A framework for an evidence-based gene list relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Mediation of 6-year mid-childhood follow-up outcomes after pre-school social communication (PACT) therapy for autistic children: randomised controlled trial.

BACKGROUND: There are very few mechanistic studies of the long-term impact of psychosocial interventions in childhood. The parent-mediated Paediatric Autism Communication Therapy (PACT) RCT showed sustained effects on autistic child outcomes from pre-school to mid-childhood. We investigated the mechanism by which the PACT intervention achieved these effects. METHODS: Of 152 children randomised to receive PACT or treatment as usual between 2 and 5 years of age, 121 (79.6%) were followed 5-6 years after the endpoint at a mean age of 10.5 years. Assessors, blind to the intervention group, measured Autism Diagnostic Observation Scale Calibrated Severity Score (ADOS CSS) for child autistic behaviours and Teacher Vineland (TVABS) for adaptive behaviour in school. Hypothesised mediators were child communication initiations with caregivers in a standard play observation (Dyadic Communication Measure for Autism, DCMA). Hypothesised moderators of mediation were baseline child non-verbal age equivalent scores (AE), communication and symbolic development (CSBS) and 'insistence on sameness' (IS). Structural equation modelling was used in a repeated measures mediation design. RESULTS: Good model fits were obtained. The treatment effect on child dyadic initiation with the caregiver was sustained through the follow-up period. Increased child initiation at treatment midpoint mediated the majority (73%) of the treatment effect on follow-up ADOS CSS. A combination of partial mediation from midpoint child initiations and the direct effect of treatment also contributed to a near-significant total effect on follow-up TVABS. No moderation of this mediation was found for AE, CSBS or IS. CONCLUSIONS: Early sustained increase in an autistic child's communication initiation with their caregiver is largely responsible for the long-term effects from PACT therapy on autistic and adaptive behaviour outcomes. This supports the theoretical logic model of PACT therapy but also illuminates fundamental causal processes of social and adaptive development in autism over time: early social engagement in autism can be improved and this can have long-term generalised outcome effects.

UK research priority setting for childhood neurological conditions.

AIM: To identify research priorities regarding the effectiveness of interventions for children and young people (CYP) with childhood neurological conditions (CNCs). These include common conditions such as epilepsies and cerebral palsy, as well as many rare conditions. METHOD: The National Institute for Health and Care Research (NIHR) and the James Lind Alliance (JLA) champion and facilitate priority setting partnerships (PSPs) between patients, caregivers, and clinicians (stakeholders) to identify the most important unanswered questions for research (uncertainties). A NIHR-JLA and British Paediatric Neurology Association collaboration used the JLA PSP methodology. This consisted of two surveys to stakeholders: survey 1 (to identify uncertainties) and survey 2 (a prioritization survey). The final top 10 priorities were agreed by consensus in a stakeholder workshop. RESULTS: One hundred and thirty-two charities and partner organizations were invited to participate. In survey 1, 701 participants (70% non-clinicians, including CYP and parent and caregivers) submitted 1800 uncertainties from which 44 uncertainties were identified for prioritization in survey 2; from these, 1451 participants (83% non-clinicians) selected their top 10 priorities. An unweighted amalgamated score across participant roles was used to select 26. In the final workshop, 14 health care professionals, 11 parent and caregivers, and two CYP ranked the 26 questions to finalize the top 10 priorities. Ten top priority questions were identified regarding interventions to treat CYP with CNCs and their associated comorbidities, for example, sleep, emotional well-being, and distressing symptoms. INTERPRETATION: The results of this study will inform research into the effectiveness of interventions for children with neurological conditions.

Autism genetics: opportunities and challenges for clinical translation.

Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this advancing insight should improve clinical care, at present there is a substantial discrepancy between research knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for the translation of autism genetics knowledge into clinical practice.

Impacts of health care service changes implemented due to COVID-19 on children and young people with long-term disability: A mapping review.

