1. Aiello S, Leonardi E, Cerasa A, Servidio R, Famà FI, Carrozza C, Campisi A, Marino F, Scifo R, Baieli S, Corpina F, Tartarisco G, Vagni D, Pioggia G, Ruta L. Video-Feedback Approach Improves Parental Compliance to Early Behavioral Interventions in Children with Autism Spectrum Disorders during the COVID-19 Pandemic: A Pilot Investigation. Children (Basel, Switzerland). 2022; 9(11).

In the field of autism intervention, a large amount of evidence has demonstrated that parent-mediated interventions are effective in promoting a child’s learning and parent caring skills. Furthermore, remote delivery treatments are feasible and can represent a promising opportunity to reach families at distance with positive results. Recently, the sudden outbreak of COVID-19 dramatically disrupted intervention services for autism and forced an immediate reorganization of the territory services toward tele-assisted intervention programs, according to professional and local resources. Our study aimed to conduct a retrospective pilot exploratory investigation on parental compliance, participation, and satisfaction in relation to three different telehealth intervention modalities, such as video feedback, live streaming, and psychoeducation, implemented in the context of a public community setting delivering early autism intervention during the COVID-19 emergency. We found that parents who attended video feedback expressed the highest rate of compliance and participation, while parental psychoeducation showed significantly lower compliance and the highest drop-out rate. Regardless of the tele-assistance modality, all the participants expressed satisfaction with the telehealth experience, finding it useful and effective. Potential benefits and advantages of different remote modalities with reference to parent involvement and effectiveness are important aspects to be taken into account and should be further investigated in future studies.

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2. Alipour V, Shabani R, Zarrindast MR, Rahmani-Nia F, Nasehi M. Treadmill Exercise Improves Stereotypical Behaviors in Autistic Rats: Treadmill Exercise Improves ASD. Galen medical journal. 2022; 11: 1-7.

Background: Autism spectrum disorder (ASD) is identified by developmental deficits that lead to repetitive/stereotypic patterns of behavior and impaired social interactions. Studies have been indicated that exercise can decrease stereotypic behaviors in animal models of ASD. This research was designed to discover the effects of different models of forced exercise on stereotypical behaviors in a rat model of ASD induced by thimerosal (THIM). Materials and Methods: Fifty-six male Wistar rats were divided into eight groups. The rats were received saline (1 ml/kg) or THIM (300 μg Hg/kg) by four intramuscular injections on 7, 9, 11, and 15 postnatal days. The rats were also treated by several protocols of treadmill exercise, including non-sedentary, sedentary, protocol 1, protocol 2, and a combination of protocols 1 and 2. Results: Our study showed that THIM decreased the grooming time compared to the control group. Moreover, protocol 2 exercise significantly decreased grooming time in stranger zone 2 compared to the THIM group. Conclusions: Our results showed that stereotypical behaviors exaggerated by THIM and moderate exercise could improve ASD-associated behaviors in the THIM-treated rats. Hence, moderate exercise may be a useful protocol for the treatment of ASD.

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3. Baker EK, Arpone M, Bui M, Kraan CM, Ling L, Francis D, Hunter MF, Rogers C, Field MJ, Santa María L, Faundes V, Curotto B, Morales P, Trigo C, Salas I, Alliende AM, Amor DJ, Godler DE. Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome. American journal of medical genetics Part A. 2022.

Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89-43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R(2) = 0.597; p = 1.4 × 10(-10) ) and buccal epithelial cells (BEC) (n = 62; R(2) = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.

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4. Bania T, Lyri R, Ntatsiou F, Fousekis K. Functional activity and communication-social ability of youths with developmental disabilities: a qualitative study. Journal of physical therapy science. 2022; 34(11): 745-51.

[Purpose] To describe the functional activity and the communication-social ability levels of youths with developmental disabilities and to determine whether demographic factors predict these levels. [Participants and Methods] A mixed, observational and qualitative, study in which parents of students with developmental disabilities were interviewed based on the WeeFIM questions. Both quantitative and qualitative data were analysed. [Results] Data were collected for 30 youths with mild to severe developmental disabilities with mean age 18.5 ± 2.7 years (19 males). Mean WeeFIM total score was 106.2 ± 10.9, indicating relatively high functional and communication-social ability. No significant difference was observed for the total WeeFIM score between males and females and between adolescents and young adults with developmental disabilities. Main themes emerged from the interviews were: Difficulties with smooth and stable walking, transfers to/from bathtub and stairs. Also, youths are expressing a need for independence in self-care, while relationships with their peers are difficult and problems are primarily solved with help from their parents. [Conclusion] Despite the high functional and communication-social ability levels of a group of youths with developmental disabilities, parents revealed that youths had certain difficulties. Therapy should address such difficulties to promote independence and participation of these young people in the community.

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5. Chen T, Shur-Fen Gau S, Wu YY, Chou TL. Neural substrates of theory of mind in adults with autism spectrum disorder: An fMRI study of the social animation task. Journal of the Formosan Medical Association = Taiwan yi zhi. 2022.

