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. To determine the major risk factors for unplanned reoperations (UROs) following corrective surgery for adult spinal deformity (ASD) and their interactions, using machine learning-based prediction algorithms and game theory. Methods. Patients who underwent surgery for ASD, with a minimum of two-year follow-up, were retrospectively reviewed. In total, 210 patients were included and randomly allocated into training (70% of the sample size) and test (the remaining 30%) sets to develop the machine learning algorithm. Risk factors were included in the analysis, along with clinical characteristics and parameters acquired through diagnostic radiology. Results. Overall, 152 patients without and 58 with a history of surgical revision following surgery for ASD were observed; the mean age was 68.9 years (SD 8.7) and 66.9 years (SD 6.6), respectively. On implementing a random forest model, the classification of URO events resulted in a balanced accuracy of 86.8%. Among machine learning-extracted risk factors, URO, proximal junction failure (PJF), and postoperative distance from the posterosuperior corner of C7 and the vertical axis from the centroid of C2 (SVA) were significant upon Kaplan-Meier survival analysis. Conclusion. The major risk factors for URO following surgery for ASD, i.e. postoperative SVA and PJF, and their interactions were identified using a machine learning algorithm and game theory. Clinical benefits will depend on patient risk profiles. Cite this article: Bone Joint Res 2023;12(4):245–255

Aims. The optimal procedure for the treatment of ossification of the posterior longitudinal ligament (OPLL) remains controversial. The aim of this study was to compare the outcome of anterior cervical ossified posterior longitudinal ligament en bloc resection (ACOE) with posterior laminectomy and fusion with bone graft and internal fixation (PTLF) for the surgical management of patients with this condition. Methods. Between July 2017 and July 2019, 40 patients with cervical OPLL were equally randomized to undergo surgery with an ACOE or a PTLF. The clinical and radiological results were compared between the two groups. Results. The Japanese Orthopaedic Association (JOA) score and recovery rate in the ACOE group were significantly higher than those in the PTLF group during two years postoperatively, provided that the canal occupying ratio (COR) was > 50%, or the K-line was negative. There was no significant difference in JOA scores and rate of recovery between the two groups in those in whom the COR was < 50%, or the K-line was positive. There was no significant difference in the Cobb angle between C2 and C7, sagittal vertical axis, cervical range of motion (ROM), and complications between the two groups. Conclusion. Compared with PTLF, ACOE is a preferred surgical approach for the surgical management of patients with cervical OPLL in that it offers a better therapeutic outcome when the COR is > 50%, or the K-line is negative, and it also preserves better cervical curvature and sagittal balance. The prognosis of ACOE is similar to that of PTLE when the COR is < 50%, or the K-line is positive. Cite this article: Bone Joint J 2023;105-B(4):412–421

Aims. Symptomatic spinal stenosis is a very common problem, and decompression surgery has been shown to be superior to nonoperative treatment in selected patient groups. However, performing an instrumented fusion in addition to decompression may avoid revision and improve outcomes. The aim of the SpInOuT feasibility study was to establish whether a definitive randomized controlled trial (RCT) that accounted for the spectrum of pathology contributing to spinal stenosis, including pelvic incidence-lumbar lordosis (PI-LL) mismatch and mobile spondylolisthesis, could be conducted. Methods. As part of the SpInOuT-F study, a pilot randomized trial was carried out across five NHS hospitals. Patients were randomized to either spinal decompression alone or spinal decompression plus instrumented fusion. Patient-reported outcome measures were collected at baseline and three months. The intended sample size was 60 patients. Results. Of the 90 patients screened, 77 passed the initial screening criteria. A total of 27 patients had a PI-LL mismatch and 23 had a dynamic spondylolisthesis. Following secondary inclusion and exclusion criteria, 31 patients were eligible for the study. Six patients were randomized and one underwent surgery during the study period. Given the low number of patients recruited and randomized, it was not possible to assess completion rates, quality of life, imaging, or health economic outcomes as intended. Conclusion. This study provides a unique insight into the prevalence of dynamic spondylolisthesis and PI-LL mismatch in patients with symptomatic spinal stenosis, and demonstrates that there is a need for a definitive RCT which stratifies for these groups in order to inform surgical decision-making. Nonetheless a definitive study would need further refinement in design and implementation in order to be feasible. Cite this article: Bone Jt Open 2023;4(8):573–579

