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Background: Effective, scalable interventions are needed to prevent poor mental health in young people. Although mental health apps can provide scalable prevention, few have been rigorously tested in high-powered trials built on models of healthy emotional functioning or tailored to individual profiles. We aimed to test a personalised emotional competence app versus a cognitive behavioural therapy (CBT) self-help app versus a self-monitoring app to prevent an increase in depression symptoms in young people., Methods: This multicentre, parallel, open-label, randomised controlled trial, within a cohort multiple randomised trial (including a parallel trial of wellbeing promotion) was done at four university trial sites in the UK, Germany, Spain, and Belgium. Participants were recruited from schools, universities, and social media from the four respective countries. Eligible participants were aged 16-22 years with increased vulnerability indexed by baseline emotional competence profile, without current or past diagnosis of major depression. Participants were randomly assigned (1:1:1) to usual practice plus either the personalised emotional competence self-help app, the generic CBT self-help app, or the self-monitoring app by an independent computerised system, minimised by country, age, and self-reported gender, and followed up for 12 months post-randomisation. Outcome assessors were masked to group allocation. The primary outcome was depression symptoms (according to Patient Health Questionnaire-9 [PHQ-9]) at 3-month follow-up, analysed in participants who completed the 3-month follow-up assessment. The study is registered with ClinicalTrials.gov, NCT04148508, and is closed., Findings: Between Oct 15, 2020, and Aug 3, 2021, 1262 participants were enrolled, including 417 to the emotional competence app, 423 to the CBT app, and 422 to the self-monitoring app. Mean age was 18·8 years (SD 2·0). Of 1262 participants self-reporting gender, 984 (78·0%) were female, 253 (20·0%) were male, 15 (1·2%) were neither, and ten (0·8%) were both. 178 participants in the emotional competence app group, 191 in the CBT app group, and 199 in the self-monitoring app group completed the follow-up assessment at 3 months. At 3 months, depression symptoms were lower with the CBT app than the self-monitoring app (mean difference in PHQ-9 -1·18 [95% CI -2·01 to -0·34]; p=0·006), but depression symptoms did not differ between the emotional competence app and the CBT app (0·63 [-0·22 to 1·49]; p=0·15) or the self-monitoring app and emotional competence app (-0·54 [-1·39 to 0·31]; p=0·21). 31 of the 541 participants who completed any of the follow-up assessments received treatment in hospital or were admitted to hospital for mental health-related reasons considered unrelated to interventions (eight in the emotional competence app group, 15 in the CBT app group, and eight in the self-monitoring app group). No deaths occurred., Interpretation: The CBT app delayed increases in depression symptoms in at-risk young people relative to the self-monitoring app, although this benefit faded by 12 months. Against hypotheses, the emotional competence app was not more effective at reducing depression symptoms than the self-monitoring app. CBT self-help apps might be valuable public mental health interventions for young people given their scalability, non-consumable nature, and affordability., Funding: European Commission., Competing Interests: Declaration of interests ERW reports royalties from Guilford Press for a CBT treatment manual he authored and is an expert member of the NICE Guidelines for treatment of adult depression. MFr is a founder and shareholder of Monsenso. BWS is a founder and shareholder of audEERING. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Based on evidence that mental health is more than an absence of mental disorders, there have been calls to find ways to promote flourishing at a population level, especially in young people, which requires effective and scalable interventions. Despite their potential for scalability, few mental wellbeing apps have been rigorously tested in high-powered trials, derived from models of healthy emotional functioning, or tailored to individual profiles. We aimed to test a personalised emotional competence self-help app versus a cognitive behavioural therapy (CBT) self-help app versus a self-monitoring app to promote mental wellbeing in healthy young people., Methods: This international, multicentre, parallel, open-label, randomised controlled trial within a cohort multiple randomised trial (including a parallel trial of depression prevention) was done at four university trial sites in four countries (the UK, Germany, Spain, and Belgium). Participants were recruited from schools and universities and via social media from the four respective countries. Eligible participants were aged 16-22 years with well adjusted emotional competence profiles and no current or past diagnosis of major depression. Participants were randomised (1:1:1) to usual practice plus either the emotional competence app, the CBT app or the self-monitoring app, by an independent computerised system, minimised by country, age, and self-reported gender, and followed up for 12 months post-randomisation. The primary outcome was mental wellbeing (indexed by the Warwick-Edinburgh Mental Well Being Scale [WEMWBS]) at 3-month follow-up, analysed in participants who completed the 3-month follow-up assessment. Outcome assessors were masked to group allocation. The study is registered with ClinicalTrials.gov, NCT04148508, and is closed., Findings: Between Oct 15, 2020, and Aug 3, 2021, 2532 participants were enrolled, and 847 were randomly assigned to the emotional competence app, 841 to the CBT app, and 844 to the self-monitoring app. Mean age was 19·2 years (SD 1·8). Of 2532 participants self-reporting gender, 1896 (74·9%) were female, 613 (24·2%) were male, 16 (0·6%) were neither, and seven (0·3%) were both. 425 participants in the emotional competence app group, 443 in the CT app group, and 447 in the self-monitoring app group completed the follow-up assessment at 3 months. There was no difference in mental wellbeing between the groups at 3 months (global p=0·47). The emotional competence app did not differ from the CBT app (mean difference in WEMWBS -0·21 [95% CI -1·08 to 0·66]) or the self-monitoring app (0·32 [-0·54 to 1·19]) and the CBT app did not differ from the self-monitoring app (0·53 [-0·33 to 1·39]). 14 of 1315 participants were admitted to or treated in hospital (or both) for mental health-related reasons, which were considered unrelated to the interventions (five participants in the emotional competence app group, eight in the CBT app group, and one in the self-monitoring app group). No deaths occurred., Interpretation: The emotional competence app and the CBT app provided limited benefit in promoting mental wellbeing in healthy young people. This finding might reflect the low intensity of these interventions and the difficulty improving mental wellbeing via universal digital interventions implemented in low-risk populations., Funding: European Commission., Competing Interests: Declaration of interests ERW receives royalties from Guilford Press for a CBT treatment manual he authored and was an expert member of the NICE Guidelines for treatment of adult depression. MFr is a founder and shareholder of Monsenso. BWS is a founder and shareholder of audEERING. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Physical rehabilitation may improve health and wellbeing outcomes for some adults living with long COVID. However, individuals living with pre-existing multiple long-term conditions (MLTCs) and long COVID may have additional rehabilitation challenges. This scoping review aims to identify the available evidence describing physical rehabilitation interventions for adults living with long COVID, to systematically map the reporting of pre-existing MLTCs, and to describe the characteristics of physical rehabilitation interventions used in adults with both pre-existing long-term conditions (LTCs) and long COVID., Methods: MEDLINE, CINAHL, Scopus, APA PsycInfo, medRxiv, OpenGrey and MedNar were searched from January 2020 to July 2023. Eligibility criteria included adults with long COVID, rehabilitation interventions including a physical component in any setting and any study design investigating interventions or intervention content except case series/reports., Results: Of 5326 unique records, 50 articles met the inclusion criteria, of which 25 (50%) made reference to pre-existing LTCs. These articles included four protocols and one consensus statement. Four of the remaining 20 studies (20%) reported the number of pre-existing LTCs, enabling the differentiation of individuals with MLTCs. One study reported outcomes of individuals with MLTCs separately to those without. The interventions described (k=24) typically consisted of combined aerobic and strength exercises (k=17 (71%)) in an outpatient setting (k=13 (54%))., Conclusions: There is limited and inconsistent reporting of the presence of MLTCs in studies of physical rehabilitation for adults with long COVID. Clarity and consistency of reporting of MLTCs is required to enable evaluation and adaptation of interventions to improve health and wellbeing for this population., Competing Interests: Conflicts of interest: E. Daynes reports lecture honoraria from Clinical Physio; honoraria from the Neuroscience and Mental Health Institute (funding committee 2023); and leadership roles with the BTS as chair of the Pulmonary Rehabilitation Specialist Advisory Group, Lead Expert Member NICE HTA EVA for Digital Rehabilitation, ATS Pulmonary Rehabilitation Assembly committee member, NRAP steering group, PRSAS steering group, CAHPR East Midlands Hub Lead and NIHR HS&DR funding committee member. R.S. Taylor reports two grants in multimorbidity research he is co-leading: Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity) – The PERFORM trial, funded by NIHR Programme Grants (NIHR202020), and Affordable Cardiac Rehabilitation: An Outreach Inter-disciplinary Strategic Study (ACROSS), funded by the NIHR Research and Innovation for Global Health Transformation (RIGHT) Programme (NIHR205540). S.J. Singh reports two grants in multimorbidity research she is co-leading: Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity) – The PERFORM trial, funded by NIHR Programme Grants (NIHR202020), and Affordable Cardiac Rehabilitation: An Outreach Inter-disciplinary Strategic Study (ACROSS), funded by the NIHR Research and Innovation for Global Health Transformation (RIGHT) Programme (NIHR205540). S.J. Singh also reports leadership roles as NIHR Senior Investigator and Clinical Lead for the NACAP Audit for Pulmonary Rehabilitation, outside the submitted work. R.A. Evans reports grants from the NIHR, UKRI, Wolfson Foundation, Genentec, Roche and Synairgen; consulting fees from AstraZeneca and Evidera; lecture honoraria from Boehringer; travel support from Chiesi; and leadership roles as ERS Group 01.02 Rehabilitation and Chronic Care Chair and ATS Pulmonary Rehabilitation Assembly Chair, outside the submitted work. The remaining authors (L. Gardiner, H.M.L. Young, H. Drover, E. Morgan-Selvaratnam, M. Natt, N. Smith and M.W. Orme) have no conflicts of interest to declare., (Copyright ©The authors 2024.)

Background: The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement has improved the quality of reporting of randomised trial protocols. Extensions to the SPIRIT statement are needed to address specific issues of trial protocol reporting, including those relevant to particular types of interventions. Methodological and reporting deficiencies in protocols of clinical trials of implantable neurostimulation devices are common. The SPIRIT-iNeurostim extension is a new reporting guideline for randomised controlled trial protocols evaluating implantable neurostimulation devices., Methods: SPIRIT-iNeurostim was developed using the EQUATOR methodological framework including a literature review and expert consultation to generate an initial list of candidate items. The candidate items were included in a two-round Delphi survey, discussed at an international consensus meeting (42 stakeholders including healthcare professionals, methodologists, journal editors and industry representatives from the United States, United Kingdom, Netherlands and other countries), and refined through a checklist pilot (18 stakeholders)., Findings: The initial extension item list included 42 candidate items relevant to SPIRIT-iNeurostim. We received 132 responses in the first round of the Delphi survey and 99 responses in the second round. Participants suggested an additional 14 candidate items for SPIRIT-iNeurostim during the first round of the survey, and those achieving initial consensus were discussed at the consensus meeting. The SPIRIT-iNeurostim extension includes 5 new checklist items, including one item for reporting the neurostimulation intervention comprising a separate checklist of 14 items., Interpretation: The SPIRIT-iNeurostim extension will help to promote increased transparency, clarity, and completeness of reporting trial protocols evaluating implantable neurostimulation devices. It will assist journal editors, peer-reviewers, and readers to better interpret the appropriateness and generalisability of the methods used for a planned clinical trial., Funding: Abbott, Boston Scientific Corp., Mainstay Medical, Medtronic Ltd, Nevro Corp., and Saluda Medical., Competing Interests: RVD reports consultancy fees from Mainstay Medical, Medtronic Ltd and Saluda Medical outside the submitted work. He is an employee of Saluda Medical; the employer had no role in the submitted work besides its contribution as a stakeholder. SE reports consultancy fees from Mainstay Medical, Medtronic Ltd, and Saluda Medical outside the submitted work. He has received Department Research funding from Saluda Medical, and Boston Scientific. ST reports consultancy fees from Boston Scientific Corp, Mainstay Medical and Saluda Medical outside the submitted work. He has received department research funding from the National Institute of Health Research. RBN serves as an unpaid officer of the nonprofit Neuromodulation Foundation, Inc., to which grants and support have been provided by Abbott, Boston Scientific Corp, Medtronic Ltd, Nevro Corp, Nuvectra, and Stimwave Inc outside the submitted work. He receives royalties from Abbott. GB has a consulting agreement with Nevro Corp, Mainstay Medical, Boston Scientific and Abbott. He has received department research funding from Mainstay Medical and Saluda Medical. RML is an uncompensated consultant for Biotronik, Abbott, Nalu, and Saluda Medical, and has stock options from Nalu and Saluda Medical. RST reports consultancy fees from Medtronic Ltd, Nevro Corp and Saluda Medical outside the submitted work. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care. All other authors declare no competing interests., (© 2024 The Author(s).)

