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Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_9 | Pages 30 - 30
1 Oct 2022
Theodoraki M Khatri M Carroll J Billington J
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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


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_8 | Pages 7 - 7
1 Aug 2022
Mathieu H Amani H Patten SA Parent S Aragon J Barchi S Joncas J Child A Moldovan F
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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


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_9 | Pages 11 - 11
1 Oct 2022
Dunstan E Wood L
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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


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_2 | Pages 7 - 7
1 Feb 2018
Jess M Ryan C Hamilton S Wellburn S Greenough C Ferguson D Coxon A Fatoye F Dickson J Jones A Atkinson G Martin D
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Aims. To investigate whether the duration of pain has an influence on the clinical outcomes of patients with low back pain (LBP) managed through the North East of England Regional Back Pain and Radicular Pain Pathway (NERBPP). Patients and Methods. The NERBPP is a clinical pathway based upon NICE guidelines (2009) for LBP. Patients with LBP referred onto the NERBPP by their General Practitioner (GP) between May 2015 and January 2017 were included in this evaluation. Data from 635 patients, who provided pre and post data for pain (Numerical rating scale [NRS]), function (Oswestry Disability Index [ODI]) and quality-of-life (EuroQol [EQ5D]), were analysed using a series of covariate adjusted models in SPSS. Patients were categorised into four groups based upon pain duration: <3months, ≥3 to <6months, ≥6months to <12months, ≥12months. Results. Each group showed improved outcomes greater than MCID for each measure as defined in NICE guidelines (2016). Preliminary analysis raises the possibility of a trend towards better outcomes for those with shorter pain durations. Conclusion. Patients with all durations of back pain showed benefit on the NERBPP. Clinical relevance. Recent changes to NICE guidelines (2016), advocate the same management of all LBP patients regardless of pain duration. These findings explore the appropriateness of those changes. Conflicts of interest: None. The study was supported by funding from the Health Foundation and the North East Academic Health Science Network. For table, please contact authors directly by clicking on ‘Info & Metrics’ at the top of the abstract for their contact details


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_9 | Pages 21 - 21
1 Sep 2019
Saunders B Bartlam B Artus M Foster N Konstantinou K
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Background. Sciatica is common and associated with significant impacts for the individual, health care and society. The SCOPiC randomised controlled trial (RCT) is investigating whether stratified primary care for sciatica is more effective and cost-effective than usual, non-stratified primary care. Stratified care involves subgrouping patients to one of three groups based on a combination of prognostic and clinical indicators. Patients in one of these groups are ‘fast-tracked’ with an MRI scan to spinal specialist opinion. Our aim was to understand the perspectives of clinicians on the acceptability of this ‘fast-track’ pathway. Methods. Qualitative, semi-structured interviews were conducted with general practitioners, spinal specialist physiotherapists and spinal surgeons (n=20 in total). Interviews were fully transcribed, and data were analysed using the constant comparison method. Results. Across all groups, clinicians identified potential added value in ‘fast-tracking’ some sciatica patients in terms of patient reassurance based on MRI scan findings. Whilst spinal physiotherapists felt that most ‘fast track’ patients were appropriate, some spinal physiotherapists and GPs had concerns that patients with symptom durations of less than 6 weeks might be inappropriately fast-tracked since their symptoms may still resolve without the need for invasive treatments. Spinal surgeons felt it was acceptable for patients with short symptom durations to be ‘fast-tracked’, but to provide early reassurance rather than direct treatment. Conclusion. Whilst clinicians saw added value in a group of sciatica patients being ‘fast-tracked’ to specialist opinion, there was some reservation about moving away from the usual stepped care, ‘wait and see’ approach for patients with short symptom duration. Conflicts of interest statement. No conflicts of interest. Sources of funding. This study is funded by the National Institute for Health Research Health Technology Assessment Programme (NIHR HTA project number 12/201/09) and will be published in full in Health Technology Assessment. Funding support is also received from an NIHR Research Professorship for Nadine Foster (NIHR-RP-011-015), who is an NIHR Senior Investigator, and a HEFCE Senior Clinical Lecturer award for Kika Konstantinou. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health and Social Care. The study was approved by the NRES Committee West Midlands – Solihull, 17/03/2015, ref: 15/WM/0078. Trial registration: ISRCTN75449581