AIM: To identify the research on childhood disability service adaptations and their impact on children and young people with long-term disability during the COVID-19 pandemic. METHOD: A mapping review was undertaken. We searched the World Health Organization Global COVID-19 database using the search terms 'children', 'chronic/disabling conditions', and 'services/therapies'. Eligible papers reported service changes for children (0-19 years) with long-term disability in any geographical or clinical setting between 1st January 2020 and 26th January 2022. Papers were charted across the effective practice and organization of care taxonomy of health system interventions and were narratively synthesized; an interactive map was produced. RESULTS: Reduction of face-to-face care and usual provision had a huge impact on children and families. Adoption of telehealth provided continuity for the care and management of some conditions. There was limited evidence of changes to mental health services, transitions of care, social care, or child-reported satisfaction or acceptability of service changes. INTERPRETATION: The long-term impacts of service change during the pandemic need full evaluation. However, widespread disruption seems to have had a profound impact on child and carer health and well-being. Service recovery needs to be specific to the individual needs of children with a disability and their families. This should be done through coproduction to ensure that service changes meet needs and are accessible and equitable.

Visual attention and dietary supplementation in children with perinatal brain injury.

AIM: To investigate whether children with perinatal brain injury have impairments in specific components of visual attention, and whether early dietary supplementation can reduce any deficits. METHOD: Children participating in the Dolphin neonatal trial of dietary supplementation were tested at age 6 months with the Infant Fixation Shift Attention Test, and at 4 to 5 years with four subtests of the Early Childhood Attention Battery (ECAB) assessing different components of attention (selective, sustained, and executive function), and the Fluid Crystallized Intelligence Index of the Kaufman Assessment Battery for Children, Second Edition (KABC-II). From 59 children originally assigned to trial groups, 33 were available for testing at 4 to 5 years (18 treatment group of whom seven, six, and five showed mild, moderate, or severe neonatal brain injury; 15 controls with one, seven, and seven in the neonatal brain injury categories respectively). Given the imbalance in numbers with mild brain injury, analysis of trial group differences is restricted to moderate and severe brain injury severities (n=25). RESULTS: Children with perinatal brain injury showed poorer attention across all components relative to age norms (mean standard scores 75-87; p<0.001 for three of the four subtests), with the greatest impairment in sustained attention. These impairments remained when compared with cognitive age assessed using the Fluid Crystallized Intelligence Index. Impairment was reduced in the treatment compared to the control group (p=0.04 for flanker test, p=0.002 for counterpointing, and p=0.027 for the overall ECAB score). INTERPRETATION: Perinatal brain injury is associated with later impaired attention, beyond that predicted from any general cognitive disability. Impairment varies across attention components, being most severe for sustained attention. The effects on flanker and counterpointing suggest that dietary supplementation from 0 to 2 years of age may reduce attention problems. Measuring the different components of attention is important when considering assessment and interventions for children with perinatal brain injury.

Understanding frames: A qualitative exploration of standing frame use for young people with cerebral palsy in educational settings.

BACKGROUND: Consensus opinion supports standing frame use as part of postural management for nonambulant young people with cerebral palsy. Most young people with cerebral palsy in the United Kingdom, who use standing frames, use them at nursery or school, rather than at home. In this paper we report professionals' and parents' experiences and views of standing frame use specifically in educational settings. This research was conducted as part of a large mixed methods study to determine the acceptability and inform the design of a future trial of standing frames. METHODS: Qualitative methods were used: focus groups with educational professionals, parents and clinicians (paediatricians, physiotherapists and occupational therapists) were convened. Data were analysed thematically using framework analysis. RESULTS: Five focus groups were conducted. The overarching theme "flexibility" encompassed four subordinate themes: (i) "balancing education and therapy," which described the way education professionals had to juggle different priorities from health professionals within a multi-disciplinary team; (ii) "young people's autonomy," which highlighted participants' belief that standing frame use should be centred on the individual young person and their needs; (iii) "working within logistical boundaries," which demonstrated that "ideal" standing frame use was not always possible due to logistical issues (e.g., staffing and standing frame availability); and (iv) "competence and confidence," which highlighted that educational professionals felt that they lacked the training to confidently position young people in their standing frame. CONCLUSIONS: This paper highlights the complexity of standing frame use in the educational setting. If a standing frame programme is prescribed to be delivered in an educational setting, strong multidisciplinary and interagency communication is essential to balance therapy versus education. Training is required to ensure staff are competent in using the standing frame with the young person understanding their individual requirements. A flexible approach-inclusive of the young person's needs, logistical demands and resource-is necessary.

