Understanding decision-making for and against oncoplastic breast-conserving surgery as an alternative to a mastectomy in early breast cancer: UK ANTHEM qualitative study.

BACKGROUND: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery. METHODS: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice. Interviews were transcribed verbatim and analysed thematically. Trial registration number: ISRCTN18238549. RESULTS: A total of 27 women from 12 centres were interviewed. Out of these, 12 had chosen oncoplastic breast-conserving surgery and 15 had chosen a mastectomy with or without immediate breast reconstruction. Overwhelmingly, women's decisions were guided by their surgical teams. Decision-making for and against oncoplastic breast-conserving surgery was influenced by three key inter-related factors: perceptions of oncological safety; the importance of maintaining/restoring femininity and body image; and practical issues. Oncological safety was paramount. Women who reported feeling reassured that oncoplastic breast-conserving surgery was oncologically safe were happy to choose this option. Those who were not reassured were more likely to opt for a mastectomy, as a perceived 'safer' option. Most women wished to maintain/restore femininity, with the offer of immediate breast reconstruction essential to make a mastectomy an acceptable option. Practical issues such as the perceived magnitude of the surgery were a lesser concern. CONCLUSION: Decision-making is complex and heavily influenced by the surgical team. High-quality, accurate information about surgical options, including appropriate reassurance about the short- and long-term oncological safety of oncoplastic breast-conserving surgery is vital if women are to make fully informed decisions.

Graded exercise therapy compared to activity management for paediatric chronic fatigue syndrome/myalgic encephalomyelitis: pragmatic randomized controlled trial.

The MAGENTA pragmatic parallel groups randomized controlled trial compared graded exercise therapy (GET) with activity management (AM) in treating paediatric myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Children aged 8-17 years with mild/moderate ME/CFS and presenting to NHS specialist paediatric services were allocated at random to either individualised flexible treatment focussing on physical activity (GET, 123 participants) or on managing cognitive, school and social activity (AM, 118 participants) delivered by NHS therapists. The primary outcome was the self-reported short-form 36 physical function subscale (SF-36-PFS) after 6 months, with higher scores indicating better functioning. After 6 months, data were available for 201 (83%) participants who received a mean of 3.9 (GET) or 4.6 (AM) treatment sessions. Comparing participants with measured outcomes in their allocated groups, the mean SF-36-PFS score changed from 54.8 (standard deviation 23.7) to 55.7 (23.3) for GET and from 55.5 (23.1) to 57.7 (26.0) for AM giving an adjusted difference in means of -2.02 (95% confidence interval -7.75, 2.70). One hundred thirty-five participants completed the mean SF-36-PFS at 12 months, and whilst further improvement was observed, the difference between the study groups remained consistent with chance. The two study groups showed similar changes on most of the secondary outcome measures: Chalder Fatigue, Hospital Anxiety and Depression Scale: Depression, proportion of full-time school attended, a visual analogue pain scale, participant-rated change and accelerometer measured physical activity, whether at the 6-month or 12-month assessment. There was an isolated finding of some evidence of an improvement in anxiety in those allocated to GET, as measured by the Hospital Anxiety and Depression Scale at 6 months, with the 12-month assessment, and the Spence Children's Anxiety scale being aligned with that finding. There was weak evidence of a greater risk of deterioration with GET (27%) than with AM (17%; p = 0.069). At conventional UK cost per QALY thresholds, the probability that GET is more cost-effective than AM ranged from 18 to 21%. Whilst completion of the SF-36-PFS, Chalder Fatigue Scale and EQ-5D-Y was good at the 6-month assessment point, it was less satisfactory for other measures, and for all measures at the 12-month assessment.  Conclusion: There was no evidence that GET was more effective or cost-effective than AM in this setting, with very limited improvement in either study group evident by the 6-month or 12-month assessment points.  Trial registration: The study protocol was registered at www.isrctn.com (3rd September 2015; ISRCTN 23962803) before the start of enrolment to the initial feasibility phase.

Short-term safety outcomes of mastectomy and immediate prepectoral implant-based breast reconstruction: Pre-BRA prospective multicentre cohort study.

