Search

Abstract Background Following the COVID-19 pandemic, millions of people continue to experience ongoing physical and mental health sequelae after recovery from acute infection. There is currently no specific treatment for the diverse symptoms associated with post-COVID-19 condition. Physical and mental health rehabilitation may help improve quality of life in such patients. This study reports the cost-effectiveness of a programme of physical and mental health rehabilitation compared to best practice usual care in people with post-COVID-19 condition who were previously hospitalised. Methods We conducted an economic evaluation within a randomised controlled trial from the perspective of the UK national health service (NHS) and personnel social services perspective (PSS). Resource used and health-related quality of life were collected using bespoke questionnaire and the EQ-5D-5 L questionnaire at three, six, and 12 months. Incremental costs and quality adjusted life years accrued over the follow-up period were estimated and reported as the incremental cost-effectiveness ratio. Estimate uncertainty was managed by multiple imputation and bootstrapping cost-effectiveness estimates; and displayed graphically on the cost-effectiveness plane. Results Over a 12-month time horizon, incremental costs and QALYs were £305 (95% CI: -123 to 732) and 0.026 (95% CI: -0.005 to 0.052) respectively. The ICER was £11,941 per QALY indicating cost-effective care. Sensitivity analyses supported the base case findings. The probability of the intervention being cost-effective at a £30,000 per QALY willingness-to-pay threshold was 84%. Conclusion The within-trial economic evaluation suggested that people with post-COVID-19 condition after hospitalisation should be offered a programme of physical and mental health rehabilitation as it likely reflects a cost-effective use of NHS resources. Hospitalisation for COVID-19 has become less commonplace: further evaluation in non-hospitalised patients may be worthwhile. Trial registration ISRCTN registry ISRCTN11466448 23rd November 2020.

Abstract Background Antibiotic resistant infections cause over 700,000 deaths worldwide annually. As antimicrobial stewardship (AMS) helps minimise the emergence of antibiotic resistance resulting from inappropriate use of antibiotics in healthcare, we developed ePAMS+ (ePrescribing-based Anti-Microbial Stewardship), an ePrescribing and Medicines Administration (EPMA) system decision-support tool complemented by educational, behavioural and organisational elements. Methods We conducted a non-randomised before-and-after feasibility trial, implementing ePAMS+ in two English hospitals using the Cerner Millennium EPMA system. Wards of several specialties were included. Patient participants were blinded to whether ePAMS+ was in use; prescribers were not. A mixed-methods evaluation aimed to establish: acceptability and usability of ePAMS+ and trial processes; feasibility of ePAMS+ implementation and quantitative outcome recording; and a Fidelity Index measuring the extent to which ePAMS+ was delivered as intended. Longitudinal semi-structured interviews of doctors, nurses and pharmacists, alongside non-participant observations, gathered qualitative data; we extracted quantitative prescribing data from the EPMA system. Normal linear modelling of the defined daily dose (DDD) of antibiotic per admission quantified its variability, to inform sample size calculations for a future trial of ePAMS+ effectiveness. Results The research took place during the SARS-CoV-2 pandemic, from April 2021 to November 2022. 60 qualitative interviews were conducted (33 before ePAMS+ implementation, 27 after). 1,958 admissions (1,358 before ePAMS+ implementation; 600 after) included 24,884 antibiotic orders. Qualitative interviews confirmed that some aspects of ePAMS+ , its implementation and training were acceptable, while other features (e.g. enabling combinations of antibiotics to be prescribed) required further development. ePAMS+ uptake was low (28 antibiotic review records from 600 admissions; 0.047 records per admission), preventing full development of a Fidelity Index. Normal linear modelling of antibiotic DDD per admission showed a residual variance of 1.086 (log-transformed scale). Unavailability of indication data prevented measurement of some outcomes (e.g. number of antibiotic courses per indication). Conclusions This feasibility trial encountered unforeseen circumstances due to contextual factors and a global pandemic, highlighting the need for careful adaptation of complex intervention implementations to the local setting. We identified key refinements to ePAMS+ to support its wider adoption in clinical practice, requiring further piloting before a confirmatory effectiveness trial. Trial registration ISRCTN Registry ISRCTN13429325, 24 March 2022.

Abstract Background The SPHERe (Supervised Pulmonary Hypertension Exercise Rehabilitation) trial is a multi-centre, pragmatic, randomised controlled trial assessing the clinical and cost-effectiveness of supervised exercise rehabilitation with psychosocial and motivational support compared to best-practice usual care for people with pulmonary hypertension (PH). The original protocol was published in BMC Pulmonary Medicine (accessible online). We randomised our first participant in January 2020. In response to the COVID-19 pandemic, the trial was stopped in March 2020. In person delivery of the SPHERe intervention to a vulnerable population was not possible during the COVID-19 pandemic. We describe here how trial procedures and intervention delivery were adapted in response to the COVID-19 pandemic. Methods Restrictions imposed by the COVID-19 pandemic on the clinically vulnerable PH population meant that trial delivery was changed from a centre-based rehabilitation programme to remotely delivered group online sessions. This led to minor alterations to the eligibility criteria. These changes followed a consultation process with stakeholders and people with PH and were approved by the funder and independent trial committees. Conclusions We describe the modified SPHERe trial protocol in response to restrictions imposed by the COVID-19 pandemic. SPHERe is the first randomised controlled trial to assess the clinical and cost-effectiveness of an online group rehabilitation programme for people with PH compared to usual care. Trial registration ISRCTN no. 10608766. Prospectively registered on 18th March 2019, updated 16th August 2023.

Abstract Background Improving outcomes after surgery is a major public health research priority for patients, clinicians and the NHS. The greatest burden of perioperative complications, mortality and healthcare costs lies amongst the population of patients aged over 50 years who undergo major non-cardiac surgery. The Volatile vs Total Intravenous Anaesthesia for major non-cardiac surgery (VITAL) trial specifically examines the effect of anaesthetic technique on key patient outcomes: quality of recovery after surgery (quality of recovery after anaesthesia, patient satisfaction and major post-operative complications), survival and patient safety. Methods A multi-centre pragmatic efficient randomised trial with health economic evaluation comparing total intravenous anaesthesia with volatile-based anaesthesia in adults (aged 50 and over) undergoing elective major non-cardiac surgery under general anaesthesia. Discussion Given the very large number of patients exposed to general anaesthesia every year, even small differences in outcome between the two techniques could result in substantial excess harm. Results from the VITAL trial will ensure patients can benefit from the very safest anaesthesia care, promoting an early return home, reducing healthcare costs and maximising the health benefits of surgical treatments. Trial registration ISRCTN62903453. September 09, 2021.

Investigations into format shifts from physical to digital access in libraries often centre print materials. Similarly, recent calls to action for an increasing focus on acquisition of materials that support equity, diversity, and inclusion (EDI) efforts within postsecondary institutions often centre print resources. For academic libraries, media like film have unique access and acquisition models that do not correspond to print and pose unique challenges extending back to the Hollywood studios that create and distribute films. This paper explores the dual shifts in academic libraries toward collecting fewer physical films and collecting more content to support EDI mandates, and asks: first, whether the shift away from collecting physical media may also be a shift away from including diverse perspectives in film collections; and second, if we have the data to draw a measurable and demonstrable conclusion. A comprehensive literature review traces efforts to assess markers of diversity in large library collections and/or film collections over the past two decades and helps establish a methodology that combines analyzing data from the library catalogue and Wikidata. Findings revealed that the completeness and consistency of the data over time makes drawing strong conclusions difficult and demonstrated the challenges of this approach in addressing EDI analysis, even when augmenting catalogue metadata with Wikidata. Curation and choice are perhaps more important in building a diverse film collection than questions of format alone, despite the challenges in assessing and collecting film which is and has always been a format in rapid and continual flux.

Aims: Fractures of the humeral shaft represent 3% to 5% of all fractures. The most common treatment for isolated humeral diaphysis fractures in the UK is non-operative using functional bracing, which carries a low risk of complications, but is associated with a longer healing time and a greater risk of nonunion than surgery. There is an increasing trend to surgical treatment, which may lead to quicker functional recovery and lower rates of fracture nonunion than functional bracing. However, surgery carries inherent risk, including infection, bleeding, and nerve damage. The aim of this trial is to evaluate the clinical and cost-effectiveness of functional bracing compared to surgical fixation for the treatment of humeral shaft fractures. Methods: The HUmeral SHaft (HUSH) fracture study is a multicentre, prospective randomized superiority trial of surgical versus non-surgical interventions for humeral shaft fractures in adult patients. Participants will be randomized to receive either functional bracing or surgery. With 334 participants, the trial will have 90% power to detect a clinically important difference for the Disabilities of the Arm, Shoulder and Hand questionnaire score, assuming 20% loss to follow-up. Secondary outcomes will include function, pain, quality of life, complications, cost-effectiveness, time off work, and ability to drive. Discussion: The results of this trial will provide evidence regarding clinical and cost-effectiveness between surgical and non-surgical treatment of humeral shaft fractures. Ethical approval has been obtained from East of England – Cambridge Central Research Ethics Committee. Publication is anticipated to occur in 2024. Cite this article: Bone Jt Open 2024;5(4):343–349.

Introduction Recurrent patellar dislocation is a debilitating musculoskeletal condition, affecting mainly adolescents and adults under the age of 30. It can persist for many decades, causing pain and cartilage and soft-tissue damage, potentially leading to osteoarthritis. Recurrent patellar dislocation can be managed with physiotherapy or surgery. However, it is not known which treatment is most effective.Methods and analysis Recurrent Patellar Dislocation: Personalised Therapy or Operative Treatment (REPPORT) is a pragmatic, multicentre, two-arm, superiority, randomised controlled trial. It will compare the clinical and cost-effectiveness of an initial management strategy of personalised, phased and progressive rehabilitation, termed personalised knee therapy versus surgery for recurrent patellar dislocation.The trial’s target sample size is 276 participants who will be recruited from approximately 20 sites across the UK. Participants will be randomly allocated to the two treatment groups via a central computer-based minimisation system. Treatment allocation will be in a 1:1 ratio, stratified by age, presence of patella alta and recruitment site.The primary outcome is participant-reported function using the Knee injury and Osteoarthritis Outcome 4-domain score at 18 months post randomisation. Health economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including patellar instability, health utility, work/education status, satisfaction with social roles and treatment, health resource use and adverse events will be collected at 6, 12, 18 and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement.Ethics and dissemination The trial was approved by the East Midlands—Nottingham 2 Research Ethics Committee on 30 March 2023.Results will be disseminated via peer-reviewed publications, presentations at national and international conferences, in lay summaries, and using the REPPORT website and social media channels.Trial registration number ISRCTN17972668.

Introduction Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective.Methods and analysis The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement.Ethics and dissemination The trial was approved by the London—Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist.Trial registration number ISRCTN87336549.

