Fracture nonunion is a severe clinical problem for the patient, as well as for the clinician. About 5-20% of fractures does not heal properly after more than six months, with a 19% nonunion rate for tibia, 12% for femur and 13% for humerus, leading to patient morbidity, prolonged hospitalization, and high costs. The standard treatment with iliac crest-derived autologous bone filling the nonunion site may cause pain or hematoma to the patient, as well as major complications such as infection. The application of mesenchymal autologous cells (MSC) to improve bone formation calls for randomized, open, two-arm clinical studies to verify safety and efficacy. The ORTHOUNION * project (ORTHOpedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonUNIONs) is a multicentric, open, randomized, comparative phase II clinical trial, approved in the framework of the H2020 funding programme, under the coordination of Enrique Gòmez Barrena of the Hospital La Paz (Madrid, Spain). Starting from January 2017, patients with nonunion of femur, tibia or humerus have been actively enrolled in Spain, France, Germany, and Italy. The study protocol encompasses two experimental arms, i.e., autologous bone marrow-derived mesenchymal cells after expansion (‘high dose’ or ‘low dose’ MSC) combined to ceramic granules (MBCP™, Biomatlante), and iliac crest-derived autologous trabecular bone (ICAG) as active comparator arm, with a 2-year follow-up after surgery. Despite the COVID 19 pandemic with several lockdown periods in the four countries, the trial was continued, leading to 42 patients treated out of 51 included, with 11 receiving the bone graft (G1 arm), 15 the ‘high dose’ MSC (200x10. 6. , G2a arm) and 16 the ‘low dose’ MSC (100x10. 6. , G2b arm). The Rizzoli Orthopaedic Institute has functioned as coordinator of the Italian clinical centres (Bologna, Milano, Brescia) and the Biomedical Science and Technologies and Nanobiotechnology Lab of the RIT Dept. has enrolled six patients with the collaboration of the Rizzoli’ 3rd Orthopaedic and Traumatological Clinic prevalently Oncologic. Moreover, the IOR Lab has collected and analysed the blood samples from all the patients treated to monitor the changes of the bone turnover markers following the surgical treatment with G1, G2a or G2b protocols. The clinical and biochemical results of the study, still under evaluation, are presented. * ORTHOUNION Horizon 2020 GA 733288

