Aims. In the Netherlands, general practitioners (GPs) can request radiographs. After a radiologically diagnosed fracture, patients are immediately referred to the emergency department (ED). Since 2020, the Máxima Medical Centre has implemented a new care pathway for minor trauma patients, referring them immediately to the traumatology outpatient clinic (OC) instead of the ED. We investigated whether this altered care pathway leads to a reduction in healthcare consumption and concomitant costs. Methods. In this retrospective cohort study, patients were included if a radiologist diagnosed a fracture on a radiograph requested by the GP from August to October 2019 (control group) or August to October 2020 (research group), on weekdays between 8.30 am and 4.00 pm. The study compared various outcomes between groups, including the length of the initial hospital visit, frequency of hospital visits and medical procedures, extent of imaging, and healthcare expenses. Results. A total of 634 patients were included. The results show a median reduction of 25 minutes in duration of initial hospital visits, one fewer hospital visit, overall fewer medical procedures, and a decrease in healthcare costs of €303.40 per patient in the research group compared to the control group. No difference was found in the amount of imaging. Conclusion. The implementation of the new care pathway has resulted in a substantial reduction in healthcare use and costs. Moreover, the pathway provides advantages for patients and helps prevent crowding at the ED. Hence, we recommend immediately referring all minor trauma patients to the traumatology OC instead of the ED. Cite this article: Bone Jt Open 2023;4(10):728–734

Aims. Day-case arthroplasty is gaining popularity in Europe. We report outcomes from the first 12 months following implementation of a day-case pathway for unicompartmental knee arthroplasty (UKA) and total hip arthroplasty (THA) in an NHS hospital. Methods. A total of 47 total hip arthroplasty (THA) and 24 unicompartmental knee arthroplasty (UKA) patients were selected for the day-case arthroplasty pathway, based on preoperative fitness and agreement to participate. Data were likewise collected for a matched control group (n = 58) who followed the standard pathway three months prior to the implementation of the day-case pathway. We report same-day discharge (SDD) success, reasons for delayed discharge, and patient-reported outcomes. Overall length of stay (LOS) for all lower limb arthroplasty was recorded to determine the wider impact of implementing a day-case pathway. Results. Patients on the day-case pathway achieved SDD in 47% (22/47) of THAs and 67% (16/24) of UKAs. The most common reasons for failed SDD were nausea, hypotension, and pain, which were strongly associated with the use of fentanyl in the spinal anaesthetic. Complications and patient-reported outcomes were not significantly different between groups. Following the introduction of the day-case pathway, the mean LOS reduced significantly by 0.7, 0.6, and 0.5 days respectively in THA, UKA, and total knee arthroplasty cases (p < 0.001). Conclusion. Day-case pathways are feasible in an NHS set-up with only small changes required. We do not recommend fentanyl in the spinal anaesthetic for day-case patients. An important benefit seen in our unit is the so-called ‘day-case effect’, with a significant reduction in mean LOS seen across all lower limb arthroplasty. Cite this article: Bone Jt Open 2021;2(11):900–908

