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Abstract Background Patellofemoral pain (PFP) is a common musculoskeletal disorder resulting in anterior knee pain. Physiotherapy is the current standard treatment, while surgical intervention (tibial tubercle transfer [TTT]) is reserved for chronic cases when nonoperative treatment has failed. TTT can result in clinically meaningful improvement in patients with patellofemoral maltracking without instability. However, to date, no randomised controlled trials (RCT) have compared TTT combined with a physiotherapy (PT) programme to PT alone as the initial treatment for PFP. Methods A single-centre nonblinded RCT in 40 patients with chronic PFP (> 1 year) and tibial tubercle-trochlear groove (TT-TG) > 15 mm will be randomised to either TTT followed by PT or to PT alone in a 1:1 ratio in a concealed manner. The primary outcome is knee pain at 18 weeks for the TTT group (6 weeks splint phase + 12 weeks PT) and at 12 weeks for the PT group, measured by the visual analog scale (VAS). Secondary outcomes include Patient-Reported Outcome Measures (PROMs) using the Kujala score, International Knee Documentation Committee (IKDC) ‘Subjective Knee Form’, Tegner Activity score and EuroQol 5D-5 L for quality of life. Range of motion (ROM) is measured using the decline step-down test (DSDT). Between-group differences will be analysed using multivariable linear regression analysis, while longitudinal differences will be assessed with linear mixed models for repeated measures. The difference in direct medical costs will also be assessed. Discussion The REVITALISE study is the first randomised study to compare surgical intervention (TTT) followed by PT to PT alone in patients with chronic PFP. This study will generate level-1 evidence on the most effective treatment for chronic PFP, which can be integrated into the national guideline to aid orthopaedic surgeons and physiotherapists in their decision-making and ultimately improve our care for patients with chronic PFP. Trial registration Study Identifier NCT06227806, registered on 26 Jan 2024 on ClinicalTrials.gov. The study underwent independent peer review and received approval from the ethical review board (number NL80956.091.22).

Abstract Background In Australia and internationally, it is men who predominately die by suicide. Men are less likely than women to seek help for their mental health difficulties and this may contribute to their higher suicide rates. We created a 4-minute music video encouraging Australian men to seek help for mental health difficulties (Boys Do Cry). We aimed to assess in a randomised controlled trial (RCT) whether the Boys Do Cry video increased men’s intentions to seek help for mental health difficulties from baseline (T1) to post-intervention (1 week = T2). Methods We conducted an online single-blind, two-arm RCT comparing the effects of Boys Do Cry against a control video. Analyses were undertaken on an intent-to-treat basis using linear mixed effects models with variables for trial arm, occasion of measurement and their interaction. Intervention effectiveness was assessed by comparing the mean difference between arms in change of the total score on the General Help-Seeking Questionnaire (GHSQ) from T1 to T2. Results 476 participants were randomised (intervention = 243; control = 233). At T1, GHSQ means were similar (intervention = 45.28; control = 45.70). After viewing the videos, GHSQ means increased in both arms (intervention = 47.33; control = 46.59), with no evidence of a difference in scores at T2 (modelled mean difference = 0.62, 95% CI -1.11 to 2.35, p = 0.485). Similar results were observed for all secondary outcomes. No adverse events were observed. Conclusions Boys Do Cry demonstrated some evidence of a positive effect on help-seeking intentions among Australian men; however, so too did the control video, and no significant difference was observed. Trial registration ANZCTR No. 2,621,001,008,819. Registered 30 July 2021.

Abstract Background Smoking rates in the UK have declined steadily over the past decades, masking considerable inequalities, as little change has been observed among people with a mental health condition. This trial sought to assess the feasibility and acceptability of supplying an electronic cigarette (e-cigarette) starter kit for smoking cessation as an adjunct to usual care for smoking cessation, to smokers with a mental health condition treated in the community, to inform a future effectiveness trial. Methods This randomised controlled feasibility trial, conducted March-December 2022, compared the intervention (e-cigarette starter kit with a corresponding information leaflet and demonstration with Very Brief Advice) with a ‘usual care’ control at 1-month follow-up. Participants were ≥ 18 years, receiving treatment for any mental health condition in primary or secondary care in three Mental Health Trusts in Yorkshire and one in London, UK. They were also willing to address their smoking through either cessation or reduction of cigarette consumption. The agreed primary outcome measure was feasibility (consent ~ 15% of eligible participants; attrition rate

Abstract Background Breast cancer is the most diagnosed cancer in women worldwide and carries a considerable psychosocial burden. Interventions based on Acceptance and Commitment Therapy (ACT) and compassion-based approaches show promise in improving adjustment and quality of life in people with cancer. The Mind programme is an integrative ACT and compassion-based intervention tailored for women with breast cancer, which aims to prepare women for survivorship by promoting psychological flexibility and self-compassion. A pilot study of the Mind programme has shown acceptability and preliminary efficacy in improving quality of life and psychological health. This paper presents the study protocol of two randomised controlled trials that aim to test the efficacy and cost-effectiveness of an optimised version of the Mind programme in women with breast cancer. Methods Participants will be women diagnosed with breast cancer randomly assigned to the Mind programme or a support group intervention (active control) in a 1:1 ratio for study 1, while study 2 includes one more arm (treatment as usual; inactive control) and a 2:2:1 ratio. Both interventions will be delivered weekly via an 8-session face-to-face or online group format. Data will be collected at baseline, post-treatment and 6-month follow-up. The efficacy and cost-effectiveness of the two interventions will be assessed. Treatment outcomes will comprise cancer-specific quality of life (primary outcome), anxiety and depressive symptoms, psychological flexibility, self-compassion, health-related quality of life, resource use, and intervention’s acceptability and feasibility. Study 1 will also include immunological and epigenetic markers associated with breast cancer prognosis and mental health. Outcome assessors will be blind to group allocation. Statistical analyses will be conducted using an intention-to-treat approach. Analyses of moderators and mediators of change will also be performed. Discussion These trials examine the efficacy and cost-effectiveness of an integrative ACT and compassion-based intervention tailored for women with breast cancer. Greater improvements in psychosocial, biological and resource use are expected in the Mind group, when compared to the control group(s). Results will likely support the potential benefits of the Mind programme for breast cancer patients and highlight the clinical relevance of integrative and holistic interventions in oncology. Trials registration {2a, 2b} ClinicalTrials.gov NCT05642897 and NCT06212414. Registered on December 8, 2022, and January 18, 2024.

Abstract Background Kidney transplantation is the ultimate treatment for end-stage kidney disease. Function of the kidney graft is not only dependent on medical factors but also on a complication-free surgical procedure. In the event of major surgical complications, the kidney graft is potentially lost and the patient will return to the waiting list which may be long. To optimise peri-operative care and reduce complications, robot-assisted kidney transplantation (RAKT) has been introduced as an alternative to open kidney transplantation (OKT), but to our knowledge, no randomised clinical trials (RCT) have compared RAKT to OKT. In this study, we will explore whether robot-assisted surgery can reduce 30-day surgical complications compared to open surgery in kidney transplantation. Methods This is a single-site, open-label, randomised clinical trial comparing RAKT to OKT. Participants are adult recipients of kidney transplantation recruited from Copenhagen University Hospital – Rigshospitalet, Denmark. The study plans to include 106 participants who will be randomised in a 1:1 manner between OKT and RAKT. Primary outcomes are vascular- and major surgical complications at 30 days post-operatively. Participants will be followed for 2 years to evaluate secondary outcomes including recovery, late complications and kidney graft function. This is designed as a superiority trial and planned analyses will follow intention-to-treat principles. Discussion Studies indicate RAKT can reduce several surgical complications, but the lack of RCTs limits the extrapolation of these results to justify replacing an open approach with a robot-assisted one. Ultimately, the introduction of new surgical techniques should be as vigorously tested as any other new treatments. However, reducing surgical complications that compromise graft viability could lead to improved patient care and survival. Trial registration The trial was prospectively registered with ClinicalTrials.gov on February 15th, 2023, with the identifier NCT05730257.

Abstract Background Cognitive impairment is common in haemodialysis patients with no known beneficial interventions. Cooler dialysate slows brain white-matter changes, but its effect on cognition is unknown. This feasibility trial was performed to inform a fully-powered, randomised trial to assess this. Methods We aimed to randomise (1:1) 90 haemodialysis patients to this double-blinded, randomised controlled feasibility trial to standard care (dialysate-temperature 36.5 °C) or intervention (35 °C). Eligible patients were adult chronic haemodialysis recipients with no established diagnosis of dementia or psychiatric disease. The primary outcome was change in Montreal Cognitive Assessment (MoCA) score at 12-months. Secondary outcomes included recruitment and attrition rates, reasons for non-recruitment, intradialytic hypotension, depression, patient burden, computerised cognition test battery, and quality of life. Findings Of 334 patients screened, 160 were eligible. 99 declined mainly for the extra non-dialysis day study visits. Sixty-one patients consented, 43 randomised – 20 in standard care, 23 in intervention arms; 13 withdrew for non-dialysis day visits and 5 without reason before randomisation. 27 patients (12 standard care, 15 intervention) completed the trial – 5 died, 1 transplanted, 4 withdrew consent, and 6 could not attend due to the pandemic. Low temperature dialysis was well tolerated. There was no difference in change in MoCA from baseline to 12 months between the standard and intervention arms; 1.0 (-2.8–3.0, p = 0.755) and − 2.0 (-1.0 - -4.0, p = 0.047) respectively. There were no differences between groups on any secondary measures. There were no significant adverse events reported. Discussion The trial was significantly affected by the COVID-19 pandemic contributing to an attrition rate of 27%. The non-dialysis day research visits were mainly responsible for low recruitment and consent withdrawal. There are several learning points, described in the article, which will inform design of definitive trials in this area in the future. Trial registration ClinicalTrials.gov Identifier NCT03645733. Registration date 24/08/2018.

Abstract Background Suicide is the leading cause of preventable death in prisons. Deaths from suicide in prison are significantly, and persistently, elevated compared to those living in the community. Psychological therapies have been shown to be a potentially effective means of alleviating suicidal thoughts, plans and behaviours, but patients located in prison often have no access to evidence-based psychological interventions targeting suicide. The objectives of this programme of research are to investigate the clinical and cost effectiveness of a new psychological therapy programme delivered to male prisoners at risk of suicide. Methods The PROSPECT trial is a two-armed single blind, pragmatic, randomised controlled trial and will recruit a target sample size of 360 male prisoners, identified as at-risk of suicide, across 4 prisons in the North of England. Participants will be randomised to receive a psychological talking therapy (Cognitive Behavioural Suicide Prevention, CBSP) plus treatment as usual, or treatment as usual alone. Co-primary outcomes (Suicide Ideation and Suicide Behaviours), as well as related secondary outcomes, will be assessed at baseline and at 6-months follow-up. An intention to treat analysis will be conducted with primary stratification based on prison site and lifetime history of suicide attempt (yes/no). A nested qualitative process evaluation will investigate the nature and context in which the intervention is delivered, with specific focus upon the facilitators and barriers to the implementation of the therapy within prisons. Discussion The key outputs from this trial will be to determine whether a psychological therapy for suicidal prisoners is clinically and cost effective; and to generate a project implementation platform that identifies how best to implement the new intervention across the broader prison estate. Trial registration ISRCTN (reference ISRCTN14056534 https://www.isrctn.com/ISRCTN14056534 ; 24th September 2021). Registration confirmed prior to participant recruitment commencing. Modifications to protocol are listed on the study website at ISRCTN.

Abstract Background Around 40% of people with major depressive disorder (MDD) experience moderate remission, with the remainder meeting the criteria for resistant major depression (RMD). It has been shown that exercise has a low-to-moderate effect on MDD, but there is a lack of evidence on exercise interventions in RMD patients. The primary purpose of the proposed study will be to investigate the effect of a 12-week supervised combined exercise program on depressive symptoms in people with RMD compared to a treatment-as-usual (TAU) group. Method This randomised, single-blind, controlled experimental trial will include 70 adults (≥ 18 years old) with RMD. Participants randomised to an exercise intervention, or a TAU group will be assessed at baseline and after a three-month intervention period. The primary variable will be participants’ depressive symptoms measured with the Montgomery-Asberg Depression Rating Scale. Secondary outcome variables will include cardiorespiratory fitness (peak oxygen uptake through peak cardiopulmonary exercise test), body composition (bioimpedance and anthropometric variables), physical activity level (the International Physical Activity Questionnaire), health-related quality of life (the Short Form-36 Health Survey), functional outcome (the Sheehan Disability Scale and Quality of Life in Depression Scale), overall disease severity (the Clinical Global Impression Scale-Severity of Illness), and biochemical variables (a fasting blood sample). Discussion This study will try to answer whether a supervised co-adjuvant combined (aerobic and resistance training) exercise program will help the prognosis of this population with RMD. Trial registration ClinicalTrials.gov NCT05136027. Last public release on 12/13/2023.

