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Background: Critical illness myopathy (CIM) is a prevalent cause of intensive care unit-acquired weakness (ICUAW). It is associated with prolonged mechanical ventilation and increased mortality and frequently evolves into postintensive care syndrome with long-term cognitive and physical impairments. Although several molecular mechanisms have been implicated in CIM, including muscle atrophy and altered contractility, its exact etiopathogenesis is not fully understood. Evidence suggests that activation of the NLRP3 inflammasome and upregulation of atrogenes significantly contribute to this condition. In murine models of sepsis and denervation, which mimic CIM, NLRP3 activation induces muscle atrophy. Physical therapy, including enhanced mobilization supported by servo-assisted devices, a nonpharmacological intervention, can regulate inflammation, reduce IL-1β and NLRP3 levels, and improve mitochondrial and autophagy processes; however, whether it reduces NLRP3 activation and alleviates atrophy in human CIM remains uncertain.

Methods: We will conduct a prospective, randomized, controlled, open-label study during the early ICU stay. Adults at risk of CIM (n = 16) will be randomized 1:1 to conventional physical therapy or to conventional therapy plus enhanced PT (an additional servo-assisted mobilization device, MOTOmed letto^®) twice daily for 60 min over seven consecutive days. An additional ICU control group without CIM (n = 8) will be included for biomarker analyses. At baseline and on day 7, blood and vastus lateralis muscle biopsies will be obtained for histologic, molecular, and transcriptomic analyses. The primary outcomes are as follows: (1) NLRP3 inflammasome priming and activity (protein and gene expression by Western blot, RT-qPCR, and ELISA) and (2) indices of muscle atrophy (fiber diameter, atrogenes expression, the myosin/actin ratio, and sarcomere organization by immunofluorescence and transmission electron microscopy). The secondary outcomes include strength and function (MRC-SS, FSS-ICU), feasibility and safety, microarray-based transcriptomic profiling, and associations between biochemical/molecular markers and CIM diagnosis by clinical assessment and ultrasound.

Discussion: We hypothesize that enhanced PT (in addition to conventional care) reduces NLRP3 activation and muscle atrophy in critically ill adults. This translational trial combines clinical assessments integrating muscle biopsies and blood measures to elucidate CIM pathogenesis and assess PT intervention. These findings may identify therapeutic targets and inform early mobilization strategies in ICU practice.

Trial registration: ClinicalTrials.gov NCT07017517. Registered on 26 May 2025.

Background: Current WHO MBMDT regimen has largely been successful in treating leprosy patients since 1984, when it was implemented worldwide. According to clinical presentation, pauci and multibacillary leprosy, the regimen is also given for 6 or 12 months. However, this regimen has its limitations, such as incomplete bacterial clearance, prolonged treatment duration and poor patient compliance, necessitating administration of alternative and more effective regimens. Secondly, there is a subset of patients who are highly bacillated and continue to harbour viable bacilli even after treatment and thus continue transmission. We present the protocol of WHOMDT vs. monthly regimen of rifampicin, moxifloxacin and clarithromycin (RMC), a randomised clinical trial designed to test the efficacy of the RMC regimen in the management of multibacillary leprosy.

Methods and analysis: MB MDT vs RMC clinical trial is multicentric which will be conducted in accordance with the CONSORT guidelines in The Leprosy Mission Trust India's tertiary care hospitals at Delhi, Uttar Pradesh, West Bengal and Chhattisgarh. Naive MB leprosy patients who consent to participate will be randomly allocated to receive 12 months of WHO MB MDT or a monthly regimen of rifampicin, moxifloxacin and clarithromycin. The primary objective will be to evaluate the efficacy of monthly RMC regimen compared to the WHOMBMDT in treating multibacillary leprosy. Molecular viability assay will be used to assess the efficacy of the regimen. Monitoring of adverse events will be closely done.

Ethics and dissemination: Results will be submitted for publication in peer-reviewed journals. Ethical approval has been obtained from The Leprosy Mission Trust India's ethics committee (TLMTI/EC/C-69). This study is registered at Clinical Trials Registry-India (CTRI) - CTRI/2024/03/064435.

Background: Growing up in adversity can create enduring deficits in children's cognitive and socio-behavioral skills that undermine later-life productivity, reduce human capital, and increase social costs. Early interventions that target caregiver mental health offer a promising pathway to strengthen the developmental environment of children exposed to severe stress. Yet, in low-resource humanitarian settings, evidence on scalable approaches that generate such intergenerational benefits remains limited. War-related displacement places mothers and young children at exceptional risk for psychological distress and impaired functioning, with potential long-term consequences for both generations. Self-Help Plus (SH+), a brief, low-intensity WHO group intervention based on Acceptance and Commitment Therapy, has shown promising short-term effects in reducing psychological distress among South Sudanese refugee women in Rhino Camp, Uganda. However, key questions remain regarding the durability of these effects and whether improvements in maternal mental health translate into measurable gains in children's own wellbeing and early development.