Purpose and background:. Cauda Equina Syndrome (CES) is a rare condition which, even in the presence of prompt surgical decompression, can have devastating consequences for patients in terms of bladder and bowel dysfunction. The aim of this project was to develop a post-operative pathway for the assessment and management of bladder and bowel dysfunction in patients with CES. Method:. Beaumont Hospital performs a high volume of spinal surgeries. A small number are lumbar decompression surgeries due to CES. While sphincter function is routinely screened by a physiotherapist post-operatively, to date there has been no protocol in place for assessment and management of bladder and bowel dysfunction in this population. This project was carried out in collaboration with consultants in urology and colorectal surgery, as well as clinical nurse specialists in both areas. Results:. All patients undergoing lumbar decompression due to CES will be referred to a colorectal surgeon for post-operatively review and out-patient monitoring. A routine bladder ultrasound will be completed post-operatively to assess for urinary retention with a post void residual > 150 mls of urine indicating the need for referral to a urologist for in-patient review and out-patient follow-up. A patient education leaflet has also been developed. Conclusions:. A pathway has been implemented at Beaumont Hospital to ensure timely referral to specialised teams for both assessment and management of bladder and bowel dysfunction in CES. This pathway will ensure prompt access to specialised and supportive multi-disciplinary teams in the days/weeks/months/years post-operatively thereby minimising the emotional distress and health risks associated with secondary complications of CES


Bone & Joint Research
Vol. 9, Issue 5 | Pages 225 - 235
1 May 2020
Peng X Zhang C Bao J Zhu L Shi R Xie Z Wang F Wang K Wu X

Aims

Inflammatory response plays a pivotal role in the pathophysiological process of intervertebral disc degeneration (IDD). A20 (also known as tumour necrosis factor alpha-induced protein 3 (TNFAIP3)) is a ubiquitin-editing enzyme that restricts nuclear factor-kappa B (NF-κB) signalling. A20 prevents the occurrence of multiple inflammatory diseases. However, the role of A20 in the initiation of IDD has not been elucidated. The aim of the study was to investigate the effect of A20 in senescence of TNF alpha (TNF-α)-induced nucleus pulposus cells (NPCs).

Methods

Immunohistochemical staining was performed to observe the expression of A20 in normal and degenerated human intervertebral discs. The NPCs were dissected from the tail vertebrae of healthy male Sprague-Dawley rats and were cultured in the incubator. In the experiment, TNF-α was used to mimic the inflammatory environment of IDD. The cell viability and senescence were examined to investigate the effect of A20 on TNF-α-treated NPCs. The expression of messenger RNA (mRNA)-encoding proteins related to matrix macromolecules (collagen II, aggrecan) and senescence markers (p53, p16). Additionally, NF-κB/p65 activity of NPCs was detected within different test compounds.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXI | Pages 27 - 27
1 Jul 2012
Sandford L Yuen S Upadhyay N Beebee M Sadler M Nesbitt J Madhavan P Steele N Thorpe P
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Surgery for spinal deformity was previously carried out only in teaching hospitals in the United Kingdom. With increasing numbers of patients especially adults, seeking treatment for spinal deformity, the number of centres offering treatment for spinal deformity is going to have to increase.

The deformity part of the Spinal Surgical Service in the District General Hospital in Taunton started in 2005. This paper is an audit of this deformity service. It looks at two key areas – that of patient satisfaction and patient reported outcomes of surgery. Patient satisfaction was assessed by a validated questionnaire that evaluated a patient's perception of consultations, consent, preoperative assessment, operative and post operative experience and follows up visits. Patient reported outcomes were evaluated using the SRS 30 questionnaire. 104 patients were contacted and 95 patients (91%) responded. The overall patient satisfaction rate was 96%, with 87% very pleased with the result of surgery, 80% felt that their body shape had improved considerably, 62% had an increased ability to carry out day to day activities to a much higher level and 78% had significantly decreased pain after surgery. The results of the different domains of the SRS questionnaire also supported this.

