Clinical and cost-effectiveness of Knee Arthroplasty versus Joint Distraction for Osteoarthritis (KARDS): protocol for a multicentre, phase III, randomised control trial.

INTRODUCTION: Knee replacement (KR) is a clinically proven procedure typically offered to patients with severe knee osteoarthritis (OA) to relieve pain and improve quality of life. However, artificial joints fail over time, requiring revision associated with higher mortality and inferior outcomes. With more young people presenting with knee OA and increasing life expectancy, there is an unmet need to postpone time to first KR. Knee joint distraction (KJD), the practice of using external fixators to open up knee joint space, is proposed as potentially effective to preserve the joint following initial studies in the Netherlands, however, has not been researched within an NHS setting. The KARDS trial will investigate whether KJD is non-inferior to KR in terms of patient-reported postoperative pain 12 months post-surgery. METHODS AND ANALYSIS: KARDS is a phase III, multicentre, pragmatic, open-label, individually randomised controlled non-inferiority trial comparing KJD with KR in patients with severe knee OA, employing a hybrid-expertise design, with internal pilot phase and process evaluation. 344 participants will be randomised (1:1) to KJD or KR. The primary outcome measure is the Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain domain score at 12 months post-operation. Secondary outcome measures include patient-reported overall KOOS, Pain Visual Analogue Scale and Oxford Knee Scores, knee function assessments, joint space width, complications and further interventions over 24 months post-operation. Per patient cost difference between KR and KJD and cost per quality-adjusted life year (QALY) gained over 24 months will be estimated within trial, and incremental cost per QALY gained over 20 years by KJD relative to KR predicted using decision analytic modelling. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Research Ethics Committee (REC) and Health Research Authority (HRA). Trial results will be disseminated at clinical conferences, through relevant patient groups and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14879004; recruitment opened April 2021.

A longitudinal-torsional mode ultrasonic needle for deep penetration into bone.

This work presents a longitudinal-torsional (L-T) composite mode ultrasonic needle device for deep bone penetration. The L-T needle is a geometrically modified version of an L-mode needle whose efficacy as a prototype ultrasonic bone biopsy device has been previously demonstrated by the authors. Finite element analysis (FEA) aided in the design of the L-T needle, with the aim of maximising the achievable torsional displacement while matching the longitudinal displacement achieved by the L-mode needle. Experimental modal analysis (EMA) of the fabricated ultrasonic device was used to identify the modal parameters and validate the FEA model. Harmonic analysis then provided an insight into how the inherent nonlinearities of the high-power transducer are affected by incorporating the geometrical features that degenerate the L mode into an L-T mode. High power characterisation shows that the longitudinal displacement amplitude of the L-T mode needle is larger than that of the L-mode needle. Comparative penetration tests in fresh Wistar rat skull were evaluated by investigating cell death and cell survival. The region of statistically significant cell death was small for both devices, with the combined axial and shear motion of the L-T device causing increased osteocyte necrosis within this region. Nevertheless, the results suggest a promising environment for post-operative healing. It is shown how this technology offers a potential technique for a surgical approach to the petrous apex, an application that requires a deep penetration into bone.

Radiographic union score for tibia (RUST) scoring system in adult diaphyseal femoral fractures treated with intramedullary nailing: an assessment of interobserver and intraobserver reliability.

OBJECTIVES: The Radiographic Union Score for Tibia (RUST) scoring system has been validated in multiple studies assessing the healing of tibial fractures. Our objective was to assess the interobserver and intraobserver reliability for the RUST in diaphyseal femoral fractures treated with intramedullary (IM) nailing. PATIENTS AND METHODS: A total of 60 sets of anteroposterior (AP) and lateral radiographs of diaphyseal femoral fractures treated by reamed IM nailing were randomly selected from a prospectively collected database. The 60 sets of radiographs were then scored by three reviewers using the RUST system. Interobserver reliability was measured at initial scoring. The 60 sets of radiographs were scored again by the three reviewers to calculate the intraobserver reliability. RESULTS: The RUST scores ranged from 4 to 12 with a mean score of 11.3 ± 1.3. The interobserver intraclass correlation coefficient (ICC) was 0.87 (95% CI, 0.81-0.92) and the intraobserver ICC was 0.91 (95% CI, 0.88-0.94), which indicated excellent agreement. CONCLUSION: This study demonstrated that the RUST system can be used reliably in the assessment of healing in diaphyseal femur fractures treated by reamed intramedullary nailing, with excellent interobserver and intraobserver reliability.