Aims: The management of fractures of the medial epicondyle is one of the greatest controversies in paediatric fracture care, with uncertainty concerning the need for surgery. The British Society of Children’s Orthopaedic Surgery prioritized this as their most important research question in paediatric trauma. This is the protocol for a randomized controlled, multicentre, prospective superiority trial of operative fixation versus nonoperative treatment for displaced medial epicondyle fractures: the Surgery or Cast of the EpicoNdyle in Children’s Elbows (SCIENCE) trial. Methods: Children aged seven to 15 years old inclusive, who have sustained a displaced fracture of the medial epicondyle, are eligible to take part. Baseline function using the Patient-Reported Outcomes Measurement Information System (PROMIS) upper limb score, pain measured using the Wong Baker FACES pain scale, and quality of life (QoL) assessed with the EuroQol five-dimension questionnaire for younger patients (EQ-5D-Y) will be collected. Each patient will be randomly allocated (1:1, stratified using a minimization algorithm by centre and initial elbow dislocation status (i.e. dislocated or not-dislocated at presentation to the emergency department)) to either a regimen of the operative fixation or non-surgical treatment. Outcomes: At six weeks, and three, six, and 12 months, data on function, pain, sports/music participation, QoL, immobilization, and analgesia will be collected. These will also be repeated annually until the child reaches the age of 16 years. Four weeks after injury, the main outcomes plus data on complications, resource use, and school absence will be collected. The primary outcome is the PROMIS upper limb score at 12 months post-randomization. All data will be obtained through electronic questionnaires completed by the participants and/or parents/guardians. The NHS number of participants will be stored to enable future data linkage to sources of routinely collected data (i.e. Hospital Episode Statistics). Cite this article: Bone Jt Open 2024;5(1):69–77.

Background The extra benefit of a programme of physiotherapy in addition to advice alone, following first-time traumatic shoulder dislocation, is uncertain. We compared the clinical and cost-effectiveness of a single session of advice with a single session of advice and a programme of physiotherapy. Objective The primary objective was to quantify and draw inferences about observed differences in the Oxford Shoulder Instability Score between the trial treatment groups 6 months post randomisation, in adults with a first-time traumatic shoulder dislocation. Design A pragmatic, multicentre, superiority, randomised controlled trial with embedded qualitative study. Setting Forty-one hospitals in the UK NHS. Participants Adults with a radiologically confirmed first-time traumatic anterior shoulder dislocation, being managed non-operatively. People with neurovascular complications or bilateral dislocations, and those unable to adhere to trial procedures or unable to attend physiotherapy within 6 weeks of injury, or who had previously been randomised, were excluded. Interventions All participants received the same initial shoulder examination followed by advice to aid self-management, lasting up to 1 hour and administered by a physiotherapist (control). Participants randomised to receive an additional programme of physiotherapy were offered sessions lasting for up to 30 minutes, over a maximum duration of 4 months from the date of randomisation (intervention). Main outcome measures The primary outcome measure was the Oxford Shoulder Instability Score. This is a self-completed outcome measure containing 12 questions (0–4 points each), with possible scores from 0 (worst function) to 48 (best function). Measurements were collected at 6 weeks, 3 months, 6 months and 12 months by postal questionnaire; 6 months was the primary outcome time point. The primary health outcome for economic evaluation was the quality-adjusted life-year, in accordance with National Institute of Health and Care Excellence guidelines. Results Between 14 November 2018 and 14 March 2022, 482 participants were randomised to advice (n = 240) or advice and a programme of physiotherapy (n = 242). Participants were 34% female, with a mean age of 45 years, and treatment arms were balanced at baseline. There was not a statistically significant difference in the primary outcome between advice only and advice plus a programme of physiotherapy at 6 months for the primary intention-to-treat adjusted analysis (favours physiotherapy: 1.5, 95% confidence interval −0.3 to 3.5) or at earlier 3-month and 6-week time points on the Oxford Shoulder Instability Score (0–48; higher scores indicate better function). The probability of physiotherapy being cost-effective at a willingness-to-pay threshold of £30,000 was 0.95. Conclusions We found little difference in the primary outcome or other secondary outcomes. Advice with additional physiotherapy sessions was found likely to be cost-effective. However, small imprecise incremental costs and quality-adjusted life-years raise questions on whether it is the best use of scarce physiotherapy resources given current service demands. Limitations Loss to follow-up was 27%; however, the observed standard deviation was much smaller than anticipated. These changes in parameters reduced the number of participants required to observe the planned target difference of four points. Our post hoc sensitivity analysis, accounting for missing data, gives similar results. Future work Further research should be directed towards optimising self-management strategies. Study registration This study is registered as ISRCTN63184243. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/167/56) and is published in full in Health Technology Assessment; Vol. 28, No. 22. See the NIHR Funding and Awards website for further award information. Plain language summary The shoulder dislocates (comes out of its socket joint) when the upper end of the arm bone is forced out during an injury. This common problem occurs mostly in men in their 20s and women aged over 80. After the bone is put back in its socket, most people are managed with physiotherapy. In the United Kingdom, once the bone is back in its socket, there is a range of physiotherapy provision: some hospitals offer advice, and some offer advice and a course of additional physiotherapy sessions. We compared advice alone to advice and physiotherapy for people who had a shoulder that had come out of its joint for the first time. Physiotherapy advice and additional sessions included education about the injury and exercises to move and strengthen the shoulder. When we started this project, this was the first time these two treatments had been compared. Our aim was to compare what activities the two groups could do 6 months after injury via a questionnaire. We also compared quality of life and the cost of rehabilitation at 6 weeks, 3 months, 6 months and 12 months after injury. Adults with a shoulder out of its joint and who were not having surgery were asked to take part. All adults who were eligible and consented to take part were assigned, by chance, to either a single session of advice or the same session followed by physiotherapy. Between 14 November 2018 and 14 March 2022 we collected data on 482 people, from 41 NHS sites across the UK. We found at 6 months there was little evidence that additional physiotherapy was better, when compared to advice alone. Cost-effectiveness analysis (comparing changes in costs and quality of life) suggests additional physiotherapy might provide value for money. However, the changes involved are small and uncertain. Scientific summary Background The shoulder is the most frequently dislocated joint; dislocation occurs in 8.2–23.9 per 100,000 people per year, and 95% of these are anterior dislocations [Brownson P, Donaldson O, Fox M, Rees JL, Rangan A, Jaggi A, et al. BESS/BOA Patient Care Pathways: Traumatic anterior shoulder instability. Shoulder Elbow 2015;7(3):214–26]. They occur when excessive forces during a traumatic event displace the humeral head frontwards, out of the shoulder socket (glenoid fossa), resulting in the joint surfaces completely losing contact [Brownson et al. 2015; Hanchard NC, Goodchild LM, Kottam L. Conservative management following closed reduction of traumatic anterior dislocation of the shoulder. Cochrane Database Syst Rev 2014;(4):CD004962; Berendes TD, Pilot P, Nagels J, Vochteloo AJ, Nelissen RG. Survey on the management of acute first-time anterior shoulder dislocation amongst Dutch public hospitals. Arch Orthop Trauma Surg 2015;135(4):447–54]. People with a traumatic anterior shoulder dislocation (TASD) may have ongoing pain, disability and substantial morbidity linked to high recurrence rates and subsequent need for repeated episodes of management (Brownson et al. 2015; Hanchard et al. 2014; Berendes et al. 2015). Re-dislocation following a first-time traumatic event typically occurs within 12 months of the index dislocation [Zacchilli MA, Owens BD. Epidemiology of shoulder dislocations presenting to emergency departments in the United States. J Bone Joint Surg Am 2010;92(3):542–9]. Rehabilitation may reduce ongoing re-dislocations and restore a functional, painless and stable shoulder through early restoration of joint movement and promotion of exercises to retrain muscles to maintain stability (Hanchard et al. 2014). However, a 2014 Cochrane review did not find an evidence base to support this (Hanchard et al. 2014). Dutch national guidelines explicitly state no referral to physiotherapy should be made, and UK guidelines cite referral ‘may be helpful’ (Brownson et al. 2015; Berendes et al. 2015). Consequently, the nature and extent of physiotherapy required for the management of patients following TASD are unclear. A typical course of six physiotherapy sessions costs around £378; a single assessment and advice session costs £63 (NHS Reference cost). In addition to the cost of providing a physiotherapy service, there was a clear message from our patient workshop that attending a typical course of six sessions of physiotherapy is burdensome. Younger people may need to take time from work or arrange care for dependents, while older people may find travel challenging, particularly if unable to drive following the dislocation. For both groups, this can be time-consuming and costly. If a single advice session were all that is required, it would have a positive impact on patient experience after TASD, lessening the burden on patients and their friends and families. Consequently, a course of supervised, tailored physiotherapy needs to be of clear additional benefit, when compared to a single session of advice, if it is to be implemented as standard care in the NHS. There is no clinical consensus or high-quality evidence on how best to manage TASDs (Brownson et al. 2015). Objective The primary objective was to test a single session of advice and physiotherapy versus a single session of advice only, for adults with first-time TASD managed non-operatively at 6 months using the Oxford Shoulder Instability Score (OSIS). Methods Design A UK multicentre, two-arm, parallel group, superiority, randomised controlled trial (RCT) with 1 : 1 treatment allocation, across 41 NHS sites, with embedded qualitative study. A protocol paper has been previously published [Kearney RS, Dhanjal G, Parsons N, Ellard D, Parsons H, Haque A, et al. Acute Rehabilitation following Traumatic anterior shoulder dISlocAtioN (ARTISAN): protocol for a multicentre randomised controlled trial. BMJ Open 2020;10(11):e040623]. The final protocol, statistical analysis plan and health economic analysis plan are publicly available. Participants People were eligible to be included in the trial if they were adults (≥ 18 years) with a first-time TASD confirmed radiologically. People were excluded if they had neurovascular complications or bilateral dislocations, were unable to adhere to trial procedures or unable to attend physiotherapy within 6 weeks of injury, or had been previously included in the trial. After potential participants were assessed, informed written consent was obtained by a site-based researcher trained in good clinical practice. Intervention All participating centres received an initial training session from an Acute Rehabilitation following Traumatic anterior shoulder dISlocAtioN (ARTISAN) trial research physiotherapist. Following this, a lead physiotherapist at each site was identified to complete subsequent training of additional physiotherapists. This training was supported with web-based materials and a trial intervention manual. A quality control programme ensured intervention fidelity. Fidelity was monitored by: (a) direct observations by a member of the trial team; (b) audio recordings, used to assess the success or failure of the therapist to introduce the aims/rationale of each component and consolidate participant learning at the end of each component; and (c) a therapist self-report form completed for every trial participant. Points (a) and (b) were evaluated twice annually for the duration of recruitment and intervention delivery. Any issues identified were discussed on a case-by-case basis by the trial management group, who were responsible for recommending appropriate action. If issues with individual sites were not resolved following the recommendations, they were escalated to the trial steering committee. All participants had an initial period where the injured arm was supported in a sling, and then received an appointment for a physiotherapy advice session within 6 weeks of their injury. At the first appointment, all participants received the same initial shoulder examination followed by advice to aid self-management, lasting up to 1 hour and administered by an ARTISAN-trained physiotherapist. This included core components on education, progressive exercises, and exercise planning to enhance self-management behaviours. These core components were available after the advice session via a password-protected website or via paper-based alternatives at the participants’ preference. Details of the intervention development were first published in December 2021 [Liew Z, Mazuquin B, Ellard DR, Karasouli E, Drew S, Modi C, et al. Development of a single-session physiotherapy and self-management intervention for the treatment of primary traumatic anterior shoulder dislocation for the ‘Acute Rehabilitation following Traumatic anterior shoulder dISlocAtioN (ARTISAN)’ multicentre RCT. Physiotherapy 2021;113:80–7]. Following completion of the advice appointment, the participant was randomised, allocating them to this advice session alone or to this advice session plus the offer of additional physiotherapy. We defined the offer of additional physiotherapy to be the intervention. Participants randomised to advice only were provided with a contact point to self-refer back to the clinical team if recovery did not occur. Participants who self-referred back to the clinical team were considered to be per protocol. Participants randomised to receive additional physiotherapy were offered additional physiotherapy sessions. Each additional session lasted for up to 30 minutes, over a maximum duration of 4 months from the date of randomisation. The course of physiotherapy involved teaching and supervising the ‘core set’ of progressive exercises offered to the control arm in addition to being able to tailor treatment according to usual practice. Outcome measures Primary outcome measure The primary outcome measure was the OSIS. The OSIS is a self-completed outcome measure containing 12 questions (0–4 points each), with possible scores from 0 (worst function) to 48 (best function) [Dawson J, Fitzpatrick R, Carr A. The assessment of shoulder instability. The development and validation of a questionnaire. J Bone Joint Surg Br 1999;81(3):420–6; Dawson J, Rogers K, Fitzpatrick R, Carr A. The Oxford shoulder score revisited. Arch Orthop Trauma Surg 2009;129(1):119–23]. These questions relate to activities of daily living particularly relevant to patients exhibiting shoulder instability. Secondary outcome measures The secondary outcome measures were as follows. QuickDASH: The QuickDASH is a self-completed shortened version of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Instead of 30 items, the QuickDASH uses 11 items to measure physical function and symptoms in people with any or multiple musculoskeletal disorders of the upper limb. The questionnaire was designed to help describe the disability experienced by people with upper-limb disorders and also to monitor changes in symptoms and function over time [Gummesson C, Ward MM, Atroshi I. The shortened Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH): validity and reliability based on responses within the full-length DASH. BMC Musculoskelet Disord 2006;7:44]. EuroQol-5 Dimensions, five-level version (EQ-5D-5L): EQ-5D-5L is a well-validated, generic health-related quality of life measure consisting of five dimensions, each with five levels of response. Each combination of answers can be converted into a health utility score. It has good test–retest reliability, is simple for participants to use, and gives a single preference-based index value for health status that can be used for broader cost-effectiveness comparative purposes [Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20(10):1727–36]. Complications: Serious adverse events (SAEs) were reported through the following mechanisms: (a) participant reported during routine collection of follow-up data; (b) local research teams reported any additional investigations or treatment of participants; (c) local physiotherapists delivering the trial interventions reported any events occurring during treatment sessions; and (d) medical records of non-responding participants were retrieved by local research teams at site. Serious adverse events not related to the intervention or TASD event were recorded on the SAE form but were not formally analysed or reported. SAEs that were predefined complications directly related to the trial interventions or directly caused by the primary TASD event were recorded as complications and were formally analysed and reported. Resource use questionnaires: The primary health economic analysis concentrated on direct intervention and healthcare/personal social services costs, while wider impact (societal) costs were included within the sensitivity analyses. Participants completed resource use questionnaires at all follow-up points to collect resource use data associated with the interventions under examination. We used techniques common in long-term studies to ensure minimum loss to follow-up, such as collection of multiple contact addresses and telephone numbers, mobile telephone numbers and e-mail addresses. All outcome measures were collected at baseline, 6 weeks, and 3, 6 and 12 months following randomisation. Qualitative interviews: One of the secondary objectives for ARTISAN was to qualitatively explore the participant experiences of receiving the trial treatments and facilitators and obstacles to adhering to them. Soon after the return of the 12-month follow-up questionnaire, a purposive sample (informed by treatment allocation, gender, age and outcome) of up to 50 participants were invited for one-off face-to-face interviews [by telephone or via Microsoft Teams® (Microsoft Corporation, Redmond, WA, USA)]. The aim was to explore the participant experience of receiving the trial treatments, and facilitators and obstacles to adhering to them. Results Between 14 November 2018 and 14 March 2022 we recruited from 41 NHS Trusts, who screened 1551 adults with a traumatic shoulder dislocation, from whom 1069 were not randomised. Forty of the 41 NHS Trust teams randomised the remaining 482 to advice only (n = 240) or advice and a programme of physiotherapy (n = 242). Ten participants withdrew prior to the primary outcome point of 6 months; 354 participants completed the primary outcome OSIS (73%) and were included in the final analysis. Across the groups there were high levels of adherence. Ninety-six physiotherapists delivered the interventions across the 41 sites. Two participants in the advice-only group (n = 240) crossed over to receive a programme of physiotherapy because in the opinion of the treating clinician a programme of further physiotherapy was needed. A further 42 participants self-referred to receive a programme of physiotherapy. A total of 194 participants received advice only, and there were missing data on two participants. In the group randomised to advice and further physiotherapy, 24 participants did not attend any additional appointments, 30 participants did not attend after one appointment, 167 had a complete programme of physiotherapy and 18 were receiving ongoing management after the 4-month period. There were three participants with missing data. There was no evidence of a statistically significant difference in OSIS between advice only and advice plus a programme of physiotherapy in the 6-month primary outcome, for the primary intention-to-treat adjusted analysis [favours physiotherapy: 1.5, 95% confidence interval (CI) −0.30 to 3.5] or at earlier 3-month and 6-week time points. At each time point the direction of change favoured a programme of physiotherapy; however, the 95% CI at each time point excluded our target four-point difference on the OSIS. There were no statistically significant differences in the QuickDASH or consistent differences in the EQ-5D-5L secondary outcomes. Secondary unadjusted and per-protocol analyses, and a sensitivity analysis accounting for missingness, were not materially different. Predefined subgroup analyses were undertaken to assess whether there was evidence that the intervention effect differed between age group (≤ 39 years old and ≥ 40 years old) and arm dominance. Our predefined subgroup analyses showed no evidence of clinically relevant effects from either age or arm dominance. Predefined complications profiles were similar across the two groups. In the advice group, there were reports of 7 shoulder re-dislocations, 3 frozen shoulders, 8 compression fractures of the shoulder, 22 rotator cuff tears and 1 report of nerve damage. In the additional physiotherapy group, there were 3 shoulder re-dislocations, 7 frozen shoulders, 21 rotator cuff tears and 4 compression fractures of the shoulder. Participants randomised to a programme of physiotherapy had non-significant increase in quality of life of 0.019 quality-adjusted life-years (QALYs) (95% CI −0.0005 to 0.0375) at a small, non-significant increased cost of £64 (95% CI −61 to 191) over the follow-up period. The probability of being cost-effective at a willingness-to-pay threshold of £30,000 was 0.946. Sensitivity analyses, including complete cases only and including broader societal costs, provided similar findings. Thirty-one participants were interviewed from both arms of the trial: ARTISAN [n = 16, 8 male and 8 female, mean age 49 years (standard deviation 21 years)] and ARTISAN Plus [n = 15, 11 male and 4 female, mean age 59 years (standard deviation 17 years)]. Four interlinked themes emerged from the data: (1) feelings about their shoulder rehabilitation outcome; (2) judgement of ARTISAN rehabilitation materials; (3) assessment of shoulder rehabilitation services provision; and (4) experiences of involvement in ARTISAN. The data reveal that generally across both arms of the trial, participants’ experiences were good. There are a number of areas where there are differences related to age and participants’ requirements to return to sporting activities. In terms of recovery following their rehabilitation journey, there is a trend towards a more positive outcome reported by those in the ARTISAN Plus arm of the trial. Conclusions We found little difference in the primary outcome (OSIS) or other secondary outcomes. Advice with additional physiotherapy sessions is cost-effective at a £30,000/QALY threshold. However, the small imprecise health gains raise questions on whether it is the best use of scarce physiotherapy resources given current service demands. The ARTISAN trial is the largest RCT for the common shoulder dislocation. The study recruited 482 participants, across 41 NHS Trusts and using 96 ARTISAN-trained physiotherapists, making the sample representative of NHS patients. Adherence to trial groups was high, with 99% in the advice group being offered advice only and 100% in the additional physiotherapy group being offered additional physiotherapy. The advice-only intervention was delivered by physiotherapists and crucially did not prohibit patients from self-referring back to the service if recovery did not meet their expectations. With this mechanism in place, 18% (42/240) self-referred back to the service. Empowering people to make their own treatment decisions was acceptable to clinicians (99% adherence) and allows flexibility for patients to decide when additional supervised treatment is required. It is acknowledged that there will be circumstances where additional supervised physiotherapy is appropriate; however, as a default referral pathway, it is not clinically superior to an advice-only intervention. The ARTISAN trial found evidence that there is little difference between referring people to a programme of physiotherapy or to a single session of advice with a physiotherapist. However, people who are not experiencing recovery as expected could self-refer for a supervised programme of physiotherapy. This will provide a balance between best use of NHS resources, empowering patients, and reducing unnecessary appointments for those who can self-manage. Further research should be directed towards optimising self-management strategies. Study registration This study is registered as ISRCTN63184243. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/167/56) and is published in full in Health Technology Assessment; Vol. 28, No. 22. See the NIHR Funding and Awards website for further award information.