Nutritional intervention and neurodevelopmental outcome in infants with suspected cerebral palsy: the Dolphin infant double-blind randomized controlled trial.

AIM: To investigate whether docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) supplementation improves neurodevelopmental outcome in infants with suspected cerebral palsy (CP) versus a comparison group of children. METHOD: Infants aged 1 to 18 months with suspected CP were recruited from UK child development centres. Participants received daily treatment or control supplementation for 2 years (double-blind randomized control design). Stratification was by age, sex, predominant pattern of motor involvement (four limbs or other), and visual impairment (or not). The primary outcome was the cognitive composite score of the Bayley Scales of Infant and Toddler Development, Third Edition (CCS-Bayley-III). Secondary outcomes included language composite and motor composite scores of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). RESULTS: Forty infants were recruited; 35 began supplementation, 29 completed 1 to 2 years' supplementation. The treatment group CCS-Bayley-III was non-significantly higher than the comparison group (mean 77.7 [SD 19.2] and 72.2 [SD 19.8] respectively, mean modelled difference 4.4 [-2.8, 11.6]). The treatment group language scores, but not motor scores, were non-significantly higher than for the comparison group. INTERPRETATION: Most families found supplementation feasible. No statistically significant differences in neurodevelopmental outcome between the treatment and comparison groups were identified. Further investigation of neurodevelopmental outcome after supplementation with DHA, choline, and UMP of infants with suspected CP is warranted. WHAT THIS PAPER ADDS: This was the first trial of phosphatidylcholine precursor supplementation in infants with suspected cerebral palsy (CP). Families of infants with suspected CP found 2-year nutritional supplementation feasible. There was no statistically significant neurodevelopmental advantage for the treatment group versus the comparison group. However, treatment group cognitive and language advantage were of clinically meaningful magnitude.

Neurodevelopmental outcome of nutritional intervention in newborn infants at risk of neurodevelopmental impairment: the Dolphin neonatal double-blind randomized controlled trial.

AIM: To investigate whether neonates at risk for neurodevelopmental impairment have improved neurodevelopment after docosahexaenoic acid, choline, and uridine-5-monophosphate supplementation versus controls. METHOD: Recruitment was from UK neonatal units. Eligible for inclusion were infants born at less than 31 weeks' gestation with a weight less than the ninth centile; infants born at less than 31 weeks' gestation with a grade II or higher intraventricular haemorrhage/preterm white matter injury; infants born between 31 weeks' and 40 weeks' gestation plus 28 days with a grade II or higher intraventricular haemorrhage/preterm white matter injury, moderate or severe hypoxic-ischaemic encephalopathy, or defined neuroimaging abnormalities. Treatment/control supplementation was for 2 years (double-blind, randomized, controlled design). Infants were stratified according to sex, gestation, and brain injury severity. Primary outcome was cognitive composite score (CCS) of the Bayley Scales of Infant Development, Third Edition (Bayley-III at 24mo). Secondary outcomes were language composite score (LCS) of the Bayley-III, motor composite score (MCS) of the Bayley-III, and Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score. RESULTS: Sixty-two neonates were recruited, 59 were randomized (34 males, 25 females). Fifty-three started supplementation. Most families found supplementation acceptable. The treatment group CCS-Bayley-III scores were non-significantly higher than controls (mean score difference at 24mo: 9.0; 95% confidence interval -0.2 to 18.2). Language and VABS-II scores, but not motor score, were non-significantly higher in the treatment group. INTERPRETATION: Most families found supplementation feasible. Improved neurodevelopmental outcomes in the treatment group were not statistically significant. A larger multicentre trial exploration is warranted. WHAT THIS PAPER ADDS: Dietary supplementation of neonates at risk of neurodevelopmental impairment is feasible. No statistically significant neurodevelopmental advantages were identified for the treatment group compared to controls. Treatment group cognitive and language advantage are of a clinically meaningful magnitude.

Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial.

BACKGROUND: It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. METHODS: PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2-4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42-5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. FINDINGS: 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI -0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI -0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI -0·23 to 0·53). INTERPRETATION: The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory. FUNDING: Medical Research Council.

A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome.

We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.

Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.

De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder.

BACKGROUND: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ∼70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. METHODS: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). RESULTS: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. CONCLUSIONS: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.

Optimising nutrition to improve growth and reduce neurodisabilities in neonates at risk of neurological impairment, and children with suspected or confirmed cerebral palsy.

BACKGROUND: Neurological impairment is a common sequelae of perinatal brain injury. Plasticity of the developing brain is due to a rich substrate of developing neurones, synaptic elements and extracellular matrix. Interventions supporting this inherent capacity for plasticity may improve the developmental outcome of infants following brain injury. Nutritional supplementation with combination docosahexaenoic acid, uridine and choline has been shown to increase synaptic elements, dendritic density and neurotransmitter release in rodents, improving performance on cognitive tests. It remains elusive whether such specific 'neurotrophic' supplementation enhances brain plasticity and repair after perinatal brain injury. METHODS/DESIGN: This is a two year double-blind, randomised placebo controlled study with two cohorts to investigate whether nutritional intervention with a neurotrophic dietary supplement improves growth and neurodevelopmental outcomes in neonates at significant risk of neurological impairment (the D1 cohort), and infants with suspected or confirmed cerebral palsy (the D2 cohort). 120 children will be randomised to receive dietetic and nutritional intervention, and either active supplement or placebo. Eligible D1 neonates are those born <30(+6) weeks gestation with weight <9(th) centile, ≤ 30(+6) weeks gestation and Grade II, III or IV Intra-Ventricular Haemorrhage or periventricular white matter injury, or those born at 31-40(+28) weeks gestation, with Sarnat grade I or II or III Hypoxic Ischaemic Encephalopathy or neuroimaging changes compatible with perinatal brain injury. Eligible D2 infants are those aged 1-18 months with a suspected or confirmed clinical diagnosis of cerebral palsy. The primary outcome measure is composite cognitive score on the Bayley Scales of Infant and Toddler Development III at 24 months. Secondary outcomes include visuobehavioural and visual neurophysiological assessments, and growth parameters including weight, height, and head circumference. DISCUSSION: This is the first study to supplement neonates and infants with perinatal brain injury with the combination of factors required for healthy brain development, throughout the period of maximal brain growth. A further study strength is the comprehensive range of outcome measures employed. If beneficial, supplementation with brain phosphatide precursors could improve the quality of life of thousands of children with perinatal brain injury. TRIAL REGISTRATION: Current Controlled trials: ISRCTN39264076 (registration assigned 09/11/2012), ISRCTN15239951 (registration assigned 23/04/2010).

Characteristics of young people with long term conditions close to transfer to adult health services.

BACKGROUND: For many young people with long term conditions (LTC), transferring from paediatric to adult health services can be difficult and outcomes are often reported to be poor. We report the characteristics and representativeness of three groups of young people with LTCs as they approach transfer to adult services: those with autism spectrum disorder with additional mental health problems (ASD); cerebral palsy (CP); or diabetes. METHODS: Young people aged 14 years-18 years 11 months with ASD, or those with diabetes were identified from children's services and those with CP from population databases. Questionnaires, completed by the young person and a parent, included the 'Mind the Gap' Scale, the Rotterdam Transition Profile, and the Warwick and Edinburgh Mental Wellbeing Scale. RESULTS: Three hundred seventy four young people joined the study; 118 with ASD, 106 with CP, and 150 with diabetes. Participants had a significant (p < 0.001) but not substantial difference in socio-economic status (less deprived) compared to those who declined to take part or did not respond. Condition-specific severity of participants was similar to that of population data. Satisfaction with services was good as the 'gap' scores (the difference between their ideal and current care) reported by parents and young people were small. Parents' satisfaction was significantly lower than their children's (p < 0.001). On every domain of the Rotterdam Transition Profile, except for education and employment, significant differences were found between the three groups. A larger proportion of young people with diabetes were in a more independent phase of participation than those with ASD or CP. The wellbeing scores of those with diabetes (median = 53, IQR: 47-58) and CP (median = 53, IQR: 48-60) were similar, and significantly higher than for those with ASD (median = 47, IQR: 41-52; p < 0.001). CONCLUSIONS: Having established that our sample of young people with one of three LTCs recruited close to transfer to adult services was representative, we have described aspects of their satisfaction with services, participation and wellbeing, noting similarities and differences by LTC. This information about levels of current functioning is important for subsequent evaluation of the impact of service features on the health and wellbeing of young people with LTCs following transfer from child services to adult services.

