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The role of biomarkers in risk-based early detection of lung cancer may enable screening to become cost effective and widely accessible. EarlyCDT-Lung is an example of such a blood-based autoantibody biomarker which may improve accessibility to Low dose Computed Tomography (LDCT) screening for those at highest risk. We randomized 12 208 individuals aged 50-75 at high risk of developing lung cancer to either the test or to standard clinical care. Outcomes were ascertained from Register of Deaths and Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio of the rate of deaths from all causes and lung cancer. Additional analyses were performed for cases of lung cancer diagnosed within two years of the initial test. After 5 years 326 lung cancers were detected (2.7% of those enrolled). The total number of deaths reported from all causes in the intervention group was 344 compared to 388 in the control group. There were 73 lung cancer deaths in the intervention arm and 90 in the controls (Adjusted HR 0.789 (0.636, 0.978). An analysis of cases of lung cancer detected within 2 years of randomization in the intervention group showed that there were 34 deaths from all causes and 29 from lung cancer. In the control group there were 56 deaths with 49 from lung cancer. In those diagnosed with lung cancer within 2 years of randomization the hazard ratio for all cause mortality was 0.615 (0.401,0.942) and for lung cancer 0.598 (0.378, 0.946). Further large-scale studies of the role of biomarkers to target lung cancer screening, in addition to LDCT, are likely to provide additional value., Competing Interests: F.M. Sullivan reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. F.S. Mair reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. W. Anderson has nothing to disclose. C. Chew has nothing to disclose. A. Dorward has nothing to disclose. J. Haughney has nothing to disclose. F. Hogarth reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and from Oncimmune, during the conduct of the study. D. Kendrick has nothing to disclose. R. Littleford reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. A. McConnachie reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. C. McCowan has nothing to disclose. N. McMeekin reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. M. Patel has nothing to disclose. P. Rauchhaus reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. L. Ritchie has nothing to disclose. J. Robertson reports other funding from Oncimmune, during the conduct of the study; and other funding from Oncimmune, outside the study. J. Robertson was a founder of Oncimmune, a company spun out from the University of Nottingham based on his academic research. Between 2003 and 2013 he was Chief Scientific Officer of Oncimmune and a Director of the company. During this time, he was responsible for the original drafting of the ECLS protocol. Since 2013 he has had no involvement in the science or management of the company. He has been and remains a shareholder in the company. J. Sarvesvaran has nothing to disclose. H. Sewell reports other funding from Oncimmune, outside the submitted work; and was an external member of the Oncimmune Scientific Advisory Board from 2006 to 2013. T. Taylor reports grants, nonfinancial support and other funding from Oncimmune, grants and personal fees from the Chief Scientist Office for Scotland, and grants and nonfinancial support from the Scottish Government, outside the submitted work. S. Treweek reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. K. Vedhara has nothing to disclose. S. Schembri reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study., (Copyright: © 2025 Sullivan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Portable ex vivo lung perfusion during lung transplantation is a resource-intensive technology. In light of its increasing use, we evaluated the cost-effectiveness of ex vivo lung perfusion at a low-volume lung transplant center in the USA., Methods: Patients listed for lung transplantation (2015-2021) in the United Network for Organ Sharing database were included. Quality-of-life was approximated by Karnofsky Performance Status scores 1-year post-transplant. Total transplantation encounter and 1-year follow-up costs accrued by our academic center for patients listed from 2018 to 2021 were obtained. Cost-effectiveness was calculated by evaluating the number of patients attaining various Karnofsky scores relative to cost., Results: Of the 13 930 adult patients who underwent lung transplant in the United Network for Organ Sharing database, 13 477 (96.7%) used static cold storage and 453 (3.3%) used ex vivo lung perfusion, compared to 30/58 (51.7%) and 28/58 (48.3%), respectively, at our center. Compared to static cold storage, median total costs at 1 year were higher for ex vivo lung perfusion ($918 000 vs. $516 000; p = 0.007) along with the cost of living 1 year with a Karnofsky functional status of 100 after transplant ($1 290 000 vs. $841 000). In simulated scenarios, each Karnofsky-adjusted life year gained by ex vivo lung perfusion was 1.00-1.72 times more expensive., Conclusions: Portable ex vivo lung perfusion is not currently cost-effective at a low-volume transplant centers in the USA, being 1.53 times more expensive per Karnofsky-adjusted life year. Improving donor lung and/or recipient biology during ex vivo lung perfusion may improve its utility for routine transplantation., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Purpose: Smoke-free prison policies have been introduced in some countries, in part to address very high levels of tobacco use in people in prison. However, relapse rates post-release remain high. This papers aims to improve understanding of post-release smoking and/or vaping behaviour is necessary to inform support for a priority population., Design/methodology/approach: The authors searched health, social science and criminal justice databases for studies about smoking/vaping behaviours among people released from smoke-free prisons. Studies were included if they reported primary data and were published between January 2017 and March 2024 in English; the population was adults/young people (16 yr+) imprisoned or formerly imprisoned, in prisons with comprehensive smoke-free policies; and at least one of the following was reported: pre-release intention to smoke, vape or remain abstinent post-release; smoking/vaping behaviour post-release and factors influencing smoking/vaping behaviour; attempts to quit again following post-release smoking/vaping relapse., Findings: Nine studies met our criteria. The evidence base is small and mainly from the USA or Australia. Evidence continues to suggest that most people resume smoking after leaving a smoke-free prison. No new interventions have been successful in reducing relapse rates. No studies report on vaping post-release, although two studies report on perceived factors affecting smoking relapse post-release from prisons allowing vaping., Research Limitations/implications: Given very high rates of relapse, there remains a significant need to better understand what approaches are feasible and acceptable for reducing return to smoking post-release., Originality/value: This review updates the limited evidence on smoking behaviours after leaving a smoke-free prison., (© Ashley Brown, Clair Woods-Brown, Kathryn Angus, Nicola McMeekin, Kate Hunt and Evangelia Demou.)