Aims: The PARAMEDIC-3 trial evaluates the clinical and cost-effectiveness of an intraosseous first strategy, compared with an intravenous first strategy, for drug administration in adults who have sustained an out-of-hospital cardiac arrest. Methods: PARAMEDIC-3 is a pragmatic, allocation concealed, open-label, multi-centre, superiority randomised controlled trial. It will recruit 15,000 patients across English and Welsh ambulance services. Adults who have sustained an out-of-hospital cardiac arrest are individually randomised to an intraosseous access first strategy or intravenous access first strategy in a 1:1 ratio through an opaque, sealed envelope system. The randomised allocation determines the route used for the first two attempts at vascular access. Participants are initially enrolled under a deferred consent model.The primary clinical-effectiveness outcome is survival at 30-days. Secondary outcomes include return of spontaneous circulation, neurological functional outcome, and health-related quality of life. Participants are followed-up to six-months following cardiac arrest. The primary health economic outcome is incremental cost per quality-adjusted life year gained. Conclusion: The PARAMEDIC-3 trial will provide key information on the clinical and cost-effectiveness of drug route in out-of-hospital cardiac arrest.Trial registration: ISRCTN14223494, registered 16/08/2021, prospectively registered.

Introduction The number of robotic-assisted hip replacement procedures has expanded globally with the intended aim of improving outcomes. Intraoperative robotic-arm systems add additional costs to total hip replacement (THR) surgery but may improve surgical precision and could contribute to diminished pain and improved function. Additionally, these systems may reduce the need for expensive revision surgery. Surgery with conventional instruments may be just as successful, quick and affordable. There is timely demand for a robust evaluation of this technology.Methods and analysis The Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial for Hips (RACER-Hip) is a multicentre (minimum of six UK sites), participant–assessor blinded, randomised controlled trial. 378 participants with hip osteoarthritis requiring THR will be randomised (1:1) to receive robotic-assisted THR, or THR using conventional surgical instruments. The primary outcome is the Forgotten Joint Score at 12 months post-randomisation; a patient-reported outcome measure assessing participants’ awareness of their joint when undertaking daily activities. Secondary outcomes will be collected post-operatively (pain, blood loss and opioid usage) and at 3, 6, 12, 24 months, then 5 and 10 years postrandomisation (including function, pain, health-related quality of life, reoperations and satisfaction). Allocation concealment will be accomplished using a computer-based randomisation procedure on the day of surgery. Blinding methods include the use of sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will adhere to Consolidated Standards of Reporting Trials statements.Ethics and dissemination The trial was approved by an ethics committee (Solihull Research Ethics Committee, 30 June 2021, IRAS: 295831). Participants will provide informed consent before agreeing to participate. Results will be disseminated using peer-reviewed journal publications, presentations at international conferences and through the use of social media. We will develop plans to disseminate to patients and public with our patient partners.Trial registration number ISRCTN13374625.

