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Alteration of the microbiota-gut-brain axis has been recently recognized as a possible contributor to the physiopathology of autism spectrum disorder (ASD). In this context, microRNA (miRNAs) dysfunction, implicated both in several neuropathological conditions including ASD and in different gastrointestinal disorders (GIDs), could represent an important modulating factor. In this contextual framework, we studied the transcriptional profile of specific circulating miRNAs associated with both ASD (miR-197-5p, miR-424-5p, miR-500a-5p, miR-664a-5p) and GID (miR-21-5p, miR-320a-5p, miR-31-5p, miR-223-5p) in a group of pre-schoolers with ASD and in typically developing (TD) peers. In the ASD group, we also assessed the same miRNAs after a 6-month supplementation with probiotics and their correlation with plasma levels of zonulin and lactoferrin. At baseline, the expression of miRNAs involved in ASD were significantly reduced in ASD pre-schoolers vs. TD controls. Regarding the miRNAs involved in GID, the expression levels of miR-320-5p, miR-31-5p, and miR-223-5p were significantly higher in ASD than in TD subjects, whereas miR-21-5p showed significantly reduced expression in the ASD group vs. TD group. Supplementation with probiotics did not significantly change the expression of miRNAs in the ASD population. We found a significative negative correlation between zonulin and miR-197-5p and miR-21-5p at baseline, as well as between lactoferrin and miR-223-5p after 6 months of probiotic supplementation. Our study confirms the presence of an altered profile of the miRNAs investigated in ASD versus TD peers that was not modified by supplementation with probiotics.

Lay Abstract: This study investigates the effects of a probiotic on preschoolers' brain electrical activity with autism spectrum disorder. Autism is a disorder with an increasing prevalence characterized by an enormous individual, family, and social cost. Although the etiology of autism spectrum disorder is unknown, an interaction between genetic and environmental factors is implicated, converging in altered brain synaptogenesis and, therefore, connectivity. Besides deepening the knowledge on the resting brain electrical activity that characterizes this disorder, this study allows analyzing the positive central effects of a 6-month therapy with a probiotic through a randomized, double-blind placebo-controlled study and the correlations between electroencephalography activity and biochemical and clinical parameters. In subjects treated with probiotics, we observed a decrease of power in frontopolar regions in beta and gamma bands, and increased coherence in the same bands together with a shift in frontal asymmetry, which suggests a modification toward a typical brain activity. Electroencephalography measures were significantly correlated with clinical and biochemical measures. These findings support the importance of further investigations on probiotics' benefits in autism spectrum disorder to better elucidate mechanistic links between probiotics supplementation and changes in brain activity.

A relationship between the presence of clinical symptoms and gastrointestinal (GI) disturbances associated with nutritional deficiencies, including vitamin D (25(OH)D) deficiency, has been observed in autism spectrum disorder (ASD). The aim was to evaluate 25(OH)D levels according to the annual rhythm cycle, gender, the severity of autism, nutritional or clinical status, inflammatory and metabolic biomarkers, GI symptoms, and the clinical response to probiotic/placebo supplementation in preschooler children with ASD. Eighty-one ASD preschoolers (67 males) were assessed with standardized tools for ASD severity (ADOS score) and GI symptoms (by GI-Index at six-items and at nine-items, the latter defined as the Total GI-Index). The 25(OH)D levels were compared among different ASD subgroups according to metabolic and inflammatory biomarkers (leptin, insulin, resistin, PAI-1, MCP-1, TNF-alfa, and IL-6), gender, and the presence or absence of: (i) GI symptoms, (ii) the response to probiotic supplementation (the improvement of GI symptomatology), (iii) the response to probiotic supplementation (improvement of ASD severity). Only 25% of the ASD children presented an adequate 25(OH)D status (≥30 ng/mL according to the Endocrine Society guidelines). All the 25(OH)D levels falling in the severe deficiency range (<10 ng/mL) were observed in the male subgroup. A significant inverse correlation between 25(OH)D and leptin was observed (R = −0.24, p = 0.037). An inverse correlation was found between 25(OH)D levels and the GI Index 6-Items and Total GI-Index (R = −0.25, p = 0.026; −0.27, = 0.009) and a direct relationship with the probiotic response (R = 0.4, p = 0.05). The monitoring of 25(OH)D levels and the co-administration of 25(OH)D and probiotic supplementation could be considered in ASD from early ages.

