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Background: Differences in the way autistic children experience the world can contribute to anxiety and stress. Carol Gray's Social Stories™ are a highly personalised intervention to support children by providing social information about specific situations in an individual story., Objectives: This randomised controlled trial aimed to establish whether Social Stories are clinically effective and cost-effective in improving social responsiveness and social and emotional health in children on the autism spectrum in schools., Design: A multisite pragmatic cluster randomised controlled trial comparing Social Stories with care as usual., Setting: Eighty-seven schools (clusters) across Yorkshire and the Humber., Participants: Two hundred and forty-nine children were randomised via a bespoke system hosted at York Trials Unit (129 Social Stories and 120 care as usual). Recruitment was completed in May 2021. Participants were children aged 4-11 years with a diagnosis of autism, alongside teachers, interventionists and caregivers. Recruitment was via schools, NHS trusts, support groups and local publicity., Intervention: The intervention included training for educational professionals and caregivers covering psychoeducation and implementation of Social Stories. Stories were written around contextualised goals around the child's need for social information. Interventionists read the Social Story™ with the child at least six times over 4 weeks during school., Main Outcome Measure: The primary outcome was the Social Responsiveness Scale-2 completed by teachers at 6 months (the primary end point), which measures social awareness, cognition, communication and behaviour. Data were collected from caregivers and educational professionals at 6 weeks and 6 months through questionnaires. Blinding of participants was not possible., Results: At 6 months, the estimated difference in expected teacher-reported Social Responsiveness Scale-2 T-score (the primary end point) was -1.61 (95% confidence interval -4.18 to 0.96, p  = 0.220), slightly favouring the intervention group. The estimated differences for the parent-reported secondary outcomes at 6 months were small and generally favoured the control group except the measure of children's quality-adjusted life-year (+ 0.001, 95% confidence interval -0.032 to 0.035) and parental stress (-1.49, 95% confidence interval -5.43 to 2.46, p  = 0.460), which favoured the intervention group. Children in the intervention group met their individual goals more frequently than children who received usual care alone (0.97 confidence interval 0.21 to 1.73, p  = 0.012). The intervention is likely to save small costs (-£191 per child, 95% confidence interval -767.7 to 337.7) and maintain a similar quality of life compared to usual care. The probability of Social Stories being a preferred option is 75% if the society is willing to pay £20,000 per quality-adjusted life-year gained. Limitations include considerable disruptions during the coronavirus disease 2019 pandemic., Conclusion: Social Stories are used in schools and represent a low-cost intervention. There is no clinically evident impact on social responsiveness, anxiety and/or depression, parental stress or general health. Benefits were observed for specific behavioural goals as assessed by the teacher, and Social Stories may serve as a useful tool for facilitating dialogue between children and school staff to address specific behavioural challenges. Usage should be at the school's discretion., Future Work: Given the uncertainty of the results in light of coronavirus disease 2019, further work to establish the impact of Social Stories is merited., Trial Registration: This trial is registered as ISRCTN11634810., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/91) and is published in full in Health Technology Assessment ; Vol. 28, No. 39. See the NIHR Funding and Awards website for further award information.

Introduction: Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require planned orthopaedic surgery to reduce pain and improve function. Currently, bDMARDs are withheld during the perioperative period due to potential infection risk. However, this predisposes patients to IA flares and loss of disease control. The question of whether to stop or continue bDMARDs in the perioperative period has not been adequately addressed in a randomised controlled trial (RCT)., Methods and Analysis: PERISCOPE is a multicentre, superiority, pragmatic RCT investigating the stoppage or continuation of bDMARDs. Participants will be assigned 1:1 to either stop or continue their bDMARDs during the perioperative period. We aim to recruit 394 adult participants with IA. Potential participants will be identified in secondary care hospitals in the UK, screened by a delegated clinician. If eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported PROMIS-29 (Patient Reported Outcome Measurement Information System) over the first 12 weeks postsurgery. Secondary outcome measures are as follows: PROMIS - Health Assessment Questionnaire (PROMIS-HAQ), EQ-5D-5L, Disease activity: generic global Numeric Rating Scale (patient and clinician), Self-Administered Patient Satisfaction scale, Health care resource use and costs, Medication use, Surgical site infection, delayed wound healing, Adverse events (including systemic infections) and disease-specific outcomes (according to IA diagnosis). The costs associated with stopping and continuing bDMARDs will be assessed. A qualitative study will explore the patients' and clinicians' acceptability and experience of continuation/stoppage of bDMARDs in the perioperative period and the impact postoperatively., Ethics and Dissemination: Ethical approval for this study was received from the West of Scotland Research Ethics Committee on 25 April 2023 (REC Ref: 23/WS/0049). The findings from PERISCOPE will be submitted to peer-reviewed journals and feed directly into practice guidelines for the use of bDMARDs in the perioperative period., Trial Registration Number: ISRCTN17691638., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: One in 57 children are diagnosed with autism in the UK, and the estimated cost for supporting these children in education is substantial. Social Stories™ is a promising and widely used intervention for supporting children with autism in schools and families. It is believed that Social Stories™ can provide meaningful social information to children that can improve social understanding and may reduce anxiety. However, no economic evaluation of Social Stories has been conducted., Aims: To assess the cost-effectiveness of Social Stories through Autism Spectrum Social Stories in Schools Trial 2, a multi-site, pragmatic, cluster-randomised controlled trial., Method: Children with autism who were aged 4-11 years were recruited and randomised ( N = 249). Costs measured from the societal perspective and quality-adjusted life-years (QALYs) measured by the EQ-5D-Y-3L proxy were collected at baseline and at 6-month follow-up for primary analysis. The incremental cost-effectiveness ratio was calculated, and the uncertainty around incremental cost-effectiveness ratios was captured by non-parametric bootstrapping. Sensitivity analyses were performed to evaluate the robustness of the primary findings., Results: Social Stories is likely to result in a small cost savings (-£191 per child, 95% CI -767.7 to 337.7) and maintain similar QALY improvements compared with usual care. The probability of Social Stories being a preferred option is 75% if society is willing to pay £20 000 per QALY gained. The sensitivity analysis results aligned with the main study outcomes., Conclusions: Compared with usual care, Social Stories did not lead to an increase in costs and maintained similar QALY improvements for primary-aged children with autism.