BACKGROUND: Prepectoral breast reconstruction (PPBR) has recently been introduced to reduce postoperative pain and improve cosmetic outcomes in women having implant-based procedures. High-quality evidence to support the practice of PPBR, however, is lacking. Pre-BRA is an IDEAL stage 2a/2b study that aimed to establish the safety, effectiveness, and stability of PPBR before definitive evaluation in an RCT. The short-term safety endpoints at 3 months after surgery are reported here. METHODS: Consecutive patients electing to undergo immediate PPBR at participating UK centres between July 2019 and December 2020 were invited to participate. Demographic, operative, oncology, and complication data were collected. The primary outcome was implant loss at 3 months. Other outcomes of interest included readmission, reoperation, and infection. RESULTS: Some 347 women underwent 424 immediate implant-based reconstructions at 40 centres. Most were single-stage direct-to-implant (357, 84.2 per cent) biological mesh-assisted (341, 80.4 per cent) procedures. Conversion to subpectoral reconstruction was necessary in four patients (0.9 per cent) owing to poor skin-flap quality. Of the 343 women who underwent PPBR, 144 (42.0 per cent) experienced at least one postoperative complication. Implant loss occurred in 28 women (8.2 per cent), 67 (19.5 per cent) experienced an infection, 60 (17.5 per cent) were readmitted for a complication, and 55 (16.0 per cent) required reoperation within 3 months of reconstruction. CONCLUSION: Complication rates following PPBR are high and implant loss is comparable to that associated with subpectoral mesh-assisted implant-based techniques. These findings support the need for a well-designed RCT comparing prepectoral and subpectoral reconstruction to establish best practice for implant-based breast reconstruction.

Recruiting Adolescents With Chronic Fatigue Syndrome/Myalgic Encephalomyelitis to Internet-Delivered Therapy: Internal Pilot Within a Randomized Controlled Trial.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in adolescents is common and disabling. Teenagers in the United Kingdom are more likely to recover if they access specialist care, but most do not have access to a local specialist CFS/ME service. Delivering treatment remotely via the internet could improve access to treatment. OBJECTIVE: This study aims to assess (1) the feasibility of recruitment and retention into a trial of internet-delivered specialist treatment for adolescents with CFS/ME and (2) the acceptability of trial processes and 2 web-based treatments (to inform continuation to full trial). METHODS: This study is an internal pilot for the initial 12 months of a full randomized controlled trial (RCT), with integrated qualitative methods (analysis of recruitment consultations and participant and clinician interviews). Recruitment and treatment were delivered remotely from a specialist pediatric CFS/ME treatment service within a hospital in South West United Kingdom. Adolescents (aged 11-17 years) from across the United Kingdom with a diagnosis of CFS/ME and no access to local specialist treatment were referred by their general practitioner to the treatment center. Eligibility assessment and recruitment were conducted via remote methods (telephone and on the web), and participants were randomized (via a computer-automated system) to 1 of 2 web-based treatments. The trial intervention was Fatigue in Teenagers on the InterNET in the National Health Service, a web-based modular CFS/ME-specific cognitive behavioral therapy program (designed to be used by young people and their parents or caregivers) supported by individualized clinical psychologist electronic consultations (regular, scheduled therapeutic message exchanges between participants and therapist within the platform). The comparator was Skype-delivered activity management with a CFS/ME clinician (mainly a physiotherapist or occupational therapist). Both treatments were intended to last for up to 6 months. The primary outcomes were (1) the number of participants recruited (per out-of-area referrals received between November 1, 2016, to October 31, 2017) and the proportion providing 6-month outcome data (web-based self-report questionnaire assessing functioning) and (2) the qualitative outcomes indicating the acceptability of trial processes and treatments. RESULTS: A total of 89 out of 150 (59.3% of potentially eligible referrals) young people and their parents or caregivers were recruited, with 75 out of 89 (84.2%) providing 6-month outcome data. Overall, web-based treatment was acceptable; however, participants and clinicians described both the advantages and disadvantages of remote methods. No serious adverse events were reported. CONCLUSIONS: Recruiting young people (and their parents or caregivers) into an RCT of web-based treatment via remote methods is feasible and acceptable. Delivering specialist treatment at home via the internet is feasible and acceptable, although some families prefer to travel across the United Kingdom for face-to-face treatment. TRIAL REGISTRATION: ISRCTN 18020851; http://www.isrctn.com/ISRCTN18020851. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-018-2500-3.

Development of an online resource for recruitment research in clinical trials to organise and map current literature.

