Dynamic modulation of the action observation network by movement familiarity.

When watching another person's actions, a network of sensorimotor brain regions, collectively termed the action observation network (AON), is engaged. Previous research suggests that the AON is more responsive when watching familiar compared with unfamiliar actions. However, most research into AON function is premised on comparisons of AON engagement during different types of task using univariate, magnitude-based approaches. To better understand the relationship between action familiarity and AON engagement, here we examine how observed movement familiarity modulates AON activity in humans using dynamic causal modeling, a type of effective connectivity analysis. Twenty-one subjects underwent fMRI scanning while viewing whole-body dance movements that varied in terms of their familiarity. Participants' task was to either predict the next posture the dancer's body would assume or to respond to a non-action-related attentional control question. To assess individuals' familiarity with each movement, participants rated each video on a measure of visual familiarity after being scanned. Parametric analyses showed more activity in left middle temporal gyrus, inferior parietal lobule, and inferior frontal gyrus as videos were rated as increasingly familiar. These clusters of activity formed the regions of interest for dynamic causal modeling analyses, which revealed attenuation of effective connectivity bidirectionally between parietal and temporal AON nodes when participants observed videos they rated as increasingly familiar. As such, the findings provide partial support for a predictive coding model of the AON, as well as illuminate how action familiarity manipulations can be used to explore simulation-based accounts of action understanding.

The salience network is responsible for switching between the default mode network and the central executive network: replication from DCM.

With the advent of new analysis methods in neuroimaging that involve independent component analysis (ICA) and dynamic causal modelling (DCM), investigations have focused on measuring both the activity and connectivity of specific brain networks. In this study we combined DCM with spatial ICA to investigate network switching in the brain. Using time courses determined by ICA in our dynamic causal models, we focused on the dynamics of switching between the default mode network (DMN), the network which is active when the brain is not engaging in a specific task, and the central executive network (CEN), which is active when the brain is engaging in a task requiring attention. Previous work using Granger causality methods has shown that regions of the brain which respond to the degree of subjective salience of a stimulus, the salience network, are responsible for switching between the DMN and the CEN (Sridharan et al., 2008). In this work we apply DCM to ICA time courses representing these networks in resting state data. In order to test the repeatability of our work we applied this to two independent datasets. This work confirms that the salience network drives the switching between default mode and central executive networks and that our novel technique is repeatable.

'ThinkCancer!' - Randomised feasibility trial of a novel practice-based early cancer diagnosis intervention.

BACKGROUND: UK cancer deaths remain high; primary care is key for earlier cancer diagnosis as half of avoidable delays occur here. Improvement is possible through lower referral thresholds, better guideline adherence, and better safety netting systems. Few interventions target whole practice teams. We developed a novel whole practice team intervention to address this. AIM: To test the feasibility and acceptability of a novel, complex behavioural intervention 'ThinkCancer!' for assessment in a subsequent Phase III trial. DESIGN & SETTING: Pragmatic, superiority pilot RCT with an embedded process evaluation and feasibility economic analysis in Welsh general practices. METHOD: Clinical outcome data were collected from practices (the unit of randomisation). Practice characteristics and cancer safety netting systems were assessed. Individual practice staff completed evaluation and feedback forms, and qualitative interviews. The intervention was adapted and refined. RESULTS: Trial recruitment and workshop deliveries took place between March 2020 to May 2021. Trial progression criteria for recruitment, intervention fidelity and routine data collection were met. Staff-level fidelity, retention and individual level data collection processes were reviewed and amended. Interviews highlighted positive participant views on all aspects of the intervention. All practices set out to liberalise referral thresholds appropriately, implement guidelines, and address safety netting plans in detail. CONCLUSION: 'ThinkCancer!' appears feasible and acceptable; the new iteration of the workshops was completed, and the Phase III trial has been funded to assess the effectiveness and cost effectiveness of this novel professional behaviour change intervention. Delivery at scale to multiple practices will likely improve fidelity and reach.

Clinical effectiveness and cost-effectiveness of Structured Psychological Support for people with probable personality disorder in mental health services in England: study protocol for a randomised controlled trial.