Background: The Consolidated Standards of Reporting Trials (CONSORT) statement has improved the quality of reporting of randomised trials. Extensions to the CONSORT statement are often needed to address specific issues of trial reporting, including those relevant to particular types of interventions. Methodological and reporting deficiencies in clinical trials of implantable neurostimulation devices are common. The CONSORT-iNeurostim extension is a new reporting guideline for randomised controlled trials evaluating implantable neurostimulation devices., Methods: CONSORT-iNeurostim was developed using the EQUATOR methodological framework including a literature review and expert consultation to generate an initial list of candidate items. The candidate items were included in a two-round Delphi survey, discussed at an international consensus meeting (42 stakeholders including healthcare professionals, methodologists, journal editors and industry representatives from the United States, United Kingdom, Netherlands and other countries), and refined through a checklist pilot (18 stakeholders)., Findings: The initial extension item list included 49 candidate items relevant to CONSORT-iNeurostim. We received 132 responses in the first round of the Delphi survey and 99 responses in the second round. Participants suggested an additional 20 candidate items for CONSORT-iNeurostim during the first round of the survey, and those achieving initial consensus were discussed at the consensus meeting. The CONSORT-iNeurostim extension includes 7 new checklist items, including one item for reporting the neurostimulation intervention comprising a separate checklist of 14 items., Interpretation: The CONSORT-iNeurostim extension will promote increased transparency, clarity, and completeness of trial reports of implantable neurostimulation devices. It will assist journal editors, peer-reviewers, and readers to better interpret the appropriateness and generalisability of the methods used and reported outcomes., Funding: Abbott, Boston Scientific Corp., Mainstay Medical, Medtronic Ltd, Nevro Corp. and Saluda Medical., Competing Interests: RVD reports consultancy fees from Mainstay Medical, Medtronic Ltd and Saluda Medical outside the submitted work. He is an employee of Saluda Medical; the employer had no role in the submitted work besides its contribution as a stakeholder. SE reports consultancy fees from Mainstay Medical, Medtronic Ltd, and Saluda Medical outside the submitted work. He has received Department Research funding from Saluda Medical, and Boston Scientific. ST reports consultancy fees from Boston Scientific Corp, Mainstay Medical and Saluda Medical outside the submitted work. He has received department research funding from the National Institute of Health Research. RBN serves as an unpaid officer of the nonprofit Neuromodulation Foundation, Inc., to which grants and support have been provided by Abbott, Boston Scientific Corp, Medtronic Ltd, Nevro Corp, Nuvectra, and Stimwave Inc outside the submitted work. He receives royalties from Abbott. GB has a consulting agreement with Nevro Corp, Mainstay Medical, Boston Scientific and Abbott. He has received department research funding from Mainstay Medical and Saluda Medical. RML is an uncompensated consultant for Biotronik, Abbott, Nalu, and Saluda Medical, and has stock options from Nalu and Saluda Medical. RST reports consultancy fees from Medtronic Ltd, Nevro Corp and Saluda Medical outside the submitted work. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care. All other authors declare no competing interests., (© 2024 The Author(s).)

Background: Frailty is of increasing interest in trials, either as a target of intervention, as an outcome or as a potential treatment modifier. However, frailty measurement is often highly variable. This scoping review assessed how frailty is quantified in randomised controlled trials (RCTs), in what context and for what purposes., Methods: We searched five electronic databases for RCTs in which frailty was measured among trial participants. We extracted data on intervention type, the frailty measure used and the purpose for which frailty was assessed. We then compared these data according to reasons for frailty assessment., Results: We identified 415 RCTs assessing frailty across a range of interventions. Frailty was used to define the target population (166 trials), as an outcome (156 trials), as an effect modifier examining interaction of frailty on treatment effect (61 trials), as a purely descriptive characteristic (42 trials) or as a prognostic marker examining the impact of frailty on future health outcome (78 trials). The trials used 28 different measures of frailty (plus 29 additional trial-specific measures). The frailty phenotype model was the most common overall (164 trials), for defining the target population (90/166 trials) and as an outcome (81/156 trials). The cumulative deficit model frailty index was also frequently used (102 trials) and was most common among trials assessing treatment effect modification (21/61 trials)., Conclusion: Frailty measurement in RCTs is highly variable. Understanding the properties of respective frailty measures and how these relate to frailty as encountered in clinical practice is a priority to ensure that trial findings can inform healthcare delivery for people living with frailty., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Aims: Adapting interventions with an existing evidence base offers a more efficient approach than developing a new intervention. The aim of this study was to describe the process of adapting a home-based cardiac rehabilitation (CR) programme (REACH-HF) intervention originally developed in the UK for people with heart failure (HF) to the Danish health system-the 'DK:REACH-HF' programme., Methods and Results: We followed methodological framework for the conduct and reporting of studies adapting interventions, utilizing documentary analysis, qualitative interviews, stakeholder consultations, and mapping of the Danish policy context. Our study found broad support for the REACH-HF intervention as an alternative to existing centre-based CR. We also identified three key areas of adaptation for the Danish context. First, reduce the word count of the intervention's resources by linking to existing publicly available CR materials. Second, while retaining REACH-HF core components, adapt its content and delivery to reflect differences between Denmark and UK. Third, develop a digital version of the intervention., Conclusion: Using an evidence-based approach, we successfully adapted the REACH-HF intervention to the context of the Danish healthcare setting, maintaining core components of the original intervention and developing both a paper-based and digital version of the programme material. To inform scaled national implementation of the DK:REACH-HF programme, we seek to undertake a pilot study to test the adapted intervention materials feasibility and acceptability to healthcare practitioners, patients, and their caregivers and confirm the positive impact on the outcomes of HF patients and caregivers., Competing Interests: Conflict of interest: R.S.T. and H.M.D. are part of the original developers of the REACH-HF intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: Conflict of interest: None declared.

Introduction: Chronic pain is a personal experience influenced by multiple biopsychosocial factors. Using a pain intensity measure alone to assess the effectiveness of a chronic pain intervention fails to fully evaluate its impact on the multifaceted chronic pain experience. The holistic minimal clinically important difference (MCID) is a composite outcome developed to provide a comprehensive assessment of chronic pain in response to intervention, across 5 outcome domains: pain intensity, health-related quality of life, sleep quality, physical, and emotional function. To focus on domains where the individual need is greatest, the holistic MCID reflects the cumulative MCID averaged over only the domains where subjects were impaired preintervention., Objectives: To assess the internal and construct validity of the Holistic MCID score to inform its future use as an evidence-based tool., Methods: This validation study was undertaken using data from the EVOKE trial with 111 patients up to 24-month follow-up. Internal consistency of the holistic MCID was assessed using Cronbach alpha statistic and dimensional exploration using principal component analysis., Results: The holistic MCID measure demonstrated strong internal consistency with Cronbach alpha >0.7 at all follow-ups. Principal component analysis showed one overarching holistic dimension to be present in the composite. Construct validity was demonstrated by an increase in the holistic MCID score being associated with both increased Patients' Global Impression of Change, EuroQol visual analogue scale score, and each of the outcome domains in a "leave-one-out" analysis (all P < 0.001)., Conclusion: The holistic MCID provides a valid measure for the comprehensive, personalized assessment of response after a chronic pain intervention. The validity of the holistic MCID requires further confirmation in other chronic pain populations and with different interventions., Competing Interests: R.S.T. reports consultancy fees from Medtronic, Nevro and Saluda Medical outside the submitted work. C.M.M. is employed by NAMSA, a company that provides consulting and testing services to medical device manufacturers. N.A.M. reports receiving grants from Neuros, Mesoblast, and Vivex Biologics, as well as consulting as a medical monitor for Saluda Medical, Nevro, Vivex Biologics, Mainstay, Sollis Therapeutics, and Vertos outside the submitted work. J.W.K. is an advisory board member for Boston Scientific, Medtronic, Abbott, and Saluda Medical. J.E.P. reports research and consulting fees from Saluda Medical during the conduct of the study; consultancy for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; has received grant and research support from: Abbott, Flowonix, Aurora, Painteq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and is a shareholder of Vertos, SPR Therapeutics, Painteq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, and Anesthetic Gas Reclamation. C.W.H. has received consultancy fees from Saluda Medical and Genecentrix outside the submitted work. S.J.C. reports receiving grants from Saluda Medical, Vertos, Mainstay, and Vivex outside the submitted work. L.K. reports receiving grants from Nevro, Neuros, Avanos, Medtronic, Neuralace, and Xalud Therapeutics and financial support from Nevro, Avanos, and Saluda Medical outside the submitted work. C.A.G. reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific and Saluda Medical outside the submitted work. E.A.P. has received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda Medical outside the submitted work, as well as personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda Medical, and Vertos outside the submitted work. She holds stock options from SynerFuse and neuro42. K.V.P. is a consultant and speaker for Abbott. S.E. reports consultancy fees from Medtronic, and Mainstay Medical outside the submitted work. He has received department research funding from the National Institute of Health Research, Saluda Medical and Medtronic. R.M.L. is an uncompensated consultant for Biotronik, Abbott, Nalu, Saluda Medical, and Mainstay Medical and has stock options from Nalu and Saluda Medical. C.G. reports payment to his institution (for part of his salary) and stock options received from Mainstay, personal fees from Mainstay, Saluda Medical, Persica, and Iliad outside the submitted work, research funded by Sollis, expert witness testimony fees, and serves as Editor-in-Chief of Pain Practice. S.D. has received consulting payments from Averitas Pharma and Biotronik outside the submitted work. A.A. reports consultancy for Medtronic, Avanos, and StimWave outside the submitted work. P.B. reports consulting fees from Abbott and PainTEQ outside the submitted work. E.H., A.L., N.S. and R.V.D. are employees of Saluda Medical. R.V.D. has previously received consultancy fees from Mainstay Medical, Medtronic, and Saluda Medical. D.J.C. has consulted for AbbVie, Heron Therapeutics, Aptinyx, Neumentum, Regeneron Pharmaceuticals, Swing Therapeutics, Virios Therapeutics, Allergan Sales, Eli Lilly and Company, H. Lundback A/S, Pfizer, Samumed, Tonix Pharmaceuticals. T.J.N. has received consultancy fees from Saluda Medical outside the submitted work. The remaining authors declare no conflict of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: The SENZA-PDN study evaluated high-frequency 10-kHz spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy (PDN). Over 24 months, 10-kHz SCS provided sustained pain relief and improved health-related quality of life. This report presents additional outcomes from the SENZA-PDN study, focusing on diabetes-related pain and quality of life outcomes., Methods: The SENZA-PDN study randomized 216 participants with refractory PDN to receive either conventional medical management (CMM) or 10-kHz SCS plus CMM (10-kHz SCS + CMM), allowing crossover after six months if pain relief was insufficient. Postimplantation assessments at 24 months were completed by 142 participants with a permanent 10-kHz SCS implant, comprising 84 initial and 58 crossover recipients. Measures included the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), Diabetes-Related Quality of Life (DQOL), Global Assessment of Functioning (GAF), and treatment satisfaction., Results: Over 24 months, 10-kHz SCS treatment significantly reduced pain severity by 66.9% ( P < .001; BPI-DPN) and pain interference with mood and daily activities by 65.8% ( P < .001; BPI-DPN). Significant improvements were also observed in overall DQOL score ( P < .001) and GAF score ( P < .001), and 91.5% of participants reported satisfaction with treatment., Conclusions: High-frequency 10-kHz SCS significantly decreased pain severity and provided additional clinically meaningful improvements in DQOL and overall functioning for patients with PDN. The robust and sustained benefits over 24 months, coupled with high participant satisfaction, highlight that 10-kHz SCS is an efficacious and comprehensive therapy for patients with PDN., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EAP has received consulting fees from Abbott Laboratories, Biotronik, Boston Scientific, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, Presidio Medical, Saluda, and Vertos Medical; research support from Mainstay, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, ReNeuron, Saluda, and SPR; and stock options from neuro42 and SynerFuse. TGS has received research support from Nevro Corp. JAS has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. MJJ is an employee of Nevro Corp. DRE received a fee from Nevro Corp for the preparation of this manuscript in her capacity as an independent medical writer. JLW has received consulting fees from California Institute for Biomedical Research and Eli Lilly and research support from Nevro Corp. SMS has received research support from Nevro Corp. KA has received consulting fees from Biotronik, Medtronic, Nalu Medical, Nevro Corp, and Saluda Medical, as well as research support from Biotronik, IPM Medical Group, Nevro Corp, Saluda Medical, SPR Therapeutics, and Vivex Biologics. MNG has received consulting fees from Abbott Laboratories, Avanos Medical, Avertis Pharmacy, Boston Scientific, Nevro Corp, and Saluda Medical, as well as research support from Abbott Laboratories, Avanos Medical, Boston Scientific, Nalu Medical, Neuros Medical, Nevro Corp, and Saluda Medical. JX has received research support from the Cleveland Clinic Velosano Program, the National Institutes of Health, the Steve and Melody Golding Foundation, and Nevro Corp. CY has received research support from Nevro Corp. AN has received consulting fees from Aurora Spine, Flowonix, and Nevro Corp, as well as research support from Nevro Corp. DGP has received consulting fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, Aurora Spine, CornerLoc, Flowonix, Lundbeck, Pajunk Medical, Saluda Medical, Spark Biomedical, and Vertos Medical; research support from Abbott Laboratories, Aurora Spine, Flowonix, Nevro Corp, and Saluda Medical; speakers’ bureau or honoraria from Abbott Laboratories, Allergan, Amgen, CornerLoc, Lundbeck, Saluda Medical, and Vertos Medical; and stock options from CornerLoc. MJC has received research support from Nevro Corp. VG has received research support from Biotronik, Medtronic, Nevro Corp, PainTEQ, SPR Therapeutics, and St. Jude. RHB has received research support from Nevro Corp. NDM has received consulting fees from Averitas, Nevro Corp, and Salix Pharmaceuticals, as well as research support from Boston Scientific and Nevro Corp. DS has received consulting fees from Abbott Laboratories, Boston Scientific, Flowonix, Medtronic, Nevro Corp, Vertiflex, and Vertos Medical, as well as research support from Abbott Laboratories, Biotronik, Nevro Corp, Vertiflex, and Vertos Medical. SPL has received consulting fees from Nevro Corp and research support from Nevro Corp. DJD has received research support from Nevro Corp, as well as funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. KAS has received research support from Nevro Corp. JHG has received consulting fees from Abbott Laboratories, Saluda Medical, and Stratus Medical. PWW has received research support from Nevro Corp. CEA has received consulting fees from AbbVie, Amgen, Biohaven, Clexio Biosciences, Collegium, Eli Lilly, Elsevier, Flowonix, Gene Pharma, Lundbeck, Nevro Corp, Novartis, Pfizer, SK Life Science, Teva Pharmaceutical, and Vertex, as well as research support from AbbVie, Allergan, Amgen, Daiichi Sankyo, Eli Lilly, Novartis, Teva Pharmaceutical, and Vertex Pharmaceuticals. CEN has received consulting fees from Exelixis, Neurogastrx, and Nevro Corp, as well as research support from Nevro Corp. RST has received consulting fees from Nevro Corp, Medtronic, and Saluda Medical. DLC is an employee of Nevro Corp. NAM has received consulting fees from Nevro Corp, Relievant Medsystems, Saluda Medical, Sollis Therapeutics, and Vertos Medical, as well as research support from Avanos Medical, Mesoblast, Neuros Medical, and Nevro Corp.