Erratum to: Development of a clinical risk score for pain and function following total knee arthroplasty: results from the TRIO study.

[This corrects the article DOI: 10.1093/rap/rky021.][This corrects the article DOI: 10.1093/rap/rky021.].

Patient-reported assessment of outcome after surgery for bone metastases.

Regardless of prognosis, surgery is often considered in metastatic bone disease (MBD) as a palliative procedure to improve function and quality of life. Traditional focus on objective outcomes such as mortality is inappropriate in this group, and there is a drive to assess outcomes via patient-reported outcome measures (PROMs). This is an overview of current understanding of MBD outcomes and how this should influence future decision-making and research. The objectives of this review were to identify difficulties in measuring PROMs in the MBD patient population and explore alternatives to patientreported outcomes. We also provide an overview of current understanding of outcomes in MBD and how this should influence decision-making and direct research.

Terminal Schwann cells at the human neuromuscular junction.

Terminal Schwann cells are non-myelinating glial cells localized to the neuromuscular junction. They play an important role in regulating many aspects of neuromuscular junction form and function, in health and during disease. However, almost all previous studies of mammalian terminal Schwann cells have used rodent models. Despite a growing awareness of differences in the cellular and molecular anatomy of rodent and human neuromuscular junctions, it remains unclear as to whether these differences also extend to the terminal Schwann cells. Here, we have adapted immunohistochemical protocols to facilitate visualization and comparative morphometric analyses of terminal Schwann cells at the human and mouse neuromuscular junction. We labelled terminal Schwann cells in the peroneus brevis muscle in six adult mice and five humans with antibodies against S100 protein. All human neuromuscular junctions were associated with at least one terminal Schwann cell, consistent with findings from other species, with an average of ∼1.7 terminal Schwann cells per neuromuscular junction in both humans and mice. In contrast, human terminal Schwann cells were significantly smaller than those of mice (P ≤ 0.01), in keeping with differences in overall synaptic size. Human terminal Schwann cell cytoplasm extended significantly beyond the synaptic boundaries of the neuromuscular junction, whereas terminal Schwann cells in mice were largely restricted to the synapse. Moreover, there was a significant difference in the location of terminal Schwann cell nuclei (P ≤ 0.01), with human terminal Schwann cells having their nuclear compartment located beyond the perimeter of the synapse more than the mouse. Taken together, these findings demonstrate that terminal Schwann cells at the human neuromuscular junction have notable differences in their morphology and synaptic relationships compared to mice. These fundamental differences need to be considered when translating the findings of both neuromuscular junction biology and pathology from rodents to humans.

Chondrocytes from osteoarthritic cartilage of obese patients show altered adiponectin receptors expression and response to adiponectin.

Obesity and osteoarthritis (OA) are well-known comorbidities and their precise molecular interactions are still unidentified. Adiponectin, a major adipokine, known to have an anti-inflammatory effect in atherosclerosis or Type 2 Diabetes Mellitus (T2DM), has also been postulated to be pro-inflammatory in OA. This dual role of adiponectin is still not explained. The precise mechanism by which adiponectin affects cartilage and chondrocytes remains to be elucidated. In the present observational study chondrocytes from 30 patients with OA (18 females and 12 males) undergoing total knee replacement (TKR) were isolated. Expression of adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) was examined both at gene and protein levels in chondrocytes. The difference in adiponectin receptor expression between lean and obese patients with OA and the role of adiponectin in regulating pro-inflammatory genes (MCP-1, IL-6, and VCAM-1, MMP-1, MMP-2, and TIMP-1) has been investigated. We found that ADIPOR1 represented the most abundant adiponectin receptor in primary OA chondrocytes. ADIPOR1 and ADIPOR2 genes and ADIPOR1 protein were differently expressed in OA chondrocytes obtained from obese compared with lean patients with OA. Adiponectin induced gene expression of MCP-1, IL-6, and MMP-1 in all OA patients' chondrocytes. In contrast, VCAM-1 and MMP-2 were differently regulated by adiponectin depending on the patient's body mass index. This study suggests that adiponectin and ADIPOR1 may have important roles in the pathogenesis of cartilage degeneration in OA of obese subjects.