The alteration of the microbiota-gut-brain axis has been recently recognized as a critical modulator of neuropsychiatric health and a possible factor in the etiopathogenesis of autism spectrum disorders (ASD). This systematic review offers practitioners an overview of the potential therapeutic options to modify dysbiosis, GI symptoms, and ASD severity by modulating the microbiota-gut-brain axis in ASD, taking into consideration limits and benefits from current findings. Comprehensive searches of PubMed, Scopus, the Web of Science Core Collection, and EMBASE were performed from 2000 to 2021, crossing terms referred to ASD and treatments acting on the microbiota-gut-brain axis. A total of 1769 publications were identified, of which 19 articles met the inclusion criteria. Data were extracted independently by two reviewers using a preconstructed form. Despite the encouraging findings, considering the variability of the treatments, the samples size, the duration of treatment, and the tools used to evaluate the outcome of the examined trials, these results are still partial. They do not allow to establish a conclusive beneficial effect of probiotics and other interventions on the symptoms of ASD. In particular, the optimal species, subspecies, and dosages have yet to be identified. Considering the heterogeneity of ASD, double-blind, randomized, controlled trials and treatment tailored to ASD characteristics and host-microbiota are recommended.

Atypical eating habits are more common in children with autism spectrum disorders (ASD) than typically developing (TD) peers. Feeding problems may lead to the double burden of specific nutrient deficiencies and excessive weight gain, with a consequent increase in obesity prevalence. The dietary intake of Italian preschoolers with ASD compared to their TD peers and the impact of their dietary choices on their weight status and relationship to food selectivity (FS) were investigated. Dietary patterns and their associations with body mass index (BMI) were evaluated in 65 children with ASD and 82 peers with TD aged 1.3-6.4 years. Eating habits were assessed with a modified version of a parent-rated semi-quantitative Food Frequency Questionnaire. Moreover, the prevalence of FS and possible links with dietary patterns and BMI were investigated in the ASD group. Children with ASD consumed significantly higher amounts of simple sugars, processed and ultra-processed carbohydrates, both low- and high-fat animal proteins, and lower amounts of vegetables and fruits compared to peers with TD. The obesity rate was 1.5% in children with TD and more than fourfold (6.2%) in children with ASD, although the difference between groups was not statistically significant. FS was significantly more frequent in children with ASD than in peers with TD. Children with ASD and FS showed significantly lower annual intakes of vegetable proteins and fiber (considered essential nutrients for a healthy diet) than children with ASD without FS. Our results showed that children with ASD showed different dietary habits than those with TD, with the higher consumption of energy-dense foods and lower amounts of food-sourced fibers, which could place them at increased risk to develop overweight, obesity, and micronutrient deficiencies later in life.

The capacity of the Child Behavior Checklist 1½-5 (CBCL 1½-5) to identify children with autism spectrum disorder (ASD) at 18 months was tested on 37 children clinically referred for ASD and 46 children at elevated likelihood of developing ASD due to having an affected brother/sister. At 30 months the clinically referred children all received a confirmatory diagnosis, and 10 out of 46 siblings received a diagnosis of ASD. CBCL 1½-5 profiles were compared with a group of matched children with typical development (effect of cognitive level controlled for). The capacity of the CBCL 1½-5 DSM Oriented-Pervasive Developmental Problems scale to differentiate correctly between children diagnosed with ASD and children with typical development appeared dependent on group ascertainment methodology., (© 2021. The Author(s).)

