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Introduction Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants’ genetic profiles.Methods and analysis EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms.Ethics and dissemination To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).

Background There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking. Objective To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness. Design Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children. Setting Twenty-one NHS Hospitals in the UK. Participants Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis. Intervention Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment. Main outcome measure Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation. Secondary outcomes The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data. Results We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period. Conclusion ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children. Study limitations and future work The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question. Trial registration This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information. Plain language summary Encephalitis (inflammation of the brain) is a serious but rare condition affecting approximately 5 in 100,000 children in England. Encephalitis can have a big impact on affected children and their families. Approximately 12 out of 100 affected children will die and half of those that survive experience varying difficulties in the long term; these might include problems with memory, physical disabilities, seizures and changes in how they think and behave. There is some evidence that a treatment called intravenous immunoglobulin may benefit people affected by encephalitis. Intravenous immunoglobulin contains antibodies obtained from blood donations by different people, which is used to treat some types of inflammation. However, there have been no research studies investigating the effect of intravenous immunoglobulin when used in large numbers of children with all types of encephalitis. Furthermore, although intravenous immunoglobulin is sometimes used to treat children with encephalitis, it is often given after other treatments have been unsuccessful. Outcomes from encephalitis are determined largely by the amount of brain inflammation; it would therefore seem logical that giving a treatment early in the illness to limit the inflammation would be beneficial. In the ImmunoglobuliN in the Treatment of Encephalitis study, we aimed to find out whether giving intravenous immunoglobulin to children with encephalitis early in the illness can help them get better more quickly and reduce the difficulties they experience later on. Half of the children in the trial received intravenous immunoglobulin and the other half received an inactive medicine, known as placebo, in addition to the normal care they would receive in a hospital. We aimed to compare the recovery and outcomes between children in these two groups. This trial was stopped early due to withdrawal of funding, as fewer children than expected were enrolled into the study. Too few children were enrolled for us to be sure whether intravenous immunoglobulin benefits children with encephalitis. However, the trial findings highlight the impact of encephalitis on affected children, with around half of children demonstrating ongoing difficulties 1 year after the illness. Scientific summary Background There is significant mortality and morbidity from encephalitis in children despite the current standard of care. Thus, strategies to improve outcomes in patients with encephalitis are urgently required. Theoretical and empirical evidence suggest a beneficial role of intravenous immunoglobulin (IVIG) for viral and auto-immune forms of encephalitis. Therefore, we set up a prospective randomised controlled trial (RCT) to ascertain the efficacy of early IVIG treatment for all-cause encephalitis in children. In the study, children with encephalitis were randomised to receive two doses of either IVIG or placebo within five working days from the suspicion of an encephalitis diagnosis, in addition to normal standard of care. They were then followed up for 12 months after randomisation. We hypothesised that IVIG could have therapeutic benefit for children with encephalitis when administered early in the illness. Objectives The primary objective was to evaluate the efficacy of early IVIG treatment in childhood encephalitis. This was assessed by comparing the proportion of children in the 2 treatment groups who made good recovery, assessed using the paediatric version of the Glasgow outcome score extended, at 12 months after randomisation. The secondary objectives were to: (1) compare clinical, neurological, neuroimaging and neuropsychological outcomes between the treatment groups, (2) evaluate the proportion of participants with autoimmune encephalitis and (3) confirm the safety of IVIG. Methods Trial design This was a phase 3b multicentre, double-blind, randomised, placebo-controlled trial to evaluate the early use IVIG in childhood encephalitis. Setting Participants were recruited from 21 NHS Hospitals in the UK. Participants Inclusion criteria Participants were eligible if they were aged between 6 weeks and 16 years they met the case definition for possible encephalitis based on the International Encephalitis Consensus parents/guardians provided written informed consent, or assent if appropriate. Exclusion criteria The exclusion criteria included: (1) a high clinical suspicion of bacterial meningitis, (2) prior receipt of IVIG during the admission or known contraindication to IVIG, (3) traumatic brain injury, (4) history of metabolic encephalopathy, stroke, toxic or hypertensive encephalopathy, (5) pre-existing demyelinating disorder, (6) significant renal impairment, (7) hypercoagulable state, (8) hyperprolinaemia, (9) participation in another research trial involving an immunomodulatory treatment, (10) known to be pregnant, (11) any significant disease or clinical research that would impact on participation, or interfere with compliance with study requirements. Randomisation Participants were randomly assigned 1 : 1 ratio to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard care. Randomisation was stratified by age and receipt of steroid treatment. Interventions Two doses of 1 g/kg/dose of either IVIG or a matching volume of placebo were given 24–36 hours apart, with the first dose administered as soon as