Survival from in-hospital cardiac arrest is approximately 18%, but for patients who require advanced airway management survival is lower. Those who do survive are often left with significant disability. Traditionally, resuscitation of cardiac arrest patients has included tracheal intubation, however insertion of a supraglottic airway has gained popularity as an alternative approach to advanced airway management. Evidence from out-of-hospital cardiac arrest suggests no significant differences in mortality or morbidity between these two approaches, but there is no randomised evidence for airway management during in-hospital cardiac arrest.The aim of the AIRWAYS-3 randomised trial, described in this protocol paper, is to determine the clinical and cost effectiveness of a supraglottic airway versus tracheal intubation during in-hospital cardiac arrest. Patients will be allocated randomly to receive either a supraglottic airway or tracheal intubation as the initial advanced airway management. We will also estimate the relative cost-effectiveness of these two approaches. The primary outcome is functional status, measured using the modified Rankin Scale at hospital discharge or 30 days post-randomisation, whichever occurs first.AIRWAYS-3 presents ethical challenges regarding patient consent and data collection. These include the enrolment of unconscious patients without prior consent in a way that avoids methodological bias. Other complexities include the requirement to randomise patients efficiently during a time-critical cardiac arrest. Many of these challenges are encountered in other emergency care research; we discuss our approaches to addressing them.Trial registration: ISRCTN17720457. Prospectively registered on 29/07/2022.

Abstract Background Antimicrobial resistance is a leading global public health threat, with inappropriate use of antimicrobials in healthcare contributing to its development. Given this urgent need, we developed a complex ePrescribing-based Anti-Microbial Stewardship intervention (ePAMS+). Methods ePAMS+ includes educational and organisational behavioural elements, plus guideline-based clinical decision support to aid optimal antimicrobial use in hospital inpatients. ePAMS+ particularly focuses on prompt initiation of antimicrobials, followed by early review once test results are available to facilitate informed decision-making on stopping or switching where appropriate. A mixed-methods feasibility trial of ePAMS+ will take place in two NHS acute hospital care organisations. Qualitative staff interviews and observation of practice will respectively gather staff views on the technical component of ePAMS+ and information on their use of ePAMS+ in routine work. Focus groups will elicit staff and patient views on ePAMS+; one-to-one interviews will discuss antimicrobial stewardship with staff and will record patient experiences of receiving antibiotics and their thoughts on inappropriate prescribing. Qualitative data will be analysed thematically. Fidelity Index development will enable enactment of ePAMS+ to be measured objectively in a subsequent trial assessing the effectiveness of ePAMS+. Quantitative data collection will determine the feasibility of extracting data and deriving key summaries of antimicrobial prescribing; we will quantify variability in the primary outcome, number of antibiotic defined daily doses, to inform the future larger-scale trial design. Discussion This trial is essential to determine the feasibility of implementing the ePAMS+ intervention and measuring relevant outcomes, prior to evaluating its clinical and cost-effectiveness in a full scale hybrid cluster-randomised stepped-wedge clinical trial. Findings will be shared with study sites and with qualitative research participants and will be published in peer-reviewed journals and presented at academic conferences. Trial registration The qualitative and Fidelity Index research were approved by the Health and Research Authority and the North of Scotland Research Ethics Service (ref: 19/NS/0174). The feasibility trial and quantitative analysis (protocol v1.0, 15 December 2021) were approved by the London South East Research Ethics Committee (ref: 22/LO/0204) and registered with ISRCTN ( ISRCTN 13429325 ) on 24 March 2022

Abstract Background Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. Methods Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. Results The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. Conclusions The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

Phase-change nanodroplets have attracted increasing interest in recent years as ultrasound theranostic nanoparticles. They are smaller compared to microbubbles and they may distribute better in tissues (e.g. in tumours). They are composed of a stabilising shell and a perfluorocarbon core. Nanodroplets can vaporise into echogenic microbubbles forming cavitation nuclei when exposed to ultrasound. Their perfluorocarbon core phase-change is responsible for the acoustic droplet vaporisation. However, methods to quantify the perfluorocarbon core in nanodroplets are lacking. This is an important feature that can help explain nanodroplet phase change characteristics. In this study, we fabricated nanodroplets using lipids shell and perfluorocarbons. To assess the amount of perfluorocarbon in the core we used two methods, 19F NMR and FTIR. To assess the cavitation after vaporisation we used an ultrasound transducer (1.1 MHz) and a high-speed camera. The 19F NMR based method showed that the fluorine signal correlated accurately with the perfluorocarbon concentration. Using this correlation, we were able to quantify the perfluorocarbon core of nanodroplets. This method was used to assess the content of the perfluorocarbon of the nanodroplets in solutions over time. It was found that perfluoropentane nanodroplets lost their content faster and at higher ratio compared to perfluorohexane nanodroplets. The high-speed imaging indicates that the nanodroplets generate cavitation comparable to that from commercial contrast agent microbubbles. Nanodroplet characterisation should include perfluorocarbon concentration assessment as critical information for their development.

Introduction Robotic-assisted knee replacement systems have been introduced to healthcare services worldwide in an effort to improve clinical outcomes for people, although high-quality evidence that they are clinically, or cost-effective remains sparse. Robotic-arm systems may improve surgical accuracy and could contribute to reduced pain, improved function and lower overall cost of total knee replacement (TKR) surgery. However, TKR with conventional instruments may be just as effective and may be quicker and cheaper. There is a need for a robust evaluation of this technology, including cost-effectiveness analyses using both within-trial and modelling approaches. This trial will compare robotic-assisted against conventional TKR to provide high-quality evidence on whether robotic-assisted knee replacement is beneficial to patients and cost-effective for healthcare systems.Methods and analysis The Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial-Knee is a multicentre, participant-assessor blinded, randomised controlled trial to evaluate the clinical and cost-effectiveness of robotic-assisted TKR compared with TKR using conventional instruments. A total of 332 participants will be randomised (1:1) to provide 90% power for a 12-point difference in the primary outcome measure; the Forgotten Joint Score at 12 months postrandomisation. Allocation concealment will be achieved using computer-based randomisation performed on the day of surgery and methods for blinding will include sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will be reported in line with the Consolidated Standards of Reporting Trials statement. A parallel study will collect data on the learning effects associated with robotic-arm systems.Ethics and dissemination The trial has been approved by an ethics committee for patient participation (East Midlands—Nottingham 2 Research Ethics Committee, 29 July 2020. NRES number: 20/EM/0159). All results from the study will be disseminated using peer-reviewed publications, presentations at international conferences, lay summaries and social media as appropriate.Trial registration number ISRCTN27624068.

Aims: To compare the cost-utility of removable brace compared with cast in the management of adult patients with ankle fracture. Methods: A within-trial economic evaluation conducted from the UK NHS and personnel social services (PSS) perspective. Health resources and quality-of-life data were collected as part of the Ankle Injury Rehabilitation (AIR) multicentre, randomized controlled trial over a 12-month period using trial case report forms and patient-completed questionnaires. Cost-utility analysis was estimated in terms of the incremental cost per quality adjusted life year (QALY) gained. Estimate uncertainty was explored by bootstrapping, visualized on the incremental cost-effectiveness ratio plane. Net monetary benefit and probability of cost-effectiveness were evaluated at a range of willingness-to-pay thresholds and visualized graphically. Results: The incremental cost and QALYs of using brace over a 12-month period were £46.73 (95% confidence interval (CI) £-9 to £147) and 0.0141 (95% CI -0.005 to 0.033), respectively. The cost per QALY gained was £3,318. The probability of brace being cost-effective at a £30,000 per QALY willingness-to-pay threshold was 88%. The results remained robust to a range of sensitivity analyses. Conclusion: This within-trial economic evaluation found that it is probable that using a removable brace provides good value to the NHS when compared to cast, in the management of adults with ankle fracture. Cite this article: Bone Jt Open 2022;3(6):455–462.

The tumor microenvironment is crucial in the initiation and progression of cancers. The interplay between cancer cells and the surrounding stroma shapes the tumor biology and dictates the response to cancer therapies. Consequently, a better understanding of the interactions between cancer cells and different components of the tumor microenvironment will drive progress in developing novel, effective, treatment strategies. Co-cultures can be used to study various aspects of these interactions in detail. This includes studies of paracrine relationships between cancer cells and stromal cells such as fibroblasts, endothelial cells, and immune cells, as well as the influence of physical and mechanical interactions with the extracellular matrix of the tumor microenvironment. The development of novel co-culture models to study the tumor microenvironment has progressed rapidly over recent years. Many of these models have already been shown to be powerful tools for further understanding of the pathophysiological role of the stroma and provide mechanistic insights into tumor-stromal interactions. Here we give a structured overview of different co-culture models that have been established to study tumor-stromal interactions and what we have learnt from these models. We also introduce a set of guidelines for generating and reporting co-culture experiments to facilitate experimental robustness and reproducibility.

This paper provides a comprehensive overview of the history of commercial poultry breeding, from domestication to the development of science and commercial breeding structures. The development of breeding goals over time, from mainly focusing on production to broad goals, including bird welfare and health, robustness, environmental impact, biological efficiency and reproduction, is detailed. The paper outlines current breeding goals, including traits (e.g., on foot and leg health, contact dermatitis, gait, cardiovascular health, robustness and livability), recording techniques, their genetic basis and how trait these antagonisms, for example, between welfare and production, are managed. Novel areas like genomic selection and gut health research and their current and potential impact on breeding are highlighted. The environmental impact differences of various genotypes are explained. A future outlook shows that balanced, holistic breeding will continue to enable affordable lean animal protein to feed the world, with a focus on the welfare of the birds and a diversity of choice for the various preferences and cultures across the world.

Abstract Background Supervised cardio-pulmonary rehabilitation may be safe and beneficial for people with pulmonary hypertension (PH) in groups 1 (pulmonary arterial hypertension) and 4 (chronic thromboembolic disease), particularly as a hospital in-patient. It has not been tested in the most common PH groups; 2 (left heart disease), 3 (lung disease), or 5 (other disorders). Further it has not been evaluated in the UK National Health Service (NHS) out-patient setting, or with long-term follow-up. The aim of this randomised controlled trial (RCT) is to test the clinical and cost-effectiveness of a supervised exercise rehabilitation intervention with psychosocial support compared to best practice usual care for people with PH in the community/outpatient setting. Methods This multi-centre, pragmatic, two-arm RCT with embedded process evaluation aims to recruit 352 clinically stable adults with PH (groups 1–5) and WHO functional class II-IV. Participants will be randomised to either the Supervised Pulmonary Hypertension Exercise Rehabilitation (SPHERe) intervention or control. The SPHERe intervention consists of 1) individual assessment and familiarisation sessions; 2) 8-week, twice-weekly, supervised out-patient exercise training; 3) psychosocial/motivational support and education; 4) guided home exercise plan. The control intervention consists of best practice usual care with a single one-to-one practitioner appointment, and general advice on physical activity. Outcomes will be measured at baseline, 4 months (post-intervention) and 12 months by researchers blinded to treatment allocation. The primary outcome is the incremental shuttle walk test at 4 months. Secondary outcomes include health-related quality of life (HRQoL), time to clinical worsening and health and social care use. A purposive sample of participants (n = 20 intervention and n = 20 control) and practitioners (n = 20) will be interviewed to explore experiences of the trial, outcomes and interventions. Discussion The SPHERe study is the first multi-centre clinical RCT to assess the clinical and cost effectiveness of a supervised exercise rehabilitation intervention compared to usual care, delivered in the UK NHS, for people in all PH groups. Results will inform clinicians and commissioners as to whether or not supervised exercise rehabilitation is effective and should be routinely provided for people with PH. Trial registration ISRCTN no. 10608766 , prospectively registered on 18th March 2019.