BACKGROUND: Although the neural mechanisms of the theory of mind (ToM) in children with autism spectrum disorder (ASD) through fMRI using the social animation task have been investigated, little is known in adults with ASD. Therefore, the present study aimed to explore the neural substrates of ToM in adults with ASD. Moreover, we aimed to elucidate the relationship between brain activation and behavior of social interaction in adults with ASD. METHODS: Twenty-four healthy controls and 24 adults with the clinical diagnosis of ASD were recruited. Participants were asked to complete the social animation task in functional magnetic resonance imaging. The imaging analyses of within (whole brain analysis) and between (5 regions of interest) group comparisons were conducted to explore the process of ToM. The correlation analyses were further conducted to explore the relationship between neural activations associated with ToM and social interaction abilities assessed by ADI-R. RESULTS: The ASD group showed greater activation in the left precuneus and right superior temporal gyrus (STG) than the control group. For correlation analyses, greater right STG activation was positively correlated with autistic symptoms assessed by the ADI-R in the ASD group. CONCLUSION: ASD adults might spend a lot of effort on identification processing, thereby influencing social communication skills. Also, the neural deficits of ToM in ASD adults might be associated with their social interaction difficulties.

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6. Chenausky KV, Maffei M, Tager-Flusberg H, Green JR. Review of methods for conducting speech research with minimally verbal individuals with autism spectrum disorder. Augmentative and alternative communication (Baltimore, Md : 1985). 2022: 1-12.

The purpose of this paper was to review best-practice methods of collecting and analyzing speech production data from minimally verbal autistic speakers. Data on speech production data in minimally verbal individuals are valuable for a variety of purposes, including phenotyping, clinical assessment, and treatment monitoring. Both perceptual (« by ear ») and acoustic analyses of speech can reveal subtle improvements as a result of therapy that may not be apparent when correct/incorrect judgments are used. Key considerations for collecting and analyzing speech production data from this population are reviewed. The definition of « minimally verbal » that is chosen will vary depending on the specific hypotheses investigated, as will the stimuli to be collected and the task(s) used to elicit them. Perceptual judgments are ecologically valid but subject to known sources of bias; therefore, training and reliability procedures for perceptual analyses are addressed, including guidelines on how to select vocalizations for inclusion or exclusion. Factors to consider when recording and acoustically analyzing speech are also briefly discussed. In summary, the tasks, stimuli, training methods, analysis type(s), and level of detail that yield the most reliable data to answer the question should be selected. It is possible to obtain rich high-quality data even from speakers with very little speech output. This information is useful not only for research but also for clinical decision-making and progress monitoring.

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7. Dirix H, Ross V, Brijs K, Bertels L, Alhajyaseen W, Brijs T, Wets G, Spooren A. Autism-friendly public bus transport: A personal experience-based perspective. Autism : the international journal of research and practice. 2022: 13623613221132106.

Transportation plays an essential role in daily life, allowing people to participate in the community and form social relationships. Many autistic people rely on public transportation to meet their mobility needs. However, research shows that it is not always easy for them to use it. The exact issues autistic individuals face when traveling with public transportation and how public transportation can be made more autism-friendly have yet to be researched. The current study allowed autistic individuals to express themselves regarding issues they face while traveling by public bus transportation, to raise awareness for making public transportation more autism-friendly. We interviewed 17 autistic individuals about their experiences riding the bus. Three main themes emerged from the results: creating predictability, limiting stimuli, and open and accessible communication. If transport companies take initiatives related to these themes, autistic people traveling by bus can have a more pleasant experience. Participants also described coping strategies for stressful or uncomfortable situations while using public bus transportation, such as using noise-cancelling headphones or digital applications for real-time route tracking, etc. These findings may lead to a more autism-friendly public transportation.

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8. Erbescu A, Papuc SM, Budisteanu M, Arghir A, Neagu M. Re-emerging concepts of immune dysregulation in autism spectrum disorders. Frontiers in psychiatry. 2022; 13: 1006612.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by communication and social interaction deficits, and by restricted interests and stereotyped, repetitive behavior patterns. ASD has a strong genetic component and a complex architecture characterized by the interplay of rare and common genetic variants. Recently, increasing evidence suggest a significant contribution of immune system dysregulation in ASD. The present paper reviews the latest updates regarding the altered immune landscape of this complex disorder highlighting areas with potential for biomarkers discovery as well as personalization of therapeutic approaches. Cross-talk between the central nervous system and immune system has long been envisaged and recent evidence brings insights into the pathways connecting the brain to the immune system. Disturbance of cytokine levels plays an important role in the establishment of a neuroinflammatory milieu in ASD. Several other immune molecules involved in antigen presentation and inflammatory cellular phenotypes are also at play in ASD. Maternal immune activation, the presence of brain-reactive antibodies and autoimmunity are other potential prenatal and postnatal contributors to ASD pathophysiology. The molecular players involved in oxidative-stress response and mitochondrial system function, are discussed as contributors to the pro-inflammatory pattern. The gastrointestinal inflammation pathways proposed to play a role in ASD are also discussed. Moreover, the body of evidence regarding some of the genetic factors linked to the immune system dysregulation is reviewed and discussed. Last, but not least, the epigenetic traits and their interactions with the immune system are reviewed as an expanding field in ASD research. Understanding the immune-mediated pathways that influence brain development and function, metabolism, and intestinal homeostasis, may lead to the identification of robust diagnostic or predictive biomarkers for ASD individuals. Thus, novel therapeutic approaches could be developed, ultimately aiming to improve their quality of life.

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9. Estes A, Munson J, St John T, Finlayson R, Pandey J, Gottlieb B, Herrington J, Schultz RT. Sleep problems in autism: Sex differences in the school-age population. Autism research : official journal of the International Society for Autism Research. 2022.