The development and implementation of Enhanced Recovery After Surgery (ERAS) protocols are of particular interest in elective orthopaedics due to clinical benefits and cost effectiveness. The Wycombe Arthroplasty Rapid-Recovery Pathway (WARP) was designed to streamline hip and knee joint arthroplasty to reduce time spent in hospital whilst optimising outcomes in an NHS District General Hospital. 966 patients were admitted to Wycombe General Hospital for primary elective joint replacement (60 UKR, 446 THR, 460 TKR) during the period 1st September 2020 to 31st September 2022. The WARP pathway was used for 357 (37%) patients (32 UKR, 155 THR, 170 TKR) and the standard “non-WARP” pathway was used for 609 (63%) patients (28 UKR 291 THR, 290 TKR). Data was collected on length of stay, time of mobilisation, number of physiotherapy sessions, and inpatient morbidity. Average length of stay following UKR was 0.75 days for WARP vs 2.96 for non-WARP patients, following THR was 2.17 days for WARP vs 4.17 for non-WARP patients, following TKR was 3.4 days for WARP vs 3.92 for non-WARP patients. Day-0 mobilisation after UKR was achieved in 97% of WARP vs 12% of non-WARP patients, after THR in 43% of WARP vs 14% of non-WARP patients, after TKR in 33% of WARP vs 11% of non-WARP patients. Same-day discharge was achieved in the WARP cohort in 63% of UKR, 10% of THR, 2% of TKR patients. There were no same-day discharges in the non-WARP cohort. Complications delaying mobilisation (pain, nausea/vomiting, dizziness/low BP) were identified in 8.4% of WARP vs 25% of non-WARP patients. Our cohort study shows that the initiation of WARP Rapid Recovery pathway for joint arthroplasty decreased the average length of stay after UKR by 2.21 days, after THR by 2 days, after TKR by 0.52 days. Time to first mobilisation was decreased significantly by increased rates of same-day mobilisation and reduced rates of postoperative anaesthetic-related complications

Background. Cauda Equina Syndrome (CES) needs to be diagnosed and managed promptly to ensure the best outcome for patients. Our current spinal service has been centralised, with referrals currently delivered via an online system. This means that patients aren't seen by spinal specialists until confirmed radiological diagnosis. To ensure patient safety, we must make sure that our CES pathway is as robust as possible. Methods & Results. A Google Forms questionnaire was emailed to various health professionals involved in the CES patient journey throughout the Lancashire & South Cumbria region. Participants were asked to identify problems with our current pathway and to provide possible solutions for improvement. 64 responses were received from 5 different departments throughout 6 NHS employers: 21 (33%) consultants, 6 (9%) middle grade doctors, 31 physiotherapists (48%), 3 (5%) GPs and 3 (5%) others. Many common themes were identified: the need to improve CES education to both referrers and patients (22% responses), addressing the issue of scan availability (39% responses), the need for a clearer pathway for GPs (26% responses) among others. Participants were asked to rate their confidence in the management of both suspected (mean=7.6 +/−2.3) and diagnosed CES (mean=8.0 +/− 2.0). Discussion. These results have made it evident that there is a need for improvement to our current CES pathway at all levels. Our current system is overloaded with poor referrals that backlog the MRI scanner, leading to delays. Providing training for referrers in the first instance may improve things, however a more thorough overhaul of the pathway is required. Conflicts of interest: No conflicts of interest. Sources of funding: No funding obtained

Aims. Rheumatoid arthritis (RA) is a common chronic immune disease. Berberine, as its main active ingredient, was also contained in a variety of medicinal plants such as Berberaceae, Buttercup, and Rutaceae, which are widely used in digestive system diseases in traditional Chinese medicine with anti-inflammatory and antibacterial effects. The aims of this article were to explore the therapeutic effect and mechanism of berberine on rheumatoid arthritis. Methods. Cell Counting Kit-8 was used to evaluate the effect of berberine on the proliferation of RA fibroblast-like synoviocyte (RA-FLS) cells. The effect of berberine on matrix metalloproteinase (MMP)-1, MMP-3, receptor activator of nuclear factor kappa-Β ligand (RANKL), tumour necrosis factor alpha (TNF-α), and other factors was determined by enzyme-linked immunoassay (ELISA) kit. Transcriptome technology was used to screen related pathways and the potential targets after berberine treatment, which were verified by reverse transcription-polymerase chain reaction (RT-qPCR) and Western blot (WB) technology. Results. Berberine inhibited proliferation and adhesion of RA-FLS cells, and significantly reduced the expression of MMP-1, MMP-3, RANKL, and TNF-α. Transcriptional results suggested that berberine intervention mainly regulated forkhead box O (FOXO) signal pathway, prolactin signal pathway, neurotrophic factor signal pathway, and hypoxia-inducible factor 1 (HIF-1) signal pathway. Conclusion. The effect of berberine on RA was related to the regulation of RAS/mitogen-activated protein kinase/FOXO/HIF-1 signal pathway in RA-FLS cells. Cite this article: Bone Joint Res 2023;12(2):91–102