Background: Decision models are increasingly used to inform policy-making processes, and there is a need to improve their credibility. The estimation of health and economic outcomes generated from decision models is influenced by the development process itself. This paper aims to present the conceptual model development process of cardiometabolic disease (CMD) policy models in the UK setting., Methods: This conceptual model followed the International Society of Pharmacoeconomics and Outcomes Research-Society of Medical Decision Making (ISPOR-SMDM) Modelling Good Research Practices Task Force-2., Results: First, for the conceptualisation of the problem, the CMD disease staging, progression and current clinical guidelines were summarised, followed by a systematic review of published policy models. We critically appraised policy models such as cardiovascular disease and type 2 diabetes. Key messages from the review emphasised the importance of understanding various determinants influencing model development, including risk factors, model structure, models' parameters, data utilisation, economic perspective, equality/equity consideration, transparency and validation process. Second, as a sequential process, is model conceptualisation, to determine which modelling types and their attributes best represent the defined problem. Expert opinions, including a clinician and experienced modellers, provided input on the state transition model to ensure the structure is clinically relevant. From this stage, the consideration and agreement to establish a disease state in a state transition model was discussed., Conclusion: This conceptual model serves as a basis for representing the systematic process for structuring a CMD policy model to enhance its transparency and credibility., (© 2024. The Author(s).)

Objectives: We report the effect of quality of therapy delivery on outcomes in a randomized, controlled trial of behavioural activation (BA) and guided self-help (GSH) for depression in adults with intellectual disabilities., Methods: A study specific measure of quality was used in a linear mixed effect model to determine the effects therapy and therapy quality on therapy outcome., Results: There was a significant interaction between quality and treatment type, with lower quality therapy associated with better outcome for GSH but poorer outcome for BA, with little difference in outcomes at higher levels of therapy quality., Conclusions: Factors suggesting high quality in individualized BA may indicate problematic engagement for GSH. More research into processes in therapy for people with intellectual disabilities is required., (© 2024 The Author(s). British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission., Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations., Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023., Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol., Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions., Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96)., Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both., Trial Registration: isrctn.org Identifier: ISRCTN10497306.

Background: Diagnostic blood tests have the potential to identify lung cancer in people at high risk. We assessed the cost-effectiveness of a lung cancer screening intervention, using the EarlyCDT ® -Lung Test (ECLS) with subsequent X-ray and low-dose chest CT scans (LDCT) for patients with a positive test result, compared to both usual care and LDCT screening for the target population., Methods: We conducted a model-based lifetime analysis from a UK NHS and personal social services perspective. We estimated incremental net monetary benefit (NMB) for the ECLS intervention compared to no screening and to LDCT screening., Results: The incremental NMB of ECLS intervention compared to no screening was GBP 33,179 (95% CI: -GBP 81,396, GBP 147,180) and GBP 140,609 (95% CI: -GBP 36,255, GBP 316,612), respectively, for a cost-effectiveness threshold of GBP 20,000 and GBP 30,000 per quality-adjusted life year. The same figures compared with LDCT screening were GBP 162,095 (95% CI: GBP 52,698, GBP 271,735) and GBP 52,185 (95% CI: -GBP 115,152, GBP 219,711)., Conclusions: The ECLS intervention is the most cost-effective screening alternative, with the highest probability of being cost-effective, when compared to no screening or LDCT screening. This result may change with modifications of the parameters, suggesting that the three alternatives considered in the main analysis are potentially cost-effective., Competing Interests: All authors report grants from Oncimmune Ltd., and grants from the Scottish Government Health & Social Care Directorate of the Chief Scientist Office (CSO), during the conduct of the study.

Background: Almost no research has been published reporting on evaluations of the effectiveness of psychological interventions for people with severe to profound intellectual disabilities and depression. This paper describes the development and initial feasibility testing of an adapted Behavioural Activation therapy (BeatIt2) for this population., Method: Phase 1 of the study examined participant recruitment and willingness to be randomised in the context of a planned Randomised Controlled Trial (RCT). Phase 2 examined the feasibility of delivering the intervention., Results: Twenty adults with a severe or profound intellectual disability and clinically significant depression were recruited to Phase 1 of the study. In Phase 2, there was 100% participant retention for those recruited to the study at 6-month follow-up. The BeatIt2 therapy was reported to be acceptable for participants., Conclusion: COVID disruption meant that it was not possible to complete the planned feasibility RCT. The positive findings suggest that additional evaluation of BeatIt2 is warranted., (© 2024 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