Spinal cord injury (SCI) is a severe lesion comporting various motor, sensory and sphincter dysfunctions, abnormal muscle tone and pathological reflex, resulting in a severe and permanent lifetime disability. The primary injury is the immediate effect of trauma and includes compression, contusion, and shear injury to the spinal cord. A secondary and progressive injury usually follows, beginning within minutes and evolving over several hours after the first ones. Because ischemia is one of the most important mechanisms involved in secondary injury, a treatment to increase the oxygen tension of the injured site, such as hyperbaric oxygen therapy, should theoretically help recovery. Although a meta-analysis concluded that hyperbaric oxygen therapy might be helpful for clinical treatment as a safe, promising and effective choice to limit secondary injury when appropriately started, useful and well-defined protocols/guidelines still need to be created, and its application is influenced by local/national practice. The topic is not a secondary issue because a well-designed randomized controlled trial requires a proper sample size to demonstrate the clinical efficacy of a treatment, and the absence of a common practice guideline represents a limit for results generalization. This narrative review aims to reassemble the evidence on hyperbaric oxygen therapy to treat SCI, focusing on adopted protocols in the studies and underlining the critical issues. Furthermore, we tried to elaborate on a protocol with a flowchart for an evidence-based hyperbaric oxygen therapy treatment. In conclusion, a rationale and shared protocol to standardize as much as possible is needed for the population to be studied, the treatment to be adopted, and the outcomes to be evaluated. Further studies, above all, well-designed randomized controlled trials, are needed to clarify the role of hyperbaric oxygen therapy as a strategic tool to prevent/reduce secondary injury in SCI and evaluate its effectiveness based on an evidence-based treatment protocol. We hope that adopting the proposed protocol can reduce the risk of bias and drive future studies.

Abstract Background A new model of care enables French physiotherapists (PT) working in collaboration with family physicians (FP) to expand their usual scope of practice for patients with acute low back pain (LBP). The aim of our study is to evaluate the impact of this new first-contact physiotherapy (FCP) advanced practice model compared to usual FP care. Methods A multicentre pragmatic non-inferiority cluster randomised controlled trial (RCT) has been conducted in six multidisciplinary primary healthcare centres in France. Patients from 20 to 55 years old with acute LBP consulted either the PT or the FP. PT independently assessed and managed patients including medication prescription. The primary outcome measure was disability at six weeks (Roland Morris Disability Questionnaire, range 0–24). Secondary outcomes include pain, risk disability prognosis, satisfaction with care, healthcare resources use and wait times. Data were collected at baseline, six and twelve weeks. Outcomes across arms were compared using mixed models regression analysis. Except for non-inferiority analysis of the primary outcome measure, other analyses were performed with a two-sided significance level of 0.05. Results Sixty patients were recruited (PT: 32, FP: 28). The adjusted mean difference between groups for disability at 6 weeks was 0.39 in favour of the FP group (95%CI: -2.03; 2.81, p = 0.753). Considering a 5 points minimal clinically important difference, the FCP-led model of care was not inferior to usual FP care for the primary outcome. There was no statistically significant difference between groups in disability at 3 months and pain at 6 weeks and 3 months. PTs prescribed significantly less medications than FPs (p

Abstract Objective Eating disorders are complex illnesses with high morbidity and mortality. Yet, there is promising evidence to support the effects of nutrition on the brain and behaviour. One proposed example is the use of tyrosine as an adjunct treatment in anorexia nervosa (AN). However, recruitment and retention in eating disorder clinical trials has posed difficulties for researchers. The aim of this study was to pilot test a parallel randomised controlled trial (RCT) of tyrosine supplementation to explore the feasibility of recruitment and retention, intervention adherence and data collection methods from the perspective of participants and researchers. Method Feasibility was assessed using numbers participating, questionnaire completion in patients and parent/carers completing and declining participation, a researcher implementation record and clinical measures. Subjects included adolescents aged 12–17 years with AN. The study was conducted over a 12-week period, with the intervention group receiving 5 mg of L-tyrosine supplement and the control group receiving a placebo. Results Recruitment targets were not met and recruitment to a full RCT based on the current study protocol and recruitment sites did not prove feasible. Of the 39 approached for RCT participation, seven were recruited to the RCT (18% response rate) despite extending recruitment periods, with 100% retained and analysed. Patients or parents/carers identified barriers to study participation including burden, the need to consume tyrosine as tablets, and the use of blood, urine and psychological testing. Blood tyrosine rose markedly for subjects in the intervention group. No side effects were reported or measured. Conclusions This study offers a unique exploration of the feasibility of a tyrosine trial in anorexia nervosa and is of relevance to assist the success of future nutrition trials. Exploring the suitability of future study designs for nutrition intervention research is warranted.

Abstract Background Open liver surgery remains a primary surgical approach for complex liver resections and liver transplantation. However, the postoperative pain management is still a major challenge. Ultrasound-guided external oblique intercostal (EOI) plane block is a novel approach of regional anaesthesia and has a great potential to relieve postoperative pain after upper abdominal surgeries. This study aims to investigate the efficacy and safety of ultrasound-guided EOI plane block in managing postoperative pain after open liver surgery. Methods Seventy-four participants scheduled for open liver surgery will be randomly assigned to either the intervention group, receiving an ultrasound-guided EOI plane block with a single dose of 30 ml 0.375% ropivacaine, or the control group, which will not receive this block. All participants will be provided with opioid-based patient-controlled intravenous analgesia (PCIA) postoperatively. The primary outcome is resting pain score at 3 h postoperatively, assessed using numerical rating scale. Secondary outcomes include pain score at 6, 24, 48, and 72 h postoperatively, perioperative opioid consumption, remedial analgesics within 72 h postoperatively, PCIA usage within postoperative 72 h, postoperative recovery, length of hospital stay, postoperative side effects, block-related complications, and ropivacaine plasma concentration of participants receiving the block. Discussion This study is a randomised controlled trial to evaluate the efficacy and safety of ultrasound-guided EOI plane block for postoperative analgesia after open liver surgery. As regional anaesthesia plays an important role in the multimodal pain management, EOI plane block may prove to be an effective regional technique for enhancing postoperative pain relief and contributing to enhanced recovery after open liver surgery. Trial registration Chinese Clinical Trial Registry ChiCTR2200065745. Registered on November 14, 2022.

Abstract Introduction Hypertensive intracerebral hemorrhage (HICH) is a condition associated with significant morbidity, mortality, and disability, particularly among the elderly population. The management of moderate thalamic-basal ganglia cerebral hemorrhage primarily relies on conservative approaches. Nevertheless, the rate of long-term disability remains high. In recent years, there has been significant advancement in minimally invasive surgery and diffusion tensor imaging techniques. Consequently, the utilization of Diffusion Tensor Imaging (DTI) technology in patients with cerebral haemorrhage allows for the identification of the haematoma’s location in relation to the Corticospinal Tract (CST). This enables the development of precise puncture pathways that can be visualized, thereby avoiding any potential damage to the CST. Methods and analysis Diffusion Tensor Imaging (DTI) is a method used to assess the structural and physiological characteristics of biological tissue by examining the diffusion behavior of water molecules.In the central nervous system, limb paralysis will be inevitable if the corticospinal tract is damaged. By employing DTI imaging techniques on individuals, it becomes possible to visualize the spatial relationship between the hematoma and the CST. This approach allows avoidance of the CST during preoperative planning of the puncture path, thus reducing secondary injuries caused by the procedure. The primary objective of this study was to assess the ability of patients in the minimally invasive surgery group and the conservative group to perform activities of daily living after 6 months of treatment. In addition, secondary outcomes included assessment of hematoma resorption/clearance ratios, cytokine levels, complication rates, and therapeutic indexes at different treatment durations, as well as long-term safety and efficacy at 2–3 years of follow-up. Furthermore, subgroup analysis, and sensitivity analysis were conducted to further analyze the data. Logistic single-variate and multivariate regression analyses were applied to understand the adverse factors affecting prognosis. Ethics and dissemination The clinical study was reviewed and approved by the Ethics Committee of the First People’s Hospital of Yibin. The ethical number is: 2023 Review (64). Registration number This protocol is registered in the Prospective Registry of Chinese Clinical Trial Registries (PROCCTR). The full date of first registration is 28/12/2023. The registration number for PROCCTR is ChiCTR2300079252.

Abstract Background The increasing prevalence of mental health disorders in the United Kingdom necessitates the exploration of novel treatment modalities. This study aimed to assess the feasibility and acceptability of conducting a randomised controlled trial (RCT) evaluating the efficacy of four osteopathic interventions on psychophysiological and mental health outcomes. Methods A mixed-methods feasibility study with an explanatory sequential design was implemented. The quantitative phase involved randomising 42 participants into four intervention groups: (1) high-velocity and articulation techniques (HVAT), (2) soft-tissue massage (STM), (3) craniosacral therapy (CST), and (4) a combination approach. Primary outcome measures encompassed recruitment rate, assessment duration, questionnaire completion, intervention attrition, and adverse events. Secondary outcomes included validated assessments of depression, anxiety, stress, psychological flexibility, heart rate variability (HRV), and interoception, administered pre- and post-intervention. Analysis of variance (ANOVA) was employed to evaluate pre-post intervention changes. The qualitative phase comprised semi-structured interviews analysed using thematic analysis. Results The study achieved a recruitment rate of 21 eligible participants per month, with 54.8% of respondents meeting eligibility criteria. All 33 participants who completed the study underwent interventions and assessments within the allocated one-hour timeframe, with full questionnaire completion. The attrition rate was 21%. No adverse events were reported. Qualitative analysis revealed positive participant experiences, with themes highlighting good practitioner communication, intervention accessibility, and increased bodily awareness. Some participants found the questionnaire battery burdensome. Exploratory quantitative analyses showed variations in effects across interventions for heart rate variability, interoceptive accuracy, and mental health measures, but these results should be interpreted cautiously due to the small sample size. Conclusions This study provides evidence supporting the feasibility and acceptability of a larger-scale RCT investigating osteopathic interventions for individuals presenting with mild psychological symptoms. The preliminary findings suggest potential efficacy in improving mental health outcomes, warranting further investigation. Trial registration NCT05674071, registered 06/01/2023.

Abstract Background This paper reports the results from a feasibility trial of an early parent-delivered social communication intervention for young children with Down syndrome (‘ASCEND’). The intervention focuses on developing children’s early social communication skills, in particular responding to shared attention. The aim was to inform the feasibility of running a full-scale trial through National Health Service (NHS) Speech and Language Therapy (SaLT) services, to assess whether the intervention is effective in improving language skills before children with Down syndrome start school. Methods This was a two-arm feasibility randomised controlled trial (RCT), with 1:1 randomisation stratified by trial site, comparing the intervention plus standard NHS SaLT provision with standard NHS SaLT alone. We recruited 20 children with Down syndrome aged between 11 and 36 months through 3 NHS SaLT services, 19 of whom were randomised (10 — intervention group, 9 —control group). Pre- and post-intervention and 6-month follow-up assessments included language, social communication skills, adaptive behaviour, quality of life (parents and children), parental anxiety and depression. The intervention was parent delivered with parents having access to SaLT services and the research team during the intervention. Data were collected on recruitment and retention, standard care, treatment fidelity, acceptability of the intervention by the parents and speech and language therapists, feasibility of collecting health economic measures and suitability of the primary outcome measure. Results The sample was sufficient for a feasibility study. The intervention (manual, support, materials) was positively received by the participating parents. Speech and language therapists also evaluated the acceptability of the intervention positively. Treatment fidelity which was measured by completion of weekly parent diaries and two adherence phone call was acceptable as 100% of the parent diaries were returned, over 90% of the parental diaries were completed correctly and 100% of adherence phone calls were completed. Retention was acceptable at 84% overall. The preliminary health economic data suggest that this intervention will be low cost. The sample size calculation suggests that 290 participants would need to be recruited, with 228 having a complete data set, for a full RCT. Conclusion Based on recruitment, retention and treatment fidelity, as well as the acceptability of the intervention to parents and speech and language therapists, a full-scale trial would be feasible in order to assess the effectiveness of the intervention. Trial registration ISRCTN13902755, registered on 25th August 2020, http://www.isrctn.com/ISRCTN13902755

Abstract Background Tackling poor mental health in university students has been identified as a priority in higher education. However, there are few evidence-based prevention initiatives designed for students. Repetitive Negative Thought (RNT, e.g. worry, rumination) is elevated in university students and is a well-established vulnerability factor for anxiety and depression. Furthermore, there are now evidence-based cognitive-behavioural interventions to tackle RNT. A mobile self-help cognitive-behavioural app targeting RNT, adapted for students may therefore be an effective, scalable, and acceptable way to improve prevention in students. Methods An online single blind, two-arm parallel-group Randomised Controlled Trial (RCT) to examine the incidence of major depression and symptoms of anxiety and depression across 12 months in university students aged over 16 who screen into the study with self-reported high levels of worry and/or rumination and no current diagnosis of major depression. Eligible participants will be randomised to the active intervention arm (usual practice plus using a self-guided mobile app targeting RNT) or to the control arm (usual practice). In total, 648 participants aged over 16, with no current major depression, bipolar disorder or psychosis will be recruited from UK universities. Assessments will take place at baseline (pre-randomisation), 3 months and 12 months post- randomisation. Primary endpoint and outcome is incidence of major depression as determined by self-reported diagnostic criteria at 12-month follow-up. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and academic outcomes are secondary outcomes. Compliance, adverse events, and potentially mediating variables will be carefully monitored. Discussion The trial aims to provide a better understanding of the causal role of tackling RNT (worry, rumination) using a self-help mobile app with respect to preventing depression in university students. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective mobile-health public health strategies for preventing common mental health problems. Trial registration https://www.isrctn.com/ISRCTN86795807 Date of registration: 27 October 2022