Abstract. OBJECTIVES. Application of deep learning approaches to marker trajectories and ground reaction forces (mocap data), is often hampered by small datasets. Enlarging dataset size is possible using some simple numerical approaches, although these may not be suited to preserving the physiological relevance of mocap data. We propose augmenting mocap data using a deep learning architecture called “generative adversarial networks” (GANs). We demonstrate appropriate use of GANs can capture variations of walking patterns due to subject- and task-specific conditions (mass, leg length, age, gender and walking speed), which significantly affect walking kinematics and kinetics, resulting in augmented datasets amenable to deep learning analysis approaches. METHODS. A publicly available (. https://www.nature.com/articles/s41597-019-0124-4. ) gait dataset (733 trials, 21 women and 25 men, 37.2 ± 13.0 years, 1.74 ± 0.09 m, 72.0 ± 11.4 kg, walking speeds ranging from 0.18 m/s to 2.04 m/s) was used as the experimental dataset. The GAN comprised three neural networks: an encoder, a decoder, and a discriminator. The encoder compressed experimental data into a fixed-length vector, while the decoder transformed the encoder's output vector and a condition vector (containing information about the subject and trial) into mocap data. The discriminator distinguished between the encoded experimental data from randomly sampled vectors of the same size. By training these networks jointly using the experimental dataset, the generator (decoder) could generate synthetic data respecting specified conditions from randomly sampled vectors. Synthetic mocap data and lower limb joint angles were generated and compared to the experimental data, by identifying the statistically significant differences across the gait cycle for a randomly selected subset of the experimental data from 5 female subjects (73 trials, aged 26–40, weighing 57–74 kg, with leg lengths between 868–931 mm, and walking speeds ranging from 0.81–1.68 m/s). By conducting these comparisons for this subset, we aimed to assess the synthetic data generated using multiple conditions. RESULTS. We visually inspected the synthetic trials to ensure that they appeared realistic. The statistical comparison revealed that, on average, only 2.5% of the gait cycle showed significantly differences in the joint angles of the two data groups. Additionally, the synthetic ground reaction forces deviated from the experimental data distribution for an average of 2.9% of the gait cycle. CONCLUSIONS. We introduced a novel approach for generating synthetic mocap data of human walking based on the conditions that influence walking patterns. The synthetic data closely followed the trends observed in the experimental data, also in the literature, suggesting that our approach can augment mocap datasets considering multiple conditions, an approach unfeasible in previous work. Creation of large, augmented datasets allows the application of other deep learning approaches, with the potential to generate realistic mocap data from limited and non-lab-based data. Our method could also enhance data sharing since synthetic data does not raise ethical concerns. You can generate and download virtual gait data using our GAN approach from . https://thisgaitdoesnotexist.streamlit.app/. . Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Abstract. Objectives. To compare the effectiveness of phonophoresis (PH) and conventional therapeutic ultrasound (US) on the functional and pain outcomes of patients with knee osteoarthritis. Methods. We conducted an electronic search through PubMed, Cochrane Central Register of Clinical Trials (CENTRAL), Web of Science (WOS), and Scopus databases. We screened the retrieved articles to include only English full-text randomized controlled trials that examined the effect of phonophoresis versus conventional therapeutic ultrasound on patients with knee osteoarthritis. Two reviewers screened, extracted the data, and independently assessed the quality of the included articles. Results. A total of five randomized controlled trials met our inclusion criteria out of 267 studies screened. Our results showed no statistically significant differences between the PH and US groups (1), (2), (3),(4), and (5). The PH group demonstrated more significant effects than the UT group in reducing VAS pain scores (P=0.009) and improving WOMAC scores, although this did not reach the level of significance (P=0.143) (5). In the long term, PH therapy was found to be superior to US in improving painless walking duration and distance VAS scores (p=0.034, 0.017) respectively, as well as walking and resting walking VAS scores (p=0.03, 0.007) respectively, which were found to be permanent (3). Conclusions. Both therapies improve pain and function. However, we suggest conducting more high-quality trials with larger sample sizes and do not recommend the use of these therapies in clinical practice due to limitations in gender selection and high risk of bias. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Introduction. The Achilles tendon is the thickest and strongest tendon in the human body. Even though the tendon is so strong, it is one of the most frequently injured tendons. Treatment of patients after rupture is planned conservatively and surgically. Conservative treatment is generally applied to elderly patients with sedentary lives. If the treatment is surgical, it can be planned as open surgery or percutaneous surgery. In our study with rabbits, we wrapped a membrane made of plga (polylactic-co-glycolic acid) nanotubes impregnated with type 1 collagen around the tendon in rabbits that underwent open Achilles tendon repair surgery. After surgery, biomechanical and histological tests were performed on the tendons. Method. In the study consisting of 24 rabbits, 2 groups were created by random distribution. In the study group, after the Achilles tendon rupture was created, a type 1 collagen-impregnated plga-based membrane was placed around the tendon after the repair of 1 modified Kesslerr suture. In the control group, after the Achilles tendon rupture was created, 1 modified Kessler suture and Tendon repair was performed with the application of 3 primary sutures. At the end of the 6th week of the study, the rabbits in 2 groups were randomly distributed and histological examination was performed. Additionally, biomechanical testing was performed. Bonar and Movın scoring were used in histological examinations. Result. As a result of biomechanical tests, it was seen that the resistance of the tendon against rupture was higher in the study group than in the control group. In addition, it was observed that the tendon rupture time was longer in the study group than in the control group. Histological examinations gave supportive results from biomechanical tests. Conclusion. We think that the use of collagen-impregnated plga-based nanotubes in the surgical treatment of Achilles tendon ruptures has a positive healing effect. Although we think that the return to normal life after surgery may be faster, we believe that more clinical studies are needed