As Total Hip Replacement (THR) rates increase healthcare providers have sought to reduce costs, while at the same time improving patient safety and satisfaction. Up to 50% of patients may be appropriate for Day Case THR, and in appropriately selected patients’ studies show no increase in complication rate while affording a significant cost saving and maintaining a high rate of patient satisfaction. Despite the potential benefits, levels of adoption of Day Case THR vary. A common cause for this is the perception that doing so would require the adoption of new surgical techniques, implants, or theatre equipment. We report on a Day-Case THR pathway in centres with an established and well-functioning Enhanced Recovery pathway, utilising the posterior approach and standard implants and positioning. We prospectively collected the data on consecutive THRs performed by a single surgeon between June 2018 and July 2021. A standardised anaesthetic regimen using short acting spinal was used. Surgical data included approach, implants, operative time, and estimated blood loss. Outcome data included time of discharge from hospital, post operative complications, readmissions, and unscheduled health service attendance. Data was gathered on 120 consecutive DCTHRs in 114 patients. 93% of patients were successfully discharged on the day of surgery. Four patients required re-admission: one infection treated with DAIR, one dislocation, one wound ooze admitted for a day of monitoring, one gastric ulcer. One patient had a short ED attendance for hypertension. Our incidence of infection, dislocation and wound problems were similar to those seen in inpatient THR. Out data show that the widely used posterior approach using standard positioning and implants can be used effectively in a Day Case THR pathway, with no increase in failure of same-day discharge or re-admission to hospital

Aims. Current National Institute for Health and Clinical Excellence (NICE) guidance advises that MRI direct from the emergency department (ED) should be considered for suspected scaphoid fractures. This study reports the current management of suspected scaphoid fractures in the UK and assesses adherence with NICE guidance. Methods. This national cross-sectional study was carried out at 87 NHS centres in the UK involving 122 EDs and 184 minor injuries units (MIUs). The primary outcome was availability of MRI imaging direct from the ED. We also report the specifics of patient management pathways for suspected scaphoid fractures in EDs, MIUs, and orthopaedic services. Overall, 62 of 87 centres (71%) had a guideline for the management of suspected scaphoid fractures. Results. A total of 11 of 87 centres (13%) had MRI directly available from the ED. Overall, 14 centres (17%) used cross-sectional imaging direct from the ED: MRI in 11 (13%), CT in three (3%), and a mixture of MRI/CT in one (1%). Four centres (6%) used cross-sectional imaging direct from the MIU: MRI in three (4%) and CT in two (2%). Of 87 centres’ orthopaedic specialist services, 74 (85%) obtained repeat radiographs, while the most common form of definitive imaging used was MRI in 55 (63%), CT in 16 (19%), mixture of MRI/CT in three (3%), and radiographs in 11 (13%). Conclusion. Only a small minority of centres currently offer MRI directly from the ED for patients with a suspected scaphoid fracture. Further research is needed to investigate the facilitators and barriers to the implementation of NICE guidance. Cite this article: Bone Jt Open 2021;2(11):997–1003