FOXP1 circular RNA sustains mesenchymal stem cell identity via microRNA inhibition.

Stem cell identity and plasticity are controlled by master regulatory genes and complex circuits also involving non-coding RNAs. Circular RNAs (circRNAs) are a class of RNAs generated from protein-coding genes by backsplicing, resulting in stable RNA structures devoid of free 5' and 3' ends. Little is known of the mechanisms of action of circRNAs, let alone in stem cell biology. In this study, for the first time, we determined that a circRNA controls mesenchymal stem cell (MSC) identity and differentiation. High-throughput MSC expression profiling from different tissues revealed a large number of expressed circRNAs. Among those, circFOXP1 was enriched in MSCs compared to differentiated mesodermal derivatives. Silencing of circFOXP1 dramatically impaired MSC differentiation in culture and in vivo. Furthermore, we demonstrated a direct interaction between circFOXP1 and miR-17-3p/miR-127-5p, which results in the modulation of non-canonical Wnt and EGFR pathways. Finally, we addressed the interplay between canonical and non-canonical Wnt pathways. Reprogramming to pluripotency of MSCs reduced circFOXP1 and non-canonical Wnt, whereas canonical Wnt was boosted. The opposing effect was observed during generation of MSCs from human pluripotent stem cells. Our results provide unprecedented evidence for a regulatory role for circFOXP1 as a gatekeeper of pivotal stem cell molecular networks.

Development of a clinical risk score for pain and function following total knee arthroplasty: results from the TRIO study.

OBJECTIVES: The aim was to develop and validate a simple clinical prediction model, based on easily collected preoperative information, to identify patients at high risk of pain and functional disability 6 months after total knee arthroplasty (TKA). METHODS: This was a multicentre cohort study of patients from nine centres across the UK, who were undergoing a primary TKA for OA. Information on sociodemographic, psychosocial, clinical and quality-of-life measures were collected at recruitment. The primary outcome measure for this analysis was the Oxford knee score (OKS), measured 6 months postoperatively by postal questionnaire. Multivariable logistic regression was used to develop the model. Model performance (discrimination and calibration) and internal validity were assessed, and a simple clinical risk score was developed. RESULTS: Seven hundred and twenty-one participants (mean age 68.3 years; 53% female) provided data for the present analysis, and 14% had a poor outcome at 6 months. Key predictors were poor clinical status, widespread body pain, high expectation of postoperative pain and lack of active coping. The developed model based on these variables demonstrated good discrimination. At the optimal cut-off, the final model had a sensitivity of 83%, specificity of 61% and positive likelihood ratio of 2.11. Excellent agreement was found between observed and predicted outcomes, and there was no evidence of overfitting in the model. CONCLUSION: We have developed and validated a clinical prediction model that can be used to identify patients at high risk of a poor outcome after TKA. This clinical risk score may be an aid to shared decision-making between patient and clinician.

Cellular and Molecular Anatomy of the Human Neuromuscular Junction.

The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an experimentally accessible model synapse routinely studied in animal models to explore fundamental aspects of synaptic form and function. Here, we combined morphological techniques, super-resolution imaging, and proteomic profiling to reveal the detailed cellular and molecular architecture of the human NMJ. Human NMJs were significantly smaller, less complex, and more fragmented than mouse NMJs. In contrast to mice, human NMJs were also remarkably stable across the entire adult lifespan, showing no signs of age-related degeneration or remodeling. Super-resolution imaging and proteomic profiling revealed distinctive distribution of active zone proteins and differential expression of core synaptic proteins and molecular pathways at the human NMJ. Taken together, these findings reveal human-specific cellular and molecular features of the NMJ that distinguish them from comparable synapses in other mammalian species.

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial.

OBJECTIVE: To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. RESEARCH DESIGN AND METHODS: In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged ≥70 years were randomized to receive once-daily lixisenatide 20 µg or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA1c from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. RESULTS: A total of 350 patients were randomized. HbA1c decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. CONCLUSIONS: In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA1c reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings.