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

Aims. Patients with differentiated thyroid carcinomas (DTCs) have a favourable long-term survival. Spinal metastases (SMs) cause a decline in performance status (PS), directly affecting mortality and indirectly preventing the use of systemic therapies. Metastasectomy is indicated, if feasible, as it yields the best local tumour control. Our study aimed to examine the long-term clinical outcomes of metastasectomy for SMs of thyroid carcinomas. Methods. We collected data on 22 patients with DTC (16 follicular and six papillary carcinomas) and one patient with medullary carcinoma who underwent complete surgical resection of SMs at our institution between July 1992 and July 2017, with a minimum postoperative follow-up of five years. The cancer-specific survival (CSS) from the first spinal metastasectomy to death or the last follow-up was determined using Kaplan-Meier analysis. Potential factors associated with survival were evaluated using the log-rank test. We analyzed the clinical parameters and outcome data, including pre- and postoperative disability (Eastern Cooperative Oncology Group PS 3), lung and non-spinal bone metastases, and history of radioiodine and kinase inhibitor therapies. Results. Lung and other bone metastases at the time of surgery were observed in ten and eight patients, respectively. Three patients experienced local tumour recurrences at the operated site. The five- and ten-year CSS rates in the 22 patients with DTC were 77% and 52%, respectively. Pre- and postoperative disability and operative site tumour recurrence were identified as risk factors for short postoperative survival. Conclusion. Metastasectomy for resectable SM from DTC yielded favourable results and has the potential to improve survival. Cite this article: Bone Joint J 2023;105-B(5):575–582

Aims. This study aimed to evaluate rasterstereography of the spine as a diagnostic test for adolescent idiopathic soliosis (AIS), and to compare its results with those obtained using a scoliometer. Methods. Adolescents suspected of AIS and scheduled for radiographs were included. Rasterstereographic scoliosis angle (SA), maximal vertebral surface rotation (ROT), and angle of trunk rotation (ATR) with a scoliometer were evaluated. The area under the curve (AUC) from receiver operating characteristic (ROC) plots were used to describe the discriminative ability of the SA, ROT, and ATR for scoliosis, defined as a Cobb angle > 10°. Test characteristics (sensitivity and specificity) were reported for the best threshold identified using the Youden method. AUC of SA, ATR, and ROT were compared using the bootstrap test for two correlated ROC curves method. Results. Of 212 patients studied, 146 (69%) had an AIS. The AUC was 0.74 for scoliosis angle (threshold 12.5°, sensitivity 75%, specificity 65%), 0.65 for maximal vertebral surface rotation (threshold 7.5°, sensitivity 63%, specificity 64%), and 0.82 for angle of trunk rotation (threshold 5.5°, sensitivity 65%, specificity 80%). The AUC of ROT was significantly lower than that of ATR (p < 0.001) and SA (p < 0.001). The AUCs of ATR and SA were not significantly different (p = 0.115). Conclusion. The rasterstereographic scoliosis angle has better diagnostic characteristics than the angle of trunk rotation evaluated with a scoliometer, with similar AUCs and a higher sensitivity. Cite this article: Bone Joint J 2023;105-B(4):431–438

Aims. The escalating demand for medical resources to address spinal diseases as society ages is an issue that requires careful evaluation. However, few studies have examined trends in spinal surgery, especially unscheduled hospitalizations or surgeries performed after hours, through large databases. Our study aimed to determine national trends in the number of spine surgeries in Japan. We also aimed to identify trends in after-hours surgeries and unscheduled hospitalizations and their impact on complications and costs. Methods. We retrospectively investigated data extracted from the Diagnosis Procedure Combination database, a representative inpatient database in Japan. The data from April 2010 to March 2020 were used for this study. We included all patients who had undergone any combination of laminectomy, laminoplasty, discectomy, and/or spinal arthrodesis. Results. This investigation included 739,474 spinal surgeries and 739,215 hospitalizations in Japan. There was an average annual increase of 4.6% in the number of spinal surgeries. Scheduled hospitalizations increased by 3.7% per year while unscheduled hospitalizations increased by 11.8% per year. In-hours surgeries increased by 4.5% per year while after-hours surgeries increased by 9.9% per year. Complication rates and costs increased for both after-hours surgery and unscheduled hospitalizations, in comparison to their respective counterparts of in-hours surgery and scheduled hospitalizations. Conclusion. This study provides important insights for those interested in improving spine care in an ageing society. The swift surge in after-hours spinal surgeries and unscheduled hospitalizations highlights that the medical needs of an increasing number of patients due to an ageing society are outpacing the capacity of existing medical resources. Cite this article: Bone Jt Open 2024;5(8):662–670