Lumbar diseases have become a major problem affecting human health worldwide. Conservative treatment of lumbar diseases is difficult to achieve ideal results, and surgical treatment of trauma, complications, it is imperative to develop a new treatment method. This study aims to explore the regulatory mechanism of cartilage endplate ossification caused by abnormal stress, and design intervention targets for this mechanism, so as to provide theoretical reference for the prevention and treatment of lumbar degeneration. In vivo, we constructed spinal instability model in mice. In vitro, we used a mechanical tensile machine to simulate the abnormal stress conditions of the endplate cartilage cells. Through the high-throughput sequencing, we found the enrichment of Hippo signaling pathway. As YAP is a key protein in the Hippo signaling pathway, we then created cartilaginous YAP elimination mice (Col2::YAPfl/fl). The lumbar spine model was constructed again in these mice for H&E, SOFG and immunofluorescence staining. In vitro lentivirus was used to knock out YAP, immunofluorescence staining, WB and qPCR were performed. Finally, we conducted therapeutic experiments by using YAP agonist and AAV5 carrying YAP plasmids. We collected 8w samples from C57/BL6 mice after modeling. We found ossification of the endplate in mice similar to human disc degeneration. High-throughput sequencing of stretched cells demonstrated high enrichment of the Hippo signaling pathway. By immunofluorescence staining, it was confirmed that Col-II decreased and Col-X gradually increased in the endplate cartilage of mice. This was also confirmed at 7 days after an in vitro stretch of 5% and 12%. Meanwhile, we found that cartilaginous YAP elimination mice developed very severe endplate degeneration. However, the endplate was well protected by intraperitoneal injection of YAP agonist or AAV5-YAP endplate injection, and the results in vitro were consistent with that. In the process of cartilaginous ossification, abnormal stress regulates Col10a1 to promote cartilage endplate ossification through Hippo signaling pathway mediated YAP, and we expect to find potential drug targets for treatment through this mechanism

Despite extensive research aimed at improving surgical outcomes of enthesis injuries, re-tears remain a common problem, as the repairs often lead to fibrovascular scar as opposed to a zonal enthesis. Zonal enthesis formation involves anchoring collagen fibers, synthesizing proteoglycan-rich fibrocartilage, and mineralizing this fibrocartilage [1]. During development, the hedgehog signaling pathway promotes the formation and maturation of fibrocartilage within the zonal tendon-to-bone enthesis [1-4]. However, whether this pathway has a similar role in adult zonal tendon-to-bone repair is not known. Therefore, we developed a murine anterior cruciate ligament (ACL) reconstruction model [5] to better understand the zonal tendon-to-bone repair process and perturb key developmental regulators to determine the extent to which they can promote successful repair in the adult. In doing so, we activated the hedgehog signaling pathway both genetically using transgenic mice and pharmacologically via agonist injections. We demonstrated that both treatments improved the formation of zonal attachments and tunnel integration strength [6]. These improved outcomes were due in part to hedgehog signaling's positive role in proliferation of the bone marrow stromal cell (bMSC) progenitor pool and subsequent fibrocartilage production of bMSC progeny cells that form the attachments. These results suggest that, similar to growth and development, hedgehog signaling promotes the production and maturation of fibrocartilage during tendon-to-bone integration in adults. Lastly, we developed localized drug delivery systems to further improve the treatment of these debilitating injuries in future translational studies. Acknowledgements: This work was supported by NIH R01AR076381, R21AR078429, R00AR067283, F31AR079840, T32AR007132, and P30AR069619, in addition to the McCabe Fund Pilot Award at the University of Pennsylvania

The aim of this study is to clarify the implication of ciliary pathway on the onset of the spinal curvature that occurs in Adolescent Idiopathic Scoliosis (AIS) patients through functional studies of two genes: POC5 and TTLL11. Since the genetic implication for AIS is accepted, many association and candidate gene analysis revealed the implication of ciliary genes. The characterisation of these two proteins was assessed by qPCR, WB and immunofluorescence in vitro using control cells and cells derived from AIS patients. The impact of genetic modification of these genes on the functionality of the proteins in vitro and in vivo was analysed in zebrafish model created by CRISPR/Cas9 using microCT and histologic analysis. Our study revealed that mutant cells, for both gene, were less ciliated and the primary cilia was significantly shorter compared to control cells. We also observed a default in cilia glutamylation by immunofluorescence and Western Blot. Moreover, we observed in both zebrafish model, a 3D spine curvature similar to the spinal deformation in AIS. Interestingly, our preliminary results of immunohistology showed a retinal defect, especially at the cone cell layer level. This study strongly supports the implication of the ciliary pathway in the onset of AIS and this is the first time that a mechanism is described for AIS. Indeed, we show that shorter cilia could be less sensitive to environmental factors due to lower glutamylation and result in altered signalling pathway. Identifying the biological mechanism involved is crucial for elucidating AIS pathogenesis

