1. Afsharnejad B, Lee EAL, Hayden-Evans M, Black MH, Alach T, Fridell A, Coco C, Johnson M, Bölte S, Girdler S. Adaptation and Feasibility of KONTAKT™ Social Skills Toolbox Group Program for Australian Autistic Children. Scand J Child Adolesc Psychiatr Psychol;2024 (Jan);12(1):20240011.

BACKGROUND: Although autistic individuals are interested in interacting with peers, they express a need for social skills programs that could support them in navigating their daily social world, which is governed by neurotypical social norms. AIM: This study investigated the feasibility and adaptability of the manualised and evidence-based program KONTAKT™ Social Skills Toolbox Group Program in supporting autistic children aged 8 to 12 years in navigating their everyday social worlds. MATERIAL AND METHODS: KONTAKT™ was delivered to 15 autistic children (Mage=10.87, SDage=1.04; 67% male) over 16, 60-minute sessions. A pre-test and post-test design was employed evaluating changes in personally meaningful social goals, social skills, quality of friendship and autistic traits. Focus groups were also conducted and analysed using thematic analysis post completion of the program, exploring participants, their parents and the KONTAKT™ trainer’s perceptions of the program. RESULTS: Findings suggest stakeholders’ satisfaction with the program’s content and structure, indicating the potential cross-age feasibility of KONTAKT™ in supporting autistic children to achieve their personally meaningful social goals and in improving their social performance navigating their daily social lives. CONCLUSION AND SIGNIFICANCE: This feasibility study supported the finalisation of KONTAKT™ children’s manual and workbooks, preparing it for further evaluation of its efficacy in a randomised controlled trial. (Australian New Zealand Clinical Registry: 12619000994189; ClinicalTrials.gov: NCT04024111).

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2. Alencar Quirino AH, Cavalcante JLR, Nogueira GN, Andrade AGM, Souza F, Bisol LW. Challenges in assessing the impact of maternal fish consumption and ω-3 supplement use on autism-related outcomes in children. Am J Clin Nutr;2024 (Dec);120(6):1457-1458.

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3. Alosaimi ME, Abduljabbar MH, Alzhrani RM, Saeed S, Ramzy S, Almalki AH. Development of a fluorescent nano-sensing probe for atomoxetine analysis: Additional clinical pharmacokinetic study. Spectrochim Acta A Mol Biomol Spectrosc;2024 (Dec 5);322:124793.

Atomoxetine is a psychostimulant drug used for the treatment of attention-deficit/hyperactivity disorder (ADHD) symptoms in people with autism. Herein, eco-friendly fluorescent carbon quantum dots (CQDs) were synthesized using black-eyed pea beans and characterized for the purpose of quantifying atomoxetine in pharmaceutical capsules and human plasma. The selectivity of these CQDs towards atomoxetine was improved by functionalizing their surface with an atomoxetine-tetraphenylborate ion complex. The quantification of atomoxetine is based on measuring the fluorescence quenching of the functionalized CQDs in response to varying concentrations of atomoxetine. The Stern-Volmer plot was employed to investigate the mechanism through which atomoxetine quenches the fluorescence intensity of the CQDs. The outcomes indicated a dynamic quenching mechanism. The applied method was optimized and validated in compliance with ICH requirements, resulting in excellent linearity across the concentration range of 50-800 ng/mL. The developed method was successfully used to quantify atomoxetine in pharmaceutical dosage form and human plasma with acceptable accuracy and precision outcomes. In addition, the method was applied for clinical pharmacokinetic study of atomoxetine in the plasma of children diagnosed with both autism and ADHD. Atomoxetine was rapidly absorbed after a single oral dose of 10 mg, reaching maximum concentration within two hours and having a half-life (t(1/2)) of 3.11 h. Moreover, the method demonstrates a notable degree of eco-friendliness, as evidenced by two greenness evaluation metrics; Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE).

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4. Ay H, Horata E, Öncü Kaya EM, Korkmaz OT. Increased Serotonin Levels and Unchanged Glutamate and GABA Levels in Thalamic Microdialysates Despite Reduced Cell Numbers in a Valproic Acid-Induced Autism Model. Neurochem Res;2024 (Dec 5);50(1):45.

Autism spectrum disorders (ASDs) are increasingly prevalent neurodevelopmental disorders characterized by deficits in social skills, abnormal sensory responses and a loss of neuronal cells. A key factor in these differences is thought to be an imbalance between excitation and inhibition. The aim of this study was to measure the levels of γ-aminobutyric acid (GABA), glutamate (GLU) and serotonin (5-HT) in the thalamus of a rat valproic acid (VPA)-induced ASD model and to correlate these levels with the number of thalamic cells. Ten pregnant Wistar rats were injected with 600 mg/kg VPA on Day 12.5 of gestation, whereas five control rats received saline. After the behavioral tests, the male pups were divided into ASD and control groups with ten animals each. At 55 days of age, pups underwent microdialysis under anesthesia, and thalamic samples were analyzed for GABA, GLU and 5-HT levels by ultrahigh-performance liquid chromatography (UHPLC). After microdialysis, the brain sections were stained, and the volumes of the thalamus and hemispheres were calculated using the Cavalieri method, with the number of neurons and glia determined using the optical fractionator method. Compared with the control group, the ASD group presented increased 5-HT levels, an increased hemispheric volume, a decreased thalamic volume and decreased numbers of thalamic neurons and glia. A negative correlation was observed between the GLU content and glial number in the control group but not in the ASD group. These results indicate a disturbed thalamic neurotransmitter balance. We suggest that the increased thalamic 5-HT levels in ASD rats indicates that 5-HT reuptake is inhibited by the GLU content, which remains unchanged, despite the reduced cell number.