Introduction. Exercise is recommended as first-line treatment for patients with hip osteoarthritis (OA). Interestingly, content and dose of exercise interventions seem to be important for the effect of exercise interventions, but the optimal content and dose is unknown. This warrants randomized controlled trials providing evidence for the optimal exercise program in Hip OA. The aim of this trial was to investigate whether progressive resistance training (PRT) is superior to neuromuscular exercise (NEMEX) for improving functional performance, hip pain and hip-related quality of life in patients with hip OA. Method. This was a multicenter, cluster-randomized, controlled, parallel-group, assessor-blinded, superiority trial. 160 participants with clinically diagnosed hip OA were recruited from hospitals and physiotherapy clinics and randomly assigned to twelve weeks of PRT or NEMEX. The PRT intervention consisted of 5 high-intensity resistance training exercises targeting muscles at the hip and knee joints. The NEMEX intervention included 10 exercises and emphasized sensorimotor control and functional stability. The primary outcome was change in the 30-second chair stand test (30s-CST). Key secondary outcomes were changes in scores on the pain and hip-related quality of life (QoL) subscales of the Hip Disability and Osteoarthritis Outcome Score (HOOS). Result. The mean changes from baseline to 12-week follow-up in the 30s-CST were 1.5 (95% CI, 0.9 to 2.1) chair stands with PRT and 1.5 (CI, 0.9 to 2.1) chair stands with NEMEX (difference, 0.0 [CI, 0.8 to 0.8] chair stands). For the HOOS pain subscale, mean changes were 8.6 (CI, 5.3 to 11.8) points with PRT and 9.3 (CI, 5.9 to 12.6) points with NEMEX. For the HOOS QoL subscale, mean changes were 8.0 (CI, 4.3 to 11.7) points with PRT and 5.7 (CI, 1.9 to 9.5) points with NEMEX. Conclusion. In patients with hip OA, PRT is not superior to NEMEX for improving functional performance, hip pain, or hip-related QoL

Introduction. There is a lack of evidence-based treatments for patients with chronic pain after total knee arthroplasty (TKA). It is well-established that knee extensor and flexor muscle strength are markedly impaired following TKA, but no studies have examined muscle strength and power in patients with chronic pain after TKA. Therefore, the aim was to investigate if neuromuscular exercises and pain neuroscience education (PNE) were superior to PNE alone for improvement of muscle strength and power in patients with chronic pain after TKA. Method. This report presents the exploratory analysis of a randomized controlled trial (NCT03886259). Participants with chronic moderate-to-severe average daily pain intensity and no signs of prosthesis failure at least one year after primary TKA were included. Participants were randomized to receive either supervised neuromuscular exercise and PNE or the same PNE sessions alone. The outcomes were changes from baseline to 12-months for peak leg extension power and maximum muscle strength, measured during maximal voluntary isometric contractions, for the knee extensors and flexors. Result. Sixty-nine participants (age 62.2±7.2, 40 females) were included. No between-group differences were observed for peak leg extension power (difference 13.6 Watts, 95% CI -22.2 to 49.3), maximum knee extensor muscle strength (difference -20.9 Newtons, 95% CI -65.8 to 24.0) or maximum knee flexor muscle strength (difference 8.6 Newtons, 95% CI -11.9 to 29.1). Peak leg extension power (26.3 Watts, 95% CI 4.3 to 48.3) and maximum knee flexor muscle strength (19.7 Newtons, 95% CI 7.6 to 31.9) improved significantly in the neuromuscular exercise and PNE group with no significant improvements observed in the PNE alone group. Conclusion. Neuromuscular exercise and PNE did not improve muscle strength and power compared to PNE alone in patients with chronic pain after TKA. Acknowledgements. This study was funded by the Danish Rheumatism Association, the Svend Andersen Foundation and Lions Club Denmark