The authors believe that this audit proves that it is possible to provide a spinal deformity service in a District General Hospital in the United Kingdom safely and effectively with a high degree of patient satisfaction. Audits of this kind are required to compare results of treatment between different centres and establish standards.


Bone & Joint Research
Vol. 12, Issue 9 | Pages 522 - 535
4 Sep 2023
Zhang G Li L Luo Z Zhang C Wang Y Kang X

Aims. This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD). Methods. The gene expression profile of GSE23130 was downloaded from the Gene Expression Omnibus (GEO) database. Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases, and we used Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze the functions and pathways of EP-DEGs. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and identify hub EP-DEGs. NetworkAnalyst was used to analyze transcription factors (TFs) and microRNAs (miRNAs) that regulate hub EP-DEGs. A search of the Drug Signatures Database (DSigDB) for hub EP-DEGs revealed multiple drug molecules and drug-target interactions. Results. A total of 56 EP-DEGs were identified in the differential expression analysis. EP-DEGs were enriched in the extracellular structure organization, ageing, collagen-activated signalling pathway, PI3K-Akt signalling pathway, and AGE-RAGE signalling pathway. PPI network analysis showed that the top ten hub EP-DEGs are closely related to IDD. Correlation analysis also demonstrated a significant correlation between the ten hub EP-DEGs (p<0.05), which were selected to construct TF–gene interaction and TF–miRNA coregulatory networks. In addition, ten candidate drugs were screened for the treatment of IDD. Conclusion. The findings clarify the roles of extracellular proteins in IDD and highlight their potential as promising novel therapeutic targets. Cite this article: Bone Joint Res 2023;12(9):522–535


Bone & Joint Research
Vol. 12, Issue 1 | Pages 80 - 90
20 Jan 2023
Xu J Si H Zeng Y Wu Y Zhang S Liu Y Li M Shen B

Aims. Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. Methods. Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis. Results. The TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile. Conclusion. Our results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment. Cite this article: Bone Joint Res 2023;12(1):80–90


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_9 | Pages 38 - 38
1 Oct 2022
Wood L Dunstan E
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Background. NHS improvement advocates same day emergency care (SDEC) for patients requiring additional specialism than can be provided in an Emergency Department. A novel physiotherapist-led spinal SDEC unit was established in January 2020, integrated within the on-call spinal service. The aim of this paper was to evaluate patient and peer satisfaction with the spinal SDEC. Methods. Patient satisfaction questionnaires and/or friends and family tests were collected from patients over a six-month period. Questionnaires evaluated satisfaction with recommendations given, service given, staff friendliness. Anonymous, completed questionnaires were uploaded onto a spreadsheet. Peer satisfaction was assessed using a google sheets document emailed to interface, primary care and community services. The questionnaire captured the respondents’ role, how many patients they had referred to the SDEC, reasons for referral, ease of referral, and compared this new pathway with the previous pathway. All patient's satisfaction responses recommended the service to family and friends (n=110 extremely likely, 8 likely) (6% total seen). All respondents were satisfied with the service they received (n=80 very satisfied, n=12 satisfied) and recommendations made (n=86 very satisfied, n=6 satisfied). Of peer satisfaction, 26 respondents (n=12 (46%) physiotherapists, n=6 (23%) first contact practitioners, n=6 (23%) advanced practice physiotherapists, n=1 (4%) GP, n=1 (4%) nurse) reported the SDEC delivered a better pathway and outcomes (n=25, 96%), and 20 (77%) respondents reported favourable comments of the service and its impact on patients and referrers. Conclusion. Peer and patient satisfaction data support the use of a physiotherapist-led spinal SDEC in emergency and urgent spinal care pathways. Conflicts of interest: No conflicts of Interest. Sources of interest: No sources of funding