Clinically significant sleep problems affect up to 86% of the autistic population in school-age. Sleep problems can have negative impacts on child cognition, behavior, and health. However, sex differences in the prevalence and types of sleep problems are not well understood in autism. To evaluate sex differences in sleep problems in the school-age autistic population, we obtained parent-report of sleep problems on the Children’s Sleep Habits Questionnaire and conducted direct assessments to establish diagnosis and intellectual ability in 6-12-year-old children (autism n = 250; typical development [TD] n = 114). Almost 85% of autistic females demonstrated sleep problems compared to 65.8% of autistic males, 44.8% of TD females, and 42.4% of TD males; a statistically significant increase for autistic females. Autistic females demonstrated increased bedtime resistance, sleep anxiety, and sleepiness, and decreased sleep duration, but did not differ in sleep onset delay, night wakings, parasomnias, or disordered breathing compared with autistic males. Intellectual ability was not related to increased sleep problems. Higher anxiety scores were associated with more sleep problems for males but not females. In one of the first studies to evaluate sex differences in sleep in the school-age, autistic population, autistic females demonstrated increased sleep problems compared to autistic males, TD females, and TD males. Current autism assessment and intervention practices may benefit from increased attention to sleep problems in autistic school-age females and to anxiety in autistic males to enhance well-being and behavioral and health outcomes.

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10. Galvin J, Richards G. The indirect effect of self-compassion in the association between autistic traits and anxiety/depression: A cross-sectional study in autistic and non-autistic adults. Autism : the international journal of research and practice. 2022: 13623613221132109.

Previous research on non-autistic adults suggests self-compassion may serve to reduce mental health problems and promote psychological well-being. Correlations between autistic traits and self-compassion have been observed in non-clinical populations. In this study, we were interested in extending previous research by exploring relationships between autistic traits, self-compassion and anxiety/depression in autistic adults without intellectual disability. The findings revealed that on average autistic people reported lower self-compassion than non-autistic people. Once we accounted for levels of self-compassion in our statistical model, this resulted in a complete loss of statistical significance in the relationships between autistic traits and anxiety/depression. Self-compassion may be a useful target for clinical intervention in autistic adults with co-occurring mental health difficulties.

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11. Ge GM, Cheung ECL, Man KKC, Ip P, Leung WC, Li GHY, Kung AWC, Cheung CL, Wong ICK. Association of maternal levothyroxine use during pregnancy with offspring birth and neurodevelopmental outcomes: a population-based cohort study. BMC medicine. 2022; 20(1): 390.

BACKGROUND: The influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring. METHODS: This population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model. RESULTS: Among 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD. CONCLUSIONS: There is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy.

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12. Greer JMH, Sood SSM, Metcalfe DR. Perceptions of autism spectrum disorder among the Swahili community on the Kenyan coast. Research in developmental disabilities. 2022; 131: 104370.

BACKGROUND: In high-income and Western societies there is great understanding and awareness of autism spectrum disorder (ASD); however, for many low-middle income countries, research and knowledge is notably lacking. In Africa, there is a growing prevalence of ASD due to increased diagnosis, yet it is still a poorly understood condition. AIMS: Emerging literature has emphasised how cultural and societal beliefs underpin the level of understanding of ASD, and which typically results in lack of awareness and acceptance. As such it is important to investigate the cultural perceptions towards ASD within low-middle income communities of African culture, to further understand the challenges and barriers individuals with ASD face. The aim of the current study was to probe participants from the Swahili community, on the coast of Kenya, of their cultural views towards ASD. METHOD: Semi-structured interviews were conducted with seven participants, and the data analysed using thematic analysis. RESULTS: Three key themes developed from the data; stigma, lack of awareness, and Government responsibility. CONCLUSION: Cultural perceptions negatively impacted awareness and are exacerbated by lack of directive from the Government in providing appropriate diagnostic and educational support.

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13. Hernandez MH, Bote V, Serra LA, Cendros M, Salazar J, Mestres C, Guijarro S, Alvarez A, Lamborena C, Mendez I, Sanchez B, Hervas A, Arranz MJ. CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders. Pharmacogenomics and personalized medicine. 2022; 15: 951-7.

PURPOSE: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety. PATIENTS AND METHODS: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype. RESULTS: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05). CONCLUSION: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

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14. Hill AT, Van Der Elst J, Bigelow FJ, Lum JAG, Enticott PG. Right anterior theta connectivity predicts autistic social traits in typically developing children. Biological psychology. 2022; 175: 108448.

Growing evidence supports functional network alterations in autism spectrum disorder, however much less is known about the neural mechanisms underlying autistic traits in typically developing children. Using resting-state electroencephalographic (EEG) recordings, we examined whether functional connectivity could predict autistic trait expression in 127 children aged between 4 and 12 years. Regression models showed that right anterior theta connectivity was a significant predictor of autistic traits (p = 0.013), with increased connectivity in this region associated with greater autistic trait expression. These results corroborate similar recent findings in adults, extending this observation to a cohort of children spanning early-to-middle childhood. These findings further highlight EEG-derived functional connectivity as a sensitive physiological correlate of autistic trait expression in typically developing children.

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15. Kainer D, Templeton AR, Prates ET, Jacboson D, Allan ERO, Climer S, Garvin MR. Structural variants identified using non-Mendelian inheritance patterns advance the mechanistic understanding of autism spectrum disorder. HGG advances. 2023; 4(1): 100150.

