1. Collis R. A response to Singer, Lutz, Escher, and Halladay’s « a full semantic toolbox is essential for autism research and practice to thrive » in Autism Research (published online 12 Dec 2022). Autism research : official journal of the International Society for Autism Research. 2023.

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2. Eldeeb SY, Ludwig NN, Wieckowski AT, Dieckhaus MF, Algur Y, Ryan V, Dufek S, Stahmer A, Robins DL. Sex differences in early autism screening using the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT-R/F). Autism : the international journal of research and practice. 2023: 13623613231154728.

This study examined a widely used autism screening tool, the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up to identify differences in screening for autism between toddler males and females. Examining sex differences in screening for autism in toddlerhood is important as it determines who will be referred for evaluations and receive diagnoses, which is critical for access to autism-specific early intervention. This study found that females were less likely to screen positive and be invited for evaluations compared with males. Females at high likelihood for autism were less likely to be diagnosed with autism, which decreases confidence in the screener’s results. Importantly, the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up accurately identified both males and females with autism. Future research should examine ways to improve accuracy in screening results for females.

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3. Hand BN, Hyer JM, Schenk A, Coyne A, Gilmore D, Wang L, Ejaz A. Comparing Kidney Transplant Rates and Outcomes Among Adults With and Without Intellectual and Developmental Disabilities. JAMA surgery. 2023.

IMPORTANCE: Improving equity in organ transplant access for people with intellectual and developmental disabilities (IDD) is a topic of social discourse in mainstream media, state legislation, and national legislation. However, few studies have compared evaluation rates, transplant rates, and outcomes among adults with and without IDD. OBJECTIVE: To compare rates of kidney transplant and transplant-specific outcomes between propensity-score matched groups of adults with end-stage kidney disease (ESKD [also referred to as end-stage renal disease (ESRD)]) with and without co-occurring IDD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included all Medicare inpatient and outpatient standard analytical files from 2013 through 2020. A total of 1 413 655 adult Medicare beneficiaries with ESKD were identified. Propensity-score matching was used to balance cohorts based on age, sex, race, follow-up duration, and Charlson Comorbidity Index. The matched cohorts consisted of 21 384 adults with ESKD (10 692 of whom had IDD) and 1258 kidney transplant recipients (629 of whom had IDD). Data were analyzed between June 1, 2022, and August 1, 2022. EXPOSURE: IDD. MAIN OUTCOMES AND MEASURES: Evaluation for kidney transplant, receipt of kidney transplant, perioperative complications, readmission, mortality, graft rejection, and graft failure. RESULTS: Of the 21 384 propensity-score matched adults with ESKD, the median (IQR) age was 55 (43-65) years, 39.2% were male, 27.4% were Black, 64.1% were White, and 8.5% identified as another race or ethnicity. After propensity score matching within the ESKD cohort, 633 patients with IDD (5.9%) received a kidney transplant compared with 1367 of adults without IDD (12.8%). Adults with IDD were 54% less likely than matched peers without IDD to be evaluated for transplant (odds ratio, 0.46; 95% CI, 0.43-0.50) and 62% less likely to receive a kidney transplant (odds ratio, 0.38; 95% CI, 0.34-0.42). Among matched cohorts of kidney transplant recipients, rates of perioperative complications, readmission, and graft failure were similar for adults with and without IDD. CONCLUSIONS AND RELEVANCE: Using the largest cohort of adult kidney transplant recipients with IDD to date, the study team found that rates of evaluation and transplant were lower despite yielding equivalent outcomes. These data support consideration of adults with IDD for kidney transplant and underscore the urgent need for antidiscrimination initiatives to promote the receipt of equitable care for this population.

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4. Jiao Y, Wang M, Li H, Jia Q, Xu L, Zhong L, Huang J, Li L, Xiang W, Yao P. Prenatal Exposure of Diabetes and Progestin-Mediated Autistic Biomarker in Peripheral Blood Mononuclear Cells. The European journal of neuroscience. 2023.