Objective: To determine the cost-effectiveness of a smoke-free prison policy in Scotland, through assessments of the trade-offs between costs (healthcare and non-healthcare-related expenditure) and outcomes (health and non-health-related non-monetary consequences) of implementing the policy., Design: A health economic evaluation consisting of three analyses (cost-consequence, cost-effectiveness and cost-utility), from the perspectives of the healthcare payer, prison service, people in custody and operational staff, assessed the trade-offs between costs and outcomes. Costs associated with the implementation of the policy, healthcare resource use and personal spend on nicotine products were considered, alongside health and non-health outcomes. The cost-effectiveness of the policy was evaluated over 12-month and lifetime horizons (short term and long term)., Setting: Scotland's national prison estate., Participants: People in custody and operational prison staff., Intervention: Implementation of a comprehensive (indoor and outdoor) smoke-free policy., Main Outcome Measures: Concentration of secondhand smoke, health-related quality of life (health utilities and quality-adjusted life-years (QALY)) and various non-health outcomes (eg, incidents of assaults and fires)., Results: The short-term analyses suggest cost savings for people in custody and staff, improvements in concentration of secondhand smoke, with no consistent direction of change across other outcomes. The long-term analysis demonstrated that implementing smoke-free policy was cost-effective over a lifetime for people in custody and staff, with approximate cost savings of £28 000 and £450, respectively, and improvement in health-related quality of life of 0.971 QALYs and 0.262, respectively., Conclusion: Implementing a smoke-free prison policy is cost-effective over the short term and long term for people in custody and staff., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Aims: To evaluate whether adding financial incentives to usual care is cost-effective in encouraging pregnant women to quit tobacco smoking, compared with usual care alone., Design: Cost-effectiveness analysis (CEA) and cost-utility analysis (CUA) from a health-care provider's perspective, embedded in the Smoking Cessation in Pregnancy Incentives Trial (CPIT III). Long-term analyses were conducted from the same perspective, using an existing Markov model over a life-time horizon., Setting: Seven maternity smoking cessation sites in Scotland, England and Northern Ireland in the United Kingdom., Participants: In the short-term analysis, CPIT III participants were assessed: women 16 years or older, self-reporting as smokers, fewer than 24 weeks pregnant and English-speaking (n = 944). The same population was used for the life-time analysis, plus their infants., Measurements: Costs included financial incentive vouchers and postage, cessation support and nicotine replacement therapy and neonatal stays. The outcome measure was a biochemically verified quit rate for the CEA and quality-adjusted life-years (QALYs) for CUA. Costs are presented in 2020 GBP sterling (£). Data for the life-time analysis came from the trial and were combined with data from published literature embedded in the model, reporting incremental cost per quitter and QALY. A 3.5% discount rate was applied., Findings: The short-term incremental cost per quitter was £4400 and cost per QALY was £150 000. Results of sensitivity analyses confirmed these results. The long-term analysis combined costs and outcomes for mother and infants; results showed a cost saving of £37 [95% confidence interval (CI]) = £35-106] and increase in QALYs of 0.171 (95% CI = 0.124-0.229). These findings indicate that, over a life-time, financial incentives are cost-saving and improve health outcomes., Conclusions: In the United Kingdom, offering up to £400 financial incentives, in addition to usual care, to support pregnant women to stop smoking appears to be highly cost-effective over a life-time for mother and infants., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: To examine effectiveness, cost effectiveness, generalisability, and acceptability of financial incentives for smoking cessation during pregnancy in addition to variously organised UK stop smoking services., Design: Pragmatic, multicentre, single blinded, phase 3, randomised controlled trial (Cessation in Pregnancy Incentives Trial phase 3 (CPIT III))., Setting: Seven UK stop smoking services provided in primary and secondary care facilities in Scotland, Northern Ireland, and England., Participants: 944 pregnant women (age ≥16 years) who self-reported as being smokers (at least one cigarette in the past week) when asked at first maternity visit, less than 24 weeks' gestation, and notified to the trial team by routine stop smoking services., Interventions: Participants in the control group were offered the standard stop smoking services, which includes the offer of counselling by specially trained workers using withdrawal orientated therapy and the offer of free nicotine replacement therapy. The intervention was the offer of usual support from the stop smoking services and the addition of up to £400 ($440; €455) of LoveToShop financial voucher incentives for engaging with current stop smoking services or to stop smoking, or both, during pregnancy., Main Outcome Measures: Self-reported smoking cessation in late pregnancy (between 34 and 38 weeks' gestation) corroborated by saliva cotinine (and anabasine if using nicotine replacement products). Results were adjusted for age, smoking years, index of multiple deprivation, Fagerström score, before or after covid, and recruitment site. Secondary outcomes included point and continuous abstinence six months after expected date of delivery, engagement with stop smoking services, biochemically validated abstinence from smoking at four weeks after stop smoking date, birth weight of baby, cost effectiveness, generalisability documenting formats of stop smoking services, and acceptability to pregnant women and their carers., Results: From 9 January 2018 to 4 April 2020, of 4032 women screened by stop smoking services, 944 people were randomly assigned to the intervention group (n=471) or the control group (n=470). Three people asked for their data to be removed. 