cognitive-behavioural intervention integrated with psychomotor and speech therapy. RESULTS: We found 113 significant differentially expressed genes enriched for the nervous system, immune system, and transcription and translation-related pathways. Some of these genes, as MALAT-1, TSPO, and CFL1, appear to be promising candidates. CONCLUSIONS: Our findings show that changes in peripheral gene expression could be used in conjunction with clinical scales to monitor a rehabilitation intervention’s effectiveness in toddlers affected by ASD. These results need to be validated in a larger cohort.

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35. Poole D, Gowen E, Poliakoff E, Jones LA. ‘No idea of time’: Parents report differences in autistic children’s behaviour relating to time in a mixed-methods study. Autism : the international journal of research and practice. 2021; 25(6): 1797-808.

Many everyday activities require us to organise our behaviours with respect to time. There is some evidence that autistic children have problems with how they perceive and understand time. However, little is currently known about this, or the ways in which behaviours related to time are impacted in daily life. In this study, 113 parents of autistic children and 201 parents of neurotypical children completed a questionnaire and open-ended questions about their child’s behaviour relating to time. Questionnaire scores were lower in the autistic group compared with neurotypicals, which suggests that behaviours relating to time are affected in autistic children. The open-ended responses further confirmed that the autistic children struggled with time and that this impacted on them and their family. Three key themes were identified. Theme 1: autistic children have problems with learning about concepts relating to time such as telling the time from a clock and using words to describe time (hours, minutes, etc.) appropriately. Theme 2: autistic children think about the future differently. Planning and working under time pressure were described as a problem. Theme 3: autistic children have strong interests which take up a lot of their attention and worrying about having sufficient time to pursue these interests causes anxiety. This research indicates that behaviours related to time can have a considerable impact on the lives of autistic children and that targeted support may be required.

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36. Reynolds M, Hoekel J, Tychsen L. Safety of phakic intraocular collamer lens implantation in 95 highly myopic special-needs children. Journal of cataract and refractive surgery. 2021; 47(12): 1519-23.

PURPOSE: To assess the safety of intraocular collamer lens (ICL) implantation in children with high ametropia by reporting rates and case specifics of perioperative and longer-term adverse events (AEs).
. SETTING: St. Louis Children’s Hospital at Washington University Medical Center, St. Louis, Missouri. DESIGN: Retrospective case series. METHODS: Clinical data were collated retrospectively for 95 special-needs children (160 eyes) implanted with a Visian ICL over the past 5 years. All surgeries were performed at St Louis Children’s Hospital under brief general anesthesia. The mean follow-up period was 2.0 ± 1.4 years (range, 0.5 to 5.2). RESULTS: The mean age at implantation was 9.3 ± 5.2 years (range, 1.8 to 25) and mean preoperative spherical equivalent refractive error was -11.20 ± 3.90 diopters (range, 4 to 22). 62 children (62/95, 65%) had a neurodevelopmental disorder. 3 eyes (3/160, 2%) reported minor AE, consisting of steroid-response ocular hypertension, which resolved with cessation of topical steroid drops. Endothelial cell loss averaged 8.1% over 2 years, comparable with that reported in ICL-implanted adults. The most common major AE (7 eyes [7/160, 4%]) was postoperative pupillary block, requiring revision of the peripheral iridotomy. 1 child (1 eye [1/160, 0.6%]) with self-injurious behavior required repair of a wound leak. 1 child (1 eye [1/160, 0.6%]) with Down syndrome developed a cataract 2.8 years after ICL surgery, and 1 child (1 eye [1/160, 0.6%]) with severe autism spectrum disorder experienced traumatic retinal detachment 1.2 years after implantation. CONCLUSIONS: The most common major AE among the cohort with Visian ICL was pupillary block due to closure of the iridotomy. Overall, the AE rate was low in this higher risk, difficult-to-manage population of special-needs children.

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37. Robea MA, Ciobica A, Curpan AS, Plavan G, Strungaru S, Lefter R, Nicoara M. Preliminary Results Regarding Sleep in a Zebrafish Model of Autism Spectrum Disorder. Brain sciences. 2021; 11(5).