The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet heritability reported from SNP-based studies are consistently lower, and few significant loci have been identified with genome-wide association studies. This gap in genomic information may reside in rare variants, interaction among variants (epistasis), or cryptic structural variation (SV) and may provide mechanisms that underlie ASD. Here we use a method to identify potential SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that they are enriched in ASD-risk genes. Most are in non-coding genic space and are over-represented in expression quantitative trait loci, suggesting that they affect gene regulation, which we confirm with their overlap of differentially expressed genes in postmortem brain tissue of ASD individuals. We then identify an SV in the GRIK2 gene that alters RNA splicing and a regulatory region of the ACMSD gene in the kynurenine pathway as significantly associated with a non-verbal ASD phenotype, supporting our hypothesis that these currently excluded loci can provide a clearer mechanistic understanding of ASD. Finally, we use an explainable artificial intelligence approach to define subgroups demonstrating their use in the context of precision medicine.

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16. Kalemaj Z, Marino MM, Santini AC, Tomaselli G, Auti A, Cagetti MG, Borsello T, Costantino A, Inchingolo F, Boccellino M, Di Domenico M, Tartaglia GM. Salivary microRNA profiling dysregulation in autism spectrum disorder: A pilot study. Frontiers in neuroscience. 2022; 16: 945278.

INTRODUCTION: Autism spectrum disorders (ASD) are the most prevalent neurobiological disorders in children. The etiology comprises genetic, epigenetic, and environmental factors such as dysfunction of the immune system. Epigenetic mechanisms are mainly represented by DNA methylation, histone modifications, and microRNAs (miRNA). The major explored epigenetic mechanism is mediated by miRNAs which target genes known to be involved in ASD pathogenesis. Salivary poly-omic RNA measurements have been associated with ASD and are helpful to differentiate ASD endophenotypes. This study aims to comprehensively examine miRNA expression in children with ASD and to reveal potential biomarkers and possible disease mechanisms so that they can be used to improve faction between individuals by promoting more personalized therapeutic approaches. MATERIALS AND METHODS: Saliva samples were collected from 10 subjects: 5 samples of children with ASD and 5 from healthy controls. miRNAs were analyzed using an Illumina Next-Generation-Sequencing (NGS) system. RESULTS: Preliminary data highlighted the presence of 365 differentially expressed miRNAs. Pathway analysis, molecular function, biological processes, and target genes of 41 dysregulated miRNAs were assessed, of which 20 were upregulated, and 21 were downregulated in children with ASD compared to healthy controls. CONCLUSION: The results of this study represent preliminary but promising data, as the identified miRNA pathways could represent useful biomarkers for the early non-invasive diagnosis of ASD.

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17. Kiyak UE, Toper O. Teaching Science Facts to Students with Autism Spectrum Disorders via Telehealth. Journal of behavioral education. 2022: 1-11.

The interruption in the education of students with autism spectrum disorders (ASD) during the COVID-19 pandemic has necessitated telehealth services offered both to the individuals and their parents. Therefore, this study aimed to examine the effects of the simultaneous prompting procedure and observational learning in teaching science facts to middle-school students with ASD by using multiple probe designs with probe trials via telehealth. The researchers also conducted follow-up and novel adult probe sessions to assess the effects of simultaneous prompting procedure and observational learning along with the opinions of students and their mothers in terms of social validity. Results indicated that students acquired the target science facts and observational learning skills, maintained them over time, and generalized them across different people. The implication of the findings and directions for future research was additionally discussed.

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18. Langwerden RJ, van der Heijden PT, Soons P, Derksen JJL, Vuijk R, Egger JIM. An Exploratory Study of MMPI-2-RF Personality and Psychopathology Profiles of Adults with Autism Spectrum Disorder without Intellectual Disability. Clinical neuropsychiatry. 2022; 19(5): 335-46.

OBJECTIVE: More empirical research is needed to disentangle the phenotypes of autism spectrum disorder (ASD) and cluster C personality symptomatology (CCPD), as both show similarities in their clinical presentation. We explored personality and psychopathology dimensions as conceptualized in contemporary dimensional taxonomies (i.e., hierarchical taxonomy of psychopathology; HiTOP) in adults with ASD without intellectual disability operationalized by the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF). METHOD: Applying secondary analytic processes using clinical data, we cross-examined the MMPI-2-RF profiles of adults with ASD (n = 28) compared to adults with Cluster C personality disorders (CCPD; n = 28) and a control group (n = 28) by conducting nonparametric tests and assessing effect sizes. RESULTS: The profiles of the ASD and CCPD groups evidenced to be similar, and both average clinical profiles diverged from the average control group profiles by elevated levels of demoralization, internalizing, and somatization symptomatology. There were small differences between the average profiles of adults with ASD and adults with CCPD. Additional research using dimensional measures of psychopathology could elucidate the dimensional phenotypes of ASD and CCPD. CONCLUSIONS: Based on the results in this study, the MMPI-2-RF may not meaningfully discriminate between the two clinical presentations, with the exception of various externalizing scales.

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19. Li Q, Weiland RF, Konvalinka I, Mansvelder HD, Andersen TS, Smit DJA, Begeer S, Linkenkaer-Hansen K. Intellectually able adults with autism spectrum disorder show typical resting-state EEG activity. Scientific reports. 2022; 12(1): 19016.