126 (27%) of 471 participants stopped smoking from the intervention group and 58 (12%) of 470 from the control group (adjusted odds ratio 2.78 (1.94 to 3.97) P<0.001). Serious adverse events were miscarriages and other expected pregnancy events requiring hospital admission; all serious adverse events were unrelated to the intervention. Most people who stopped smoking from both groups relapsed after their baby was born., Conclusions: The offer of up to £400 of financial voucher incentives to stop smoking during pregnancy as an addition to current UK stop smoking services is highly effective. This bolt-on intervention supports new guidance from the UK National Institute for Health and Care Excellence, which includes the addition of financial incentives to support pregnant women to stop smoking. Continuing incentives to 12 months after birth is being examined to prevent relapse., Trial Registration: ISRCTN Registry ISRCTN15236311., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Cancer Research UK; Chief Scientist Office; Scottish Government; HSC Public Health Agency Northern Ireland (NI); HSC R&D Division NI; Chest Heart and Stroke Northern Ireland; The Scottish Cot Death Trust; The Lullaby Trust for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early warning signs monitoring by service users with schizophrenia has shown promise in preventing relapse but the quality of evidence is low. We aimed to establish the feasibility of undertaking a definitive randomised controlled trial to determine the effectiveness of a blended digital intervention for relapse prevention in schizophrenia., Methods: This multicentre, feasibility, cluster randomised controlled trial aimed to compare Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) with treatment as usual in community mental health services (CMHS) in Glasgow and Melbourne. CMHS were the unit of randomisation, selected on the basis of those that probably had five or more care coordinators willing to participate. Participants were eligible if they were older than 16 years, had a schizophrenia or related diagnosis confirmed via case records, were able to provide informed consent, had contact with CMHS, and had had a relapse within the previous 2 years. Participants were randomised within stratified clusters to EMPOWER or to continue their usual approach to care. EMPOWER blended a smartphone for active monitoring of early warning signs with peer support to promote self-management and clinical triage to promote access to relapse prevention. Main outcomes were feasibility, acceptability, usability, and safety, which was assessed through face-to-face interviews. App usage was assessed via the smartphone and self-report. Primary end point was 12 months. Participants, research assistants and other team members involved in delivering the intervention were not masked to treatment conditions. Assessment of relapse was done by an independent adjudication panel masked to randomisation group. The study is registered at ISRCTN (99559262)., Findings: We identified and randomised eight CMHS (six in Glasgow and two in Melbourne) comprising 47 care coordinators. We recruited 86 service users between Jan 19 and Aug 8, 2018; 73 were randomised (42 [58%] to EMPOWER and 31 [42%] to treatment as usual). There were 37 (51%) men and 36 (49%) women. At 12 months, main outcomes were collected for 32 (76%) of service users in the EMPOWER group and 30 (97%) of service users in the treatment as usual group. Of those randomised to EMPOWER, 30 (71%) met our a priori criterion of more than 33% adherence to daily monitoring that assumed feasibility. Median time to discontinuation of these participants was 31·5 weeks (SD 14·5). There were 29 adverse events in the EMPOWER group and 25 adverse events in the treatment as usual group. There were 13 app-related adverse events, affecting 11 people, one of which was serious. Fear of relapse was lower in the EMPOWER group than in the treatment as usual group at 12 months (mean difference -7·53 (95% CI -14·45 to 0·60; Cohen's d -0·53)., Interpretation: A trial of digital technology to monitor early warning signs blended with peer support and clinical triage to detect and prevent relapse appears to be feasible, safe, and acceptable. A further main trial is merited., Funding: UK National Institute for Health Research Health Technology Assessment programme and the Australian National Health and Medical Research Council., Competing Interests: Declaration of interests AIG reports personal fees from University of Manchester, personal fees from University of Exeter, personal fees from British Association for Behavioural and Cognitive Psychotherapies and other interests with UK National Health Service (NHS) Education for Scotland outside the submitted work. JA, SL, and SB report other interests with CareLoop Health, outside the submitted work. SB reports grants from the Medical Research Council and UK National Institute for Health Research (NIHR) during the conduct of the study. SL reports grants from the UK Medical Research Council (MRC) during the conduct of the study. JA reports grants from MRC, Engineering and Physical Sciences Research Council, Economic and Social Research Council, NIHR, and the US National Institute for Health, and was a Fellow of the Alan Turing Institute during the conduct of the study. AB reports personal fees from Bayer, Merck, Janssen, Novartis, Sword Health, Amgen, and Daiichi Sankyo outside the submitted work. JF reports grants from National Health and Medical Research Council (Australia) during the conduct of the study and other interests with Melbourne Health (NorthWestern Mental Health) outside the submitted work. HMcL reports grants from NIHR Health Technology Assessment (HTA) during the conduct of the study, and grants with Academy of Medical Sciences, Glasgow Children's Hospital Charity, and Scotland's Chief Scientist's Office. CM reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. JN reports grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study and declares membership of the following NIHR boards: Cardio Pulmonary Resusitation decision making committee; HTA commissioning board; HTA commissioning sub-board (expression of interest); HTA funding boards policy group; HTA general board; HTA post-board funding teleconference; NIHR clinical trials unit standing advisory committee; NIHR HTA and Efficacy Mechanism Evaluation editorial board; pre-exposure prophylaxis impact review panel. PF is a member of the HTA mental health prioritisation panel. CW reports grants from NIHR during the conduct of the study and from the Royal College of Psychiatrists, and other interests with Five Areas outside the submitted work. AY reports an NIHR Senior Investigator Grant. JG reports grants from the National Health Medical Research Council. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse., Objective: How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse?, Design: A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up., Settings: Glasgow, UK, and Melbourne, Australia., Participants: Service users were aged > 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user., Interventions: The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted., Main Outcome Measures: The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse., Results: We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement (> 33%). The median time to discontinuation of > 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference -4.29, 95% confidence interval -7.29 to -1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained., Limitations: This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness., Conclusions: A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible., Future Work: A main trial with a sample size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3-0.4)., Trial Registration: This trial is registered as ISRCTN99559262., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