Aims. To investigate the correlations among cytokines and regulatory T cells (T-regs) in ankylosing spondylitis (AS) patients, and their changes after anti-tumour necrosis factor-α (TNF-α) treatment. Methods. We included 72 AS patients with detailed medical records, disease activity score (Bath Ankylosing Spondylitis Disease Activity Index), functional index (Bath Ankylosing Spondylitis Functional Index), and laboratory data (interleukin (IL)-2, IL-4, IL-10, TNF-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, ESR, and CRP). Their peripheral blood mononuclear cells (PBMCs) were marked with anti-CD4, anti-CD25, and anti-FoxP3 antibodies, and triple positive T cells were gated by flow cytometry as T-regs. Their correlations were calculated and the changes after anti-TNF-α therapy were compared. Results. The frequency of T-regs in PBMCs was positively correlated to ESR and CRP in AS (r = 0.35 and 0.43; p = 0.032 and 0.027, respectively), and there was also a significant correlation between serum level of TNF-α and CRP (p = 0.041). The frequency of T-regs in PBMCs positively correlated to serum levels of TNF-α, IL-10, and TGF-β, while IL-2, IL-4, and IFN-γ showed opposite results. After anti-TNF-α treatment, there were significantly lower serum levels of TNF-α, IL-10, TGF-β, and frequency of T-regs in PBMCs among these AS patients (p = 0.026, 0.032, 0.029, and 0.037, respectively). Conclusion. In AS patients, proinflammatory cytokine may give positive feedback to induce more T-reg production and anti-inflammatory cytokine secretion to suppress this inflammatory status, and they can be reversed by anti-TNF-α therapy. However, the detailed interactions among T-regs and complex cytokine networks in autoinflammatory diseases still need more studies and further functional assay. Cite this article: Bone Joint Res 2023;12(2):133–137

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

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

Aims. Scoliosis is a lateral curvature of the spine with associated rotation, often causing distress due to appearance. For some curves, there is good evidence to support the use of a spinal brace, worn for 20 to 24 hours a day to minimize the curve, making it as straight as possible during growth, preventing progression. Compliance can be poor due to appearance and comfort. A night-time brace, worn for eight to 12 hours, can achieve higher levels of curve correction while patients are supine, and could be preferable for patients, but evidence of efficacy is limited. This is the protocol for a randomized controlled trial of ‘full-time bracing’ versus ‘night-time bracing’ in adolescent idiopathic scoliosis (AIS). Methods. UK paediatric spine clinics will recruit 780 participants aged ten to 15 years-old with AIS, Risser stage 0, 1, or 2, and curve size (Cobb angle) 20° to 40° with apex at or below T7. Patients are randomly allocated 1:1, to either full-time or night-time bracing. A qualitative sub-study will explore communication and experiences of families in terms of bracing and research. Patient and Public Involvement & Engagement informed study design and will assist with aspects of trial delivery and dissemination. Discussion. The primary outcome is ‘treatment failure’ (Cobb angle progression to 50° or more before skeletal maturity); skeletal maturity is at Risser stage 4 in females and 5 in males, or ‘treatment success’ (Cobb angle less than 50° at skeletal maturity). The comparison is on a non-inferiority basis (non-inferiority margin 11%). Participants are followed up every six months while in brace, and at one and two years after skeletal maturity. Secondary outcomes include the Scoliosis Research Society 22 questionnaire and measures of quality of life, psychological effects of bracing, adherence, anxiety and depression, sleep, satisfaction, and educational attainment. All data will be collected through the British Spine Registry. Cite this article: Bone Jt Open 2023;4(11):873–880

Aims. The aim of this study was to assess the accuracy of pedicle screw placement, as well as intraoperative factors, radiation exposure, and complication rates in adult patients with degenerative disorders of the thoracic and lumbar spines who have undergone robotic-navigated spinal surgery using a contemporary system. Methods. The authors reviewed the prospectively collected data on 196 adult patients who had pedicle screws implanted with robot-navigated assistance (RNA) using the Mazor X Stealth system between June 2019 and March 2022. Pedicle screws were implanted by one experienced spinal surgeon after completion of a learning period. The accuracy of pedicle screw placement was determined using intraoperative 3D fluoroscopy. Results. A total of 1,123 pedicle screws were implanted: 1,001 screws (89%) were placed robotically, 63 (6%) were converted from robotic placement to a freehand technique, and 59 (5%) were planned to be implanted freehand. Of the robotically placed screws, 942 screws (94%) were determined to be Gertzbein and Robbins grade A with median deviation of 0.8 mm (interquartile range 0.4 to 1.6). Skive events were noted with 20 pedicle screws (1.8%). No adverse clinical sequelae were noted in the 90-day follow-up. The mean fluoroscopic exposure per screw was 4.9 seconds (SD 3.8). Conclusion. RNA is highly accurate and reliable, with a low rate of abandonment once mastered. No adverse clinical sequelae occurred after implanting a large series of pedicle screws using the latest generation of RNA. Understanding of patient-specific anatomical features and the real-time intraoperative identification of risk factors for suboptimal screw placement have the potential to improve accuracy further. Cite this article: Bone Joint J 2023;105-B(5):543–550