Despite the importance of early diagnosis and intervention, the diagnosis of autism spectrum disorders (ASD) remains delayed as it is mostly based on clinical symptoms and abnormal behaviors appearing after 2 years of age. Identification of autistic markers remains a top priority in achieving an early and effective ASD diagnosis. We have previously reported that prenatal exposure of hormones or diabetes triggers epigenetic changes and oxidative stress, resulting in gene suppression with autism-like behaviors in offspring. Here, a potential biomarker for ASD diagnosis was established through gene analysis in peripheral blood mononuclear cells (PBMC). The study from in vivo mouse showed that prenatal hormone exposure or maternal diabetes suppresses mRNA expression of ERRα, SOD2, GPER and RORA in the brain as well as oxidative stress and mitochondrial dysfunction, subsequently triggering autism-like behavior in mouse offspring. Also, similar gene suppression was found in hematopoietic stem cells (HSC) and PBMC, with inherited epigenetic changes being identified on the related promoters. The human case-control study found that mRNA levels of ERRα, SOD2, GPER and RORA were significantly reduced in PBMC from ASD subjects (n=132) compared with typically developing (n=135) group. The Receiver Operating Characteristic curve showed a 0.869 ± 0.021 of Area Under the Curve for ASD subjects with 95% confidence interval of 0.829-0.909, together with 1.000 of sensitivity and 0.856 of specificity. In conclusion, the combined mRNA expression in PBMC based on prenatal factor exposure-mediated gene suppression could be a potential biomarker for ASD diagnosis.

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5. Lee B, Lee J, Cheon JH, Sung HK, Cho SH, Chang GT. Corrigendum to « The Efficacy and Safety of Acupuncture for the Treatment of Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis ». Evidence-based complementary and alternative medicine : eCAM. 2023; 2023: 9840285.

[This corrects the article DOI: 10.1155/2018/1057539.].

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6. Louros SR, Seo SS, Maio B, Martinez-Gonzalez C, Gonzalez-Lozano MA, Muscas M, Verity NC, Wills JC, Li KW, Nolan MF, Osterweil EK. Excessive proteostasis contributes to pathology in fragile X syndrome. Neuron. 2023; 111(4): 508-25.e7.

In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1(-/y)) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1(-/y) mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1(-/y) neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention.

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7. Ma H, Cao Y, Li M, Zhan L, Xie Z, Huang L, Gao Y, Jia X. Abnormal amygdala functional connectivity and deep learning classification in multifrequency bands in autism spectrum disorder: A multisite functional magnetic resonance imaging study. Human brain mapping. 2023; 44(3): 1094-104.

Previous studies have explored resting-state functional connectivity (rs-FC) of the amygdala in patients with autism spectrum disorder (ASD). However, it remains unclear whether there are frequency-specific FC alterations of the amygdala in ASD and whether FC in specific frequency bands can be used to distinguish patients with ASD from typical controls (TCs). Data from 306 patients with ASD and 314 age-matched and sex-matched TCs were collected from 28 sites in the Autism Brain Imaging Data Exchange database. The bilateral amygdala, defined as the seed regions, was used to perform seed-based FC analyses in the conventional, slow-5, and slow-4 frequency bands at each site. Image-based meta-analyses were used to obtain consistent brain regions across 28 sites in the three frequency bands. By combining generative adversarial networks and deep neural networks, a deep learning approach was applied to distinguish patients with ASD from TCs. The meta-analysis results showed frequency band specificity of FC in ASD, which was reflected in the slow-5 frequency band instead of the conventional and slow-4 frequency bands. The deep learning results showed that, compared with the conventional and slow-4 frequency bands, the slow-5 frequency band exhibited a higher accuracy of 74.73%, precision of 74.58%, recall of 75.05%, and area under the curve of 0.811 to distinguish patients with ASD from TCs. These findings may help us to understand the pathological mechanisms of ASD and provide preliminary guidance for the clinical diagnosis of ASD.

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8. Mishra R, Kapoor S. Genetic Counselling for Global Developmental Delay/Intellectual Disability (GDD/ID) – Changing Landscapes and Persisting Challenges. Indian pediatrics. 2023; 60(1): 142-5.

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9. Peng L, Chen Z, Gao X. Altered rich-club organization of brain functional network in autism spectrum disorder. BioFactors (Oxford, England). 2023.