INTRODUCTION: Evidence-based psychological treatments for people with personality disorder usually involve attending group-based sessions over many months. Low-intensity psychological interventions of less than 6 months duration have been developed, but their clinical effectiveness and cost-effectiveness are unclear. METHODS AND ANALYSIS: This is a multicentre, randomised, parallel-group, researcher-masked, superiority trial. Study participants will be aged 18 and over, have probable personality disorder and be treated by mental health staff in seven centres in England. We will exclude people who are: unwilling or unable to provide written informed consent, have a coexisting organic or psychotic mental disorder, or are already receiving psychological treatment for personality disorder or on a waiting list for such treatment. In the intervention group, participants will be offered up to 10 individual sessions of Structured Psychological Support. In the control group, participants will be offered treatment as usual plus a single session of personalised crisis planning. The primary outcome is social functioning measured over 12 months using total score on the Work and Social Adjustment Scale (WSAS). Secondary outcomes include mental health, suicidal behaviour, health-related quality of life, patient-rated global improvement and satisfaction, and resource use and costs. The primary analysis will compare WSAS scores across the 12-month period using a general linear mixed model adjusting for baseline scores, allocation group and study centre on an intention-to-treat basis. In a parallel process evaluation, we will analyse qualitative data from interviews with study participants, clinical staff and researchers to examine mechanisms of impact and contextual factors. ETHICS AND DISSEMINATION: The study complies with the Helsinki Declaration II and is approved by the London-Bromley Research Ethics Committee (IRAS ID 315951). Study findings will be published in an open access peer-reviewed journal; and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN13918289.

Group cognitive stimulation therapy versus usual care for people with intellectual disabilities and dementia (CST-IDD) in the UK: protocol for a mixed-methods feasibility randomised controlled trial.

INTRODUCTION: The prevalence of dementia is almost five times higher in people with intellectual disabilities compared with the general population. However, evidence-based treatments for this population are lacking, as most randomised controlled trials for dementia interventions have not included people with intellectual disabilities. Cognitive stimulation therapy (CST) has a robust evidence base in the general dementia population, consistently showing benefits to cognition, quality of life and being cost-effective. We are conducting a mixed-methods feasibility trial of group CST for people with intellectual disabilities and dementia, to determine if a future definitive randomised controlled trial is feasible. METHODS AND ANALYSIS: Fifty individuals with intellectual disabilities and dementia will be randomised to either the intervention arm (14 sessions of group CST plus treatment as usual) or the control arm (treatment as usual). Randomisation will occur after informed consent has been obtained and baseline assessments completed. Each arm will have 25 participants, with the intervention arm divided into five or more CST groups with three to five participants in each. The outcomes will be feasibility of recruitment, acceptability and adherence of the intervention, suitability of study outcome measures and feasibility of collecting resource use data. Quantitative and qualitative approaches, including semistructured interviews with group participants, carers and group facilitators, will be employed to assess these outcomes. ETHICS AND DISSEMINATION: This study has been approved by Essex REC (Ref: 21/EE/027) and the HRA ethical approval process through the Integrated Research Application System (IRAS ID: 306 756). We plan to publish the results in peer-reviewed journals and conferences as well as provide feedback to funders, sponsors and study participants. TRIAL REGISTRATION NUMBER: ISRCTN88614460.

Earlier cancer diagnosis in primary care: a feasibility economic analysis of ThinkCancer!

BACKGROUND: UK cancer survival rates are much lower compared with other high-income countries. In primary care, there are opportunities for GPs and other healthcare professionals to act more quickly in response to presented symptoms that might represent cancer. ThinkCancer! is a complex behaviour change intervention aimed at primary care practice teams to improve the timely diagnosis of cancer. AIM: To explore the costs of delivering the ThinkCancer! intervention to expedite cancer diagnosis in primary care. DESIGN & SETTING: Feasibility economic analysis using a micro-costing approach, which was undertaken in 19 general practices in Wales, UK. METHOD: From an NHS perspective, micro-costing methodology was used to determine whether it was feasible to gather sufficient economic data to cost the ThinkCancer! INTERVENTION: Owing to the COVID-19 pandemic, ThinkCancer! was mainly delivered remotely online in a digital format. Budget impact analysis (BIA) and sensitivity analysis were conducted to explore the costs of face-to-face delivery of the ThinkCancer! intervention as intended pre-COVID-19. RESULTS: The total costs of delivering the ThinkCancer! intervention across 19 general practices in Wales was £25 030, with an average cost per practice of £1317 (standard deviation [SD]: 578.2). Findings from the BIA indicated a total cost of £34 630 for face-to-face delivery. CONCLUSION: Data collection methods were successful in gathering sufficient health economics data to cost the ThinkCancer! INTERVENTION: Results of this feasibility study will be used to inform a future definitive economic evaluation alongside a pragmatic randomised controlled trial (RCT).