The development of pGALSplus: evaluating feasibility and acceptability of an assessment to facilitate the identification and triage of children with musculoskeletal presentations.

Objectives: Healthcare professionals (HCPs) need to identify potentially serious musculoskeletal (MSK) presentations in children and refer them to specialists appropriately. Our aim was to develop 'pGALSplus' (paediatric gait, arms, legs and spine plus) to support clinical assessment, aid decision-making and assess feasibility and acceptability in exemplar MSK pathologies. Methods: We used a three-phase mixed methods approach: phase 1, preliminary stakeholder engagement and scoping review to propose pGALSplus; phase 2, iterative development of pGALSplus involving an expert working group; and phase 3, testing the feasibility of pGALSplus in exemplar MSK conditions [JIA, mucopolysaccharidoses (MPS), muscular dystrophy (MD), developmental coordination disorder (DCD) and healthy controls (HCs)]. The final pGALSplus was derived from analysis of phase 3 data and feedback from HCPs, families and expert consensus input from an international e-survey (n = 22) and virtual event (n = 13). Results: Feasibility was tested in 45 children (JIA, n = 10; MPS, n = 6; MD, n = 9; DCD, n = 10; HCs, n = 10). Overall the assessment was achievable in the target age range (2-10 years) and quick to complete [median 12 min (range 8-20)], with high acceptability from families. Expert feedback deemed pGALSplus to be very useful and of particular use to non-specialists in MSK paediatrics. The final pGALSplus comprises 26 clinical observations/skills with a colour-coding approach to aid decision-making and identification of more serious MSK presentations and additional resources to support its use in clinical practice. Conclusions: pGALSplus is a novel evidence- and consensus-based assessment building on pGALS, with high acceptability and feasibility. As community-based MSK assessment in children becomes more established, we propose that pGALSplus will facilitate and inform decision-making to promote access to specialist care.

The lived experiences of relatives of autistic adults, and their perceptions of their relationships with autistic adults across multiple age-related transitions and demands: A qualitative interview study with reflexive thematic analysis.

BACKGROUND: There is a need to better understand autism across the life course, including the lives of both autistic people and supporting relatives. As part of a larger mixed methods cohort study involving autistic adults, carers and relatives this sub-study focused on the experiences of relatives alone to learn more about the lives of people from the wider personal networks. Our research questions were: 1. What are the experiences of family members who care for and/or support autistic adults, 2. How can the viewpoints of relatives add to what we know about transitions and challenges experienced by autistic adults, and 3. What strategies/support have been helpful for adults and relatives? METHODS: Relatives of autistic adults were purposively sampled and recruited using the Relatives/Carers cohort from the Adult Autism Spectrum Cohort-UK. 18 participants aged 31-81years who were related to 16 autistic adults aged 18-57years were interviewed for 24-91minutes. Interview transcripts were examined using reflexive thematic analysis. MAIN FINDINGS: Two overarching themes were developed, 'Family support goes a long way in caring for autistic adults' and 'When families turn to society for support' with subthemes. Relatives described benefits they had gained and their admiration for autistic adults. They reflected on how they gave support for independence in various contexts of dependence. They also identified the challenges that both autistic adults and families face navigating support systems (for example for healthcare and employment). An important novel outcome was the advocated value of role-models with lived experience who come from outside of the family. RECOMMENDATIONS: The findings lead to recommendations for: (i) Strategies to reduce the barriers for support that are faced by autistic individuals and relatives during crisis points; (ii) recognition and support for what enables both relatives and autistic adults to function independently (e.g. funded activities, flexible employment); (iii) future planning conversations to include relatives who can enhance knowledge and help plan for future care or support needs for autistic adults and (iv) opportunities for role models (persons with lived experience, autistic adults and relatives) to inspire others and disseminate knowledge. CONCLUSIONS: These findings add valuable insights into the experiences of relatives of autistic adults and challenge the reader to have greater appreciation of the many roles relatives can contribute across time and in a variety of contexts. These perspectives add important information for those working with and planning provision for autistic adults.