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5. Ayoub G. Nutritional Aspects in the Neurodevelopment of Autism: Folate, Stress, and Critical Periods. J Med Food;2024 (Dec 5)

Autism spectrum disorder (ASD) is a developmental disability that can create significant challenges in behavior and communication. The prevalence of ASD is over 2% among 8-year-old children and the prevalence is similar across the globe. We suggest there are multiple critical periods during the fetal period and early post-natal years that set conditions for neurotypical development or for autism, via mechanisms that impact immunity. One critical period requires folate, a key methyl donor, with insufficient folate conditioning for ASD. Another critical period is altered by oxidative stress or inflammation, possibly linked to insufficient taurine to support microglial immunity, causing inflammatory-triggered alterations of neurotypical development, or by excessive oxidation related to low cysteine availability. We propose that supplementing reduced folate and taurine early in development, including both fetal and post-natal periods, may be most effective in reducing the severity of ASD symptoms by facilitating neurotypical passage through critical neurodevelopmental periods.

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6. Bertelli MO, Boniotti V, Scior K. Is it still autism? The increasing broadening of the autism spectrum. Autism Res;2024 (Dec 5)

Clinical significance of a broad autism phenotype (BAP) seems to be increasingly supported by growing reports of high prevalence of subthreshold autism spectrum disorder (sASD) or autistic traits (AT) in various demographic samples, particularly in individuals with psychiatric conditions. We question this increasing extension of the autism spectrum and its potential negative consequences for clinical services, research, cultural attitudes, and resource allocation, as well as alternative explanations of what is currently attributed to sASD and AT. In modern psychiatry the diagnostic threshold is paramount and associated with a significant impairment of functioning, implying that symptom specificity is more relevant than sensitivity. Within a syndrome, symptoms have to be present together, with the parts related to and interconnected with the whole. Single autism symptomatic dimensions have low syndromic specificity and can be observed in many different mental disorders. For instance, communication problems may present in communication disorders, social-cognitive difficulties can be found in schizophrenia, and rigid and/or repetitive behaviors can be found in obsessive compulsive disorder. One alternative interpretation of AT and/or sASD relates to personality traits. For example, within the Big 5 Model, low openness is associated with a dislike of change and a narrow range of interests, low extraversion with social withdrawal and coldness, and low agreeableness with disinterest in others and disregard for their feelings. These risks of overreliance on non-specific aspects of autism are particularly likely to occur with screening checklists, self-assessment, or assessment by a lay interviewer with only limited expertise in clinical assessment.

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7. Chen YF, Tsao CY, Chen YT, Chang HC, Li WY, Chiang JL, Chen CF, Chen CH, Gau SS, Lee KY, Lee LJ, Wang YC. Altered odor perception in Dlgap2 mutant mice, a mouse model of autism spectrum disorder. Behav Brain Res;2024 (Dec 2);480:115365.

Olfactory dysfunction has been observed in patients with Autism Spectrum Disorder (ASD). A microdeletion at the 8p23 terminal regions of chromosome 8p23 was identified in a Taiwanese patient with ASD, suggesting a potential association with mutations in the DLGAP2 gene. DLGAP2 is expressed in the olfactory bulb in rodents. The current study investigated olfactory phenotypes of Dlgap2 mutant mice. The results indicated that odor detection capabilities were comparable between wild-type (WT) and Dlgap2 mutant mice. However, homozygous mutant (Homo) mice showed less interest in sniffing odors of banana and almond but greater sniffing activity in response to bedding from unfamiliar cages. Notably, exposure to banana odor elicited significant c-fos expression in most olfaction-related brain regions of WT mice, while Homo mice did not show much increase in c-fos levels in major olfactory areas, which may correlate with their diminished sniffing behavior. Bedding stimuli induced pronounced c-fos expression in WT brains and some olfaction-related regions, including the olfactory bulb, amygdala, hypothalamus, and medial prefrontal cortex, in Homo mice. These mutants may still process olfactory signals from the bedding through a relatively narrow channel, which might elicit their interest, leading to increased sniffing behaviors that may compensate for their olfactory deficits. The DLGAP2 protein was absent in the olfactory bulb of Homo mice, and the levels of PSD95 and CaMKIIβ were also affected, indicating alterations in synaptic transmission and signaling within the olfactory system. This study evaluated olfactory perception in a mouse model of ASD, which may advance diagnostic and therapeutic strategies.