possible after enrolment and within five working days from the suspicion of an encephalitis diagnosis. The active treatment (IVIG) used in the study was Privigen (100 mg/ml solution), manufactured and provided by CSL Behring. The placebo was a mixture of 0.9% saline + 0.1% human albumin solution, manufactured at the Royal Broadgreen and Liverpool Aseptic Production Unit, Liverpool, UK, under current good manufacturing practice conditions and its Manufacturer’s Importer’s Authorisation licence. The addition of albumin to saline was necessary to make the placebo visually identical to IVIG. Blinding Participants, treating clinicians, parents/guardians and outcome assessors were blinded to the allocated treatment. Primary outcome The primary outcome was good recovery (i.e. score of ≤2) on the paediatric version of the Glasgow Outcome Score-Extended (GOS-E Peds) at 12 months after randomisation. Secondary outcomes Clinical, neurological and neuropsychological outcomes Multiple clinical and neurological measures were collected during the hospital admission, at 4–8 weeks after discharge from acute care, and at 6 and 12 months after randomisation. A blinded neuropsychologist assessment of cognitive function was carried out at 12 months after randomisation. Radiological outcomes Brain magnetic resonance imaging (MRI) findings at 6 months after randomisation were compared with imaging results obtained during the acute illness. Safety data Safety and adverse events (AEs) data were collected until 12 months after randomisation. Identification of immune-mediated encephalitis Presence of specific auto-antibodies in serum was assessed. Statistical methods The analyses were performed on the intention-to-treat population; this included all participants who were randomised, irrespective of study treatment received. In the analysis of the AEs, all participants who received study treatment were included. Since 20% of participants were recruited before the trial was halted, all analyses are descriptive. Results Recruitment took place between 23 December 2015 and 26 September 2017. Recruitment was paused in September 2017 following withdrawal of funding due to slower than anticipated recruitment. Despite strategies implemented to improve recruitment, funding was not reinstated. Attempts at securing alternative funding were unsuccessful; therefore, the trial was closed on 24 October 2017. Participants and demographics At the time of halting the study, 18 participants had been randomised (IVIG n = 10; placebo n = 8). One participant each from the IVIG and placebo groups were withdrawn from the study before receipt of study treatment and one participant in the placebo arm refused a second dose of study treatment. Therefore 16 participants (IVIG n = 9; placebo n = 7) received at least one dose of the study treatment and 15 participants (IVIG n = 9, placebo n = 6) received two full doses of the study treatment. One participant in the placebo group was lost to follow up after the 6 months visit and 1 participant in the IVIG group withdrew consent prior to the visit 12 months after randomisation. The median age at randomisation was 4.09 years [interquartile range (IQR) = 2.0–11.8], 44% were male and 89% were of white ethnicity. Baseline characteristics were well matched across treatment arms. Primary outcome At 12 months after randomisation, 9 participants [50%; IVIG n = 5 (50%); placebo n = 4 (50%)] made a good recovery (score ≤2 on the GOS-E Peds) and 5 participants [28%; IVIG n = 3 (30%), placebo n = 2 (25%)] made a poor recovery (score > 2). Four participants (22%; IVIG n = 2 (20%), placebo n = 2 (25%)] did not undergo a GOS-E Peds assessment at 12 months after randomisation. Secondary outcomes Inpatient data Ten participants [56%; IVIG n = 5 (50%), placebo = 5 (63%)] were admitted to intensive care, and nine of these [90%; IVIG n = 4 (80%), placebo n = 5(100%)] required invasive ventilation, for a median duration of two days (IQR 2.0–3.0). The median length of stay on intensive care was 4.5 days (3.0–6.8) and the overall median length of hospitalisation for acute care was 11 days (7.8–19.5). Epilepsy diagnosis Three participants [17%; IVIG n = 1 (10%), placebo n = 2 (25%)] had a new diagnosis of epilepsy during the study period. Five participants [28%; IVIG n = 2 (20%), placebo n = 3 (38%)] had incomplete data for this outcome. Glasgow Outcome Score-Extended-Peds at 6 months after randomisation Eight participants [44%; IVIG n = 4 (40%), placebo n = 4 (50%)] made a good recovery at 6 months after randomisation, whereas seven participants [39%; IVIG n = 4 (50%), placebo n = 3 (38%)] made a poor recovery. Three participants [17%; IVIG n = 2 (20%), placebo n = 1 (13%)] did not undergo a GOS-E Peds assessment at 6 months after randomisation. Liverpool outcome score At 4–8 weeks after discharge from acute care, 5 participants [28%; IVIG n = 3 (30%), placebo n = 2 (25%)] made a full recovery [defined as a Liverpool Outcome Score (LOS) of >4], whereas 10 participants [56%; IVIG n = 5 (50%), placebo n = 5 (63%)] had minor to severe sequelae. Three participants [17%; IVIG n = 2 (20%); placebo n = 1 (13%)] did not have LOS data collected at this timepoint. At 12 months after randomisation, six participants [33%; IVIG n = 4 (40%), placebo n = 2 (25%)] made full recovery on the LOS assessment, while 8 participants [44%; IVIG n = 4 (40%), placebo n = 4 (50%)] reported minor to severe sequelae. Four participants [22%; IVIG n = 2 (20%); placebo n = 2 (25%)] did not have LOS data collected at this timepoint. Paediatric quality of life assessment Paediatric quality of life scores were available for seven participants [39%; IVIG n = 5 (50%), placebo n = 2 (25%)] at 4–8 weeks after discharge from acute care and for eight participants [44%; IVIG n = 6 (60%), placebo n = 2 (25%)] at 12 months post randomisation. At 4–8 weeks after discharge from acute care, the mean PedsQL score was 77.9 (standard deviation, SD, 11.10) and 56.5 (SD 7.8) for the IVIG and placebo group, respectively. At 12 months, mean PedsQL scores were 79.9 (SD 21.6) and 63.7 (SD 30.1) for the IVIG and placebo groups, respectively. Gross motor function classification system At 4–8 weeks after discharge from acute care, seven participants [39%; IVIG n = 5 (50%); placebo n = 2 (25%)] had mild impairment of gross motor functioning. These data were not available for 11 participants [61%; IVIG n = 5 (50%), placebo n = 6 (75%)] at this timepoint. At 12 months after randomisation, eight participants [44%; IVIG n = 6 (60%); placebo n = 2 (25%)] experienced mild or severe impairment of gross motor function. These data were not available for ten participants [56%; IVIG n = 4 (40%), placebo n = 6 (75%)] at this timepoint. Strengths and difficulties assessment Strengths and Difficulties Questionnaire (SDQ) results were available for seven participants (IVIG n = 5, placebo n = 2) at 4–8 weeks after discharge from acute care and eight participants (IVIG n = 6, placebo n = 2) at 12 months after randomisation. At 4–8 weeks after discharge from acute care, five participants [28%; IVIG n = 4 (40%); placebo n = 1 (13%)] had a close to average SDQ score, one participant [6%, IVIG n = 1 (10%), placebo n = 0] had a slightly raised SDQ score and one participant [6%, IVIG n = 0, placebo n = 1 (13%)] had a very high SDQ score. At 12 months after randomisation, the same number of participants had a close to average score and slightly raised score, but two participants [11%; IVIG n = 1 (10%), placebo n = 1 (13%)] had a very high SDQ score. Adaptive Behaviors Assessment System – second edition At 4–8 weeks after discharge from acute care, five participants [28%; IVIG n = 4 (40%), placebo n = 1 (13%)] had an Adaptive Behaviors Assessment System-second edition (ABAS-II) score that was either similar or higher than the average score of the normative population. At the same time point, three participants [17%; IVIG n = 2 (20%), placebo n = 1 (13%)] had a score that was lower than the average score. Ten participants [56%; IVIG n = 4 (40%), placebo n = 6 (75%)] did not have ABAS-II assessment at this timepoint. At 12 months after randomisation, the same number of participants had a score that was below the average, but four participants [22%; IVIG n = 3 (30%), placebo n = 1 (13%)] had a score that was either similar or higher than the average score, and 11 participants [61%; IVIG n = 5 (50%), placebo n = 6 (75%)] did not have ABAS-II assessment at this timepoint. Neuropsychology assessment Thirteen participants (72%; IVIG n = 8 (80%); placebo n = 5 (63%)] had blinded neuropsychology assessment at 12 months after randomisation; four [30%; IVIG n = 2 (25%), placebo n = 2 (40%)] of these participants were unable to complete the full battery of assessments due to attention or behavioural needs. Five participants [28%; IVIG n = 2 (20%), placebo n = 3 (38%)] did not undergo neuropsychology assessment. Five participants [28%; IVIG n = 4 (40%), placebo n = 1 (13%)] had a score of ≥85 (indicating normal development) for Full-Scale IQ, six [33%; IVIG n = 4 (40%); placebo n = 2 (25%)] for Verbal Comprehension Index (VCI), five [28%; IVIG n = 4 (40%), placebo n = 1 (13%)] for visual spatial; four [22%; IVIG n = 4 (40%), placebo n = 0 (0%)] for working memory index (WMI); and four [22%; IVIG n = 3 (30%); placebo n = 1 (13%)] for Perceptual Reasoning Index (PRI). Two participants (one in each treatment arm) were assessed using the Bayley scale of infant and toddler development, one participant (IVIG arm) had severe neurodevelopmental impairment while the other (placebo arm) had a normal neurodevelopmental outcome. Neuroimaging Nineteen acute neuroimaging scans were available for 13 participants. Five scans (for five unique participants) had abnormal findings; all of these were MRI scans. Four of the abnormal scans showed bilateral lesions. There were nine follow-up scans for eight unique participants of which six scans (for five unique participants) were normal and unchanged from the acute scan. Three follow-up scans (for three unique participants) had abnormal findings; two of these were unchanged from the acute scans and an acute scan was not available for comparison one participant. Autoantibody testing Twelve participants had autoantibody testing. One participant (placebo n = 1) was positive for LGI1 antibodies, and one participant (placebo n = 1) was positive for myelin oligodendrocyte glycoprotein (MOG) antibodies. Two additional participants (IVIG n = 2) were positive for IgG to live neurons, indicating the presence of IgG antibodies binding to neurons, but negative for antibodies to the specific antigens tested for in the study. Safety reporting One participant in the IVIG group reported an AE of special interest; the participant developed a fever during IVIG infusion; however, this was judged to be unrelated to the study treatment. Ten serious AEs occurred in three participants in the placebo group and none in the IVIG group. None of the serious adverse events (SAEs) were judged to be related to the study treatment. No deaths occurred during the study period. Conclusions ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was the first RCT to prospectively evaluate the efficacy of IVIG in childhood encephalitis. It was anticipated that data from IgNiTE would provide definitive evidence on which to base the management of children with encephalitis in the UK and worldwide. However, due to slow recruitment, the trial was terminated early. Therefore, the trial did not reach its pre-determined sample size and was underpowered, making it impossible to reach a conclusion on the role of IVIG in treatment of childhood encephalitis. Nonetheless, IgNiTE has highlighted several key learning points. Firstly, IgNiTE has demonstrated the feasibility of setting up a large multi-centre trial efficacy trial in a cohort of children with a rare condition such as encephalitis. Secondly, data from IgNiTE, albeit derived from a small sample size, suggest the safety of IVIG and provide some insight into the burden that encephalitis places on children and the NHS. Over half of the study participants were admitted to the intensive care unit with 90% of those admitted requiring invasive ventilation, with a prolonged overall length of hospitalisation. In addition, a notable proportion of children experienced some degree of disability at follow-up, highlighting the need to prioritise studies aimed at identifying strategies to alleviate the burden from this rare but debilitating disease. For future studies aimed at addressing the efficacy of early IVIG treatment in childhood encephalitis, consideration should be given to practical challenges with setting up RCTs for rare diseases. These include the necessity to recruit from multiple sites to achieve the sample size, the importance of clinical equipoise amongst treating clinicians, and the trade-off between having a stringent but robust set of entry criteria and the impact of this on recruitment. Trial registration This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information.