Objective: To collect data on content/face validity and interobserver agreement for a Neonatal Coma Score (NCS) in well full-term neonates and on construct validity in unwell and preterm babies, specifically how the NCS changed with gestational age and illness., Design: Prospective cohort studies., Setting: Two UK tertiary neonatal units (Sheffield and Leeds)., Patients: 151 well full-term (≥37 weeks gestational age) newborn babies recruited between January and February 2020 in Sheffield and April and May 2021 in Leeds; 101 sick preterm and full-term babies admitted to Sheffield neonatal unit between January 2021 and May 2022., Intervention: A new NCS., Main Outcome Measures: Determination of normal values in well babies born ≥37 weeks gestational age; data on how the NCS changes with gestational age and illness., Results: Face validity was demonstrated during development of the NCS. The median NCS of well, full-term newborn babies was 15 and the intraclass correlation coefficient was 0.78 (95% CI 0.70 to 0.84). In the 'well' preterm population, 95% <28 weeks had a score ≥11; 28-31 weeks ≥11; 32-36 weeks ≥13 and 37-44 weeks 14-15. The NCS dropped during periods of deterioration, demonstrating evidence of construct validity. Criterion validity was not assessed., Conclusions: The NCS has good intraobserver agreement in well full-term babies, with a normal NCS 14-15. The NCS in preterm neonates depended on gestational age, and deterioration from baseline was associated with illness. Further work is needed to determine normal scores each gestational age, reliability at lower levels, how early the NCS identifies deterioration and comparison with other assessment tools to demonstrate criterion validity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Older patients often experience safety issues when transitioning from hospital to home. The 'Your Care Needs You' (YCNY) intervention aims to support older people to 'know more' and 'do more' whilst in hospital so that they are better prepared for managing at home., Methods: A multi-centre cluster randomised controlled trial (cRCT) will evaluate the effectiveness and cost-effectiveness of the YCNY intervention. Forty acute hospital wards (clusters) in England from varying medical specialities will be randomised to deliver YCNY or care-as-usual on a 1:1 basis. The primary outcome will be unplanned hospital readmission rates within 30 days of discharge. This will be extracted from routinely collected data of at least 5440 patients (aged 75 years and older) discharged to their own homes during the 4- to 5-month YCNY intervention period. A nested cohort of up to 1000 patients will be recruited to the study to collect secondary outcomes via follow-up questionnaires at 5-, 30- and 90-day post-discharge. These will include measures of patient experience of transitions, patient-reported safety events, quality of life and healthcare resource use. Unplanned hospital readmission rates at 60 and 90 days of discharge will be collected from routine data. A process evaluation (primarily interviews and observations with patients, carers and staff) will be conducted to understand the implementation of the intervention and the contextual factors that shape this, as well as the intervention's underlying mechanisms of action. Fidelity of intervention delivery will also be assessed across all intervention wards., Discussion: This study will establish the effectiveness and cost-effectiveness of the YCNY intervention which aims to improve patient safety and experience for older people during transitions of care. The process evaluation will generate insights about how the YCNY intervention was implemented, what elements of the intervention work and for whom, and how to optimise its implementation so that it can be delivered with high fidelity in routine service contexts., Trial Registration: UK Clinical Research Network Portfolio: 44559; ISTCRN: ISRCTN17062524. Registered on 11/02/2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The 'Your Care Needs You' (YCNY) intervention aims to increase the safety and experience of transitions for older people through greater patient involvement during the hospital stay., Methods: A cluster randomised controlled feasibility trial was conducted on NHS inpatient wards (clusters) where ≥ 40% of patients were routinely ≥ 75 years. Wards were randomised to YCNY or usual care using an unequal allocation ratio (3:2). We aimed to recruit up to 20 patients per ward. Follow-up included routine data collection and questionnaires at 5-, 30-, and 90-days post-discharge. Eligible patients were ≥ 75 years, discharged home, stayed overnight on participating wards, and could read and understand English. The trial assessed the feasibility of delivering YCNY and the trial methodology through recruitment rates, outcome completion rates, and a qualitative evaluation. The accuracy of using routinely coded data for the primary outcome in the definitive trial was assessed by extracting discharge information for up to ten nonindividual consenting patients per ward., Results: Ten wards were randomised (6 intervention, 4 control). One ward withdrew, and two wards were unable to deliver the intervention. Seven-hundred twenty-one patients were successfully screened, and 161 were recruited (95 intervention, 66 control). The patient post-discharge attrition rate was 17.4% (n = 28). Primary outcome data were gathered for 91.9% of participants with 75.2% and 59.0% providing secondary outcome data at 5 and 30 days post-discharge respectively. Item completion within questionnaires was generally high. Post-discharge follow-up was terminated early due to the COVID-19 pandemic affecting 90-day response rates (16.8%). Data from 88 nonindividual consenting patients identified an error rate of 15% when using routinely coded data for the primary outcome. No unexpected serious adverse events were identified. Most patients viewed YCNY favourably. Staff agreed with it in principle, but ward pressures and organisational contexts hampered implementation. There was a need to sustain engagement, provide clarity on roles and responsibilities, and account for fluctuations in patients' health, capacity, and preferences., Conclusions: If implementation challenges can be overcome, YCNY represents a step towards involving older people as partners in their care to improve the safety and experience of their transitions from hospital to home., Trial Registration: ISRCTN: 51154948., (© 2022. The Author(s).)