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8. Chuah JSM, Manahan AMA, Chan SY, Ngoh ZM, Huang P, Tan AP. Subregion-specific thalamocortical functional connectivity, executive function, and social behavior in children with autism spectrum disorders. Autism Res;2024 (Dec 5)

The thalamus has extensive cortical connections and is an integrative hub for cognitive functions governing social behavior. This study examined (1) associations between thalamocortical resting-state functional connectivity (RSFC) and social behavior in children and (2) how various executive function (EF) subdomains mediate the association between thalamocortical RSFC and social behavior. Children from the autism brain imaging data exchange (ABIDE) initiative with neuroimaging, behavioral, and demographic data were included in our study (age < 14, ASD; n = 207, typically developing; n = 259). Thalamocortical RSFC was examined for associations with social communication and interaction (SCI) scores (SRS; social responsiveness scale) using Spearman's rank-order correlation, first in ASD children and then in typically developing children. This was followed by a more granular analysis at the thalamic subregion level. We then examined the mediating roles of eight EF subdomains in ASD children (n = 139). Right thalamus-default mode network (DMN) RSFC was significantly associated with SCI scores in ASD children (ρ = 0.23, p(FDR) = 0.012), primarily driven by the medial (ρ = 0.22, p(FDR) = 0.013), ventral (ρ = 0.17, p(FDR) = 0.036), and intralaminar (ρ = 0.17, p(FDR) = 0.036) thalamic subregions. Cognitive flexibility (ACME = 0.13, p(unc) = 0.016) and emotional control (ACME = 0.08, p(unc) = 0.020) significantly mediated the association between right thalamus-DMN RSFC and SCI scores. This study provided novel insights into the association between thalamocortical RSFC and social behavior in ASD children at the thalamic subregion level, providing higher levels of precision in brain-behavior mapping. Cognitive flexibility and emotion regulation were highlighted as potential targets to ameliorate the downstream effects of altered thalamocortical connectivity to improve social outcomes in ASD children.

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9. Damkier P, Gram EB, Ceulemans M, Panchaud A, Cleary B, Chambers C, Weber-Schoendorfer C, Kennedy D, Hodson K, Grant KS, Diav-Citrin O, Običan SG, Shechtman S, Alwan S. Acetaminophen in Pregnancy and Attention-Deficit and Hyperactivity Disorder and Autistic Spectrum Disorder. Obstet Gynecol;2024 (Dec 5)

Acetaminophen is a common over-the-counter medication that recently gained substantial media attention regarding its use by pregnant individuals. In this clinical perspective, we discuss the strengths and limitations of the published literature on the effect of maternal acetaminophen use in pregnancy on the child’s risk of developing attention-deficit and hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD). Studies included were specifically selected on the basis of the quality and validity of ADHD or ASD outcome definitions. From a total of 56 identified studies, commentaries, and editorials of relevance, we critically reviewed nine studies with original data that satisfied our inclusion criteria and three meta-analyses. Most studies that have reported positive findings are difficult to interpret because they have important biases, notably a high degree of selection bias, variability in selection and adjustment for various potential confounders, and unmeasured familial confounding. When unobserved familial confounding through sibling analysis was controlled for, associations weakened substantially. This suggests that residual confounding from shared genetic and environmental factors may have caused an upward bias in the original observations. According to the current scientific evidence, in utero exposure to acetaminophen is unlikely to confer a clinically important increased risk of childhood ADHD or ASD. The current level of evidence does not warrant changes to clinical guidelines on the treatment of fever or pain in pregnancy. Prospective research designed to account for familial and psychosocial environmental factors related to both maternal use of acetaminophen and children’s neurodevelopment should be undertaken.

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10. Dong MY, Meredith L, Forrester-Jones R, Kothari A, Ryan D, Ryan BL, Mathews M, Sibbald SL. Individualized participatory care planning for individuals with intellectual and developmental disabilities: a qualitative descriptive study. BMC Health Serv Res;2024 (Dec 5);24(1):1547.

BACKGROUND: Goal setting for persons within health and social care environments can be a challenging task; although health and social care settings aim to address a person’s care needs, the literature tends to focus on health. Person-centred care should encompass the goals/needs/wants of the person, whether these goals focus on career, relationship, and/or health domains. To understand how a person-centred participatory goal setting process is carried out in a care environment, we used an integrated knowledge translation approach. METHODS: We conducted 11 semi-structured interviews with community-care staff to understand a person-centred planning process, including key components and impacts. RESULTS: The interviews provide a thorough understanding of an implemented approach to person-centred plans, including its creation, implementation, and benefits (for the person-supported, family, friends, and staff). Person-centred plans provide a map with which to plan activities based on a persons’ goals, interests, and capacities, and have positive impacts for the person-supported, family, friends, and staff. CONCLUSIONS: Our study highlights how a community-care organization can facilitate person-centred services through person-centred plans and has implications for wider uptake of person-centred plans in community-care organizations.