Autism spectrum disorders (ASD) make up a heterogeneous group of neurodevelopmental disorders characterized by social and communication difficulties associated with repetitive and restrictive behaviors. Besides core features, metabolic imbalances, inflammation, gastrointestinal (GI) symptoms, and altered gut microbiota composition were often described in association with ASD, but their connection with the severity of autism (SA) remains unexplored. In this study, fecal metabolome, microbiota, and calprotectin levels of 80 ASD preschoolers were quantified and correlated with SA. Twelve of the fifty-nine molecules that were quantified by fecal metabolome analysis were significantly associated with SA. No links between SA or GI symptoms and microorganisms' relative abundance were highlighted. Significant correlations between bifidobacteria, Sutterella , lactobacilli relative abundance, and metabolomics profiles were found. These results suggest that fecal metabolome discriminates the SA and intestinal microorganisms mediate the link between metabolome and SA regardless of GI symptomatology. The study raises the possibility that grouping ASD populations through metabolomics and fecal microbiota could aid the identification of specific ASD endophenotypes, on the basis of the SA. Mechanistic studies focusing on detected biomarkers might be an option for future studies.

Background: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions whose etiopathogenesis derives from a complex interaction between genetic liability and environmental factors. In this framework, mounting evidence suggests that immune system dysfunction could be a risk factor contributing to the development of ASD in at least a subpopulation of individuals. In particular, some studies suggest an association between celiac disease (CD)-a long-term autoimmune disorder that primarily affects the small intestine triggered by the ingestion of gluten-and ASD, while others hypothesized a random link. This investigation aimed to evaluate the prevalence of CD in a large sample of school-aged children with ASD and to characterize their clinical profile., Methods: Medical records of 405 children with ASD aged 5-11 years (mean age: 7.2 years; SD: 1.8 years) consecutively referred to a tertiary-care university hospital between January 2014 and December 2018 were reviewed; among them, 362 had carried out serological testing for CD., Results: Nine patients with positive CD serology were identified, eight of which satisfied the criteria for CD diagnosis. The estimated CD prevalence in ASD children was 2.18% (95% CI, 0.8-3.7), which was not statistically different (1.58%; p = 0.36) from that of an Italian population, matched for age range, considered as a control group (95% CI, 1.26-1.90). Three out of the eight ASD patients with CD did not have any symptoms suggestive of CD., Conclusions: Our findings did not show a higher prevalence of CD in ASD children than in the control population, but could suggest the utility of routine CD screening, given its frequent atypical clinical presentation in this population.

Findings regarding sex differences in autism spectrum disorder (ASD), as far as core symptoms and psychiatric comorbidities (PC) are concerned, are inconsistent, inconclusive, or conflicting among studies. The lower prevalence of ASD in females than in males and the age and intelligence quotient (IQ) heterogeneity among samples made it difficult to investigate these differences. This case-control study tries to deepen the impact of sex differences on core symptoms of autism and PC in 214 preschoolers with ASD (mean age, 45.26) without impairment in non-verbal IQ (nvIQ ≥70). A total of 107 ASD females (mean age, 44.51 ± 13.79 months) were matched one by one with 107 males (mean age, 46.01 ± 13.42 months) for chronological age (±6 months) and nvIQ (±6 points). We used the Autism Diagnostic Observation Schedule 2 (ADOS-2) and the Child Behavior Checklist (CBCL) 1.5-5 to explore autism severity and PC. The results highlight that ASD females did not significantly differ from ASD males regarding the severity of autism. Statistically significant lower levels of emotionally reactive ( p = 0.005, η 2 = 0.04), anxious-depressed ( p = 0.001, η 2 = 0.05), internalizing problems ( p = 0.04, η 2 = 0.02), and DSM-Oriented Scales anxiety problems ( p = 0.02, η 2 = 0.04) in ASD females than in ASD males were also detected. Our findings of no difference in the autism severity and lower internalizing problems in females than males with ASD extend the knowledge of autism in females during preschool years. Compared to other similar studies on this topic, we can state that these results are not supported by differences in nvIQ between sexes nor by the presence of cognitive impairment. It confirms the need for clinicians to consider sex differences when describing autism psychopathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Prosperi, Turi, Guerrera, Napoli, Tancredi, Igliozzi, Apicella, Valeri, Lattarulo, Gemma, Santocchi, Calderoni, Muratori and Vicari.)