Glenoid and humeral head bone defects have long been recognized as major determinants in recurrent shoulder instability as well as main predictors of outcomes after surgical stabilization. However, a universally accepted method to quantify them is not available yet. The purpose of the present study is to describe a new CT method to quantify bipolar bone defects volume on a virtually generated 3D model and to evaluate its reproducibility. A cross-sectional observational study has been conducted. Forty CT scans of both shoulders were randomly selected from a series of exams previously acquired on patients affected by anterior shoulder instability. Inclusion criterion was unilateral anterior shoulder instability with at least one episode of dislocation. Exclusion criteria were: bilateral shoulder instability; posterior or multidirectional instability, previous fractures and/or surgery to both shoulders; congenital or acquired inflammatory, neurological, or degenerative diseases. For all patients, CT exams of both shoulders were acquired at the same time following a standardized imaging protocol. The CT data sets were analysed on a standard desktop PC using the software 3D Slicer. Computer-based reconstruction of the Hill-Sachs and glenoid bone defect were performed through Boolean subtraction of the affected side from the contralateral one, resulting in a virtually generated bone fragment accurately fitting the defect. The volume of the bone fragments was then calculated. All measurements were conducted by two fellowship-trained orthopaedic shoulder surgeons. Each measurement was performed twice by one observer to assess intra-observer reliability. Inter and intra-observer reliability were calculated. Intraclass Correlation Coefficients (ICC) were calculated using a two-way random effect model and evaluation of absolute agreement. Confidence intervals (CI) were calculated at 95% confidence level for reliability coefficients. Reliability values range from 0 (no agreement) to 1 (maximum agreement). The study included 34 males and 6 females. Mean age (+ SD) of patients was 36.7 + 10.10 years (range: 25 – 73 years). A bipolar bone defect was observed in all cases. Reliability of humeral head bone fragment measurements showed excellent intra-observer agreement (ICC: 0.92, CI 95%: 0.85 – 0.96) and very good interobserver agreement (ICC: 0.89, CI 95%: 0.80 – 0.94). Similarly, glenoid bone loss measurement resulted in excellent intra-observer reliability (ICC: 0.92, CI 95%: 0.85 – 0.96) and very good inter-observer agreement (ICC: 0.84, CI 95%:0.72 – 0.91). In conclusion, matching affected and intact contralateral humeral head and glenoid by reconstruction on a computer-based virtual model allows identification of bipolar bone defects and enables quantitative determination of bone loss

The aim of the ongoing projects was to demonstrate the efficacy of autologous bone marrow derived stem cells (MSC) combined with biomaterial to induced new bone formation in a randomized multicenter controlled clinical trial. Patients with a need for bone reconstruction of residual edentulous ridges in both the mandible and maxilla due to bone defects with a vertical loss of alveolar bone volume and/or knife edge ridges (≤ than 4,5 mm) unable to provide adequate primary stabilization for dental implants were included in the clinical study. Autologous bone marrow MSC were expanded, loaded on BCP and used to augment the alveolar ridges. After five months bone biopsies were harvested at the implant position site and implants were installed in the regenerated bone. The implants were loaded after 8–12 weeks. Safety, efficacy, quality of life and success/survival were assessed. Five clinical centers, 4 different countries participated. Bone grafts harvested from the ramus of the mandibles were used as control in the projects

Artificial Intelligence (AI) is becoming more powerful but is barely used to counter the growth in health care burden. AI applications to increase efficiency in orthopedics are rare. We questioned if (1) we could train machine learning (ML) algorithms, based on answers from digitalized history taking questionnaires, to predict treatment of hip osteoartritis (either conservative or surgical); (2) such an algorithm could streamline clinical consultation. Multiple ML models were trained on 600 annotated (80% training, 20% test) digital history taking questionnaires, acquired before consultation. Best performing models, based on balanced accuracy and optimized automated hyperparameter tuning, were build into our daily clinical orthopedic practice. Fifty patients with hip complaints (>45 years) were prospectively predicted and planned (partly blinded, partly unblinded) for consultation with the physician assistant (conservative) or orthopedic surgeon (operative). Tailored patient information based on the prediction was automatically sent to a smartphone app. Level of evidence: IV. Random Forest and BernoulliNB were the most accurate ML models (0.75 balanced accuracy). Treatment prediction was correct in 45 out of 50 consultations (90%), p<0.0001 (sign and binomial test). Specialized consultations where conservatively predicted patients were seen by the physician assistant and surgical patients by the orthopedic surgeon were highly appreciated and effective. Treatment strategy of hip osteoartritis based on answers from digital history taking questionnaires was accurately predicted before patients entered the hospital. This can make outpatient consultation scheduling more efficient and tailor pre-consultation patient education