Circulating cell-free mRNA holds great promise as a non-invasive diagnostic biomarker. Here the authors show that cell-free mRNA captures transcripts from the bone marrow and can be used to non-invasively monitor dynamic changes in bone marrow physiology.

Acquired Hemophilia A (AHA) is a very rare autoimmune condition involving immune-mediated depletion of Factor VIII, resulting in spontaneous hemorrhage. Failure to recognize AHA as a possible etiology of hemorrhage can result in delayed diagnosis and treatment. The COVID-19 pandemic has given rise to several hematologic conditions and complications, with a rare manifestation being Acquired Hemophilia A (AHA). An interesting case of AHA following SARS-CoV-2 infection is described, along with the treatment approach and a brief review of several cases describing AHA in association with COVID-19.

Abstract Background There is widespread concern across the clinical and research communities that clinical trials, powered for patient-reported outcomes, testing new surgical procedures are often expensive and time-consuming, particularly when the new intervention is shown to be no better than the standard. Conventional (non-adaptive) randomised controlled trials (RCTs) are perceived as being particularly inefficient in this setting. Therefore, we have developed an adaptive group sequential design that allows early endpoints to inform decision making and show, through simulations and a worked example, that these designs are feasible and often preferable to conventional non-adaptive designs. The methodology is motivated by an ongoing clinical trial investigating a saline-filled balloon, inserted above the main joint of the shoulder at the end of arthroscopic debridement, for treatment of tears of rotor cuff tendons. This research question and setting is typical of many studies undertaken to assess new surgical procedures. Methods Test statistics are presented based on the setting of two early outcomes, and methods for estimation of sequential stopping boundaries are described. A framework for the implementation of simulations to evaluate design characteristics is also described. Results Simulations show that designs with one, two and three early looks are feasible and, with appropriately chosen futility stopping boundaries, have appealing design characteristics. A number of possible design options are described that have good power and a high probability of stopping for futility if there is no evidence of a treatment effect at early looks. A worked example, with code in R, provides a practical demonstration of how the design might work in a real study. Conclusions In summary, we show that adaptive designs are feasible and could work in practice. We describe the operating characteristics of the designs and provide guidelines for appropriate values for the stopping boundaries for the START:REACTS (Sub-acromial spacer for Tears Affecting Rotator cuff Tendons: a Randomised, Efficient, Adaptive Clinical Trial in Surgery) study. Trial registration ISRCTN Registry, ISRCTN17825590. Registered on 5 March 2018.

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.

Background: Chronic constipation affects 1–2% of adults and significantly affects quality of life. Beyond the use of laxatives and other basic measures, there is uncertainty about management, including the value of specialist investigations, equipment-intensive therapies using biofeedback, transanal irrigation and surgery. Objectives: (1) To determine whether or not standardised specialist-led habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback is more clinically effective than standardised specialist-led habit training alone, and whether or not outcomes of such specialist-led interventions are improved by stratification to habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback or habit training alone based on prior knowledge of anorectal and colonic pathophysiology using standardised radiophysiological investigations; (2) to compare the impact of transanal irrigation initiated with low-volume and high-volume systems on patient disease-specific quality of life; and (3) to determine the clinical efficacy of laparoscopic ventral mesh rectopexy compared with controls at short-term follow-up. Design: The Chronic Constipation Treatment Pathway (CapaCiTY) research programme was a programme of national recruitment with a standardised methodological framework (i.e. eligibility, baseline phenotyping and standardised outcomes) for three randomised trials: a parallel three-group trial, permitting two randomised comparisons (CapaCiTY trial 1), a parallel two-group trial (CapaCiTY trial 2) and a stepped-wedge (individual-level) three-group trial (CapaCiTY trial 3). Setting: Specialist hospital centres across England, with a mix of urban and rural referral bases. Participants: The main inclusion criteria were as follows: age 18–70 years, participant self-reported problematic constipation, symptom onset > 6 months before recruitment, symptoms meeting the American College of Gastroenterology’s constipation definition and constipation that failed treatment to a minimum basic standard. The main exclusion criteria were secondary constipation and previous experience of study interventions. Interventions: CapaCiTY trial 1: group 1 – standardised specialist-led habit training alone (n = 68); group 2 – standardised specialist-led habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback (n = 68); and group 3 – standardised radiophysiological investigations-guided treatment (n = 46) (allocation ratio 3 : 3 : 2, respectively). CapaCiTY trial 2: transanal irrigation initiated with low-volume (group 1, n = 30) or high-volume (group 2, n = 35) systems (allocation ratio 1 : 1). CapaCiTY trial 3: laparoscopic ventral mesh rectopexy performed immediately (n = 9) and after 12 weeks’ (n = 10) and after 24 weeks’ (n = 9) waiting time (allocation ratio 1 : 1 : 1, respectively). Main outcome measures: The main outcome measures were standardised outcomes for all three trials. The primary clinical outcome was mean change in Patient Assessment of Constipation Quality of Life score at the 6-month, 3-month or 24-week follow-up. The secondary clinical outcomes were a range of validated disease-specific and psychological scoring instrument scores. For cost-effectiveness, quality-adjusted life-year estimates were determined from individual participant-level cost data and EuroQol-5 Dimensions, five-level version, data. Participant experience was investigated through interviews and qualitative analysis. Results: A total of 275 participants were recruited. Baseline phenotyping demonstrated high levels of symptom burden and psychological morbidity. CapaCiTY trial 1: all interventions (standardised specialist-led habit training alone, standardised specialist-led habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback and standardised radiophysiological investigations-guided habit training alone or habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback) led to similar reductions in the Patient Assessment of Constipation Quality of Life score (approximately –0.8 points), with no statistically significant difference between habit training alone and habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback (–0.03 points, 95% confidence interval –0.33 to 0.27 points; p = 0.8445) or between standardised radiophysiological investigations and no standardised radiophysiological investigations (0.22 points, 95% confidence interval –0.11 to 0.55 points; p = 0.1871). Secondary outcomes reflected similar levels of benefit for all interventions. There was no evidence of greater cost-effectiveness of habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback or stratification by standardised radiophysiological investigations compared with habit training alone (with the probability that habit training alone is cost-effective at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year gain; p = 0.83). Participants reported mixed experiences and similar satisfaction in all groups in the qualitative interviews. CapaCiTY trial 2: at 3 months, there was a modest reduction in the Patient Assessment of Constipation Quality of Life score, from a mean of 2.4 to 2.2 points (i.e. a reduction of 0.2 points), in the low-volume transanal irrigation group compared with a larger mean reduction of 0.6 points in the high-volume transanal irrigation group (difference –0.37 points, 95% confidence interval –0.89 to 0.15 points). The majority of participants preferred high-volume transanal irrigation, with substantial crossover to high-volume transanal irrigation during follow-up. Compared with low-volume transanal irrigation, high-volume transanal irrigation had similar costs (median difference –£8, 95% confidence interval –£240 to £221) and resulted in significantly higher quality of life (0.093 quality-adjusted life-years, 95% confidence interval 0.016 to 0.175 quality-adjusted life-years). CapaCiTY trial 3: laparoscopic ventral mesh rectopexy resulted in a substantial short-term mean reduction in the Patient Assessment of Constipation Quality of Life score (–1.09 points, 95% confidence interval –1.76 to –0.41 points) and beneficial changes in all other outcomes; however, significant increases in cost (£5012, 95% confidence interval £4446 to £5322) resulted in only modest increases in quality of life (0.043 quality-adjusted life-years, 95% confidence interval –0.005 to 0.093 quality-adjusted life-years), with an incremental cost-effectiveness ratio of £115,512 per quality-adjusted life-year. Conclusions: Excluding poor recruitment and underpowering of clinical effectiveness analyses, several themes emerge: (1) all interventions studied have beneficial effects on symptoms and disease-specific quality of life in the short term; (2) a simpler, cheaper approach to nurse-led behavioural interventions appears to be at least as clinically effective as and more cost-effective than more complex and invasive approaches (including prior investigation); (3) high-volume transanal irrigation is preferred by participants and has better clinical effectiveness than low-volume transanal irrigation systems; and (4) laparoscopic ventral mesh rectopexy in highly selected participants confers a very significant short-term reduction in symptoms, with low levels of harm but little effect on general quality of life. Limitations: All three trials significantly under-recruited [CapaCiTY trial 1, n = 182 (target 394); CapaCiTY trial 2, n = 65 (target 300); and CapaCiTY trial 3, n = 28 (target 114)]. The numbers analysed were further limited by loss before primary outcome. Trial registration: Current Controlled Trials ISRCTN11791740, ISRCTN11093872 and ISRCTN11747152. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 14. See the NIHR Journals Library website for further project information.

Abstract Objectives The primary objective is to determine which of two interventions: 1) an eight week, online, home-based, supervised, group rehabilitation programme (REGAIN); or 2) a single online session of advice (best-practice usual care); is the most clinically and cost-effective treatment for people with ongoing COVID-19 sequelae more than three months after hospital discharge. Trial design Multi-centre, 2-arm (1:1 ratio) parallel group, randomised controlled trial with embedded process evaluation and health economic evaluation. Participants Adults with ongoing COVID-19 sequelae more than three months after hospital discharge Inclusion criteria: 1) Adults ≥18 years; 2) ≥ 3 months after any hospital discharge related to COVID-19 infection, regardless of need for critical care or ventilatory support; 3) substantial (as defined by the participant) COVID-19 related physical and/or mental health problems; 4) access to, and able/supported to use email and internet audio/video; 4) able to provide informed consent; 5) able to understand spoken and written English, Bengali, Gujarati, Urdu, Punjabi or Mandarin, themselves or supported by family/friends. Exclusion criteria: 1) exercise contraindicated; 2) severe mental health problems preventing engagement; 3) previous randomisation in the present study; 4) already engaged in, or planning to engage in an alternative NHS rehabilitation programme in the next 12 weeks; 5) a member of the same household previously randomised in the present study. Intervention and comparator Intervention 1: The Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN (REGAIN) programme: an eight week, online, home-based, supervised, group rehabilitation programme. Intervention 2: A thirty-minute, on-line, one-to-one consultation with a REGAIN practitioner (best-practice usual care). Main outcomes The primary outcome is health-related quality of life (HRQoL) – PROMIS® 29+2 Profile v2.1 (PROPr) – measured at three months post-randomisation. Secondary outcomes include dyspnoea, cognitive function, health utility, physical activity participation, post-traumatic stress disorder (PTSD) symptom severity, depressive and anxiety symptoms, work status, health and social care resource use, death - measured at three, six and 12 months post-randomisation. Randomisation Participants will be randomised to best practice usual care or the REGAIN programme on a 1:1.03 basis using a computer-generated randomisation sequence, performed by minimisation and stratified by age, level of hospital care, and case level mental health symptomatology. Once consent and baseline questionnaires have been completed by the participant online at home, randomisation will be performed automatically by a bespoke web-based system. Blinding (masking) To ensure allocation concealment from both participant and REGAIN practitioner at baseline, randomisation will be performed only after the baseline questionnaires have been completed online at home by the participant. After randomisation has been performed, participants and REGAIN practitioners cannot be blind to group allocation. Follow-up outcome assessments will be completed by participants online at home. Numbers to be randomised (sample size) A total of 535 participants will be randomised: 263 to the best-practice usual care arm, and 272 participants to the REGAIN programme arm. Trial Status Current protocol: Version 3.0 (27th October 2020) Recruitment will begin in December 2020 and is anticipated to complete by September 2021. Trial registration ISRCTN:11466448 , 23rd November 2020 Full protocol The full protocol Version 3.0 (27th October 2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death that typically presents at an advanced stage. No reliable markers for early detection presently exist. The prominent tumor stroma represents a source of circulating biomarkers for use together with cancer cell-derived biomarkers for earlier PDAC diagnosis. CA19-9 and CEA (cancer cell-derived biomarkers), together with endostatin and collagen IV (stroma-derived) were examined alone, or together, by multivariable modelling, using pre-diagnostic plasma samples (n = 259 samples) from the Northern Sweden Health and Disease Study biobank. Serial samples were available for a subgroup of future patients. Marker efficacy for future PDAC case prediction (n = 154 future cases) was examined by both cross-sectional (ROC analysis) and longitudinal analyses. CA19-9 performed well at, and within, six months to diagnosis and multivariable modelling was not superior to CA19-9 alone in cross-sectional analysis. Within six months to diagnosis, CA19-9 (AUC = 0.92) outperformed the multivariable model (AUC = 0.81) at a cross-sectional level. At diagnosis, CA19-9 (AUC = 0.995) and the model (AUC = 0.977) performed similarly. Longitudinal analysis revealed increases in CA19-9 up to two years to diagnosis which indicates a window of opportunity for early detection of PDAC.