ObjectivesThere is limited evidence on the effectiveness of parenting interventions to improve disruptive behaviour in children with intellectual developmental disabilities. This clinical trial evaluated whether an adapted group parenting intervention for preschool children with intellectual developmental disabilities who display challenging behaviour is superior to treatment as usual in England.Study design261 children aged 30-59 months with moderate to severe intellectual developmental disabilities and challenging behaviour were randomised to either the intervention (Stepping Stones Triple P) and treatment as usual or treatment as usual alone. The primary outcome was the parent-rated Child Behaviour Checklist at 52 weeks after randomisation. A health economic evaluation was also completed.ResultsWe found no significant difference between arms on the primary outcome (mean difference -4.23; 95% CI: -9.99 to 1.53; p = 0.147). However, a subgroup analysis suggests the intervention was effective for participants randomised before the COVID-19 pandemic (mean difference -7.12; 95% CI: -13.44 to -0.81; p = 0.046). Furthermore, a complier average causal effects analysis (mean difference -11.53; 95% CI: -26.97 to 3.91; p = 0.143) suggests the intervention requires participants to receive a sufficient intervention dose. The intervention generated statistically significant cost savings (-£1,057.88; 95% CI -£3,218.6 to -£46.67) but the mean point estimate in Quality Adjusted Life Years was similar in both groups.ConclusionThis study did not find an effect of the intervention on reducing challenging behaviour, but this may have been influenced by problems with engagement. The intervention could be considered by services as an early intervention if families are supported to attend, especially given its low cost.

Background Stepping Stones Triple P is an adapted intervention for parents of young children with developmental disabilities who display behaviours that challenge, aiming at teaching positive parenting techniques and promoting a positive parent–child relationship. Objective To evaluate the clinical and cost-effectiveness of level 4 Stepping Stones Triple P in reducing behaviours that challenge in children with moderate to severe intellectual disabilities. Design, setting, participants A parallel two-arm pragmatic multisite single-blind randomised controlled trial recruited a total of 261 dyads (parent and child). The children were aged 30–59 months and had moderate to severe intellectual disabilities. Participants were randomised, using a 3 : 2 allocation ratio, into the intervention arm (Stepping Stones Triple P; n = 155) or treatment as usual arm (n = 106). Participants were recruited from four study sites in Blackpool, North and South London and Newcastle. Intervention Level 4 Stepping Stones Triple P consists of six group sessions and three individual phone or face-to-face contacts over 9 weeks. These were changed to remote sessions after 16 March 2020 due to the coronavirus disease 2019 pandemic. Main outcome measure The primary outcome measure was the parent-reported Child Behaviour Checklist, which assesses the severity of behaviours that challenge. Results We found a small non-significant difference in the mean Child Behaviour Checklist scores (−4.23, 95% CI −9.98 to 1.52, p = 0.146) in the intervention arm compared to treatment as usual at 12 months. Per protocol and complier average causal effect sensitivity analyses, which took into consideration the number of sessions attended, showed the Child Behaviour Checklist mean score difference at 12 months was lower in the intervention arm by −10.77 (95% CI −19.12 to −2.42, p = 0.014) and −11.53 (95% CI −26.97 to 3.91, p = 0.143), respectively. The Child Behaviour Checklist mean score difference between participants who were recruited before and after the coronavirus disease 2019 pandemic was estimated as −7.12 (95% CI −13.44 to −0.81) and 7.61 (95% CI −5.43 to 20.64), respectively (p = 0.046), suggesting that any effect pre-pandemic may have reversed during the pandemic. There were no differences in all secondary measures. Stepping Stones Triple P is probably value for money to deliver (−£1057.88; 95% CI −£3218.6 to −£46.67), but decisions to roll this out as an alternative to existing parenting interventions or treatment as usual may be dependent on policymaker willingness to invest in early interventions to reduce behaviours that challenge. Parents reported the intervention boosted their confidence and skills, and the group format enabled them to learn from others and benefit from peer support. There were 20 serious adverse events reported during the study, but none were associated with the intervention. Limitations There were low attendance rates in the Stepping Stones Triple P arm, as well as the coronavirus disease 2019-related challenges with recruitment and delivery of the intervention. Conclusions Level 4 Stepping Stones Triple P did not reduce early onset behaviours that challenge in very young children with moderate to severe intellectual disabilities. However, there was an effect on child behaviours for those who received a sufficient dose of the intervention. There is a high probability of Stepping Stones Triple P being at least cost neutral and therefore worth considering as an early therapeutic option given the long-term consequences of behaviours that challenge on people and their social networks. Future work Further research should investigate the implementation of parenting groups for behaviours that challenge in this population, as well as the optimal mode of delivery to maximise engagement and subsequent outcomes. Study registration This study is registered as NCT03086876 (https://www.clinicaltrials.gov/ct2/show/NCT03086876?term=Hassiotis±Angela&draw=1&rank=1). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: HTA 15/162/02) and is published in full in Health Technology Assessment; Vol. 28, No. 6. See the NIHR Funding and Awards website for further award information. Plain language summary Research shows that in children without learning disabilities, parenting groups which support parents to develop skills to manage behaviours that challenge in their child can be helpful. The National Institute of Health and Care Excellence recommended that more research was needed to strengthen the evidence for such interventions for children with moderate to severe learning disability who are more likely to display behaviours that challenge in England. In this study, we tested in real-world conditions a programme called level 4 Stepping Stones Triple P, which has shown positive results in trials outside of the United Kingdom. Trained therapists delivered six groups and three individual sessions over 9 weeks to parents of children aged 30–59 months with moderate to severe learning disabilities. Two hundred and sixty-one parents were allocated to one of two arms by chance (randomisation): one received Stepping Stones Triple P and treatment as usual and the other treatment as usual only. Treatment as usual included support and advice by general practitioners or community child development teams. Our primary outcome was parent-reported child behaviour at 12 months after randomisation. We also collected data on other outcomes and carried out interviews with parents, service managers and therapists to find out their views about Stepping Stones Triple P. We did not find that Stepping Stones Triple P reduces behaviours that challenge in the child more than treatment as usual at 12 months. However, when we looked at people who received more than half of the sessions, there was a larger reduction in behaviours which suggests