Low back pain (LBP) is the main cause of disability worldwide and is primarily triggered by intervertebral disc degeneration (IDD). Although several treatment options exist, no therapeutic tool has demonstrated to halt the progressive course of IDD. Therefore, several clinical trials are being conducted to investigate different strategies to regenerate the intervertebral disc, with numerous studies not reaching completion nor being published. The aim of this study was to analyze the publication status of clinical trials on novel regenerative treatments for IDD by funding source and identify critical obstacles preventing their conclusion. Prospective clinical trials investigating regenerative treatments for IDD and registered on 25 clinical trials were identified. Among these, only 6 (24%) have been published. The most common source of funding was university (52%), followed by industry (36%) and private companies (12%). Investigational treatments included autologous (56%) or allogeneic (12%) products alone or in combination with a carrier or delivery system (32%). The latter were more likely utilized in industry or privately funded studies (Fig. 1, p=0.0112). No significant difference was found in terms of funding regarding the publication status of included trials (Table 1, p=0.9104). Most clinical trials investigating regenerative approaches for the treatment of IDD were never completed nor published. This is likely due to multiple factors, including difficult enrollment, high dropout rate, and publication bias3. More accurate design and technical support from stakeholders and clinical research organization (CROs) may likely increase the quality of future clinical trials in the field. For any figures or tables, please contact the authors directly.
Musculoskeletal diseases are leading causes of disability, morbidity and economic loss across the globe today. Yet for much of the world's population access to cheap, safe and effective intervention is lacking, while others choose not to accept best practice and best evidence, or significantly more expensive treatment. Great advances have been made in some diseases like rheumatoid arthritis, but the cost of many new treatments is unaffordable, and individuals, insurance and governments struggle to, or cannot fund it. Anchor bias and politics determines national policies and research funding, often favouring other illnesses while musculoskeletal disorders lack the support proportional to their frequency and impact. This is not appreciated by policy makers and governments, and the consequences of lack of care or poor-quality care. The need has never been greater for a treatment for osteoarthritis, the most common disease in the world; but the search for a cure needs funding, and if discovered, who will pay for it?
Background. Immersive virtual reality (VR) demonstrates potential benefits in patients with chronic low back pain (CLBP). However, few studies have investigated the feasibility and the acceptability of introducing immersive VR for use with patients with CLBP and in the Kingdom of Saudi Arabia (KSA). Aim. To investigate immersive VR's feasibility, tolerability, and acceptability as a rehabilitation intervention for adult patients with CLBP and explore the views of relevant Health Care Practitioners (HCPs) in the KSA. Methodology and Methods. A multi-centre, mixed-methods, explanatory sequential design was adopted to test immersive VR's feasibility, tolerability, and acceptability. An uncontrolled feasibility trial was conducted. The immersive VR intervention involved a training session followed by three sessions over one week using commercially available hardware and software. Feasibility outcomes were collected from patients immediately post-intervention. Patients and HCPs were recruited for semi-structured interviews. Results. Thirty-three patients and three HCPs were recruited. The feasibility a priori criteria were met for recruitment, retention, dropout, completeness of questionnaire data, treatment compliance and fidelity. Adverse events included one who reported aggravation of tinnitus, whereas two experienced dizziness. Qualitative data suggested that entertainment and motivation were key enablers. Barriers included technological capability and HCPs’ perceptions that immersive VR was time-consuming. Conclusion. The results suggested that immersive VR was feasible, acceptable, and tolerable among patients with CLBP and HCPs in clinical settings in the KSA. Further research focusing on the effectiveness is warranted in this field. Conflicts of Interest. None. Sources of
Background. Chronic pain is a significant burden and represents a major issue for world healthcare systems. Interventions include medication, surgery, pain management programmes, and social support through peer support groups. These groups are often informal, providing informational, emotional, and social support to members. The aim of this project is to co-produce guidance on how to establish a peer support programme for people living with chronic, non-cancer pain that is informed by evidence, theory, and stakeholder experience. Methods. This project is using Steps 1–4 of the Intervention Mapping (IM) approach to inform the research. Online workshops consisting of people living with chronic pain, third sector representatives, healthcare professionals, and researchers are being used to co-produce the guidance. Results. To date, 2 of the 4 planned