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6-180 months). Patients received a single intramuscular vaccination of 1 × 10 10 viral particles (v.p.; adults only) or 7.5 × 10 10 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway., Competing Interests: Declaration of interests C.J.N.L., P.M.K., and T.A. are co-authors of a patent protecting the gene insert used in candidate vaccine ChAd63-KH (Europe 10719953.1; India 315101). The authors otherwise declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We describe 64 foetuses with cortical formation abnormalities (CFA) who had two in utero magnetic resonance (iuMR) exams, paying particular detail to those in which the original classification of CFA category changed between the two studies. The goal was to attempt to quantify the value of third-trimester follow-up studies in CFA foetuses on second-trimester iuMR imaging., Methods: The 64 foetuses reviewed came from a CFA cohort of 374 foetuses reported in an earlier publication, which detailed a classification for foetal CFA. A consensus panel of senior paediatric neuroradiologists reviewed both studies, described any change in the category of CFA between them, and attempted to predict the possible clinical significance of any differences based on the combined clinical experience of the panel., Results: In 40/64 (62%) foetuses, the CFA description was the same on both studies. In 24/64 (38%) cases, there was a category change which included three foetuses without CFA on first examination, six foetuses where the difference involved change in laterality/symmetry, and in 15 cases the re-classification involved categorical change within the same group. Brain abnormalities other than CFA were present in 30/64 (47%) foetuses on the first study and in 33/64 (52%) on the second. We predicted that prognosis would have changed on the basis of the second study in 8% of cases, all indicating worse prognosis., Conclusions: We have shown that the extra diagnostic and predicted prognostic yield justifies follow-up studies in the third trimester if a CFA is shown on the second-trimester iuMR imaging., Key Points: • Sixty-four foetuses with cortical formation abnormalities had two iuMR studies, for the vast majority the baseline in the second trimester and the sequential in the third. • In three foetuses, the cortical formation abnormality (CFA) was not visible on the first study. In a further 21 foetuses, the categorical description of the CFA changed between the two studies. Prognosis changed in 8% of the cases following the second iuMR study, and in all cases, the prognosis was worse. • Multiple iuMR studies provide information about the natural history of CFA; the extra diagnostic and predicted prognostic yield justifies follow-up studies.

Objectives: To undertake a process evaluation of an adherence support intervention for people with cystic fibrosis (PWCF), to assess its feasibility and acceptability., Setting: Two UK cystic fibrosis (CF) units., Participants: Fourteen adult PWCF; three professionals delivering adherence support ('interventionists'); five multi-disciplinary CF team members., Interventions: Nebuliser with data recording and transfer capability, linked to a software platform, and strategies to support adherence to nebulised treatments facilitated by interventionists over 5 months (± 1 month)., Primary and Secondary Measures: Feasibility and acceptability of the intervention, assessed through semistructured interviews, questionnaires, fidelity assessments and click analytics., Results: Interventionists were complimentary about the intervention and training. Key barriers to intervention feasibility and acceptability were identified. Interventionists had difficulty finding clinic space and time in normal working hours to conduct review visits. As a result, fewer than expected intervention visits were conducted and interviews indicated this may explain low adherence in some intervention arm participants. Adherence levels appeared to be >100% for some patients, due to inaccurate prescription data, particularly in patients with complex treatment regimens. Flatlines in adherence data at the start of the study were linked to device connectivity problems. Content and delivery quality fidelity were 100% and 60%-92%, respectively, indicating that interventionists needed to focus more on intervention 'active ingredients' during sessions., Conclusions: The process evaluation led to 14 key changes to intervention procedures to overcome barriers to intervention success. With the identified changes, it is feasible and acceptable to support medication adherence with this intervention., Trial Registration Number: ISRCTN13076797; Results., Competing Interests: Competing interests: MJW received funding from Zambon and support from Philips Respironics for the early intervention development work. This has not had any direct influence on the feasibility study reported here. In addition, MJW has worked with Pari to carry out studies using the e-track. This has not had any direct influence on the feasibility study reported here. The University of Manchester software team received funding from Pari to create a medication reporting component within the CFHealthHub software. This has not had any direct influence on the feasibility study reported here., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Alcohol interventions are important to the developing public health role of community pharmacies. The Medicines and Alcohol Consultation (MAC) is a new intervention, co-produced with community pharmacists (CPs) and patients, which involves a CP practice development programme designed to integrate discussion of alcohol within existing NHS medicine review services. We conducted a pilot trial of the MAC and its delivery to investigate all study procedures to inform progression to a definitive trial., Methods: This cluster pilot RCT was conducted in 10 community pharmacies in Yorkshire, UK, with a CP from each who regularly conducted Medicine Use Review (MUR) and New Medicine Service (NMS) consultations. Randomisation was conducted using a secure remote randomisation service. Intervention CPs (n = 5) were trained to deliver the MAC in MUR/NMS consultations. Control CPs (n = 5) provided these services as usual. Consecutive MUR/NMS patients were asked by CPs to participate, screened for eligibility (consumption of alcohol at least twice per week), and baseline data collected for those eligible. A two-month follow-up telephone interview was conducted. Blinding of CPs was not possible, but patients were blinded to the alcohol focus of the trial. Primary outcomes were total weekly UK units (8 g of ethanol per unit) of alcohol consumption in the week prior to follow-up, and confidence in medications management. Trial procedures were assessed by recruitment, attrition, and follow-up rates., Results: 260 patients were approached by CPs to take part in the trial, 68% (n = 178) were assessed for eligibility and 30% (n = 54) of these patients were eligible. Almost all eligible patients (n = 51; 94%) consented to participate, of whom 92% (n = 47) were followed-up at 2 months; alcohol consumption was lower in the intervention arm and confidence in medication management reduced slightly for both groups. Exploration of recall issues at follow-up showed a high level of agreement between a two-item quantity/frequency measure and 7-day guided recall of alcohol consumption., Conclusions: The pilot trial demonstrates the feasibility of implementing the MAC in community pharmacy and trial recruitment and data collection procedures. However, decommissioning of MURs means that it is not possible to conduct a definitive trial of the intervention in this service., Trial Registration: ISRCTN57447996.