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_9 | Pages 39 - 39
1 Oct 2022
Dixon M Dunstan E Wiltshire K Wood L
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Background. Advanced spinal practitioner physiotherapists (ASPPs) assess and manage spinal referrals, as advocated by the National Low Back Pain Pathway in the United Kingdom. The ASPP pathway relies on multi-disciplinary team (MDT) meetings where potential surgically appropriate or complex cases can be discussed. Meetings were held with two different Consultant Spinal Neurosurgeons (total 2 meetings per month). The aim of this service evaluation was to assess MDT meeting outcomes and surgical listing. Methods. This retrospective service evaluation used routinely collected MDT meeting documentation between May 2019 and October 2021. Data was extracted by two ASPPs, and 20% checked by a third ASPP. Extracted data included: number of patients discussed, Consultant, reason for discussion, and outcome (surgical listing or other). Data was analysed by two ASPPs using pivot tables in Microsoft Excel and was reported using counts and percentages across month and year. Results. The majority of MDT discussions were for a surgical opinion (n=293, 25% clinician led, n=351, 30% patient led). Of these, 46% (n=135) of clinician surgical opinions were directly listed compared to 20% (n=70) of patient led discussions. Similar rates of consultant clinic review were seen between the two groups (22% and 32%), suggesting that the majority of patients discussed for surgical consideration were appropriate. 517 (45%) were discussed for management opinion. Conclusions. This evaluation demonstrates that a majority of cases (68%) identified by ASPPs for surgical opinion were either directly listed or had consultant clinic surgical review. The results and trends identified will guide future patient pathway development and ASPP training. Conflicts of interest: No conflicts of interest. Sources of funding: No sources of funding


Bone & Joint Research
Vol. 12, Issue 3 | Pages 202 - 211
7 Mar 2023
Bai Z Shou Z Hu K Yu J Meng H Chen C

Aims. This study was performed to explore the effect of melatonin on pyroptosis in nucleus pulposus cells (NPCs) and the underlying mechanism of that effect. Methods. This experiment included three patients diagnosed with lumbar disc herniation who failed conservative treatment. Nucleus pulposus tissue was isolated from these patients when they underwent surgical intervention, and primary NPCs were isolated and cultured. Western blotting, reverse transcription polymerase chain reaction, fluorescence staining, and other methods were used to detect changes in related signalling pathways and the ability of cells to resist pyroptosis. Results. Western blot analysis confirmed the expression of cleaved CASP-1 and melatonin receptor (MT-1A-R) in NPCs. The cultured NPCs were identified by detecting the expression of CD24, collagen type II, and aggrecan. After treatment with hydrogen peroxide, the pyroptosis-related proteins NLR family pyrin domain containing 3 (NLRP3), cleaved CASP-1, N-terminal fragment of gasdermin D (GSDMD-N), interleukin (IL)-18, and IL-1β in NPCs were upregulated, and the number of propidium iodide (PI)-positive cells was also increased, which was able to be alleviated by pretreatment with melatonin. The protective effect of melatonin on pyroptosis was blunted by both the melatonin receptor antagonist luzindole and the nuclear factor erythroid 2–related factor 2 (Nrf2) inhibitor ML385. In addition, the expression of the transcription factor Nrf2 was up- or downregulated when the melatonin receptor was activated or blocked by melatonin or luzindole, respectively. Conclusion. Melatonin protects NPCs against reactive oxygen species-induced pyroptosis by upregulating the transcription factor Nrf2 via melatonin receptors. Cite this article: Bone Joint Res 2023;12(3):202–211


Aims. In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD. Methods. An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD. Results. A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in rats. Conclusion. DDIT4 is a key player in mediating pyroptosis and IVDD in NPCs through the ROS-TXNIP-NLRP3 axis. Additionally, siDDIT4@G5-P-HA hydrogel has been found to relieve IVDD in rats. Our research offers an innovative treatment option for IVDD. Cite this article: Bone Joint Res 2024;13(5):247–260