Inhaled Corticosteroids Alone and in Combination With Long-Acting ß2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children: A Randomized Clinical Trial.

Importance: Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited. Objective: To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting ß2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019. Interventions: Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 µg, with placebo; fluticasone propionate, 50 µg, with salmeterol, 25 µg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA. Main Outcomes and Measures: The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted. Results: Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment. Conclusions and Relevance: The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children. Trial Registration: EudraCT number: 2015-003712-20.

Effects of an e-health intervention 'iSupport' for reducing distress of dementia carers: protocol for a randomised controlled trial and feasibility study.

INTRODUCTION: In the UK, National Health Service (NHS) guidelines recommend that informal carers of people living with dementia should be offered training to help them develop care skills and manage their own physical and mental health. The WHO recommends access to affordable, proven, well-designed, online technologies for education, skills training and support for dementia carers. In response to these recommendations, this multisite randomised controlled trial (RCT) is the first study in the UK to evaluate the clinical and cost-effectiveness of an online support programme developed by the WHO called 'iSupport for dementia carers'. METHODS AND ANALYSIS: 350 informal carers (age 18+ years) living in Britain who self-identify as experiencing stress and depression will be recruited. They will be randomised to receive 'iSupport', or standardised information about caring for someone with dementia (control-comparison). Data will be collected via videoconferencing (eg, Zoom) or telephone interview at baseline, 3 months and 6 months. Intention-to-treat analysis will ascertain effectiveness in the primary outcomes (distress and depression) and combined cost, and quality-adjusted life-year data will be used to assess cost-effectiveness compared with usual care from a public sector and wider societal perspective. A mixed-methods process evaluation with a subgroup of carers in the intervention (~N=50) will explore the barriers and facilitators to implementing 'iSupport'. A non-randomised feasibility study will adapt 'iSupport' for young carers (n=38 participants, age 11-17 years). ETHICS AND DISSEMINATION: The research plan was scrutinised by National Institute for Health Research reviewers ahead of funding being awarded. Ethical approval was granted by Bangor University's School of Health and Medical Sciences Academic Ethics Committee, reference number 2021-16915. Dissemination plans include delivering events for stakeholders, social media, a project website, developing policy briefings, presenting at conferences and producing articles for open access publications. TRIAL REGISTRATION NUMBER: ISRCTN17420703.

Neuropsychological evaluation and rehabilitation in multiple sclerosis (NEuRoMS): protocol for a mixed-methods, multicentre feasibility randomised controlled trial.

BACKGROUND: Cognitive problems affect up to 70% of people with multiple sclerosis (MS), which can negatively impact mood, ability to work, and quality of life. Addressing cognitive problems is a top 10 research priority for people with MS. Our ongoing research has systematically developed a cognitive screening and management pathway (NEuRoMS) tailored for people with MS, involving a brief cognitive evaluation and rehabilitation intervention. The present study aims to assess the feasibility of delivering the pathway and will inform the design of a definitive randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of the intervention and eventually guide its clinical implementation. METHODS: The feasibility study is in three parts. Part 1 involves an observational study of those who receive screening and support for cognitive problems, using routinely collected clinical data. Part 2 is a two-arm, parallel group, multicentre, feasibility RCT with a nested fidelity evaluation. This part will evaluate the feasibility of undertaking a definitive trial comparing the NEuRoMS intervention plus usual care to usual care only, amongst people with MS with mild cognitive problems (n = 60). In part 3, semi-structured interviews will be undertaken with participants from part 2 (n = 25), clinicians (n = 9), and intervention providers (n = 3) involved in delivering the NEuRoMS cognitive screening and management pathway. MS participants will be recruited from outpatient clinics at three UK National Health Service hospitals. DISCUSSION: Timely screening and effective management of cognitive problems in MS are urgently needed due to the detrimental consequences of cognitive problems on people with MS, the healthcare system, and wider society. The NEuRoMS intervention is based on previous and extant literature and has been co-constructed with relevant stakeholders. If effective, the NEuRoMS pathway will facilitate timely identification and management of cognitive problems in people with MS. TRIAL REGISTRATION: ISRCTN11203922 . Prospectively registered on 09.02.2021.