Autism spectrum disorder (ASD) is one of the most salient developmental neurological diseases and remarkable similarities have been found between humans and model animals of ASD. A common method of inducing ASD in zebrafish is by administrating valproic acid (VPA), which is an antiepileptic drug that is strongly linked with developmental defects in children. In the present study we replicated and extended the findings of VPA on social behavior in zebrafish by adding several sleep observations. Juvenile zebrafish manifested hyperactivity and an increase in ASD-like social behaviors but, interestingly, only exhibited minimal alterations in sleep. Our study confirmed that VPA can generate specific ASD symptoms, indicating that the zebrafish is an alternative model in this field of research.

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38. Rojas-Torres LP, Alonso-Esteban Y, López-Ramón MF, Alcantud-Marín F. Mindfulness-Based Stress Reduction (MBSR) and Self Compassion (SC) Training for Parents of Children with Autism Spectrum Disorders: A Pilot Trial in Community Services in Spain. Children (Basel, Switzerland). 2021; 8(5).

This study aims to develop a clinical trial to test the efficacy of a mindfulness-based stress reduction (MBSR) and self-compassion (SC) program on self-reported values of anxiety, depression, and stress in parents of children with autism spectrum disorder (ASD) in primary school, in order to assess their integration into the framework of community intervention programs in Spain. METHODS: A brief 8-week training program using mindfulness-based intervention (MBSR) and self-compassion (SC) has been applied to twelve Valencian ASD parents, ten of whom completed the program. Participants were assigned to two groups; both groups received the same treatment but at two different measurement moments. Depression, anxiety, stress, satisfaction with life and mindful attention awareness measurements were performed, in all participants, in three testing stages. RESULTS: Analysis of variance results suggested that MBSR and SC training reduces stress and anxiety and increases mindful attention awareness. No significant changes were found in life satisfaction measurements. CONCLUSIONS: The small number of participants prevents us from generalizing the results found. More MBSR and SC clinical trials are needed in parents of ASD with results on anxiety, depression and stress in order to demonstrate the relevance of the inclusion of these programs in community-based early intervention services.

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39. Rostami Haji Abadi M, Neumeyer A, Misra M, Kontulainen S. Bone health in children and youth with ASD: a systematic review and meta-analysis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2021; 32(9): 1679-91.

Higher risk of fracture reported in individuals with autism spectrum disorder (ASD) might be linked to poor bone health and development in childhood. This study aimed to systematically review studies comparing imaged bone outcomes between children with ASD and typically developing children (TDC) or reference data, and to perform a meta-analysis comparing commonly reported bone outcomes. We searched articles published since August 2020 from PubMed, Cochrane Library, Web of Science, EMBASE, and Scopus databases. We included studies comparing areal bone mineral density (aBMD) between children with ASD and TDC in the qualitative analysis (meta-analysis), and evaluated other imaged bone outcomes qualitatively. Seven publications were identified for the systematic review, and four studies were included in the meta-analysis. The meta-analysis indicated lower aBMD at the total body (standardized mean difference = – 0.77; 95% CI, – 1.26 to – 0.28), lumbar spine (- 0.69; – 1.00 to – 0.39), total hip (- 1.00; – 1.82 to – 0.17), and femoral neck (- 1.07; – 1.54 to – 0.60) in children with ASD compared to TDC. Based on our qualitative review, limited evidence suggested 13% lower bone mineral content at the total body and 10-20% lower cortical area, cortical and trabecular thickness, and bone strength at the distal radius and tibia in children with ASD. Children with ASD have lower aBMD at the total body, lumbar spine, and hip and femoral neck compared to TDC. Limited evidence also suggests deficits in bone mineral content, micro-architecture, and strength in children with ASD.

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40. Siegel M, McGuire K, Veenstra-VanderWeele J, Stratigos K, King B, Bellonci C, Hayek M, Keable H, Rockhill C, Bukstein OG, Walter HJ. Practice Parameter for the Assessment and Treatment of Psychiatric Disorders in Children and Adolescents With Intellectual Disability (Intellectual Developmental Disorder). Journal of the American Academy of Child and Adolescent Psychiatry. 2020; 59(4): 468-96.