Background and Objective: The minimum sample size for multistakeholder Delphi surveys remains understudied. Drawing from three large international multistakeholder Delphi surveys, this study aimed to: 1) investigate the effect of increasing sample size on replicability of results; 2) assess whether the level of replicability of results differed with participant characteristics: for example, gender, age, and profession., Methods: We used data from Delphi surveys to develop guidance for improved reporting of health-care intervention trials: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extension for surrogate end points (n = 175, 22 items rated); CONSORT-SPI [CONSORT extension for Social and Psychological Interventions] (n = 333, 77 items rated); and core outcome set for burn care (n = 553, 88 items rated). Resampling with replacement was used to draw random subsamples from the participant data set in each of the three surveys. For each subsample, the median value of all rated survey items was calculated and compared to the medians from the full participant data set. The median number (and interquartile range) of medians replicated was used to calculate the percentage replicability (and variability). High replicability was defined as ≥80% and moderate as 60% and <80% RESULTS: The average median replicability (variability) as a percentage of total number of items rated from the three datasets was 81% (10%) at a sample size of 60. In one of the datasets (CONSORT-SPI), a ≥80% replicability was reached at a sample size of 80. On average, increasing the sample size from 80 to 160 increased the replicability of results by a further 3% and reduced variability by 1%. For subgroup analysis based on participant characteristics (eg, gender, age, professional role), using resampled samples of 20 to 100 showed that a sample size of 20 to 30 resulted to moderate replicability levels of 64% to 77%., Conclusion: We found that a minimum sample size of 60-80 participants in multistakeholder Delphi surveys provides a high level of replicability (≥80%) in the results. For Delphi studies limited to individual stakeholder groups (such as researchers, clinicians, patients), a sample size of 20 to 30 per group may be sufficient., Competing Interests: Declaration of competing interest There are no competing interests for any author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Context: Randomized trials have demonstrated the superiority of intraosseous basivertebral nerve ablation (BVNA) compared with sham and standard care in terms of improvements in pain, disability, and health-related quality of life in patients with vertebrogenic chronic low back pain (cLBP)., Purpose: To assess the cost effectiveness of BVNA in patients with vertebrogenic cLBP compared to standard care alone., Study Design/setting: A model-based economic analysis., Patient Sample: Base case analysis used INTRACEPT, a randomized trial comparing BVNA with standard care in 140 patients with vertebrogenic cLBP, recruited from 23 sites across the United States, with a follow-up, up to 5 years. Scenario analyses compared data from the Surgical Multicenter Assessment of Radiofrequency Ablation for the Treatment of Vertebrogenic Back Pain (SMART) randomized trial against a sham control, and a single-arm study., Outcome Measures: Costs and quality-adjusted life years (QALYs) were calculated to determine the incremental cost-effectiveness ratio (ICER)., Methods: A cost-effectiveness model was built in Microsoft Excel to evaluate the costs and health outcomes of patients undergoing BVNA using the Intracept Procedure (Relievant Medsystems) to treat vertebrogenic cLBP from a US payor perspective. Alternative scenario sensitivity analyses and probabilistic sensitivity analyses were conducted to assess the robustness of the model results. QALYs were discounted at 3.0% per year., Results: Base case analysis showed that BVNA relative to standard care alone was a cost-effective strategy for the management of patients with vertebrogenic cLBP, with an ICER of US$11,376 per QALY at a 5-year time horizon from introduction of the procedure. Modeling demonstrated a >99% probability that this was cost effective in the US, based on a willingness-to-pay threshold of US$100,000 to US$150,000. Various sensitivity and scenario analyses produced ICERs that all remained below this threshold., Conclusions: BVNA with the Intracept Procedure offers patients with vertebrogenic cLBP, clinicians, and healthcare systems a cost-effective treatment compared to standard care alone., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, disrupts the heart's rhythm through numerous small re-entry circuits in the atrial tissue, leading to irregular atrial contractions. The condition poses significant health risks, including increased stroke risk, heart failure, and reduced quality of life. Given the complexity of AF and its growing incidence globally, exercise-based cardiac rehabilitation (ExCR) may provide additional benefits for people with AF or those undergoing routine treatment for the condition., Objectives: To assess the benefits and harms of ExCR compared with non-exercise controls for people who currently have AF or who have been treated for AF., Search Methods: We searched the following electronic databases: CENTRAL in the Cochrane Library, MEDLINE Ovid, Embase Ovid, PsycINFO Ovid, Web of Science Core Collection Thomson Reuters, CINAHL EBSCO, LILACS BIREME, and two clinical trial registers on 24 March 2024. We imposed no language restrictions., Selection Criteria: We included randomised clinical trials (RCTs) that investigated ExCR interventions compared with any type of non-exercise control. We included adults 18 years of age or older with any subtype of AF or those who had received treatment for AF., Data Collection and Analysis: Five review authors independently screened and extracted data in duplicate. We assessed risk of bias using Cochrane's RoB 1 tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed clinical and statistical heterogeneity by visual inspection of the forest plots and by using standard Chi² and I² statistics. We performed meta-analyses using random-effects models for continuous and dichotomised outcomes. We calculated standardised mean differences where different scales were used for the same outcome. We used the GRADE approach to assess the certainty of the evidence., Main Results: We included 20 RCTs involving a total of 2039 participants with AF. All trials were conducted between 2006 and 2024, with a follow-up period ranging from eight weeks to five years. We assessed the certainty of evidence as moderate to very low. Five trials assessed comprehensive ExCR programmes, which included educational or psychological interventions, or both; the remaining 15 trials compared exercise-only cardiac rehabilitation with controls. The overall risk of bias in the included studies was mixed. Details on random sequence generation, allocation concealment, and use of intention-to-treat analysis were typically poorly reported. Evidence from nine trials (n = 1173) suggested little to no difference in mortality between ExCR and non-exercise controls (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.76 to 1.49; I² = 0%; 101 deaths; low-certainty evidence). Based on evidence from 10 trials (n = 825), ExCR may have little to no effect on SAEs (RR 1.30, 95% CI 0.63 to 2.67; I² = 0%; 28 events; low-certainty evidence). Evidence from four trials (n = 378) showed that ExCR likely reduced AF recurrence (measured via Holter monitoring) compared to controls (RR 0.70, 95% CI 0.56 to 0.88; I² = 2%; moderate-certainty evidence). ExCR may reduce AF symptom severity (mean difference (MD) -1.59, 95% CI -2.98 to -0.20; I² = 61%; n = 600; low-certainty evidence); likely reduces AF symptom burden (MD -1.61, 95% CI -2.76 to -0.45; I² = 0%; n = 317; moderate-certainty evidence); may reduce AF episode frequency (MD -1.29, 95% CI -2.50 to -0.07; I² = 75%; n = 368; low-certainty evidence); and likely reduces AF episode duration (MD -0.58, 95% CI -1.14 to -0.03; I² = 0%; n = 317; moderate-certainty evidence), measured via the AF Severity Scale (AFSS) questionnaire. Moderate-certainty evidence from six trials (n = 504) showed that ExCR likely improved the mental component summary measure in health-related quality of life (HRQoL) of the 36-item Short Form Health Survey (SF-36) (MD 2.66, 95% CI 1.22 to 4.11; I² = 2%), but the effect of ExCR on the physical component summary measure was very uncertain (MD 1.75, 95% CI -0.31 to 3.81; I² = 52%; very low-certainty evidence). ExCR also may improve individual components of HRQoL (general health, vitality, emotional role functioning, and mental health) and exercise capacity (peak oxygen uptake (VO 2peak ) and 6-minute walk test) following ExCR. The effects of ExCR on serious adverse events and exercise capacity were consistent across different models of ExCR delivery: centre compared to home-based, exercise dose, exercise only compared to comprehensive programmes, and aerobic training alone compared to aerobic plus resistance programmes. Using univariate meta-regression, there was evidence of significant association between location of trial and length of longest follow-up on exercise capacity., Authors' Conclusions: Due to few randomised participants and typically short-term follow-up, the impact of ExCR on all-cause mortality or serious adverse events for people with AF is uncertain. ExCR likely improves AF-specific measures including reduced AF recurrence, symptom burden, and episode duration, as well as the mental components of HRQoL. ExCR may improve AF symptom severity, episode frequency, and VO 2peak . Future high-quality RCTs are needed to assess the benefits of ExCR for people with AF on patient-relevant outcomes including AF symptom severity and burden, AF recurrence, AF-specific quality of life, and clinical events such as mortality, readmissions, and serious adverse events. High-quality trials are needed to investigate how AF subtype and clinical setting (i.e. primary and secondary care) may influence ExCR effectiveness., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Adaptation seeks to transfer and implement healthcare interventions developed and evaluated in one context to another. The aim of this scoping review was to understand current approaches to the adaptation of complex interventions for people with long-term conditions (LTCs) and to identify issues for studies performed in low- and middle-income countries (LMICs). Bibliographic databases were searched from 2000 to October 2022. This review involved five stages: (i) definition of the research question(s); (ii) identifying relevant studies; (iii) study selection; (iv) data charting; and (v) data synthesis. Extraction included an assessment of the: rationale for adaptation; stages and levels of adaptation; use of theoretical frameworks, and quality of reporting using a checklist based on the 2021 ADAPT guidance. Twenty-five studies were included from across 21 LTCs and a range of complex interventions. The majority (16 studies) focused on macro (national or international) level interventions. The rationale for adaptation included intervention transfer across geographical settings [high-income country (HIC) to LMIC: six studies, one HIC to another: eight studies, one LMIC to another: two studies], or transfer across socio-economic/racial groups (five studies), or transfer between different health settings within a single country (one study). Overall, studies were judged to be of moderate reporting quality (median score 23, maximum 46), and typically focused on early stages of adaptation (identification and development) with limited outcome evaluation or implementation assessment of the adapted version of the intervention. Improved reporting of the adaptation for complex interventions targeted at LTCs is needed. Development of future adaptation methods guidance needs to consider the needs and priorities of the LMIC context., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Aim: Depression and anxiety occur frequently in individuals with cardiovascular disease and are associated with poor prognosis. This Cochrane systematic review and meta-analysis assessed the effectiveness of psychological interventions on psychological and clinical outcomes in adults with coronary heart disease (CHD), heart failure (HF) or atrial fibrillation (AF)., Methods and Result: CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL databases were searched from January 2009 to July 2022 for randomised controlled trials of psychological interventions versus controls in adults with CHD, HF or AF. Twenty-one studies (n = 2591) were assessed using random-effects models. We found psychological interventions reduced depression (standardised mean difference [SMD] -0.36; 95% confidence interval [CI] -0.65 to -0.06; P = 0.02), anxiety (SMD -0.57; 95% CI -0.96 to -0.18; P = 0.004), and improved mental health-related quality of life (HRQoL) (SMD 0.63, 95% CI 0.01 to 1.26; P = 0.05) (follow-up 6-12 months), but not physical health-related quality of life, all-cause mortality or major adverse cardiovascular events compared with controls. High heterogeneity was present across meta-analyses. Meta-regression analysis showed that psychological interventions designed to target anxiety, were more effective than non-targeted interventions., Conclusion: This review found that psychological interventions improved depression, anxiety and mental HRQoL, with those targeting anxiety to show most benefit. Given the statistical heterogeneity, the precise magnitude of effects remains uncertain. Increasing use of multifactorial psychological interventions shows promise for incorporating patient needs and preferences. Investigation of those at high risk of poor outcomes, comparison of intervention components and those with AF is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflict of interest: none declared.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the UK Medical Research Council for the submitted work. SB is a member of the NICE Decision Support Unit and NICE Guidelines Technical Support Unit; has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA, and RTI Health Solutions; received payments for educational events from Roche; and has received research funding from European Federation of Pharmaceutical Industries and Associations and Johnson & Johnson. MOu works for and has shares in AstraZeneca. JSR is a deputy editor at JAMA, was formerly an associate editor at The BMJ, and is co-founder (unpaid) of medRxiv; has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation programme (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (R01HS025164, R01HL144644), and from Arnold Ventures; was an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in September 2022. NJB has received consulting fees from Nobias Therapeutics. AA and YR are associate editors at BMC Trials. OC is an associate editor for Value in Health and has received consulting fees from MSD and Janssen. RC is a founding member of the OMERACT Technical Advisory Group, which might be perceived as a possible conflict of interest. RH has shares in Johnson & Johnson. JHP has been a consultant for AdaptivePhage, Arrevus, Atheln, BavariaNordic, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark, SpineBioPPharma, and UTIlity,Vir. GSC is a statistics editor for The BMJ, and director of the UK EQUATOR Centre. CJW has undertaken consultancy for AB Science, for which his institution has received a fee. DD is an associate editor of Value in Health.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the UK Medical Research Council for the submitted work. SB is a member of the NICE Decision Support Unit and NICE Guidelines Technical Support Unit; has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA, and RTI Health Solutions; received payments for educational events from Roche; and has received research funding from European Federation of Pharmaceutical Industries and Associations and Johnson & Johnson. MOu works for and has shares in AstraZeneca. JSR is a deputy editor at JAMA, was formerly an associate editor at The BMJ, and is co-founder (unpaid) of medRxiv; has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation programme (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (R01HS025164, R01HL144644), and from Arnold Ventures; was an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in September 2022. NJB has received consulting fees from Nobias Therapeutics. AA and YR are associate editors at BMC Trials. OC is an associate editor for Value in Health and has received consulting fees from MSD and Janssen. RC is a founding member of the OMERACT Technical Advisory Group, which might be perceived as a possible conflict of interest. RH has shares in Johnson & Johnson. JHP has been a consultant for AdaptivePhage, Arrevus, Atheln, BavariaNordic, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark, SpineBioPPharma, and UTIlity,Vir. GSC is a statistics editor for The BMJ, and director of the UK EQUATOR Centre. CJW has undertaken consultancy for AB Science, for which his institution has received a fee. DD is an associate editor of Value in Health.