BACKGROUND: Recruiting the target number of participants within the pre-specified time frame agreed with funders remains a common challenge in the completion of a successful clinical trial and addressing this is an important methodological priority. While there is growing research around recruitment, navigating this literature to support an evidence-based approach remains difficult. The Online resource for Recruitment Research in Clinical triAls project aims to create an online searchable database of recruitment research to improve access to existing evidence and to identify gaps for future research. METHODS: MEDLINE (Ovid), Scopus, Cochrane Database of Systematic Reviews and Cochrane Methodology Register, Science Citation Index Expanded and Social Sciences Citation Index within the ISI Web of Science and Education Resources Information Center were searched in January 2015. Search strategy results were screened by title and abstract, and full text obtained for potentially eligible articles. Studies reporting or evaluating strategies, interventions or methods used to recruit patients were included along with case reports and studies exploring reasons for patient participation or non-participation. Eligible articles were categorised as systematic reviews, nested randomised controlled trials and other designs evaluating the effects of recruitment strategies (Level 1); studies that report the use of recruitment strategies without an evaluation of impact (Level 2); or articles reporting factors affecting recruitment without presenting a particular recruitment strategy (Level 3). Articles were also assigned to 1, or more, of 42 predefined recruitment domains grouped under 6 categories. RESULTS: More than 60,000 records were retrieved by the search, resulting in 56,030 unique titles and abstracts for screening, with a further 23 found through hand searches. A total of 4570 full text articles were checked; 2804 were eligible. Six percent of the included articles evaluated the effectiveness of a recruitment strategy (Level 1), with most of these assessing aspects of participant information, either its method of delivery (33%) or its content and format (28%). DISCUSSION: Recruitment to clinical trials remains a common challenge and an important area for future research. The online resource for Recruitment Research in Clinical triAls project provides a searchable, online database of research relevant to recruitment. The project has identified the need for researchers to evaluate their recruitment strategies to improve the evidence base and broaden the narrow focus of existing research to help meet the complex challenges faced by those recruiting to clinical trials.

Strategies to address recruitment to a randomised trial of surgical and non-surgical treatment for cancer: results from a complex recruitment intervention within the Mesothelioma and Radical Surgery 2 (MARS 2) study.

OBJECTIVES: Recruiting to randomised trials is often challenging particularly when the intervention arms are markedly different. The Mesothelioma and Radical Surgery 2 randomised controlled trial (RCT) compared standard chemotherapy with or without (extended) pleurectomy decortication surgery for malignant pleural mesothelioma. Anticipating recruitment difficulties, a QuinteT Recruitment Intervention was embedded in the main trial phase to unearth and address barriers. The trial achieved recruitment to target with a 4-month COVID-19 pandemic-related extension. This paper presents the key recruitment challenges, and the strategies delivered to optimise recruitment and informed consent. DESIGN: A multifaceted, flexible, mixed-method approach to investigate recruitment obstacles drawing on data from staff/patient interviews, audio recorded study recruitment consultations and screening logs. Key findings were translated into strategies targeting identified issues. Data collection, analysis, feedback and strategy implementation continued cyclically throughout the recruitment period. SETTING: Secondary thoracic cancer care. RESULTS: Respiratory physicians, oncologists, surgeons and nursing specialists supported the trial, but recruitment challenges were evident. The study had to fit within a framework of a thoracic cancer service considered overstretched where patients encountered multiple healthcare professionals and treatment views, all of which challenged recruitment. Clinician treatment biases, shaped in part by the wider clinical and research context alongside experience, adversely impacted several aspects of the recruitment process by restricting referrals for study consideration, impacting eligibility decisions, affecting the neutrality in which the study and treatment was presented and shaping patient treatment expectations and preferences. Individual and group recruiter feedback and training raised awareness of key equipoise issues, offered support and shared good practice to safeguard informed consent and optimise recruitment. CONCLUSIONS: With bespoke support to overcome identified issues, recruitment to a challenging RCT of surgery versus no surgery in a thoracic cancer setting with a complex recruitment pathway and multiple health professional involvement is possible. TRIAL REGISTRATION NUMBER: ISRCTN ISRCTN44351742, Clinical Trials.gov NCT02040272.

Needle fasciotomy versus limited fasciectomy for the treatment of Dupuytren's contractures of the fingers (Hand-2): study protocol for a randomised controlled trial.