Secondary bone healing is impacted by the extent of interfragmentary motion at the fracture site. It provides mechanical stimulus that is required for the formation of fracture callus. In clinical settings, interfragmentary motion is induced by physiological loading of the broken bone – for example, by weight-bearing. However, there is no consensus about when mechanical stimuli should be applied to achieve fast and robust healing response. Therefore, this study aims to identify the effect of the immediate and delayed application of mechanical stimuli on secondary bone healing. A partial tibial osteotomy was created in twelve Swiss White Alpine sheep and stabilized using an active external fixator that induced well-controlled interfragmentary motion in form of a strain gradient. Animals were randomly assigned into two groups which mimicked early (immediate group) and late (delayed group) weight-bearing. The immediate group received daily stimulation (1000 cycles/day) from the first day post-op and the delayed group from the 22nd day post-op. Healing progression was evaluated by measurements of the stiffness of the repair tissue during mechanical stimulation and by quantifying callus area on weekly radiographs. At the end of the five weeks period, callus volume was measured on the post-mortem high-resolution computer tomography (HRCT) scan. Stiffness of the repair tissue (p<0.05) and callus progression (p<0.01) on weekly radiographs were significantly larger for the immediate group compared to the delayed group. The callus volume measured on the HRCT was nearly 3.2 times larger for the immediate group than for the delayed group (p<0.01). This study demonstrates that the absence of immediate mechanical stimuli delays callus formation, and that mechanical stimulation already applied in the early post-op phase promotes bone healing

Total Knee Arthroplasty (TKA) improves the quality of life of osteoarthritic and rheumatoid arthritis patients, however, is associated with moderate to severe postoperative pain. There are multiple methods of managing postoperative pain that include epidural anesthesia but it prevents early mobilization and results in postoperative hypotension and spinal infection. Controlling local pain pathways through intra-articular administration of analgesics is a novel method and is inexpensive and simple. Hence, we assess the effects of postoperative epidural bupivacaine injection along with intra-articular injection in total knee replacement patients. The methodology included 100 patients undergoing TKA randomly divided into two groups, one administered with only epidural bupivacaine injection and the other with intra-articular cocktail injection. The results were measured based on a 10-point pain assessment scale, knee's range of motion (ROM), and Lysholm knee score. The VAS score was lower in the intra-articular cocktail group compared to the bupivacaine injection group until the end of 1-week post-administration (p<0.01). Among inter-group comparisons, we observed that the range of motion was significantly more in cocktail injection as compared to the bupivacaine group till the end of one week (p<0.05). Lysholm's score was significantly more in cocktail injection as compared to the bupivacaine group till the end of one week (p<0.05). Our study showed that both epidural bupivacaine injection and intra-articular injection were effective in reducing pain after TKA and have a comparable functional outcome at the end of 4 weeks follow up. However, the pain relief was faster in cases with intra-articular injection, providing the opportunity for early rehabilitation. Thus, we recommend the use of intra-articular cocktail injection for postoperative management of pain after total knee arthroplasty, which enables early rehabilitation and faster functional recovery of these patients