workshops have been conducted. These have identified the needs of people living with chronic pain, goals for the peer support programme, and expectations of how a peer support programme should be executed. Topics for inclusion in the programme and their content have been identified, with further workshops to refine this planned. The final stage of this project will identify methods of delivery, specific resources that should be developed, and the training to be provided to peer support volunteers. Conclusion. The project has identified the diverse needs of people living with chronic pain and how these may be addressed by a peer support programme. It has identified flexible options that can be recommended to those who want to set up a programme and a variety content that may be included. Conflicts of Interest. None. Sources of
Although day surgery has a good patient satisfaction and safety profile, accurate episode-of-care costs (EOCC) calculation for of this procedure compared to standard same-day admission (SDA), while considering functional outcomes, is not well known. This study assesses the EOCC for patients with a THA while comparing DS and Same Day Admission (SDA) (with a 1-day hospitalization) pathways. The episode-of-care cost (EOCC) of 50 consecutive day surgery and SDA patients who underwent a THA was evaluated. The episode-of-care cost was determined using a bottom-up Time Driven- Activity Based
Purpose and background. Cauda Equina Syndrome (CES), a rare (<1 per 100,000) and potentially devasting condition, involves compression of the lumbosacral nerve roots. If not quickly identified and treated, it can lead to lasting disability, and high medicolegal costs (>£186 million in the decade to 2018). This study identified why people with suspected CES attend the emergency department (ED) and explored any delays in attending. Methods and Results. The design was a secondary analysis of a qualitative dataset comprising patients with back pain who attended the ED, undertaken using an interpretivist approach. Fourteen patients (8M:6F, aged 23–63 years) with suspected CES were purposively sampled from 4 EDs (2 Northern and 2 Southern) in England between August and December 2021. Semi-structured interviews were conducted online, audio-recorded, transcribed verbatim and analysed thematically. Acopia with pain was the biggest factor in a participant's decision to attend the ED, along with the need for a diagnosis. This pain was the worst ever experienced and debilitating, leaving people unable to cope and desperate for relief. 12/14 were advised to attend the ED following identification of red flags by: GPs (n=9); physiotherapists (n=2); surgical colleague (n=1); and 111 (n=1). Factors such as guilt, previous experience of being disregarded, and symptom misattribution were seen to cause delays in seeking care. Conclusion. This paper revealed a disconnect between the priorities of patients and clinicians prior to attending the ED. Clinicians need to validate the pain experience, communicate clearly why signs and symptoms are concerning, and convey the urgency and potential impact of CES. Conflicts of interest. None. Sources of funding.
Achilles tendon mechanical properties depend on a complex hierarchical design, with collagen being the smallest load-bearing unit. At the nanoscale, collagen molecules are organized into fibrils, which at the microscale are assembled into fibers, followed by larger structures such as sub-tendons or fascicles. Degree of in vivo loading affects the collagen content, and organization and consequently the tissue's mechanical response. We aim to unravel how composition, structural organization, and mechanical response are affected by degree of in vivo loading at each length scale. The presentation will outline the results to date about to the use of high-resolution synchrotron-based tissue characterisation methods on several length scales in combination with in situ mechanical tests. We use a rat model, where the tendons are subjected to varying loading in vivo. To characterize the tissue microstructure, phase-contrast enhanced synchrotron micro-tomography is performed. The 3D fiber organization in fully loaded tendons is highly aligned, whereas the fibers in unloaded tendons are significantly more heterogeneously arranged and crimped. To characterize the collagen fibril response, Small Angle X-ray Scattering is performed. Two types of fibril organizations are found; a single population oriented towards the main load direction and two fibril subpopulations with clearly distinct orientations. Scattering during loading showed that the fibrils in unloaded tendons did not strain as much in fully loaded. In situ loading concurrently with high resolution synchrotron experiments show the complex tendon response to in situ load and its relation to in vivo loading and tendon hierarchical structure. Unloading seems to alter the organization of the fibrils and fibers, e.g. increased crimping and more pronounced sub-tendon twists. Acknowledgements:
Purpose and background. Nearly 70% of UK physiotherapists experience work-related musculoskeletal disorders (WRMSDs) during their career, with a significant proportion occurring in the back and being attributed to patient handling tasks. Evidence suggests that manual handling training alone is ineffective and interventions among nurses indicate that a tailored approach, including targeted exercise (TE), can reduce WRMSD rates. This study aimed to explore physiotherapists’ perspectives of WRMSDs, patient handling, and the role of TE in reducing WRMSDs among physiotherapists. Methods and Results. Key informant interviews were conducted with 4 physiotherapy operational leads and 1 manual handling trainer from NHS Grampian. Interviews were transcribed and Framework Analysis was utilised to identify key themes, including challenges, barriers, and facilitators. Following this, two online focus groups were conducted with 7 qualified NHS physiotherapists across the UK. Views of manual handling training varied across specialities, with some finding it comprehensive and adaptable, and others finding it less applicable to patients in their speciality or community setting. Physiotherapist views on fitness for work varied, with some highlighting the necessity of TE to ensure workforce health whilst others considered exercise to be a personal matter. Facilitators to implementation identified by participants were having support from management and a strong justification for the exercise content. Varied work schedules and facilities were identified as barriers to implementation of a work-based TE intervention. Conclusion. Varying perspectives on TE interventions and barriers to implementation were identified. This work will inform future research to develop TE interventions in consultation with key stakeholders. Conflicts of Interest. No conflicts of interest. Source of
Purpose and background. Understanding patients’ expectations of back pain treatment can help improve their experiences, adherence and outcomes. Patients typically expect a diagnosis and exercise-based physiotherapy, but often undervalue the role of psychological factors. This study explored patients’ expectations of outpatient physiotherapy treatment for back pain in primary care. Methods and Results. The design, a secondary analysis of a qualitative cross-sectional study, involved 25 patients (13M:12F), aged 20–81, referred with low back pain (duration 7 weeks to 9 years). This sample did not include patients with serious spinal pathologies, known psychological disorders, or those unable to communicate without assistance. Face-to-face interviews were undertaken in patients’ homes, which were audio-recorded, transcribed verbatim and analysed using the six stages of thematic analysis outlined by Braun and Clarke. Patients expected a caring clinician and a strong therapeutic relationship, where they felt believed, openly communicated with and valued as an individual. Most patients expected a diagnosis and credible explanation for their pain. There was an almost equal split between those keen to take responsibility for their care and those who felt this was the clinicians’ role. Expectations of passive therapies were slightly higher in this study than existing research. Most patients were realistic about outcomes and expected treatment to reduce their pain, but not cure it. Conclusion. A positive experience mattered most to patients, valuing the relational aspects of their care more than the clinical content provided. Patients saw back pain through a biomedical lens, and most failed to recognise the role of psychosocial factors in their condition or treatment. Conflicts of interest. None. Sources of funding.
Statement of purpose of study and background. As the treatment of low back pain (LBP) continues to evolve, there is greater recognition of the importance of optimising the therapeutic relationship to better deliver improved patient outcomes. Contextual effects, such as communication, have been shown to influence the therapeutic relationship, but it is not known how these factors evolve over time. This study analysed interviews from two studies (one cross-sectional and one longitudinal) to explore patients’ and physiotherapists’ perspectives of treatment outcomes and experiences in episodes of LBP in the same dialogic space. The objective was to explore the alignment between these perceptions to identify factors that influence the therapeutic relationship over time. Summary of methods used and results. Two secondary thematic analyses were undertaken, one analysing cross-sectional data and the other analysing longitudinal data, from an existing data set from the programme: “Exploring the relationship between communication and clinical decision-making in physiotherapy consultations for back pain”. All data were thematically analysed and organised using a framework approach. Six themes emerged from the cross-sectional data reporting consistency of opinion in the initial consultation stages, but highlighting inadequate patient involvement in shared decision making. Four main themes emerged from the longitudinal data, all of which reported interactional fears and anxieties identified on both the parts of the patient and the physiotherapist. Conclusion. These findings suggest that failing to involve the patient in adequately personalised treatment from the initial consultation may lead to diagnosis hunting and stereotyping behaviours within the therapeutic relationship, in turn leading to increased health resource usage. Conflicts of interest. None. Sources of