Abstract Healthcare organisations worldwide are affected by the shortage of health professionals due to work-related stress and health professional leaders play an important role by implementing effective strategies. Therefore, this study aims to investigate whether the STRAIN intervention program (using evidence-based training for health professional leaders) can reduce work-related stress among health professionals. This study is based on a cluster randomised controlled trial, consists of three measurements and includes 165 participating hospitals, nursing homes and home care organisations. A total of 206 health professional leaders took part in the intervention programme and 19,340 health professionals participated in the study. Results showed no significant differences (p > 0.05) between the intervention and control group regarding the effort-reward imbalance ratio, quantitative demands, opportunities for development, bond with the organisation, quality of leadership, social community, role clarity, rewards, difficulties with demarcation and work–private life conflict. Pre-/post-test analysis revealed a tendency for significant positive results (p

Abstract Background Suicide has become a first-order public health concern, especially following the negative impact of COVID-19 on the mental health of the general population. Few studies have analysed the effects of early psychotherapeutic interventions on subjects who have attempted suicide, and even fewer have focused on those hospitalized in non-psychiatric units after a Medically Serious Suicide Attempt (MSSA). The main aim of this study is to describe the protocol designed to evaluate the effectiveness of individual psychological treatment for patients hospitalized after an MSSA. The secondary objectives of the study are: (1) to evaluate the impact on quality of life and other psychosocial variables of patients with a recent MSSA who receive early psychological intervention; (2) to analyse the biological, psychological, and clinical impact of early psychotherapeutic treatment on subjects hospitalized after an MSSA. Methods A longitudinal randomised controlled trial will be conducted with patients over 16 years of age admitted to two general hospitals. The case intervention group will enrol for 8-sessions of individual psychotherapy, Suicide Attempts Multi-component Intervention Treatment (SAMIT), combining Dialectical Behaviour Therapy (DBT), Mentalization-Based Therapy (MBT), and Narrative approaches, while the control group will receive a treatment-as-usual intervention (TAU). Longitudinal assessment will be conducted at baseline (before treatment), post-treatment, and 3, 6, and 12 months after. The main outcome variable will be re-attempting suicide during follow-up. Discussion Some psychotherapeutic interventions, usually implemented in outpatient, have proven to be effective in preventing suicidal behaviours. The combination of some of these may be a powerful treatment for preventing future SA in patients hospitalised after an MSSA, which is the most severely suicidal subgroup. Moreover, assessment of the biological, clinical and psychometric impact of this new intervention on patients during the first year after the attempt may help understand some of the multi-level factors associated with the effectiveness of psychotherapeutic interventions in MSSAs. The prevalence of high suicide rates requires the design of effective psychological interventions for their prevention, and also in order to design new pharmacological and psychological treatments. Trial registration ClinicalTrials.gov ID: NCT06238414. Date of registration: 1st February 2024, final update is protocol version 3.0, 19th March 2024.

Abstract Background Loneliness is common among older adults in institutional settings. It leads to adverse effects on health and wellbeing, for which nature contact with peers in turn may have positive impact. However, the effects of nature engagement among older adults have not been studied in randomised controlled trials (RCT). The “Friends in Nature” (FIN) group intervention RCT for lonely older adults in Helsinki assisted living facilities (ALFs) aims to explore the effects of peer-related nature experiences on loneliness and health-related quality of life (HRQoL). In this study we aim describe the participants’ baseline characteristics of the RCT, feasibility of FIN intervention and intervention participants’ feedback on the FIN. Methods Lonely participants were recruited from 22 ALFs in Helsinki area, Finland, and randomised into two groups: 1) nature-based social intervention once a week for nine weeks (n = 162) and 2) usual care (n = 157). Demographics, diagnoses and medication use were retrieved from medical records, and baseline cognition, functioning, HRQoL, loneliness and psychological wellbeing were assessed. Primary trial outcomes will be participants’ loneliness (De Jong Giervald Loneliness Scale) and HRQoL (15D). Results The mean age of participants was 83 years, 73% were female and mean Minimental State Examination of 21 points. The participants were living with multiple co-morbidities and/or disabilities. The intervention and control groups were comparable at baseline. The adherence with intervention was moderate, with a mean attendance of 6.8 out of the nine sessions. Of the participants, 14% refused, fell ill or were deceased, and therefore, participated three sessions or less. General subjective alleviation of loneliness was achieved in 57% of the intervention participants. Of the respondents, 96% would have recommended a respective group intervention to other older adults. Intervention participants appreciated their nature excursions and experiences. Conclusions We have successfully randomised 319 lonely residents in assisted living facilities into a trial about the effects of nature experiences in a group-format. The feedback from participants was favourable. The trial will provide important information about possibilities of alleviating loneliness with peer-related nature-based experiences in frail residents. Trial registration ClinicalTrials.gov, ID: NCT05507684. Registration 19/08/2022.

Abstract Background Computerised cognitive training (CCT) can improve the cognitive abilities of people with mild cognitive impairment (MCI), especially when the CCT contains a learning system, which is a type of machine learning (ML) that automatically selects exercises at a difficulty that corresponds to the person’s peak performance and thus enables individualised training. Methods We developed one individualised CCT (iCCT) with ML and one basic CCT (bCCT) for an active control group (CG). The study aimed to determine whether iCCT in the intervention group (IG) resulted in significantly greater enhancements in overall cognitive functioning for individuals with MCI (age 60+) compared with bCCT in the CG across a 6-month period. This double-blind randomised controlled study was conducted entirely virtually. The 89 participants were community-dwelling people with a psychometric diagnosis of MCI living in Germany. The iCCT stimulates various cognitive functions, especially working memory, visuo-constructional reasoning, and decision-making. The bCCT includes fewer and simpler tasks. Both CCTs were used at home. At baseline and after 6 months, we assessed cognitive functioning with the Montreal Cognitive Assessment (MoCA). A mixed-model ANCOVA was conducted as the main analysis. Results Both CCTs led to significant increases in average global cognition. The estimated marginal means of the MoCA score increased significantly in the CG by an average of 0.9 points (95% CI [0.2, 1.7]) from 22.3 (SE = 0.25) to 23.2 (SE = 0.41) points (p = 0.018); in the IG, the MoCA score increased by an average of 2.2 points (95% CI [1.4, 2.9]) from 21.9 (SE = 0.26) to 24.1 (SE = 0.42) points (p

Abstract Introduction Restorative sleep is essential for the maintenance of overall health and for the prevention of chronic diseases, including hypertension. The aim of this study was to determine the effect of motivational interviewing (MI) on sleep quality in patients with hypertension. Methods The study was a randomised controlled trial (PACTR202301917477205) of 250 adult patients aged 18 to 65 years (125 in each group) with hypertension presenting to the Family Medicine Clinics of Irrua Specialist Teaching Hospital, Irrua, Nigeria from April to December 2023. Patients were selected through systematic random sampling and randomised into intervention and control group with the intervention group having monthly sessions of motivational interviewing in addition to standard care for hypertension and the control group having standard care only. Data were analysed with Stata with level of significance set at p

Abstract Background Randomised controlled trials (RCTs) are considered the gold standard for generating clinical evidence. The focus on high internal validity in RCTs challenges the external validity and generalisability of findings, potentially hindering their application in routine care. In neurorehabilitation, limited literature addresses conducting RCTs feasibly and efficiently. We investigated barriers and facilitators to conducting RCTs within routine care of neurorehabilitation centres from the perspective of stakeholders in neurorehabilitation in Germany and Austria. Methods We conducted semi-structured interviews with stakeholders in neurorehabilitation from four centres in Germany and Austria, informed by the Theoretical Domains Framework (TDF) and the Capability, Opportunity, Motivation and Behaviour model (COM-B). Employing a hybrid approach, the interview analysis integrated both deductive, theory-driven analysis based on the TDF domains and COM-B model and inductive, reflexive thematic analysis. Results Twelve stakeholders (4 physicians, 4 therapy managers, 4 therapists; 5 females, 7 males; with research experience spanning 0–40 years) were interviewed. Key barriers to conducting RCTs in neurological rehabilitation centres include limited financial, human, and time resources, high clinical workloads, and a lack of interest of some therapists. Ineffective leadership, perceived lack of research expertise, and communication issues were also significant barriers. Social influence factors such as lack of employer support and inadequate training access further contributed to the challenges. Additionally, barriers included insufficient research infrastructure, limited space, internal power struggles, and rigid cost bearer specifications. Key facilitators included physicians’ and therapists’ motivation to advance the field, contribute to knowledge, and to prioritise patient health. Support from supervisors, joint decision-making, and efficient organisation were crucial facilitators. Flexible therapy planning, mutual support, and interdisciplinary collaboration also played important roles. Conclusion Our results suggest that increasing professional development and understanding, along with providing adequate financial, human, time, and spatial resources to support research endeavours, implementing effective communication strategies to enhance interdisciplinary collaboration and coordination among team members may contribute to increased motivation and facilitate RCTs within the setting of neurorehabilitation centres. Trial registration This study was prospectively registered with the German Clinical Trials Register (08.04.2021 DRKSID DRKS00024982).

Abstract Background Chronic diseases are a significant and growing problem of our time. They impair the ability to work and increase the risk of early retirement. To support the return to work, rehabilitation services can be applied for in Germany. Currently, the application system for rehabilitation allows only a limited degree of individualisation of the treatment and is associated with a lack of multidisciplinary communication. To facilitate rehabilitation care planning, we developed a complex intervention. A digital, platform-based case management approach (intervention) will ensure multidisciplinary communication and the tailored selection of medical treatments and/or non-medical support measures. The overall objective is to assess the effectiveness of the intervention compared to treatment as usual (control condition). The German Federal Ministry of Labour and Social Affairs (BMAS) funds the RehaPro-SERVE study (grant number: 661R0053K1). Methods This is the protocol for an investigator-initiated, pragmatic, multicentre, randomised and controlled two-arm parallel-group superiority trial with embedded qualitative process evaluation. The study will be conducted in Hesse state, Germany. N = 59 primary care physicians will be recruited and tasked with the recruitment of six eligible patients each. Eligibility criteria: age 40–60; minimum of 4-week work disability due to musculoskeletal, oncologic or psychological conditions or the post-COVID-19 syndrome within the last 6 months; at high risk for early retirement. In total, n = 352 patients will be randomised with a 1:1 allocation to intervention or control group and stratified by primary care practice using permuted blocks. The primary outcome is the number of days of sick leave during a 12-month period after the assumed completion of treatments (t1 to t2). Secondary outcomes include the number of days of sick leave (self-report), work ability, and health-related quality of life, as well as data from the qualitative process evaluation. Discussion The results of the study will inform the design of future care services and provide valuable information on multidisciplinary case management in the context of rehabilitation care planning. The results of the qualitative process evaluation will further contribute to the understanding of facilitating and hindering factors. Trial registration DRKS-German Clinical Trials Register, DRKS0 00242 07. Registered on 22 March 2021.

Background In Norway, municipal acute wards (MAWs) were implemented as alternatives to hospitalisation. Evaluations of the quality of MAW services are lacking. The primary objective of this study was to compare patient experiences after admission to a MAW versus to a hospital. The secondary objective was to compare ‘readmissions’, ‘length of stay’, ‘self-assessed health-related quality of life’ as measured by the EuroQol 5 items 5 level (EQ-5D-5L) index, and ‘health status’ measured by the RAND-12, in patients admitted to a MAW versus a hospital.Methods A multicentre randomised controlled trial (RCT), randomising patients to either MAW or hospital.Results In total, 164 patients were enrolled in the study; 115 were randomised to MAW and 49 to hospital. There were no significant differences between the MAW and hospital groups regarding patient experience, which was rated positively in both groups. Patients in the MAW group reported significantly better physical health status as measured by the RAND-12 four to six weeks after admittance than those randomised to hospital (physical component summary score, 31.7 versus 27.1, p = 0.04). The change in EQ-5D index score from baseline to four to six weeks after admittance was significantly greater among patients randomised to MAWs versus hospitals (0.20 versus 0.02, p = 0.03). There were no other significant differences between the MAW and hospital groups.Conclusions In this study, patient experiences and readmissions were similar, whether patients were admitted to a MAW or a hospital. The significant differences in health status and quality of life favouring the MAWs suggest that these healthcare services may be better for elderly patients. However, unfortunately we did not reach the planned sample size due to challenges in the data collection posed by the Covid-19 pandemic.