Background: Resistant hypertension (rHTN) is defined as blood pressure (BP) of ≥ 140/90 mmHg despite treatment with at least three antihypertensive medications, including a diuretic. Endovascular ultrasound renal denervation (uRDN) aims to control BP alongside conventional BP treatment with antihypertensive medication. This analysis assesses the cost effectiveness of the addition of the Paradise uRDN System compared with standard of care alone in patients with rHTN from the perspective of the United Kingdom (UK) health care system., Methods: Using RADIANCE-HTN TRIO trial data, we developed a state-transition model. Baseline risk was calculated using Framingham and Prospective Cardiovascular Münster (PROCAM) risk equations to estimate the long-term cardiovascular risks in patients treated with the Paradise uRDN System, based on the observed systolic BP (SBP) reduction following uRDN. Relative risks sourced from a meta-analysis of randomised controlled trials were then used to project cardiovascular events in patients with baseline SBP ('control' patients); utility and mortality inputs and costs were derived from UK data. Costs and outcomes were discounted at 3.5% per annum. Modelled outcomes were validated against trial meta-analyses and the QRISK3 algorithm and real-world evidence of RDN effectiveness. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty surrounding the model inputs and sensitivity of the model results to changes in parameter inputs. Results were reported as incremental cost-effectiveness ratios (ICERs)., Results: A mean reduction in office SBP of 8.5 mmHg with uRDN resulted in an average improvement in both absolute life-years (LYs) and quality-adjusted life-years (QALYs) gained compared with standard of care alone (0.73 LYs and 0.67 QALYs). The overall base-case ICER with uRDN was estimated at £5600 (€6500) per QALY gained (95% confidence interval £5463-£5739 [€6341-€6661]); modelling demonstrated > 99% probability that the ICER is below the £20,000-£30,000 (€23,214-€34,821) per QALYs gained willingness-to-pay threshold in the UK. Results were consistent across sensitivity analyses and validation checks., Conclusions: Endovascular ultrasound RDN with the Paradise system offers patients with rHTN, clinicians, and healthcare systems a cost-effective treatment option alongside antihypertensive medication., (© 2024. The Author(s).)

Background: It remains unclear how to meaningfully classify people living with multimorbidity (multiple long-term conditions (MLTCs)), beyond counting the number of conditions. This paper aims to identify clusters of MLTCs in different age groups and associated risks of adverse health outcomes and service use., Methods: Latent class analysis was used to identify MLTCs clusters in different age groups in three cohorts: Secure Anonymised Information Linkage Databank (SAIL) (n = 1,825,289), UK Biobank (n = 502,363), and the UK Household Longitudinal Study (UKHLS) (n = 49,186). Incidence rate ratios (IRR) for MLTC clusters were computed for: all-cause mortality, hospitalisations, and general practice (GP) use over 10 years, using <2 MLTCs as reference. Information on health outcomes and service use were extracted for a ten year follow up period (between 01 st Jan 2010 and 31st Dec 2019 for UK Biobank and UKHLS, and between 01 st Jan 2011 and 31st Dec 2020 for SAIL)., Findings: Clustering MLTCs produced largely similar results across different age groups and cohorts. MLTC clusters had distinct associations with health outcomes and service use after accounting for LTC counts, in fully adjusted models. The largest associations with mortality, hospitalisations and GP use in SAIL were observed for the " Pain+ " cluster in the age-group 18-36 years (mortality IRR = 4.47, hospitalisation IRR = 1.84; GP use IRR = 2.87) and the " Hypertension, Diabetes & Heart disease " cluster in the age-group 37-54 years (mortality IRR = 4.52, hospitalisation IRR = 1.53, GP use IRR = 2.36). In UK Biobank, the " Cancer, Thyroid disease & Rheumatoid arthritis " cluster in the age group 37-54 years had the largest association with mortality (IRR = 2.47). Cardiometabolic clusters across all age groups, pain/mental health clusters in younger groups, and cancer and pulmonary related clusters in older age groups had higher risk for all outcomes. In UKHLS, MLTC clusters were not significantly associated with higher risk of adverse outcomes, except for the hospitalisation in the age-group 18-36 years., Interpretation: Personalising care around MLTC clusters that have higher risk of adverse outcomes may have important implications for practice (in relation to secondary prevention), policy (with allocation of health care resources), and research (intervention development and targeting), for people living with MLTCs., Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020)., Competing Interests: SJS is Clinical Lead for National Respiratory Audit Programme–Pulmonary Rehabilitation and also a National Institute for Health Research (NIHR) Senior Investigator. This work was supported by the NIHR Leicester Biomedical Research Centre (BRC). KJ declares funding from NIHR Applied Research Collaboration West Midlands and Sub-committee chair for NIHR Programme Grants for Applied Health Research (payment to institution). BIN declares receiving funding from NIHR, vs. Arthritis, NIHR-EPSRC, Glasgow Knowledge Exchange Fund and for external PhD examination. RAE declares receipt of speaker fees (Boeringher June 2021; Moderna April 2023) and ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary (unpaid), and ATS Pulmonary Rehabilitation Assembly Chair (unpaid). SD declares NIHR Applied Research Collaboration: South West Peninsula (PenARC; payment to institution), receipt of the following NIHR grants (payment to institution): NIHR151938; NIHR204099; RP-PG-0514-20,002; NIHR201038; NIHR201070; NIHR200428, receipt of grants (payment to institution): Gillings Family foundation (ID 943008); The Stroke Association (ID 901902); NIHR School for Primary Care Research—Exeter internal fund (ID 856766); Academic Health Science Network South West (ID 1355693), receipt of textbook royalties (John Wiley & Sons), support for meeting attendance from NIHR (p-PG-0514- 20,002) and Health Research Council New Zealand (21/826; 18/254), and membership of NIHR Programme Grant for Applied Research funding panel committee and The Stroke Association research funding panel. SJK declares receipt of conference funding from School of Health and Wellbeing, University of Glasgow. SAS declares presidency of the UK Society of Behavioural Medicine, membership of HTA Clinical Evaluations and Trials Committee (2016–2020), membership of Commissioning Panel for the National Institute of Health Research (NIHR) Policy Research Programme (2019–2022), and membership of Chief Scientist Office HIPS committee (2018–2023). FSM declares grants from NIHR during the conduct of the study; grants from Wellcome, grants from Innovate UK, grants from Innovative Medicines Initiative (IMI2), grants from UKRI, grants from EPSRC, grants from MRC, grants from Chief Scientist office Scotland, outside the submitted work; and MRC CARP Panel membership. Dr Greaves reports grants from National Institute for Health Research (NIHR) during the conduct of the study., (© 2024 The Authors.)