Intellectual disability (intellectual developmental disorder) (ID/IDD) is both a psychiatric disorder and a risk factor for co-occurring psychiatric disorders in children and adolescents. DSM-5 introduced important changes in the conceptualization and diagnosis of ID/IDD, and current research studies clarify assessment and treatment of co-occurring psychiatric disorders in this population. Optimal assessment and treatment of psychiatric illness in children and adolescents with ID/IDD includes modifications in diagnostic and treatment techniques, appreciation of variations in the clinical presentation of psychiatric disorders, an understanding of the spectrum of etiologies of behavioral disturbance, and knowledge of psychosocial and medical interventions.

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41. Signorini C, Leoncini S, Durand T, Galano JM, Guy A, Bultel-Poncé V, Oger C, Lee JC, Ciccoli L, Hayek J, De Felice C. Circulating 4-F(4t)-Neuroprostane and 10-F(4t)-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome. International journal of molecular sciences. 2021; 22(8).

Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between MECP2 mutations or RTT disease progression and plasma levels of 4(RS)-4-F(4t)-neuroprostane (4-F(4t)-NeuroP) and 10(RS)-10-F(4t)-neuroprostane (10-F(4t)-NeuroP) in typical RTT patients with proven MECP2 gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F(4t)-NeuroP and 10-F(4t)-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to MECP2 mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F(4t)-NeuroP and 10-F(4t)-NeuroP were significantly related to (i) the type of MECP2 mutations where higher levels were associated to gene deletions (p ≤ 0.001); (ii) severity of common hotspot MECP2 mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II (p ≤ 0.002); and (iv) deficiency in walking (p ≤ 0.0003). This study indicates the biological significance of 4-F(4t)-NeuroP and 10-F(4t)-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype-phenotype associations in RTT.

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42. Siracusano M, Postorino V, Riccioni A, Emberti Gialloreti L, Terribili M, Curatolo P, Mazzone L. Sex Differences in Autism Spectrum Disorder: Repetitive Behaviors and Adaptive Functioning. Children (Basel, Switzerland). 2021; 8(5).

Sex differences in restricted and repetitive behaviors (RRBs) in individuals with Autism Spectrum Disorder (ASD) have been explored with mixed findings. We aimed to investigate sex differences in RRBs through a specific measure-i.e., the Repetitive Behavior Scale Revised (RBS-R)-in a sample of preschool-age and school-age children with ASD. Additionally, we evaluated if RRBs were differently related to adaptive functioning within the male and the female age groups. A sample of 210 ASD individuals (3-18 years; 145 males, 65 females) underwent an in-depth assessment including a cognitive, adaptive functioning evaluation (i.e., the Adaptive Behavior Assessment System, Second Edition (ABAS-II)) and RRBs assessment (i.e., RBS-R). No significant sex differences on the RBS-R total score or any RBS-R subscale emerged. Within the group of older participants, RRBs were negatively associated with all adaptive skill domains independently from sex and age. Our results suggest a lack of sex differences in RRBs in our sample. Additionally, our findings highlight the possible negative impact of RRBs on adaptive skills in older individuals with autism, emphasizing the need for autistic individuals of both sexes to undergo an early intervention targeting RRBs, in order to improve their adaptive skills.

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43. Tomczak MT, Szulc JM, Szczerska M. Inclusive Communication Model Supporting the Employment Cycle of Individuals with Autism Spectrum Disorders. International journal of environmental research and public health. 2021; 18(9).

Difficulties with interpersonal communication experienced by individuals with autism spectrum disorders (ASD) significantly contribute to their underrepresentation in the workforce as well as problems experienced while in employment. Consistently, it is vital to understand how communication within the employment cycle of this group can be improved. This study aims to identify and analyze the possibilities of modifying the communication processes around recruitment, selection, onboarding, and job retention to address the specific characteristics and needs of the representatives of this group. This qualitative study is based on 15 in-depth interviews conducted with 21 field experts, i.e.,: therapists, job trainers, and entrepreneurs employing people with ASD. The findings of this research informed the creation of an inclusive communication model supporting the employment cycle of individuals with ASD. The most important recommendations within the model that was created include the modification of job advertisements, use of less structured job interviews, providing opportunities for mentorship, and supportive and non-direct, electronically mediated communication. To apply the above-mentioned solutions and take full advantage of the talents of people with ASD, it is also necessary to provide tailored sensitivity and awareness training programs for their direct addressees as well as their neurotypical colleagues, including managerial staff.