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

Aims. The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study. Methods. A total of 2,053 children with idiopathic short stature and 4,106 age- and sex-matched (1:2) children without short stature with available whole-spine radiographs were enrolled in the cross-sectional study. Among them, 1,056 with idiopathic short stature and 790 controls who had radiographs more than twice were recruited to assess the development and progression of scoliosis, and the need for bracing and surgery. Results. In the cross-sectional study, there was an unexpectedly higher prevalence of scoliosis (33.1% (681/2,053) vs 8.52% (350/4,106)) in children with idiopathic short stature compared with controls (odds ratio 3.722; p < 0.001), although most cases were mild. In the longitudinal study, children with idiopathic short stature had a higher risk of the development and progression of scoliosis than the controls. Among children with idiopathic short stature without scoliosis at baseline, treatment with growth hormone significantly increased the risk of developing scoliosis (p = 0.015) and the need for bracing (p < 0.001). Among those with idiopathic short stature and scoliosis at baseline, treatment with growth hormone did not increase the risk of progression of the scoliosis, the need for bracing, or surgery. Conclusion. The impact of treatment with growth hormone on scoliosis in children with idiopathic short stature was considered controllable. However, physicians should pay close attention to the assessment of spinal curves in these children. Cite this article: Bone Joint J 2023;105-B(4):439–448

Aims. Patients with cauda equina syndrome (CES) require emergency imaging and surgical decompression. The severity and type of symptoms may influence the timing of imaging and surgery, and help predict the patient’s prognosis. Categories of CES attempt to group patients for management and prognostication purposes. We aimed in this study to assess the inter-rater reliability of dividing patients with CES into categories to assess whether they can be reliably applied in clinical practice and in research. Methods. A literature review was undertaken to identify published descriptions of categories of CES. A total of 100 real anonymized clinical vignettes of patients diagnosed with CES from the Understanding Cauda Equina Syndrome (UCES) study were reviewed by consultant spinal surgeons, neurosurgical registrars, and medical students. All were provided with published category definitions and asked to decide whether each patient had ‘suspected CES’; ‘early CES’; ‘incomplete CES’; or ‘CES with urinary retention’. Inter-rater agreement was assessed for all categories, for all raters, and for each group of raters using Fleiss’s kappa. Results. Each of the 100 participants were rated by four medical students, five neurosurgical registrars, and four consultant spinal surgeons. No groups achieved reasonable inter-rater agreement for any of the categories. CES with retention versus all other categories had the highest inter-rater agreement (kappa 0.34 (95% confidence interval 0.27 to 0.31); minimal agreement). There was no improvement in inter-rater agreement with clinical experience. Across all categories, registrars agreed with each other most often (kappa 0.41), followed by medical students (kappa 0.39). Consultant spinal surgeons had the lowest inter-rater agreement (kappa 0.17). Conclusion. Inter-rater agreement for categorizing CES is low among clinicians who regularly manage these patients. CES categories should be used with caution in clinical practice and research studies, as groups may be heterogenous and not comparable. Cite this article: Bone Joint J 2023;105-B(9):1007–1012