Importance: Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals., Objective: To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases., Data Sources: The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023., Study Selection: Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded., Data Extraction and Synthesis: Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes., Main Outcomes and Measures: Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized., Results: Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result., Conclusions and Relevance: Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

Introduction: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant., Methods: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed., Results: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group., Conclusion: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS., Trial Registration Number: NCT02924129., Competing Interests: Competing interests: NM reports personal fees from Saluda Medical for acting as independent medical monitor for the EVOKE study during the conduct of the study; he reports receiving grants from Neuros and Mesoblast, as well as consulting as a medical monitor for Nevro, Vivex, Mainstay, and Vertos outside the submitted work. RL is an uncompensated consultant for Nalu, Saluda Medical, and Mainstay Medical and has stock options from Nalu and Saluda Medical obtained before 2019, not exercisable through the duration of his term as International Neuromodulation Society President and editor-in-chief of the journal Neuromodulation: Technology at the Neural Interface. TD reports personal fees from Saluda Medical during the conduct of the study; consultancy for Axonics, Abbott, Nalu, Vertos, SpineThera, Mainstay, Cornerloc, Ethos, SPR Therapeutics, Medtronic, Boston Scientific, PainTeq, Tissue Tech, Spinal Simplicity, and Avanos outside the submitted work. He is a minor equity holder for Saluda Medical, Nalu, SpineThera, Stimgenics, Vertiflex, Vertos, and Bioness and an advisory board member for Abbott, Vertos, Nalu, SPR Therapeutics, and Tissue Tech. LK reports receiving grants from Nevro, Neuros, Avanos, Medtronic, Neuralace, and Xalud Therapeutics and financial support from Nevro, Avanos, and Saluda Medical outside the submitted work. SL reports receiving grants and personal fees from Saluda Medical during the conduct of the study; he reports grants from Avanos, Boston Scientific, Nalu Medical, SPR Therapeutics, Averitas Pharma, Biotronik, SGX Therapeutics, and PainTeq, as well as consultancy for Abbott, Avanos, Boston Scientific, Nevro, SPR Therapeutics, Averitas Pharma, Biotronik, Nalu Medical, and PainTeq, outside the submitted work, as well as holding stock options for Nalu Medical. KA reports consultancy for Medtronic, Nevro, Boston Scientific, Nalu, Presidio, Biotronik, Mesoblast, Vivex Laboratories outside the submitted work. JP reports research and consulting fees from Saluda Medical during the conduct of the study; consultancy for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; has received grant and research support from: Abbott, Flowonix, Aurora, Painteq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and is a shareholder of Vertos, SPR Therapeutics, Painteq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, and Anesthetic Gas Reclamation. CH reports grants from Saluda Medical during the conduct of the study; consultancy fees from Genecentrix outside the submitted work. SC reports grants from Cleveland Clinic during the conduct of the study; and grants from Vertos, Mainstay, and Vivex outside the submitted work. SMF reports consulting fees from Abbott, Medtronic, Saluda, VertiFlex, Vertos, Surgentec, CornerLoc, Mainstay and Relievant outside the submitted work, has received grant for research funding from Mainstay, Relievant, Medtronic, Abbott, VertiFlex, Saluda, Nalu, CornerLoc, Aurora, Biotronik, and Stimgenics outside the submitted work, and has an equity position in SynerFuse, Aurora Spine, Thermaquil. SPR Therapeutics, Saluda, CornerLoc, PainTEQ, Stimgenics, Anesthetic Gas Reclamation, Neural Integrative Solutions, SpineThera, and Celeri Health. CG reports clinical trial funding from Saluda Medical during the conduct of the study; reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, and Boston Scientific outside the submitted work. PSS has received consultancy fees from Medtronic, Saluda Medical, Nalu, and Biotronic outside the submitted work, and has stock options from Saluda Medical and Nalu. JS reports personal fees from Nevro during the conduct of the study and personal fees from Saluda Medical and Boston Scientific outside the submitted work. TM reports research fees from Saluda Medical during the conduct of the study and personal fees from Nevro outside the submitted work. JC reports personal fees from Saluda Medical during the conduct of the study; personal fees from Abbott, Boston Scientific, Nevro, Medtronic, Mainstay, SPR Therapeutics, CornerLoc, PillNurse, Biotronik, and Vivex outside the submitted work; and stock from Mainstay, CornerLoc, and PillNurse. EP has received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda Medical outside the submitted work, as well as personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda Medical, and Vertos outside the submitted work. She holds stock options from SynerFuse and neuro42. JMH reports consulting fees from Abbott, Boston Scientific, Nevro, and Saluda Medical outside the submitted work. RR reports grants from SPR, Nalu and Nevro outside the submitted work,l fees from Presidio, and grants and personal fees from Boston Scientific and Saluda Medical outside the submitted work. JWK is an advisory board member for Boston Scientific, Medtronic, Abbott, and Saluda Medical. GB reports consulting fees from Medtronic, Boston Scientific, and Saluda Medical outside the submitted work, and has a consulting agreement and is on the advisory board for Nevro Corp, Nalu Medical Inc, Abbott, and Boston Scientific. RST reports consulting fees from Medtronic, Nevro and Saluda Medical outside the submitted work. LP reports personal fees from Saluda Medical; is a member of the data monitoring board of Saluda Medical during the conduct of the study; and reports personal consulting fees from Medtronic and Nalu outside the submitted work. Members of the EVOKE study group report being employees of Saluda Medical. No other disclosures were reported., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Almost half of the global population face significant challenges from long-term conditions (LTCs) resulting in substantive health and socioeconomic burden. Exercise is a potentially key intervention in effective LTC management., Methods: In this overview of systematic reviews (SRs), we searched six electronic databases from January 2000 to October 2023 for SRs assessing health outcomes (mortality, hospitalisation, exercise capacity, disability, frailty, health-related quality of life (HRQoL), and physical activity) related to exercise-based interventions in adults (aged >18 years) diagnosed with one of 45 LTCs. Methodological quality was assessed using AMSTAR-2. International Prospective Resister of Systematic Reviews (PROSPERO) ID: CRD42022319214., Findings: Forty-two SRs plus three supplementary RCTs were included, providing 990 RCTs in 936,825 people across 39 LTCs. No evidence was identified for six LTCs. Predominant outcome domains were HRQoL (82% of SRs/RCTs) and exercise capacity (66%); whereas disability, mortality, physical activity, and hospitalisation were less frequently reported (≤25%). Evidence supporting exercise-based interventions was identified in 25 LTCs, was unclear for 13 LTCs, and for one LTC suggested no effect. No SRs considered multimorbidity in the delivery of exercise. Methodological quality varied: critically-low (33%), low (26%), moderate (26%), and high (12%)., Interpretation: Exercise-based interventions improve HRQoL and exercise capacity across numerous LTCs. Key evidence gaps included limited mortality and hospitalisation data and consideration of multimorbidity impact on exercise-based interventions., Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020)., Competing Interests: GOD is co-author of one, and RST is co-author of two of the SRs included in this overview. LG is currently in receipt of/undertaking a Wellcome Trust doctoral fellowship (UNS144807) and declares receipt of payment for lecture on pulmonary rehabilitation (University College London, annual), Council of Allied Health Professions Research (CAHPR)/National Institute for Health and Care Research (NIHR) Research Champion: West Midlands (unpaid), British Thoracic Society (BTS): Pulmonary Rehabilitation (PR) Specialist Advisory Group (SAG) member (unpaid), Association of Chartered Physiotherapists in Respiratory Care (ACPRC) committee (honoraria received). HMLY is funded by the NIHR Advanced Fellowship (NIHR202926). SJS is Clinical Lead for National Respiratory Audit Programme—Pulmonary Rehabilitation. KJ declares funding from NIHR Applied Research Collaboration West Midlands and Sub-committee chair for NIHR Programme Grants for Applied Health Research (payment to institution). RAE declares receipt of speaker fees (Boeringher June 2021; Moderna April 2023) and ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary (unpaid), and ATS Pulmonary Rehabilitation Assembly Chair (unpaid). SD declares NIHR Applied Research Collaboration: South West Peninsula (PenARC; payment to institution), receipt of the following NIHR grants (payment to institution): NIHR151938; NIHR204099; RP-PG-0514-20002; NIHR201038; NIHR201070; NIHR200428, receipt of grants (payment to institution): Gillings Family foundation (ID 943008); The Stroke Association (ID 901902); NIHR School for Primary Care Research—Exeter internal fund (ID 856766); Academic Health Science Network South West (ID 1355693), receipt of textbook royalties (John Wiley & Sons), support for meeting attendance from NIHR (p-PG-0514-20002) and Health Research Council New Zealand (21/826; 18/254), and membership of NIHR Programme Grant for Applied Research funding panel committee and The Stroke Association research funding panel. SJK declares receipt of conference funding from School of Health and Wellbeing, University of Glasgow. SAS declares presidency of the UK Society of Behavioural Medicine, membership of HTA Clinical Evaluations and Trials Committee (2016–2020), membership of Commissioning Panel for the National Institute of Health Research (NIHR) Policy Research Programme (2019–2022), and membership of Chief Scientist Office HIPS committee (2018–2023)., (© 2024 The Authors.)