that Stepping Stones Triple P works for families if they attend the full programme. Stepping Stones Triple P seems to be good value for money, as we found that at 12 months (covering 10 months of costs), the Stepping Stones Triple P cost £1058 less than treatment as usual from a health and social care perspective. As such, Stepping Stones Triple P is fairly cheap to deliver and a suitable early intervention for behaviours that challenge especially because of positive feedback from parents. Throughout the trial, we included a Parent Advisory Group that oversaw study materials, interview topic guides and promotion of the study. Scientific summary Background Intellectual disability is a lifelong condition impairing an individual’s intellectual and adaptive functioning, affecting approximately 1.2 million children, young people and adults in England. Between 10% and 45% of children with intellectual disability display behaviours that challenge, including self-injury, aggression, destructiveness and stereotypical behaviours. These behaviours can be very distressing for both the parent and the child, and parents may find them difficult to manage. Interventions for early-onset conduct problems and disruptive behaviour in the general population are known to reduce such behaviours, improve long-term outcomes and reduce care costs. Early interventions are often delivered through group parenting programmes, which are known to increase parent efficacy through learning positive parenting techniques and contingency management strategies within a social learning framework. One such intervention, adapted for children with intellectual disability and socio-emotional disabilities, is Stepping Stones Triple P (SSTP). The SSTP programme combines psycho-educational and behavioural components, which aim to promote a positive parent–child relationship. The intervention also encourages the development of children’s skills within everyday parenting situations, for example during mealtimes, bathing or dressing. Studies outside the UK have shown that SSTP is effective, acceptable to parents, reduces behaviours that challenge and improves parenting styles. The current study (EPICC-ID) describes a randomised multicentre evaluation of level 4 group SSTP in very young children with moderate to severe intellectual disability. To our knowledge, it is the first study to test such an intervention in this population group in the UK (England). Objectives To undertake a pragmatic randomised controlled trial to evaluate level 4 group SSTP in addition to treatment as usual (TAU); To undertake an economic evaluation to assess the cost-effectiveness of the intervention compared to TAU. Research questions Does the addition of level 4 SSTP to TAU reduce behaviour that challenges displayed by children aged 30–59 months with moderate to severe intellectual disability at 12 months post randomisation compared to TAU alone? Does the addition of level 4 SSTP to TAU reduce behaviours that challenge at 12 months post randomisation in blind-rated observations and caregiver/teacher outcome measures? Is the addition of level 4 SSTP to TAU more cost-effective than TAU alone? Methods The current study was a pragmatic parallel two-armed multisite single-blind randomised control trial with a 3 : 2 randomisation ratio (SSTP vs. TAU). The chief investigator, researchers and the lead statistician were blinded to participant allocation. Altogether, 261 dyads (parent with index child) were enrolled in this trial, of whom 155 were allocated to the SSTP and TAU arm and 106 were allocated to the TAU arm alone. The inclusion criteria were (1) to be a parent aged 18 years or over, (2) consenting to take part, (3) having a child with moderate to severe intellectual disability, (4) the child to be aged 30–59 months at identification and (5) the child to display behaviours that challenge as reported by a parent over a 6-month period prior to the study. The participant was excluded if the child had mild, profound or no intellectual disability, if a sibling was participating in the study, or if the parent had insufficient English language skills to complete or understand the study questionnaires. Participants were recruited from various community services including Participant Identification Centres in four main areas in England: North West of England (Blackpool, Site 1), North London (Site 2), South London (Site 3) and North East of England (Newcastle, Site 4). The primary outcome measure was the parent-reported Child Behaviour Checklist (CBCL). We also assessed secondary outcomes using parent–child observations, other caregiver/teacher reports, questionnaires of parents’ mental health, stress, sense of competence and parent and child health-related quality of life. We further conducted a process evaluation using a mixed methods approach to assess intervention delivery (fidelity, dose, adaptations, reach) and to capture the views of the participants, therapists and service managers. The study was ethically reviewed and approved by the London – Camden and Kings Cross Research Ethics Committee (reference: 17/LO/0659). The last 18 months of the trial took place during the coronavirus disease 2019 (COVID-19) pandemic. Fifty-one out of 261 families were randomised after 16 March 2020 (i.e. the beginning of the pandemic) with 219 baseline and follow-up assessments carried out from that date to the end of the study (the last participant follow-up was completed in December 2021). We made changes to the study to comply with the public health measures implemented by the UK government. This ensured participant and researcher safety and allowed us to safeguard the study validity and quantify, where possible, the impact of this event. After the start of the pandemic, all study procedures, for example obtaining consent, carrying out assessments and delivering the intervention, were carried out remotely. We also adjusted the a priori statistical and health economic analysis plans to account for these changes. We were unable to continue carrying out behavioural observations and completing cognitive assessments with the children, as techniques for doing so remotely were unavailable at the time. Stepping Stones Triple P In the EPICC-ID study, we delivered a manualised level 4 SSTP intervention composed of six group sessions and three individual telephone or face-to-face contacts with the parent over a period of 9 weeks. Each group session lasted approximately 2.5 hours. Individual sessions took around 30 minutes. SSTP has the most evidence for efficacy, and while available in the UK via Triple P UK, it has not been formally tested for its clinical and cost-effectiveness and is not rolled out in the National Health Service or a part of the local offer (resources available from Local Authorities for children with disabilities). The group sessions were delivered in person until March 2020 and on the online platforms zoom and Microsoft Teams thereafter. Parents allocated to both arms also received a list of national resources and the Contact (a Family) charity guide for managing behaviours that challenge, which included signposting to social and health care support. Treatment as usual Treatment as usual was available to participants in both trial arms. The local services provided professional health and social care support, which was available at the time of the study at all of the sites. Our survey of parenting programmes showed that none of the sites offered SSTP to parents of children with intellectual disabilities. However, it is possible that parents of children with mild developmental delay who were ineligible for the trial could have been attending other