Objective: To formulate a classification system for foetal cortical formation abnormalities (CFAs) based on in utero magnetic resonance (iuMR) appearances and trial it in 356 cases., Methods: This retrospective study included all cases of foetal CFA diagnosed between 2000 and 2017 from seven centres in Italy and UK. All of the studies were reviewed by a panel of paediatric neuroradiologists experienced in iuMR with the aid of an algorithm designed to categorise the abnormalities., Results: Consensus expert review confirmed 356 foetuses with CFA and the first level of classification distinguished bilateral CFA (229/356-64%) from unilateral CFA (127/356-36%) cases with sub-classification of the bilateral cases into asymmetric (65/356-18%) and symmetric (164/356-46%) involvement. There was a statistically significant excess of foetuses with small head size, e.g. 17% of the cohort had a bi-parietal diameter < 3rd centile. There was a small but statistically significant excess of males in the cohort. Further categorisation was made on fine anatomical structure., Conclusions: It is often not possible to classify foetal CFA using the principles and nomenclature used in paediatric neuroradiology. We have created a classification system for foetal CFA based on the analysis of 356 cases and believe that this will assist future research designed to correlate ante-natal and post-natal imaging features and understand the clinical sequelae of CFA described in utero., Key Points: • We describe a morphological classification system of foetal brain cortical formation abnormalities that can be used in clinical practice. • This classification system can be used in future research studies to evaluate the long-term imaging and clinical outcomes of foetal brain cortical formation abnormalities in 17- to 38-week gestational age range. • The practical value of the work is in providing a framework and language to look for imaging clues that may differentiate between different CFA in further studies.

Background : The CHAMP-1 ( Community pharmacy: Highlighting Alcohol use in Medication a Ppointments) pilot trial aimed to explore an intervention discussing alcohol during medication consultations with community pharmacists. It presented various challenges regarding patient retention, as participants were recruited by their pharmacist and followed-up remotely by a trained researcher, who they had not met, two months later.  We discuss our actions and experiences of completing follow-up activities. Methods : Community pharmacists recruited patients aged 18 and over, attending a Medicine Use Review (MUR) or New Medicine Service (NMS) consultation, and drinking alcohol at least twice per week. Pharmacies were randomised to conduct their consultations as usual (control), or to incorporate the Medicines and Alcohol Consultation (MAC) intervention. All participants were followed-up by a researcher after two months to complete data collection via telephone or post. We employed standard follow-up strategies, including a plan to text participants with a reminder in advance of their follow-up. Results : Forty-seven of 51 participants (92%) completed the two month follow-up. Thirty-eight (81%) responses were provided by telephone and nine (19%) by post. Of the 38 follow-up calls completed by telephone, 17 (45%) participants were reached at first attempt; 16 (42%) at second attempt; and five (13%) at the third attempt. We observed a high percentage of data completion across telephone and postal collection methods.  Participants were willing to discuss potentially sensitive issues, such as alcohol consumption, anxiety, and depression, with a researcher who was external to the pharmacy team.  Conclusions : The results suggest that patients recruited to a trial by community pharmacists are willing to take part in data collection activities, and remote follow-up can be successfully conducted by researchers. The techniques employed to encourage high levels of retention should be investigated further in a larger study, alongside consideration of optimal strategies to collect data within community pharmacies., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Watson M et al.)