The principal of “function priority, early rehabilitation, and return to sports” is now the goal for sports injury rehabilitation. Neuromuscular electrical stimulation for anterior cruciate ligament (ACL) reconstruction is a rising procedure for early rehabilitation. This paper systematically assessed the effects of neuromuscular electrical stimulation on postoperative ACL reconstruction to provide guidance for physiotherapist and patient when designing a suitable rehabilitation protocol. To evaluate the interventional outcomes of neuromuscular electrical stimulation following ACL reconstruction, we searched PubMed, EMbase, the Cochrane Library, Web of Science and CNKI to collect all randomized controlled trials (RCTs) comparing the effects with neuromuscular electrical stimulation and without intervention on rehabilitation after ACL reconstruction up to January 30, 2022. Two investigators independently performed literature screening, data extraction, bias assessment of risk, and used RevMan 5.3 software to conduct a meta-analysis. A total of six RCTs were included, and the results showed that the use of neuromuscular electrical stimulation after anterior cruciate ligament reconstruction significantly improved the International Knee Documentation Committee (IKDC) scores (MD 6.33, 95% CI [-0.43, 12.22]; I2 = 66%; p = 0.040), the Lysholm score (MD 7.94, 95% CI [6.49, 9.39]; I2 = 89%; p < 0.001), and the range of motion (ROM) (MD 9.99, 95% CI [7.97, 12.02]; I2 = 81%; p < 0.001) in the knees when compared to the control group without using neuromuscular electrical stimulation. Existing evidence show that neuromuscular electrical stimulation is beneficial for early rehabilitation after ACL reconstruction. The use of neuromuscular electrical stimulation is encouraged in the design of rehabilitation protocol. However, due to the limited number of RCT studies and the small sample size, further multi-center RCTs with more participants are needed for a higher-level evidence

A novel EP4 selective agonist (KMN-159) was developed [1] and has been proven that it can act as an osteopromotive factor to repair critical-size femoral bone defects in rats at a dose-dependent manner [2]. Based on its osteopromotive properties, we hypothesized that KMN-159 could also aid in bone formation for spinal fusion. Therefore, the aim of this study was to investigate its spinal fusion effect in a dorsolateral spinal fusion model in rats. This study was performed on 192, 10-week-old male Wistar rats. The rats were randomized into 8 groups (n = 12 per group): 1) SHAM (negative control), 2) MCM (scaffold only), 3) MCM + 20 µg BMP-2 (positive control), 4-8) MCM + 0.2, 2, 20, 200 or 2000 µg KMN-159. A posterolateral intertransverse process spinal fusion at L4 to L5 was performed bilaterally by implanting group dependent scaffolds (see above) or left empty in the SHAM group (protocol no. 25-5131/474/38). Animals were euthanized after 3 weeks and 6 weeks for µCT and biomechanical testing analysis. The results showed that KMN-159 promoted new bone formation in a dose-dependent manner at 3 weeks and 6 weeks as verified by µCT. The biomechanical testing showed that the dose of 20, 200 and 2000 µg KMN-159 groups obtained comparable strength with BMP-2 group, which higher than SHAM, MCM and lower doses of 0.2 and 2 µg KMN-159 groups. In conclusion, KMN-159 could be a potential replacement of BMP-2 as a novel osteopromotive factor for spinal fusion. Acknowledgements: We are grateful to Ulrike Heide, Anna-Maria Placht (assistance with surgeries) as well as Suzanne Manthey & Annett Wenke (histology)