Introduction. A long nail is often recommended for treatment of complex trochanteric fractures but requires longer surgical and fluoroscopy times. A possible solution could be a nail with an appropriate length which can be locked in a minimally invasive manner by the main aiming device. We aimed to determine if such a nail model* offers similar structural stability on biomechanical testing on artificial bone as a standard long nail when used to treat complex trochanteric fractures. Method. An artificial osteoporotic bone model was chosen. As osteosynthesis material two cephalomedullary nails (CMN) were chosen: a superior locking nail (SL-Nail) which can be implanted with a singular targeting device, and a long nail (long-nail) with distal locking using free-hand technique. AO31-A2.2 fractures were simulated in a standardized manner. The insertion of the nail was strictly in accordance with the IFU and surgical manual of the manufacturer. The nail was locked dynamically proximally and statically distally. Axial height of the construct, varus collapse, and rotational deformity directly after nail insertion were simulated. A Universal Testing Machine was used. Measurements were made with a stereo-optic tracking system. Reactive movements were recorded and evaluated in all six degrees of freedom. A comparative analysis provided information about the stability and deformation of the assemblies to be compared. Result. There was a detectable difference in the axial fracture movement resulting in narrowing of the fracture gap. The load displacement was 1.7mm higher for the SL-Nail. There was no difference in varus collapse or rotational deformity between the nail variants. Conclusion. We conclude that there are small differences which are clinically insignificant and that a superior locking nail can safely be used to manage complex trochanteric fractures. *DCN SL nail, SWEMAC, Linköping, Sweden.
Study purpose and background. Kinematic variables have been identified as potential biomarkers for low back pain patients; however, an in-depth comparison between chronic (n=22), acute (n=15), and healthy controls (n=136) has not been done. This retrospective data analysis compared intervertebral lumbar motion parameters, angular range of motion, translation, maximum disc height, motion share inequality (MSI) and variability (MSV), and laxity, between these groups. Methods and results. Kinematic parameters were determined using video tracking techniques utilising quantitative fluoroscopy (QF), during both weight-bearing and recumbent controlled sagittal bending tasks. Data was analysed for normality, and appropriate statistical tests were applied to determine differences between groups. There were no significant differences between the groups for age, height, weight and sex. Whilst few differences were found between acute and healthy groups, differences were shown between both chronic and healthy, and acute and chronic groups for all six parameters. Of particular note were examples of differences in the motion share parameters between the acute and chronic populations, with an increased MSI in the chronic group during recumbent flexion, and MSV during recumbent extension, and inversely an increase in MSV in the acute group during weight-bearing flexion. Conclusion. Analysis of intervertebral lumbar motion provides valuable insights into kinematic differences between chronic, acute, and healthy control populations. These findings suggest that there is variation between the groups which is knowledge that may benefit management strategies. Further exploration of the time varying data is warranted to explore how such differences may relate to the motion share inequalities and variability shown. Conflicts of Interest. No conflicts of interest. Sources of
Introduction. Degenerative meniscal tears are the most common meniscal lesions, representing huge clinical and socio-economic burdens. Their role in knee osteoarthritis (OA) onset and progression is well established and demonstrated by several retrospective studies. Effective preventive measures and non-surgical treatments for degenerative meniscal lesions are still lacking, also because of the lack of specific and accurate animal models in which test them. Thus, we aim to develop and validate an accurate animal model of meniscus degeneration. Method. Three different surgical techniques to induce medial meniscus degenerative changes in ovine model were performed and compared. A total of 32 sheep (stifle joints) were subjected to either one of the following surgical procedures: a) direct arthroscopic mechanical meniscal injury; b) peripheral devascularization and denervation of medial meniscus; c) full thickness medial femoral condyle cartilage lesion. In all the 3 groups, the contralateral joint served as a control. Result. From a visual examination of the knee joint emerged a clear difference between control and operated groups, in the menisci but also in the cartilage, indicating the onset of OA-related cartilage degeneration. The meniscal and cartilaginous lesions were characterized by different severity and location in the different groups. For instance, a direct meniscal injury caused cartilaginous lesions especially in the medial part of the condyles, and the other approaches presented specific signature. Evaluation of scoring scales (e.g. ICRS score) allowed the quantification of the damage and the identification of differences among the four groups. Conclusion. We were effectively able to develop and validate a sheep model of meniscal degeneration which led to the onset of OA. This innovative model will allow to test in a pre-clinical relevant setting innovative approaches to prevent meniscal-related OA.