Despite numerous research showing the association between brain network abnormalities and autism spectrum disorder (ASD), contrasting findings have been reported from broad functional underconnectivity to broad overconnectivity. Thus, the significance of rich-hub organizations in the brain functional connectome of individuals with ASD remains largely unknown. High-quality data subset of ASD (n = 45) and healthy controls (HC; n = 47) children (7-15 years old) were retrieved from the ABIDE data set, and rich-club organization and network-based statistic (NBS) were assessed from resting-state functional magnetic resonance imaging (rs-fMRI). The rich-club organization functional network (normalized rich-club coefficients >1) was observed in all subjects under a range of thresholds. Compared with HC, ASD patients had higher degree of feeder connections and lower degree of local connections (degree of feeder connections: ASD = 259.20 ± 32.97, HC = 244.98 ± 30.09, p = 0.041; degree of local connections: ASD = 664.02 ± 39.19, HC = 679.89 ± 34.05, p = 0.033) but had similar in rich-club connections. Further, nonparametric NBS analysis showed the presence of abnormal connectivity in the functional network of ASD individuals. Our findings indicated that local connection might be more vulnerable, and feeder connection may compensate for its disruption in ASD, enhancing our understanding on the mechanism of functional connectome dysfunction in ASD.

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10. Rodriguez-Perez M, Kennedy M, Barker ED, Kreppner J, Solerdelcoll M, Sonuga-Barke EJS. The adult outcome of childhood quasi-autism arising following extreme institutional deprivation. Journal of child psychology and psychiatry, and allied disciplines. 2023.

BACKGROUND: Rutter and colleagues’ seminal observation that extended early life exposure to extreme institutional deprivation can result in what he termed quasi-autism (QA), informed both our understanding of the effects of adversity on development and the nature of autism. Here we provide the first detailed analysis of the adult outcomes of the group of institutionally deprived-then-adopted children identified as displaying QA. METHODS: Twenty-six adult adoptees identified with QA in childhood (Childhood QA+) were compared to 75 adoptees who experienced extended institutional deprivation (>6 months) but no QA (Childhood QA-), and 116 adoptees exposed to Low/No institutional deprivation. The outcomes were child-to-adult developmental trajectories of neuro-developmental symptoms (autism, attention-deficit/hyperactivity disorder (ADHD), disinhibited social engagement (DSE) and cognitive impairment), adult functioning, life satisfaction and mental health. RESULTS: Childhood QA+ was associated with elevated and persistent trajectories of broad-based autism-related difficulties, ADHD and DSE symptoms and low IQ, as well as adult mental health difficulties and functional impairment, including high rates of low educational attainment and unemployment. Life satisfaction and self-esteem were unaffected. Autism-related communication problems, in particular, predicted negative adult outcomes. Childhood QA+ was still associated with poor outcomes even when ADHD, DSE and IQ were controlled. CONCLUSIONS: Early and time-limited institutional deprivation has a critical impact on adult functioning, in part via its association with an early established and persistent variant of autism, especially related to communication difficulties. Apparent similarities and differences to non-deprivation related autism are discussed.

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11. Urbinati C, Lanzillotta C, Cosentino L, Valenti D, Quattrini MC, Di Crescenzo L, Prestia F, Pietraforte D, Perluigi M, Di Domenico F, Vacca RA, De Filippis B. Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome. Neuropharmacology. 2023; 224: 109350.

Metformin is the most common anti-diabetic drug and a promising therapy for disorders beyond diabetes, including Rett syndrome (RTT), a rare neurologic disease characterized by severe intellectual disability. A 10-day-long treatment rescued aberrant mitochondrial activity and restrained oxidative stress in a female RTT mouse model. However, this treatment regimen did not improve the phenotype of RTT mice. In the present study, we demonstrate that a 4-month-long treatment with metformin (150 mg/Kg/day, delivered in drinking bottles) provides a selective normalization of cognitive flexibility defects in RTT female mice at an advanced stage of disease, but it does not affect their impaired general health status and abnormal motor skills. The 4-month-long treatment also rescues the reduced activity of mitochondrial respiratory chain complex activities, the defective brain ATP production and levels as well as the increased production of reactive oxidizing species in the whole blood of RTT mice. A significant boost of PGC-1α-dependent pathways related to mitochondrial biogenesis and antioxidant defense occurs in the brain of RTT mice that received the metformin treatment. Further studies will have to verify whether these effects may underlie its long-lasting beneficial effects on brain energy metabolism.