Ankle fractures are among the most common types of fractures. If surgery is not performed within 12 to 24 hours, ankle swelling is likely to develop and delay the operative fixation. This leads to patients staying longer in the ward waiting and increased hospital occupancy. This prolonged stay has significant financial implication as well as it is frustrating for both patients and health care professionals. The aim was to formulate a pathway for the ankle fracture patients coming to the emergency department, outpatients and planned for operative intervention. To identify whether pre-operative hospital admissions of stable ankle fracture patients are reduced with the implementation of the pathway. We formulated an ankle fracture fixation pathway, which was approved for use in December 2020. A retrospective analysis of 6 months hospital admissions of ankle fracture patients in the period between January to June 2020. The duration from admission to the actual surgery was collected to review if some admissions could have been avoided and patients brought directly on the surgery day. A total of 23 patients were included. Mean age was 60.5 years and SD was 17years. 94% of patients were females. 10 patients were appropriately discharged.7 Patients were appropriately admitted. 6 Patients were unnecessarily admitted. These 6 patients were admitted on presentation to ED. Retrospective analysis of this audit showed that this cohort of patients met the safe discharge criteria and could have been discharged. Duration of unnecessary stay ranged from 1 to 11 days (21 days in total). Total saving could have been £6300. Standards were met in 74% of cases. Preoperative hospital admission could be reduced with the proposed pathway. It is a valuable tool to be used and should be implemented to reduce unnecessary hospital admissions

Aims. Osteoarthritis (OA) is a prevalent joint disorder with inflammatory response and cartilage deterioration as its main features. Dihydrocaffeic acid (DHCA), a bioactive component extracted from natural plant (gynura bicolor), has demonstrated anti-inflammatory properties in various diseases. We aimed to explore the chondroprotective effect of DHCA on OA and its potential mechanism. Methods. In vitro, interleukin-1 beta (IL-1β) was used to establish the mice OA chondrocytes. Cell counting kit-8 evaluated chondrocyte viability. Western blotting analyzed the expression levels of collagen II, aggrecan, SOX9, inducible nitric oxide synthase (iNOS), IL-6, matrix metalloproteinases (MMPs: MMP1, MMP3, and MMP13), and signalling molecules associated with nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Immunofluorescence analysis assessed the expression of aggrecan, collagen II, MMP13, and p-P65. In vivo, a destabilized medial meniscus (DMM) surgery was used to induce mice OA knee joints. After injection of DHCA or a vehicle into the injured joints, histological staining gauged the severity of cartilage damage. Results. DHCA prevented iNOS and IL-6 from being upregulated by IL-1β. Moreover, the IL-1β-induced upregulation of MMPs could be inhibited by DHCA. Additionally, the administration of DHCA counteracted IL-1β-induced downregulation of aggrecan, collagen II, and SOX9. DHCA protected articular cartilage by blocking the NF-κB and MAPK pathways. Furthermore, DHCA mitigated the destruction of articular cartilage in vivo. Conclusion. We present evidence that DHCA alleviates inflammation and cartilage degradation in OA chondrocytes via suppressing the NF-κB and MAPK pathways, indicating that DHCA may be a potential agent for OA treatment. Cite this article: Bone Joint Res 2023;12(4):259–273