Introduction. Osteoarthritis (OA) is a prevalent joint disorder characterized by cartilage degeneration, inflammation, and pain. Current treatments provide only symptomatic relief, necessitating novel molecular targets. The caspase family, known for its roles in apoptosis and inflammation regulation, may additionally influence crucial processes for cartilage homeostasis such as differentiation and proliferation. However, the specific roles of individual caspases in OA pathogenesis remain unclear. This study aims to investigate the involvement of the caspase family in OA and as potential targets for therapy, with a focus on caspase-1 and -8. Method. Chondrocytes from both healthy and OA donors were cultured in 2D and 3D culture models and stimulated with TNF-α or IL-1β. The expression and activation of caspase-1 and -8 was assessed using RT-PCR, ELISA. Transcriptome analysis of OA and healthy cartilage samples, along with Mendelian randomization (MR) analysis were conducted to explore the involvement of caspase family in OA and to assess its potential as therapeutic targets. Result. Higher expression levels of caspase-1, -8 were observed in OA cartilage compared to healthy cartilage. TNF-α stimulation increased their expression in both healthy and OA chondrocytes, while IL-1β had limited impact. Caspase-8 expression was causally associated with knee OA in MR analysis, suggesting a potential therapeutic target. The caspase-1 inhibitor VX-765 mildly reduced chondrocyte viability, with no significant effect in the presence of TNF-α. While the caspase-8 inhibitor Z-IETD-FMK exhibited slight enhancements in cell viability, these improvements were not statistically significant. Nevertheless, its effectiveness significantly increased in the presence of TNF-α. Conclusion. This study highlights the involvement of caspase-1 and caspase-8 in OA pathology, with caspase-8 emerging as a potential therapeutic target for knee OA treatment. Further investigation into the roles of caspase-1 and -8 in OA pathophysiology, including the efficacy and potential side effects of their corresponding inhibitors, is warranted. Acknowledgements.
Intra-articular injection is a common way to deliver biologics to joints, but their effectiveness is limited by rapid clearance from the joint space. This barrier can be overcome by genetically modifying cells within the joint such that they produce anti-arthritic gene products endogenously, thereby achieving sustained, therapeutic, intra-articular concentrations of the transgene products without re-dosing. A variety of non-viral and viral vectors have been subjected to preclinical testing to evaluate their suitability for delivering genes to joints. The first transfer of a gene to a human joint used an ex vivo protocol involving retrovirally transduced, autologous, synovial fibroblasts. Recent advances in vector technology allow in vivo delivery using adeno-associated virus (AAV). We have developed an AAV vector encoding the interleukin-1 receptor antagonist (AAV.IL-1Ra) for injection into joints with osteoarthritis (OA). It showed efficacy and safety in equine and rat models of OA, leading to a recently-completed, investigator-initiated, Phase I, dose-escalation clinical trial in 9 subjects with mid-stage OA of the knee (. ClinicalTrials.gov. Identifier: NCT02790723). Three cohorts of three subjects with mild to moderate OA in the index knee were injected intra-articularly under ultrasound guidance with a low (10e11 viral genomes) medium (10e12 viral genomes) or high (10e13 viral genomes) dose of AAV.IL-1Ra and followed for one year. The data confirm safety, with evidence of sustained intra-articular expression of IL-1Ra and a clinical response in certain subjects.