BACKGROUND: Dupuytren's contractures (DC) are fibrous cords under the skin of the hand that cause one or more fingers to curl gradually and irreversibly towards the palm. These contractures are usually painless but can cause a loss of hand function. Two treatments for Dupuytren's contractures are widely used within the National Health Service (NHS) in the UK: removal of the contractures via surgery (limited fasciectomy) and division of the contractures via a needle inserted through the skin (needle fasciotomy). This study aims to establish the clinical and cost-effectiveness of needle fasciotomy (NF) versus limited fasciectomy (LF) for the treatment of DC in the NHS, in terms of patient-reported hand function and resource utilisation. METHODS/DESIGN: Hand-2 is a national multi-centre, two-arm, parallel-group randomised, non-inferiority trial. Patients will be eligible to join the trial if they are aged 18 years or older, have at least one previously untreated finger with a well-defined Dupuytren's contracture of 30° or greater that causes functional problems and is suitable for treatment with either LF or NF. Patients with a contracture of the distal interphalangeal joint only are ineligible. Eligible consenting patients will be randomised 1:1 to receive either NF or LF and will be followed up for 24 months post-treatment. A QuinteT Recruitment Intervention will be used to optimise recruitment. The primary outcome measure is the participant-reported assessment of hand function, assessed by the Hand Health Profile of the Patient Evaluation Measure (PEM) questionnaire at 12 months post-treatment. Secondary outcomes include other patient-reported measures, loss of finger movement, and cost-effectiveness, reported over the 24-month post-treatment. Embedded qualitative research will explore patient experiences and acceptability of treatment at 2 years post-surgery. DISCUSSION: This study will determine whether treatment with needle fasciotomy is non-inferior to limited fasciectomy in terms of patient-reported hand function at 12 months post-treatment. TRIAL REGISTRATION: International Standard Registered Clinical/soCial sTudy ISRCTN12525655. Registered on 18th September 2020.

Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Nebuliser systems for drug delivery in cystic fibrosis.

BACKGROUND: Nebuliser systems are used to deliver medications to control the symptoms and the progression of lung disease in people with cystic fibrosis. Many types of nebuliser systems are available for use with various medications; however, there has been no previous systematic review which has evaluated these systems. OBJECTIVES: To evaluate effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems for people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching of relevant journals and abstract books of conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data. Date of the most recent search: 15 Oct 2012. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials comparing nebuliser systems including conventional nebulisers, vibrating mesh technology systems, adaptive aerosol delivery systems and ultrasonic nebuliser systems. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third author assessed studies where agreement could not be reached. MAIN RESULTS: The search identified 40 studies with 20 of these (1936 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other solutions through the different nebuliser systems. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. Conventional nebuliser systems providing higher flows, higher respirable fractions and smaller particles decrease treatment time, increase deposition and may be preferred by people with CF, as compared to conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Nebulisers using adaptive aerosol delivery or vibrating mesh technology reduce treatment time to a far greater extent. Deposition (as a percentage of priming dose) is greater than conventional with adaptive aerosol delivery. Vibrating mesh technology systems may give greater deposition than conventional when measuring sputum levels, but lower deposition when measuring serum levels or using gamma scintigraphy. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved with systems which use these newer technologies, but also that some nebuliser systems using vibrating mesh technology may be subject to increased failures. AUTHORS' CONCLUSIONS: Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use.

Inspiratory muscle training for cystic fibrosis.

BACKGROUND: Cystic fibrosis is the most common life-limiting genetic condition in Caucasians and the life-expectancy of those newly diagnosed is increasing. Inspiratory muscle training may be a way of improving the lung function and quality of life of people with cystic fibrosis. Hence there is a need to establish whether this intervention is beneficial. OBJECTIVES: To determine the effect of inspiratory muscle training on health-related quality of life, pulmonary function and exercise tolerance. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials register comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 08 July 2013. SELECTION CRITERIA: Randomised or quasi-randomised clinical controlled trials comparing different inspiratory muscle training regimens with each other or a control in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Three review authors independently applied the inclusion and exclusion criteria to publications and assessed the quality of the included studies. MAIN RESULTS: Fourteen studies were identified. Of these eight studies with 180 participants met the review inclusion criteria. There was wide variation in the quality of the included studies. Data were not published in sufficient detail or with sufficiently similar outcome measures in these studies to perform meta-analyses. AUTHORS' CONCLUSIONS: We have not found any evidence to suggest that this treatment is either beneficial or not. We would advise that practitioners evaluate on a case-by-case basis whether or not to employ this therapy. We recommend that future studies make more use of health-related quality of life and exercise tolerance measures; and that there is an agreement upon a single standard measure of classifying the clinical status of the participants.

Autistic adults' views on the design and processes within randomised controlled trials: The APRiCoT study.