There is broad interest in discovering quantifiable physiological biomarkers for psychiatric disorders to aid diagnostic assessment. However, finding biomarkers for autism spectrum disorder (ASD) has proven particularly difficult, partly due to high heterogeneity. Here, we recorded five minutes eyes-closed rest electroencephalography (EEG) from 186 adults (51% with ASD and 49% without ASD) and investigated the potential of EEG biomarkers to classify ASD using three conventional machine learning models with two-layer cross-validation. Comprehensive characterization of spectral, temporal and spatial dimensions of source-modelled EEG resulted in 3443 biomarkers per recording. We found no significant group-mean or group-variance differences for any of the EEG features. Interestingly, we obtained validation accuracies above 80%; however, the best machine learning model merely distinguished ASD from the non-autistic comparison group with a mean balanced test accuracy of 56% on the entirely unseen test set. The large drop in model performance between validation and testing, stress the importance of rigorous model evaluation, and further highlights the high heterogeneity in ASD. Overall, the lack of significant differences and weak classification indicates that, at the group level, intellectually able adults with ASD show remarkably typical resting-state EEG.

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20. Li Y, Fan T, Li X, Liu L, Mao F, Li Y, Miao Z, Zeng C, Song W, Pan J, Zhou S, Sunday ME, Wang H, Wang Y, Sun ZS. Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors. Cell reports. 2022; 41(6): 111551.

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21. 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. 2022.

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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22. Mankovich A, Blume J, Wittke K, Mastergeorge AM, Paxton A, Naigles LR. Say that again: Quantifying patterns of production for children with autism using recurrence analysis. Frontiers in psychology. 2022; 13: 999396.

The current research study characterized syntactic productivity across a range of 5-year-old children with autism and explored the degree to which this productivity was associated with standardized measures of language and autism symptomatology. Natural language samples were transcribed from play-based interactions between a clinician and participants with an autism diagnosis. Speech samples were parsed for grammatical morphemes and were used to generate measures of MLU and total number of utterances. We applied categorical recurrence quantification analysis, a technique used to quantify patterns of repetition in behaviors, to the children’s noun-related and verb-related speech. Recurrence metrics captured the degree to which children repeated specific lexical/grammatical units (i.e., recurrence rate) and the degree to which children repeated combinations of lexical/grammatical units (i.e., percent determinism). Findings indicated that beyond capturing patterns shown in traditional linguistic analysis, recurrence can reveal differences in the speech productions of children with autism spectrum disorder at the lexical and grammatical levels. We also found that the degree of repeating noun-related units and grammatical units was related to MLU and ADOS Severity Score, while the degree of repeating unit combinations (e.g., saying « the big fluffy dog » or the determiner-adjective-adjective-noun construction multiple times), in general, was only related to MLU.

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23. May T, Williams K. Mother and child mental health over time in children with Autism and/or ADHD in the Longitudinal Study of Australian Children. Development and psychopathology. 2022: 1-11.

This study utilised a longitudinal population-based study to explore mother and child mental health trajectories over time from child age 0 to 14 years, between children with ASD, ADHD, or ASD + ADHD. It explored whether a bidirectional relationship between mother psychological distress and child emotional and behavioural problems (EBPs) existed. The birth cohort from the Longitudinal Study of Australian Children was used. Child EBPs were assessed using the Strengths and Difficulties Questionnaire; and mother emotional distress using the Kessler K6. Generalised estimating equations and structured equation modelling was used to understand changes over time, differences between groups and bidirectional relationships. As expected, children with ASD, ADHD or ASD + ADHD had higher EBPs than children without, and their mothers had higher levels of psychological distress across most time points, but with differing trajectories. Mothers of children with ASD (with or without ADHD) showed increasing psychological distress over time, while mothers of children with ADHD had reducing distress. The bidirectional relationship between mother and child mental health found in children without diagnoses was only partially present in children with ASD/ADHD. Findings highlight support needs and discuss implications for transactional models of parent/child emotional problems in children with neurodevelopmental disorders.

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24. Moraes Í AP, Lima JA, Silva NM, Simcsik AO, Silveira AC, Menezes LDC, Araújo LV, Crocetta TB, Voos MC, Tonks J, Silva TD, Dawes H, Monteiro CBM. Effect of Longitudinal Practice in Real and Virtual Environments on Motor Performance, Physical Activity and Enjoyment in People with Autism Spectrum Disorder: A Prospective Randomized Crossover Controlled Trial. International journal of environmental research and public health. 2022; 19(22).

(1) Background: People with ASD commonly present difficulty performing motor skills and a decline in physical activity (PA) level and low enjoyment of PA. We aimed to evaluate whether longitudinal practice of an activity in virtual and real environments improves motor performance and whether this improvement is transferred to a subsequent practice when changing the environment, promoting PA and providing enjoyment; (2) Methods: People with ASD, aged between 10 and 16 years, were included and distributed randomly into two opposite sequences. The participants performed a 10 session protocol, with five sessions practicing in each environment (virtual or real). Heart rate measurement was carried out and an enjoyment scale was applied; (3) Results: 22 participants concluded the protocol. Sequence A (virtual first) presented an improvement in accuracy and precision and transferred this when changing environment; they also had a greater change in heart rate reserve. The majority of participants reported « fun » and « great fun » levels for enjoyment; (4) Conclusions: The virtual reality activity presented a higher level of difficulty, with greater gains in terms of transference to the real environment. Considering PA, our task provided very light to light activity and the majority of participants enjoyed the task.

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25. Mukherjee D, Bhavnani S, Lockwood Estrin G, Rao V, Dasgupta J, Irfan H, Chakrabarti B, Patel V, Belmonte MK. Digital tools for direct assessment of autism risk during early childhood: A systematic review. Autism : the international journal of research and practice. 2022: 13623613221133176.