Background: In utero MRI (iuMRI) detects fetal brain abnormalities more accurately than ultrasonography and provides additional clinical information in around half of pregnancies. We aimed to study whether postnatal neuroimaging after age 6 months changes the diagnostic accuracy of iuMRI and its ability to predict developmental outcome., Methods: Families enrolled in the MERIDIAN study whose child survived to age 3 years were invited to have a case note review and assessment of developmental outcome with the Bayley Scales of Infant and Toddler Development, the Ages and Stages Questionnaire, or both. A paediatric neuroradiologist, masked to the iuMRI results, reviewed the postnatal neuroimaging if the clinical report differed from iuMRI findings. Diagnostic accuracy was recalculated. A paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iuMRI and ultrasonography to predict developmental outcome were assessed., Findings: 210 participants had case note review, of whom 81 (39%) had additional investigations after age 6 months. The diagnostic accuracy of iuMRI remained higher than ultrasonography (proportion of correct cases was 529 [92%] of 574 vs 387 [67%] of 574; absolute difference 25%, 95% CI 21 to 29; p<0·0001). Developmental outcome data were analysed in 156 participants, and 111 (71%) were categorised as normal or at risk. Of these 111 participants, prognosis was normal or favourable for 56 (51%) using ultrasonography and for 76 (69%) using iuMRI (difference in specificity 18%, 95% CI 7 to 29; p=0·0008). No statistically significant difference was seen in infants with abnormal outcome (difference in sensitivity 4%, 95% CI -10 to 19; p=0·73)., Interpretation: iuMRI remains the optimal tool to identify fetal brain abnormalities. It is less accurate when used to predict developmental outcome, although better than ultrasonography for identifying children with normal outcome. Further work is needed to determine how the prognostic abilities of iuMRI can be improved., Funding: National Institute for Health Research Health Technology Assessment programme., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There is currently insufficient evidence for the clinical effectiveness and cost-effectiveness of psychological therapies for post-stroke depression., Objective: To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical effectiveness and cost-effectiveness of behavioural activation (BA) compared with usual stroke care for treating post-stroke depression., Design: Parallel-group, feasibility, multicentre, randomised controlled trial with nested qualitative research and a health economic evaluation., Setting: Acute and community stroke services in three sites in England., Participants: Community-dwelling adults 3 months to 5 years post stroke who are depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) or the Visual Analogue Mood Scales 'Sad' item. Exclusions: patients who are blind and/or deaf, have dementia, are unable to communicate in English, do not have mental capacity to consent, are receiving treatment for depression at the time of stroke onset or are currently receiving psychological intervention., Randomisation and Blinding: Participants were randomised (1 : 1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, but outcome assessors were blind., Interventions: The intervention arm received up to 15 sessions of BA over 4 months. BA aims to improve mood by increasing people's level of enjoyable or valued activities. The control arm received usual care only., Main Outcome Measures: Primary feasibility outcomes concerned feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants and potential value of conducting the definitive trial. Secondary feasibility outcomes concerned the delivery of the intervention. The primary clinical outcome 6 months post randomisation was the PHQ-9. Secondary clinical outcomes were Stroke Aphasic Depression Questionnaire - Hospital version, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol-5 Dimensions, five-level version and health-care resource use questionnaire., Results: Forty-eight participants were recruited in 27 centre-months of recruitment, at a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 therapy sessions [standard deviation (SD) 4.4 therapy sessions]; 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (BA, n  = 18; usual care, n  = 21). Mean PHQ-9 scores at 6-month follow-up were 10.1 points (SD 6.9 points) and 14.4 points (SD 5.1 points) in the BA and control groups, respectively, a difference of -3.8 (95% confidence interval -6.9 to -0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value-of-information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. It is estimated that a sample size of between 580 and 623 participants would be needed for a definitive trial., Limitations: Target recruitment was not achieved, although we identified methods to improve recruitment., Conclusions: The Behavioural Activation Therapy for Depression after Stroke trial was feasible with regard to the majority of outcomes. The outstanding issue is whether or not a sufficient number of participants could be recruited within a reasonable time frame for a definitive trial. Future work is required to identify whether or not there are sufficient sites that are able to deliver the services required for a definitive trial., Trial Registration: Current Controlled Trials ISRCTN12715175., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 47. See the NIHR Journals Library website for further project information., Competing Interests: Shirley A Thomas and Avril ER Drummond report grants from the National Institute for Health Research (NIHR) and the Stroke Association outside the submitted work. Rebecca L Palmer is an author of the Consent Support Tool, which was piloted in the work and is discussed in the report. Roshan das Nair is a member of the NIHR Health Services and Delivery Research Board. Nicholas R Latimer is supported by the NIHR (NIHR Post Doctoral Fellowship PDF-2015-08-022). Stephen J Walters is a member of the NIHR Health Technology Assessment (HTA) Clinical Trials Board and the NIHR HTA Funding Boards Policy Group; he also reports grants from the NIHR HTA programme during the conduct of the study, personal fees from royalties, research grants from the NIHR and the Medical Research Council, personal fees from external examining fees and book royalties outside the submitted work. Cindy L Cooper is a member of the NIHR Clinical Trials Unit Standing Advisory Committee.

Background: Ultrasonography has been the mainstay of antenatal screening programmes in the UK for many years. Technical factors and physical limitations may result in suboptimal images that can lead to incorrect diagnoses and inaccurate counselling and prognostic information being given to parents. Previous studies suggest that the addition of in utero magnetic resonance imaging (iuMRI) may improve diagnostic accuracy for fetal brain abnormalities. These studies have limitations, including a lack of an outcome reference diagnosis (ORD), which means that improvements could not be assessed accurately., Objectives: To assess the diagnostic impact, acceptability and cost consequence of iuMRI among fetuses with a suspected fetal brain abnormality., Design: A pragmatic, prospective, multicentre, cohort study with a health economics analysis and a sociological substudy., Setting: Sixteen UK fetal medicine centres., Participants: Pregnant women aged ≥ 16 years carrying a fetus (at least 18 weeks' gestation) with a suspected brain abnormality detected on ultrasonography., Interventions: Participants underwent iuMRI and the findings were reported to their referring fetal medicine clinician., Main Outcome Measures: Pregnancy outcome was followed up and an ORD from postnatal imaging or postmortem autopsy/imaging collected when available. Developmental data from the Bayley Scales of Infant Development and questionnaires were collected from the surviving infants aged 2-3 years. Data on the management of the pregnancy before and after the iuMRI were collected to inform the economic evaluation. Two surveys collected data on patient acceptability of iuMRI and qualitative interviews with participants and health professionals were undertaken., Results: The primary analysis consisted of 570 fetuses. The absolute diagnostic accuracies of ultrasonography and iuMRI were 68% and 93%, respectively [a difference of 25%, 95% confidence interval (CI) 21% to 29%]. The difference between ultrasonography and iuMRI increased with gestational age. In the 18-23 weeks group, the figures were 70% for ultrasonography and 92% for iuMRI (difference of 23%, 95% CI 18% to 27%); in the ≥ 24 weeks group, the figures were 65% for ultrasonography and 94% for iuMRI (difference of 29%, 95% CI 23% to 36%). Patient acceptability was high, with at least 95% of respondents stating that they would have iuMRI again in a similar situation. Health professional interviews suggested that iuMRI was acceptable to clinicians and that iuMRI was useful as an adjunct to ultrasonography, but not as a replacement. Across a range of scenarios, iuMRI resulted in additional costs compared with ultrasonography alone. The additional cost was consistently < £600 per patient and the cost per management decision appropriately changed was always < £3000. There is potential for reporting bias from the referring clinicians on the diagnostic and prognostic outcomes. Lower than anticipated follow-up rates at 3 years of age were observed., Conclusions: iuMRI as an adjunct to ultrasonography significantly improves the diagnostic accuracy and confidence for the detection of fetal brain abnormalities. An evaluation of the use of iuMRI for cases of isolated microcephaly and the diagnosis of fetal spine abnormalities is recommended. Longer-term follow-up studies of children diagnosed with fetal brain abnormalities are required to fully assess the functional significance of the diagnoses., Trial Registration: Current Controlled Trials ISRCTN27626961., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 49. See the NIHR Journals Library website for further project information., Competing Interests: Paul D Griffiths was a member of Health Technology Assessment Commissioning Board (2014–18) and Cindy L Cooper is a member of National Institute for Health Research Clinical Trials Unit Standing Advisory Committee (2015 to present).