Background: Depression and anxiety occur frequently (with reported prevalence rates of around 40%) in individuals with coronary heart disease (CHD), heart failure (HF) or atrial fibrillation (AF) and are associated with a poor prognosis, such as decreased health-related quality of life (HRQoL), and increased morbidity and mortality. Psychological interventions are developed and delivered by psychologists or specifically trained healthcare workers and commonly include cognitive behavioural therapies and mindfulness-based stress reduction. They have been shown to reduce depression and anxiety in the general population, though the exact mechanism of action is not well understood. Further, their effects on psychological and clinical outcomes in patients with CHD, HF or AF are unclear., Objectives: To assess the effects of psychological interventions (alone, or with cardiac rehabilitation or pharmacotherapy, or both) in adults who have a diagnosis of CHD, HF or AF, compared to no psychological intervention, on psychological and clinical outcomes., Search Methods: We searched the CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL databases from 2009 to July 2022. We also searched three clinical trials registers in September 2020, and checked the reference lists of included studies. No language restrictions were applied., Selection Criteria: We included randomised controlled trials (RCTs) comparing psychological interventions with no psychological intervention for a minimum of six months follow-up in adults aged over 18 years with a clinical diagnosis of CHD, HF or AF, with or without depression or anxiety. Studies had to report on either depression or anxiety or both., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were depression and anxiety, and our secondary outcomes of interest were HRQoL mental and physical components, all-cause mortality and major adverse cardiovascular events (MACE). We used GRADE to assess the certainty of evidence for each outcome., Main Results: Twenty-one studies (2591 participants) met our inclusion criteria. Sixteen studies included people with CHD, five with HF and none with AF. Study sample sizes ranged from 29 to 430. Twenty and 17 studies reported the primary outcomes of depression and anxiety, respectively. Despite the high heterogeneity and variation, we decided to pool the studies using a random-effects model, recognising that the model does not eliminate heterogeneity and findings should be interpreted cautiously. We found that psychological interventions probably have a moderate effect on reducing depression (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.65 to -0.06; 20 studies, 2531 participants; moderate-certainty evidence) and anxiety (SMD -0.57, 95% CI -0.96 to -0.18; 17 studies, 2235 participants; moderate-certainty evidence), compared to no psychological intervention. Psychological interventions may have little to no effect on HRQoL physical component summary scores (PCS) (SMD 0.48, 95% CI -0.02 to 0.98; 12 studies, 1454 participants; low-certainty evidence), but may have a moderate effect on improving HRQoL mental component summary scores (MCS) (SMD 0.63, 95% CI 0.01 to 1.26; 12 studies, 1454 participants; low-certainty evidence), compared to no psychological intervention. Psychological interventions probably have little to no effect on all-cause mortality (risk ratio (RR) 0.81, 95% CI 0.39 to 1.69; 3 studies, 615 participants; moderate-certainty evidence) and may have little to no effect on MACE (RR 1.22, 95% CI 0.77 to 1.92; 4 studies, 450 participants; low-certainty evidence), compared to no psychological intervention., Authors' Conclusions: Current evidence suggests that psychological interventions for depression and anxiety probably result in a moderate reduction in depression and anxiety and may result in a moderate improvement in HRQoL MCS, compared to no intervention. However, they may have little to no effect on HRQoL PCS and MACE, and probably do not reduce mortality (all-cause) in adults who have a diagnosis of CHD or HF, compared with no psychological intervention. There was moderate to substantial heterogeneity identified across studies. Thus, evidence of treatment effects on these outcomes warrants careful interpretation. As there were no studies of psychological interventions for patients with AF included in our review, this is a gap that needs to be addressed in future studies, particularly in view of the rapid growth of research on management of AF. Studies investigating cost-effectiveness, return to work and cardiovascular morbidity (revascularisation) are also needed to better understand the benefits of psychological interventions in populations with heart disease., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Introduction: Chronic pain patients may experience impairments in multiple health-related domains. The design and interpretation of clinical trials of chronic pain interventions, however, remains primarily focused on treatment effects on pain intensity. This study investigates a novel, multidimensional holistic treatment response to evoked compound action potential-controlled closed-loop versus open-loop spinal cord stimulation as well as the degree of neural activation that produced that treatment response., Methods: Outcome data for pain intensity, physical function, health-related quality of life, sleep quality and emotional function were derived from individual patient level data from the EVOKE multicenter, participant, investigator, and outcome assessor-blinded, parallel-arm randomized controlled trial with 24 month follow-up. Evaluation of holistic treatment response considered whether the baseline score was worse than normative values and whether minimal clinical important differences were reached in each of the domains that were impaired at baseline. A cumulative responder score was calculated to reflect the total minimal clinical important differences accumulated across all domains. Objective neurophysiological data, including spinal cord activation were measured., Results: Patients were randomized to closed-loop (n=67) or open-loop (n=67). A greater proportion of patients with closed-loop spinal cord stimulation (49.3% vs 26.9%) were holistic responders at 24-month follow-up, with at least one minimal clinical important difference in all impaired domains (absolute risk difference: 22.4%, 95% CI 6.4% to 38.4%, p=0.012). The cumulative responder score was significantly greater for closed-loop patients at all time points and resulted in the achievement of more than three additional minimal clinical important differences at 24-month follow-up (mean difference 3.4, 95% CI 1.3 to 5.5, p=0.002). Neural activation was three times more accurate in closed-loop spinal cord stimulation (p<0.001 at all time points)., Conclusion: The results of this study suggest that closed-loop spinal cord stimulation can provide sustained clinically meaningful improvements in multiple domains and provide holistic improvement in the long-term for patients with chronic refractory pain., Trial Registration Number: NCT02924129., Competing Interests: Competing interests: LK reports receiving grants from Nevro, Neuros, Avanos, Medtronic, Neuralace, and Xalud Therapeutics and financial support from Nevro, Avanos, and Saluda Medical. NM reports receiving grants from Neuros and Mesoblast, as well as consulting as a medical monitor for Saluda Medical, Nevro, Vivex, Mainstay, and Vertos. SC reports receiving grants from Saluda Medical, Vertos, Mainstay, and Vivex. CG reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific, Saluda Medical, and Shiratronics. JP serves as a consultant for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil; has received grant and research support from: Abbott, Flowonix, Saluda Medical, Aurora, Painteq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil; and is a shareholder of Vertos, SPR Therapeutics, Painteq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, and Anesthetic Gas Reclamation. SL reports receiving grants from Avanos, Boston Scientific, Nalu Medical, SPR Therapeutics, Saluda Medical, Averitas Pharma, Biotronik, SGX Therapeutics, and PainTeq, as well as serving as a consultant for Abbott, Avanos, Boston Scientific, Nevro, SPR Therapeutics, Averitas Pharma, Biotronik, Nalu Medical, PainTeq, and Saluda Medical, as well as holding stock options for Nalu Medical. CH has received consultancy fees from Saluda Medical and Genecentrix. PSS has received consultancy fees from Medtronic, Saluda Medical, Nalu, and Biotronic and has stock options from Saluda Medical and Nalu. RST reports consultancy fees from Medtronic, Nevro and Saluda Medical. SE reports consultancy fees from Medtronic, Mainstay Medical, Boston Scientific, and Abbott. He has received department research funding from the National Institute of Health Research, Medtronic and Nevro. JWK is an advisory board member for Boston Scientific, Medtronic, Abbott, and Saluda Medical. ST has received consultancy fees from Boston Scientific, Mainstay Medical, and Saluda Medical. He has received department research funding from the National Institute for Health Research, Boston Scientific, Saluda Medical, and Mainstay Medical. EP has received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda Medical, as well as personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda Medical, and Vertos. She holds stock options from SynerFuse and neuro42. DS is a consultant for Abbott, Medtronic, Nevro, SPR, Vertos, PainTEQ, and Saluda Medical and has received research funding from and holds minority equity in Vertos. TD is a consultant for Abbott, Vertos, SpineThera, Saluda Medical, Cornerloc, SPR Therapeutics, PainTeq, Spinal Simplicity, and Biotronik. He has minor equity in form of stock options for Vertos, Saluda Medical, Cornerloc, Nalu, PainTeq, and Spinal Simplicity, and minor equity in common stock for SpineThera, and Ethos. He is an advisory board member or participates on a data safety monitoring board for Abbott, Vertos, SPR Therapeutics, and Biotronik. AA reports consultancy fees from Boston Scientific. AL, NS and RD are employees of Saluda Medical. RD has previously received consultancy fees from Mainstay Medical, Medtronic Ltd, and Saluda Medical. RL is an uncompensated consultant for Nalu, Saluda Medical, and Mainstay Medical and has stock options from Nalu and Saluda Medical obtained before 2019, not exercisable through the duration of his term as International Neuromodulation Society President and editor-in-chief of the journal Neuromodulation: Technology at the Neural Interface., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: People with heart failure experience substantial disease burden that includes low exercise tolerance, poor health-related quality of life (HRQoL), increased risk of mortality and hospital admission, and high healthcare costs. The previous 2018 Cochrane review reported that exercise-based cardiac rehabilitation (ExCR) compared to no exercise control shows improvement in HRQoL and hospital admission amongst people with heart failure, as well as possible reduction in mortality over the longer term, and that these reductions appear to be consistent across patient and programme characteristics. Limitations noted by the authors of this previous Cochrane review include the following: (1) most trials were undertaken in patients with heart failure with reduced (< 45%) ejection fraction (HFrEF), and women, older people, and those with heart failure with preserved (≥ 45%) ejection fraction (HFpEF) were under-represented; and (2) most trials were undertaken in a hospital or centre-based setting., Objectives: To assess the effects of ExCR on mortality, hospital admission, and health-related quality of life of adults with heart failure., Search Methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and Web of Science without language restriction on 13 December 2021. We also checked the bibliographies of included studies, identified relevant systematic reviews, and two clinical trials registers., Selection Criteria: We included randomised controlled trials (RCTs) that compared ExCR interventions (either exercise only or exercise as part of a comprehensive cardiac rehabilitation) with a follow-up of six months or longer versus a no-exercise control (e.g. usual medical care). The study population comprised adults (≥ 18 years) with heart failure - either HFrEF or HFpEF., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were all-cause mortality, mortality due to heart failure, all-cause hospital admissions, heart failure-related hospital admissions, and HRQoL. Secondary outcomes were costs and cost-effectiveness. We used GRADE to assess the certainty of the evidence., Main Results: We included 60 trials (8728 participants) with a median of six months' follow-up. For this latest update, we identified 16 new trials (2945 new participants), in addition to the previously identified 44 trials (5783 existing participants). Although the existing evidence base predominantly includes patients with HFrEF, with New York Heart Association (NYHA) classes II and III receiving centre-based ExCR programmes, a growing body of trials includes patients with HFpEF with ExCR undertaken in a home-based setting. All included trials employed a usual care comparator with a formal no-exercise intervention as well as a wide range of active comparators, such as education, psychological intervention, or medical management. The overall risk of bias in the included trials was low or unclear, and we mostly downgraded the certainty of evidence of outcomes upon GRADE assessment. There was no evidence of a difference in the short term (up to 12 months' follow-up) in the pooled risk of all-cause mortality when comparing ExCR versus usual care (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.71 to 1.21; absolute effects 5.0% versus 5.8%; 34 trials, 36 comparisons, 3941 participants; low-certainty evidence). Only a few trials reported information on whether participants died due to heart failure. Participation in ExCR versus usual care likely reduced the risk of all-cause hospital admissions (RR 0.69, 95% CI 0.56 to 0.86; absolute effects 15.9% versus 23.8%; 23 trials, 24 comparisons, 2283 participants; moderate-certainty evidence) and heart failure-related hospital admissions (RR 0.82, 95% CI 0.49 to 1.35; absolute effects 5.6% versus 6.4%; 10 trials; 10 comparisons, 911 participants; moderate-certainty evidence) in the short term. Participation in ExCR likely improved short-term HRQoL as measured by the Minnesota Living with Heart Failure (MLWHF) questionnaire (lower scores indicate better HRQoL and a difference of 5 points or more indicates clinical importance; mean difference (MD) -7.39 points, 95% CI -10.30 to -4.77; 21 trials, 22 comparisons, 2699 participants; moderate-certainty evidence). When pooling HRQoL data measured by any questionnaire/scale, we found that ExCR may improve HRQoL in the short term, but the evidence is very uncertain (33 trials, 37 comparisons, 4769 participants; standardised mean difference (SMD) -0.52, 95% CI -0.70 to -0.34; very-low certainty evidence). ExCR effects appeared to be consistent across different models of ExCR delivery: centre- versus home-based, exercise dose, exercise only versus comprehensive programmes, and aerobic training alone versus aerobic plus resistance programmes., Authors' Conclusions: This updated Cochrane review provides additional randomised evidence (16 trials) to support the conclusions of the previous 2018 version of the review. Compared to no exercise control, whilst there was no evidence of a difference in all-cause mortality in people with heart failure, ExCR participation likely reduces the risk of all-cause hospital admissions and heart failure-related hospital admissions, and may result in important improvements in HRQoL. Importantly, this updated review provides additional evidence supporting the use of alternative modes of ExCR delivery, including home-based and digitally-supported programmes. Future ExCR trials need to focus on the recruitment of traditionally less represented heart failure patient groups including older patients, women, and those with HFpEF., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Ageing populations and improved survival, have contributed to a rise in the number of people living with multimorbidity, raising issues related to polypharmacy, treatment burden, competing priorities and poor coordination of care. Self-management programs are increasingly included as an essential component of interventions to improve outcomes in this population. However, an overview of how interventions supporting self-management in patients with multimorbidity is missing. This scoping review focused on mapping the literature on patient-centered interventions for people living with multimorbidity. We searched several databases, clinical registries, and grey literature for RCTs published between 1990-2019 describing interventions that supported self-management in people with multimorbidity. We included 72 studies that were found to be very heterogeneous when it comes to the population, delivery modes and modalities, intervention elements and facilitators. The results pointed to an extensive use of cognitive behavioral therapy as a basis for interventions, as well as behavior change theories and disease management frameworks. The most coded behavior change techniques stemmed from the categories Social Support, Feedback and monitoring and Goals and Planning. To allow for implementation of effective interventions in clinical practice, improved reporting of intervention mechanisms in RCTs is warranted.

Evidence suggests that digitally delivered cardiac rehabilitation (CR) is likely to be an effective alternative to centre-based CR. However, there is limited understanding of the behaviour change techniques (BCTs) and intervention characteristics included in digital CR programmes. This systematic review aimed to identify the BCTs and intervention characteristics that have been used in digital CR programmes, and to study those associated with effective programmes. Twenty-five randomised controlled trials were included in the review. Digital CR was associated with significant improvements in daily steps, light physical activity, medication adherence, functional capacity, and low-density lipoprotein-cholesterol when compared to usual care, and produced effects on these outcomes comparable to centre-based CR. The evidence for improved quality of life was mixed. Interventions that were effective at improving behavioural outcomes frequently employed BCTs relating to feedback and monitoring, goals and planning, natural consequences, and social support. Completeness of reporting on the TIDieR checklist across studies ranged from 42% to 92%, with intervention material descriptions being the most poorly reported item. Digital CR appears effective at improving outcomes for patients with cardiovascular disease. The integration of certain BCTs and intervention characteristics may lead to more effective interventions, however better intervention reporting is required.