The challenge of finding autistic children, and finding them early enough to make a difference for them and their families, becomes all the greater in parts of the world where human and material resources are in short supply. Poverty of resources delays interventions, translating into a poverty of outcomes. Digital tools carry potential to lessen this delay because they can be administered by non-specialists in children’s homes, schools or other everyday environments, they can measure a wide range of autistic behaviours objectively and they can automate analysis without requiring an expert in computers or statistics. This literature review aimed to identify and describe digital tools for screening children who may be at risk for autism. These tools are predominantly at the ‘proof-of-concept’ stage. Both portable (laptops, mobile phones, smart toys) and fixed (desktop computers, virtual-reality platforms) technologies are used to present computerised games, or to record children’s behaviours or speech. Computerised analysis of children’s interactions with these technologies differentiates children with and without autism, with promising results. Tasks assessing social responses and hand and body movements are the most reliable in distinguishing autistic from typically developing children. Such digital tools hold immense potential for early identification of autism spectrum disorder risk at a large scale. Next steps should be to further validate these tools and to evaluate their applicability in a variety of settings. Crucially, stakeholders from underserved communities globally must be involved in this research, lest it fail to capture the issues that these stakeholders are facing.

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26. Sakamornchai W, Dumrongwongsiri O, Siwarom S. Case Report: Vitamin C combined with multiple micronutrient deficiencies is associated with pulmonary arterial hypertension in children with autistic spectrum disorder. Frontiers in nutrition. 2022; 9: 928026.

Children with developmental and behavioral problems including autistic spectrum disorders (ASDs) may have inappropriate feeding behaviors, which leads to an increased risk of multiple nutrient deficiencies. Vitamin C deficiency is one of the common nutrient deficiencies reported in children with inappropriate feeding. This case report illustrates two cases of ASD children with a clinical presentation of pulmonary arterial hypertension, a rare presentation of vitamin C deficiency. Vitamin C supplementation, pulmonary vasodilator, and supportive treatment were provided. Patients could recover from the illness and could be discharged from the hospital in a short time. In addition to vitamin C, the patients also had multiple micronutrient deficiencies. Nutrition counseling was given and micronutrient supplement was continued until follow-up. Regular nutrition assessment and counseling among children with ASD are needed to prevent nutrient deficiencies which may lead to life-threatening complications.

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27. Sharma S, Govindan R, Kommu JVS. Effectiveness of Parent-to-Parent Support Group in Reduction of Anxiety and Stress Among Parents of Children With Autism and Attention Deficit Hyperactivity Disorder. Indian journal of psychological medicine. 2022; 44(6): 575-9.

BACKGROUND: Parental interventions are efficacious and robust in managing children’s behavioral problems. Yet, research addressing their role in parental stress and anxiety is sparse. Our first aim was to assess the extent of anxiety and stress among parents of children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The second was to assess the effectiveness of a parent-to-parent support group for addressing the stress and anxiety among those parents. METHODS: We selected a single group pretest posttest design. We recruited 24 parents from the two in-patient facilities of child and adolescent psychiatry. The intervention consisted of a parent-to-parent support group. We assessed parental stress and anxiety before and after the intervention. RESULTS: The differences in anxiety and stress scores prior to and after the intervention were statistically significant (P < 0.001). Before the intervention, low level of parents' education and lower family income had a statistically significant relationship with higher parental stress. Also, parents who were employed had lesser anxiety. CONCLUSION: The parent-to-parent support group effectively reduced stress and anxiety among parents of children with ASD and ADHD. These are preliminary findings. The lack of a control group is a major limitation.

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28. Ukkirapandian K, E K, Udaykumar KP, Kandhi S, R M. The Neuroprotective Role of Acorus calamus in Developmental and Histopathological Changes in Autism-Induced Wistar Rats. Cureus. 2022; 14(9): e29717.

Introduction Autism spectrum disorder (ASD) is a neurodevelopmental disorder, and a tremendous increase in the incidence of autism poses challenges in identifying the different treatment modalities. Since the defined etiology, pathophysiology, and treatment of autism are unavailable, translational research is being done by creating animal models of autism. This study aimed to assess the effects of Acorus calamus on developmental and histopathological changes in autism-induced Wistar rats. Materials and methods A rat model of autism was created by administering sodium valproate on the 12th day of pregnancy, and rat pups of this group were considered autism-induced. Rat pups of pregnant rats who had received normal saline on the 12th day of pregnancy were considered group I (negative control group). Neural reflexes were assessed in early postnatal days (PND) to confirm the development of autism. Autism-induced rat pups were divided into the following two groups: group II, autism (positive control group), and group III, autism + A. calamus (drug-treated group). On the 21st postnatal day (PND), group III was given an ethanolic extract of A. calamus (200 mg/kg), and group I and group II were given normal saline orally for 15 days. After 15 days of drug exposure, at 36thPND, the rats were sacrificed, and brain tissue was collected for histopathological analysis. Results When compared to the negative control group, autism-induced rat pups showed delayed appearance of neurological reflexes. Neurodegenerative changes were well appreciated in group II (autism-induced rats) than in group III (autism + A. calamus). In the histomorphometric analysis, group II showed a significant reduction in the number of neurons in the frontal cortex and Purkinje cells in the cerebellum. However, when compared to group II, group III (autism treated with A. calamus) did not show significant alteration. Conclusion Valproate exposure at mid-pregnancy creates autism by disturbing neural structures among rat pups. This was clinically represented as the delayed appearance of neural reflexes. Acorus calamus in the early postnatal period protects rat pups’ brain morphology against autism pathology.