Improving the oral health of older people in care homes (TOPIC): a protocol for a feasibility study.

BACKGROUND: Evidence for interventions promoting oral health amongst care home residents is weak. The National Institute for Health and Care Excellence (NICE) guideline NG48 aims to maintain and improve the oral health of care home residents. A co-design process that worked with residents and care home staff to understand how the NG48 guideline could be best implemented in practice has been undertaken to refine a complex intervention. The aim of this study is to assess the feasibility of the intervention to inform a future larger scale definitive trial. METHODS: This is a protocol for a pragmatic cluster randomised controlled trial with a 12-month follow-up that will be undertaken in 12 care homes across two sites (six in London, six in Northern Ireland). Care homes randomised to the intervention arm (n = 6) will receive the complex intervention based on the NG48 guideline, whilst care homes randomised to the control arm (n = 6) will continue with routine practice. The intervention will include a training package for care home staff to promote knowledge and skills in oral health promotion, the use of the Oral Health Assessment Tool on residents by trained care home staff, and a 'support worker assisted' daily tooth-brushing regime with toothpaste containing 1500 ppm fluoride. An average of ten residents, aged 65 years or over who have at least one natural tooth, will be recruited in each care home resulting in a recruited sample of 120 participants. Assessments will be undertaken at baseline, 6 months and 12 months, and will include a dental examination and questionnaires on general health and oral health administered by a research assistant. A parallel process evaluation involving semi-structured interviews will be undertaken to explore how the intervention could be embedded in standard practice. Rates of recruitment and retention, and intervention fidelity will also be recorded. A cost-consequence model will determine the relevance of different outcome measures in the decision-making context. DISCUSSION: The study will provide valuable information for trialists, policymakers, clinicians and care home staff on the feasibility and associated costs of oral health promotion in UK care homes. TRIAL REGISTRATION: ISRCTN10276613. Registered on 17th April 2020. http://www.isrctn.com/ISRCTN10276613 .

Protocol for a feasibility study incorporating a randomised pilot trial with an embedded process evaluation and feasibility economic analysis of ThinkCancer!: a primary care intervention to expedite cancer diagnosis in Wales.

BACKGROUND: Compared to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing COVID-19 pandemic and its major impact on cancer referrals. The ThinkCancer! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! intervention for a future definitive randomised controlled trial. METHODS: The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect primary care intervals (PCI), 2-week wait (2WW) referral rates, conversion rates and detection rates at baseline and 6 months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. DISCUSSION: This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04823559 .

A comparison of permutation and parametric testing for between group effective connectivity differences using DCM.

Effective connectivity is becoming an increasingly popular technique for obtaining additional information from functional magnetic resonance imaging (fMRI) cognitive activation studies. It is potentially important for investigating psychiatric illnesses, which are thought to depend on disrupted connections and in observing the action of psychoactive drugs used to treat these disorders. If researchers are to apply these techniques confidently then it is important to establish the level of power that is available in an experiment. This study compares the level of power available when applying effective connectivity to test for differences between groups using parametric tests and permutation testing. Permutation testing has previously been shown to have superior sensitivity to parametric tests in fMRI studies. As an illustrative example, both the parametric t-test and equivalent permutation test were applied to a comparison between healthy controls and remitted depressed volunteers performing an emotional face processing task. Permutation testing was found to provide superior power compared with the nonparametric equivalent.

Carer administration of as-needed subcutaneous medication for breakthrough symptoms in people dying at home: the CARiAD feasibility RCT.

