1. Ballester P, Espadas C, Londoño AC, Almenara S, Aguilar V, Belda C, Pérez E, Muriel J, Peiró AM. The challenge of detecting adverse events in adults with autism spectrum disorder who have intellectual disability. Autism research : official journal of the International Society for Autism Research. 2022; 15(1): 192-202.

Adults with autism spectrum disorder (ASD) and associated intellectual disability (ID) take a high number of different psychotropic drugs simultaneously. Nowadays, little is known about this multidrug pattern efficacy and safety. The present study has endeavored to fill this gap creating a local pharmacovigilance system. A 36-month, retrospective and prospective, observational, and multicenter pharmacovigilance study was carried out in adults with ASD and ID (n = 83). Information regarding ongoing medications (polypharmacy: taking simultaneously >4 drugs; safety profile: adverse events’ number, adverse drug reactions’ number, and affected system; and observed-to-expected [O/E] ratio using the summary of product characteristics), and current diagnoses were recorded. A median of four ongoing medications per participant was registered, half of the sample was under polypharmacy regimen. Regarding all ongoing medications, 50% were antipsychotic drugs, and 47% of participants had >1 antipsychotic prescribed. In contrast, only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related either to nervous or metabolic systems, and almost a third were not previously described in the corresponding drug summary of products characteristics. Extrapyramidalism, gynecomastia, hypercholesterolemia, and urinary retention were some AEs that occurred more frequently than expected (O/E ratio > 6 times) according to our data. The highest O/E ratio scores (>120 times) were for hypercholesterolemia and rhabdomyolysis caused by valproic acid. According to the number of adverse events and adverse drug reactions reported in electronic health records locally and nationally by clinicians, we need to increase awareness about medications safety. LAY SUMMARY: A 36-month study in adults with autism, ID, and polypharmacy (>4 drugs) was done to investigate drug safety on everyone. A median of four medications per person was registered, half were antipsychotic drugs, and 47% of participants had >1 antipsychotic medication simultaneously. Only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related to nervous or metabolic systems and a third were not previously described in the drug information sheet.

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2. Botha M. Academic, Activist, or Advocate? Angry, Entangled, and Emerging: A Critical Reflection on Autism Knowledge Production. Frontiers in psychology. 2021; 12: 727542.

There has been a focus on autistic-led and participatory research in autism research, but minimal discussion about whether the field is hospitable to autistic involvement. While the focus on participatory and/or autistic-led research is abundantly welcome, a wider conversation should also happen about how autistic people are treated in the process of knowledge creation. As such, I present a critical reflection on my experiences of academia as an autistic autism researcher. I open by questioning whether I am an academic, an activist, or an advocate before discussing my journey through academia, and my exposure to dehumanizing, objectifying, and violent accounts of autism. I highlight how the construction of objectivity has resulted in a failure to question the validity of these dehumanizing accounts of autism, which are regarded as « scientifically-sound » by virtue of their perceived « objectivity. » Furthermore, I discuss how the idea of objectivity is used to side-line autistic expertise in disingenuous ways, especially when this knowledge challenges the status-quo. Despite claiming to be value-free, these dehumanizing accounts of autism embody social and cultural values, with a complete lack of transparency or acknowledgment. I then discuss how these dehumanizing accounts and theories-entangled in values-reverberate into autistic people’s lives and come to be ways of constituting us. Following this, I discuss the rationality of the anger autistic people feel when encountering these accounts, and instead of urging people to distance themselves from these emotions, I discuss the value of « leaning-in » as a radical act of dissent in the face of research-based violence. I then make a call to action urging all those who write or speak about autism to engage reflexively with how their values shape their understanding and construction of autistic people. Lastly, I conclude by answering my opening question: I have emerged as an advocate, activist, and academic. For me, belonging to the autistic community, acknowledging our marginalization, and recognizing our suffering within society means that hope for a better and just future has always, and will always underpin my work.

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3. Dan B. Complex developmental disability: a case of ‘simplexity’?. Developmental medicine and child neurology. 2021; 63(11): 1240.

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4. Ferraro S, de Zavalia N, Belforte N, Amir S. In utero Exposure to Valproic-Acid Alters Circadian Organisation and Clock-Gene Expression: Implications for Autism Spectrum Disorders. Frontiers in behavioral neuroscience. 2021; 15: 711549.