Abstract Background The World Health Organization’s (WHO) Mental Health Gap Action Programme (mhGAP) is a validated intervention that can be provided by non-specialised healthcare workers to individuals with unhealthy alcohol use. However, it typically requires several in-person sessions at a health facility, which may limit its feasibility and effectiveness in remote settings. This trial compares mhGAP-Standard, a 4 to 6 in-person session intervention, to mhGAP-Remote, a 1 in-person session intervention followed by 8 week of short message service (SMS) in Lesotho. We hypothesise that mhGAP-Remote is superior to mhGAP-Standard in reducing alcohol use (as detailed by the primary and secondary outcomes below). Methods This is a two-arm randomised open-label multicentre superiority trial. Participants allocated to mhGAP-Standard receive 4 in-person sessions using motivational interviewing, identifying triggers, and alternative behaviours, with the option of two additional booster sessions. Participants in the mhGAP-Remote arm receive 1 in-person session covering the same content, followed by standardised SMSs over 8 weeks that reinforce intervention content. Non-specialist providers deliver the intervention and receive weekly supervision. Adults (N planned = 248) attending participating health facilities for any reason and who meet criteria for unhealthy alcohol use based on the Alcohol Use Disorders Identification Test ([AUDIT] score ≥ 6 for women, ≥ 8 for men) are individually randomised to the two arms (1:1 allocation, stratified by participant sex and age (≥ 50 vs

Abstract Background The aim of this study is to evaluate the efficacy and safety of faecal microbiota transplantation (FMT) for the treatment of irritable bowel syndrome (IBS). Methods We searched four databases for randomised controlled trials (RCTs) that compared FMT with a control intervention in patients with IBS. The revised Cochrane risk-of-bias (RoB) tool was chosen for appraisal. Meta-analysis with trial sequential analysis (TSA) was conducted. Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence (CoE). Results We included 12 RCTs with a total of 615 participants. Meta-analyses showed no significant difference between the FMT and control groups in terms of clinical responses (relative risk [RR] = 1.44, 95% confidence interval [CI] 0.88–2.33) and changes in IBS Severity Scoring System (IBS-SSS) scores (standardised mean difference [SMD] = − 0.31, 95% CI − 0.72 to 0.09) and IBS Quality of Life (IBS-QOL) scores (SMD = 0.30, 95% CI − 0.09 to 0.69). Subgroup analysis revealed that in studies with low RoB and using endoscopy, nasojejunal tube and rectal enema delivery, FMT led to a significant improvement in clinical responses and changes in IBS-SSS and IBS-QOL scores. TSA suggested that the current evidence is inconclusive and that the CoE is very low. Conclusion This study suggests that patients with IBS may benefit from FMT especially when it is administered via endoscopy, nasojejunal tube or rectal enema. However, the certainty of evidence is very low. Further research is needed to confirm the efficacy and safety of FMT for IBS treatment. Trial Registration: PROSPERO registration number CRD42020211002.

Abstract Background Experimental studies of wound healing often use survival analysis and time to event outcomes or differences in wound area at a specific time point. However, these methods do not use a potentially large number of observations made over the course of a trial and may be inefficient. A model-based approach can leverage all trial data, but there is little guidance on appropriate models and functional forms to describe wound healing. Methods We derive a general statistical model and review a wide range of plausible mathematical models to describe wound healing. We identify a range of possible derived estimands and their derivation from the models. Using data from a trial of an intervention to promote ulcer healing in patients affected by leprosy that included three measurement methods repeated across the course of the study, we compare the goodness-of-fit of the models using a range of methods and estimate treatment effects and healing rate functions with the best-fitting models. Results Overall, we included 5,581 ulcer measurements of 1,578 unique images from 130 patients. We examined the performance of a range of models. The square root, log square root, and log quadratic models were the best fitting models across all outcome measurement methods. The estimated treatment effects magnitude and sign varied by time post-randomisation, model type, and outcome type, but across all models there was little evidence of effectiveness. The estimated effects were significantly more precise than non-parametric alternatives. For example, estimated differences from the three outcome measurements at 42-days post-randomisation were − 0.01 cm2 (-0.77, 0.74), -0.44 cm2 (-1.64, 0.76), and 0.11 cm2 (-0.87, 1.08) using a non-parametric method versus − 0.03 cm2 (-0.14, 0.06), 0.06 cm2 (-0.05, 0.17), and 0.03 cm2 (-0.07, 0.17) using a square-root model. Conclusions Model-based analyses can dramatically improve the precision of estimates but care must be taken to carefully compare and select the best fitting models. The (log) square-root model is strongly recommended reflecting advice from a century ago.

Abstract Background Reusable surgical drapes have a lower lifetime environmental impact than disposable drapes in most cases. There is limited evidence regarding whether drape choice impacts patient outcomes including post-operative wound complications. The aim of this study is to compare wound complication rates following routine neutering surgeries in cats and dogs when reusable drapes are used as compared with disposable drapes. Methods The trial will be conducted as a pragmatic, multi-centre, parallel group randomised controlled trial in the UK. Dogs and cats undergoing routine neutering will be randomised to disposable or reusable drapes with all other aspects of care occurring as they usually would at the practice. The required sample size is 2,850, with 4750 animals to be recruited from up to ten practices to allow for a 40% loss to follow-up. Demographic data and details on peri-operative care will be collected at the time of surgery. Post-operative wound complications will be assessed and recorded as usual at each practice using clinical codes. The post-operative wound clinical codes and any antibiotic use within 30 days of surgery will be retrieved from the practice management software. The primary outcome that will be compared between the two groups is the rate of post-operative wound complications within 30 days of surgery which will be analysed by multivariable logistic regression with a binary outcome of wound complication (yes/no). Secondary outcomes are the prevalence of different types of complications and antibiotic use within 30 days of surgery which will be compared between the two groups by chi square analysis. Discussion Our hypothesis is that there will be no difference in post-operative wound complication rates between disposable and reusable drapes. If the likely rate of post-surgical wound complications with reusable drapes is similar to that with disposable drapes, then veterinary clinical teams can choose the more sustainable option, confident that their patients will not be impacted by this choice. Trial registration We have retrospectively registered the protocol on the Open Science Framework on 14 Nov 2023 (Trial registration entry: https://doi.org/10.17605/OSF.IO/72HMA ).

Abstract Background An adaptive design allows modifying the design based on accumulated data while maintaining trial validity and integrity. The final sample size may be unknown when designing an adaptive trial. It is therefore important to consider what sample size is used in the planning of the study and how that is communicated to add transparency to the understanding of the trial design and facilitate robust planning. In this paper, we reviewed trial protocols and grant applications on the sample size reporting for randomised adaptive trials. Method We searched protocols of randomised trials with comparative objectives on ClinicalTrials.gov (01/01/2010 to 31/12/2022). Contemporary eligible grant applications accessed from UK publicly funded researchers were also included. Suitable records of adaptive designs were reviewed, and key information was extracted and descriptively analysed. Results We identified 439 records, and 265 trials were eligible. Of these, 164 (61.9%) and 101 (38.1%) were sponsored by industry and public sectors, respectively, with 169 (63.8%) of all trials using a group sequential design although trial adaptations used were diverse. The maximum and minimum sample sizes were the most reported or directly inferred (n = 199, 75.1%). The sample size assuming no adaptation would be triggered was usually set as the estimated target sample size in the protocol. However, of the 152 completed trials, 15 (9.9%) and 33 (21.7%) had their sample size increased or reduced triggered by trial adaptations, respectively. The sample size calculation process was generally well reported in most cases (n = 216, 81.5%); however, the justification for the sample size calculation parameters was missing in 116 (43.8%) trials. Less than half gave sufficient information on the study design operating characteristics (n = 119, 44.9%). Conclusion Although the reporting of sample sizes varied, the maximum and minimum sample sizes were usually reported. Most of the trials were planned for estimated enrolment assuming no adaptation would be triggered. This is despite the fact a third of reported trials changed their sample size. The sample size calculation was generally well reported, but the justification of sample size calculation parameters and the reporting of the statistical behaviour of the adaptive design could still be improved.

Abstract Background Azithromycin has been shown to be beneficial in preventing infectious diseases, including malaria, infectious diarrhoea and pneumonia. A cluster randomised control trial on azithromycin MDA in children in Niger, Malawi and Tanzania found a reduction in all-cause under-five (U5) mortality in communities who received azithromycin compared to placebo. However, the reduction was largest and statistically significant only in Niger. The purpose of this trial is to evaluate the impact of azithromycin plus intermittent preventive treatment in infants (IPTi), recently renamed by the World Health Organisation as perennial malaria chemoprevention (PMC), with sulfadoxine-pyrimethamine (SP) on all-cause mortality up to 18 months of age in children living in areas of high mortality burden through the Expanded Program on Immunisation (EPI) in Sierra Leone. Methods The Improving Care through Azithromycin Research for Infants in Africa (ICARIA) trial is a phase III two-arm, individually randomised, double-blinded, placebo-controlled trial administering oral AZI (20 mg/kg bodyweight) at three time points to children attending EPI visits in Sierra Leone. A total of 20,560 infants attending the first EPI contact at around 6 weeks of age are recruited and randomised to AZI or placebo in a 1:1 ratio. The second and third AZI/placebo doses are given at 9 and 15 months of age. The primary outcome of the trial is all-cause mortality rate at 18 months of age assessed through mortality surveillance. Other trial outcomes include the impact on antimicrobial resistance, and on the immune response to certain key routine EPI immunisations, the safety of the intervention, the prevalence of SP resistance markers and the feasibility, and acceptability of adding AZI to the EPI programme. Discussion The trial will provide the evidence needed to inform policy regarding the adoption and large-scale implementation of AZI in areas of high-mortality burden in sub-Saharan Africa. Trial registration ClinicalTrials.gov NCT04235816. Registered on 22 January 2020. Pan-African Clinical Trials Registry PACTR202004540256535. Registered on 14 April 2020.

Abstract Background The number of surgical trials is increasing but such trials can be complex to deliver and pose specific challenges. A multi-centre, Phase III, RCT comparing Posterior Cervical Foraminotomy versus Anterior Cervical Discectomy and Fusion in the Treatment of Cervical Brachialgia (FORVAD Trial) was unable to recruit to target. A rapid qualitative study was conducted during trial closedown to understand the experiences of healthcare professionals who participated in the FORVAD Trial, with the aim of informing future research in this area. Methods Semi-structured interviews were conducted with 18 healthcare professionals who had participated in the FORVAD Trial. Interviews explored participants’ experiences of the FORVAD trial. A rapid qualitative analysis was conducted, informed by Normalisation Process Theory. Results Four main themes were generated in the data analysis: (1) individual vs. community equipoise; (2) trial set-up and delivery; (3) identifying and approaching patients; and (4) timing of randomisation. The objectives of the FORVAD trial made sense to participants and they supported the idea that there was clinical or collective equipoise regarding the two FORVAD interventions; however, many surgeons had treatment preferences and lacked individual equipoise. The site which had most recruitment success had adopted a more structured process for identification and recruitment of patients, whereas other sites that adopted more “ad hoc” screening strategies struggled to identify patients. Randomisation on the day of surgery caused both medico-legal and practical concerns at some sites. Conclusions Organisation and implementation of a surgical trial in neurosurgery is complex and presents many challenges. Sites often reported low recruitment and discussed the logistical issues of conducting a complex surgical RCT. Future trials in neurosurgery may need to offer more flexibility and time during set-up to maximise opportunities for larger recruitment numbers. Rapid qualitative analysis informed by Normalisation Process Theory was able to quickly identify key issues with trial implementation so rapid qualitative analysis may be a useful approach for teams conducting qualitative research in trials. Trial registration ISRCTN, ISRCTN reference: 10,133,661. Registered 23rd November 2018.

Abstract Background Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities. Building upon preliminary evidence and the successful completion of an open-label pilot trial of microdosing LSD for depression (LSDDEP1), this protocol outlines a phase 2b randomised controlled trial (LSDDEP2). The main objective of LSDDEP2 is to assess the modification of depressive symptoms, measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), following a regimen of LSD microdoses versus placebo. Methods This is a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients meeting DSM-5 criteria for major depressive disorder. Participants will undergo an 8-week LSD microdosing regimen using the titratable MB-22001 formulation taking two doses a week. All doses will be self-administered at home and will be titratable from 4 to 20 μg based on subjective perception and tolerability. In addition to depression symptoms, outcome will include psychiatric and personality inventories, sleep and activity tracking, electroencephalography (EEG), blood biomarkers, semi-structured interviews, and safety (e.g. adverse event, laboratory exam) measures. Discussion This study will be the first randomised controlled trial to administer controlled microdoses of LSD for treatment of MDD in participants’ naturalistic environment. The measures included are designed to assess the drug’s safety, mechanism, and treatment efficacy over placebo in this population. The results of this study will be important for assessing the viability of psychedelic microdosing as an additional treatment option and for informing the direction of future clinical trials. Trial registration ANZCTR, ACTRN12624000128594. Prospectively Registered on 13 February 2024.