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12. van der Westhuizen ET. Single nucleotide variations encoding missense mutations in G protein-coupled receptors may contribute to autism. British journal of pharmacology. 2023.

Autism is a neurodevelopmental condition with a range of symptoms that vary in intensity and severity from person to person. Genetic sequencing has identified thousands of genes containing mutations in autistic individuals, which may contribute to the development of autistic symptoms. Several of these genes encode G protein-coupled receptors (GPCRs) which are cell surface expressed proteins that transduce extracellular messages to the intracellular space. Mutations in GPCRs can impact their function, resulting in aberrant signalling within cells, and across neurotransmitter systems in the brain. This review summarises the current knowledge on autism-associated single nucleotide variations encoding missense mutations in GPCRs, and the impact of these genetic mutations on GPCR function. For some autism-associated mutations, changes in GPCR expression levels, ligand affinity, potency and efficacy have been observed; however, for many the functional consequences remain unknown. Thus, further work to characterise the functional impacts of the genetically identified mutations is required.

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13. Waizbard-Bartov E, Fein D, Lord C, Amaral DG. Autism severity and its relationship to disability. Autism research : official journal of the International Society for Autism Research. 2023.

Autism severity is currently defined and measured based exclusively on the severity levels of the two core symptom domains: social-communication and restricted or repetitive patterns of behaviors and interests. Autistic individuals, however, are often diagnosed with other medical, developmental, and psychological co-occurring conditions. These additional challenges such as intellectual disability, limited expressive and/or receptive language, and anxiety disorders, can have a tremendous impact on the day-to-day lives of autistic individuals, for both their adaptive functioning as well as their sense of wellbeing. Furthermore, the initial presentation of core symptoms and their likelihood of changing over time are influenced by the presence of such co-occurring conditions. In order to truly understand how a person’s autism impacts their life, both core symptoms as well as other challenges should be considered. This approach was recently taken byThe Lancet Commission on the future of care and clinical research in autism, which proposed the term « profound autism » for a subgroup of individuals presenting with high core symptom severity, co-occurring intellectual disability, and little or no language, who require extensive long-term care. Considering other individual factors such as daily living skills, specific support needs and environmental resources would also enhance the evaluation of disability in autistic individuals. As currently employed in the assessment of intellectual disability, a multidimensional approach to autism could provide a more comprehensive system for classification of impairment. At present, however, there is no formal way to designate the combined effect of these different aspects of autism on a person’s life. A comprehensive outlook that acknowledges impairments, capabilities, co-occurring conditions, and environmental factors would be useful for identifying subgroups of individuals as well as for determining individual needs and strengths in clinical assessments.

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14. Weigel B, Tegethoff JF, Grieder SD, Lim B, Nagarajan B, Liu YC, Truberg J, Papageorgiou D, Adrian-Segarra JM, Schmidt LK, Kaspar J, Poisel E, Heinzelmann E, Saraswat M, Christ M, Arnold C, Ibarra IL, Campos J, Krijgsveld J, Monyer H, Zaugg JB, Acuna C, Mall M. MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention. Molecular psychiatry. 2023.

MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

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15. Yang B, Wang M, Zhou W, Wang X, Chen S, Potenza MN, Yuan LX, Dong GH. Disrupted network integration and segregation involving the default mode network in autism spectrum disorder. Journal of affective disorders. 2023; 323: 309-19.

Changes in the brain’s default mode network (DMN) in the resting state are closely related to autism spectrum disorder (ASD). Module segmentation can effectively elucidate the neural mechanism of ASD and explore intra- and inter-network connections by means of the participation coefficient (PC). We used that resting-state fMRI data from 269 ASD patients and 340 healthy controls (HCs) in the current study. From the results, ASD subjects showed a significantly higher PC of the DMN than HC subjects. This difference was related to lower intra-module connections within the DMN and higher inter-network connections between the DMN and other networks. When the subjects were split into age groups, the results were verified in the 7-12- and 12-18-year-old age groups but not in the young adult group (18-25 years). When the subjects were divided according to different subtypes of ASD, the results were also observed in the classic autism and pervasive developmental disorder groups, but not in the Asperger disorder group. In conclusions, less developed network segregation in the DMN could be a valid biomarker for ASD. This provides network scientists with new insights into the intermodular connectivity configurations of complex networks from different dimensions in a systematic and comprehensive manner.

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