Hip and knee arthroplasty (HKA) are two of the most successful orthopaedic procedures. However, one major complication necessitating revision surgery is osteolysis causing aseptic loosening of the prosthesis. JAK-STAT has been demonstrated to influence bone metabolism and can be regulated by microRNA (miRNA). Adult patients with osteolysis or aseptic loosening undergoing revision HKA were recruited. Age and gender matched patients undergoing primary hip or knee arthroplasty were our controls. Samples of bone, tissue and blood were collected and RNA isolation was performed. The best quality samples were used for RNA-sequencing. Data analysis was performed using RStudio and Galaxy to identify differentially expressed genes. Western blotting of IL6 was used to confirm protein expression. Five circulating miRNA were identified which had 10 differentially expressed genes in bone and 11 differentially expressed genes in tissue related to the JAK-STAT pathway. IL6 in bone and EpoR in bone were highly significant and IL6 in tissue, MPL in bone, SOCS3 in tissue, JAK3 in bone and SPRED1 in bone were borderline significant. Western blot results demonstrated up-expression of IL6 in bone tissue of revision patients. Periprosthetic osteolysis and aseptic loosening can be attributed to miRNA regulation of the JAK-STAT pathway in osteoblasts and osteoclasts, leading to increased bone resorption. These findings can be used for further experiments to determine utility in the clinical setting for identifying diagnostic markers or therapeutic targets

Aims. To explore the novel molecular mechanisms of histone deacetylase 4 (HDAC4) in chondrocytes via RNA sequencing (RNA-seq) analysis. Methods. Empty adenovirus (EP) and a HDAC4 overexpression adenovirus were transfected into cultured human chondrocytes. The cell survival rate was examined by real-time cell analysis (RTCA) and EdU and flow cytometry assays. Cell biofunction was detected by Western blotting. The expression profiles of messenger RNAs (mRNAs) in the EP and HDAC4 transfection groups were assessed using whole-transcriptome sequencing (RNA-seq). Volcano plot, Gene Ontology, and pathway analyses were performed to identify differentially expressed genes (DEGs). For verification of the results, the A289E/S246/467/632 A sites of HDAC4 were mutated to enhance the function of HDAC4 by increasing HDAC4 expression in the nucleus. RNA-seq was performed to identify the molecular mechanism of HDAC4 in chondrocytes. Finally, the top ten DEGs associated with ribosomes were verified by quantitative polymerase chain reaction (QPCR) in chondrocytes, and the top gene was verified both in vitro and in vivo. Results. HDAC4 markedly improved the survival rate and biofunction of chondrocytes. RNA-seq analysis of the EP and HDAC4 groups showed that HDAC4 induced 2,668 significant gene expression changes in chondrocytes (1,483 genes upregulated and 1,185 genes downregulated, p < 0.05), and ribosomes exhibited especially large increases. The results were confirmed by RNA-seq of the EP versus mutated HDAC4 groups and the validations in vitro and in vivo. Conclusion. The enhanced ribosome pathway plays a key role in the mechanism by which HDAC4 improves the survival rate and biofunction of chondrocytes. Cite this article: Bone Joint Res 2023;12(7):433–446

Traditionally, sports Injuries have been sub-optimally managed through Emergency Departments (ED) in the public health system due to a lack of adequate referral processes. Fractures are ruled out through plain radiographs followed by a reactive process involving patient initiated further follow up and investigation. Consequently, significant soft tissue and chondral injuries can go undiagnosed during periods in which early intervention can significantly affect natural progression. The purpose of this quality improvement project was to assess the efficacy of an innovative Sports Injury Pathway introduced to detect and treat significant soft tissue injuries. A Sports Injury Pathway was introduced at Fiona Stanley Hospital (WA, Australia) in April 2019 as a collaboration between the ED, Physiotherapy and Orthopaedic Departments. ED practitioners were advised to have a low threshold for referral, especially in the presence of a history of a twisting knee injury, shoulder dislocation or any suggestion of a hip tendon injury. All referrals were triaged by the Perth Sports Surgery Fellow with early follow-up in our Sports Trauma Clinics with additional investigations if required. A detailed database of all referrals was maintained, and relevant data was extracted for analysis over the first 3 years of this pathway. 570 patients were included in the final analysis. 54% of injuries occurred while playing sport, with AFL injuries constituting the most common contact-sports injury (13%). Advanced Scope Physiotherapists were the largest source of referrals (60%). A total of 460 MRI scans were eventually ordered comprising 81% of total referrals. Regarding Knee MRIs, 86% identified a significant structural injury with ACL injuries being the most common (33%) followed by isolated meniscal tears (16%) and multi-ligament knee injuries (11%). 95% of Shoulder MRI scans showed significant pathology. 39% of patients required surgical management, and of these 50% were performed within 3 months from injury. The Fiona Stanley Hospital Sports Injury Pathway has demonstrated its clear value in successfully diagnosing and treating an important cohort of patients who present to our Emergency Department. This low threshold/streamlined referral pathway has found that the vast majority of these patients suffer significant structural injuries that may have been otherwise missed, while providing referring practitioners and patients access to prompt imaging and high-quality Orthopaedic sports trauma services. We recommend the implementation of a similar Sports Injury Pathway at all secondary and tertiary Orthopaedic Centres