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44. Upadhyay J, Patra J, Tiwari N, Salankar N, Ansari MN, Ahmad W. Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder. Cells. 2021; 10(4).

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like « novel drugs for ASD » and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.

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45. Yeh TC, Bai YM, Tsai SJ, Chen TJ, Liang CS, Chen MH. Risks of Major Mental Disorders and Irritable Bowel Syndrome among the Offspring of Parents with Irritable Bowel Syndrome: A Nationwide Study. International journal of environmental research and public health. 2021; 18(9).

Irritable bowel syndrome (IBS) is a functional bowel disorder that is highly comorbid with mental disorders. However, few studies have examined the risk of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), and schizophrenia in the offspring of parents with IBS. We used nationally representative cross-sectional survey data to analyze cross-generational transmission patterns of both IBS and major mental disorders. Odds ratio (OR) was calculated by using logistic regression models with adjustment for potential confounding factors. Offspring of parents with IBS were more likely to develop IBS themselves (OR = 2.41, 95% confidence interval (CI), 2.09-2.78), ADHD (OR = 1.33, 95% CI, 1.08-1.62), and MDD (OR = 1.32, 95% CI, 1.04-1.68) than the controls. Data stratification by parental sex revealed that paternal IBS increased risk of ADHD (OR = 1.34, 95% CI, 1.01-1.77) in the offspring, while maternal IBS increased the risk of MDD (OR = 1.51, 95% CI, 1.11-2.06). This is the first study to reveal parental IBS is associated with IBS, ADHD, and MDD among offspring, suggesting the necessity for early implementation of prevention strategies for at-risk children.

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46. Zanghieri M, Menichetti G, Retico A, Calderoni S, Castellani G, Remondini D. Node Centrality Measures Identify Relevant Structural MRI Features of Subjects with Autism. Brain sciences. 2021; 11(4).

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental conditions characterized by impairments in social interaction and communication and restricted patterns of behavior, interests, and activities. Although the etiopathogenesis of idiopathic ASD has not been fully elucidated, compelling evidence suggests an interaction between genetic liability and environmental factors in producing early alterations of structural and functional brain development that are detectable by magnetic resonance imaging (MRI) at the group level. This work shows the results of a network-based approach to characterize not only variations in the values of the extracted features but also in their mutual relationships that might reflect underlying brain structural differences between autistic subjects and healthy controls. We applied a network-based analysis on sMRI data from the Autism Brain Imaging Data Exchange I (ABIDE-I) database, containing 419 features extracted with FreeSurfer software. Two networks were generated: one from subjects with autistic disorder (AUT) (DSM-IV-TR), and one from typically developing controls (TD), adopting a subsampling strategy to overcome class imbalance (235 AUT, 418 TD). We compared the distribution of several node centrality measures and observed significant inter-class differences in averaged centralities. Moreover, a single-node analysis allowed us to identify the most relevant features that distinguished the groups.

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47. Zoccante L, Marconi M, Ciceri ML, Gagliardoni S, Gozzi LA, Sabaini S, Di Gennaro G, Colizzi M. Effectiveness of Equine-Assisted Activities and Therapies for Improving Adaptive Behavior and Motor Function in Autism Spectrum Disorder. Journal of clinical medicine. 2021; 10(8).

Equine-assisted activities and therapies (EAAT) have been suggested to improve adaptive behavior, and possibly motor function, in autism spectrum disorder (ASD). This study investigated the effects of EAAT on adaptive behavior and motor function in 15 children with ASD (13 males) aged 7-15 years as well as the impact of EAAT on the magnitude of stress in the parent-child system and the evolution in the child interaction with both the trained therapist and the therapeutic animal through the 20 weekly sessions of EAAT. EAAT were associated with greater adaptive behavior and coordination (all p ≤ 0.01) as well as a progressive improvement in the child’s abilities to respond to the increasing complexity of such form of positive behavioral support (all p < 0.001). However, EAAT did not prove to be effective in reducing parental distress. Collectively, preliminary evidence presented here may have important public health implications and gives reason to hope that EAAT could possibly be an effective option in ASD, warranting further investigation of its potential benefits in clinical trials among larger samples.

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