Since 2016, the project "Early Bird Diagnostic Protocol for Autism Spectrum Disorders (ASD)" funded by the Italian Ministry of Health has been operative at IRCCS Fondazione Stella Maris (FSM), Pisa (IT), with the main aim of developing early age-specific diagnostic protocols by longitudinally enrolling two different populations at risk for ASD: (i) toddlers with older siblings with ASD (FR) and (ii) toddlers referred by a child psychiatrist or pediatrician for suspected ASD (CR). On January 30, 2020, when the World Health Organization declared the outbreak of coronavirus disease 2019 (COVID-19), 136 patients (85 FR; 51 CR; 93 males; 43 females) had been enrolled in the project with 324 completed time points and 64 still missing. Considering both the huge psychological burden on families with toddlers at risk for ASD during the lockdown and the longitudinal studies reporting the positive "surveillance effect" in terms of a better outcome in at-risk toddlers, our priority has been to maintain regular contact and support to enrolled families. To do this, the research team, being authorized for smart-working research activities, has set up a detailed remote surveillance protocol (RSP). The RSP includes three online interviews and one online video registration of parent-child play. In the current community case study, the authors report the telehealth procedure and discuss possible future directions in developing remote assessment and new evaluation modalities for ecological parent-child play video recordings in at-risk populations. Hopefully, the surveillance protocol will further improve our ability to detect risk and activate early tailored intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Conti, Chericoni, Costanzo, Lasala, Mancini, Prosperi, Tancredi, Muratori, Calderoni and Apicella.)

The microbiota-gut-brain axis has been recently recognized as a key modulator of neuropsychiatric health. In this framework, probiotics (recently named "psychobiotics") may modulate brain activity and function, possibly improving the behavioral profiles of children with Autism Spectrum Disorder (ASD). We evaluated the effects of probiotics on autism in a double-blind randomized, placebo-controlled trial of 85 preschoolers with ASD (mean age, 4.2 years; 84% boys). Participants were randomly assigned to probiotics (De Simone Formulation) (n=42) or placebo (n=43) for six months. Sixty-three (74%) children completed the trial. No differences between groups were detected on the primary outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated Severity Score (ADOS-CSS). An exploratory secondary analysis on subgroups of children with or without Gastrointestinal Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated with probiotics a significant decline in ADOS scores as compared to that in the placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months. In the GI group treated with probiotics we found greater improvements in some GI symptoms, adaptive functioning, and sensory profiles than in the GI group treated with placebo. These results suggest potentially positive effects of probiotics on core autism symptoms in a subset of ASD children independent of the specific intermediation of the probiotic effect on GI symptoms. Further studies are warranted to replicate and extend these promising findings on a wider population with subsets of ASD patients which share targets of intervention on the microbiota-gut-brain axis., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02708901., (Copyright © 2020 Santocchi, Guiducci, Prosperi, Calderoni, Gaggini, Apicella, Tancredi, Billeci, Mastromarino, Grossi, Gastaldelli, Morales and Muratori.)