Bone & Joint Research
Vol. 12, Issue 3 | Pages 189 - 198
7 Mar 2023
Ruiz-Fernández C Ait Eldjoudi D González-Rodríguez M Cordero Barreal A Farrag Y García-Caballero L Lago F Mobasheri A Sakai D Pino J Gualillo O

Aims. CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration. Methods. We investigated the effects of mCRP and the signalling pathways that are involved in cultured human primary annulus fibrosus (AF) cells and in the human nucleus pulposus (NP) immortalized cell line HNPSV-1. We determined messenger RNA (mRNA) and protein levels of relevant factors involved in inflammatory responses, by quantitative real-time polymerase chain reaction (RT-qPCR) and western blot. We also studied the presence of mCRP in human AF and NP tissues by immunohistochemistry. Results. We demonstrated that mCRP increases nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion molecule 1 (VCAM1), interleukin (IL)-6, IL-8, and Lipocalin 2 (LCN2) expression in human AF and NP cells. We also showed that nuclear factor-κβ (NF-κβ), extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase (PI3K) are at play in the intracellular signalling of mCRP. Finally, we demonstrated the presence of mCRP in human AF and NP tissues. Conclusion. Our results indicate, for the first time, that mCRP can be localized in IVD tissues, where it triggers a proinflammatory and catabolic state in degenerative and healthy IVD cells, and that NF-κβ signalling may be implicated in the mediation of this mCRP-induced state. Cite this article: Bone Joint Res 2023;12(3):189–198


Bone & Joint Research
Vol. 12, Issue 6 | Pages 387 - 396
26 Jun 2023
Xu J Si H Zeng Y Wu Y Zhang S Shen B

Aims. Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. Methods. We conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. Results. TWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as ‘chemical carcinogenesis - reactive oxygen species’ (LogP value = −2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = −2.811). Conclusion. This study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS. Cite this article: Bone Joint Res 2023;12(6):387–396


The Bone & Joint Journal
Vol. 106-B, Issue 7 | Pages 713 - 719
1 Jul 2024
Patel MS Shah S Elkazaz MK Shafafy M Grevitt MP

Aims. Historically, patients undergoing surgery for adolescent idiopathic scoliosis (AIS) have been nursed postoperatively in a critical care (CC) setting because of the challenges posed by prone positioning, extensive exposures, prolonged operating times, significant blood loss, major intraoperative fluid shifts, cardiopulmonary complications, and difficulty in postoperative pain management. The primary aim of this paper was to determine whether a scoring system, which uses Cobb angle, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and number of levels to be fused, is a valid method of predicting the need for postoperative critical care in AIS patients who are to undergo scoliosis correction with posterior spinal fusion (PSF). Methods. We retrospectively reviewed all AIS patients who had undergone PSF between January 2018 and January 2020 in a specialist tertiary spinal referral centre. All patients were assessed preoperatively in an anaesthetic clinic. Postoperative care was defined as ward-based (WB) or critical care (CC), based on the preoperative FEV1, FVC, major curve Cobb angle, and the planned number of instrumented levels. Results. Overall, 105 patients were enrolled. Their mean age was 15.5 years (11 to 25) with a mean weight of 55 kg (35 to 103). The mean Cobb angle was 68° (38° to 122°). Of these, 38 patients were preoperatively scored to receive postoperative CC. However, only 19% of the cohort (20/105) actually needed CC-level support. Based on these figures, and an average paediatric intensive care unit stay of one day before stepdown to ward-based care, the potential cost-saving on the first postoperative night for this cohort was over £20,000. There was no statistically significant difference between the Total Pathway Score (TPS), the numerical representation of the four factors being assessed, and the actual level of care received (p = 0.052) or the American Society of Anesthesiologists grade (p = 0.187). Binary logistic regression analysis of the TPS variables showed that the preoperative Cobb angle was the only variable which significantly predicted the need for critical care. Conclusion. Most patients undergoing posterior fusion surgery for AIS do not need critical care. Of the readily available preoperative measures, the Cobb angle is the only predictor of the need for higher levels of care, and has a threshold value of 74.5°. Cite this article: Bone Joint J 2024;106-B(7):713–719