Ultrasonic Needles for Bone Biopsy.

Bone biopsy is an invasive clinical procedure, where a bone sample is recovered for analysis during the diagnosis of a medical condition. When the architecture of the bone tissue is required to be preserved, a core-needle biopsy is taken. Although this procedure is performed while the patient is under local anaesthesia, the patient can still experience significant discomfort. Additionally, large haematoma can be induced in the soft tissue surrounding the biopsy site due to the large axial and rotational forces, which are applied through the needle to penetrate bone. It is well documented that power ultrasonic surgical devices offer the advantages of low cutting force, high accuracy, and preservation of soft tissues. This paper reports a study of the design, analysis, and test of two novel power ultrasonic needles for bone biopsy that operate using different configurations to penetrate bone. The first utilizes micrometric vibrations generated at the distil tip of a full-wavelength resonant ultrasonic device, while the second utilizes an ultrasonic-sonic approach, where vibrational energy generated by a resonant ultrasonic horn is transferred to a needle via the chaotic motion of a free-mass. It is shown that the dynamic behavior of the devices identified through experimental techniques closely match the behavior calculated through numerical and finite-element analysis methods, demonstrating that they are effective design tools for these devices. Both devices were able to recover trabecular bone from the metaphysis of an ovine femur, and the biopsy samples were found to be comparable to a sample extracted using a conventional biopsy needle. Furthermore, the resonant needle device was also able to extract a cortical bone sample from the central diaphysis, which is the strongest part of the bone, and the biopsy was found to be superior to the sample recovered by a conventional bone biopsy needle.

Fracture management in HIV positive individuals: a systematic review.

PURPOSE: Human immunodeficiency virus (HIV) infection could potentially play an important role in the management of fractures as they have been shown to affect fracture healing and the post-operative risk of implant sepsis. METHODS: A systematic review of the relevant literature was performed on PubMed and Scopus databases. Twenty-six studies were identified, critiqued and analysed accordingly. No randomised controlled trials were identified. RESULTS: HIV positivity was not shown to influence an individual's risk of early wound infection in operatively managed closed fractures. The rate of pin track infection in open injuries managed with external fixators was low. However, in open injuries managed with internal fixation, early wound infection rates were increased in the HIV-positive population compared to HIV-negative individuals. Regarding late implant infection, in closed fractures there appeared to be no increased risk of infection but there is limited evidence for open injuries. Additionally, further evidence is needed to establish if the rate of union in both open and closed fractures are influenced by HIV status. CONCLUSION: Overall, no evidence was found to suggest that surgical management of fractures in the HIV population should be avoided, and fixation of closed fractures in the HIV population appeared to be safe. The effect of anti-retroviral therapy is unclear and this should be further researched. However, based on the limited evidence, caution should be taken in the management of open fractures due to the potentially increased infection risk. The impact of anti-retroviral therapy on the outcomes of surgery needs further evaluation.

An ultrasonic orthopaedic surgical device based on a cymbal transducer.

An ultrasonic orthopaedic surgical device is presented, where the ultrasonic actuation relies on a modification of the classical cymbal transducer. All current devices consist of a Langevin ultrasonic transducer with a tuned cutting blade attached, where resonance is required to provide sufficient vibrational amplitude to cut bone. However, this requirement restricts the geometry and offers little opportunity to propose miniaturised devices or complex blades. The class V flextensional cymbal transducer is proposed here as the basis for a new design, where the cymbal delivers the required vibrational amplitude, and the design of the attached cutting insert can be tailored for the required cut. Consequently, the device can be optimised to deliver an accurate and precise cutting capability. A prototype device is presented, based on the cymbal configuration and designed to operate at 25.5kHz with a displacement amplitude of 30µm at 300V. Measurements of vibrational and impedance responses elucidate the mechanical and electrical characteristics of the device. Subsequent cutting tests on rat femur demonstrate device performance consistent with a commercial Langevin-based ultrasonic device and show that cutting is achieved using less electrical power and a lower piezoceramic volume. Histological analysis exhibits a higher proportion of live cells in the region around the cut site for the cymbal device than for a powered sagittal or a manual saw, demonstrating the potential for the ultrasonic device to result in faster healing.