LAY ABSTRACT: Large randomised controlled trials are used to test healthcare treatments. Yet there are no large randomised controlled trials on effective treatments for common mental health issues affecting autistic adults. The purpose of this study was to learn what autistic adults think about randomised controlled trials in preparation for a randomised controlled trial testing a medication for anxiety. This means we wanted to know their opinions about the way randomised controlled trials are done, such as how people are chosen to be in the study and how the study is carried out. We did this by talking to 49 autistic adults individually and asking them questions. We found that most of the people we talked to were okay with the way randomised controlled trials are done. They thought it was fair and they liked that it was based on evidence. However, some autistic people might find it hard to take part in randomised controlled trials. Some people did not like the uncertainty of not knowing what treatment they would receive in a randomised controlled trial. Others felt too vulnerable and may have had bad experiences with healthcare in the past. We found that it is important to involve autistic people early on and at every stage when designing a clinical trial. Care about how clear and precise the study communication is will build trust and improve access to research. Our study indicates that it is possible to conduct large randomised controlled trials with and for autistic people. This can ultimately contribute to the improvement of healthcare outcomes for this population.

Lockdown Experiences and Views on Future Research Participation of Autistic Adults in the UK During the First 6 Months of the COVID-19 Pandemic.

Background: The COVID-19 pandemic resulted in large-scale public health restrictions and lockdowns across many countries. There is an increasing literature on the varied impact of such lockdowns in autistic adults. However, there is very little research on how the pandemic and related public health measures may impact the willingness of autistic people in engaging and taking part in research. The aim of this qualitative study was to explore autistic adults' experiences of the COVID-19 lockdown and how the pandemic may affect future research participation. Methods: We conducted in-depth interviews with 31 autistic adults between March and July 2020. Transcripts were analyzed thematically within a critical realism framework. Results: Participants identified positive aspects of lockdown such as enjoying the lack of social pressures and using their well-developed skills for dealing with uncertainty. Autistic people also shared challenges of adjusting to lockdown, for example, rapid change in daily routines. While hopeful about the freedom gained from easing restrictions, participants were concerned about the inconsistent communication and application of rules during the transition out of lockdown. This may have exacerbated already rising mental health issues among autistic people. The participants viewed research participation and engagement with increased relevance during the pandemic and welcomed efforts to conduct research using online methods of communication. Conclusion: The COVID-19 lockdown had a varied effect in the lives and routines of autistic people. However, health care providers and researchers need to be mindful of rising mental health issues in the aftermath of the pandemic, especially for people who were already vulnerable. The response to the pandemic may have offered opportunities for innovation in research processes enabling more autistic people to engage with research and making studies more inclusive.

Why is this an important issue?: We did not know how the pandemic and the strict restrictions that followed would affect autistic people's well-being and mental health.Also, there was a worry that the pandemic would affect the number of volunteers taking part in research that matters the most to autistic people. Thus, it was important to understand any implications for the way we conduct research with the autistic community after the pandemic. What was the purpose of this study?: We explored the experiences of autistic people living through the first 6 months of the COVID-19 lockdown in the United Kingdom. We were particularly interested in autistic people's views on how the pandemic may affect them taking part in research. What did the researchers do?: We co-produced this interview study to answer our research questions. We carried out in-depth interviews with 31 autistic people. We looked for patterns or themes in what the participants said. What were the results of the study?: Autistic people we interviewed reported being able to enjoy a quieter pace of life. They felt less anxious early in the lockdown. But they also faced great challenges adjusting to changes in their daily routines. Inconsistent public health communication caused worry during the transition out of lockdown. Unnecessary stress might have led to worsening of mental health issues in some people. Our participants held positive views on taking part in and engage with research, despite the pandemic. We identified opportunities that could make research more inclusive for autistic people, for example, online methods for taking consent and taking part in research remotely. What do these findings add to what was already known?: Our study adds to the evidence of the varied responses of autistic people to the pandemic and the public health measures that it led to. One important strength of our work is our focus on the impact of the pandemic on research and implications of future research. We learnt that autistic people welcome and value the use of online technology to reach study participants. Wider use of remote technology can make research more inclusive and participatory. What are potential weaknesses in the study?: Many of our participants were already had experience participating in research. Also most had relatively high education levels. We did not include autistic people with intellectual disabilities. We did not collect information on ethnicity. Our sample is likely to have little ethnic diversity. How will these findings help autistic adults now or in the future?: We describe the experiences of autistic people in the face of unprecedented circumstances. We found the need for clear public health communication to avoid unnecessary stress. The pandemic has provided the opportunity for a wider use of remote methods of research, even in areas where this was not done in the past (e.g., clinical trials). Our study found that such approaches would make research more inclusive.

Non-COVID-19 UK clinical trials and the COVID-19 pandemic: impact, challenges and possible solutions.