Abstract Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT). Methods We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events. Results At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported. Conclusion Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018).

Background Roux-en-Y gastric bypass is an established treatment option for type 2 diabetes and obesity. However, the optimal lengths for the small intestinal limbs remain controversial with variation in practice. A longer biliopancreatic limb length of 150 cm (‘Long Limb’) was hypothesised to better improve glycaemia compared to the standard Roux-en-Y gastric bypass with a biliopancreatic limb of 50 cm (‘Standard Limb’). The aim of the trial was to evaluate the short-term mechanistic outcomes and the long-term clinical outcomes and safety of Long Limb versus Standard Limb Roux-en-Y gastric bypass. Methods We undertook a prospective double-blinded randomised controlled parallel group clinical trial across two sites in London. Participants were randomly assigned (1 : 1) to Long Limb or Standard Limb Roux-en-Y gastric bypass with a fixed alimentary limb of 100 cm. Mixed-meal tolerance tests and a hyperinsulinaemic-euglycaemic clamp were used to measure postprandial gut hormone response, glucose tolerance and insulin sensitivity. The primary outcome for the mechanistic study was the secretion of active glucagon-like peptide-1 at 2 weeks after intervention. Secondary outcomes were insulin sensitivity and fasting/postprandial glucose and insulin concentrations. Clinical outcomes, including HbA1c, number of glucose-lowering medications, weight loss, blood pressure and low-density lipoprotein cholesterol, and adverse events, were collected up to 60 months postoperatively to assess the durability of postoperative weight and glycaemic improvements. Results Of the 53 participants randomised, 48 completed the 12-month mechanistic investigation (Standard Limb 24, Long Limb 24) and 38 completed the 60-month follow-up (Standard Limb 18, Long Limb 20). The 24- to 60-month extension study coincided with two waves of the COVID-19 pandemic. There was no difference between the Standard Limb and Long Limb groups for postprandial active glucagon-like peptide-1 secretion (70 ± 32 pmol/L vs. 70 ± 19 pmol/L, respectively; p = 0.43), hepatic insulin sensitivity (3.4 ± 0.9 µmol/kg/min vs. 3.4 ± 1.4 µmol/kg/min, respectively; p = 0.94) and peripheral insulin sensitivity (29.0 ± 9.1 µmol/kg/min vs. 29.2 ± 9.9 µmol/kg/min, respectively; p = 0.98) at 2 weeks post intervention. There was no difference between the Standard Limb and Long Limb groups at 60-month follow-up for glycaemic remission (33% vs. 45%, respectively; p = 0.52), percentage total weight loss (27 ± 9% vs. 26 ± 8%, respectively; p = 0.34), systolic blood pressure (127 ± 11 mmHg vs. 125 ± 14 mmHg, respectively; p = 0.63) and low-density lipoprotein cholesterol (2.0 ± 1.0 mmol/L vs. 2.4 ± 1.0 mmol/L, respectively; p = 0.27). Conclusion In conclusion, this study has demonstrated the substantial clinical benefit of Roux-en-Y gastric bypass to people living with type 2 diabetes and obesity; however, this trial did not demonstrate a clinical rationale for the elongation of the biliopancreatic limb of Roux-en-Y gastric bypass to 150 cm to enhance metabolic outcomes for type 2 diabetes and obesity. Limitations Although the surgical procedures were designed according to United Kingdom clinical practice at the time of study inception, there is substantial variation in practice internationally. Our original investigation was powered for mechanistic outcomes and is not powered to detect differences in clinical outcomes. Lastly, the loss of participants to follow-up may have limited our statistical power to detect significant differences in the clinical outcomes. We therefore cannot derive definitive conclusions on the relative clinical efficacy of the two variants of Roux-en-Y gastric bypass. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR130639. Plain language summary Weight loss surgery, such as gastric bypass, is routinely used to treat people with type 2 diabetes and obesity worldwide. This is because the surgery is effective at lowering weight and improving blood sugar. In some people with diabetes this means that they can come off medications and still have normal blood sugar: this is called diabetes remission. However, the standard gastric bypass surgery only results in diabetes remission in 4 out of 10 patients, and it would be better if we could improve this success rate. In this trial a new surgery called ‘Long Limb’ gastric bypass was tested. It was designed to be better at improving diabetes mellitus than the older ‘Standard Limb’ gastric bypass surgery, while being just as safe. It was expected that this new procedure would work better than the Standard Limb gastric bypass by increasing the release of insulin and other hormones from the gut and by improving weight loss and blood sugar over and above the standard operation. We found that the Standard and Long Limb operations were equally effective in reducing blood sugar and reducing weight. When followed up to 60 months (5 years) after the surgery, people who had either Standard or Long Limb had similar experiences, with lasting weight loss and improvement in blood sugar levels, but there was no significant difference between the older and the newer type of surgery. Our study shows that there does not appear to be a large difference between the two types of surgery: both seem to be similarly effective at helping people to lose weight and improve their diabetes.

BackgroundLow back pain and lower extremity sensory and functional abnormalities are common symptoms of lumbar disc herniation (LDH), which can easily cause walking dysfunction and significantly impair the quality of life of patients. Tuina and traditional Chinese exercises (TCEs) are effective in relieving pain and restoring dysfunction, and both are often used in China as a combination of passive therapy and active exercise to ease symptoms in patients with LDH. However, the majority of current clinical trials on the treatment of LDH with Tuina or TCEs are single-centre clinical studies, and the quality of these studies is generally low. Furthermore, clear evidence of clinical efficacy as to whether Tuina combined with TCEs is superior to single TCEs for improving dysfunction and pain in patients with LDH is lacking.Methods/designThe design is a multicentre, assessor-blinded clinical randomised controlled trial. A total of 166 patients with LDH (aged 18–65 years) were recruited from four centres and randomly assigned at a 1:1 ratio to two groups: the TCE group and the Tuina combined with the TCE group. Each group received three treatments over the course of 1 week for a total of 4 weeks. The primary outcome indicator was the Oswestry Disability Index, whereas the secondary outcome indicators were the Short Form of Quality of Life Scale, the Short-Form McGill Pain Questionnaire Scale, and gait analysis. Assessments were made before the treatment, at the end of the treatment, and at the third and sixth months’ follow-ups. Gait analysis was only used for comparison between the two groups before and after treatment, and did not involve follow-up. Adverse events occurring during the trial were faithfully recorded.ConclusionThe results of this study are expected to provide a more effective research protocol for symptomatic LDH and an evidence-based rationale for the efficacy and safety of Tuina combined with TCEs in the treatment of symptomatic LDH.Clinical trial registrationhttps://www.chictr.org.cn/showproj.html?proj=209956, identifier ChiCTR2300077361.

Background A priority setting partnership for eczema (syn atopic eczema, atopic dermatitis) has identified that bathing frequency is a key area of patient interest. However, there are nolarge, high-quality randomised controlled trials (RCTs) investigating this. The Rapid Eczema Trials project is a novel programme of research that aims to deliver multiple online RCTs, using a citizen science approach. This project involves working with members of the public to co-design and conduct studies that answer questions of importance to them. The first trial to be conducted through this project is assessing the impact of bathing frequency on eczema. Methods This is an online, two-arm, parallel-group superiority RCT with internal pilot phase. People aged ≥1 year with eczemaliving in the United Kingdom are eligible. Exclusion criteria are: people with other types of eczema such as venous eczema, hand eczema and contact eczema; recently started a new eczema treatment; taking part in another eczema trial; Patient Oriented Eczema Measure (POEM) ≤2; planning to swim more than twice a week; unable/unwilling to change bathing practices. Participants are allocated 1:1 to either the weekly bathing group (bathe 1 or 2 times a week) or the daily bathing group (bathe 6 or more times a week) for 4 weeks. The primary outcome is POEM, assessed weekly over 4 weeks. Secondary outcomes include skin specific quality of life, eczema control, itch severity, use of usual eczema treatments, proportion who achieve an improvement in POEM of ≥3 points, global change in eczema and safety outcomes. A sample of participants will also be invited to a semi-structured interview to discuss their experience. The primary comparative analysis will be according to randomised allocation regardless of actual frequency of bathing. The trial will be reported in accordance with CONSORT guidelines. The study has received ethical approval by the London - Surrey Research Ethics Committee (2 Redman Place, London, E20 1JQ, United Kingdom) on 11/10/2023 ( approval number: 23/PR/0899). Trial registration ISRCTN12016473, 22/11/2023, https://doi.org/10.1186/ISRCTN12016473

Background There is no clear evidence about how to support people with borderline personality disorder (BPD) during the perinatal period. Perinatal emotional skills groups (ESGs) may be helpful, but their efficacy has not been tested. Aims To test the feasibility of conducting a randomised controlled trial (RCT) of perinatal ESGs for women and birthing people with BPD. Method Two-arm parallel-group feasibility RCT. We recruited people from two centres, aged over 18 years, meeting DSM-5 diagnostic criteria for BPD, who were pregnant or within 12 months of a live birth. Eligible individuals were randomly allocated on a 1:1 ratio to ESGs + treatment as usual (TAU), or to TAU. Outcomes were assessed at 4 months post randomisation. Results A total of 100% of the pre-specified sample (n = 48) was recruited over 6 months, and we obtained 4-month outcome data on 92% of randomised participants. In all, 54% of participants allocated to perinatal ESGs attended 75% of the full group treatment (median number of sessions: 9 (interquartile range 6–11). At 4 months, levels of BPD symptoms (adjusted coefficient −2.0, 95% CI −6.2 to 2.1) and emotional distress (−2.4, 95% CI −6.2 to 1.5) were lower among those allocated to perinatal ESGs. The directionality of effect on well-being and social functioning also favoured the intervention. The cost of delivering perinatal ESGs was estimated to be £918 per person. Conclusions Perinatal ESGs may represent an effective intervention for perinatal women and birthing people with BPD. Their efficacy should be tested in a fully powered RCT, and this is a feasible undertaking. Trial registration ISRCTN80470632.

Summary: Background: Sustaining the capabilities of dementia carers is a global priority. ‘iSupport’ is a self-guided online intervention designed by the World Health Organization (WHO) to reduce mental health problems in dementia carers. iSupport is undergoing global implementation, however there is an absence of effectiveness evidence. This study tested the effectiveness of iSupport to reduce distress and depression in dementia carers. Methods: A pragmatic randomised controlled trial was conducted in three centres. Adult carers (18+) living in the community were recruited in England, Wales and Scotland and randomly assigned (1:1) through a web-based system to iSupport or usual care. Outcome assessors were masked to allocation. The primary outcomes assessed the difference in distress and depression between baseline and six-months. The target sample size was 350 to enable 90% power, significance at 2.5% including 25% attrition (262 completers) on either outcome. Analysis followed the intention-to-treat (ITT) principle. The trial was registered with ISRCTN registry (17420703). Findings: Between 12th November 2021 and 31st March 2023,177 carers (50.3%) were randomised to usual care and 175 (49.7%) to iSupport. 263 (74.7%) completed the trial. All were included in the ITT analysis. Mean distress scores at six-months were 20.0 (SD = 8.3) for usual care and 20.6 (SD = 8.6) for iSupport. The mean difference was 0.16 (95% CI −1.17 to 1.49, p = 0.29) after adjusting for covariates. Mean depression scores at six-months were 9.5 (SD = 7.0) for usual care and 9.8 (SD = 6.5) for iSupport. The mean difference at six-months was −0.54 (95% CI = −1.70 to 0.62, p = 0.44). No serious adverse events were linked to the trial. Interpretation: To our knowledge this is the largest trial evaluating a self-guided online intervention in UK dementia carers, and the first to successfully evaluate the effectiveness of iSupport. The null findings are significant given the ongoing global implementation of iSupport by the WHO and the adoption of self-guided interventions into mainstream care delivery as part of digital health transformations. Funding: NIHR.