Background: Intestinal inflammation in Crohn's disease (CD) is caused by mucosal immune system reactivity to luminal antigen and results in debilitating symptoms, reduced quality of life, impaired work productivity and significant health care costs. Not all patients respond to conventional and biologic therapies, with chronic inflammation ensuing. Although surgical resection may be required, disease frequently returns and surgery may not be an option, or may be declined. Case reports suggest potential benefit after haematopoietic stem cell transplant (HSCT) for patients with refractory CD. The ASTIC trial asked whether HSCT could cure CD. Few patients achieved the primary endpoint of clinical remission for 3 months, off all medication with no evidence of active disease, and there were a high number of adverse events (AEs) and serious adverse events (SAEs), including one patient death. However, beneficial effects were observed in some aspects of disease activity. The ASTIClite trial will investigate these potential benefits and safety using a lower intensity regimen than ASTIC., Methods: Ninety-nine participants will be recruited from secondary care IBD centres in the UK into a multicentre, randomised controlled trial (RCT, ASTIClite) and an observational follow-up, and randomised to autologous HSCT versus standard care (ratio 2:1). The primary endpoint is treatment success at week 48, defined as mucosal healing without surgery or death. Secondary endpoints relating to efficacy, safety and mechanistic analyses will be evaluated at week 8, 14, 24, 32, 40 and 48. Long-term safety of the low intensity HSCT regimen forms the primary endpoint for the EBMT follow-up study and will be assessed annually for 4-7 years., Discussion: ASTIClite will compare HSCTlite with standard care with respect to safety, efficacy and quality of life, and capture outcomes allowing findings to be generalised to current clinical practice in the UK. It will also provide significant mechanistic insights into the immunological consequences of HSCTlite and its impact on treatment outcomes. The observational follow-up will provide information, which is currently unavailable for this population., Trial Registration: The ASTIClite RCT was registered on 31st October 2017 ( ISRCTN17160440 ) and the EBMT follow-up study on 19th January 2018 ( ISRCTN31981313 ).

Purpose: To refine methods that assess structural brain abnormalities and calculate intracranial volumes in fetuses with congenital heart diseases (CHD) using in utero MR (iuMR) imaging. Our secondary objective was to assess the prevalence of brain abnormalities in this high-risk cohort and compare the brain volumes with normative values., Methods: We performed iuMR on 16 pregnant women carrying a fetus with CHD and gestational age ≥ 28-week gestation and no brain abnormality on ultrasonography. All cases had fetal echocardiography by a pediatric cardiologist. Structural brain abnormalities on iuMR were recorded. Intracranial volumes were made from 3D FIESTA acquisitions following manual segmentation and the use of 3D Slicer software and were compared with normal fetuses. Z scores were calculated, and regression analyses were performed to look for differences between the normal and CHD fetuses., Results: Successful 2D and 3D volume imaging was obtained in all 16 cases within a 30-min scan. Despite normal ultrasonography, 5/16 fetuses (31%) had structural brain abnormalities detected by iuMR (3 with ventriculomegaly, 2 with vermian hypoplasia). Brain volume, extra-axial volume, and total intracranial volume were statistically significantly reduced, while ventricular volumes were increased in the CHD cohort., Conclusion: We have shown that it is possible to perform detailed 2D and 3D studies using iuMR that allow thorough investigation of all intracranial compartments in fetuses with CHD in a clinically appropriate scan time. Those fetuses have a high risk of structural brain abnormalities and smaller brain volumes even when brain ultrasonography is normal.

Background: Preventative medication reduces hospitalisations in people with cystic fibrosis (PWCF) but adherence is poor. We assessed the feasibility of a randomised controlled trial of a complex intervention, which combines display of real time adherence data and behaviour change techniques., Methods: Design: Pilot, open-label, parallel-group RCT with concurrent semi-structured interviews., Participants: PWCF at two Cystic Fibrosis (CF) units. Eligible: aged 16 or older; on the CF registry. Ineligible: post-lung transplant or on the active list; unable to consent; using dry powder inhalers., Interventions: Central randomisation on a 1:1 allocation to: (1) intervention, linking nebuliser use with data recording and transfer capability to a software platform, and behavioural strategies to support self-management delivered by trained interventionists (n = 32); or, (2) control, typically face-to-face meetings every 3 months with CF team (n = 32)., Outcomes: RCT feasibility defined as: recruitment of ≥ 48 participants (75% of target) in four months (pilot primary outcome); valid exacerbation data available for ≥ 85% of those randomised (future RCT primary outcome); change in % medication adherence; FEV 1 percent predicted (key secondaries in future RCT); and perceptions of trial procedures, in semi-structured interviews with intervention (n = 14) and control (n = 5) participants, interventionists (n = 3) and CF team members (n = 5)., Results: The pilot trial recruited to target, randomising 33 to intervention and 31 to control in the four-month period, June-September 2016. At study completion (30th April 2017), 60 (94%; Intervention = 32, Control =28) participants contributed good quality exacerbation data (intervention: 35 exacerbations; control: 25 exacerbation). The mean change in adherence and baseline-adjusted FEV 1 percent predicted were higher in the intervention arm by 10% (95% CI: -5.2 to 25.2) and 5% (95% CI -2 to 12%) respectively. Five serious adverse events occurred, none related to the intervention. The mean change in adherence was 10% (95% CI: -5.2 to 25.2), greater in the intervention arm. Interventionists delivered insufficient numbers of review sessions due to concentration on participant recruitment. This left interventionists insufficient time for key intervention procedures. A total of 10 key changes that were made to RCT procedures are summarised., Conclusions: With improved research processes and lower monthly participant recruitment targets, a full-scale trial is feasible., Trial Registration: ISRCTN13076797 . Prospectively registered on 07/06/2016.