Surrogate endpoints are biomarkers or intermediate outcomes that are used as substitutes for clinical outcomes of interest, often to expedite research or decision-making. In contrast, patient-important (or patient-centered) outcomes are health outcomes that are of direct relevance and importance to patients themselves; clinical trials may have measured the impact of the intervention on other endpoints related to, but different from, those of primary importance to patients. This article aims to elaborate on the use and understanding of surrogate endpoints. There should be a well-understood and scientifically grounded relationship between the surrogate (replacement) and the patient-important (target) endpoint it is intended to represent. It should be biologically plausible that changes in the surrogate will consistently and predictably reflect changes in the patient-important endpoint. The surrogate endpoint should show a threshold effect, meaning that a specific change (or state) in the surrogate with an intervention (relative to the comparator) is associated with a predictable (change in the) patient-important outcome. This helps establish a meaningful cutoff or target for the treatment effect on the surrogate endpoint. While surrogate endpoints offer advantages in certain situations, it is important to remember that their use requires careful validation to ensure they reliably predict the true clinical outcome. The validity of "surrogate endpoints" should be supported by robust scientific evidence and rigorous evaluation before these can be considered and labeled as surrogate endpoints., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) is a home-based cardiac rehabilitation intervention designed for patients with heart failure and their caregivers. We present a pooled analysis of patients >18 years with a confirmed diagnosis of HF recruited to two REACH-HF randomized controlled trials. Where identified by patients and consented to participate, caregivers were randomly assigned with patients to receive the REACH-HF intervention plus usual care or usual care alone. Our analysis demonstrated that compared to control group, the REACH-HF group had a greater gain in their disease-specific health-related quality of life at follow-up., Competing Interests: Conflict of interest: R.S.T. and H.M.D. were co-chief investigators for the REACH-HF trials. R.S.T. is a member of the ACNAP Scientific Committee., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

During the past century, there have been major developments in the medical and surgical treatment of cardiovascular disease (CVD). These advancements have resulted in more people surviving initial events and having reduced length of stay in hospital; consequently, there is an increasing number of people in need of ongoing and lifelong cardiovascular risk management. The physical and emotional effects of living with CVD are ongoing with broad challenges ranging from the individual to system level. However, post-discharge care of people with coronary disease continues to follow a 50-year-old cardiac rehabilitation model which focuses on the sub-acute phase and is of a finite in duration. The aim of this paper is to consider the concept of supporting survivors to live well with CVD rather than 'rehabilitating' them and propose factors for consideration in reframing secondary prevention towards optimizing cardiovascular health. We discuss deeply-held potential considerations and challenges associated with the concept of supporting survivors achieve optimal cardiovascular health and live well with CVD rather than 'rehabilitating' them. We propose the concept of 5 x P's for reframing traditional cardiac rehabilitation towards the concept of cardiovascular health for survivors beyond 'rehabilitation'. These include the need for personalization, processes, patient-centered care, parlance, and partnership. Taken together, consideration of challenges at the systems and population level will ultimately improve engagement with secondary prevention as well as outcomes for all people who need it., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Competing Interests: Competing interests: None declared.

Aims: Alternative models of cardiac rehabilitation (CR) are required to improve CR access and uptake. Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) is a comprehensive home-based rehabilitation and self-management programme, facilitated by trained health professionals, for people with heart failure (HF) and their caregivers. REACH-HF was shown to be clinically effective and cost-effective in a multi-centre randomized trial. The SCOT:REACH-HF study assessed implementation of REACH-HF in routine clinical practice in NHS Scotland., Methods and Results: A mixed-method implementation study was conducted across six regional Health Boards. Of 136 people with HF and 56 caregivers recruited, 101 people with HF and 26 caregivers provided 4-month follow-up data, after participating in the 12-week programme. Compared with baseline, REACH-HF participation resulted in substantial gains in the primary outcome of health-related quality of life, as assessed by the Minnesota Living with Heart Failure Questionnaire (mean difference: -9.8, 95% CI: -13.2 to -6.4, P < 0.001). Improvements were also seen in secondary outcomes (PROM-CR+; EQ-5D-5L; Self-Care of Heart Failure Index (SCHFI) domains of maintenance and symptom perception; Caregiver Contribution to Self-Care domains of symptom perception and management). Twenty qualitative interviews were conducted with 11 REACH-HF facilitators, five supporting clinicians, and four national stakeholders. Interviewees were largely positive about REACH-HF, considering it to have 'filled a gap' where centre-based CR was not an option. Key issues to support future roll-out were also identified., Conclusion: Our findings support wider roll-out of REACH-HF as an alternative to centre-based models, to improve CR access and uptake for people with HF., Competing Interests: Conflict of interest: These affiliations had no influence on the interpretation or presentation of the results of the presentstudy. J.G.F.C. is supported by a British Heart Foundation Centre of Research Excellence award RE/18/6/34217. J.G.F.C. reports research funding and personal honoraria from Abbott, Amgen, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cytokinetics, Idorsia, Johnson & Johnson, Medtronic, Myokardia, Novartis, NI Medical, Pharmacosmos, Pharma Nord, Philips, Respicardia, Servier, Torrent, Vifor, Viscardia. The other authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Despite strong evidence, access to exercise-based cardiac rehabilitation (ExCR) remains low across global healthcare systems. We provide a contemporary update of the Cochrane review randomized trial evidence for ExCR for adults with heart failure (HF) and compare different delivery modes: centre-based, home-based (including digital support), and both (hybrid)., Methods and Results: Databases, bibliographies of previous systematic reviews and included trials, and trials registers were searched with no language restrictions. Randomized controlled trials, recruiting adults with HF, assigned to either ExCR or a no-exercise control group, with follow-up of ≥6 months were included. Two review authors independently screened titles for inclusion, extracted trial and patient characteristics, outcome data, and assessed risk of bias. Outcomes of mortality, hospitalization, and health-related quality of life (HRQoL) were pooled across trials using meta-analysis at short-term (≤12 months) and long-term follow-up (>12 months) and stratified by delivery mode. Sixty trials (8728 participants) were included. In the short term, compared to control, ExCR did not impact all-cause mortality (relative risk [RR] 0.93; 95% confidence interval [CI] 0.71-1.21), reduced all-cause hospitalization (RR 0.69; 95% CI 0.56-0.86, number needed to treat: 13, 95% CI 9-22), and was associated with a clinically important improvement in HRQoL measured by the Minnesota Living with Heart Failure Questionnaire (MLWHF) overall score (mean difference: -7.39; 95% CI -10.30 to -4.47). Improvements in outcomes with ExCR was seen across centre, home (including digitally supported), and hybrid settings. A similar pattern of results was seen in the long term (mortality: RR 0.87, 95% CI 0.72-1.04; all-cause hospitalization: RR 0.84, 95% CI 0.70-1.01, MLWHF: -9.59, 95% CI -17.48 to -1.50)., Conclusions: To improve global suboptimal levels of uptake for HF patients, global healthcare systems need to routinely recommend ExCR and offer a choice of mode of delivery, dependent on an individual patient's level of risk and complexity., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Peripheral neuropathic pain, including painful diabetic neuropathy (PDN), is associated with marked negative impact on health-related quality of life (HRQoL). The magnitude of reduction of HRQoL experienced by individual PDN patients appears to be strongly associated with their level of pain and disease severity. In spite of the availability of a range of pharmacotherapy, a substantive proportion of PDN patients continue to experience suboptimal HRQoL. Such patients are potential candidates for spinal cord stimulation (SCS) devices. Three randomised controlled trials in over 300 patients with refractory PDN have shown that the addition of SCS to standard of care therapy results in important health gains, including pain reduction and enhancement of HRQoL. Sham-controlled RCTs that enable blinding of patients, clinicians and researchers are needed to confirm the role of SCS in PDN., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rod Taylor has been a consultant/advisor for Nevro and a co-investigator/consultant on the Nevro-funded SENZA-PDN trial., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: Patients who suffer from long-term, neuropathic pain that proves refractory to conventional medical management are high consumers of health care resources and experience poorer physical and mental health than people with other forms of pain. Pharmacologic treatments have adverse effects; nonpharmacologic interventions have limitations. Spinal cord stimulation (SCS) is an effective treatment for neuropathic pain, although 30% to 40% of patients fail to achieve acceptable levels of pain relief. There are currently no objective methods to predict the success of SCS to treat neuropathic pain, and therefore, it is important to understand which patient factors may be predictive of a lack of response to SCS, to inform future patient treatment options. This study proposes a protocol for a systematic review and meta-analysis of published studies to examine these predictive factors., Materials and Methods: Several bibliographic databases will be searched to identify relevant studies published since 2012 that provide data on patient characteristics (eg, age, gender, pain severity) as predictors of SCS outcomes of pain, function, and health-related quality of life. Two independent reviewers will screen citations; data will be extracted after full-text screening. Risk of bias will be assessed using the Quality In Prognosis Studies tool., Results: A formal quantitative synthesis is planned in which data from studies with the same predictive factors are available; this will be considered for pooling into separate meta-analyses. In cases of high heterogeneity or inconsistency in the data, subgroup analysis will be conducted., Conclusions: This study seeks to provide a contemporary review of patient predictors of success of neuromodulation for neuropathic pain. We anticipate that findings may guide the use of neuromodulation in patient subgroups and the design and reporting of future clinical studies in this field., (Copyright © 2022 International Neuromodulation Society. All rights reserved.)

Background: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based and technology-supported cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation, especially during the SARS-CoV-2 pandemic. This is an update of a review previously published in 2009, 2015, and 2017., Objectives: To compare the effect of home-based (which may include digital/telehealth interventions) and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 16 September 2022. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied., Selection Criteria: We included randomised controlled trials that compared centre-based cardiac rehabilitation (e.g. hospital, sports/community centre) with home-based programmes (± digital/telehealth platforms) in adults with myocardial infarction, angina, heart failure, or who had undergone revascularisation., Data Collection and Analysis: Two review authors independently screened all identified references for inclusion based on predefined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Certainty of evidence was assessed using GRADE., Main Results: We included three new trials in this update, bringing a total of 24 trials that have randomised a total of 3046 participants undergoing cardiac rehabilitation. A further nine studies were identified and are awaiting classification. Manual searching of trial registers until 16 September 2022 revealed a further 14 clinical trial registrations - these are ongoing. Participants had a history of acute myocardial infarction, revascularisation, or heart failure. Although there was little evidence of high risk of bias, a number of studies provided insufficient detail to enable assessment of potential risk of bias; in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in our primary outcomes up to 12 months of follow-up: total mortality (risk ratio [RR] = 1.19, 95% confidence interval [CI] 0.65 to 2.16; participants = 1647; studies = 12/comparisons = 14; low-certainty evidence) or exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.24 to 0.04; participants = 2343; studies = 24/comparisons = 28; low-certainty evidence). The majority of evidence (N=71 / 77 comparisons of either total or domain scores) showed no significant difference in health-related quality of life up to 24 months follow-up between home- and centre-based cardiac rehabilitation. Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate-certainty evidence). There was a similar level of trial completion (RR 1.03, 95% CI 0.99 to 1.08; participants = 2638; studies = 22/comparisons = 26; low-certainty evidence) between home-based and centre-based participants. The cost per patient of centre- and home-based programmes was similar., Authors' Conclusions: This update supports previous conclusions that home- (± digital/telehealth platforms) and centre-based forms of cardiac rehabilitation formally supported by healthcare staff seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction, or revascularisation, or with heart failure. This finding supports the continued expansion of healthcare professional supervised home-based cardiac rehabilitation programmes (± digital/telehealth platforms), especially important in the context of the ongoing global SARS-CoV-2 pandemic that has much limited patients in face-to-face access of hospital and community health services. Where settings are able to provide both supervised centre- and home-based programmes, consideration of the preference of the individual patient would seem appropriate. Although not included in the scope of this review, there is an increasing evidence base supporting the use of hybrid models that combine elements of both centre-based and home-based cardiac rehabilitation delivery. Further data are needed to determine: (1) whether the short-term effects of home/digital-telehealth and centre-based cardiac rehabilitation models of delivery can be confirmed in the longer term; (2) the relative clinical effectiveness and safety of home-based programmes for other heart patients, e.g. post-valve surgery and atrial fibrillation., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials., Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials., Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators., Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence., Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded., Competing Interests: Sylwia Bujkiewicz is a member of the NICE Decision Support Unit (DSU) and NICE Guidelines Technical Support Unit (TSU), has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA and RTI Health Solutions, received payments for educational events from NICE and Roche and has received research funding from European Federation of Pharmaceutical Industries & Associations (EEPIA) and Johnson & Johnson. Mario Ouwens works for and has shares in AstraZeneca. Joseph Ross is an Associate Editor at BMJ and co-founder (unpaid) of medRxiv; research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Nancy Butcher has received consulting fees from Nobias Therapeutics, Inc. Alain Amstutz and Yousef Rezaei are Associate Editors at BMC Trials. Robin Christensen is a founding member of the OMERACT Technical Advisory Group which might be perceived as a possible conflict of interest. Ray Harris has shares in Johnson and Johnson. John Powers has been a consultant for Adaptive Phage, Arrevus, Atheln, Bavaria Nordic, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark, SpineBioPPharma, UTIlity, Vir. Achilles Thoma received royalties from Springer Publishing for his book “Evidence Based Surgery: A Guide to Understanding and Interpreting the Surgical Literature”, 2019., (© 2023 The Author(s).)