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11. Dorsey SG, Mocci E, Lane MV, Krueger BK. Rapid effects of valproic acid on the fetal brain transcriptome: implications for brain development and autism. Transl Psychiatry;2024 (Dec 4);14(1):482.

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 258 genes that have been reported to modulate fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. Notably, at least 40 genes that are known to regulate embryonic neurogenesis were dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or downregulated by VPA in the fetal brain and (b) associated with autism and/or known to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The genes meeting these criteria provide potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.

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12. Garcia-Cabau C, Bartomeu A, Tesei G, Cheung KC, Pose-Utrilla J, Picó S, Balaceanu A, Duran-Arqué B, Fernández-Alfara M, Martín J, De Pace C, Ruiz-Pérez L, García J, Battaglia G, Lucas JJ, Hervás R, Lindorff-Larsen K, Méndez R, Salvatella X. Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD. Nature;2024 (Dec 4)

The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders(1). We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD)(2). Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.

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13. Gogate A, Kaur K, Khalil R, Bashtawi M, Morris MA, Goodspeed K, Evans P, Chahrour MH. The genetic landscape of autism spectrum disorder in an ancestrally diverse cohort. NPJ Genom Med;2024 (Dec 4);9(1):62.

Autism spectrum disorder (ASD) comprises neurodevelopmental disorders with wide variability in genetic causes and phenotypes, making it challenging to pinpoint causal genes. We performed whole exome sequencing on a modest, ancestrally diverse cohort of 195 families, including 754 individuals (222 with ASD), and identified 38,834 novel private variants. In 68 individuals with ASD (~30%), we identified 92 potentially pathogenic variants in 73 known genes, including BCORL1, CDKL5, CHAMP1, KAT6A, MECP2, and SETD1B. Additionally, we identified 158 potentially pathogenic variants in 120 candidate genes, including DLG3, GABRQ, KALRN, KCTD16, and SLC8A3. We also found 34 copy number variants in 31 individuals overlapping known ASD loci. Our work expands the catalog of ASD genetics by identifying hundreds of variants across diverse ancestral backgrounds, highlighting convergence on nervous system development and signal transduction. These findings provide insights into the genetic underpinnings of ASD and inform molecular diagnosis and potential therapeutic targets.

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14. Huang Y, Chen W, Gan Y, Liu X, Tian Y, Zhang J, Li F. Prenatal exposure to per- and polyfluoroalkyl substances, genetic factors, and autistic traits: Evidence from the Shanghai birth cohort. J Hazard Mater;2024 (Dec 5);480:135857.

The epidemiological evidence regarding prenatal PFAS exposure and its interaction with genetic factors on the autistic traits risk is unclear. This study included 1610 mother-child pairs from the Shanghai Birth Cohort (SBC). Ten PFAS were quantified in blood serum collected in the first trimester. Child autistic traits were evaluated at age 4 using a Chinese version of the social responsiveness scale-short form (SRS-SF). We calculated the polygenic risk score (PRS) to evaluate the cumulative genetic effects of autism. Additive interaction models were established to explore whether genetic susceptibility modified the effects of prenatal PFAS exposure. After adjusting for confounders, we found prenatal PFOA exposure was associated with an increased risk of autistic traits in children (OR, 3.05; 95 % CI, 1.14-7.58), and the increased risk associated with PFOA was mitigated among women who reported pre-pregnancy folic acid supplementation. Additionally, an increased risk of autistic traits was observed in children with higher levels of prenatal PFHxS exposure and a high PRS (p for interaction = 0.021). Our findings suggest prenatal PFAS exposure may increase the risk of autistic traits in children, especially in those with a high genetic risk. Further research is warranted to confirm this association and explore the underlying mechanisms.

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15. Jansakova K, Hill M, Celusakova H, Repiska G, Bicikova M, Macova L, Polonyiova K, Kopcikova M, Ostatnikova D. Steroidogenic pathway in girls diagnosed with autism spectrum disorders. PLoS One;2024;19(12):e0312933.

The diagnostic prevalence of autism spectrum disorders (ASD) shows boys to be more affected than girls. Due to this reason, there is a lack of research including and observing ASD girls. Present study was aimed to detect hormones of steroidogenesis pathway in prepubertal girls (n = 16) diagnosed with ASD and sex and age matched neurotypical controls (CTRL, n = 16). Collected plasma served for detection of conjugated and unconjugated steroids using gas chromatography tandem-mass spectrometry. We observed higher levels of steroids modulating ionotropic receptors, especially, GABAergic steroids and pregnenolone sulfate in ASD group. Concentration of many steroids throughout the pathway tend to be higher in ASD girls compared to CTRL. Pregnenolone and its isomers together with polar progestins and androstanes, i.e. sulfated steroids, were found to be higher in ASD group in comparison with CTRL group. Based on steroid product to precursor ratios, ASD group showed higher levels of sulfated/conjugated steroids suggesting higher sulfotransferase or lower steroid sulfatase activity and we also obtained data indicating lower activity of steroid 11β-hydroxylase compared to CTRL group despite higher corticosterone level observed in ASD. These findings need to be generalized in future studies to examine both genders and other age groups.