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by restrictive patterns of behaviour and alterations in social interaction and communication. Up to 80% of children with ASD exhibit sleep-wake cycle disturbances, emphasising the pressing need for novel approaches in the treatment of ASD-associated comorbidities. While sleep disturbances have been identified in ASD individuals, little has been done to assess the contribution of the circadian system to these findings. The objective of this study is to characterise circadian behaviour and clock-gene expression in a valproic acid (VPA)-induced animal model of autism to highlight perturbations potentially contributing to these disturbances. Male and female VPA-exposed offspring underwent circadian challenges, including baseline light-dark cycles, constant dark/light and light pulse protocols. Baseline analysis showed that VPA-exposed males, but not females, had a greater distribution of wheel-running behaviour across light-dark phases and a later activity offset (p < 0.0001), while controls showed greater activity confinement to the dark phase (p = 0.0256). Constant light analysis indicated an attenuated masking response and an increase in the number of days to reach arrhythmicity (p < 0.0001). A 1-h light pulse (150 lux) at CT 15 after 6 days of constant dark showed that both sexes exposed to VPA exhibited a lesser phase-shift when compared to controls (p = 0.0043). Immunohistochemical and western-blot assays reveal no alterations in retinal organisation or function. However, immunohistochemical assay of the SCN revealed altered expression of BMAL1 expression in VPA-exposed males (p = 0.0016), and in females (p = 0.0053). These findings suggest alterations within the core clockwork of the SCN and reduced photic-entrainment capacity, independent of retinal dysfunction. The results of this study shed light on the nature of circadian dysregulation in VPA-exposed animals and highlights the urgent need for novel perspectives in the treatment of ASD-associated comorbidities.

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5. Gabis LV, Gross R, Barbaro J. Editorial: Personalized Precision Medicine in Autism Spectrum-Related Disorders. Frontiers in neurology. 2021; 12: 730852.

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6. Haffner DN, Bartram LR, Coury DL, Rice CE, Steingass KJ, Moore-Clingenpeel M, Maitre NL. The Autism Detection in Early Childhood Tool: Level 2 autism spectrum disorder screening in a NICU Follow-up program. Infant behavior & development. 2021; 65: 101650.

OBJECTIVE: Children born preterm are at increased risk for autism spectrum disorder (ASD). However, early diagnosis of ASD is challenging because conventional screening Level 1 tools are less reliable in this population. We sought to determine whether the Autism Detection in Early Childhood (ADEC) and Child Behavior Checklist (CBCL) could accurately identify children at risk for ASD in a NICU Follow-up setting and thus facilitate referral for formal ASD evaluation. METHOD: Children aged 18-36 months were recruited from a NICU Follow-up program. All children received presumptive diagnoses based on DSM-5 criteria and were screened for ASD risk with the ADEC and CBCL. Children scoring in the « at risk » range on either tool were referred for a full diagnostic ASD evaluation. RESULTS: Sixty-nine patients (median birth weight 1140 g; median gestational age 28 weeks) were included with 18 designated « at risk » for ASD. Nine (13 %) scored « at risk » on the ADEC and 12 (17 %) on the CBCL. Thirteen children underwent diagnostic ASD evaluation with 9 receiving a formal diagnosis of ASD. The ADEC demonstrated the best performance (sensitivity 89 %, specificity 98 %). The CBCL was less sensitive (sensitivity 50 %, specificity 90 %). Requiring elevated scores on both the CBCL and ADEC was specific but not sensitive (sensitivity 33 %, specificity 100 %). CONCLUSION: The ADEC performed well in identifying children at risk for ASD within this high-risk NICU cohort, adding benefit as an autism-specific screening tool over the CBCL alone.

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7. Hsueh YP, Lin YC. Editorial: Autism Signaling Pathways. Frontiers in cellular neuroscience. 2021; 15: 760994.

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8. Justus SA, Powell PS, Duarte A. Intact context memory performance in adults with autism spectrum disorder. Scientific reports. 2021; 11(1): 20482.