Background: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease., Methods: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV 1 < 80% predicted, FEV 1 /FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers., Discussion: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally., Trial Registration: Current controlled trials ISRCTN10497306 . Registered on 16 August 2018., (© 2022. The Author(s).)

Background: Internationally, smoking prevalence among people in prison custody (ie, people on remand awaiting trial, awaiting sentencing, or serving a custodial sentence) is high. In Scotland, all prisons implemented a comprehensive smoke-free policy in 2018 after a 16-month anticipatory period. In this study, we aimed to use data on medication dispensing to assess the impact of this policy on cessation support, health outcomes, and potential unintended consequences among people in prison custody., Methods: We did an interrupted time-series analysis using dispensing data for 44 660 individuals incarcerated in 14 closed prisons in Scotland between March 30, 2014, and Nov 30, 2019. We estimated changes in dispensing rates associated with the policy announcement (July 17, 2017) and full implementation (Nov 30, 2018) using seasonal autoregressive integrated moving average models. Medication categories of primary interest were treatments for nicotine dependence (as an indicator of smoking cessation or abstinence attempts), acute smoking-associated illnesses, and mental health (antidepressants). We included antiepileptic medications as a negative control., Findings: A 44% step increase in dispensing of treatments for nicotine dependence was observed at implementation (2250 items per 1000 people in custody per fortnight, 95% CI 1875 to 2624) due primarily to a 42% increase in dispensing of nicotine replacement therapy (2109 items per 1000 people in custody per fortnight, 1701 to 2516). A 9% step decrease in dispensing for smoking-related illnesses was observed at implementation, largely accounted for by respiratory medications (-646 items per 1000 people in custody per fortnight, -1111 to -181). No changes associated with announcement or implementation were observed for mental health dispensing or antiepileptic medications (control)., Interpretation: Smoke-free prison policies might improve respiratory health among people in custody and encourage smoking abstinence or cessation without apparent short-term adverse effects on mental health dispensing., Funding: National Institute of Health Research Public Health Research programme, Scottish Government Chief Scientist Office, and UK Medical Research Council., Competing Interests: Declaration of interests HS was a member of Action on Smoking and Health (ASH) Scotland's Board (2017–20) and the Policy and Development Committee (2013–20), chair of the Scottish Tobacco-free Alliance Research Group (2012–20), and a council member for the Tobacco-free Alliance (2015–20). KH was previously a member of the National Institute for Health Research (NIHR) Public Health Research funding board., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2 years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2 years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT., Competing Interests: Conflict of interest: F.M. Sullivan reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: F.S. Mair reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: W. Anderson has nothing to disclose. Conflict of interest: P. Armory reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: A. Briggs reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: C. Chew has nothing to disclose. Conflict of interest: A. Dorward has nothing to disclose. Conflict of interest: J. Haughney has nothing to disclose. Conflict of interest: F. Hogarth reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and from Oncimmune, during the conduct of the study. Conflict of interest: D. Kendrick has nothing to disclose. Conflict of interest: R. Littleford reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: A. McConnachie reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: C. McCowan has nothing to disclose. Conflict of interest: N. McMeekin reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: M. Patel has nothing to disclose. Conflict of interest: P. Rauchhaus reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: L. Ritchie has nothing to disclose. Conflict of interest: C. Robertson reports personal fees and other funding from Oncimmune, outside the study. Conflict of interest: J. Robertson reports other funding from Oncimmune, during the conduct of the study; and other funding from Oncimmune, outside the study. J. Robertson was a founder of Oncimmune, a company spun out from the University of Nottingham based on his academic research. Between 2003 and 2013 he was Chief Scientific Officer of Oncimmune and a Director of the company. During this time, he was responsible for the original drafting of the ECLS protocol. Since 2013 he has had no involvement in the science or management of the company. He has been and remains a shareholder in the company. Conflict of interest: J. Robles-Zurita reports grants from the Scottish Government Health and Social Care Directorate of the Chief Scientist Office and Oncimmune, during the conduct of the study. Conflict of interest: J. Sarvesvaran has nothing to disclose. Conflict of interest: H. Sewell reports other funding from Oncimmune, outside the submitted work; and was an external member of the Oncimmune Scientific Advisory Board from 2006 to 2013. Conflict of interest: M. Sproule has nothing to disclose. Conflict of interest: T. Taylor reports grants, nonfinancial support and other funding from Oncimmune, grants and personal fees from the Chief Scientist Office for Scotland, and grants and nonfinancial support from the Scottish Government, outside the submitted work. Conflict of interest: A. Tello reports grants from Oncimmune, during the conduct of the study. Conflict of interest: S. Treweek reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study. Conflict of interest: K. Vedhara has nothing to disclose. Conflict of interest: S. Schembri reports grants from Oncimmune and the Scottish Government Health and Social Care Directorate of the Chief Scientist Office, during the conduct of the study; and nonfinancial support from GlaxoSmithKline and AstraZeneca, outside the submitted work., (Copyright ©ERS 2021.)

Introduction: Smoking results in an average 10-year loss of life, but smokers who permanently quit before age 40 can expect a near normal lifespan. Pregnancy poses a good opportunity to help women to stop; around 80% of women in the UK have a baby, most of whom are less than 40 years of age. Smoking prevalence during pregnancy is high: 17%-23% in the UK. Smoking during pregnancy causes low birth weight and increases the risk of premature birth. After birth, passive smoking is linked to sudden infant death syndrome, respiratory diseases and increased likelihood of taking up smoking. These risks impact the long-term health of the child with associated increase in health costs. Emerging evidence suggests that offering financial incentives to pregnant women to quit is highly cost effective.This protocol describes the economic evaluation of a multi-centre randomised controlled trial (Cessation in Pregnancy Incentives Trial III, CPIT III) designed to establish whether offering financial incentives, in addition to usual care, is effective and cost effective in helping pregnant women to quit., Methods and Analysis: The economic evaluation will identify, measure and value resource use and outcomes from CPIT III, comparing participants randomised to either usual care or usual care plus up to £400 financial incentives. Within-trial and long-term analyses will be conducted from a National Health Service and Personal Social Services perspective; the outcome for both analyses will be quality adjusted life-years measured using EQ-5D-5L. Patient level data collected during the trial will be used for the within-trial analysis, with an additional outcome of cotinine validated quit rates at 34-38 weeks gestation and 6 months postpartum. The long-term model will be informed by data from the trial and published literature., Ethics and Dissemination: TRIAL REGISTRATION NUMBER: ISRCTN15236311; Pre-results (https://doi.org/10.1186/ISRCTN15236311)., Competing Interests: Competing interests: None declared, (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Although the benefits of using methodological frameworks are increasingly recognised, to date, there is no formal definition of what constitutes a 'methodological framework', nor is there any published guidance on how to develop one. For the purposes of this study we have defined a methodological framework as a structured guide to completing a process or procedure. This study's aims are to: (a) map the existing landscape on the use of methodological frameworks; (b) identify approaches used for the development of methodological frameworks and terminology used; and (c) provide suggestions for developing future methodological frameworks. We took a broad view and did not limit our study to methodological frameworks in research and academia., Methods: A scoping review was conducted, drawing on Arksey and O'Malley's methods and more recent guidance. We systematically searched two major electronic databases (MEDLINE and Web of Science), as well as grey literature sources and the reference lists and citations of all relevant papers. Study characteristics and approaches used for development of methodological frameworks were extracted from included studies. Descriptive analysis was conducted., Results: We included a total of 30 studies, representing a wide range of subject areas. The most commonly reported approach for developing a methodological framework was 'Based on existing methods and guidelines' (66.7%), followed by 'Refined and validated' (33.3%), 'Experience and expertise' (30.0%), 'Literature review' (26.7%), 'Data synthesis and amalgamation' (23.3%), 'Data extraction' (10.0%), 'Iteratively developed' (6.7%) and 'Lab work results' (3.3%). There was no consistent use of terminology; diverse terms for methodological framework were used across and, interchangeably, within studies., Conclusions: Although no formal guidance exists on how to develop a methodological framework, this scoping review found an overall consensus in approaches used, which can be broadly divided into three phases: (a) identifying data to inform the methodological framework; (b) developing the methodological framework; and (c) validating, testing and refining the methodological framework. Based on these phases, we provide suggestions to facilitate the development of future methodological frameworks.