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_8 | Pages 1 - 1
1 Aug 2022
Nicholson T Foster N Haj AE Ede MN Jones S
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We previously reported that osteoblasts at the curve apex in adolescent idiopathic scoliosis (AIS) exhibit a differential phenotype, compared to non-curve osteoblasts(1). However, the Hueter-Volkmann principle on vertebral body growth in spinal deformities (2) suggests this could be secondary to altered biomechanics. This study examined whether non-curve osteoblasts subjected to mechanical strain resemble the transcriptomic phenotype of curve apex osteoblasts. Facet spinal tissue was collected perioperatively from three sites, (i) the concave and (ii) convex side at the curve apex and (iii) from outside the curve (non-curve) from six AIS female patients (age 13–18 years; NRES 19/WM/0083). Non-curve osteoblasts were subjected to strain using a 4-point bending device. Osteoblast phenotype was determined by RNA sequencing and bioinformatic pathway analysis. RNAseq revealed that curve apex osteoblasts exhibited a differential transcriptome, with 1014 and 1301 differentially expressed genes (DEGs; p<0.05, fold-change >1.5) between convex/non-curve and concave/non-curve sites respectively. Non-curve osteoblasts subjected to strain showed increased protein expression of the mechanoresponsive biomarkers COX2 and C-Fos. Comparing unstimulated vs strain-induced non-curve osteoblasts, 423 DEGs were identified (p<0.05, fold-change >1.5). Of these DEGs, only 5% and 6% were common to the DEGs found at either side of the curve apex, compared to non-curve cells. Bioinformatic analysis of these strain-induced DEGs revealed a different array of canonical signalling pathways and cellular processes, to those significantly affected in cells at the curve apex. Mechanical strain of AIS osteoblasts in vitro did not induce the differential transcriptomic phenotype of AIS osteoblasts at the curve apex


Bone & Joint Open
Vol. 3, Issue 5 | Pages 348 - 358
1 May 2022
Stokes S Drozda M Lee C

This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review


Bone & Joint Open
Vol. 2, Issue 12 | Pages 1096 - 1101
23 Dec 2021
Mohammed R Shah P Durst A Mathai NJ Budu A Woodfield J Marjoram T Sewell M

Aims. With resumption of elective spine surgery services in the UK following the first wave of the COVID-19 pandemic, we conducted a multicentre British Association of Spine Surgeons (BASS) collaborative study to examine the complications and deaths due to COVID-19 at the recovery phase of the pandemic. The aim was to analyze the safety of elective spinal surgery during the pandemic. Methods. A prospective observational study was conducted from eight spinal centres for the first month of operating following restoration of elective spine surgery in each individual unit. Primary outcome measure was the 30-day postoperative COVID-19 infection rate. Secondary outcomes analyzed were the 30-day mortality rate, surgical adverse events, medical complications, and length of inpatient stay. Results. In all, 257 patients (128 males) with a median age of 54 years (2 to 88) formed the study cohort. The mean number of procedures performed from each unit was 32 (16 to 101), with 118 procedures (46%) done as category three prioritization level. The majority of patients (87%) were low-medium “risk stratification” category and the mean length of hospital stay was 5.2 days. None of the patients were diagnosed with COVID-19 infection, nor was there any mortality related to COVID-19 during the 30-day follow-up period, with 25 patients (10%) having been tested for symptoms. Overall, 32 patients (12%) developed a total of 34 complications, with the majority (19/34) being grade 1 to 2 Clavien-Dindo classification of surgical complications. No patient required postoperative care in an intensive care setting for any unexpected complication. Conclusion. This study shows that safe and effective planned spinal surgical services can be restored avoiding viral transmission, with diligent adherence to national guidelines and COVID-19-secure pathways tailored according to the resources of the individual spinal units. Cite this article: Bone Jt Open 2021;2(12):1096–1101