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29. Williams EG, Smith MJ, Boyd B. Perspective: The role of diversity advisory boards in autism research. Autism : the international journal of research and practice. 2022: 13623613221133633.

This article argues that using groups of individuals that specifically focus on addressing issues with diversity in autism research and autism intervention development are key in ensuring that a greater amount of racial, ethnic, and gender diverse autistic individuals are included in the research and that the research is addressing the needs of these individuals and groups. We call these groups a diversity advisory board. A diversity advisory board will help improve diversity in autism research and intervention development by making sure that autism researchers (1) are intentional about addressing issues of diversity in their research and (2) are able to recruit a greater number of autistic individuals with diverse identities, and (3) by giving greater consideration to the context of diverse autistic individuals which will help autism-focused interventions work better in community settings. We give a short description of these arguments and ideas for how to form and use a diversity advisory board.

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30. Ye F, Du L, Liu B, Gao X, Yang A, Liu D, Chen Y, Lv K, Xu P, Chen Y, Liu J, Zhang L, Li S, Shmuel A, Zhang Q, Ma G. Application of pseudocontinuous arterial spin labeling perfusion imaging in children with autism spectrum disorders. Frontiers in neuroscience. 2022; 16: 1045585.

INTRODUCTION: Pseudocontinuous Arterial Spin Labeling (pCASL) perfusion imaging allows non-invasive quantification of regional cerebral blood flow (CBF) as part of a multimodal magnetic resonance imaging (MRI) protocol. This study aimed to compare regional CBF in autism spectrum disorders (ASD) individuals with their age-matched typically developing (TD) children using pCASL perfusion imaging. MATERIALS AND METHODS: This cross-sectional study enrolled 17 individuals with ASD and 13 TD children. All participants underwent pCASL examination on a 3.0 T MRI scanner. Children in two groups were assessed for clinical characteristics and developmental profiles using Autism Behavior Checklist (ABC) and Gesell development diagnosis scale (GDDS), respectively. We compared CBF in different cerebral regions of ASD and TD children. We also assessed the association between CBF and clinical characteristics/developmental profile. RESULTS: Compared with TD children, individuals with ASD demonstrated a reduction in CBF in the left frontal lobe, the bilateral parietal lobes, and the bilateral temporal lobes. Within the ASD group, CBF was significantly higher in the right parietal lobe than in the left side. Correlation analysis of behavior characteristics and CBF in different regions showed a positive correlation between body and object domain scores on the ABC and CBF of the bilateral occipital lobes, and separately, between language domain scores and CBF of the left frontal lobe. The score of the social and self-help domain was negatively correlated with the CBF of the left frontal lobe, the left parietal lobe, and the left temporal lobe. CONCLUSION: Cerebral blood flow was found to be negatively correlated with scores in the social and self-help domain, and positively correlated with those in the body and object domain, indicating that CBF values are a potential MRI-based biomarker of disease severity in ASD patients. The findings may provide novel insight into the pathophysiological mechanisms of ASD.

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31. Yoshida A, Kumazaki H, Muramatsu T, Yoshikawa Y, Ishiguro H, Mimura M. Intervention with a humanoid robot avatar for individuals with social anxiety disorders comorbid with autism spectrum disorders. Asian journal of psychiatry. 2022; 78: 103315.

For some individuals with social anxiety disorders (SAD) comorbid with autism spectrum disorders (ASD), it is difficult to speak in front of others. Herein, we report the case of a patient with SAD comorbid with ASD who could not speak in front of others until she used a humanoid robot as her avatar. During the intervention, her personality changed from shy to outgoing, which is explained by the Proteus effect. These case findings suggest that interventions with a robot avatar might improve the motivation for individuals with SAD comorbid with ASD who cannot speak in front of others to communicate.

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32. Zhang X, Smits M, Curfs L, Spruyt K. An investigation of the sleep macrostructure of girls with Rett syndrome. Sleep medicine. 2022; 101: 77-86.

OBJECTIVE/BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2) is of utmost importance in neuronal function. We aim to characterize phenotypic traits in the sleep of individuals with Rett Syndrome (RTT, OMIM # 312750), a rare disorder predominantly caused by mutations of the MECP2 gene. PATIENTS/METHODS: An overnight polysomnographic recording was performed. Outcomes investigated were parameters of nocturnal sleep macrostructure, and sample stratification per genetic and clinical characteristics, and six key features of clinical severity was applied. RESULTS: The sleep of our 21 RTT female subjects with a mutant MECP2 gene, aged 8.8 ± 5.4 years, showed no significant differences within strata. However, compared to a normative dataset, we found longer duration of wake time after sleep onset and total sleep time (TST) but shorter sleep onset latency, in RTT. Regarding the proportion of sleep stages per TST, higher stage N3 (%) with lower stage N2 (%) and REM (%) were generally seen. Such abnormalities became more uniformly expressed at the severe level of clinical features, particularly for hand functioning and walking. CONCLUSIONS: RTT girls with MECP2 mutations in our study demonstrated an increased deep sleep and reduced rapid eye movement sleep proportion, which is mostly allied with their hand dysfunction severity. Poor sleep-on/off switching in RTT since embryogenesis is possibly linked to (psycho)motor impairment in the cases with MECP2 mutations.

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33. Zhong NH, Grimm RP, Kanne SM, Mazurek MO. Measurement invariance of the Autism Impact Measure (AIM) across sex in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2022.