Background: Lewy body dementia, comprising both dementia with Lewy bodies and Parkinson’s disease dementia, is the second commonest cause of neurodegenerative dementia. Existing evidence suggests that it is underdiagnosed and without a consistent approach to management. Objectives: To improve the diagnosis and management of Lewy body dementia by (1) understanding current diagnostic practice for dementia with Lewy bodies and Parkinson’s disease dementia; (2) identifying barriers to and facilitators of diagnosis and management; (3) developing evidence-based assessment toolkits to improve diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia; (4) producing a management toolkit to facilitate management; and (5) undertaking a pilot cluster randomised clinical trial. Design: Work package 1 assessed clinical diagnostic rates from case notes for dementia with Lewy bodies and Parkinson’s disease dementia before and after (work package 1 repeated) introduction of an assessment toolkit. In work package 2, we developed a management toolkit for Lewy body dementia. In work package 3, we developed assessment toolkits for dementia with Lewy bodies and Parkinson’s disease dementia and piloted these and the management toolkit in a clinical service. In work package 4, we undertook a pilot study of 23 services in nine NHS trusts that were cluster randomised to receiving and using the management toolkit or standard care. Work package 5 comprised a series of qualitative studies, examining barriers to and facilitators of diagnosis and management. Setting: Secondary care memory assessment and movement disorder services in England. Interventions: Assessment toolkits for Lewy body dementia consisted of questions for diagnostic symptoms, and management toolkits comprised 161 guidance statements grouped under five symptom domains. Review methods: The systematic reviews of pharmacological and non-pharmacological management were based on published literature, with meta-analysis when possible, following a search of several electronic databases and the grey literature using terms related to Lewy body dementia, without restriction on time or language. Participants: Participants aged ≥ 50 years diagnosed with dementia with Lewy bodies or Parkinson’s disease dementia and, for work package 1 and work package 1 repeated, non-dementia with Lewy bodies and non-Parkinson’s disease dementia controls. The qualitative studies included people with Lewy body dementia, carers and professionals. Main outcome measures: For work packages 1 and 1 repeated, diagnostic rates for dementia with Lewy bodies and Parkinson’s disease dementia as a proportion of all dementia or Parkinson’s disease. For work packages 2 and 3, the production of diagnostic and management toolkits. For work package 4, feasibility of undertaking a cluster randomised trial of the toolkits, measured by number of participants recruited and use of the toolkits, assessed qualitatively. Results: Work package 1 – 4.6% of dementia cases in secondary care received a dementia with Lewy bodies diagnosis (with significant differences in diagnostic rates between services) and 9.7% of those with Parkinson’s disease had a diagnosis of Parkinson’s disease dementia. There was evidence of delays in diagnosis for both dementia with Lewy bodies and Parkinson’s disease dementia compared with control patients, and the costs of dementia with Lewy bodies and Parkinson’s disease dementia were also greater than those for matched controls (p 80% were retained in the study at 6 months. Work package 5 – barriers to diagnosis and management of Lewy body dementia were complex. Managing Lewy body dementia often requires input from a range of specialties and, therefore, care pathways may be fragmented. Positive attitudes to diagnosing Lewy body dementia, working with a team with expertise in Lewy body dementia and opportunities for cross-specialty discussion of patients with complex needs facilitated diagnosis and management. The toolkits were generally well received, particularly the management toolkit. Implementation, however, varied, reflecting differences in attitudes, skills, time and local leadership. Work package 1 repeated – following introduction of the assessment toolkit, we found that 9.7% of dementia cases had dementia with Lewy bodies (a significant increase from baseline; p = 0.0019), but Parkinson’s disease dementia rates were similar (8.2%) to baseline. Limitations: We included only two geographical regions and evidence informing the management toolkit was limited. Work package 4 was a pilot study and, therefore, we did not set out to assess the extent to which use of the management toolkit altered outcomes at the individual patient level. We noted implementation of the toolkits was variable. The increase in diagnostic rates in dementia with Lewy bodies following introduction of the assessment toolkits cannot be necessarily causally attributed to them. Conclusions: Dementia with Lewy bodies and Parkinson’s disease dementia were diagnosed in secondary care NHS services, with a lower frequency (around half) than that expected from known prevalence rates. The introduction of assessment toolkits for dementia with Lewy bodies and Parkinson’s disease dementia was associated with increased diagnostic rates of dementia with Lewy bodies, but not Parkinson’s disease dementia. Qualitative studies indicated inherent complexities of the disease itself, with treatment requiring input from different specialties and the potential for fragmented services, a workforce with variable training and confidence in Lewy body dementia, and negative attitudes towards diagnosis. The cluster randomised pilot trial demonstrated that patients could be successfully recruited, and provided preliminary evidence that the toolkits could be implemented in clinical services. Future work: The evidence base informing the management of Lewy body dementia is limited, especially for non-pharmacological interventions. More well-designed randomised controlled trials for both cognitive and non-cognitive symptoms are needed. Trial registration: Current Controlled Trials ISRCTN11083027. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 7. See the NIHR Journals Library website for further project information.

The increasing adoption of Local Area Coordination across the United Kingdom as a strengths-based approach to acting on inequalities which impact on individual health and well-being, and reducing reliance and avoidable use of health and social care services, has catalysed increasing calls for evidence to justify economic commitment. In a time of austerity where extreme pressure is on resources to prove short-term outputs, Pawson and Tilley’s realist evaluation methodology holds significant promise in asking critical questions of how and why programmes work. Ultimately, such philosophical standpoints facilitate opportunities to examine whether the sustainability of programmes are cost-effective for the system in the longer term. This article draws upon the findings of a realist evaluation of Local Area Coordination on the Isle of Wight and establishes how and why the programme works for people and local communities. A blend of realist approaches, Q-method and realist interviews were adopted within this study. The study’s sample was a cross section of 18 people who engaged with the Local Area Coordination programme across the Isle of Wight. The findings of the evaluation established that the Local Area Coordinators’ ability to facilitate a ‘golden triangle’ of listening, trust and time were factors which made Local Area Coordination work. It was also clear that Local Area Coordination worked for different people in different ways, demonstrated through the contextual differences between three subgroups who were categorised based on shared viewpoints, and presented through the holistic narratives and corroborating interview data.

Objective To compare clinical and health economic outcomes after manubrium-limited mini-sternotomy (intervention) and conventional median sternotomy (usual care).Design A single-blind, randomised controlled trial.Setting Single centre UK National Health Service tertiary hospital.Participants Adult patients undergoing aortic valve replacement (AVR) surgery.Interventions Intervention was manubrium-limited mini-sternotomy performed using a 5–7 cm midline incision. Usual care was median sternotomy performed using a midline incision from the sternal notch to the xiphisternum.Primary and secondary outcome measures The primary outcome was the proportion of patients who received a red cell transfusion postoperatively and within 7 days of index surgery. Secondary outcomes included proportion of patients receiving a non-red cell blood component transfusion and number of units transfused within 7 days and during index hospital stay, quality of life and cost-effectiveness analyses.Results 270 patients were randomised, received surgery and contributed to the intention to treat analysis. No difference between mini and conventional sternotomy in red-cell transfusion within 7 days was found; 23/135 patients in each arm received a transfusion, OR 1.0 (95% CI 0.5 to 2.0) and risk difference 0.0 (95% CI −0.1 to 0.1). Mini-sternotomy reduced chest drain losses (mean 181.6 mL (SD 138.7) vs conventional, mean 306·9 mL (SD 348.6)); this did not reduce red-cell transfusions. Mean valve size and postoperative valve function were comparable between mini-sternotomy and conventional groups; 23 mm vs 24 mm and 6/134 moderate or severe aortic regurgitation vs 3/130, respectively. Mini-sternotomy resulted in longer bypass (82.7 min (SD 23.5) vs 59.6 min (SD 15.1)) and cross-clamp times (64.1 min (SD 17.1) vs 46·3 min (SD 10.7)). Conventional sternotomy was more cost-effective with only a 5.8% probability of mini-sternotomy being cost-effective at a willingness to pay of £20 000/QALY (Quality Adjusted Life Years).Conclusions AVR via mini-sternotomy did not reduce red blood cell transfusion within 7 days following surgery when compared with conventional sternotomy.Trial registration number ISRCTN29567910; Results.