Background Dupuytren’s contracture is caused by nodules and cords which pull the fingers towards the palm of the hand. Treatments include limited fasciectomy surgery, collagenase injection and needle fasciotomy. There is limited evidence comparing limited fasciectomy with collagenase injection. Objectives To compare whether collagenase injection is not inferior to limited fasciectomy when treating Dupuytren’s contracture. Design Pragmatic, two-arm, unblinded, randomised controlled non-inferiority trial with a cost-effectiveness evaluation and nested qualitative and photographic substudies. Setting Thirty-one National Health Service hospitals in England and Scotland. Participants Patients with Dupuytren’s contracture of ≥ 30 degrees who had not received previous treatment in the same digit. Interventions Collagenase injection with manipulation 1–7 days later was compared with limited fasciectomy. Main outcome measures The primary outcome was the Patient Evaluation Measure score, with 1 year after treatment serving as the primary end point. A difference of 6 points in the primary end point was used as the non-inferiority margin. Secondary outcomes included: Unité Rhumatologique des Affections de la Main scale; Michigan Hand Outcomes Questionnaire; recurrence; extension deficit and total active movement; further care/re-intervention; complications; quality-adjusted life-year; resource use; and time to function recovery. Randomisation and blinding Online central randomisation, stratified by the most affected joint, and with variable block sizes allocates participants 1 : 1 to collagenase or limited fasciectomy. Participants and clinicians were not blind to treatment allocation. Results Between 31 July 2017 and 28 September 2021, 672 participants were recruited (n = 336 per group), of which 599 participants contributed to the primary outcome analysis (n = 285 limited fasciectomy; n = 314 collagenase). At 1 year (primary end point) there was little evidence to support rejection of the hypothesis that collagenase is inferior to limited fasciectomy. The difference in Patient Evaluation Measure score at 1 year was 5.95 (95% confidence interval 3.12 to 8.77; p = 0.49), increasing to 7.18 (95% confidence interval 4.18 to 10.88) at 2 years. The collagenase group had more complications (n = 267, 0.82 per participant) than the limited fasciectomy group (n = 177, 0.60 per participant), but limited fasciectomy participants had a greater proportion of ‘moderate’/‘severe’ complications (5% vs. 2%). At least 54 participants (15.7%) had contracture recurrence and there was weak evidence suggesting that collagenase participants recurred more often than limited fasciectomy participants (odds ratio 1.39, 95% confidence interval 0.74 to 2.63). At 1 year, collagenase had an insignificantly worse quality-adjusted life-year gain (−0.003, 95% confidence interval −0.006 to 0.0004) and a significant cost saving (−£1090, 95% confidence interval −£1139 to −£1042) than limited fasciectomy with the probability of collagenase being cost-effective exceeding 99% at willingness to pay thresholds of £20,000–£30,000 per quality-adjusted life-year. At 2 years, collagenase was both significantly less effective (−0.048, 95% confidence interval −0.055 to −0.040) and less costly (−£1212, 95% confidence interval −£1276 to −£1147). The probability of collagenase being cost-effective was 72% at the £20,000 threshold but limited fasciectomy became the optimal treatment at thresholds over £25,488. The Markov model found the probability of collagenase being cost-effective at the lifetime horizon dropped below 22% at thresholds over £20,000. Semistructured qualitative interviews found that those treated with collagenase considered the outcome to be acceptable, though not perfect. The photography substudy found poor agreement between goniometry and both participant and clinician taken photographs, even after accounting for systematic differences from each method. Limitations Impacts of the COVID-19 pandemic resulted in longer waits for Dupuytren’s contracture treatment, meaning some participants could not be followed up for 2 years. This resulted in potential underestimation of Dupuytren’s contracture recurrence and/or re-intervention rates, which may particularly have impacted the clinical effectiveness and long-term Markov model findings. Conclusions Among adults with Dupuytren’s contracture, collagenase delivered in an outpatient setting is less effective but more cost-saving than limited fasciectomy. Further research is required to establish the longer-term implications of both treatments. Future work Recurrence and re-intervention usually occur after 1 year, and therefore follow-up to 5 years or more could resolve whether the differences observed in the Dupuytren’s interventions surgery versus collagenase trial to 2 years worsen. Study registration Current Controlled Trials ISRCTN18254597. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/102/04) and is published in full in Health Technology Assessment; Vol. 28, No. 78. See the NIHR Funding and Awards website for further award information. Plain language summary Dupuytren’s contracture happens when fibrous tissue builds up and over time bends the finger(s) into the palm, causing problems with hand function. To treat this, surgery is usually used to straighten the finger. A less intrusive alternative is an injection (collagenase), which softens the tissue after which the finger is moved to straighten it. The Dupuytren's interventions surgery versus collagenase trial recruited 672 patients who were equally and randomly assigned to have either surgery or collagenase injection. The study assessed whether the injection was as good and as safe as surgery at straightening the finger and how long the finger remained straightened. For up to 2 years after treatment, the participant’s hand function and general health were assessed. Some participants provided photographs to monitor changes to the finger, and some were asked about their experiences of Dupuytren’s contracture and treatments. We found: Hand health improved following both treatments. Initially, the injection treatment improved hand health more than surgery. However, by 1 year, surgery improved hand health more than the injection treatment. Recovery of hand function was quicker for participants who received the injection; however, they were more likely to need further treatment (i.e. further care and/or re-intervention). Participants said that the less positive longer-term outcome was acceptable for a better treatment experience. For both treatments, interviews found that participants were happy with the hand improvement they experienced at 3 months after treatment. More than half of participants had no complications, moderate or severe complications were rare, and participants who had surgery had more of these. The injection was cheaper but less effective than surgery at 1 year and was considered good value for money. However, by 2 years surgery became the better option due to its greater improvement in health benefits. Participant-taken photographs can help monitor Dupuytren’s contracture but do not give the same results as measurements taken in a clinic. Scientific summary Background Dupuytren’s disease affects over 2 million UK adults. Cords pull the fingers down towards the palm. This interferes with hand function and dexterity, impacting on quality of life. Current treatments to remove, dissolve or break the cords include surgical correction [limited fasciectomy (LF)], collagenase injection (an enzyme injected into the cord), and percutaneous needle fasciotomy (a needle is used to puncture, weaken and cut the cord). None of these treatments cure the tendency to develop Dupuytren’s contracture (DC) and so the cords and contracture can recur over time. Collagenase has some benefits over LF surgery including shorter recovery and no dependence on operating theatre availability for delivery of the intervention. There is, however, limited robust evidence comparing surgical correction and collagenase injection in terms of clinical effectiveness, cost-effectiveness, and in terms of patient’s experiences and preferences. Objectives The primary objective was to compare whether collagenase injection is not inferior to LF in the treatment of DC. Secondary objectives included investigation of recurrence at 1 and 2 years after treatment and cost-effectiveness. A qualitative substudy explored patients’ views of collagenase and LF, and a photography substudy investigated whether measurements of extension and flexion made on photographs taken by patients reflect goniometric measurements to assess recurrence. Methods Design The Dupytren's interventions surgery vs collagenase (DISC) trial was a multicentre, pragmatic, parallel two-arm randomised controlled non-inferiority trial with a cost-effectiveness evaluation, and nested qualitative and photography substudies. Participants were randomised on an equal basis to receive either of the two treatment options via a remote randomisation service. Randomisation was blocked, with randomly varying block sizes, and stratified by reference (worst-affected) joint [metacarpophalangeal (MCP) joint or proximal interphalangeal (PIP) joint]. Participants were followed up at 3 months, 6 months, 1 year and 2 years after treatment. Data collection included joint measurements and photography at baseline, and all follow-up time points. Setting Trial recruitment was undertaken in 31 NHS hand units across England and Scotland between June 2017 and September 2021. Participants Patients aged 18 years and over with a discrete, palpable Dupuytren’s cord causing contracture of ≥ 30 degrees and who were appropriate for both study treatments, were eligible for inclusion. Patients were excluded if they had severe contractures (> 135 degrees); had received treatment to the study digit; had other pre-existing disorders affecting hand function; had contraindications to collagenase; had a coagulation disorder; were female and pregnant or breastfeeding; had participated in a study involving another investigational medicinal product within 12 weeks or had another disease or disorder which would put them at risk if participating. Interventions The intervention was collagenase Clostridium histolyticum injection, supplied through routine NHS stocks. Collagenase was injected as three aliquots at set anatomical points in line with the current approved summary of product characteristics. After an interval of 1–7 days, participants returned to the clinic, where under local anaesthetic the cord was snapped to correct the contracture. The control group received LF surgery to remove the diseased nodules and cord to correct the contracture. Participants were followed up at routine wound check appointments following intervention. Outcomes The primary outcome was the Patient Evaluation Measure (PEM) score (0–100 with higher scores indicating worse outcome) at 1 year after treatment. The PEM was also completed at 3 months, 6 months and 2 years after treatment. Secondary outcomes included the Unité Rhumatologique des Affections de la Main (URAM) scale, Michigan Hand Outcomes Questionnaire (MHQ), recurrence, extension deficit and total active movement, complications, further treatments (including further care and/or re-intervention), health-related quality of life [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)], resource use, time to recovery of function (using a single assessment numeric evaluation measure) and overall hand assessment. All outcomes were collected at 3 months, 6 months, 1 year and 2 years. The PEM was also recollected immediately prior to treatment delivery, and the time to recover function and quality of life were also collected at 2 and 6 weeks after treatment. Outcomes were collected primarily in hospital clinics, with some participants being followed up for postal, telephone, or video data collection during the COVID-19 pandemic. The qualitative substudy explored participants experiences of DC and treatments. The photography substudy explored the agreement between measurements obtained using a goniometer and photographs taken by participants at home, to determine whether the two methods of measurement might feasibly be used interchangeably. Results Clinical effectiveness In total 672 participants (64.6%) were recruited and randomised; 336 to receive collagenase injection and 336 to receive LF. Baseline characteristics were similar across groups. Of the 672 randomised participants, 621 (92.4%) received treatment as part of the trial. Cross-over was limited: one participant (0.3%) allocated to collagenase received LF; seven participants allocated to LF received collagenase (2.1%). On average participants received collagenase by 12.1 weeks [standard deviation (SD) 13.7] and LF in 17.7 weeks (SD 16.5) after randomisation. Most participants (n = 315, 95.2%) had just one digit treated. No participants required an unplanned inpatient admission following treatment and 62.0% (n = 201) collagenase participants and 78.3% (n = 224) LF participants had full correction following treatment. At 1 year (primary time-point) the difference in PEM scores showed that collagenase was inferior to LF; difference 5.95 [95% confidence interval (CI) 3.12 to 8.77; p = 0.49]. The benefit of LF over collagenase continued to increase to 2 years (7.18, 95% CI 4.18 to 10.88; p = 0.82). There were no material changes in these results for any of the sensitivity or additional analyses undertaken. The primary analysis therefore shows that there is little evidence to support rejection of the hypothesis that collagenase is inferior to LF at 1 and 2 years post treatment. Indeed, the observed data are highly compatible with LF being superior to collagenase with regard to the primary outcome measure at both these time points. Patient Evaluation Measure overall assessment scores corresponded with the primary outcome analyses and participants in both groups reported positive experiences of treatment. The estimated difference in URAM scores followed those of PEM, increasing in favour of LF over time from 3 months (0.82, 95% CI −0.21 to 1.84; p = 0.12) to 5.37 (95% CI 3.85 to 6.88; p ≤ 0.00005) at 2 years. At 1 year MHQ scores were higher (better) in the LF group (1 year: −4.69, 95% CI −7.27 to −2.12; p = 0.0004) and this continued at 2 years (2 years: −6.71, 95% CI −9.60 to −3.82; p ≤ 0.00005). Return to function was better in the short term for the collagenase group (week 2: 14.93, 95% CI 11.66 to 18.19; p ≤ 0.00005; 6 weeks: 5.00, 95% CI 2.29 to 7.70; p = 0.003) but by 1 year function was superior after LF (−4.93, 95% CI −7.63 to −2.22; p = 0.0004). At 1 year participants who received LF were more likely to respond as being ‘cured’ or ‘much better’ than participants who received collagenase [odds ratio (OR) 3.01, 95% 2.15 to 4.23; p ≤ 0.00005]. Passive extension deficit was similar between the groups at baseline (mean: 45.8°; SD 17.0). Following collagenase treatment, extension deficit seemed to be worse at all time points ranging from a difference of 5.73° (95% CI 2.88 to 8.59; p = 0.0001) at 3 months to 10.10° (95% CI 6.46 to 13.73; p ≤ 0.00005) at 1 year and increasing again up to 2 years. Results when imputed data were included were similar. Increases in reference joint passive range of movement (RoM) were similar between the two groups following treatment. However, from 6 months there was strong evidence that collagenase resulted in poorer passive RoM (−7.42°, 95% CI −11.54 to −3.29; p = 0.0004) and this difference increased further over time. Measurements of active extension deficit were similar between the two groups at baseline (mean: 51.9°, SD 16.1). Like passive extension deficit, active extension deficit was worse following collagenase treatment at all time points, ranging from a difference at 3 months of 5.57° (95% CI 3.02 to 8.12; p ≤ 0.00005) to 11.52° (95% CI 8.13 to 14.91; p

Background Awake prone positioning (APP) may be beneficial in patients with respiratory failure who are not receiving mechanical ventilation. Randomized controlled trials of APP have been performed during peak COVID-19 periods in unvaccinated populations, with limited data on compliance or patient acceptability. We aimed to evaluate the efficacy and acceptability of APP in a lower-middle income country in an open-label randomized controlled trial using a dedicated APP implementation team and wearable continuous-monitoring devices. Methods The trial was performed at a tertiary level hospital in Ho Chi Minh City, Vietnam, recruiting adults (≥18 years) hospitalized with moderate or severe COVID-19 and receiving supplemental oxygen therapy via nasal/facemask systems or high-flow nasal cannula (HFNC). Patients were allocated by a computer-generated random number sequence in a 1:1 ratio to standard care or APP, where a dedicated team provided bedside support. Wearable devices continuously recorded pulse oximetry and body position continuously. Our primary outcome was escalation of respiratory support within 28 days of randomization. Results Ninety-three patients were enrolled in this study between March 2022 and March 2023. Eighty (86%) patients had received ≥2 doses of SARS-CoV2 vaccine. The study was terminated early because of a reduction in the number of eligible patients. Data from 46 patients allocated to APP and 47 to standard care were available for analysis. At baseline, 19/47 (40%) patients allocated to the standard care group and 14/46 (30%) patients allocated to the APP group received HFNC. Continuous monitoring data were available for all patients monitored with wearable devices. Significantly greater mean daily APP times were achieved in those allocated to APP, however, most achieved less than the target 8 h/day. We did not detect clear differences in the primary outcome (relative risk,RR, 0.85, 95% CI 0.40-1.78, p=0.67) or secondary outcomes, including intubation rate and 28-day mortality. Patients reported prone positioning was comfortable, although almost all patients preferred supine positioning. No adverse events associated with the intervention were observed. Conclusions APP was not associated with benefit, but there was no sign of harm. Continuous monitoring with wearable devices is both feasible and acceptable for patients. In our population, achieving prolonged APP time was challenging despite a dedicated support team, and patients preferred supine positioning. Clinical Trials Registration NCT05083130.