INTRODUCTION: The COVID-19 pandemic impacted the operationalisation of non-COVID-19 clinical trials globally, particularly site and participant recruitment and trial success/stoppage. Trials which anticipate recruitment challenges may embed methods such as the QuinteT Recruitment Intervention (QRI) to help identify and understand the sources of challenges. Such interventions can help shed light on pandemic-related challenges. This paper reports our experience of the impact of the COVID-19 pandemic on conducting clinical trials with an embedded QRI, highlighting how the QRI aided in identifying challenges and potential solutions, particularly related to the site set-up and participant recruitment. MAIN BODY: We report on 13 UK clinical trials which included a QRI. Information is from QRI data and researchers' experience and reflections. In most trials, recruitment was lower than even the lowest anticipated rates. The flexibility of the QRI facilitated rapid data collection to understand and document, and in some instances respond to, operational challenges. Challenges were mostly logistical, pandemic-related and beyond the control of the site or central trial teams. Specifically: disrupted and variable site opening timelines -often due to local research and development (R&D) delays- shortages of staff to recruit patients; fewer eligible patients or limited access to patients; and intervention-related factors. Almost all trials were affected by pandemic-related staffing issues including redeployment, prioritisation of COVID-19 care and research, and COVID-19-related staff illness and absence. Trials of elective procedures were particularly impacted by the pandemic, which caused changes to care/recruitment pathways, deprioritisation of services, reduced clinical and surgical capacity and longer waiting lists. Attempted solutions included extra engagement with staff and R&D departments, trial protocol changes (primarily moving online) and seeking additional resourcing. CONCLUSION: We have highlighted wide-ranging, extensive and consistent pandemic-related challenges faced by UK clinical trials, which the QRI helped to identify and, in some cases, address. Many challenges were insurmountable at individual trials or trials unit level. This overview highlights the need to streamline trial regulatory processes, address staffing crises, improve recognition of NHS research staff and for clearer, more nuanced central guidance on the prioritisation of studies and how to deal with the backlog. Pre-emptively embedding qualitative work and stakeholder consultation into trials with anticipated difficulties, moving some processes online, and flexible trial protocols may improve the resilience of trials in the current challenging context.

Multimodality local consolidative treatment versus conventional care of advanced lung cancer after first-line systemic anti-cancer treatment: study protocol for the RAMON multicentre randomised controlled trial with an internal pilot.

INTRODUCTION: Lung cancer is the most common cause of cancer death worldwide and most patients present with extensive disease. One-year survival is improving but remains low (37%) despite novel systemic anti-cancer treatments forming the current standard of care. Although new therapies improve survival, most patients have residual disease after treatment, and little is known on how best to manage it. Therefore, residual disease management varies across the UK, with some patients receiving only maintenance systemic anti-cancer treatment while others receive local consolidative treatment (LCT), alongside maintenance systemic anti-cancer treatment. LCT can be a combination of surgery, radiotherapy and/or ablation to remove all remaining cancer within the lung and throughout the body. This is intensive, expensive and impacts quality of life, but we do not know if it results in better survival, nor the extent of impact on quality of life and what the cost might be for healthcare providers. The RAMON study (RAdical Management Of Advanced Non-small cell lung cancer) will evaluate the acceptability, effectiveness and cost-effectiveness of LCT versus no LCT after first-line systemic treatment for advanced lung cancer. METHODS AND ANALYSIS: RAMON is a pragmatic open multicentre, parallel group, superiority randomised controlled trial. We aim to recruit 244 patients aged 18 years and over with advanced non-small-cell lung cancer from 40 UK NHS hospitals. Participants will be randomised in a 1:1 ratio to receive LCT alongside maintenance treatment, or maintenance treatment alone. LCT will be tailored to each patient's specific disease sites. Participants will be followed up for a minimum of 2 years. The primary outcome is overall survival from randomisation. ETHICS AND DISSEMINATION: The West of Scotland Research Ethics Committee (22/WS/0121) gave ethical approval in August 2022 and the Health Research Authority in September 2022. Participants will provide written informed consent before participating in the study. Findings will be presented at international meetings, in peer-reviewed publications, through patient organisations and notifications to patients. TRIAL REGISTRATION NUMBER: ISRCTN11613852.

Understanding the perspectives of recruiters is key to improving randomised controlled trial enrolment: a qualitative evidence synthesis.