Research on memory in autism spectrum disorder (ASD) finds increased difficulty encoding contextual associations in episodic memory and suggests executive dysfunction (e.g., selective attention, cognitive flexibility) and deficient metacognitive monitoring as potential contributing factors. Findings from our lab suggest that age-related impairments in selective attention contribute to those in context memory accuracy and older adults tended to show dependence in context memory accuracy between relevant and irrelevant context details (i.e., hyper-binding). Using an aging framework, we tested the effects of selective attention on context memory in a sample of 23 adults with ASD and 23 typically developed adults. Participants studied grayscale objects flanked by two types of contexts (color, scene) on opposing sides and were told to attend to only one object-context relationship, ignoring the other context. At test, participants made object and context recognition decisions and judgment of confidence decisions allowing for an evaluation of context memory performance, hyper-binding, and metacognitive performance for context judgments in a single task. Results showed that adults with ASD performed similarly to typically developed adults on all measures. These findings suggest that context memory performance is not always disrupted in adults with ASD, even when demands on selective attention are high. We discuss the need for continued research to evaluate episodic memory in a wider variety of adults with ASD.

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9. Kanako KI, Sakakibara N, Murayama K, Nagatani K, Murata S, Otake A, Koga Y, Suzuki H, Uehara T, Kosaki K, Yoshiura KI, Mishima H, Ichimiya Y, Mushimoto Y, Horinouchi T, Nagano C, Yamamura T, Iijima K, Nozu K. BCS1L mutations produce Fanconi syndrome with developmental disability. Journal of human genetics. 2022; 67(3): 143-8.

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.

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10. Mulé CM, Sliwinski SK, Israel R, Lavelle TA. Developmental Behavioral Pediatrician Perspectives on Decision-Making in Early Treatment Planning for Children with Autism Spectrum Disorder. Journal of developmental and behavioral pediatrics : JDBP. 2022; 43(2): 71-9.

OBJECTIVE: Providers of children with autism spectrum disorder (hereafter « autism ») report higher levels of shared decision-making during initial diagnostic and treatment planning visits than observed. The goal of this study was to qualitatively explore this discrepancy by investigating provider perceptions of the parent-provider decision-making process in early treatment planning and the role for parents in this process. METHODS: We conducted semistructured qualitative interviews with developmental behavioral pediatricians (DBPs; n = 15) to investigate how they approach early treatment planning with parents. We analyzed participant characteristics using descriptive statistics. Interviews were audio-recorded, transcribed, and independently coded by 2 researchers until consensus was reached. Analyses were conducted using a modified grounded theory framework. RESULTS: DBPs reported that their primary role during early treatment planning was to provide diagnostic clarification and that parents’ primary role was to learn as much as they can about autism. Most DBPs wanted treatment planning to be collaborative, and perceived that parents had the same preference but might not have the knowledge or skills to effectively participate. DBPs identified additional barriers that influence the extent to which they engage parents in the collaborative decision-making and provided recommendations for enhancing the process. CONCLUSION: DBPs are proponents of collaborative treatment planning between parents and providers; however, there are many obstacles that prevent this. Strategies such as decision tools or aids and larger systemic reforms are necessary to support DBPs and parents in this process.

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11. Ocansey S, Pullen D, Atkinson P, Clarke A, Hadonou M, Crosby C, Short J, Lloyd IC, Smedley D, Assunta A, Shah P, McEntagart M. Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Clinical dysmorphology. 2022; 31(1): 11-7.

DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.

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12. Santoro G, Cuman M, Pizzuto A, Haxhiademi D, Lunardini A, Franchi E, Marrone C, Pak V, Assanta N, Cantinotti M. GORE® Cardioform ASD Occluder experience in transcatheter closure of « complex » atrial septal defects. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2022; 99(1): E22-e30.