Introduction First-time traumatic anterior shoulder dislocation (TASD) is predominantly managed non-operatively. People sustaining TASD have ongoing pain, disability and future risk of redislocation. There are no published randomised controlled trials (RCTs) comparing different non-operative rehabilitation strategies to ascertain the optimum clinically effective approach after TASD.Methods and analysis In this multicentre adaptive RCT, with internal pilot, adults with a radiologically confirmed first time TASD treated non-surgically will be screened at a minimum of 30 sites. People with neurovascular complications, bilateral dislocations or are unable to attend physiotherapy will be excluded.Randomisation will be on a 1:1 treatment allocation, stratified by age, hand dominance and site. Participants will receive a single session of advice; or a single session of advice plus offer of further physiotherapy (maximum 4 months). The primary analysis will be the difference in Oxford Shoulder Instability Score at 6 months. A sample size of a minimum of 478 participants will allow us to show a four point difference with 90% power.An embedded qualitative study will explore the participants’ experiences of the trial interventions.Ethics, registration and dissemination Funded by NIHR HTA (16/167/56), 1 June 2018; National Research Ethic Committee approved (18/WA/0236), 26 July 2018. First site opened 5 November 2018 and final results will be updated on trial registries and submitted to a peer-reviewed journal and will inform rehabilitation strategies after a TASD. Study Within A Trial (SWAT) funded by MRC (MR/R013748/1), 1 May 2019; registered on the MRC-HTMR All-Ireland Hub (reference number SWAT 121).Trial registration number ISRCTN63184243. (Trial stage: Pre-results)

Introduction Shoulder pain due to irreparable rotator cuff tears can cause substantial disability, but treatment options are limited. A balloon spacer is a relatively simple addition to a standard arthroscopic debridement procedure, but it is costly and there is no current randomised trial evidence to support its use. This trial will evaluate the clinical and cost-effectiveness of a subacromial balloon spacer for individuals undergoing arthroscopic debridement for irreparable rotator cuff tears.New surgical procedures can provide substantial benefit to patients. Good quality randomised controlled trials (RCTs) are needed, but trials in surgery are typically long and expensive, exposing patients to risk and the healthcare system to substantial costs. One way to improve the efficiency of trials is with an adaptive sample size. Such methods are well established in drug trials but have rarely, if ever, been used in surgical trials.Methods and analysis Subacromial spacer for Tears Affecting Rotator cuff Tendons: a Randomised, Efficient, Adaptive Clinical Trial in Surgery (START:REACTS) is a participant and assessor blinded, adaptive, multicentre RCT comparing arthroscopic debridement with the InSpace balloon (Stryker, USA) to arthroscopic debridement alone for people with a symptomatic irreparable rotator cuff tear. It uses a group sequential adaptive design where interim analyses are performed using all of the 3, 6 and 12-month data that are available at each time point. A maximum of 221 participants will be randomised (1:1 ratio), this will provide 90% power (at the 5% level) for a 6 point difference in the primary outcome; the Oxford Shoulder Score at 12 months. A substudy will use deltoid-active MRI scans in 56 participants to assess the function of the balloon. Analysis will be on an intention-to-treat basis and reported according to principles established in the Consolidated Standards of Reporting Trials statement.Ethics and dissemination NRES number 18/WM/0025. The results will be disseminated via peer-reviewed publications, presentations at conferences, lay summaries and social media.Trial registration number ISRCTN17825590

Abstract Background Laparoscopic ventral mesh rectopexy (LVMR) is an established treatment for external full-thickness rectal prolapse. However, its clinical efficacy in patients with internal prolapse is uncertain due to the lack of high-quality evidence. Methods An individual level, stepped-wedge randomised trial has been designed to allow observer-blinded data comparisons between patients awaiting LVMR with those who have undergone surgery. Adults with symptomatic internal rectal prolapse, unresponsive to prior conservative management, will be eligible to participate. They will be randomised to three arms with different delays before surgery (0, 12 and 24 weeks). Efficacy outcome data will be collected at equally stepped time points (12, 24, 36 and 48 weeks). The primary objective is to determine clinical efficacy of LVMR compared to controls with reduction in the Patient Assessment of Constipation Quality of Life (PAC-QOL) at 24 weeks serving as the primary outcome. Secondary objectives are to determine: (1) the clinical effectiveness of LVMR to 48 weeks to a maximum of 72 weeks; (2) pre-operative determinants of outcome; (3) relevant health economics for LVMR; (4) qualitative evaluation of patient and health professional experience of LVMR and (5) 30-day morbidity and mortality rates. Discussion An individual-level, stepped-wedge, randomised trial serves the purpose of providing an untreated comparison for the active treatment group, while at the same time allowing the waiting-listed participants an opportunity to obtain the intervention at a later date. In keeping with the basic ethical tenets of this design, the average waiting time for LVMR (12 weeks) will be shorter than that for routine services (24 weeks). Trial registration ISRCTN registry, ISRCTN11747152. Registered on 30 September 2015. The trial was prospectively registered (first patient enrolled on 21 March 2016).

Abstract Background Constipation is common in adults and up to 20% of the population report this symptom. Chronic constipation (CC), usually defined as more than 6 months of symptoms, is less common but results in 0.5 million UK GP consultations per annum. The effect of symptoms on measured quality of life (QOL) is significant, and CC consumes significant health care resources. In the UK, it is estimated that 10% of district nursing time is spent on constipation. Trans-anal irrigation therapy has become a widely used treatment despite a lack of robust efficacy data to support its use. The long-term outcome of treatment is also unclear. A randomised comparison of two different methods of irrigation (high- and low-volume) will provide valuable evidence of superiority of one system over the other, as well as providing efficacy data for the treatment as a whole. Methods Participants will be recruited based on predetermined eligibility criteria. Following informed consent, they will be randomised to either high-volume (HV) or low-volume (LV) irrigation and undergo standardised radiological and physiological investigations. Following training, they will commence home irrigation with the allocated device. Data will be collected at 1, 3, 6 and 12 months according to a standardised outcomes framework. The primary outcome is PAC-QOL, measured at 3 months. The study is powered to detect a 10% difference in outcome between systems at 3 months; this means that 300 patients will need to be recruited. Discussion This study will be the first randomised comparison of two different methods of trans-anal irrigation. It will also be the largest prospective study of CC patients treated with irrigation. It will provide evidence for the effectiveness of irrigation in the treatment of CC, as well as the comparative effectiveness of the two methods. This will enable more cost-effective and evidence-based use of irrigation. Also, the results will be combined with the other studies in the CapaCiTY programme to generate an evidence-based treatment algorithm for CC in adults. Trial registration ISRCTN, identifier: ISRCTN11093872 . Registered on 11 November 2015. Trial not retrospectively registered. Protocol version 3 (22 January 2016).

An amendment to this paper has been published and can be accessed via the original article.

Schmallenberg virus (SBV), initially identified in Germany in 2011, spread rapidly throughout Europe causing significant economic losses in ruminant livestock. The ability to correctly detect emerging and re-emerging diseases such as SBV with reliable tests is of high importance. Firstly, we tested diagnostic performance, specificity, and sensitivity of three different assays used in SBV antibody detection using control sheep samples of determined status. After obtaining the results from the control samples, we assessed the potential of the assays to detect previously infected animals in field situations. The samples were investigated using IDEXX Schmallenberg virus Antibody Test Kit, ID Screen Schmallenberg virus Competition Multi-species ELISA and Serum Neutralisation Test (SNT). Analysis of control samples revealed that SNT was the most suitable test, which was therefore used to calculate concordance and test performance for the two other ELISA tests. To evaluate whether different assay performances had an impact under field conditions, sheep samples from two different contexts were tested: the emergence of SBV in Ireland and the re-emergence of SBV in Belgium. Comparing the results obtained from different assays to the non-reference standard assay SNT, we showed considerable differences in estimates of their sensitivity to detect SBV antibodies and to measure seroprevalence of the sheep flocks. Finally, a calculation of the number of randomly selected animals that needs to be screened from a finite flock, showed that SNT and ID.Vet are the most suitable to detect an introduction of the disease in low seroprevalence situations. The IDEXX ELISA test was only able to detect SBV antibodies in a higher seroprevalence context, which is not optimal for monitoring freedom of disease and surveillance studies.

Background: Gastroenteritis is a common, transient disorder usually caused by infection and characterised by the acute onset of diarrhoea. Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously identify common bacterial, viral and parasitic pathogens using molecular testing. By providing test results more rapidly than conventional testing methods, GPP tests might positively influence the treatment and management of patients presenting in hospital or in the community. Objective: To systematically review the evidence for GPP tests [xTAG® (Luminex, Toronto, ON, Canada), FilmArray (BioFire Diagnostics, Salt Lake City, UT, USA) and Faecal Pathogens B (AusDiagnostics, Beaconsfield, NSW, Australia)] and to develop a de novo economic model to compare the cost-effectiveness of GPP tests with conventional testing in England and Wales. Data sources: Multiple electronic databases including MEDLINE, EMBASE, Web of Science and the Cochrane Database were searched from inception to January 2016 (with supplementary searches of other online resources). Review methods: Eligible studies included patients with acute diarrhoea; comparing GPP tests with standard microbiology techniques; and patient, management, test accuracy or cost-effectiveness outcomes. Quality assessment of eligible studies used tailored Quality Assessment of Diagnostic Accuracy Studies-2, Consolidated Health Economic Evaluation Reporting Standards and Philips checklists. The meta-analysis included positive and negative agreement estimated for each pathogen. A de novo decision tree model compared patients managed with GPP testing or comparable coverage with patients managed using conventional tests, within the Public Health England pathway. Economic models included hospital and community management of patients with suspected gastroenteritis. The model estimated costs (in 2014/15 prices) and quality-adjusted life-year losses from a NHS and Personal Social Services perspective. Results: Twenty-three studies informed the review of clinical evidence (17 xTAG, four FilmArray, two xTAG and FilmArray, 0 Faecal Pathogens B). No study provided an adequate reference standard with which to compare the test accuracy of GPP with conventional tests. A meta-analysis (of 10 studies) found considerable heterogeneity; however, GPP testing produces a greater number of pathogen-positive findings than conventional testing. It is unclear whether or not these additional ‘positives’ are clinically important. The review identified no robust evidence to inform consequent clinical management of patients. There is considerable uncertainty about the cost-effectiveness of GPP panels used to test for suspected infectious gastroenteritis in hospital and community settings. Uncertainties in the model include length of stay, assumptions about false-positive findings and the costs of tests. Although there is potential for cost-effectiveness in both settings, key modelling assumptions need to be verified and model findings remain tentative. Limitations: No test–treat trials were retrieved. The economic model reflects one pattern of care, which will vary across the NHS. Conclusions: The systematic review and cost-effectiveness model identify uncertainties about the adoption of GPP tests within the NHS. GPP testing will generally correctly identify pathogens identified by conventional testing; however, these tests also generate considerable additional positive results of uncertain clinical importance. Future work: An independent reference standard may not exist to evaluate alternative approaches to testing. A test–treat trial might ascertain whether or not additional GPP ‘positives’ are clinically important or result in overdiagnoses, whether or not earlier diagnosis leads to earlier discharge in patients and what the health consequences of earlier intervention are. Future work might also consider the public health impact of different testing treatments, as test results form the basis for public health surveillance. Study registration: This study is registered as PROSPERO CRD2016033320. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder with increased morbidity and mortality in the elderly. Objectives: To evaluate the effectiveness, safety and cost-effectiveness of a strategy of initiating BP treatment with oral doxycycline or oral prednisolone. We hypothesised that starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral prednisolone. Design: Pragmatic multicentre two-armed parallel-group randomised controlled trial with an economic evaluation. Setting: A total of 54 dermatology secondary care centres in the UK and seven in Germany. Participants: Adults with BP [three or more blisters at two sites and positive direct and/or indirect immunofluorescence (immunoglobulin G and/or complement component 3 immunofluorescence at the dermal-epidermal junction)] and able to give informed consent. Interventions: Participants were allocated using online randomisation to initial doxycycline treatment (200 mg/day) or prednisolone (0.5 mg/kg/day). Up to 30 g/week of potent topical corticosteroids was permitted for weeks 1–3. After 6 weeks, clinicians could switch treatments or alter the prednisolone dose as per normal practice. Main outcome measures: Primary outcomes: (1) the proportion of participants with three or fewer blisters at 6 weeks (investigator blinded) and (2) the proportion with severe, life-threatening and fatal treatment-related events at 52 weeks. A regression model was used in the analysis adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Secondary outcomes included the effectiveness of blister control after 6 weeks, relapses, related adverse events and quality of life. The economic evaluation involved bivariate regression of costs and quality-adjusted life-years (QALYs) from a NHS perspective. Results: In total, 132 patients were randomised to doxycycline and 121 to prednisolone. The mean patient age was 77.7 years and baseline severity was as follows: mild 31.6% (three to nine blisters), moderate 39.1% (10–30 blisters) and severe 29.3% (> 30 blisters). For those starting on doxycycline, 83 out of 112 (74.1%) had three or fewer blisters at 6 weeks, whereas for those starting on prednisolone 92 out of 101 (91.1%) had three or fewer blisters at 6 weeks, an adjusted difference of 18.6% in favour of prednisolone [90% confidence interval (CI) 11.1% to 26.1%], using a modified intention-to-treat (mITT) analysis. Per-protocol analysis showed similar results: 74.4% compared with 92.3%, an adjusted difference of 18.7% (90% CI 9.8% to 27.6%). The rate of related severe, life-threatening and fatal events at 52 weeks was 18.2% for those started on doxycycline and 36.6% for those started on prednisolone (mITT analysis), an adjusted difference of 19.0% (95% CI 7.9% to 30.1%; p = 0.001) in favour of doxycycline. Secondary outcomes showed consistent findings. There was no significant difference in costs or QALYs per patient at 1 year between doxycycline-initiated therapy and prednisolone-initiated therapy (incremental cost of doxycycline-initiated therapy £959, 95% CI –£24 to £1941; incremental QALYs of doxycycline-initiated therapy –0.024, 95% CI –0.088 to 0.041). Using a willingness-to-pay criterion of