universal parenting groups. Results Clinical effectiveness Our primary analysis was based on intention-to-treat in which we adjusted for baseline CBCL total score, centre, level of intellectual disability and therapist clustering, showed a mean difference between arms of −4.23 [95% confidence interval (CI) −9.98 to 1.52, p = 0.146]. We found that SSTP, as delivered in this trial, did not reduce behaviours that challenge compared to TAU at 12 months post-randomisation. Our initial sample size estimation was predicated on a minimal clinically significant difference of eight points between the two study arms. Of the 155 patients who were randomised to the SSTP arm, 50 participants were adherent to the SSTP intervention, meaning they attended at least 4 (out of 6) group sessions and 2 (out of 3) individual sessions. We carried out a per-protocol analysis which excluded non-adherent participants; we found that the intervention effect at 12 months was −10.77 (95% CI −19.12 to −2.42, p = 0.014). We also carried out a complier-average causal effect (CACE) analysis to measure the effect of the intervention on CBCL total scores at 12 months. We found a reduction of −11.53 (95% CI −26.97 to 3.91, p = 0.143) compared to TAU. We further performed a subgroup analysis to investigate whether the effect of SSTP differed depending on whether recruitment was before or after 16 March 2020. In this model, the mean difference of the effect of SSTP on CBCL total scores at 12 months was estimated as −7.12 (95% CI −13.44 to −0.81) and 7.61 (95% CI −5.43 to 20.64), respectively, with a p = 0.046. This suggests that the effect of SSTP was different before and during the pandemic. The point estimates suggest the direction of effect may have reversed during the pandemic. There were no statistically significant differences between arms in any of the secondary outcome measures. However, we noted a reduction in negative child behaviours as shown in observations of parent–child interaction. A total of 20 serious adverse events were reported, with 12 in the SSTP and 8 in the TAU arms. Of these, 13 were reported for children and 7 for parents. None of these were determined to be related to the intervention. Cost-effectiveness We found that training in level 4 SSTP costs £26 per participant. From a health and social care perspective, SSTP is cost-effective at −£1057.88 per participant (95% CI −£3218.6 to −£46.67). A cost-utility analysis within the cost-effectiveness approach indicates a non-significant quality-adjusted life-year (QALY) difference of 0.005 (95% CI −0.023 to 0.051). Using National Institute of Health and Care Excellence (NICE) thresholds for willingness to pay (WPT) for the intervention, there is an 89% probability that SSTP is cost-effective compared to TAU at a WTP for a QALY gained of £20,000 and £30,000. There is a 90% probability that SSTP is cost-effective compared to TAU at a WTP for a QALY gained of £13,000. Therefore, a rollout of an alternative parenting programme such as SSTP is likely dependent on how behaviours that challenge may be prioritised within a host of other clinical considerations at local and national levels. Process evaluation A total of 155 parents were randomised to receive SSTP and 91 (59%) attended at least one group session. The remainder of parents did not attend any sessions. Group sizes ranged from 1 to 8 [M = 3.64, standard deviation (SD) = 1.66]. Eleven therapists delivered the intervention across all sites. Fidelity scores ranged from 7 to 10 (M = 9.38, SD = 0.96). Eight sessions (62%) were scored as having the maximum score for fidelity. In terms of quality, two sessions were rated as 3 (adequate), with the remainder of the sessions being rated at 4 (good). We interviewed service managers to understand their views on possible challenges with the implementation and delivery of this intervention. They expressed concerns about potential low interest by parents due to competition with other therapies being offered in their services. However, none of those other therapies specifically address behaviours that challenge displayed by children with developmental disabilities nor were delivered in groups. Service managers described challenges finding a venue with a good location, appropriate equipment and parking facilities. There were several adaptations made to the delivery of SSTP, especially during COVID-19 when all sessions were moved online. The benefits and challenges of remote delivery were discussed with therapists and advice was obtained from the UK Triple P providers. Some benefits included larger group sizes and increased flexibility for parents and therapists with the timings and length of sessions. However, remote delivery limited opportunities for informal conversations between participants and was a challenge for rapport building, which is essential for group therapy. Overall, therapists found the intervention helpful and enjoyed the training and delivery. They also appreciated the opportunity to have expert group supervision. Therapists expressed concerns about some parents’ ability to comprehend and apply the skills taught. Therapists felt that flexibility may be needed in the number of sessions offered for parents who struggle with learning new skills or managing behaviour change. We also conducted interviews with 18 parents from the study (9 in each arm). Parents who received the SSTP enjoyed learning new techniques and strategies for managing their child’s behaviours, such as distraction the child during a meltdown, planning activities, setting house rules using visual aids (e.g. symbols, timetables) and using reward charts. The intervention boosted their confidence as a parent and helped them to better understand and accept their child’s behaviours. Most of the respondents were in favour of the group format, which provided peer support, normalised their situation and allowed them to create valuable networks with others. Parents described timing, group size, transport and setting as barriers affecting the accessibility of the groups, which are important to consider when delivering this programme. Conclusion The main statistical analysis did not reveal any statistical differences in mean CBCL scores between the intervention arms, suggesting that SSTP at 12 months is not effective compared with TAU. However, the sensitivity analyses showed that those receiving the intervention experienced a positive, albeit non-statistically significant change in the child’s behaviours of concern (reduction). Parents reported that the intervention boosted their confidence and skills, and the group format enabled them to learn from others and receive peer support. Overall, the findings suggest the intervention has clinical utility and should be available to underserved children who are more likely to have long-term adverse consequences due to the early onset of behaviours that challenge. Further, SSTP appears to be cost-effective and well within the NICE threshold for cost-effectiveness at £20,000–30,000 and at the lower cost of £13,000. Therefore, there are indications the intervention may be beneficial under certain conditions and can be delivered within NHS care. Further research is needed to explore and find solutions to the implementation of parenting groups for behaviours that challenge in this underserved population, as well as the optimal mode of delivery to maximise engagement and outcomes. Study registration This study is registered as NCT03086876. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: HTA 15/162/02) and is published in full in Health Technology Assessment; Vol. 28, No. 6. See the NIHR Funding and Awards website for further award information.