There remains much debate regarding the optimal method for surgical management of patients with long head of biceps pathology. The aim of this study was to compare the outcomes of tenotomy versus tenodesis. This systematic review and meta-analysis was registered on PROSPERO (ref: CRD42020198658). Electronic databases searched included EMBASE, Medline, PsycINFO, and Cochrane Library. Randomized controlled trials (RCTs) comparing tenotomy versus tenodesis were included. Risk of bias within studies was assessed using the Cochrane risk of bias v2.0 tool and the Jadad score. The primary outcome included patient reported functional outcome measures pooled using standardized mean difference (SMD) and a random effects model. Secondary outcome measures included pain (visual analogue scale VAS), rate of Popeye deformity, and operative time. 860 patients from 11 RCTs (426 tenotomy vs 434 tenodesis) were included in the meta-analysis. Pooled analysis of all PROMs data demonstrated comparable outcomes between tenotomy vs tenodesis (SMD 0.14, 95% CI −0.04 to 0.32; p=0.13). Sensitivity analysis comparing RCTs involving patients with and without an intact rotator cuff did not change the primary outcome. There was no significant difference for pain (VAS). Tenodesis resulted in a lower rate of Popeye deformity (OR 0.29, 95% CI 0.19 to 0.45, p < 0.00001). Tenotomy demonstrated a shorter operative time (MD 15.21, 95% CI 1.06 to 29.36, p < 0.00001). Aside from a lower rate of cosmetic deformity, tenodesis yielded no measurable significant benefit to tenotomy for addressing pathology in the long head of biceps. A large multi-centre clinical effectiveness randomised controlled trial is needed to provide clarity in this area

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. Funding Inter-Action/Inter-Excellence project (BTHA-JC-2022-36/LUABA22019)

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: Funding was provided by the European Commission (ERC-2021-CoG-O-Health-101044828)

Treatment for delayed wound healing resulting from peripheral vascular diseases and diabetic foot ulcers remain a challenge. A novel surgical technique named Tibial Cortex Transverse Transport has been developed for treating peripheral ischaemia, with encouraging clinical effects. However, its underlying mechanisms remain unclear. In present study, we aimed to explore the wound healing effects after undergoing this novel technique via multiple ways. A novel rat model of Tibial Cortex Transverse Transport was established with a designed external fixator and effects on wound healing were investigated. All rats were randomized into 3 groups, with 12 rats per group: sham group (negative control), fixator group (positive control) and Tibial Cortex Transverse Transport group. Laser speckle perfusion imaging, vessel perfusion, histology and immunohistochemistry were used to evaluate the wound healing processes. Gross and histological examinations showed that Tibial Cortex Transverse Transport technique accelerated wound closure and enhanced the quality of the newly formed skin tissues. In Tibial Cortex Transverse Transport group, HE staining demonstrated a better epidermis and dermis recovery, while immune-histochemical staining showed that Tibial Cortex Transverse Transport technique promoted local collagen deposition. Tibial Cortex Transverse Transport technique also benefited to angiogenesis and immunomodulation. In Tibial Cortex Transverse Transport group, blood flow in the wound area was higher than that ofother groups according to laser speckle imaging with more blood vessels observed. Enhanced neovascularization was seen in the Tibial Cortex Transverse Transport group with double immune-labelling of CD31 and α-SMA. The M2 macrophages at the wound site in the Tibial Cortex Transverse Transport group was also increased. Tibial cortex transverse transport technique accelerated wound healing through enhanced angiogenesis and immunomodulation

This study aims to compare the outcomes of Volar locking plating (VLP) versus percutaneous Kirschner wires (K-wire) fixation for surgical management of distal radius fractures. We systematically searched multiple databases, including MEDLINE for randomized controlled trials (RCTs) comparing outcomes of VLP fixation and K-wire for treatment of distal radius fracture in adults. The methodological quality of each study was assessed by the Cochrane Risk of Bias tool. Patient-reported outcomes, functional outcomes, and complications at 1 year follow up were evaluated. Meta-analysis was performed using random-effects models and results presented as risk ratios (RRs) or mean differences (MDs) with 95% confidence interval (CI). 13 RCTs with 1336 participants met the inclusion criteria. Disabilities of the Arm, Shoulder and Hand (DASH) scores were significantly better for VLP fixation (MD= 2.15; 95% CI, 0.56-3.74; P = 0.01; I2=23%). No significant difference between the two procedures for grip strength measured in kilograms (MD= −3.84; 95% CI,-8.42-0.74; P = 0.10; I2=52%) and Patient-Rated Wrist Evaluation (PRWE) scores (MD= −0.06; 95% CI,-0.87-0.75; P = 0.89; I2=0%). K-wire treatment yielded significantly improved extension (MD= −4.30; P=0.04) but with no differences in flexion, pronation, supination, and radial deviation (P >0.05). The risk of complications and rate of reoperation were similar for the two procedures (P >0.05). This meta-analysis suggests that VLP fixation improves DASH score at 12 months follow up, however, the difference is small and unlikely to be clinically important. Existing literature does not provide sufficient evidence to demonstrate the superiority of either VLP or K-wire treatment in terms of patient-reported outcomes, functional outcomes, and complications