Methods: This two-arm, parallel-group cluster-randomized controlled trial will enroll 720 mother-preschool-aged child (3-5 years) dyads from 24 villages in Rhino Refugee Settlement, Uganda. Villages are randomized 1:1 to receive either SH+ and Enhanced Usual Care (EUC), or EUC only. Assessments are conducted at baseline (T0), 3 months (T1), and 12 months (T2) post-intervention. The primary outcome is maternal psychological distress (Kessler-6) at 12 months (T2). The key secondary outcome is parent-reported child psychosocial wellbeing (Kiddy-KINDLR) at T2. Secondary outcomes include additional indicators of maternal wellbeing and mental health, parenting practices, and child outcomes assessed across study time points, including psychosocial difficulties and child self-reported wellbeing. Analyses will follow an intention-to-treat approach, adjusting for clustering and relevant covariates.

Discussion: This trial replicates and extends prior evidence on SH+ in a large refugee population. It will examine whether early mental health gains are sustained, and whether intergenerational benefits emerge for preschool-aged children. Findings will inform scalable intervention strategies to promote psychological resilience and child development in humanitarian contexts.

Trial registration: ClinicalTrials.gov NCT07062341. Prospectively registered on July 11, 2025.

Background: Nursing students frequently experience high levels of stress, which can impact their psychological, physiological, and social well-being. Stress among nursing students is closely associated with cognitive, motivational, and behavioral determinants. The information-motivation-behavioral skills (IMB) model provides a coherent framework for conceptualizing these determinants and promoting adaptive stress regulation. Based on this model, the present study will implement an IMB-based stress self-management health education program to mitigate stress among nursing students.

Methods: This cluster-randomized controlled trial aims to evaluate the effectiveness of an IMB-based stress self-management health education program on reducing stress among nursing students. The 8-week program includes eight modules, with the first seven covering distinct topics and the final module for discussion. One hundred and six nursing students from 22 clusters, based on sample size estimation, will be randomly allocated to either the intervention or waitlist control group. The primary outcome is stress, with secondary outcomes including stress knowledge, stress mindset, perceived social support, self-compassion, and resilience. Baseline characteristics and outcome variables will be summarized using descriptive statistics. The program's effectiveness will be evaluated using an intention-to-treat approach, with longitudinal changes and between-group differences analyzed using a generalized linear mixed model that accounts for clusters as random effects.

Discussion: The IMB-based stress self-management health education program is expected to enhance stress management among nursing students and highlight the innovative application of the IMB theory.

Trial registration: ChiCTR2400088589. Registered on August 21, 2024.

Background and aims: Patient and public involvement (PPI) is well established in clinical trials and trial oversight groups in the UK. But public contributors are rarely involved in Independent Data Monitoring Committees (IDMCs), meaning there is little or no evidence for how to include the public in these complex meetings or the impact PPI may have. As a Cancer Research UK core-funded clinical trials unit, the Southampton Clinical Trials Unit (SCTU) coordinates numerous phase II and III cancer drug trials with IDMCs. We aimed to establish a process to include PPI in these committees, but first needed to assess the feasibility of including public contributors and determine what training and resources they need to take part. Here we summarise our process of developing these training and resources to inform others who wish to include public contributors onto trial IDMCs.

Methods and findings: We used design-based and action research methods to develop an initial training programme, working with trial managers and statisticians at the SCTU to ensure key elements of the IDMC process were covered and explained. This was piloted in a SCTU cancer trial, and feedback from the public contributor, trial staff, Chief Investigator and IDMC chair was used to refine the process. The programme was then further evaluated in three more SCTU trials, and feedback was again gathered through participant questionnaires. Our findings show that the training was useful and informative for public contributors, allowing them to contribute meaningfully to IDMC meetings, while constructive feedback allowed us to refine the process further for future roll-out across SCTU trials.

Conclusions: The findings of this project allowed us to develop, review and refine the training materials and resources required for public contributors to meaningfully take part in IDMCs. Furthermore, feedback received from public contributors, trial teams and IDMC chairs was largely positive and suggests that the inclusion of public contributors, when adequate training and resources are provided, is feasible, can enhance the work of these committees and is welcomed by those involved. Limitations to the research and future work have been identified to further assess the impact of including public contributors in IDMCs.

Background: The incidence of anterior cruciate ligament (ACL) ruptures is notably high among young athletes participating in ball sports. Injury prevention strategies have recently emphasized the integration of multidimensional training with motor learning approaches. Emerging evidence suggests that integrating movement variability effectively reduces modifiable risk factors for ACL injuries. This study aimed to compare the effects of integrating plyometric training with either non-linear pedagogy (NLP) or differential learning (DL) on functional performance and biomechanical risk factors in athletes at high risk of ACL injury.