BACKGROUND: Most people who are dying want to be cared for at home, but only half of them achieve this. The likelihood of a home death often depends on the availability of able and willing lay carers. When people who are dying are unable to take oral medication, injectable medication is used. When top-up medication is required, a health-care professional travels to the dying person's home, which may delay symptom relief. The administration of subcutaneous medication by lay carers, although not widespread UK practice, has proven to be key in achieving better symptom control for those dying at home in other countries. OBJECTIVES: To determine if carer administration of as-needed subcutaneous medication for common breakthrough symptoms in people dying at home is feasible and acceptable in the UK, and if it would be feasible to test this intervention in a future definitive randomised controlled trial. DESIGN: We conducted a two-arm, parallel-group, individually randomised, open pilot trial of the intervention versus usual care, with a 1 : 1 allocation ratio, using convergent mixed methods. SETTING: Home-based care without 24/7 paid care provision, in three UK sites. PARTICIPANTS: Participants were dyads of adult patients and carers: patients in the last weeks of their life who wished to die at home and lay carers who were willing to be trained to give subcutaneous medication. Strict risk assessment criteria needed to be met before approach, including known history of substance abuse or carer ability to be trained to competency. INTERVENTION: Intervention-group carers received training by local nurses using a manualised training package. MAIN OUTCOME MEASURES: Quantitative data were collected at baseline and 6-8 weeks post bereavement and via carer diaries. Interviews with carers and health-care professionals explored attitudes to, experiences of and preferences for giving subcutaneous medication and experience of trial processes. The main outcomes of interest were feasibility, acceptability, recruitment rates, attrition and selection of the most appropriate outcome measures. RESULTS: In total, 40 out of 101 eligible dyads were recruited (39.6%), which met the feasibility criterion of recruiting > 30% of eligible dyads. The expected recruitment target (≈50 dyads) was not reached, as fewer than expected participants were identified. Although the overall retention rate was 55% (22/40), this was substantially unbalanced [30% (6/20) usual care and 80% (16/20) intervention]. The feasibility criterion of > 40% retention was, therefore, considered not met. A total of 12 carers (intervention, n = 10; usual care, n = 2) and 20 health-care professionals were interviewed. The intervention was considered acceptable, feasible and safe in the small study population. The context of the feasibility study was not ideal, as district nurses were seriously overstretched and unfamiliar with research methods. A disparity in readiness to consider the intervention was demonstrated between carers and health-care professionals. Findings showed that there were methodological and ethics issues pertaining to researching last days of life care. CONCLUSION: The success of a future definitive trial is uncertain because of equivocal results in the progression criteria, particularly poor recruitment overall and a low retention rate in the usual-care group. Future work regarding the intervention should include understanding the context of UK areas where this has been adopted, ascertaining wider public views and exploring health-care professional views on burden and risk in the NHS context. There should be consideration of the need for national policy and of the most appropriate quantitative outcome measures to use. This will help to ascertain if there are unanswered questions to be studied in a trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11211024. 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. 24, No. 25. See the NIHR Journals Library website for further project information.

Most people in the UK would prefer to die at home, but only half of them achieve this. This usually depends on having able and willing lay carers (family or friends) to help look after them. Once swallowing is not possible, medicine is given continually under the skin (syringe driver). If common problems such as pain, vomiting or agitation break through, health-care professionals attend to give extra doses. The wait for a health-care professional to arrive can be distressing. In the UK, it is legal (but not routine) for lay carers to give needle-free subcutaneous injections themselves. We reworked an Australian carer education package for UK use. The best way to find out if this would work well is to do a randomised controlled trial. This is a test in which, at random, half of the people taking part receive 'usual care' and the other half receive the 'new care' or intervention. A pilot randomised controlled trial (a 'test' trial to see if a larger one is worth doing) was carried out to determine if lay carer injections were possible in the UK. We approached 90 dyads (a dying person and a key carer) and, of these, 40 were willing to take part and 22 completed the follow-up visit, so we could analyse their data. Of these 22 dyads, 16 were in the intervention group (lay carer injects) and six were in the control group (usual care). All carers were asked to keep a diary. Carers and health-care professionals were interviewed (qualitative study) and carer preferences were assessed. This new practice was safe, acceptable and welcomed. Carer confidence increased rapidly, symptom control was quicker and the interviews backed up these findings. Recruitment was low owing to overstretched health-care professionals. Only certain families were picked. Dyads in the usual-care group often wished they were in the intervention group. Carers found it difficult to complete some of the questionnaires that were used to measure the effect of the intervention. Therefore, uncertainty remains as to whether or not a full trial should proceed. Because the practice is already legal, some areas in the UK are already undertaking it. We plan to study what makes this practice possible or less possible to achieve.