Background: Eighty per cent of UK women have at least one baby, making pregnancy an opportunity to help women stop smoking before their health is irreparably compromised. Smoking cessation during pregnancy helps protect infants from miscarriage, still birth, low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. UK national guidelines highlight lack of evidence for effectiveness of financial incentives to help pregnant smokers quit. This includes a research recommendation: within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit?, Methods: The Cessation in Pregnancy Incentives Trial (CPIT) III is a pragmatic, 42-month, multi-centre, parallel-group, individually randomised controlled superiority trial of the effect on smoking status of adding to usual Stop Smoking Services (SSS) support, the offer of up to £400 of financial voucher incentives, compared with usual support alone, to quit smoking during pregnancy. Participants (n = 940) are pregnant smokers (age > 16 years, < 24 weeks pregnant, English speaking), who consent via telephone to take part and are willing to be followed-up in late pregnancy and 6 months after birth. The primary outcome is cotinine/anabasine-validated abstinence from smoking in late pregnancy. Secondary outcomes include engagement with SSS, quit rates at 4 weeks from agreed quit date and 6 months after birth, and birth weight. Outcomes will be analysed by intention to treat, and regression models will be used to compare treatment effects on outcomes. A meta-analysis will include data from the feasibility study in Glasgow. An economic evaluation will assess cost-effectiveness from a UK NHS perspective. Process evaluation using a case-study approach will identify opportunities to improve recruitment and learning for future implementation. Research questions include: what is the therapeutic efficacy of incentives; are incentives cost-effective; and what are the potential facilitators and barriers to implementing incentives in different parts of the UK?, Discussion: This phase III trial in Scotland, England and Northern Ireland follows a successful phase II trial in Glasgow, UK. The participating sites have diverse SSS that represent most cessation services in the UK and serve demographically varied populations. If found to be acceptable and cost-effective, this trial could demonstrate that financial incentives are effective and transferable to most UK SSS for pregnant women., Trial Registration: Current Controlled Trials, ISRCTN15236311. Registered on 9 October 2017.

Background: Relapse in schizophrenia is a major cause of distress and disability and is predicted by changes in symptoms such as anxiety, depression, and suspiciousness (early warning signs [EWSs]). These can be used as the basis for timely interventions to prevent relapse. However, there is considerable uncertainty regarding the implementation of EWS interventions., Objective: This study was designed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) against treatment as usual (TAU). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, safety, and outcome signals of a digital health intervention as an adjunct to usual care that is deliverable in the UK National Health Service and Australian community mental health service (CMHS) settings. We will assess the feasibility of candidate primary outcomes, candidate secondary outcomes, and candidate mechanisms for a definitive trial., Methods: We will randomize CMHSs to EMPOWER or TAU. We aim to recruit up to 120 service user participants from 8 CMHSs and follow them for 12 months. Eligible service users will (1) be aged 16 years and above, (2) be in contact with local CMHSs, (3) have either been admitted to a psychiatric inpatient service or received crisis intervention at least once in the previous 2 years for a relapse, and (4) have an International Classification of Diseases-10 diagnosis of a schizophrenia-related disorder. Service users will also be invited to nominate a carer to participate. We will identify the feasibility of the main trial in terms of recruitment and retention to the study and the acceptability, usability, safety, and outcome signals of the EMPOWER intervention. EMPOWER is a mobile phone app that enables the monitoring of well-being and possible EWSs of relapse on a daily basis. An algorithm calculates changes in well-being based on participants' own baseline to enable tailoring of well-being messaging and clinical triage of possible EWSs. Use of the app is blended with ongoing peer support., Results: Recruitment to the trial began September 2018, and follow-up of participants was completed in July 2019. Data collection is continuing. The database was locked in July 2019, followed by analysis and disclosing of group allocation., Conclusions: The knowledge gained from the study will inform the design of a definitive trial including finalizing the delivery of our digital health intervention, sample size estimation, methods to ensure successful identification, consent, randomization, and follow-up of participants, and the primary and secondary outcomes. The trial will also inform the final health economic model to be applied in the main trial., Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 99559262; http://isrctn.com/ISRCTN99559262., International Registered Report Identifier (irrid): DERR1-10.2196/15058., (©Andrew Gumley, Simon Bradstreet, John Ainsworth, Stephanie Allan, Mario Alvarez-Jimenez, Louise Beattie, Imogen Bell, Max Birchwood, Andrew Briggs, Sandra Bucci, Emily Castagnini, Andrea Clark, Sue M Cotton, Lidia Engel, Paul French, Reeva Lederman, Shon Lewis, Matthew Machin, Graeme MacLennan, Claire Matrunola, Hamish McLeod, Nicola McMeekin, Cathrine Mihalopoulos, Emma Morton, John Norrie, Frank Reilly, Matthias Schwannauer, Swaran P Singh, Lesley Smith, Suresh Sundram, David Thomson, Andrew Thompson, Helen Whitehill, Alison Wilson-Kay, Christopher Williams, Alison Yung, John Farhall, John Gleeson. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 09.01.2020.)