Aims. We present the development of a day-case total hip arthroplasty (THA) pathway in a UK National Health Service institution in conjunction with an extensive evidence-based summary of the interventions used to achieve successful day-case THA to which the protocol is founded upon. Methods. We performed a prospective audit of day-case THA in our institution as we reinitiate our full capacity elective services. In parallel, we performed a review of the literature reporting complication or readmission rates at ≥ 30-day postoperative following day-case THA. Electronic searches were performed using four databases from the date of inception to November 2020. Relevant studies were identified, data extracted, and qualitative synthesis performed. Results. Our evaluation and critique of the evidence-based literature identifies day-case THA to be safe, effective, and economical, benefiting both patients and healthcare systems alike. We further validate this with our institutional elective day surgery arthroplasty pathway (EDSAP) and report a small cohort of successful day-case THA cases as an example in the early stages of this practice in our unit. Conclusion. Careful patient selection and education, adequate perioperative considerations, including multimodal analgesia, surgical technique and blood loss management protocols and appropriate postoperative pathways comprising reliable discharge criteria are essential for successful day-case THA. Cite this article: Bone Jt Open 2021;2(2):93–102

Aims. To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism. Methods. In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed. Results. The CM and exosomes collected from senescent MLO-Y4 cells inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing detected significantly lower expression of miR-494-3p in senescent MLO-Y4 cell-derived exosomes compared with normal exosomes. The upregulation of exosomal miR-494-3p by miRNA mimics attenuated the effects of senescent MLO-Y4 cell-derived exosomes on osteogenic differentiation. Luciferase reporter assay demonstrated that miR-494-3p targeted phosphatase and tensin homolog (PTEN), which is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overexpression of PTEN or inhibition of the PI3K/AKT pathway blocked the functions of exosomal miR-494-3p. In SAMP6 mice, senescent MLO-Y4 cell-derived exosomes accelerated bone loss, which was rescued by upregulation of exosomal miR-494-3p. Conclusion. Reduced expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenic differentiation and accelerates age-related bone loss via PTEN/PI3K/AKT pathway. Cite this article: Bone Joint Res 2024;13(2):52–65

Introduction. Advanced practice physiotherapists (APPs) manage the national low back and radicular pain pathway across the UK. A novel spinal APP-led same-day emergency care (SDEC) pathway in Nottingham, manages patients referred from community services and the emergency department (ED). Patients may attend ED in the belief their pain is due to sinister or ‘red flag’ pathology. Little data exists on prevalence of spinal ‘red flag’ pathologies within a secondary care setting. This paper aims to review the number of ‘red flag’ pathology identified by APP's on a same-day emergency care pathway. Methods. Retrospective data from 1 year of routinely collected information was extracted and analysed by two APPs. Counts were reported as a percentage of total patients seen on the SDEC unit over a one-year period and compared to nationally reported figures. A total of 2042 patients were assessed on the unit in 2021, of which, 293 (14%) had serious pathology identified. Patients were classified into type of serious pathology: myelopathy (126, 6.1%), fractures (72, 3.5%), cauda equine compression (40, 1.9%), infection (37, 1.8%), cancers (28, 1.3%), neurological conditions (14, 0.6%) and other (16, 0.8%) serious pathology. Conclusion. APP's working within an emergency pathway are highly likely to see and diagnose serious spinal pathology. The most common include cord or cauda equina compression, fractures, infection and cancers. Figures reported are slightly higher than previously documented. Knowledge and training to identify ‘red flags’ and robust pathways of escalation are essential in support of APP roles and services. Conflict of interest: No conflicts of interest. Sources of funding: No sources of funding