Lessons learnt from a discontinued randomised controlled trial: adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica (Subcutaneous Injection of Adalimumab Trial compared with Control: SCIATiC).

BACKGROUND: Adalimumab, a biological treatment targeting tumour necrosis factor α, might be useful in sciatica. This paper describes the challenges faced when developing a new treatment pathway for a randomised controlled trial of adalimumab for people with sciatica, as well as the reasons why the trial discussed was stopped early. METHODS: A pragmatic, parallel group, randomised controlled trial with blinded (masked) participants, clinicians, outcome assessment and statistical analysis was conducted in six UK sites. Participants were identified and recruited from general practices, musculoskeletal services and outpatient physiotherapy clinics. They were adults with persistent symptoms of sciatica of 1 to 6 months' duration with moderate to high level of disability. Eligibility was assessed by research physiotherapists according to clinical criteria, and participants were randomised to receive two doses of adalimumab (80 mg then 40 mg 2 weeks later) or saline placebo subcutaneous injections in the posterior lateral thigh. Both groups were referred for a course of physiotherapy. Outcomes were measured at baseline, 6-week, 6-month and 12-month follow-up. The main outcome measure was disability measured using the Oswestry Disability Index. The planned sample size was 332, with the first 50 in an internal pilot phase. RESULTS: The internal pilot phase was discontinued after 10 months from opening owing to low recruitment (two of the six sites active, eight participants recruited). There were several challenges: contractual delays; one site did not complete contract negotiations, and two sites signed contracts shortly before trial closure; site withdrawal owing to patient safety concerns; difficulties obtaining excess treatment costs; and in the two sites that did recruit, recruitment was slower than planned because of operational issues and low uptake by potential participants. CONCLUSIONS: Improved patient care requires robust clinical research within contexts in which treatments can realistically be provided. Step changes in treatment, such as the introduction of biologic treatments for severe sciatica, raise complex issues that can delay trial initiation and retard recruitment. Additional preparatory work might be required before testing novel treatments. A randomised controlled trial of tumour necrosis factor-α blockade is still needed to determine its cost-effectiveness in severe sciatica. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN14569274 . Registered on 15 December 2014.

Subcutaneous Injection of Adalimumab Trial compared with Control (SCIATiC): a randomised controlled trial of adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica.