Background: Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes., Objective: To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection., Design: Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%., Setting: Twenty-six NHS hospitals., Participants: Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively)., Interventions: Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm., Main Outcome Measure: The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data., Results: Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial., Limitations: The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded., Conclusions: PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy., Future Work: Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics., Trial Registration: Current Controlled Trials ISRCTN91566927., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 38. See the NIHR Journals Library website for further project information., Competing Interests: Adrian Taylor reports personal fees from Zimmer Inc., Corin Group and DePuy Synthes Companies outside the submitted work. Martin McNally reports personal fees from Bonesupport AB outside the submitted work. R Andrew Seaton reports personal fees from previous consultancy and funding for speaking at educational meetings (Novartis Pharma) and consultancy for Merck Sharp & Dohme Corp. (MSD) outside the submitted work. Harriet Hughes reports other competing interests from Gilead Sciences Inc., MSD, Biocomposites, and personal fees from Biocomposites and Cubist Pharmaceuticals outside the submitted work. Jennifer Bostock was a member of the Health Services and Delivery Research Commissioned Panel Members during this project.

Background:  Bone and joint infections are becoming increasingly common and are usually treated with surgery and a course of intravenous antibiotics. However, there is no evidence to support the superiority of intravenous therapy and there is a growing body of literature showing that oral therapy is effective in treating these infections.Given this lack of evidence the clinical trial 'Oral Versus Intravenous Antibiotics' (OVIVA) was designed to assess the clinical and cost-effectiveness of intravenous versus oral antibiotics for the treatment of bone and joint infections, using a non-inferiority design. Clinical results from the trial indicate that oral antibiotics are non-inferior to intravenous antibiotics. The aim of this paper is to evaluate the cost-effectiveness of intravenous compared to oral antibiotics for treating bone and joint infections, using data from OVIVA. Methods:  A cost-utility analysis was carried out, the main economic outcome measure was the quality adjusted life-year, measured using the EQ-5D-3L questionnaire, combined with costs to estimate cost-effectiveness over 12-months follow-up. Results:  Results show that costs were significantly lower in the oral arm compared to the intravenous arm, a difference of £2,740 (95% confidence interval £1,488 to £3,992). Results of four sensitivity analyses were consistent with the base-case results. QALYs were marginally higher in the oral arm, however this difference was not statistically significant; -0.007 (95% confidence interval -0.045 to 0.031). Conclusions:  Treating patients with bone and joint infections for the first six weeks of therapy with oral antibiotics is both less costly and does not result in detectable differences in quality of life compared to treatment with intravenous antibiotics. Adopting a practice of treating bone and joint infections with oral antibiotics early in the course of therapy could potentially save the UK National Health Service over £17 million annually., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 McMeekin N et al.)

Background: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD., Objective: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation., Design: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial., Setting: The trial was conducted in 121 UK primary and secondary care sites., Participants: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV 1 )/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year., Interventions: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status., Primary Outcome: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs., Results: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV 1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV 1 ), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms., Limitations: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment ( n  = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study., Conclusion: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses., Future Work: To promote consideration of the findings of this trial in national and international COPD guidelines., Trial Registration: Current Controlled Trials ISRCTN27066620., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 37. See the NIHR Journals Library website for further project information., Competing Interests: Graham Burns reports personal fees from Boehringer Ingelheim GmbH (Ingelheim am Rhein, Germany), Teva Pharmaceutical Industries Ltd (Petah Tikva, Israel), Chiesi Farmaceutici SpA (Parma, Italy), Pfizer Inc. (New York City, NY, USA) and AstraZeneca plc (Cambridge, UK), and non-financial support from Chiesi and Boehringer Ingelheim, outside the submitted work. Rekha Chaudhuri reports personal fees from AstraZeneca, GlaxoSmithKline (GSK) plc (London, UK), Teva and Novartis International AG (Basel, Switzerland) for advisory board meetings, outside the submitted work. Anthony De Soyza reports grants and non-financial support from AstraZeneca and Chiesi, non-financial support from Boehringer Ingelheim, grants and personal fees from GSK, Bayer AG (Leverkusen, Germany) and Pfizer, and grants from Forest Laboratories (New York City, NY, USA)/Teva, outside the submitted work. He is also a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Elective and Emergency Specialist Care (EESC) Panel. Simon Gompertz reports personal fees from Pfizer and GSK, outside the submitted work. John Norrie reports grants from the NIHR HTA programme during the conduct of the study, was a member of the NIHR HTA Commissioning Board (2010–16) and is currently Deputy Chairperson of the NIHR HTA General Board (2016–present) and a NIHR Journals Library Editor (2014–present). Andrew Wilson reports grants from F. Hoffmann-La Roche (Basel, Switzerland), outside the submitted work. David Price reports grants and personal fees from Aerocrine AB (Stockholm, Sweden), AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan NV (Canonsburg, PA, USA), Mundipharma International Ltd (Cambridge, UK), Napp Pharmaceuticals Ltd (Cambridge, UK), Novartis, Pfizer, Teva, Theravance Biopharma (San Francisco, CA, USA) and Zentiva Group a.s. (Prague, Czech Republic); personal fees from Almirall SA (Barcelona, Spain), Amgen Inc. (Newbury Park, CA, USA), Cipla Ltd (Mumbai, India), GSK, Kyorin Pharmaceutical Co. Ltd (Tokyo, Japan), Merck Sharp & Dohme (Kenilworth, NJ, USA), Skyepharma Production SAS (Saint-Quentin-Fallavier, France); grants from AKL Research and Development Ltd (Stevenage, UK), the British Lung Foundation, the Respiratory Effectiveness Group and the UK NHS; and non-financial support from the NIHR Efficacy and Mechanism Evaluation and HTA programmes, outside the submitted work. He also reports stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals and owns 74% of the social enterprise Optimum Patient Care Ltd (Cambridge, UK, and Australia and Singapore) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore).