Background : Several studies have tried to investigate the role of inflammatory biomarkers in Autism Spectrum Disorder (ASD), and their correlations with clinical phenotypes. Despite the growing research in this topic, existing data are mostly contradictory. Methods : Eighty-five ASD preschoolers were assessed for developmental level, adaptive functioning, gastrointestinal (GI), socio-communicative and psychopathological symptoms. Plasma levels of leptin, resistin, plasminogen activator inhibitor-1 (PAI-1), macrophage chemoattractant protein-1 (CCL2), tumor necrosis factor-alfa (TNF-α), and interleukin-6 (IL-6) were correlated with clinical scores and were compared among different ASD subgroups according to the presence or absence of: (i) GI symptoms, (ii) regressive onset of autism. Results : Proinflammatory cytokines (TNF-α, IL-6 and CCL2) were lower than those reported in previous studies in children with systemic inflammatory conditions. GI symptoms were not correlated with levels of inflammatory biomarkers except for resistin that was lower in ASD-GI children ( p = 0.032). Resistin and PAI-1 levels were significantly higher in the group with "regression plus a developmental delay" onset (Reg+DD group) compared to groups without regression or with regression without a developmental delay ( p < 0.01 for all). Conclusions : Our results did not highlight the presence of any systemic inflammatory state in ASD subjects neither disentangling children with/without GI symptoms. The Reg + DD group significantly differed from others in some plasmatic values, but these differences failed to discriminate the subgroups as possible distinct ASD endo-phenotypes.

Background: Gastrointestinal (GI) problems are one of the most frequent comorbidities in Autism Spectrum Disorder (ASD) but can be under-recognized due to the concomitant communication difficulties of this population. Accordingly, some associated behaviors (AB) such as verbal and motor behaviors (VB and MB, respectively) have been identified as a possible expression of an underlying GI problem and evaluated through an ad hoc questionnaire (the Associated Behaviors Questionnaire -ABQ-). The aims of this study were to investigate the presence and the type of AB in an Italian sample of ASD preschoolers, and to determine their correlations with GI problems., Methods: We included 85 ASD preschoolers (mean age 4.14 years; SD 1.08) splitted into two groups (GI and No-GI) through the GI Severity Index instrument. AB were evaluated through the ABQ that includes VB, MB and Changes in overall state (C) clusters. Specific tools were administered to evaluate the ASD core ad associated symptoms, as well as the intellective and adaptive functioning., Results: The GI group (N = 30) showed significantly higher scores in all the three ABQ areas (VB, MB and C) than the No-GI group (N = 55), with a positive correlation between GI symptoms and some specific AB as well as ABQ Total score. By dividing the whole sample in verbal and non-verbal individuals, both specific and shared AB emerged in the two groups., Conclusions: Our results alert clinicians to consider behavioral manifestations as a possible expression of GI problems in ASD subjects. Therefore, the evaluation of AB may be useful to identify the presence of GI problems in the ASD populations, and especially in non-verbal ASD children.

An increased prevalence of psychiatric comorbidity (PC) in individuals with Autism Spectrum Disorders (ASD) is consistently reported. While several studies have examined PC in school-aged children, adolescents and adults with ASD, investigations on PC in preschoolers are less common. In this study, we explore the prevalence and the type of PC in a sample of 989 preschoolers with ASD through the DSM-Oriented Scales (DOS) of the Child Behavior Checklist (CBCL 1½-5) and their possible links with the core features of ASD and cognitive functioning. Results indicated that 37.8% of the sample had at least one PC in addition to ASD; these subjects displayed significantly higher Total score ( p = 0.02) and Social Affect score ( p = 0.003) on the ADOS-based calibrated severity scores (CSS), as well as lower ( p ≤ 0.0001) performance IQ (pIQ) compared to ASD individuals without PC. As far as the specific DOS, Affective Problems (AP) were detected in 23.4% of the whole sample, ADHD Problems (ADHD) in 17.3%, Anxiety Problems (AXP) in 16.7%, and Oppositional Problems (OP) in 7.9%. These different comorbidities were isolated in 195 subjects (Mono-comorbid group: 19.7% of the whole sample), while 179 subjects (18.1% of the whole sample) had two or more types of PC (Multi-comorbid group). One-way ANOVA revealed that subjects with multi-comorbidity have statistically significant lower pIQ and higher Total score and Social Affect score on CSS-ADOS. Specific differences for each type of comorbidity and gender differences were also discussed. Taken together, results indicate a considerable presence of PC in preschoolers with ASD that should be accurately considered during the assessment and diagnosis process in order to plan a tailored intervention based not only on core symptoms of ASD, but also on comorbid psychiatric condition since preschool age.