Measurement invariance, or the degree to which an instrument measures constructs consistently across subgroups, is critical for appropriate interpretations of measures. Given sex differences in the phenotypic and clinical presentation of autism spectrum disorder (ASD), it is particularly important to examine measurement invariance in autism instruments to ensure that ASD measures are not biased toward the more common male ASD phenotype. This study represents an important preliminary investigation evaluating the measurement equivalence of the Autism Impact Measure (AIM) across children and adolescents with ASD. The results indicated that the AIM demonstrated measurement invariance at the configural, metric, and scalar levels across sex in all five domains, including Repetitive Behavior, Communication, Atypical Behavior, Social Reciprocity, and Peer Interaction. These results suggest that ASD core symptoms assessed by the AIM were similar among male and female groups. In addition, the latent means for all five factors were not statistically significantly different across sex groups, revealing no systematic differences on any of the AIM subscales for males and females. Overall, this study showed that the AIM detects core ASD symptoms across all five areas equivalently in males and females and is not biased toward males with ASD.

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34. Zhou T, Zhang C, Yi C. Caregivers and interventionists: Developing a Dual Role Behaviors Scale for parents of children with autism spectrum disorders. Family process. 2022.

The integration of the roles of caregivers and interventionists is important in parenting a child with autism spectrum disorder (ASD). However, an instrument to measure dual-role behaviors is unavailable. This study developed and validated the Dual Role Behaviors Scale for parents of autistic children (DRBS-A). Initial items were generated using the interview transcripts of a previous qualitative study. The initial scale was administered to 422 parents. Data were randomly halved to generate Samples 1 and 2. Exploratory factor analysis conducted using Sample 1 (autism spectrum disorder = 216) screened items based on factor loadings and explored the scale’s structure. Confirmatory factor analysis (CFA) conducted with Sample 2 (N = 206) examined structural validity. Among the participants, 121 (Sample 3) derived from the two samples were followed up after 1 month to examine the test-retest reliability. Convergent validity was examined with another sample of 105 parents (Sample 4). The formal version of the DRBS-A comprised 20 items across four dimensions: parental acceptance, parental disengagement, persistence in interventions, and punishment in interventions. The four-factor structure with two higher order factors was supported by the CFA results (χ(2) = 290.90, df = 165, CFI = 0.94, TLI = 0.93, RMSEA = 0.061, SRMR = 0.063). The subscales’ test-retest reliabilities ranged from 0.61 to 0.78. The internal consistencies were satisfactory (Cronbach’s αs: 0.67-0.93). Convergent validity was supported by correlations of the DRBS-A dimensions with parental involvement and positive parenting practice. Other factors related to dual-role behaviors were also explored. The DRBS-A has good validity and reliability and can be used to explore the effects of role integration.

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35. Zylbersztejn A, Stilwell PA, Zhu H, Ainsworth V, Allister J, Horridge K, Stephenson T, Wijlaars L, Gilbert R, Heys M, Hardelid P. Trends in hospital admissions during transition from paediatric to adult services for young people with learning disabilities or autism: Population-based cohort study. The Lancet regional health Europe. 2023; 24: 100531.

BACKGROUND: Transition from paediatric to adult health care may disrupt continuity of care, and result in unmet health needs. We describe changes in planned and unplanned hospital admission rates before, during and after transition for young people with learning disability (LD), or autism spectrum disorders (ASD) indicated in hospital records, who are likely to have more complex health needs. METHODS: We developed two mutually exclusive cohorts of young people with LD, and with ASD without LD, born between 1990 and 2001 in England using national hospital admission data. We determined the annual rate of change in planned and unplanned hospital admission rates before (age 10-15 years), during (16-18 years) and after (19-24 years) transition to adult care using multilevel negative binomial regression models, accounting for area-level deprivation, sex, birth year and presence of comorbidities. FINDINGS: The cohorts included 51,291 young people with LD, and 46,270 autistic young people. Admission rates at ages 10-24 years old were higher for young people with LD (54 planned and 25 unplanned admissions per 100 person-years) than for autistic young people (17/100 and 16/100, respectively). For young people with LD, planned admission rates were highest and constant before transition (rate ratio [RR]: 0.99, 95% confidence interval [CI] 0.98-0.99), declined by 14% per year of age during (RR: 0.86, 95% CI: 0.85-0.88), and remained constant after transition (RR: 0.99, 95% CI: 0.99-1.00), mainly due to fewer admissions for non-surgical care, including respite care. Unplanned admission rates increased by 3% per year of age before (RR: 1.03, 95% CI: 1.02-1.03), remained constant during (RR: 1.01, 95% CI: 1.00-1.03) and increased by 3% per year after transition (RR: 1.03, 95% CI: 1.02-1.04). For autistic young people, planned admission rates increased before (RR: 1.06, 95% CI: 1.05-1.06), decreased during (RR: 0.95, 95% CI: 0.93-0.97), and increased after transition (RR: 1.05, 95%: 1.04-1.07). Unplanned admission rates increased most rapidly before (RR: 1.16, 95% CI: 1.15-1.17), remained constant during (RR: 1.01, 95% CI: 0.99-1.03), and increased moderately after transition (RR: 1.03, 95% CI: 1.02-1.04). INTERPRETATION: Decreases in planned admission rates during transition were paralleled by small but consistent increases in unplanned admission rates with age for young people with LD and autistic young people. Decreases in non-surgical planned care during transition could reflect disruptions to continuity of planned/respite care or a shift towards provision of healthcare in primary care and community settings and non-hospital arrangements for respite care. FUNDING: National Institute for Health Research Policy Research Programme.

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