Background: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication., Methods: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points., Results: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%)., Conclusions: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD., Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD., Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites., Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787)., Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period., Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%)., Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations., Trial Registration: isrctn.org Identifier: ISRCTN27066620.

Background: Depression is the most prevalent mental health problem among people with learning disabilities., Objective: The trial investigated the clinical effectiveness and cost-effectiveness of behavioural activation for depression experienced by people with mild to moderate learning disabilities. The intervention was compared with a guided self-help intervention., Design: A multicentre, single-blind, randomised controlled trial, with follow-up at 4, 8 and 12 months post randomisation. There was a nested qualitative study., Setting: Participants were recruited from community learning disability teams and services and from Improving Access to Psychological Therapies services in Scotland, England and Wales., Participants: Participants were aged ≥ 18 years, with clinically significant depression, assessed using the Diagnostic Criteria for Psychiatric Disorders for use with Adults with Learning Disabilities. Participants had to be able to give informed consent and a supporter could accompany them to therapy., Interventions: BeatIt was a manualised behavioural activation intervention, adapted for people with learning disabilities and depression. StepUp was an adapted guided self-help intervention., Main Outcome Measures: The primary outcome measure was the Glasgow Depression Scale for people with a Learning Disability (GDS-LD). Secondary outcomes included carer ratings of depressive symptoms and aggressiveness, self-reporting of anxiety symptoms, social support, activity and adaptive behaviour, relationships, quality of life (QoL) and life events, and resource and medication use., Results: There were 161 participants randomised (BeatIt, n  = 84; StepUp, n  = 77). Participant retention was strong, with 141 completing the trial. Most completed therapy (BeatIt: 86%; StepUp: 82%). At baseline, 63% of BeatIt participants and 66% of StepUp participants were prescribed antidepressants. There was no statistically significant difference in GDS-LD scores between the StepUp (12.94 points) and BeatIt (11.91 points) groups at the 12-month primary outcome point. However, both groups improved during the trial. Other psychological and QoL outcomes followed a similar pattern. There were no treatment group differences, but there was improvement in both groups. There was no economic evidence suggesting that BeatIt may be more cost-effective than StepUp. However, treatment costs for both groups were approximately only 4-6.5% of the total support costs. Results of the qualitative research with participants, supporters and therapists were in concert with the quantitative findings. Both treatments were perceived as active interventions and were valued in terms of their structure, content and perceived impact., Limitations: A significant limitation was the absence of a treatment-as-usual (TAU) comparison., Conclusions: Primary and secondary outcomes, economic data and qualitative results all clearly demonstrate that there was no evidence for BeatIt being more effective than StepUp., Future Work: Comparisons against TAU are required to determine whether or not these interventions had any effect., Trial Registration: Current Controlled Trials ISRCTN09753005., Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 53. See the NIHR Journals Library website for further project information., Competing Interests: Christopher Williams reports personal fees from Taylor and Francis (Abingdon, UK) and from Five Areas Ltd (Clydebank, UK) outside the submitted work and is president of the British Association for Behavioural and Cognitive Psychotherapies (BABCP). Sally-Ann Cooper reports grants from the National Institute for Health Research Health Technology Assessment programme during the conduct of the study.

Background: Psychological therapies are first-line interventions for depression, but existing provision is not accessible for many adults with intellectual disabilities. We investigated the clinical and cost-effectiveness of a behavioural activation intervention (BeatIt) for people with intellectual disabilities and depression. BeatIt was compared with a guided self-help intervention (StepUp)., Methods: We did a multicentre, single-blind, randomised, controlled trial with follow-up at 4 months and 12 months after randomisation. Participants aged 18 years or older, with mild to moderate intellectual disabilities and clinically significant depression were recruited from health and social care services in the UK. The primary outcome was the Glasgow Depression Scale for people with a Learning Disability (GDS-LD) score at 12 months. Analyses were done on an intention-to-treat basis. This trial is registered with ISCRTN, number ISRCTN09753005., Findings: Between Aug 8, 2013, and Sept 1, 2015, 161 participants were randomly assigned (84 to BeatIt; 77 to StepUp); 141 (88%) participants completed the trial. No group differences were found in the effects of BeatIt and StepUp based on GDS-LD scores at 12 months (12·03 [SD 7·99] GDS-LD points for BeatIt vs 12·43 [SD 7·64] GDS-LD points for StepUp; mean difference 0·26 GDS-LD points [95% CI -2·18 to 2·70]; p=0·833). Within-group improvements in GDS-LD scores occurred in both groups at 12 months (BeatIt, mean change -4·2 GDS-LD points [95% CI -6·0 to -2·4], p<0·0001; StepUp, mean change -4·5 GDS-LD points [-6·2 to -2·7], p<0·0001), with large effect sizes (BeatIt, 0·590 [95% CI 0·337-0·844]; StepUp, 0·627 [0·380-0·873]). BeatIt was not cost-effective when compared with StepUp, although the economic analyses indicated substantial uncertainty. Treatment costs were only approximately 3·6-6·8% of participants' total support costs. No treatment-related or trial-related adverse events were reported., Interpretation: This study is, to our knowledge, the first large randomised controlled trial assessing individual psychological interventions for people with intellectual disabilities and mental health problems. These findings show that there is no evidence that BeatIt is more effective than StepUp; both are active and potentially effective interventions., Funding: National Institute for Health Research., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use., Objective: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity., Design: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs., Setting: Multicentre study involving all five UK officially designated NHS adult lung transplant centres., Participants: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list., Intervention: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation., Main Outcome Measures: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs., Results: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study., Conclusions: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation., Trial Registration: Current Controlled Trials ISRCTN44922411., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.