Objective To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.Design Phase 3b multicentre, double-blind, randomised placebo-controlled trial.Setting Twenty-one hospitals in the UK.Participants Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.Intervention Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.Main outcome measure The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.Secondary outcome measures The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.Results 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.Conclusions The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.Trial registration number Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Summary: Background: We aimed to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection, its effect on COVID-19 presentation, and post-vaccination symptoms in children and adolescents (CA) in the UK during periods of Delta and Omicron variant predominance. Methods: In this prospective longitudinal cohort study, we analysed data from 115,775 CA aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2, and described the illness profile of CA with post-vaccination SARS-CoV-2 infection, compared to unvaccinated CA, and post-vaccination side-effects. Findings: Between August 5, 2021 and February 14, 2022, 25,971 UK CA aged 12-17 years received one dose of BNT162b2 vaccine. The probability of testing positive for infection diverged soon after vaccination, and was lower in CA with prior SARS-CoV-2 infection. Vaccination reduced proxy-reported infection risk (-80·4% (95% CI -0·82 -0·78) and -53·7% (95% CI -0·62 -0·43) at 14–30 days with Delta and Omicron variants respectively, and -61·5% (95% CI -0·74 -0·44) and -63·7% (95% CI -0·68 -0.59) after 61–90 days). Vaccinated CA who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CA; during the Omicron period this was only evident in children aged 12-15 years. Overall disease profile was similar in both vaccinated and unvaccinated CA. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved within few days (3 days in most cases). Interpretation: One dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CA aged 12-17 years. Vaccine protection varied for SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination was generally milder, although unvaccinated CA also had generally mild disease. Overall, vaccination was well-tolerated. Funding: UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimer's Society, and ZOE Limited.

Abstract Background Individuals with co-occurring hyperactivity disorder/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) can have complex presentations that may complicate diagnosis and treatment. There are established guidelines with regard to the identification and treatment of ADHD and ASD as independent conditions. However, ADHD and ASD were not formally recognised diagnostically as co-occurring conditions until the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) was published in 2013. Hence, awareness and understanding of both conditions when they co-occur is less established and there is little guidance in the clinical literature. This has led to uncertainty among healthcare practitioners when working with children, young people and adults who present with co-existing ADHD and ASD. The United Kingdom ADHD Partnership (UKAP) therefore convened a meeting of professional experts that aimed to address this gap and reach expert consensus on the topic that will aid healthcare practitioners and allied professionals when working with this complex and vulnerable population. Method UK experts from multiple disciplines in the fields of ADHD and ASD convened in London in December 2017. The meeting provided the opportunity to address the complexities of ADHD and ASD as a co-occurring presentation from different perspectives and included presentations, discussion and group work. The authors considered the clinical challenges of working with this complex group of individuals, producing a consensus for a unified approach when working with male and female, children, adolescents and adults with co-occurring ADHD and ASD. This was written up, circulated and endorsed by all authors. Results The authors reached a consensus of practical recommendations for working across the lifespan with males and females with ADHD and ASD. Consensus was reached on topics of (1) identification and assessment using rating scales, clinical diagnostic interviews and objective supporting assessments; outcomes of assessment, including standards of clinical reporting; (2) non-pharmacological interventions and care management, including psychoeducation, carer interventions/carer training, behavioural/environmental and Cognitive Behavioural Therapy (CBT) approaches; and multi-agency liaison, including educational interventions, career advice, occupational skills and training, and (3) pharmacological treatments. Conclusions The guidance and practice recommendations (Tables 1, 4, 5, 7, 8 and 10) will support healthcare practitioners and allied professionals to meet the needs of this complex group from a multidisciplinary perspective. Further research is needed to enhance our understanding of the diagnosis, treatment and management of individuals presenting with comorbid ADHD and ASD.

Abstract Background Children with intellectual disabilities are likely to present with challenging behaviour. Parent mediated interventions have shown utility in influencing child behaviour, although there is a paucity of UK research into challenging behaviour interventions in this population. NICE guidelines favour Stepping Stones Triple P (SSTP) as a challenging behaviour intervention and this trial aims to evaluate its clinical and cost effectiveness in preschool children with moderate to severe intellectual disabilities. Methods This trial launched in 2017 at four sites across England, with the aim of recruiting 258 participants (aged 30–59 months). The Intervention Group receive nine weeks of SSTP parenting therapy (six group sessions and three individualised face to face or telephone sessions) in addition to Treatment as Usual, whilst the Treatment as Usual only group receive other available services in each location. Both study groups undergo the study measurements at baseline and at four and twelve months. Outcome measures include parent reports and structured observations of behaviour. Service use and health related quality of life data will also be collected to carry out a cost effectiveness and utility evaluation. Discussion Findings from this study will inform policy regarding interventions for challenging behaviour in young children with moderate to severe intellectual disabilities. Trial registration number Clinicaltrials.gov, NCT03086876. Registered 22nd March 2017, https://clinicaltrials.gov/ct2/show/NCT03086876.