OBJECTIVE: To evaluate the GORE® Cardioform ASD Occluder (GCO) (WL Gore & Associates, Flagstaff, AZ) device for « complex » atrial septal defects (ASD) closure. BACKGROUND: Transcatheter ASD closure is still challenging in « complex » clinical/anatomic settings. This study evaluated the results of GCO in closure of « complex » ASD in a tertiary referral center. METHODS: Between January 2020 and March 2021, 72 patients with significant ASD were submitted to transcatheter closure with GCO at our Institution. Based on clinical/anatomic characteristics, they were classified as « complex » (n = 36, Group I) or « simple » (n = 36, Group II). We considered as « complex », defects with rim deficiency (< 5 mm) other than antero-superior, relatively large (diameter/patient weight > 1.2 or diameter/patient BSA > 20 mm/m(2) ) or within a multifenestrated septum. Procedure results and early outcome were compared between the groups. RESULTS: Absolute and relative ASD size (20 ± 4 vs. 15 ± 3 mm, p < 0.0001; 0.9 ± 0.3 vs. 0.4 ± 0.2 mm/kg, p < 0.0001; 23 ± 7 vs. 12 ± 5 mm/m(2) , p < 0.0001), QP/QS (2.0 ± 0.8 vs. 1.4 ± 0.3, p < 0.001), procedure and fluoroscopy times (73 ± 36 vs. 43 ± 21 min, p < 0.0001; 16 ± 9 vs. 9 ± 4 min, p < 0.0001, procedure feasibility (94.4 vs. 100%, p < 0.0001) and overall complication rate (13.9 vs. 0%, p < 0.0001) were significantly different between the groups. Successful closure of "surgical" ASDs was achieved in 92% of cases. Complete closure at last follow-up evaluation did not significantly differ between the groups (97.1 vs. 100%, p = NS), as was wireframe fractures rate (49.1% in the overall population), without clinical, EKG and echocardiographic consequences. CONCLUSIONS: Percutaneous treatment with GCO device is effective and safe in high percentage of "complex" ASDs.

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13. Scholten I, Hartman CA, Hendriks P. Prediction Impairment May Explain Communication Difficulties in Autism. Frontiers in psychology. 2021; 12: 734024.

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14. Sipsock D, Tokadjian H, Righi G, Morrow EM, Sheinkopf SJ. Autism severity aggregates with family psychiatric history in a community-based autism sample. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2524-32.

The purpose of this study was to examine family psychiatric history in individuals with autism spectrum disorder (ASD) and its association with clinical presentation. Participants were 798 individuals with a clinical diagnosis of ASD, confirmed by the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), enrolled in Rhode Island Consortium for Autism Research and Treatment, a statewide research registry. Prior research suggests a specific behavioral phenotype in individuals with ASD who have family members with psychiatric diagnoses, including higher IQ and less severe language impairment. However, studies have not specifically investigated autism severity. We hypothesized that increased psychiatric family history would be associated with increased autism severity symptoms. Results show a strong association of increased burden of first-degree family psychiatric history with higher autism symptom severity as measured by Social Responsiveness Scale, Second Edition (SRS-2), but not with ADOS-2 severity scores, IQ, or adaptive functioning. These findings support the importance of investigating the contribution of psychiatric family history toward clinical ASD presentation. LAY SUMMARY: This study explored how family psychiatric history is related to clinical presentation of Autism Spectrum Disorder (ASD). Higher amounts of first-degree family psychiatric history was associated with higher autism symptom severity as measured by the Social Responsiveness Scale, Second Edition (SRS-2). The contribution of psychiatric family history requires ongoing investigation.

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15. Yáñez C, Maira P, Elgueta C, Brito M, Crockett MA, Troncoso L, López C, Troncoso M. [Prevalence estimation of Autism Spectrum disorders in chilean urban population]. Andes pediatrica : revista Chilena de pediatria. 2021; 92(4): 519-25.

INTRODUCTION: The prevalence of Autism Spectrum Disorder has increased, varying between 0.5 and 1% around the world. The prevalence of ASD in Chile is unknown. OBJECTIVE: To estimate the prevalence of ASD in two urban communes of Santiago, Chile. SUBJECTS AND METHOD: Cross-sectional epidemiological study. 272 children aged between 18-30 months who attended well-child visits at two Family Health Centers in two urban communes of Santiago participated. Consecutive sampling was used and chil dren who were already being monitored by neurology were excluded. Screening was performed using the Modified Checklist for Autism in Toddlers (M-CHAT). Those children with altered M-CHAT were evaluated by a pediatric neurologist at the San Borja Arriarán Clinical Hospital and diagnosed with ASD according to clinical criteria. The Autism Diagnostic Observation Schedule – Second Ver sion (ADOS-2) was used as a diagnostic complement. The prevalence of ASD was estimated with a 95% confidence interval. RESULTS: 44 children had altered M-CHAT; 5 of them were clinically diagno sed with ASD. A 1.95% prevalence of ASD (95% CI 0.81-4.63) was obtained, with a sex distribution of 4 boys per 1 girl. CONCLUSIONS: This study is the first estimate of ASD prevalence in two communes of Santiago, Chile. A high prevalence of this condition was observed, which highlights the need for obtaining resources for an early multidisciplinary approach for these patients.

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