BACKGROUND: Recruiting patients to randomised controlled trials (RCTs) is often reported to be challenging, and the evidence base for effective interventions that could be used by staff (recruiters) undertaking recruitment is lacking. Although the experiences and perspectives of recruiters have been widely reported, an evidence synthesis is required in order to inform the development of future interventions. This paper aims to address this by systematically searching and synthesising the evidence on recruiters' perspectives and experiences of recruiting patients into RCTs.  METHODS: A qualitative evidence synthesis (QES) following Thomas and Harden's approach to thematic synthesis was conducted. The Ovid MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, ORRCA and Web of Science electronic databases were searched. Studies were sampled to ensure that the focus of the research was aligned with the phenomena of interest of the QES, their methodological relevance to the QES question, and to include variation across the clinical areas of the studies. The GRADE CERQual framework was used to assess confidence in the review findings. RESULTS: In total, 9316 studies were identified for screening, which resulted in 128 eligible papers. The application of the QES sampling strategy resulted in 30 papers being included in the final analysis. Five overlapping themes were identified which highlighted the complex manner in which recruiters experience RCT recruitment: (1) recruiting to RCTs in a clinical environment, (2) enthusiasm for the RCT, (3) making judgements about whether to approach a patient, (4) communication challenges, (5) interplay between recruiter and professional roles. CONCLUSIONS: This QES identified factors which contribute to the complexities that recruiters can face in day-to-day clinical settings, and the influence recruiters and non-recruiting healthcare professionals have on opportunities afforded to patients for RCT participation. It has reinforced the importance of considering the clinical setting in its entirety when planning future RCTs and indicated the need to better normalise and support research if it is to become part of day-to-day practice. TRIAL REGISTRATION: PROSPERO CRD42020141297 (registered 11/02/2020).

Development of a new adapted QuinteT Recruitment Intervention (QRI-Two) for rapid application to RCTs underway with enrolment shortfalls-to identify previously hidden barriers and improve recruitment.

BACKGROUND: Many randomised controlled trials (RCTs) struggle to recruit, despite valiant efforts. The QRI (QuinteT Recruitment Intervention) uses innovative research methods to optimise recruitment by revealing previously hidden barriers related to the perceptions and experiences of recruiters and patients, and targeting remedial actions. It was designed to be integrated with RCTs anticipating difficulties at the outset. A new version of the intervention (QRI-Two) was developed for RCTs already underway with enrolment shortfalls. METHODS: QRIs in 12 RCTs with enrolment shortfalls during 2007-2017 were reviewed to document which of the research methods used could be rapidly applied to successfully identify recruitment barriers. These methods were then included in the new streamlined QRI-Two intervention which was applied in 20 RCTs in the USA and Europe during 2018-2019. The feasibility of the QRI-Two was investigated, recruitment barriers and proposed remedial actions were documented, and the QRI-Two protocol was finalised. RESULTS: The review of QRIs from 2007 to 2017 showed that previously unrecognised recruitment barriers could be identified but data collection for the full QRI required time and resources usually unavailable to ongoing RCTs. The streamlined QRI-Two focussed on analysis of screening/accrual data and RCT documents (protocol, patient-information), with discussion of newly diagnosed barriers and potential remedial actions in a workshop with the RCT team. Four RCTs confirmed the feasibility of the rapid application of the QRI-Two. When the QRI-Two was applied to 14 RCTs underway with enrolment shortfalls, an array of previously unknown/underestimated recruitment barriers related to issues such as equipoise, intervention preferences, or study presentation was identified, with new insights into losses of eligible patients along the recruitment pathway. The QRI-Two workshop enabled discussion of the newly diagnosed barriers and potential remedial actions to improve recruitment in collaboration with the RCT team. As expected, the QRI-Two performed less well in six RCTs at the start-up stage before commencing enrolment. CONCLUSIONS: The QRI-Two can be applied rapidly, diagnose previously unrecognised recruitment barriers, and suggest remedial actions in RCTs underway with enrolment shortfalls, providing opportunities for RCT teams to develop targeted actions to improve recruitment. The effectiveness of the QRI-Two in improving recruitment requires further evaluation.

Assessment of cosmesis after breast reconstruction surgery: a systematic review.