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16. Jyothi BN, Angel S, Ravi Kumar CP, Tamhankar PM. Child with KBG syndrome. BMJ Case Rep;2024 (Dec 4);17(12)

We report a male child with developmental delay, microcephaly and facial dysmorphism in the form of a turri-brachycephaly-shaped skull, triangular face, posteriorly rotated lop ears, thick bushy eyebrows, synophrys, long deep philtrum and prominent incisors. The mobile application Face2Gene was used to screen the patient’s facial photographs for known syndromes. The application suggested a high likelihood of KBG syndrome. Exome sequencing confirmed this by identifying a heterozygous pathogenic known mutation p.Tyr1406Ter in the ANKRD11 gene. Thus, the diagnosis of KBG syndrome was suggested only by the Face2Gene application, and the confirmation required DNA testing such as exome sequencing analysis.

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17. Kim LY, Zehner KM, Halperin SJ, Grauer JN. Outcomes After Total Knee Arthroplasty in Patients With Autism: A Retrospective Database Study. J Am Acad Orthop Surg Glob Res Rev;2024 (Dec 1);8(12)

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with osteoarthritis for which total knee arthroplasty (TKA) may be considered. The safety and efficacy of TKA in patients with ASD had been poorly characterized. METHODS: Total knee arthroplasty patients were identified using the M157 PearlDiver database. Patients with autism spectrum disorder were matched 1:4 with control TKA patients based on age, sex, and Elixhauser Comorbidity Index (ECI). 90-day adverse events were compared by multivariable regression, controlling for age, sex, and ECI. 5-year rates of revision were compared using Kaplan-Meier survival analyses. RESULTS: Of 1,194,063 TKA patients, ASD was identified in 352 (0.02%). Patients with autism spectrum disorder were younger (60.0 vs. 65.8 years, P < 0.001) with higher ECIs (7.8 vs. 4.2, P < 0.001) than control patients. Patients with autism spectrum disorder had higher odds of aggregated adverse events driven by sepsis (odds ratio [OR] 3.11), pneumonia (OR 3.55), and urinary tract infection (OR 3.02) (P < 0.0036 for each). 5-year revision rates were not significantly different for the matched cohorts (P = 0.8000). CONCLUSION: Total knee arthroplasty patients with ASD had elevated odds of several infectious adverse events and may warrant additional perioperative precautions. No notable differences were observed in most adverse outcomes investigated, nor in 5-year implant survival, suggesting that patients with ASD can safely be considered for TKA.

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18. Lacroix A, Torija E, Logemann A, Baciu M, Cserjesi R, Dutheil F, Gomot M, Mermillod M. Cognitive flexibility in autism: How task predictability and sex influence performances. Autism Res;2024 (Dec 5)

While cognitive flexibility challenges are frequently reported in autistic individuals, inconsistencies in the findings prompt further investigation into the factors influencing this flexibility. We suggest that unique aspects of the predictive brain in autistic individuals might contribute to these challenges, potentially varying by sex. Our study aimed to test these hypotheses by examining cognitive flexibility under different predictability conditions in a sample including a similar number of males and females. We conducted an online study with 263 adults (127 with an autism diagnosis), where participants completed a flexibility task under varying levels of predictability (unpredictable, moderately predictable, and predictable). Our results indicate that as task predictability increases, performance improves; however, the response time gap between autistic and non-autistic individuals also widens. Moreover, we observe significant differences between autistic males and females, which differ from non-autistic individuals, highlighting the need to consider sex differences in research related to the cognition of autistic individuals. Overall, our findings contribute to a better understanding of cognitive flexibility and sex differences in autism in light of predictive brain theories and suggest avenues for further research.

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19. Li Y, Hu W, Lin B, Ma T, Zhang Z, Hu W, Zhou R, Kwok LY, Sun Z, Zhu C, Zhang H. Omic characterizing and targeting gut dysbiosis in children with autism spectrum disorder: symptom alleviation through combined probiotic and medium-carbohydrate diet intervention – a pilot study. Gut Microbes;2024 (Jan-Dec);16(1):2434675.