Background: Knee osteoarthritis (OA) is a leading contributor to global disability, with exercise proven to be an effective treatment. Tai Chi is a recommended type of exercise, but it is primarily done in person which imposes an accessibility issue. This study aims to evaluate the effects of an online unsupervised program, when provided with online educational information and exercise adherence support, on changes in knee pain and physical function, when compared to online education control for people with knee OA. Methods: A two-arm, superiority parallel-design, pragmatic randomised controlled trial will be conducted involving 178 people with a clinical diagnosis of knee OA. After completing baseline assessment, participants will be randomly assigned to either: i) “My Joint Education”, an education control website containing OA information only; or ii) “My Joint Tai Chi”, an intervention website containing the same information as the control, a 12-week unsupervised online Tai Chi program to be undertaken at home 3 times a week, and information about an exercise adherence support app. All participants will be reassessed at 12 weeks after randomisation. Primary outcomes are overall knee pain during walking and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index subscale. Discussion: This randomised controlled trial will provide evidence about the effectiveness of the “My Joint Tai Chi” website compared to “My Joint Education” website on self-reported knee pain and physical function for people with knee OA. Trial registration: Prospectively registered with the Australia New Zealand Clinical Trials Registry (ID: ACTRN12623000780651) on 18th July 2023.

Background: Trauma exposure in Indonesia is high despite the fact that there is limited accessibility to mental healthcare. Pulihkan Luka (PL) is a web-based trauma psychoeducation intervention that aims to provide a practical solution to overcome barriers to accessing mental healthcare.Objectives: This article aimed to (1) describe the cultural adaptation process of PL for Indonesian students and (2) describe the design of the pilot randomised controlled trial (RCT) that examines the feasibility and acceptability of PL.Methods: First, we describe the cultural adaptation process of PL following the 5-phase Formative Method for Adapting Psychotherapy (FMAP) approach: (1) knowledge generation, (2) information integration, (3) review and revision, (4) mini-testing, and (5) finalisation. Focus Group Discussion (FGD) was conducted to gather the views of 15 stakeholders on psychoeducation material and trauma-related mental health problems. Based on the outcomes, we decided to utilise the informal Indonesian language, incorporate practical worksheets and infographics, which include illustrations that reflect Indonesia’s cultural diversity, and provide guidance on seeking help that aligns with the mental health system in Indonesia. Second, we describe the design of a pilot RCT. Undergraduate students (N = 130) will be randomised to (1) four to seven sessions of PL + Enhanced Usual Care (PL + EUC; n = 65) or (2) Enhanced Usual Care only (EUC only; n = 65). Assessments will be conducted at baseline, post-intervention, and three and six-month follow-up. Additionally, 20 participants will be invited for an FGD to explore their experiences with the intervention. Quantitative data will be analysed using linear mixed-effect models, and qualitative data will be analysed using thematic analysis.Discussion: Cultural adaptation is crucial for optimally developing and assessing the feasibility and acceptability of a web-based trauma psychoeducation intervention in Indonesia. The outcomes of the RCT will inform the feasibility and acceptability of web-based trauma psychoeducation in the Indonesian undergraduate student population.

ABSTRACTBackground: In China, mental health services do not currently meet the needs of bereaved people with symptoms of prolonged grief disorder (PGD). Internet-based grief interventions may help fill this gap, but such programmes have not yet been developed or evaluated in China. The proposed study aims to investigate the effectiveness, acceptability, and feasibility of an online self-help intervention programme named Healing Grief for bereaved Chinese with prolonged grief, and to explore the psychological mechanisms of potential improvements.Methods: We designed a two-arm randomised controlled trial. At least 128 participants will be randomly assigned to either an Internet-based intervention group or a waitlist-control group. The Internet-based intervention will be developed based on the dual process model, integrating techniques of psychoeducation, behavioural activation, cognitive reappraisal, and meaning reconstruction, and will be delivered via expressive writing. The intervention comprises six modules, with two sessions in each module, and requires participants to complete two sessions per week and complete the intervention in 6 weeks. The primary outcomes include effectiveness, acceptability, and feasibility. The effectiveness will be assessed by measures of prolonged grief, posttraumatic stress, anxiety, and depressive symptoms. Acceptability and feasibility will be evaluated using survey and interview on user experience characteristics. Secondary outcomes include moderators and mediators, such as dual process coping, grief rumination, mindfulness, and continuing bond, to explore the psychological mechanisms of potential improvement. Assessments will take place at pre-intervention, post-intervention, and 3-month follow-up.Conclusion: The proposed study will determine the effectiveness, acceptability, and feasibility of the newly developed online self-help intervention for bereaved Chinese with prolonged grief and clarify how the intervention helps with symptom improvements. Such an intervention may play an important role in easing the imbalance between the delivery and receipt of bereavement psychological services in China.

Trial design Randomised, multicentre, double-blind crossover trial (with 2 × 16-week periods) of active neurostimulation versus sham stimulation with subsequent open-label follow-up to 58 weeks. Embedded mechanistic sub-study using magnetoencephalography to study bidirectional functional connectivity between brain and anorectum. Methods Participants: adults aged 18–80 years, with chronic symptoms of faecal incontinence refractory to first-line treatments (and meeting national criteria for sacral neuromodulation). Interventions: active: chronic, subsensory (low amplitude) stimulation of a mixed sacral nerve (usually S3) using a commercially available surgically implanted pulse generator; sham: identical implant but turned off (or to 0.05 V). Patient-chosen sub- or supra-sensory open-label stimulation from week 32 to week 58. Primary objectives: (1) to determine whether sub-sensory sacral neuromodulation led to a reduction in total faecal incontinence episodes per week compared to sham stimulation; (2) to identify whether clinical responses to sub-sensory sacral neuromodulation were biologically related to changes in evoked and induced activity between the brain and anorectum. Primary outcome: total faecal incontinence episodes per week based on paper bowel diary performed in the final 4 weeks of each crossover period (allowing 12-week washout). Randomised allocation (1 : 1) to arm 1 (sacral neuromodulation/sham) or arm 2 (sham/sacral neuromodulation) at time of surgery was stratified by sex and centre. Blinding: participants, surgeons and assessors; tamper-proof tape masked stimulation settings. Statistical methods: Poisson regression models failed to converge for the count outcomes, hence paired t-tests were used, and treatment effects summarised by mean differences [with 95% confidence intervals (CIs)]. Sample size: a total of 90 patients (45 per group) were required to detect a 30% reduction in episodes, allowing for 10% loss to follow-up (alpha = 0.05; power 90%). Results Recruitment: a total of 39 patients of 220 screened and 65 pre-enrolled (arm 1: N = 17; arm 2: N = 22) were recruited to the crossover trial at nine sites from the United Kingdom and one site from Ireland between February 2018 and July 2022, of whom only 16 (arm 1: N = 9; arm 2: N = 7) had complete primary outcome data. Nineteen completed follow-up to 58 weeks. Trial delivery was severely affected and terminated early due to COVID-19. Main barriers were the inability to continue face-to-face patient visits, redeployment of research staff to COVID-19 facing clinical roles and cancelling of sacral neuromodulation procedures due to lack of priority for non-urgent surgery. A total of 25 patients underwent magnetoencephalography studies compared to 20 healthy volunteers. Primary outcome (N = 16): sacral neuromodulation conferred a non-significant reduction in mean faecal incontinence episodes per week compared to sham (−0.7, 95% CI −1.5 to 0.0; p = 0.06). Secondary outcomes: in participants who also used the e-event recorder to record the number of faecal incontinence episodes in both periods (n = 7), estimate of effect size was greater but less precise (−1.5, −3.5 to +0.5; p = 0.12). Data suggested successful allocation concealment. Improvements were observed in faecal incontinence symptoms in the follow-up cohort (at 58 weeks) compared to baseline (approx. 3 fewer faecal incontinence episodes per week). A small number of expected adverse events all resolved. Magnetoencephalography studies demonstrated bidirectional afferent evoked cortical and efferent induced anal activity that did not vary greatly from control subjects (n = 20) and appeared unchanged by sacral neuromodulation. Conclusions Due to under-recruitment it is important to interpret the findings on the experimental efficacy of sacral neuromodulation as exploratory. Effects on symptoms observed during double-blinded crossover point to some efficacy over sham, though not large in comparison with placebo responses. The magnitude of effect was highly dependent on method and interpretation of event recording. Study registration Current Controlled Trials ISRCTN98760715. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/144/08) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 19. See the NIHR Funding and Awards website for further award information. Plain language summary A treatment called sacral neuromodulation is commonly offered to adults experiencing bowel (faecal) incontinence. A battery powered unit is implanted into the lower back in the region of the sacrum (tailbone). This is connected to a specially developed lead with electrodes that rest on the nerves of the lower spine. This stimulator then continuously sends electrical impulses to the nerves and muscles that control the lower bowel (rectum and anus). The aim is to improve bowel control. Previous studies have reported a great benefit of sacral neuromodulation in some patients, but others have little or no response. The SUBsensory Sacral Neuromodulation for InContinence trial recruited 39 patients (of 90 intended) who met the current national criteria for sacral neuromodulation. It compared the effect on numbers of weekly faecal incontinence episodes with the device either on (active) or off (sham) using a special study design called a randomised crossover trial. All participants had the device on and off for 16 weeks in random order (crossing over in the middle). Using stimulation below the level that can be felt (subsensory), both the patients and the research team were unaware of whether the stimulator was on or off (called double blinding). Due to COVID-19, only 16 patients had complete data for analysis, which was much less than the intended number of 90. The results showed that patients experienced reductions in faecal incontinence episodes during both on and off periods (i.e. there was a strong placebo effect). However, slightly greater effects were seen during the on period suggesting a possible genuine biological effect of sacral neuromodulation. The study also showed that the way we record symptoms during research trials for example with paper bowel diaries needs improvement, as the bowel diaries were not fully completed by some participants. Although this is the first double-blind trial of its kind for sacral neuromodulation, all conclusions must bear in mind the poor recruitment and retention of patients. Scientific summary Background Faecal incontinence (FI), defined as the recurrent involuntary loss of faecal material leading to a social or hygienic problem, is a common and debilitating condition with profound effects on quality-of-life and high societal costs. Initial treatments including pharmacological and behavioural therapies (e.g. biofeedback) have variable outcomes and are poorly evidenced. Traditional surgical approaches focusing on anal sphincter reconstruction or augmentation are invasive, irreversible, and risk significant morbidity. A stoma is the final option. Chronic low-amplitude stimulation of the mixed sacral spinal nerves using an implanted electrode and pulse generator – sacral neuromodulation (SNM) is a less invasive alternative, now considered the first-line surgical treatment option for adults with FI in whom non-operative therapies have failed to alleviate symptoms. Current evidence for SNM is based on extensive observational data and few randomised trials that are heterogeneous in design and outcomes. Despite having widespread regulatory approval, SNM remains an expensive intervention with need for greater confidence in efficacy. A further concern regarding SNM therapy is the lack of evidence and understanding of the mechanism of any effect. Objectives Our primary aim was to determine the clinical efficacy of sub-sensory chronic low voltage electrical SNM using a commercially-available implantable device in adults with FI in whom conservative treatment has failed. We sought to determine whether SNM, compared to sham, led to a clinically important reduction in weekly FI episodes. The study also included mechanistic studies to examine whether clinical responses to sub-sensory SNM were biologically related to changes in the central pathway between the brain and anorectum. Methods Trial design SUBsensory Sacral Neuromodulation for InContinence (SUBSoNIC) was a multicentre, randomised double-blind crossover trial at nine UK sites and one site in Ireland in which SNM was compared to sham stimulation. We aimed to randomise 90 eligible participants (adults aged 18–80 years, where non-surgical approaches to National Institute for Health and Care Excellence (NICE) standard have failed and meeting minimum FI severity criterion) to two study arms after SNM implantation. Both arms had two intervention periods (ON-OFF or OFF-ON) of 16-week duration (T0–T16 and T16–T32). Efficacy outcomes were derived from assessments in the final 4 weeks of each cross-over period (T12–T16 and T28–T32) thus allowing for almost 3 months intervention before outcome assessments (and adequate washout for participants in the ON–OFF sequence). Mechanistic studies were performed in the final 2 weeks of the 4-week assessment periods in a subgroup of consecutively consenting participants from both arms until data saturation. After completing the crossover phase of the study, participants were followed up for a further 26 weeks. During this time, participants had either sub- or supra-sensory ‘open label’ stimulation based on preference as would have been normal for routine clinical practice. Further efficacy outcomes were recorded at T54–T58 to provide an indication of the short-term effectiveness of SNM within the rigor of a clinical trial unit (CTU)-monitored prospective study. Interventions Chronic low voltage stimulation of the third or fourth sacral root was achieved by surgical implantation of a commercially available Conformité Européenne-marked active implantable (class III) medical device [Medtronic InterStimTM (Medtronic, Minneapolis, MN, USA)] used in accord with the manufacturer’s instructions and local practice. For the active intervention (ON), the clinical team programmed the device using standard settings of a 14-Hz frequency and 210-µs pulse width. Optimal electrode configuration was determined by cumulatively increasing the amplitude of stimulation by 0.1 V from zero for each electrode until the sensory threshold was reached. The amplitude and site of stimulation were recorded for each electrode with the electrode configuration that achieved sensation in the anus or perineum at lowest amplitude being chosen for chronic stimulation. Sub-sensory chronic stimulation was initiated by reducing the amplitude to a level just below the habituated sensory threshold (for blinding). For the sham intervention (OFF), sensory thresholds were recorded identically; however, the level was then adjusted to zero volts or 0.05 V (the latter was required in some participants due to the new device handset limitations). Mechanistic studies were undertaken at the Institute of Health and Neurodevelopment (IHN) at Aston University in a subgroup of patients identified in the Midlands region (compared to 20 healthy volunteers without FI). A protocol including spatial registration (magnetic resonance imaging head) and a series of magnetoencephalographic (MEG) acquisitions measured induced and evoked cortical activity relevant to determining functional connectivity between the anus and brain (using anal electrical stimulation) and brain and anorectum (using volitional anal squeeze). Control paradigms (tibial nerve stimulation and fist clench) were used respectively. Outcomes The primary clinical outcome was reduction in FI events per week (recorded on paper bowel diaries over a 4-week period) in SNM versus sham phase of crossover (16 and 32 weeks). Secondary clinical outcomes including other bowel diary measures, e-event recording and a panel of summative questionnaires were recorded at 16, 32 and 58 weeks. Mechanistic outcomes included spatial localisation, relative cortical source signal strength and latencies of evoked and induced responses. Allocation and blinding Randomised allocation (1 : 1) to group 1 (SNM/sham) or group 2 (sham/SNM) was performed at the time of surgery using an online randomisation system managed by the Pragmatic Clinical Trials Unit at QMUL, with a randomisation list generated by an independent statistician to ensure allocation concealment. Randomisation was stratified by sex and centre with block sizes of four. Members of the research team, statisticians, surgeons who performed the surgical procedure, and participants were blinded to intervention status (SNM or sham). Participants were informed of the allocation ratio of 1 : 1 and that blinding prevented them from knowing in which group they were participating. Tamper-proof tape was used to mask stimulation settings. Sample size and statistics The study was designed to detect a mean 30% reduction between SNM and sham stimulation in FI event rate (ratio 0.7). At 90% power and 5% significance level with a cross-over design this required 90 participants (45 per group), allowing for 10% loss to follow-up. The pre-specified analysis for the primary outcome involved a mixed Poisson regression applied to the counts of FI events, with fixed effects of cross-over period and stratification factors, a random effect of individual, and a random effect of period within individual (the latter to allow for an over-dispersed Poisson distribution). When it came to the analysis, owing in part to the small numbers, the Poisson regression models did not converge for the count outcomes. Instead we applied a paired t-test to the FI rates in order to estimate the difference between SNM and sham with a 95% confidence interval and p-value. Results Clinical results The COVID-19 pandemic had a major effect on trial recruitment and patient retention. The trial was terminated on 24 July 2022 with just 39 patients randomised. Trial delivery was severely affected and terminated early due to COVID-19. Main barriers were the inability to continue face-to-face patient visits, redeployment of research staff to COVID-19 facing clinical roles and cancelling of SNM procedures due to lack of priority for non-urgent surgery. In total, 220 patients were screened for eligibility at nine sites from the UK and one site from Ireland between February 2018 and July 2022. Of these, 155 patients declined study participation or were ineligible due to study specific exclusion criteria. A total of 65 patients were pre-enrolled and consented to the study, of whom 26 did not meet the baseline minimum frequency criteria of FI episodes per week or did not receive an implant. The remaining 39 patients were randomised (arm 1: N = 17; arm 2: N = 22); however, only 16 completed the primary outcome during both cross-over periods (arm 1: N = 9; arm 2: N = 7). The remaining 23 participants withdrew from the study (N = 12), were excluded on the basis of problems of eligibility (N = 5) or did not complete the primary outcome data (N = 6: still included in the cohort follow-up phase). A total of 22 participants started the cohort follow-up phase, although 3 of these participants did not complete the final follow-up visit, leaving 19 participants for the 1-year effectiveness assessment. There were no major differences at baseline between allocated groups. As predicted, about 90% participants were female with mean age about 57 years. Almost all participants reported symptoms of urgency, combined with varying combinations of passive and urge FI. All participants reported previous conservative management for their FI symptoms (as per NICE guidance). Numbers of FI events at baseline were concordant with design assumptions (based on approx. seven events in a 1-week period). Median St Mark’s incontinence score was 19 in both groups, indicating severe symptoms (max score 24). E-event recordings were only undertaken by a minority (14/39) of participants. Test stimulation was performed using a tined lead in 68.6% participants. General anaesthesia was used in 70.6% of procedures and median operating time was 36 minutes (range 30–55 minutes). The lead was positioned in foramina S3 in most participants (91.4%) with some variations in fidelity of siting based on individual electrode responses (only 50% lead placements achieved the ideal published standard of motor or sensory responses for three electrodes