Methods: This single-assessor blind randomized controlled trial will include 48 male athletes (aged 18-26 years) identified as being at high risk for ACL injury. Participants will be randomly allocated to one of three groups: (1) NLP combined with plyometric training (n = 16; 24 intervention sessions over 8 weeks, three sessions per week); (2) DL combined with plyometric training (n = 16; 24 intervention sessions over 8 weeks, three sessions per week); or (3) a control group. outcome assessors will be blinded to their group allocation. The primary outcomes will include kinematic and kinetic variables, while secondary outcomes will assess functional performance. All outcomes will be measured at baseline and following the 8-week intervention period.

Discussion: This protocol can be an effective and innovative injury prevention strategy for athletes at high risk of an ACL injury. Designed for practical application in both clinical and field settings, the protocol incorporates plyometric exercises performed under variable conditions. Physiotherapists, athletic trainers, coaches, and return-to-sport specialists can implement it to mitigate the risk of injury.

Trial registration: The study was prospectively registered with the Iranian Registry of Clinical Trials (IRCT) on March 15, 2025, under the identifier IRCT20210602051477N3 (https://www.irct.ir/trial/69146).

Background: Periprosthetic joint infection (PJI) is one of the most severe complications in hip arthroplasty, and treatment of PJI is associated with high re-infection rates and significant loss of quality of life for patients, as well as socio-economic impact to health systems. Antimicrobial coating of implants with silver is a promising option to improve the outcome of PJI. However, there is no data from randomized control trials on silver-coated versus standard non-silver-coated implants in patients with PJI. Therefore, the aim of the current study is to assess clinical outcome for the use of silver-coated hip implants (further referred to as IP-coated) versus non-IP-coated implants in patients requiring surgical revision for hip PJI.

Methods: This is a multicenter confirmatory interventional randomized controlled superiority single-blinded study with two stages: pilot stage (part A) and pivotal stage (part B). Patients indicated for unilateral cementless acetabular and hip stem revision due to chronic periprosthetic infection planned for single-stage or two-stage surgical procedures are included. Patients will randomly be assigned either to the IP-coated or the non-IP-coated implant group. The primary outcome parameter is infection-free survival within 12 months after hip PJI. The underlying hypothesis is that the IP coating significantly reduces the risk of periprosthetic reinfection compared to the non-IP-coated implants. Secondary outcome parameters include data on the safety and performance of the prostheses through a 2-year clinical follow-up, including patient-related outcome parameters, such as Harris Hip Score, EQ-5D, radiographical assessment, and blood silver concentrations. An adaptive study design is planned with the inclusion of 268 subjects according to initial sample size calculations. Upon follow-up of 134 patients for 12 months or inclusion of 90% of the study patients, preliminary study results will be used to re-estimate the sample size, which may be extended up to 400 subjects.

Discussion: The current study aims to fill the evidence gap for the idea of IP-coated implants to reduce re-infection rates in the treatment of hip PJI. To the authors' best knowledge, this is the first randomized controlled superiority trial evaluating the outcome of a silver-coated versus a non-silver-coated prosthesis for the treatment of hip PJI. The adaptive study design allows an adjustment of the initial sample size to reduce the risk of an underpowered superiority.

Trial registration: ClinicalTrials.gov NCT06737809 (date of publication 17.12.2024).

Background: Neurosurgical trials have a high burden on participants, which underscores the need to involve patients, carers, and the public in trial design to ensure their needs and expectations are met. However, there is currently limited guidance on the establishment, retention, and role of patient and public involvement (PPI) groups in neurosurgical trials, beyond generic guidance, which may contribute to the very low use of PPI in surgical trials. To promote meaningful public involvement in neurosurgical trials based on lived experience, we evaluated our public involvement and developed actionable recommendations. We also co-created a novel support package for neurosurgical trial participants.

Methods: During the planning of a neurosurgical trial, 14 individuals formed a PPI group, including people with Parkinson's, care partners, and charity staff. This reflective evaluation of the group used mixed-methods data collected using the PIRIT Tracking Tool, meeting polls/reflections, and reflective diaries. Our PPI group co-created the resulting reflections and recommendations, which follow the UK Standards for Public Involvement framework. The support package was co-designed in two online workshops, with 12 participants, including people with Parkinson's and care partners.

Results: Our recommendations for meaningful PPI cover inclusive opportunities, working together, support and learning, governance, communications, and impact. For example, we recommend providing all public contributors with an approachable point of contact, defining a clear plan for evaluation and addressing concerns identified through evaluation, and ensuring co-created tasks have clearly defined, tangible outcomes. The support package for neurosurgical trial participants spans before (psychological assessment and support; trial buddies; videos and written case studies from participants in similar trials), during (medical advice and support; Patient Liaison; psychological support), and after (medical, social, and psychological support) trial support.

Conclusions: Our practical, generalisable recommendations and novel participant support package aim to strengthen public involvement and enhance care in neurosurgical trials. The support package needs testing within a trial to determine its feasibility and effectiveness.