Aims. This systematic review aims to identify 3D predictors derived from biplanar reconstruction, and to describe current methods for improving curve prediction in patients with mild adolescent idiopathic scoliosis. Methods. A comprehensive search was conducted by three independent investigators on MEDLINE, PubMed, Web of Science, and Cochrane Library. Search terms included “adolescent idiopathic scoliosis”,“3D”, and “progression”. The inclusion and exclusion criteria were carefully defined to include clinical studies. Risk of bias was assessed with the Quality in Prognostic Studies tool (QUIPS) and Appraisal tool for Cross-Sectional Studies (AXIS), and level of evidence for each predictor was rated with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. In all, 915 publications were identified, with 377 articles subjected to full-text screening; overall, 31 articles were included. Results. Torsion index (TI) and apical vertebral rotation (AVR) were identified as accurate predictors of curve progression in early visits. Initial TI > 3.7° and AVR > 5.8° were predictive of curve progression. Thoracic hypokyphosis was inconsistently observed in progressive curves with weak evidence. While sagittal wedging was observed in mild curves, there is insufficient evidence for its correlation with curve progression. In curves with initial Cobb angle < 25°, Cobb angle was a poor predictor for future curve progression. Prediction accuracy was improved by incorporating serial reconstructions in stepwise layers. However, a lack of post-hoc analysis was identified in studies involving geometrical models. Conclusion. For patients with mild curves, TI and AVR were identified as predictors of curve progression, with TI > 3.7° and AVR > 5.8° found to be important thresholds. Cobb angle acts as a poor predictor in mild curves, and more investigations are required to assess thoracic kyphosis and wedging as predictors. Cumulative reconstruction of radiographs improves prediction accuracy. Comprehensive analysis between progressive and non-progressive curves is recommended to extract meaningful thresholds for clinical prognostication. Cite this article: Bone Jt Open 2024;5(3):243–251

Aims. The aim of this study was to investigate the incidence and characteristics of instrumentation failure (IF) after total en bloc spondylectomy (TES), and to analyze risk factors for IF. Methods. The medical records from 136 patients (65 male, 71 female) with a mean age of 52.7 years (14 to 80) who underwent TES were retrospectively reviewed. The mean follow-up period was 101 months (36 to 232). Analyzed factors included incidence of IF, age, sex, BMI, history of chemotherapy or radiotherapy, tumour histology (primary or metastasis; benign or malignant), surgical approach (posterior or combined), tumour location (thoracic or lumbar; junctional or non-junctional), number of resected vertebrae (single or multilevel), anterior resection line (disc-to-disc or intravertebra), type of bone graft (autograft or frozen autograft), cage subsidence (CS), and local alignment (LA). A survival analysis of the instrumentation was performed, and relationships between IF and other factors were investigated using the Cox regression model. Results. A total of 44 patients (32.4%) developed IF at a median of 31 months (interquartile range 23 to 74) following TES. Most IFs were rod fractures preceded by a mean CS of 6.1 mm (2 to 18) and LA kyphotic enhancement of 10.8° (-1 to 36). IF-free survival rates were 75.8% at five years and 56.9% at ten years. The interval from TES to IF peaked at two to three years postoperatively and continued to occur over a period of time thereafter; the early IF-developing group had greater CS at one month postoperatively (CS1M) and more lumbar TES. CS1M ≥ 3 mm and sole use of frozen autografts were identified as independent risk factors for IF. Conclusion. IF is a common complication following TES. We have demonstrated that robust spinal reconstruction preventing CS, and high-quality bone grafting are necessary for successful reconstruction. Cite this article: Bone Joint J 2023;105-B(2):172–179

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

Aims. Gram-negative infections are associated with comorbid patients, but outcomes are less well understood. This study reviewed diagnosis, management, and treatment for a cohort treated in a tertiary spinal centre. Methods. A retrospective review was performed of all gram-negative spinal infections (n = 32; median age 71 years; interquartile range 60 to 78), excluding surgical site infections, at a single centre between 2015 to 2020 with two- to six-year follow-up. Information regarding organism identification, antibiotic regime, and treatment outcomes (including clinical, radiological, and biochemical) were collected from clinical notes. Results. All patients had comorbidities and/or non-spinal procedures within the previous year. Most infections affected lumbar segments (20/32), with Escherichia coli the commonest organism (17/32). Causative organisms were identified by blood culture (23/32), biopsy/aspiration (7/32), or intraoperative samples (2/32). There were 56 different antibiotic regimes, with oral (PO) ciprofloxacin being the most prevalent (13/56; 17.6%). Multilevel, contiguous infections were common (8/32; 25%), usually resulting in bone destruction and collapse. Epidural collections were seen in 13/32 (40.6%). In total, five patients required surgery, three for neurological deterioration. Overall, 24 patients improved or recovered with a mean halving of CRP at 8.5 days (SD 6). At the time of review (two to six years post-diagnosis), 16 patients (50%) were deceased. Conclusion. This is the largest published cohort of gram-negative spinal infections. In older patients with comorbidities and/or previous interventions in the last year, a high level of suspicion must be given to gram-negative infection with blood cultures and biopsy essential. Early organism identification permits targeted treatment and good initial clinical outcomes; however, mortality is 50% in this cohort at a mean of 4.2 years (2 to 6) after diagnosis. Cite this article: Bone Jt Open 2024;5(5):435–443