Background and purpose: We developed the Melacare nurse-led intervention, which combines education in skin self-examination as a resource-conscious approach to detecting recurrence and management of fear of cancer recurrence in patients treated for melanoma. This publication presents the Melacare study protocol and evaluates the feasibility and acceptability of Melacare prior to a larger randomised controlled trial. Material and methods: Feasibility and acceptability of Melacare were evaluated in an intervention-only feasibility study, in which patients attended two nurse-led intervention sessions coupled with an educational booklet. Participants completed patient-reported outcome (PRO) questionnaires at baseline and before each session. After the intervention, participants completed a study-specific feedback questionnaire. Feasibility was evaluated in terms of recruitment, adherence, and attendance. Self-reported outcomes from the study-specific questionnaire on intervention effects were also collected. Results of the feasibility study: Fourteen patients (nine stage IA, five stage IB melanoma) participated. Attendance and recruitment rates were 100%, all participants completed the baseline and PRO questionnaires, and 100% read at least half of the educational booklet. In terms of intervention effects, all patients reported improved knowledge of performing skin self-examination and coping with the fear of cancer recurrence. Interpretation: Results indicate that the Melacare nurse-led intervention is highly feasible and acceptable for use with patients treated for early-stage melanoma. Prior to clinical trial commencement, minor refinements include changing the method of recruiting by telephone and offering

BackgroundPeople with severe mental illness experience physical health inequalities and a 15–20-year premature mortality rate. Forensic inpatients are particularly affected by restrictions on movement, long admissions, and obesogenic/sedative psychotropic medication. We aimed to establish the feasibility and acceptability of Motiv8, a multidisciplinary weight management intervention co-produced with service users for forensic inpatients.MethodsA randomised waitlist-controlled trial of Motiv8(+Treatment-As-Usual) vs.TAU was conducted in medium-secure forensic services in Greater Manchester. Motiv8 is a 9-week programme of exercise sessions, diet/cooking classes, psychology, physical health/sleep education, and peer support. Physical and mental health assessments were conducted at baseline/10-weeks/3-months. A nested qualitative study captured participant experiences. A staff sub-study explored ward environment.ResultsWe aimed to recruit 32 participants (four cohorts). The trial met recruitment targets (n=29, 90.9%; 4 cohorts, 100%), participants were randomised to Motiv8+TAU (n=12) or waitlist (control) (n=17). Acceptable retention rates were observed (93.1%, 10-weeks; 72.4%, 3-months), and participants engaged well with the intervention. The blind was maintained, and no safety concerns raised. Assessment completion was high suggesting acceptability (>90% for people retained and engaged in the study). Participants reported high levels of satisfaction.ConclusionsThe trial was not powered to detect group differences. However, data suggests it is feasible to conduct a rigorous, methodologically robust study of Motiv8 vs.TAU for adults on forensic inpatient units. Motiv8 was acceptable with potential promise providing evidence to proceed to a definitive trial for males. A larger trial is needed to explore potential effectiveness and reduce physical health inequalities for people with SMI.Clinical trial registrationhttps://doi.org/10.1186/ISRCTN13539285, identifier ISRCTN13539285.

BackgroundPostmenopausal osteoporosis (PMOP) is a serious condition that affects elderly individuals. Our previous study revealed that Yigu decoction (YGD) effectively improved bone mineral density (BMD) in elderly individuals, but the mechanism underlying this effect remains unclear. In this study, we investigated the relationships among YGD, microRNAs (miRNAs), and bone metabolism by assessing the effects of YGD on the miRNA levels in patient plasma to provide a scientific basis for treating PMOP with YGD.MethodsIn this clinical trial, 60 patients were randomly assigned to the YGD group or the control group (ratio of 1:1) and treated for 3 months. The primary outcome measure was BMD, and the secondary outcome measures included plasma miRNA levels, visual analogue scale (VAS) scores, alkaline phosphatase (ALP) levels, anti-tartrate acid phosphatase (TRACP-5b) levels and traditional Chinese medicine (TCM) syndrome scores. We assessed the regulatory roles of miRNAs in PMOP patients by analysing publicly available data from the Gene Expression Omnibus (GEO) database. Bioinformatics methods were also used to explore the mechanism by which YGD regulates miRNAs that are involved in bone metabolism.ResultsCompared with those before treatment, the BMD, ALP levels, TRACP-5b levels, TCM syndrome scores and VAS scores improved in both groups after 3 months of treatment (P < 0.05). A total of 82 miRNAs differed between the groups. After analysing data from the GEO database, we confirmed that miR-133a-3p is the key molecule that mediates the effects of YGD intervention on PMOP. GO analysis of key genes suggested that gene enrichment was more pronounced in response to hormones, cellular response to growth factor stimulation, and positive regulation of physiological and metabolic processes. KEGG analysis revealed that these genes were enriched mainly in the PI3K-Akt, FOXO, and JAK-STAT pathways and other pathways. The results of the protein‒protein interaction (PPI) network analysis revealed that epidermal growth factor receptor (EGFR), Insulin-like growth factor 1 (IGF-1), Caveolin-1 (Cav-1) and others were core proteins.ConclusionThis study demonstrated that YGD is beneficial in the treatment of PMOP, ameliorating clinical symptoms and bone turnover indices. Moreover, the inhibition of miR-133a-3p expression may be the key mechanisms by which YGD regulates bone metabolism in the treatment of PMOP, although YGD regulates bone metabolism in a multitarget and multipathway manner.

Background and aim: The most effective among the acupoints remains to be determined for treating diabetic gastroparesis (DGP). This study aimed to compare single and combination acupoints for their effectiveness in DGP. Experimental procedure: A prospective, patient-assessor-blinded randomised controlled trial was designed to compare the efficacy of 8-week acupuncture at a single acupoint (Zhongwan, CV-12), combination acupoints (Zhongwan, CV-12 and Zusanli, ST-36), and a sham-acupoint, in 99 adults with DGP. The primary clinical outcome was measured using the Gastroparesis Cardinal Symptom Index (GCSI), while barium meal examination, fasting plasma glucose, the 2-h plasma glucose, short-form health survey (SF-36), and GCSI subscales were performed for evaluating secondary clinical outcomes. These results were analysed by two factorial analysis of variance (ANOVA) test, Chi-Square, Fisher Exact, Kruskal–Wallis tests and Tukey's Honest Significant Difference (HSD) test. Results: After randomization, 97 patients completed the study. GCSI scores of all groups decreased during both post-treatment and the follow-up period, they were statistically significant compared to the baseline period (p 0.05) during the post-treatment period. GCSI scores improved more in the combination acupoints group than in the single acupoint group which was better than the sham group after treatment. During the follow-up period, the same trend was observed. Conclusions: Among patients with DGP, the combination acupoints were more beneficial compared with single and sham acupoints. Trial registration number: NCT02452489.