Gait measurements can vary due to various intrinsic and extrinsic factors, and this variability becomes more pronounced using inertial sensors in a free-living environment. Therefore, identifying and quantifying the sources of variability is essential to ensure measurement reliability and maintain data quality. This study aimed to determine the variability of daily accelerations recorded by an inertial sensor in a group of healthy individuals. Ten participants, four males and six females, with a mean age of 50 years (range: 29–61) and BMI of 26.9 kg/m. 2. (range: 21.4–36.8), were included. A single accelerometer continuously recorded lower limb accelerations over two weeks. We extracted and analyzed the accelerations of three consecutive strides within walking bouts if the time difference between the bouts was more than two hours. Multivariate mixed-effects modeling was performed on both the discretized acceleration waveforms at 101 points (0–100) and the harmonics of the signals in the frequency domain to determine the variance components for different subjects, days, bouts, and steps as the random effect variables. Intraclass correlation coefficients (ICCs) were calculated for between-day, between-bout, and between-step comparisons. The results showed that the ICCs for the between-day, between-bout, and between-step comparisons were 0.73, 0.82, 0.99 for the vertical axis; 0.64, 0.75, 0.99 for the anteroposterior axis; and 0.55, 0.96, 0.97 for the mediolateral axis. For the signal harmonics, the respective ICCs were 0.98, 0.98, 0.99 for the vertical axis; 0.54, 0.93, 0.98 for the anteroposterior axis; and 0.69, 0.78, 0.95 for the mediolateral axis. Overall, this study demonstrated that accelerations recorded continuously for multiple days in a free-living environment exhibit high variability, mainly between days, and some variability arising from differences between walking bouts during different times within days. However, reliable and repeatable gait measurements can be obtained by identifying and quantifying the sources of variability

Introduction. Approximately 20-25% of patients having joint replacement in the UK have moderate-severe frailty. Frailty is associated with poorer outcomes after joint replacement. Targeting frailty pre-operatively with exercise and protein supplementation could improve post-operative outcomes. Prior to conducting a randomised controlled trial (RCT), a feasibility study was necessary to inform trial design and delivery. Method. We conducted a randomised feasibility study with embedded qualitative work. Patients aged ≥65 years, frail and undergoing THR or TKR were recruited from three UK hospitals. Participants were randomly allocated on a 1:1 ratio to the intervention or usual care group. The intervention group had a 1:1 appointment with a physiotherapist and were provided with a home-based, tailored daily exercise programme and a daily protein supplement for 12 weeks before their operation, supported by six telephone calls from a physiotherapist. Questionnaires were administered at baseline and 12 weeks after randomisation. Interviews were conducted with 19 patients. Feasibility outcomes were eligibility and recruitment rates, intervention adherence, and acceptability of the trial and the intervention. Result. 411 patients were sent a screening pack. Of the 168 patients who returned a screening questionnaire, 79 were eligible and consented to participate, and 64 were randomised. Of the 33 participants randomised to the intervention, 26 attended the intervention appointment. Eighteen participants (69%) received all six intervention follow-up telephone calls. Nineteen participants completed an intervention adherence log; 13 (68%) adhered to the exercise programme and 11 (58%) adhered to the protein supplementation. The overall retention rate was 86% at 12 weeks. The 12-week follow-up questionnaire was returned by 84% of participants who were sent a questionnaire. Interviews found that the trial and intervention were generally acceptable, but areas of potential improvements were identified. Conclusion. This study demonstrated that a larger study is possible and has identified improvements to optimise the design of a RCT