Autism spectrum disorder (ASD) currently lacks effective diagnostic and therapeutic approaches. Disruptions in the gut ecosystem have been observed in individuals with ASD, suggesting that targeting gut microbiota through probiotic and dietary supplementation may serve as a potential treatment strategy. This two-phase study aimed to characterize the fecal metagenome of children with ASD and investigate the beneficial effects of a combined probiotic and medium-carbohydrate intervention in ASD. Fecal metagenomes of children with ASD were compared to those of typically developing children, revealing intestinal dysbiosis in ASD, characterized by reduced levels of Prevotella sp. Dialister invisus, and Bacteroides sp. along with increased predicted abundances of inosine, glutamate, xanthine, and methylxanthine. The gut bacteriome and phageome exhibited high cooperativity. In a 3-month pilot study, Bifidobacterium animalis subsp. lactis Probio-M8 (Probio-M8) was administered alongside a medium-carbohydrate diet to Chinese children with ASD. The primary endpoint was the Childhood Autism Rating Scale (CARS), while the secondary endpoint was the Gastrointestinal Symptom Rating Scale (GSRS). A total of 72 autistic children were initially recruited for the intervention study, but only 53 completed the intervention. Probio-M8, in combination with dietary intervention, significantly improved CARS and GSRS scores, increased fecal levels of Bifidobacterium animalis, Akkermansia muciniphila, Fusicatenibacter saccharivorans, and Sutterella sp. while also reducing Blautia obeum (Benjamini-Hochberg corrected p ≤ 0.05 for all cases). The intervention also modulated fecal metabolites associated with the metabolism of amino acids (lysine), neurotransmitters (glutamate, γ-aminobutyric acid), polyunsaturated fatty acids (arachidonate, myristic acid), and vitamin B(3). In conclusion, Probio-M8 combined with medium-carbohydrate diet effectively improved ASD symptoms, with associated changes in the gut microbiome and metabolome, supporting its potential as an adjunctive therapy for ASD.

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20. Markfeld JE, Kiemel Z, Santapuram P, Bordman SL, Pulliam G, Clark SM, Hampton LH, Keçeli-Kaysili B, Feldman JI, Woynaroski TG. Links Between Early Prelinguistic Communication and Later Expressive Language in Toddlers With Autistic and Non-Autistic Siblings. J Speech Lang Hear Res;2024 (Dec 5):1-15.

PURPOSE: The present study explored the extent to which early prelinguistic communication skills predict expressive language in toddlers with autistic siblings (Sibs-autism), who are known to be at high likelihood for autism and language disorder, and a comparison group of toddlers with non-autistic older siblings (Sibs-NA). METHOD: Participants were 51 toddlers (29 Sibs-autism, 22 Sibs-NA) aged 12-18 months at the first time point in the study (Time 1). Toddlers were seen again 9 months later (Time 2). Three prelinguistic communication skills (i.e., intentional communication, vocalization complexity, and responding to joint attention) were measured at Time 1 via the Communication and Symbolic Behavior Scales Developmental Profile-Behavior Sample. An expressive language aggregate was calculated for each participant at Time 2. A series of correlation and multiple regression models was run to evaluate associations of interest between prelinguistic communication skills as measured at Time 1 and expressive language as measured at Time 2. RESULTS: Vocalization complexity and intentional communication displayed significant zero-order correlations with expressive language across sibling groups. Vocal complexity and responding to joint attention did not have significant added value in predicting later expressive language, after covarying for intentional communication across groups. However, sibling group moderated the association between vocalization complexity and later expressive language, such that vocal complexity displayed incremental validity for predicting later expressive language, covarying for intentional communication, only within Sibs-NA. CONCLUSIONS: Results indicate that prelinguistic communication skills, in particular intentional communication, show promise for predicting later expressive language in siblings of autistic children. These findings provide additional empirical support for the notion that early preemptive interventions targeting prelinguistic communication skills, especially intentional communication, may have the potential to scaffold language acquisition and support more optimal language outcomes in this population at high likelihood for a future diagnosis of both autism and language disorder. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.27745437.

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21. Raghavendra P, Hobbs D, Welz N, Trembath D, Petticrew R, Hinze E, Lange B. A pilot evaluation of school-based LEGO® robotics therapy for autistic students. Disabil Rehabil Assist Technol;2024 (Dec 5):1-13.

There is emerging evidence that LEGO® therapy is an effective way of supporting younger autistic children develop their communication and social skills. LEGO® robotics therapy – which uses the principles of LEGO® therapy applied to LEGO® robotics – may be an age-appropriate intervention to reduce anxiety and increase social skills in autistic adolescents. The aims of this study, involving 24 autistic students aged 13-16 years, were to examine (a) the effect of an 8-week LEGO® robotics therapy on students’ anxiety, social skills, academic motivation, and engagement, and (b) the views and perceptions of all stakeholders (students, parents, school staff and facilitators) regarding the program. An adapted explanatory sequential basic mixed-methods design was used. Groups of three students supported by two facilitators participated in the LEGO® robotics therapy for eight sessions at school. Quantitative data was collected before and after therapy using the Anxiety Scale for children-Autism Spectrum Disorder, Social Skills Improvement System and the Motivation and Engagement scale. Qualitative data was collected using open-ended online questionnaires, interviews, and focus groups from all stakeholders. No statistically significant within group differences were found in relation to students’ anxiety, social skills, motivation and engagement before and after the program. Qualitative findings indicated predominantly positive student experiences and outcomes such as better school attendance, increased confidence, and social skills. The findings suggest that LEGO® robotics therapy may be associated with a range of nuanced positive experiences and outcomes for individuals and groups of students, suggesting potential value in further efforts to refine the program. LEGO® robotics therapy, a combination of principles of LEGO® therapy and robotics was feasible to deliver in high school settings, implemented at school during school hours.Pilot evaluation shows that LEGO® robotics therapy has good acceptability by all stakeholders (autistic students, their parents, school staff and facilitators).All stakeholders reported positive effects of LEGO® robotics therapy on students’ social connection, engagement, and confidence.There was no statistically significant within-group changes using standardised measures on anxiety, social skills and motivation and engagement. eng

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22. Roh JD, Bae M, Kim H, Yang Y, Lee Y, Cho Y, Lee S, Li Y, Yang E, Jang H, Kim H, Kim H, Kang H, Ellegood J, Lerch JP, Bae YC, Kim JY, Kim E. Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice. Mol Psychiatry;2024 (Dec 5)

Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.