Objectives: The effectiveness of Evoke closed-loop spinal cord stimulation (CL-SCS), a novel modality of neurostimulation, has been demonstrated in a randomized controlled trial (RCT). The objective of this cost-utility analysis was to develop a de novo economic model to estimate the cost-effectiveness of Evoke CL-SCS when compared with open-loop SCS (OL-SCS) for the management of chronic back and leg pain., Methods: A decision tree followed by a Markov model was used to estimate the costs and outcomes of Evoke CL-SCS versus OL-SCS over a 15-year time horizon from the UK National Health Service perspective. A "high-responder" health state was included to reflect improved levels of SCS pain reduction recently reported. Results are expressed as incremental cost per quality-adjusted life year (QALY). Deterministic and probabilistic sensitivity analysis (PSA) was conducted to assess uncertainty in the model inputs., Results: Evoke CL-SCS was estimated to be the dominant treatment strategy at ~5 years postimplant (ie, it generates more QALYs while cost saving compared with OL-SCS). Probabilistic sensitivity analysis showed that Evoke CL-SCS has a 92% likelihood of being cost-effective at a willingness to pay threshold of £20,000/QALY. Results were robust across a wide range of scenario and sensitivity analyses., Discussion: The results indicate a strong economic case for the use of Evoke CL-SCS in the management of chronic back and leg pain with or without prior spinal surgery with dominance observed at ~5 years., Competing Interests: This study was funded by Saluda Medical. R.V.D. has received consultancy fees from Mainstay Medical, Medtronic Ltd, and Saluda Medical. The work reported within this manuscript was finalized before R.V.D. joined Saluda Medical as an employee. AB MTech Access was commissioned by Saluda Medical to undertake this project. R.V.D., N.S., and A.L. are employees of Saluda Medical. A.G. has received honoraria for consulting as well as advisory board meetings for Nevro Corp, Boston Scientific Corp, and Abbott. P.S.S. serves as a consultant for Abbott, Nevro and Medtronic. He has received research support from Boston Scientific, Abbott, Vertos, Nevro, Saluda Medical and Grunenthal Halyard. D.S. is a consultant for Abbott, Boston Scientific, Flowonix, Medtronic, Nevro, PainTEQ, SPR Therapeutics, Vertos, and Vertiflex. S.M.F. serves as a consultant for Abbott, Medtronic, Nevro, Saluda, SPR, and Vertiflex. He has received research support from Abbott, Medtronic, Nuvectra, and Saluda Medical. C.W.H. has ownership in Axonics, PainTEQ, Nalu, Spine BioPharma, and Mainstay; consults for Saluda Medical and Genecentrix; is on the speaker’s bureau for Tersera; has research funding from Abbott, Biotronik, DiscGenics, Mesoblast, Saluda, TissueGene, and Vivex; and serves on the advisory boards of Abbott, Mainstay, Nalu, Spine BioPharma, and Vertiflex. R.S.T. has received consultancy fees from Medtronic Ltd, Nevro Corp, and Saluda Medical. The remaining author declares no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

BACKGROUND: Diabetic peripheral neuropathy, a common comorbidity of diabetes, is a neurodegenerative disorder that targets sensory, autonomic, and motor nerves frequently associated with painful diabetic neuropathy (PDN). PDN carries an economic burden as the result of reduced work and productivity. A recent multicenter randomized controlled trial, SENZA-PDN (NCT03228420), assessed the impact of high-frequency (10 kHz) spinal cord stimulation (SCS) on pain relief. The effects of high-frequency SCS on health care resource utilization and medical costs are not known. OBJECTIVE: To evaluate the effect of high-frequency (10 kHz) SCS on health care resource utilization (HRU) and medical costs in patients with PDN using data from the SENZA-PDN trial. METHODS: Participants with PDN were randomly assigned 1:1 to receive either 10 kHz SCS plus conventional medical management (CMM) (SCS treatment group) or CMM alone (CMM treatment group). Patient outcomes and HRU up to the 6-month follow-up are reported here. Costs (2020 USD) for each service was estimated based on publicly available Medicare fee schedules, Medicare claims data, and literature. HRU metrics of inpatient and outpatient contacts and costs are reported as means and SDs. Univariate and bivariate analyses were used to compare SCS and CMM treatment groups at 6 months. RESULTS: At 6-month follow up, the SCS arm experienced approximately half the mean rate of hospitalizations per patient compared with the CMM treatment group (0.08 vs 0.15; P = 0.066). The CMM treatment group's total health care costs per patient were approximately 51% higher compared with the SCS treatment group (equivalent to mean annual cost per patient of $9,532 vs $6,300). CONCLUSIONS: Our analysis of the SENZA-PDN trial indicates that the addition of 10 kHz SCS therapy results in lower rates of hospitalization and consequently lower health care costs among patients with PDN compared with those receiving conventional management alone.

Aims: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN)., Methods: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding., Results: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection., Conclusions: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN., Trial Registration: ClincalTrials.gov Identifier, NCT03228420., Competing Interests: Declaration of competing interest Author Erika A. Petersen has received consulting fees from Abbott Laboratories, Biotronik, Boston Scientific, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, Presidio Medical, Saluda, and Vertos Medical, research support from Mainstay, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, ReNeuron, Saluda, and SPR, and stock options from neuro42 and SynerFuse. Author Thomas G. Stauss has received research support from Nevro Corp. Author James A. Scowcroft has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. Author Michael J. Jaasma is an employee of Nevro Corp. Author Elizabeth S. Brooks was an employee of Nevro Corp during her contributions to the work associated with this manuscript. Author Deborah R. Edgar received consulting fees from Nevro in her capacity as an independent medical writer. Author Judith L. White has received consulting fees from California Institute for Biomedical Research and Eli Lilly and research support from Nevro Corp. Author Shawn M. Sills has received research support from Nevro Corp. Author Kasra Amirdelfan has received consulting fees from Biotronik, Medtronic, Nalu Medical, Nevro Corp, and Saluda Medical, as well as research support from Biotronik, IPM Medical Group, Nevro Corp, Saluda Medical, SPR Therapeutics, and Vivex Biologics. Author Maged N. Guirguis has received consulting fees from Abbott Laboratories, Avanos Medical, Avertis Pharmacy, Boston Scientific, Nevro Corp, and Saluda Medical, as well as research support from Abbott Laboratories, Avanos Medical, Boston Scientific, Nalu Medical, Neuros Medical, Nevro Corp, and Saluda Medical. Author Jijun Xu has received research support from the Cleveland Clinic Velosano Program, the National Institutes of Health, the Steve and Melody Golding Foundation, and Nevro Corp. Author Cong Yu has received research support from Nevro Corp. Author Ali Nairizi has received consulting fees from Aurora Spine, Flowonix, and Nevro Corp as well as research support from Nevro Corp. Author Denis G. Patterson has received consulting fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, Aurora Spine, CornerLoc, Flowonix, Lundbeck, Pajunk Medical, Saluda Medical, Spark Biomedical, and Vertos Medical, research support from Abbott Laboratories, Aurora Spine, Flowonix, Nevro Corp, and Saluda Medical, speakers’ bureau or honoraria from Abbott Laboratories, Allergan, Amgen, CornerLoc, Lundbeck, Saluda Medical, and Vertos Medical, and stock options from CornerLoc. Author Michael J. Creamer has received research support from Nevro Corp. Author Vincent Galan has received research support from Biotronik, Medtronic, Nevro Corp, PainTEQ, SPR Therapeutics, and St. Jude. Author Richard H. Bundschu has received research support from Nevro Corp. Author Neel D. Mehta has received consulting fees from Averitas, Nevro Corp, and Salix Pharmaceuticals, as well as research support from Boston Scientific and Nevro Corp. Author Dawood Sayed has received consulting fees from Abbott Laboratories, Boston Scientific, Flowonix, Medtronic, Nevro Corp, Vertiflex, and Vertos Medical, as well as research support from Abbott Laboratories, Biotronic, Nevro Corp, Vertiflex, and Vertos Medical. Author Shivanand P. Lad has received consulting fees from Nevro Corp and research support from Nevro Corp. Author David J. DiBenedetto has received research support from Nevro Corp, as well as funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. Author Khalid A. Sethi has received research support from Nevro Corp. Author Johnathan H. Goree has received consulting fees from Abbott Laboratories and Stratus Medical. Author Paul W. Wu has received research support from Nevro Corp. Author Charles E. Argoff has received consulting fees from AbbVie, Amgen, Biohaven, Clexio Biosciences, Collegium, Eli Lilly, Elsevier, Flowonix, Gene Pharma, Lundbeck, Nevro Corp, Novartis, Pfizer, SK Life Science, Teva Pharmaceutical, and Vertex as well as research support from AbbVie, Allergan, Amgen, Daiichi Sankyo, Eli Lilly, Novartis, Teva Pharmaceutical, and Vertex Pharmaceuticals. Author Christian E. Nasr has received consulting fees from Exelixis, Neurogastrx, and Nevro Corp as well as research support from Nevro Corp. Author Rod S. Taylor has received consulting fees from Nevro Corp, Medtronic, and Saluda Medical. Author David L. Caraway is an employee of Nevro Corp. Author Nagy A. Mekhail has received consulting fees from Nevro Corp, Relievant Medsystems, Saluda Medical, Sollis Therapeutics, and Vertos Medical, as well as research support from Avanos Medical, Mesoblast, Neuros Medical, and Nevro Corp., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into trial reporting items., Study Design and Setting: Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items., Results: After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1-6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7-9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11-14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15-16); and informing trial participants about using surrogate end points (item 17)., Conclusion: The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials-SURROGATE and Consolidated Standards of Reporting Trials-SURROGATE extensions., Competing Interests: Declaration of competing interest Sylwia Bujkiewicz is a member of the NICE Decision Support Unit and NICE Guidelines Technical Support Unit. She has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA, and RTI Health Solutions, received payments for educational events from Roche, and has received research funding from European Federation of Pharmaceutical Industries and Associations and Johnson & Johnson. Mario Ouwens works for and has shares in AstraZeneca. Joseph Ross is an Associate Editor at BMJ and co-founder (unpaid) of medRxiv; research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (U01FD005938); from the Agency for Healthcare Research and Quality (R01HS022882); from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644); and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Nancy Butcher has received consulting fees from Nobias Therapeutics, Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Intrusive mental imagery is associated with anxiety and mood instability within bipolar disorder and therefore represents a novel treatment target. Imagery Based Emotion Regulation (IBER) is a brief structured psychological intervention developed to enable people to use the skills required to regulate the emotional impact of these images., Methods: Participants aged 18 and over with a diagnosis of bipolar disorder and at least a mild level of anxiety were randomly assigned (1:1) to receive IBER plus treatment as usual (IBER + TAU) or treatment as usual alone (TAU). IBER was delivered in up to 12 sessions overs 16 weeks. Clinical and health economic data were collected at baseline, end of treatment and 16-weeks follow-up. Objectives were to inform the recruitment process, timeline and sample size estimate for a definitive trial and to refine trial procedures. We also explored the impact on participant outcomes of anxiety, depression, mania, and mood stability at 16-weeks and 32-weeks follow-up., Results: Fifty-seven (28: IBER + TAU, 27: TAU) participants from two sites were randomised, with 50 being recruited within the first 12 months. Forty-seven (82%) participants provided outcome data at 16 and 32-weeks follow-up. Thirty-five participants engaged in daily mood monitoring at the 32-week follow-up stage. Retention in IBER treatment was high with 27 (96%) attending ≥ 7 sessions. No study participants experienced a serious adverse event., Discussion: The feasibility criteria of recruitment, outcome completion, and intervention retention were broadly achieved, indicating that imagery-focused interventions for bipolar disorder are worthy of further investigation., (© 2023. The Author(s).)