Objectives: In utero magnetic resonance (iuMR) imaging to diagnose foetal brain abnormalities has been established and is supported by meta-analyses of retrospective and prospective studies. In this paper we describe and classify the iuMR errors made in the largest diagnostic accuracy study to date (MERIDIAN). We also correlate the error rates and types with the prior experience of the reporting radiologists in order to inform how to provide a national programme with the best diagnostic accuracy achievable., Methods: The MERIDIAN cohort of 570 foetus formed the basis of this study and included 40 cases with a confirmed diagnostic error, compared with the Outcome Reference Diagnosis. Analysis included the potential clinical effect of the error and classification of error type through an Expert Neuroradiological Panel re-reporting the study. Assessments were made regarding radiologists experience prior to MERIDIAN., Results: The overall confirmed error rate for iuMR was 7·0% and it was considered that there would have been an adverse effect on prognostic information in 22/40 cases if the iuMR had informed counselling. The experienced central reporter made statistically significant fewer errors than the less experienced non-central reporters (3·8% v 11·0%) and the central reporter made fewer clinically significant errors. Furthermore, the type of cognitive errors differed between central and non-central reporters., Conclusions: Although iuMR imaging improves the diagnostic accuracy of detecting foetal brain abnormalities there remains a substantial error rate, which can have major clinical significance. We have shown that error rates are lower for more experienced reporting radiologists with fewer potential deleterious clinical implications. We discuss the implications of these findings in terms of providing a uniform national service., Key Points: • Overall confirmed error rate for iuMR diagnosing foetal brain abnormalities was 7·0%. • IuMR reports had an adverse effect on counselling in 55% of error cases. • Error rates are consistently lower for more experienced radiologists. • Collaboration between radiologists, dual reporting, overseeing scan and formal training can reduce errors.

Introduction: Behavioural and mental disorders have become a public health crisis and by 2020 may surpass physical illness as a major cause of disability. Early prevention is key. Two Incredible Years (IY) parent programmes that aim to enhance child well-being and development, IY Infant and IY Toddler, will be delivered and evaluated in a proportionate universal intervention model called Enhancing Social-Emotional Health and Wellbeing in the Early Years (E-SEE) Steps. The main research question is: Does E-SEE Steps enhance child social emotional well-being at 20 months when compared with services as usual?, Methods and Analysis: E-SEE Steps will be delivered in community settings by Early Years Children's Services and/or Public Health staff across local authorities. Parents of children aged 8 weeks or less, identified by health visitors, children's centre staff or self-referral, are eligible for participation in the trial. The randomisation allocation ratio is 5:1 (intervention to control). All intervention parents will receive an Incredible Years Infant book (universal level), and may be offered the Infant and/or Toddler group-based programme/s-based on parent depression scores on the Patient Health Questionnaire or child social emotional well-being scores on the Ages and Stages Questionnaire: Social Emotional, Second Edition (ASQ:SE-2). Control group parents will receive services as usual. A process and economic evaluation are included. The primary outcome for the study is social emotional well-being, assessed at 20 months, using the ASQ:SE-2. Intention-to-treat and per protocol analyses will be conducted. Clustering and hierarchical effects will be accounted for using linear mixed models., Ethics and Dissemination: Ethical approvals have been obtained from the University of York Education Ethics Committee (ref: FC15/03, 10 August 2015) and UK NHS REC 5 (ref: 15/WA/0178, 22 May 2015. The current protocol is Version 9, 26 February 2018. The sponsor of the trial is the University of York. Dissemination of findings will be via peer-reviewed journals, conference presentations and public events., Trial Registration Number: ISRCTN11079129; Pre-results., Competing Interests: Competing interests: All authors, with the exception of TB, declare no competing interests. TB is Chair of the Board of Trustees for Children’s Early Intervention Trust (CEIT). CEIT is committed to improving the lives of children and their families by researching and delivering evidence-based programmes in community and school-based settings. Early Intervention Wales Training (EIWT). EIWT is owned by CEIT. EIWT offers training courses in a variety of programmes such as the Incredible Years. The trustees do not benefit financially from any such trainings, or other CEIT/EIWT activities. All trainings for the Enhancing Social-Emotional Health and Wellbeing in the Early Years study were arranged via the developer in Seattle and delivered by accredited IY trainers and not through CEIT/EIWT., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In individually randomised trials we might expect interventions delivered in groups or by care providers to result in clustering of outcomes for participants treated in the same group or by the same care provider. In partially nested randomised controlled trials (pnRCTs) this clustering only occurs in one trial arm, commonly the intervention arm. It is important to measure and account for between-cluster variability in trial design and analysis. We compare analysis approaches for pnRCTs with continuous outcomes, investigating the impact on statistical inference of cluster sizes, coding of the non-clustered arm, intracluster correlation coefficient (ICCs), and differential variance between intervention and control arm, and provide recommendations for analysis., Methods: We performed a simulation study assessing the performance of six analysis approaches for a two-arm pnRCT with a continuous outcome. These include: linear regression model; fully clustered mixed-effects model with singleton clusters in control arm; fully clustered mixed-effects model with one large cluster in control arm; fully clustered mixed-effects model with pseudo clusters in control arm; partially nested homoscedastic mixed effects model, and partially nested heteroscedastic mixed effects model. We varied the cluster size, number of clusters, ICC, and individual variance between the two trial arms., Results: All models provided unbiased intervention effect estimates. In the partially nested mixed-effects models, methods for classifying the non-clustered control arm had negligible impact. Failure to account for even small ICCs resulted in inflated Type I error rates and over-coverage of confidence intervals. Fully clustered mixed effects models provided poor control of the Type I error rates and biased ICC estimates. The heteroscedastic partially nested mixed-effects model maintained relatively good control of Type I error rates, unbiased ICC estimation, and did not noticeably reduce power even with homoscedastic individual variances across arms., Conclusions: In general, we recommend the use of a heteroscedastic partially nested mixed-effects model, which models the clustering in only one arm, for continuous outcomes similar to those generated under the scenarios of our simulations study. However, with few clusters (3-6), small cluster sizes (5-10), and small ICC (≤0.05) this model underestimates Type I error rates and there is no optimal model.