Purpose and background. Low back pain (LBP), a leading cause of chronic disability, is associated with high and disproportionate socioeconomic costs. Clinical assessment and triage via the NHS 111 service aims to reduce pressure on the urgent and emergency care system. Studies show that many attend the emergency department (ED) against advice, when they could be better managed elsewhere. The aim of this research was to explore how patients with LBP perceive and interact with NHS 111, and how this may have influenced their decision to attend ED. Methods and Results. This was a secondary analysis of a cross-sectional, qualitative dataset of 47 patients (26M:21F, aged 23–79 years) purposively sampled with LBP, who attended 1 of 4 EDs in the UK in 2021, (during the pandemic). The participants took part in online, semi-structured interviews, mean duration 45-minutes (range 23–156 minutes), within six weeks of their ED visit. The interviews were audio-recorded, transcribed verbatim and thematically analysed. Three key themes were identified: purpose, process and performance. The themes showed mixed understanding and low awareness of the purpose of NHS 111, despite its strong triage role. Long waits for call backs however, sometimes resulted in patients attending ED, along with previous negative perspectives and experiences. Conclusion. This research suggests enhanced visibility and knowledge of NHS 111 would increase its use by people with LBP. Further exploration comparing outcomes of callers to NHS 111 with those who seek care elsewhere, could help evaluate how NHS 111 can best help people with LBP and prevent unnecessary ED attendance. No conflicts of interest. . Sources of funding.
Osteoarthritis (OA) leads to articular cartilage degradation, following complex dysregulation of chondrocyte's metabolism towards a catabolic state. Mechanical and biochemical signals are involved and need to be considered to understand the condition. Regulatory network-based models (RNM) successfully simulated the biological activity of the chondrocyte and the transduction of mechanical signals at the molecular and cell levels. However, the knowledge gap between single-cell regulation and intercellular communication in tissue volumes hinders the interpretability of such models at larger scales. Accordingly, a novel tissue-level biochemical model is proposed. We hypothesise that it is possible to simulate interacting network effects through the transport of diluted species in a finite-element model, to grasp relevant dynamics of cell and tissue regulation in OA. Chondrocyte RNM equations were translated into a reaction term of 18 multi-species diffusion model (e.g., 3 anti-inflammatory and 8 pro-inflammatory interleukins, 3 pro-anabolic and 1 pro-catabolic growth factors, 2 nociceptive factors and 2 pro-inflammatory cytokines). Elements with RNM reaction terms represented the chondrocytes and were distributed randomly through the model, according to known cellular density in the knee cartilage, and could both react to and produce diffusive entities through the pericellular matrix, associated with reduced diffusion coefficients. The model was constructed over a 2D square of 0.47 mm sides considered to be in the middle of the cartilage, so boundary conditions were settled as periodic. Different simulations were initialised with initial concentrations of either healthy or pro-OA mediators. Preliminary results showed that, independently of the initial conditions, the chondrocytes successfully evolved into anabolic states, in absence of sustained pro-catabolic external stimulations, in contrast to single-cell RNM [2]. Our intercellular model suggests that paracrine communication may increase robustness towards cartilage maintenance, and future tests shall reveal new OA dynamics. Acknowledgements:
Purpose and background. Low back pain burdens individuals, society and services, including Emergency Departments (ED), straining services and prolonging wait times. Despite reported personal influences on deciding to attend ED, the role of third-party advice remains underexplored. Sparse guidance for clinicians and service-users highlights the need for effective back pain management strategies, to alleviate system pressure and optimise patient outcomes. This study explored how advice influences the decision to attend the ED for back pain. Methods and Results. From a subtle realist stance, the design was a secondary analysis of qualitative data, where 47 patients (26M:21F, aged 23–79 years) with back pain were purposively sampled from four EDs (2 Northern and 2 Southern) in England between August and December 2021. Eight patients had previously visited ED for this episode of back pain. As this was during the pandemic, semi-structured interviews were conducted online, audio-recorded, transcribed verbatim and analysed using a reflective thematic analysis. Three themes were identified as crucial in making the decision to attend ED: The Healthcare professional; Trusted others; and the Individual. Healthcare professionals often dictated decisions, leaving participants feeling powerless. Trusted others provided varying support levels, often acting as allies. Individuals grappled with anxieties around their condition and treatment expectations. Conclusion. This study highlights the need for clinicians to provide clarity and guidance to individuals and their Trusted others, seeking advice regarding escalation to visit the ED with back pain. There was evidence that worrying about pain was a significant motivator for attending ED, resulting in malalignment with current practice guidelines. No conflicts of interest. . Sources of funding.