This study investigated the prevalence and type of gastrointestinal (GI) and food selectivity (FS) symptoms in 163 preschoolers with ASD, and their possible links with core ASD features and emotional/behavioural problems. 40.5% of children with ASD had at least one severe GI symptom or FS. Preschoolers with and without GI symptoms and with and without FS were significantly different on several emotional/behavioural problems and restrictive/repetitive behaviours, whereas they did not differ significantly on performance IQ and autistic severity. The GI plus FS group presented with Sleep Problems, Self-injurious Behaviors and Anxiety Problems. Results indicated the need for early identification of GI disturbances and FS in order to design tailored intervention for these symptoms frequently associated to challenging behaviours in ASD.

The complexity and heterogeneity of Autism Spectrum Disorders (ASD) require the implementation of dedicated analysis techniques to obtain the maximum from the interrelationship among many variables that describe affected individuals, spanning from clinical phenotypic characterization and genetic profile to structural and functional brain images. The ARIANNA project has developed a collaborative interdisciplinary research environment that is easily accessible to the community of researchers working on ASD (https://arianna.pi.infn.it). The main goals of the project are: to analyze neuroimaging data acquired in multiple sites with multivariate approaches based on machine learning; to detect structural and functional brain characteristics that allow the distinguishing of individuals with ASD from control subjects; to identify neuroimaging-based criteria to stratify the population with ASD to support the future development of personalized treatments. Secure data handling and storage are guaranteed within the project, as well as the access to fast grid/cloud-based computational resources. This paper outlines the web-based architecture, the computing infrastructure and the collaborative analysis workflows at the basis of the ARIANNA interdisciplinary working environment. It also demonstrates the full functionality of the research platform. The availability of this innovative working environment for analyzing clinical and neuroimaging information of individuals with ASD is expected to support researchers in disentangling complex data thus facilitating their interpretation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Recent investigations suggest a possible common genetic background between Autism Spectrum Disorders (ASD) and Celiac Disease (CD). However, studies regarding this association are scarce and often limited by the small sample sizes and/or large heterogeneity among ASD groups in terms of demographic and clinical features. The present study aims to investigate the overall CD prevalence (biopsy proven-CD patients plus screening detected tTG and EMA positive cases) in a large population of pre-schoolers with ASD referred to a tertiary care University Hospital., Methods: We retrospectively collected data about 382 children (mean age: 46.97 ± 13.55 months; age-range: 18-72 months) consecutively diagnosed as ASD (according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria) over the period 2010-2013, and who performed a serological CD screening., Results: The overall CD prevalence was 2.62%, which is statistically significant higher to that reported in the Italian paediatric population (p = 0.0246). Half of these children had no symptoms or risk factors related to CD when they performed the serological screening., Conclusions: If replicated, these data suggest the importance of regular screening for CD in young patients with ASD, and are of relevance for clinical and public health.

Archives for the history of malaria and malariology in Italy have been 'rediscovered' in the recent past. The Sezione di Storia della Medicina at Rome University conserves many different personal and institutional archives closely or loosely related to this topic. Many of them had been originally gathered and kept at the Istituto di Igiene at Rome University. Among them the Fondo Casini, of the 20th century, documenting the activity of public institutions such as the Società per gli Studi della Malaria and the Scuola Superiore di Malariologia; archives of the end of the 19th and beginning of the 20th century, such as the Fondo Bignami, Celli; and many others.

The life and activity of Adriano Buzzati-Traverso are significantly linked to the birth and development of genetics in Italy, as well as to the achievements and the shortcomings of the creation of a 'modern' notion and policy of science in our country. His archive sheds light on public and private aspects of his activity, especially the creation of important research centers.