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23. Sáez-Suanes GP. Structure and dynamics of anxiety in people with ASD and ID: A network analysis. Autism Res;2024 (Dec 5)

Anxiety is a very common mental health disorder in the ASD population. Despite the common comorbidity this association is not well understood. To understand the relationship between anxiety symptoms and ASD in a sample of people with ASD and intellectual disability, a network analysis was carried out. One hundred and twenty-eight adults (M = 36.63 age, SD = 8,54) were evaluated to know the structure of anxiety symptoms in autism and their relationship with ASD symptomatology. The results showed a single network where both symptomatologies were mixed. Bridging symptoms such as fear of being touched, fear of something bad happening to them, and the need for invariance and anticipation were identified. Moreover, social issues such as difficulty in making friends were associated with anxiety symptoms. Knowing and identifying ASD symptoms that are strongly linked to the anxiety network has important implications for the prevention of anxiety in this case in people with autism and intellectual disabilities.

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24. Shen X, Huang P, Su M, Liu Z, Liu Q, Guo Y, Zheng L. Impact of remote collaboration-based family physical activity on activity levels and quality of life in children with intellectual developmental disabilities. Front Public Health;2024;12:1464099.

BACKGROUND: Low levels of physical activity (PA) are prevalent among children with intellectual and developmental disabilities (IDD). Implementing family-based physical activities as extracurricular interventions offers a promising approach to enhancing their PA levels and promoting overall health. PURPOSE: This study aims to explore a novel integrative strategy by combining family-based activities with school physical education classes, with the objective of enhancing PA levels and improving the quality of life (QoL) for children with IDD. Methods: A total of 36 children with IDD (mean age = 16.4 years) were randomly assigned to a 6-month intervention group (IG) or a control group (CG). Both groups received adjusted adaptive physical education, while the IG received additional family support. Assessments of PA, QoL, and the Physical Activity Enjoyment Scale (PACES) were conducted at baseline, after 6 months, and at a 2-month follow-up post-intervention. RESULTS: The 6-month intervention results showed that the IG had a significant increase in moderate to vigorous physical activity (MVPA) compared to the CG (p < 0.001, d = 3.87) and a reduction in sedentary behavior (p < 0.001, d = 2.28). Additionally, there were improvements in WHOQOL-DIS scores (p < 0.001, d = 1.61) and PACES scores (p < 0.001, d = 1.14). At the 2-month follow-up, the IG also showed significant improvements in MVPA, sedentary behavior, and PACES scores, all with p-values below 0.001, while no significant change was observed in WHOQOL-DIS scores (p = 0.914). CONCLUSION: Family-based physical activities facilitated through remote collaboration not only improved the PA levels of children with IDD and enhanced their quality of life, but also positively contributed to the maintenance of long-term healthy behaviors.

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25. Srividhya D, Parambath SV, Sathyanarayanan R, Huligerepura Sosalegowda A, Korlimarla A, Niranjana Murthy AS, Prabhakaran N, Vijayanand M, Gowda NKC. Whole Exome Sequencing of a Multiplex Family of Indian Origin Identifies Variants in the RAI1 and FLII Genes within the 17p11.2 Region in Siblings with Autism and Smith Magenis Syndrome. Mol Syndromol;2024 (Dec);15(6):537-544.

INTRODUCTION: Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by restrictive repetitive behavior and impairment in social and communication skills. They are extremely heterogeneous with a strong genetic preponderance. They are clinically highly convoluted, presenting with multiple comorbid conditions and syndromic features. More than 100 genes have been identified to date. METHOD: Whole exome sequencing (WES) has emerged as a valuable tool in evaluating the genetic underpinnings of ASDs, be it the syndromic or the idiopathic variants. In the current study, we performed WES on a multiplex family of Indian origin to investigate the disease etiology in the siblings (S1 [Female] and S2 [Male]) exhibiting ASD syndromic features, at both clinical and genetic aspects. RESULTS: Exome sequencing identified a missense variant (NM_030665.4:c.5320C>T; p.Arg1774Trp) in S1 resulting in RAI1 haploinsufficiency. Validation by Sanger sequencing confirmed that the variant was true positive and maternally transmitted in the subject. Likewise, we report an inherited missense variant at the same locus (17p11.2) corresponding to the FLII gene (NM_002018.4:c.2030A>C; p.Glu677Ala) in the other sibling, S2. Both the variants were reported in the Smith Magenis syndrome (SMS) critical region justifying their contribution to the presentation of the syndromic SMS features. These WES findings were consistent with the clinical findings that imply SMS features in both siblings. CONCLUSION: The current study employed WES to provide insights into the genetic complexity associated with syndromic ASD and how that contributes to the disease heterogeneity. Moving forward, combinatorial approaches and findings from syndromic ASDs can potentially act as indicators to understand the genetic and phenotypic variations seen in idiopathic ASD.