A national research survey of childhood autism assessment services in the UK: empirical evidence of diagnostic practice, challenges and improvement opportunities.

BACKGROUND: The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction. This empirical research investigated current childhood diagnostic practice provision, and changes made by teams to address challenges faced. METHODS: Data were collected using an online semi-structured research questionnaire. UK childhood autism diagnostic assessment services (for children aged 1-18 years) were invited to participate through multidisciplinary clinical networks, special interest groups and professionals mailing lists. The study was on the National Institute for Health Research Clinical Research Network portfolio. RESULTS: 128 clinicians from diverse NHS services responded including: 10 (8%) integrated services, 46 (36%) Child and Adolescent Mental Health Services (CAMHS) and 72 (56%) paediatric services. A minority of services (23, 17.9%) reported always meeting the National Institute for Health and Care Excellence guidance for assessment. Referrals rose 115% between 2015 and 2019. Clinicians described increased child and family complexity compared with previously; children had more co-occurring physical, mental health and neurodevelopmental conditions and there were more frequent family health problems and safeguarding concerns. Most services (97, 75.8%) reported recent funding stayed constant/decreased. Incomplete multidisciplinary teams (MDTs) were frequently reported; a minority of services reported increased availability of professionals, and some experienced reductions in key professionals. Many teams were unable to undertake assessments or make recommendations for associated neurodevelopmental and co-existing conditions. Teams described improvement strategies implemented (eg, adapting professionals' roles, supporting parents). CONCLUSIONS: Most UK autism paediatric and CAMHS diagnostic teams experience significant challenges affecting the assessment of children with possible autism, and recommendations regarding treatment/intervention. Where CAMHS or paediatric services work in isolation, there are often competency gaps in MDTs and ability to deliver full neurodevelopmental and mental health assessments. Teams identified service improvement strategies; however, investment in MDT expertise is required to enable services to implement changes to meet the needs of children and families.

Generalisation of Social Communication Skills by Autistic Children During Play-Based Assessments Across Home, School and an Unfamiliar Research Setting.

We investigated autistic children's generalisation of social communication over time across three settings during a play-based assessment with different adults and explore the potential moderating effects on generalisation of age, nonverbal IQ and level of restricted and repetitive behaviours. The social communication abilities of 248 autistic children (2-11 years, 21% female, 22% single parent, 60% white) from three UK sites were assessed from 1984 video interactions in three contexts with three different interaction partners (parent/home, teaching assistant/school, researcher/clinic) at baseline, midpoint (+ 7m) and endpoint (+ 12m) within the Paediatric Autism Communication Trial-Generalised (PACT-G), a parent-mediated social communication intervention. Children's midpoint social communication at home generalised to school at midpoint and to clinic at endpoint. Generalisation was stronger from home to school and clinic than school to home and clinic. Generalisation was not moderated by age, nonverbal IQ or restricted and repetitive behaviour. Broader child development did not explain the pattern of results. The current study is the largest study to date to explore generalisation with autistic children and provides novel insight into their generalisation of social communication skills. Further research is needed to gain a more comprehensive understanding of facilitators of generalisation across settings and interaction partners in order to develop targeted strategies for interventions to enhance outcomes for young autistic children.