BACKGROUND: Breast reconstruction (BR) is undertaken to improve cosmetic outcomes, but how this is optimally assessed is uncertain. This review summarises current methods for assessing cosmesis after reconstructive surgery and makes recommendations for future practice. METHODS: A comprehensive systematic review identified all studies with 20 or more participants that evaluated the cosmetic outcome of BR. Four evaluation criteria (reporting of study inclusion criteria, type and timing of BR and timing of assessment) were used to assess study quality. Articles reporting at least three of the four criteria were considered robust and further summarised to report methods of cosmetic assessment, assessor details and the scoring systems used. RESULTS: 122 primary papers assessed cosmesis in 11,308 women with median follow-up of 28.8 months (range 18.0-42.9 months). Cosmesis was assessed by either healthcare professionals or patients in 33 (27.1%) and 37 studies (30.3%), respectively, and by both professionals and patients in 52 (42.6%). Professional assessments included 43 (40.2%) clinical, 49 (45.8%) photographic and 13 (12.1%) geometric assessments conducted by between 1 and 26 observers. Surgeons were most frequently involved in assessments (n = 71, 67.6%), but in 38 (36.1%) papers the assessor's profession was not reported. Twenty-seven (25.7%) papers used previously published assessment scale. Patients' views were assessed in 89 studies, using questionnaires (n = 63) or interviews (n = 12); 14 (15.7%) did not report how patients' views were obtained. CONCLUSIONS: Current methods for assessing the cosmetic outcome of BR vary widely. A valid patient-centred assessment method is required to fully understand the outcomes of BR and to inform decision-making.

Best-BRA (Is subpectoral or prepectoral implant placement best in immediate breast reconstruction?): a protocol for a pilot randomised controlled trial of subpectoral versus prepectoral immediate implant-based breast reconstruction in women following mastectomy.

BACKGROUND: Implant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure following mastectomy. IBBR techniques are evolving rapidly, with mesh-assisted subpectoral reconstruction becoming the standard of care and more recently, prepectoral techniques being introduced. These muscle-sparing techniques may reduce postoperative pain, avoid implant animation and improve cosmetic outcomes and have been widely adopted into practice. Although small observational studies have failed to demonstrate any differences in the clinical or patient-reported outcomes of prepectoral or subpectoral reconstruction, high-quality comparative evidence of clinical or cost-effectiveness is lacking. A well-designed, adequately powered randomised controlled trial (RCT) is needed to compare the techniques, but breast reconstruction RCTs are challenging. We, therefore, aim to undertake an external pilot RCT (Best-BRA) with an embedded QuinteT Recruitment Intervention (QRI) to determine the feasibility of undertaking a trial comparing prepectoral and subpectoral techniques. METHODS AND ANALYSIS: Best-BRA is a pragmatic, two-arm, external pilot RCT with an embedded QRI and economic scoping for resource use. Women who require a mastectomy for either breast cancer or risk reduction, elect to have an IBBR and are considered suitable for both prepectoral and subpectoral reconstruction will be recruited and randomised 1:1 between the techniques.The QRI will be implemented in two phases: phase 1, in which sources of recruitment difficulties are rapidly investigated to inform the delivery in phase 2 of tailored interventions to optimise recruitment of patients.Primary outcomes will be (1) recruitment of patients, (2) adherence to trial allocation and (3) outcome completion rates. Outcomes will be reviewed at 12 months to determine the feasibility of a definitive trial. ETHICS AND DISSEMINATION: The study has been approved by the National Health Service (NHS) Wales REC 6 (20/WA/0338). Findings will be presented at conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN10081873.

What empirical research has been undertaken on the ethics of clinical research in India? A systematic scoping review and narrative synthesis.

INTRODUCTION: The post-2005 rise in clinical trials and clinical research conducted in India was accompanied by frequent reports of unethical practices, leading to a series of regulatory changes. We conducted a systematic scoping review to obtain an overview of empirical research pertaining to the ethics of clinical trials/research in India. METHODS: Our search strategy combined terms related to ethics/bioethics, informed consent, clinical trials/research and India, across nine databases, up to November 2019. Peer-reviewed research exploring ethical aspects of clinical trials/research in India with any stakeholder groups was included. We developed an evidence map, undertook a narrative synthesis and identified research gaps. A consultation exercise with stakeholders in India helped contextualise the review and identify additional research priorities. RESULTS: Titles/Abstracts of 9699 articles were screened, full text of 282 obtained and 80 were included. Research on the ethics of clinical trials/research covered a wide range of topics, often conducted with little to no funding. Studies predominantly examined what lay (patients/public) and professional participants (eg, healthcare staff/students/faculty) know about topics such as research ethics or understand from the information given to obtain their consent for research participation. Easily accessible groups, namely ethics committee members and healthcare students were frequently researched. Research gaps included developing a better understanding of the recruitment-informed consent process, including the doctor-patient interaction, in multiple contexts and exploring issues of equity and justice in clinical trials/research. CONCLUSION: The review demonstrates that while a wide range of topics have been studied in India, the focus is largely on assessing knowledge levels across different population groups. This is a useful starting point, but fundamental questions remain unanswered about informed consent processes and broader issues of inequity that pervade the clinical trials/research landscape. A priority-setting exercise and appropriate funding mechanisms to support researchers in India would help improve the clinical trials/research ecosystem.