Background: The Delta (B.1.617.2) SARS-CoV-2 variant was the predominant UK circulating strain between May and November 2021. We investigated whether COVID-19 from Delta infection differed from infection with previous variants in children. Methods: Through the prospective COVID Symptom Study, 109,626 UK school-aged children were proxy-reported between 28 December 2020 and 8 July 2021. We selected all symptomatic children who tested positive for SARS-CoV-2 and were proxy-reported at least weekly, within two timeframes: 28 December 2020 to 6 May 2021 (Alpha (B.1.1.7), the main UK circulating variant) and 26 May to 8 July 2021 (Delta, the main UK circulating variant), with all children unvaccinated (as per national policy at the time). We assessed illness profiles (symptom prevalence, duration, and burden), hospital presentation, and presence of long (≥28 day) illness, and calculated odds ratios for symptoms presenting within the first 28 days of illness. Results: 694 (276 younger (5–11 years), 418 older (12–17 years)) symptomatic children tested positive for SARS-CoV-2 with Alpha infection and 706 (227 younger and 479 older) children with Delta infection. Median illness duration was short with either variant (overall cohort: 5 days (IQR 2–9.75) with Alpha, 5 days (IQR 2–9) with Delta). The seven most prevalent symptoms were common to both variants. Symptom burden over the first 28 days was slightly greater with Delta compared with Alpha infection (in younger children, 3 (IQR 2–5) symptoms with Alpha, 4 (IQR 2–7) with Delta; in older children, 5 (IQR 3–8) symptoms with Alpha, 6 (IQR 3–9) with Delta infection ). The odds of presenting several symptoms were higher with Delta than Alpha infection, including headache and fever. Few children presented to hospital, and long illness duration was uncommon, with either variant. Conclusions: COVID-19 in UK school-aged children due to SARS-CoV-2 Delta strain B.1.617.2 resembles illness due to the Alpha variant B.1.1.7., with short duration and similar symptom burden.

Background: Despite evidence-based national guidelines for ADHD in the United Kingdom (UK), ADHD is under-identified, under-diagnosed, and under-treated. Many seeking help for ADHD face prejudice, long waiting lists, and patchy or unavailable services, and are turning to service-user support groups and/or private healthcare for help.Methods: A group of UK experts representing clinical and healthcare providers from public and private healthcare, academia, ADHD patient groups, educational, and occupational specialists, met to discuss shortfalls in ADHD service provision in the UK. Discussions explored causes of under-diagnosis, examined biases operating across referral, diagnosis and treatment, together with recommendations for resolving these matters.Results: Cultural and structural barriers operate at all levels of the healthcare system, resulting in a de-prioritization of ADHD. Services for ADHD are insufficient in many regions, and problems with service provision have intensified as a result of the response to the COVID-19 pandemic. Research has established a range of adverse outcomes of untreated ADHD, and associated long-term personal, social, health and economic costs are high. The consensus group called for training of professionals who come into contact with people with ADHD, increased funding, commissioning and monitoring to improve service provision, and streamlined communication between health services to support better outcomes for people with ADHD.Conclusions: Evidence-based national clinical guidelines for ADHD are not being met. People with ADHD should have access to healthcare free from discrimination, and in line with their legal rights. UK Governments and clinical and regulatory bodies must act urgently on this important public health issue.

Children and young people (CYP) with neurodevelopmental disorders (NDDs) may be particularly vulnerable to adverse mental health effects due to the COVID-19 pandemic. We conducted a cross-sectional U.K. parent-reported study from 2nd April–2nd June 2020, using the Strengths and Difficulties Questionnaire. CYP with NDDs (n = 371), compared to neurotypical controls, had a higher prevalence of emotional symptoms (42% vs. 15%) and conduct problems (28% vs. 9%), and fewer prosocial behaviours (54% vs. 22%). All groups had worse emotional symptoms than pre-COVID groups, and those with attention-deficit/hyperactivity disorder showed inflated conduct problems, while those with autism spectrum disorder exhibited decreased prosocial behaviours. Females with ASD had higher emotional symptoms compared to males. CYP with NDDs, and those without, showed higher levels of parent-reported mental health problems than comparable cohorts pre-COVID-19.

Background: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. Objective: To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. Design: A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. Participants: Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). Interventions: Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. Main outcome measures: Primary outcome measure – American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures – ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. Results: In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. Conclusions: The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. Trial registration: EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).

To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children in Great Britain.A nationally representative cross-sectional study survey of children (1102) aged 4-18 years (999 white, 570 male) living in private households (January 1997-1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0-2.4]).We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children.

Aims and method This survey of 66 specialist mental health services aimed to provide an up-to-date description of pathways of care and interventions available to children with an intellectual disability referred for behaviours that challenge or with suspected mental health problems. Results Overall, 24% of services made contact with a family at referral stage, whereas 29% contacted families at least once during the waiting list phase. Only two in ten services offered any therapeutic input during the referral or waiting list stages. During the active caseload phase, services offered mostly psychoeducation (52–59%), followed by applied behaviour analytic approaches for behaviours that challenge (52%) and cognitive–behavioural therapy (41%). Thirty-six per cent of services had not offered any packaged or named intervention in the past 12 months. Clinical implications With increasing waiting times for specialist mental health support, services need to consider increasing the amount of contact and therapeutic input on offer throughout all stages of a child's journey with the service.