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26. Su Q, Wong OWH, Lu W, Wan Y, Zhang L, Xu W, Li MKT, Liu C, Cheung CP, Ching JYL, Cheong PK, Leung TF, Chan S, Leung P, Chan FKL, Ng SC. Author Correction: Multikingdom and functional gut microbiota markers for autism spectrum disorder. Nat Microbiol;2024 (Dec 4)

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27. Su WC, Mutersbaugh J, Huang WL, Bhat A, Gandjbakhche A. Using deep learning to classify developmental differences in reaching and placing movements in children with and without autism spectrum disorder. Sci Rep;2024 (Dec 5);14(1):30283.

Autism Spectrum Disorder (ASD) is among the most prevalent neurodevelopmental disorders, yet the current diagnostic procedures rely on behavioral analyses and interviews, without objective screening methods to support the diagnostic process. This study seeks to address this gap by integrating upper limb kinematics and deep learning methods to identify potential biomarkers that could be validated in younger age groups in the future to enhance the identification of ASD. Forty-one school-age children, with and without an ASD diagnosis (mean age ± SE: TD group: 10.3 ± 0.8, 8 males and 7 females; ASD group: 10.3 ± 0.5, 21 males and 5 females), participated in the study. A single Inertial Measurement Unit (IMU) was affixed to the child’s wrist as they engaged in a continuous reaching and placing task. Deep learning techniques were employed to classify children with and without ASD. Our findings suggest differential movement kinematics in school-age children compared to healthy adults. Compared to TD children, children with ASD exhibited poor feedforward/feedback control of arm movements as seen by greater number of movement units, more movement overshooting, and prolonged time to peak velocity/acceleration. Unique movement strategies such as greater velocity and acceleration were also seen in the ASD group. More importantly, using Multilayer Perceptron (MLP) model, we demonstrated an accuracy of ~ 78.1% in classifying children with and without ASD. These findings underscore the potential use of studying upper limb movement kinematics during goal-directed arm movements and deep learning methods as valuable tools for classifying and, consequently, aiding in the diagnosis and early identification of ASD upon further validation of their specificity among younger children.

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28. Yoon S, Penzes P. Roles of ANK2/ankyrin-B in neurodevelopmental disorders: Isoform functions and implications for autism spectrum disorder and epilepsy. Curr Opin Neurobiol;2024 (Dec 3);90:102938.

The ANK2 gene, encoding ankyrin-B, is a high-confidence risk factor for neurodevelopmental disorders (NDDs). Evidence from exome sequencing studies have repeatedly implicated rare variants in ANK2 in autism spectrum disorder. Recently, the functions of ankyrin-B isoforms on neuronal phenotypes have been investigated using a number of techniques including electrophysiology, proteomic screens and behavioral analysis using animal models with loss of distinct Ank2 isoforms or with targeted loss of Ank2 in different cell types and time points during brain development. ANK2 variants and their pathophysiology could provide valuable insights into the molecular mechanisms underlying NDDs. In this review, we focus on recently reported studies to help understand the pathological mechanisms of ANK2 loss and how it may facilitate the development of treatments for NDDs in the future.

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29. Zhang L, Ji J, Wang Y, Wang L, Zheng R, Jiang Y. Plasma vitamin levels and pathway analysis in boys with autism spectrum disorders. Sci Rep;2024 (Dec 5);14(1):30344.

Abnormal feeding behaviors and inadequate nutrient intake of children with autism spectrum disorder (ASD) have been reported. This study aimed to examine the plasma vitamin status of boys with autism spectrum disorder (ASD) and to analyze the association between vitamin status and symptoms of ASD. A total of 45 boys with ASD (age = 3.25 ± 0.68 years) and 45 typically developing (TD) boys (age = 3.33 ± 0.66 years) were enrolled. The developmental levels were evaluated using the Gesell Developmental Schedules (GDS), the severity of ASD was evaluated using the Childhood Autism Rating Scale (CARS). The plasma vitamin levels were determined using metabolomics method. The Vitamin B1, nicotinamide, pyridoxamine dihydrochloride and Vitamin E were found to be significantly higher in the boys with ASD compared with those without ASD. In addition, no significant differences in vitamin metabolic pathways were found between the ASD group and the TD group.The nicotinamide and pyridoxamine dihydrochloride concentration were found to be negatively correlated with GDS score. In comparison with TD boys, the plasma vitamin concentration of ASD boys was not insufficient. Further studies are required to investigate whether it is necessary to use vitamin nutritional supplements in children with ASD.

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