OBJECTIVE:Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously identify bacterial, viral and parasitic pathogens from the stool samples of patients with suspected infectious gastroenteritis presenting in hospital or the community. We undertook a systematic review to compare the accuracy of GPP tests with standard microbiology techniques. REVIEW METHODS:Searches in Medline, Embase, Web of Science and the Cochrane library were undertaken from inception to January 2016. Eligible studies compared GPP tests with standard microbiology techniques in patients with suspected gastroenteritis. Quality assessment of included studies used tailored QUADAS-2. In the absence of a reference standard we analysed test performance taking GPP tests and standard microbiology techniques in turn as the benchmark test, using random effects meta-analysis of proportions. RESULTS:No study provided an adequate reference standard with which to compare the test accuracy of GPP and conventional tests. Ten studies informed a meta-analysis of positive and negative agreement. Positive agreement across all pathogens was 0.93 (95% CI 0.90 to 0.96) when conventional methods were the benchmark and 0.68 (95% CI: 0.58 to 0.77) when GPP provided the benchmark. Negative agreement was high in both instances due to the high proportion of negative cases. GPP testing produced a greater number of pathogen-positive findings than conventional testing. It is unclear whether these additional 'positives' are clinically important. CONCLUSIONS:GPP testing has the potential to simplify testing and accelerate reporting when compared to conventional microbiology methods. However the impact of GPP testing upon the management, treatment and outcome of patients is poorly understood and further studies are needed to evaluate the health economic impact of GPP testing compared with standard methods. The review protocol is registered with PROSPERO as CRD42016033320.

Background: Skin diseases are very common and can have a large impact on the quality of life of patients and caregivers. This programme addressed four diseases: (1) eczema, (2) vitiligo, (3) squamous cell skin cancer (SCC) and (4) pyoderma gangrenosum (PG). Objective: To set priorities and reduce uncertainties for the treatment and prevention of skin disease in our four chosen diseases. Design: Mixed methods including eight systematic reviews, three prioritisation exercises, two pilot randomised controlled trials (RCTs), three feasibility studies, two core outcome initiatives, four funding proposals for national RCTs and one completed national RCT. Setting: Secondary care, primary care and the general population. Participants: Patients (and their caregivers) with eczema, vitiligo, SCC and PG, plus health-care professionals with an interest in skin disease. Interventions: Our three intervention studies included (1) barrier enhancement using emollients from birth to prevent eczema (pilot RCT); (2) handheld narrowband ultraviolet light B therapy for treating vitiligo (pilot RCT); and (3) oral ciclosporin (Neoral®, Novartis Pharmaceuticals) compared with oral prednisolone for managing PG (pragmatic national RCT). Results: Systematic reviews included two overarching systematic reviews of RCTs of treatments for eczema and vitiligo, an umbrella review of systematic reviews of interventions for the prevention of eczema, two reviews of treatments for SCC (one included RCTs and the second included observational studies), and three reviews of outcome measures and outcome reporting. Three prioritisation partnership exercises identified 26 priority areas for future research in eczema, vitiligo and SCC. Two international consensus initiatives identified four core domains for future eczema trials and seven core domains for vitiligo trials. Two pilot RCTs and three feasibility studies critically informed development of four trial proposals for external funding, three of which are now funded and one is pending consideration by funders. Our pragmatic RCT tested the two commonly used systemic treatments for PG (prednisolone vs. ciclosporin) and found no difference in their clinical effectiveness or cost-effectiveness. Both drugs showed limited benefit. Only half of the participants’ ulcers had healed by 6 months. For those with healed ulcers, recurrence was common (30%). Different side effect profiles were noted for each drug, which can inform clinical decisions on an individual patient basis. Three researchers were trained to PhD level and a dermatology patient panel was established to ensure patient involvement in all aspects of the programme. Conclusions: Findings from this programme of work have already informed clinical guidelines and patient information resources. Feasibility studies have ensured that large national pragmatic trials will now be conducted on important areas of treatment uncertainty that address the needs of patients and the NHS. There is scope for considerable improvement in terms of trial design, conduct and reporting for RCTs of skin disease, which can be improved through wider collaboration, registration of trial protocols and complete reporting and international consensus over core outcome sets. Three national trials have now been funded as a result of this work. Two international initiatives to establish how best to measure the core outcome domains for eczema and vitiligo are ongoing. Trial registration: Current Controlled Trials Barrier Enhancement for Eczema Prevention (BEEP) (ISRCTN84854178 and NCT01142999), Study of Treatments fOr Pyoderma GAngrenosum Patients (STOP GAP) (ISRCTN35898459) and Hand Held NB-UVB for Early or Focal Vitiligo at Home (HI-Light Pilot Trial) (NCT01478945). Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 4, No. 18. See the NIHR Journals Library website for further project information.

Hip replacement is one of the most commonly performed surgical procedures worldwide; hundreds of implant configurations provide options for femoral head size, joint surface material and fixation method with dramatically varying costs. Robust comparative evidence to inform the choice of implant is needed. This retrospective cohort study uses linked national databases from England and Wales to determine the optimal type of replacement for patients over 60 years undergoing hip replacement for osteoarthritis.Implants included were the commonest brand from each of the four types of replacement (cemented, cementless, hybrid and resurfacing); the reference prosthesis was the cemented hip procedure. Patient reported outcome scores (PROMs), costs and risk of repeat (revision) surgery were examined. Multivariable analyses included analysis of covariance to assess improvement in PROMs (Oxford hip score, OHS, and EQ5D index) (9159 linked episodes) and competing risks modelling of implant survival (79,775 procedures). Cost of implants and ancillary equipment were obtained from National Health Service procurement data.EQ5D score improvements (at 6 months) were similar for all hip replacement types. In females, revision risk was significantly higher in cementless hip prostheses (hazard ratio, HR = 2.22, p

BACKGROUND: With advances of research on fetal behavioural development, the question of whether we can identify fetal facial expressions and determine their developmental progression, takes on greater importance. In this study we investigate longitudinally the increasing complexity of combinations of facial movements from 24 to 36 weeks gestation in a sample of healthy fetuses using frame-by-frame coding of 4-D ultrasound scans. The primary aim was to examine whether these complex facial movements coalesce into a recognisable facial expression of pain/distress. METHODOLOGY/FINDINGS: Fifteen fetuses (8 girls, 7 boys) were observed four times in the second and third trimester of pregnancy. Fetuses showed significant progress towards more complex facial expressions as gestational age increased. Statistical analysis of the facial movements making up a specific facial configuration namely "pain/distress" also demonstrates that this facial expression becomes significantly more complete as the fetus matures. CONCLUSIONS/SIGNIFICANCE: The study shows that one can determine the normal progression of fetal facial movements. Furthermore, our results suggest that healthy fetuses progress towards an increasingly complete pain/distress expression as they mature. We argue that this is an adaptive process which is beneficial to the fetus postnatally and has the potential to identify normal versus abnormal developmental pathways.

BACKGROUND: Although some research suggests that fetuses yawn, others disagree arguing that is it simple mouth opening. Furthermore there is no developmental account of fetal yawning compared with simple mouth opening. The aim of the present study was to establish in a repeated measures design the development of fetal yawning compared with simple mouth opening. METHODOLOGY/FINDINGS: Video recordings were made of the fetal face and upper torso visualized by means of 4D full frontal or facial profile ultrasound recordings. Fifteen healthy fetuses were scanned four times at 24, 28, 32 and 36 weeks gestation. Yawning was distinguished from non-yawning in terms of the length of time it took to reach the apex of the mouth stretch, with yawns being defined as more than 50% of the total time observed. To assess changes in frequency, a Poisson mixed effects model was fitted to the count of number of yawn and simple mouth opening events with age and gender as fixed effects, and person as a random effect. For both yawns and simple mouth openings a smooth varying age effect was significant. The number of yawns observed declined with age from 28 weeks gestation, whereas simple mouth openings were less frequent and the decline was observed from 24 weeks. Gender was not significant either for yawn and simple mouth openings. CONCLUSIONS/SIGNIFICANCE: Yawning can be reliably distinguished from other forms of mouth opening with the potential of using yawning as an index of fetal healthy development.

Mobile devices have become commonplace, and are increasingly capable of accessing multi-media resources such as audio and video. Many libraries maintain multi-media digital collections that could be accessed on mobile devices. Mobile devices, however, offer unique display and technical challenges that need to be addressed. The benefits of mobile access to library collections include the promise of increased use and an enhanced user experience. In this article we provide a detailed discussion of the issues related to mobile delivery of digital media, including a literature review, an overview of significant technical issues, and three case studies.

BACKGROUND: Fetal facial development is essential not only for postnatal bonding between parents and child, but also theoretically for the study of the origins of affect. However, how such movements become coordinated is poorly understood. 4-D ultrasound visualisation allows an objective coding of fetal facial movements. METHODOLOGY/FINDINGS: Based on research using facial muscle movements to code recognisable facial expressions in adults and adapted for infants, we defined two distinct fetal facial movements, namely "cry-face-gestalt" and "laughter- gestalt," both made up of up to 7 distinct facial movements. In this conceptual study, two healthy fetuses were then scanned at different gestational ages in the second and third trimester. We observed that the number and complexity of simultaneous movements increased with gestational age. Thus, between 24 and 35 weeks the mean number of co-occurrences of 3 or more facial movements increased from 7% to 69%. Recognisable facial expressions were also observed to develop. Between 24 and 35 weeks the number of co-occurrences of 3 or more movements making up a "cry-face gestalt" facial movement increased from 0% to 42%. Similarly the number of co-occurrences of 3 or more facial movements combining to a "laughter-face gestalt" increased from 0% to 35%. These changes over age were all highly significant. SIGNIFICANCE: This research provides the first evidence of developmental progression from individual unrelated facial movements toward fetal facial gestalts. We propose that there is considerable potential of this method for assessing fetal development: Subsequent discrimination of normal and abnormal fetal facial development might identify health problems in utero.