BACKGROUND: Biological treatments such as adalimumab (Humira®; AbbVie Ltd, Maidenhead, UK) are antibodies targeting tumour necrosis factor alpha, released from ruptured intervertebral discs, which might be useful in sciatica. Recent systematic reviews concluded that they might be effective, but that a definitive randomised controlled trial was needed. Usual care in the NHS typically includes a physiotherapy intervention. OBJECTIVES: To test whether or not injections of adalimumab plus physiotherapy are more clinically effective and cost-effective than injections of saline plus physiotherapy for patients with sciatica. DESIGN: Pragmatic, parallel-group, randomised controlled trial with blinded participants and clinicians, and an outcome assessment and statistical analysis with concurrent economic evaluation and internal pilot. SETTING: Participants were referred from primary care and musculoskeletal services to outpatient physiotherapy clinics. PARTICIPANTS: Adults with persistent symptoms of sciatica of 1-6 months' duration and with moderate to high levels of disability. Eligibility was assessed by research physiotherapists according to clinical criteria for diagnosing sciatica. INTERVENTIONS: After a second eligibility check, trial participants were randomised to receive two doses of adalimumab (80 mg and then 40 mg 2 weeks later) or saline injections. Both groups were referred for a course of physiotherapy. MAIN OUTCOME MEASURES: Outcomes were measured at the start, and after 6 weeks' and 6 months' follow-up. The main outcome measure was the Oswestry Disability Index (ODI). Other outcomes: leg pain version of the Roland-Morris Disability Questionnaire, Sciatica Bothersomeness Index, EuroQol-5 Dimensions, 5-level version, Hospital Anxiety and Depression Scale, resource use, risk of persistent disabling pain, pain trajectory based on a single question, Pain Self-Efficacy Questionnaire, Tampa Scale of Kinesiophobia and adverse effects. SAMPLE SIZE: To detect an effect size of 0.4 with 90% power, a 5% significance level for a two-tailed t-test and 80% retention rate, 332 participants would have needed to be recruited. ANALYSIS PLAN: The primary effectiveness analysis would have been linear mixed models for repeated measures to measure the effects of time and group allocation. An internal pilot study would have involved the first 50 participants recruited across all centres. The primary economic analysis would have been a cost-utility analysis. RESULTS: The internal pilot study was discontinued as a result of low recruitment after eight participants were recruited from two out of six sites. One site withdrew from the study before recruitment started, one site did not complete contract negotiations and two sites signed contracts shortly before trial closure. In the two sites that did recruit participants, recruitment was slow. This was partly because of operational issues, but also because of a low rate of uptake from potential participants. LIMITATIONS: Although large numbers of invitations were sent to potential participants, identified by retrospective searches of general practitioner (GP) records, there was a low rate of uptake. Two sites planned to recruit participants during GP consultations but opened too late to recruit any participants. CONCLUSION: The main failure was attributable to problems with contracts. Because of this we were not able to complete the internal pilot or to test all of the different methods for primary care recruitment we had planned. A trial of biological therapy in patients with sciatica still needs to be done, but would require a clearer contracting process, qualitative research to ensure that patients would be willing to participate, and simpler recruitment methods. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14569274. 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. 21, No. 60. See the NIHR Journals Library website for further project information.

Sample size estimation for comparing parameters using dynamic causal modeling.

Functional magnetic resonance imaging (fMRI) has proved to be useful for analyzing the effects of illness and pharmacological agents on brain activation. Many fMRI studies now incorporate effective connectivity analyses on data to assess the networks recruited during task performance. The assessment of the sample size that is necessary for carrying out such calculations would be useful if these techniques are to be confidently applied. Here, we present a method of estimating the sample size that is required for a study to have sufficient power. Our approach uses Bayesian Model Selection to find a best fitting model and then uses a bootstrapping technique to provide an estimate of the parameter variance. As illustrative examples, we apply this technique to two different tasks and show that for our data, ~20 volunteers per group is sufficient. Due to variability between task, volunteers, scanner, and acquisition parameters, this would need to be evaluated on individual datasets. This approach will be a useful guide for Dynamic Causal Modeling studies.

Reversed frontotemporal connectivity during emotional face processing in remitted depression.

BACKGROUND: Vulnerability to relapse persists after remission of an acute episode of major depressive disorder. This has been attributed to abnormal biases in the processing of emotional stimuli in limbic circuits. However, neuroimaging studies have not so far revealed consistent evidence of abnormal responses to emotional stimuli in limbic structures, such as the amygdala, in remitted depression. This suggests the problem might lie in the integrated functioning of emotion processing circuits. METHODS: We recruited 22 unmedicated patients in remission from major depressive disorder (rMDD) and 21 age-matched healthy control subjects. Functional magnetic resonance imaging was performed during a face emotion processing task. Dynamic causal modeling was used with Bayesian model selection to determine the most likely brain networks and valence-specific modulation of connectivity in healthy control subjects and rMDD. RESULTS: In healthy volunteers, sad faces modulated bi-directional connections between amygdala and orbitofrontal cortex and between fusiform gyrus and orbitofrontal cortex. Happy faces modulated unidirectional connections from fusiform gyrus to orbitofrontal cortex. In rMDD, the opposite pattern was observed, with evidence of happy faces modulating bidirectional frontotemporal connections and sad faces modulating unidirectional fusiform-orbitofrontal connections. CONCLUSIONS: Participants with rMDD have abnormal modulation of frontotemporal effective connectivity in response to happy and sad face emotions, despite normal activations within each region. Specifically, processing of mood incongruent happy information was associated with a more richly modulated frontotemporal brain network, whereas mood congruent sad information was associated with less network modulation. This supports a hypothesis of dysfunction within cortico-limbic connections in individuals vulnerable to depression.