Objectives: The objective of this study was to compare the response rates, data completeness, and representativeness of survey data produced by online and postal surveys., Study Design and Setting: A randomized trial nested within a cohort study in Yorkshire, United Kingdom. Participants were randomized to receive either an electronic (online) survey questionnaire with paper reminder (N = 2,982) or paper questionnaire with electronic reminder (N = 2,855)., Results: Response rates were similar for electronic contact and postal contacts (50.9% vs. 49.7%, difference = 1.2%, 95% confidence interval: -1.3% to 3.8%). The characteristics of those responding to the two groups were similar. Participants nevertheless demonstrated an overwhelming preference for postal questionnaires, with the majority responding by post in both groups., Conclusion: Online survey questionnaire systems need to be supplemented with a postal reminder to achieve acceptable uptake, but doing so provides a similar response rate and case mix when compared to postal questionnaires alone. For large surveys, online survey systems may be cost saving., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Interpretation of magnetic resonance (MR) imaging of the fetal brain in utero is primarily undertaken using 2D images to provide anatomical information about structural abnormalities. It is now possible to obtain 3D image acquisitions that allow measurement of fetal brain volumes that are potentially useful clinically. The aim of our current work is to provide reference values of total brain volumes obtained from a cohort of low risk fetuses with no abnormalities on ante-natal ultrasonography and in utero MR imaging., Method: Images from volume MR acquisitions of 132 fetuses were used to extract brain volumes by manual segmentation. Reproducibility and reliability were assessed by analysis of the results of two subgroups who had repeated measurements made by the primary and a secondary observer., Results: Intra-observer and inter-observer agreement was high with no statistically significant differences between and within observers (p = 0.476 and p = 0.427, respectively). The results of the brain volume assessments are presented graphically with mean and 95% prediction limits alongside estimates of normal growth rates., Conclusion: We have shown that fetal brain volumes can be reliably extracted from in utero MR (iuMR) imaging 3D datasets with a high degree of reproducibility. The resultant data could potentially be used as a reference tool in the clinical setting. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Background: In an individually randomised controlled trial where the treatment is delivered by a health professional it seems likely that the effectiveness of the treatment, independent of any treatment effect, could depend on the skill, training or even enthusiasm of the health professional delivering it. This may then lead to a potential clustering of the outcomes for patients treated by the same health professional, but similar clustering may not occur in the control arm. Using four case studies, we aim to provide practical guidance and recommendations for the analysis of trials with some element of clustering in one arm., Methods: Five approaches to the analysis of outcomes from an individually randomised controlled trial with clustering in one arm are identified in the literature. Some of these methods are applied to four case studies of completed randomised controlled trials with clustering in one arm with sample sizes ranging from 56 to 539. Results are obtained using the statistical packages R and Stata and summarised using a forest plot., Results: The intra-cluster correlation coefficient (ICC) for each of the case studies was small (<0.05) indicating little dependence on the outcomes related to cluster allocations. All models fitted produced similar results, including the simplest approach of ignoring clustering for the case studies considered., Conclusions: A partially clustered approach, modelling the clustering in just one arm, most accurately represents the trial design and provides valid results. Modelling homogeneous variances between the clustered and unclustered arm is adequate in scenarios similar to the case studies considered. We recommend treating each participant in the unclustered arm as a single cluster. This approach is simple to implement in R and Stata and is recommended for the analysis of trials with clustering in one arm only. However, the case studies considered had small ICC values, limiting the generalisability of these results.

Background: There is currently insufficient evidence for the clinical and cost-effectiveness of psychological therapies for treating post-stroke depression., Methods/design: BEADS is a parallel group feasibility multicentre randomised controlled trial with nested qualitative research and economic evaluation. The aim is to evaluate the feasibility of undertaking a full trial comparing behavioural activation (BA) to usual stroke care for 4 months for patients with post-stroke depression. We aim to recruit 72 patients with post-stroke depression over 12 months at three centres, with patients identified from the National Health Service (NHS) community and acute services and from the voluntary sector. They will be randomly allocated to receive behavioural activation in addition to usual care or usual care alone. Outcomes will be measured at 6 months after randomisation for both participants and their carers, to determine their effectiveness. The primary clinical outcome measure for the full trial will be the Patient Health Questionnaire-9 (PHQ-9). Rates of consent, recruitment and follow-up by centre and randomised group will be reported. The acceptability of the intervention to patients, their carers and therapists will also be assessed using qualitative interviews. The economic evaluation will be undertaken from the National Health Service and personal social service perspective, with a supplementary analysis from the societal perspective. A value of information analysis will be completed to identify the areas in which future research will be most valuable., Discussion: The feasibility outcomes from this trial will provide the data needed to inform the design of a definitive multicentre randomised controlled trial evaluating the clinical and cost-effectiveness of behavioural activation for treating post-stroke depression., Trial Registration: Current controlled trials ISRCTN12715175.