Abstract. Introduction. The NHS long term plan endorses ‘personalised’, ‘digitally enabled’, ‘out of hospital’ care. Multiagency guidance (CPOC(2021)/NICE(2021)/GIRFT(2021)/NHSX(2021)) advocates an integrated ‘pathway’ approach to information sharing, shared-decision making and patient support. Digital solutions are the vehicle to deliver these agendas. Methods. In 2018 we developed a digital joint pathway (DJP) spanning the surgical care pathway (prehabilitation to rehabilitation) using the GoWellHealth platform. Patients listed for joint replacement are offered the DJP as routine care. Activity and engagement are monitored using the DJP data library. We sought to evidence our DJP by assessing patient engagement, experience and outcomes (OKS/EQ5D/Readmission). Results. Engagement. Consecutive cohort of the first 1195 patients registered. Activation rates were >85% and >70% viewed content within the DJP (median=15 access/pt; mean=83 minutes on DJP/pt). Engagement was similar irrespective of age and gender (p=NS). Older patients preferred to access via a computer. Experience. Qualitative interviews (n=14) demonstrated patients felt the DJP impacted positively on their health behaviours and contributed to their recovery. They spoke positively about the use of technology and the accessibility of the DJP. Outcomes. Comparison of patients on the DJP versus those not on the DJP using adjusted regression models demonstrated improved EQ5D=0.070 (95%CI=0.004-0.135,p=0.04), OKS=5.0 (95%CI=2.2-7.8,p<0.001) and readmission rates (3.6% versus 5.6%,p<0.01) for DJP patients. Conclusions. A DJP model for information delivery and patient support, across the entirety of the surgical pathway, is feasible and demonstrates high levels of patient engagement, experience and improved patient outcomes

Abstract. Introduction. Approximately 15–20% of patients report chronic pain three months after total knee replacement (TKR). The STAR care pathway is a clinically important and cost-effective personalised intervention for patients with pain 3 months after TKR. The pathway comprises screening, assesment, onward referral for treatment and follow-up over one year. In a multicentre randomised controlled trial comparing the pathway with usual care, the pathway improved pain at 6 and 12 months. This study examined the longer-term clinical and cost-effectiveness of the STAR care pathway. Methodology. STAR trial participants were followed-up at a median of 4 years post-randomisation. Co-primary outcomes were self-reported pain severity and interference in the replaced knee, assessed with the Brief Pain Inventory (BPI). Resource use from electronic hospital records was valued with UK reference costs. Results. Of the 337 participants active at trial completion, 326 had confirmed vital status, and 226 (69%) provided outcome data at a median of 4 years. The between-group difference in mean BPI severity score was −0.42 (95% CI −1.07, 0.23; p=0.20) and for BPI interference was −0.64 (95% CI −1.41, 0.12; p=0.10), favouring the intervention. Multiple imputation analyses led to attenuations of about 0.2 points. Mean hospital admission costs over four years were £2461.49 (95% CI £1354.42, £3568.57) in the intervention arm and £3791.68 (95% CI £2095.12, to £5488.24) in usual care. Conclusion. These data are consistent with sustained benefits from the STAR care pathway at 4 years, albeit attenuated and with wider confidence intervals, in part attributable to attrition after 1 year