Aims. This Delphi study assessed the challenges of diagnosing soft-tissue knee injuries (STKIs) in acute settings among orthopaedic healthcare stakeholders. Methods. This modified e-Delphi study consisted of three rounds and involved 32 orthopaedic healthcare stakeholders, including physiotherapists, emergency nurse practitioners, sports medicine physicians, radiologists, orthopaedic registrars, and orthopaedic consultants. The perceived importance of diagnostic components relevant to STKIs included patient and external risk factors, clinical signs and symptoms, special clinical tests, and diagnostic imaging methods. Each round required scoring and ranking various items on a ten-point Likert scale. The items were refined as each round progressed. The study produced rankings of perceived importance across the various diagnostic components. Results. In Round 1, the study revealed widespread variability in stakeholder opinions on diagnostic components of STKIs. Round 2 identified patterns in the perceived importance of specific items within each diagnostic component. Round 3 produced rankings of perceived item importance within each diagnostic component. Noteworthy findings include the challenges associated with accurate and readily available diagnostic methods in acute care settings, the consistent acknowledgment of the importance of adopting a patient-centred approach to diagnosis, and the transition from divergent to convergent opinions between Rounds 2 and 3. Conclusion. This study highlights the potential for a paradigm shift in acute STKI diagnosis, where variability in the understanding of STKI diagnostic components may be addressed by establishing a uniform, evidence-based framework for evaluating these injuries. Cite this article: Bone Jt Open 2024;5(11):984–991

The surgical treatment of typical pathological conditions of the knee combined with deflections along the sagittal axis is complex, especially when the angles of such deflections are considerable in size. Prior to treatment, the first problem concerns detecting the origin of the deflection, whether it is osseous, ligamentous or mixed, especially in cases of knee recurvation. The possibility of finding patients with what is known as “prophylactic” correction of the deflection is very rare. Orthopaedic surgeons may encounter some cases in which deformation along the sagittal axis represents the primum movens of the pathology and others in which this deflection represents a further problem in curing the condition. The different situations may require the following different treatments: (a) Correction of the deflection; (b) correction of the deflection and the pathological condition; and (c) correction of the pathological condition and not the deflection. We believe that, in the most serious cases, the deflection must be corrected and then meticulous pre-operative preparation is required. However, in order to select the most appropriate treatment, it is essential, in our opinion, to determine the cause of the deflection along the sagittal axis. In our experience, the treatment of pathological conditions of the knee such as ligamentous reconstruction, knee arthroplasty and corrective osteotomies combined with deflection along the sagittal axis increase the difficulties of surgery, especially in cases of relevant knee recurvation, both osseous and ligamentous

Introduction Two commonly used labels for low back pain (LBP) are that of “mechanical” (. 1. ) or “inflammatory” (. 2. ). These labels have no universally accepted definitions. However, there are two distinct types of treatment for low back pain that seem to follow this definitional separation. That is, mechanical treatments (mobilisation, manipulation, traction and exercise) contrasted with anti-inflammatory treatments (medication and injections). The objective of this study was to obtain the opinion of five groups of experts about symptoms/ signs that may identify inflammatory and mechanical LBP. Methods A convenience sample of 125 practitioners including spine surgeons, rheumatologists, musculoskeletal physicians, chiropractors and physiotherapists was asked to complete a questionnaire. Participants were asked to use a Likert (0–10) scale to indicate the strength of agreement or disagreement with respect to potential signs/symptoms identifying inflammatory or mechanical LBP. Ethics approval was obtained. Results One hundred and five practitioners responded (81% response). No signs/symptoms were found to clearly distinguish between inflammatory and mechanical LBP. Nevertheless, seven signs/symptoms did show a higher score for either inflammatory or mechanical LBP, and a lower score for the other. Morning pain on waking, pain that wakes the person up, constant pain, and stiffness after resting (including sitting) were more likely to suggest inflammatory LBP, while intermittent pain during the day, pain when lifting and pain on repetitive bending were more likely to suggest mechanical LBP. There was however some disagreement between professions about the extent to which these signs/symptoms indicated mechanical or inflammatory LBP. Discussion There was no clear agreement either within or between professions regarding the signs and symptoms that suggest mechanical or inflammatory low back pain. There was however weak agreement on seven signs/symptoms. Further research should be aimed at testing these for their ability to predict the outcome of mechanical and anti-inflammatory treatments of LBP

Lesions of the fibrocartilaginous triangle of the carpus (FCTC) and lunatopyramidal (LP) instability are the most frequently treated situations involving ulnar instability of the wrist. Most publications to date have examined results obtain for the treatment of isolated lesions, few have reported associated injuries. Outcome could be better in terms of pain relief: 25–64% of pain-free results for the treatment of FCTC and unpredictable results for the treatment of LP instability.

Considering the column theory proposed by Navarro-Taleisnik we have developed a concept based on fixation of the pyramidal and an adaptation of the Mayfield lines (where kinetic energy is considered exclusively on the ulnar side); we present here what we call the «peripyramidal ring lesion».

In our series of surgical cases, pain-free outcome for combined ulnar lesions treated as FCTC lesions was achieved in 48% of cases. For cases treated as LP instability, the rate was 71.4%. Many combinations are underdiagnosed: pyramidal-median hamate, pyramidal-pisiform. By treating these combined lesions we have increased the rate of excellent results from 64% to 91% for FCTC and obtained 86% pain-free wrists for LP instability.

Purpose and background. Cauda Equina Syndrome (CES), a rare (<1 per 100,000) and potentially devasting condition, involves compression of the lumbosacral nerve roots. If not quickly identified and treated, it can lead to lasting disability, and high medicolegal costs (>£186 million in the decade to 2018). This study identified why people with suspected CES attend the emergency department (ED) and explored any delays in attending. Methods and Results. The design was a secondary analysis of a qualitative dataset comprising patients with back pain who attended the ED, undertaken using an interpretivist approach. Fourteen patients (8M:6F, aged 23–63 years) with suspected CES were purposively sampled from 4 EDs (2 Northern and 2 Southern) in England between August and December 2021. Semi-structured interviews were conducted online, audio-recorded, transcribed verbatim and analysed thematically. Acopia with pain was the biggest factor in a participant's decision to attend the ED, along with the need for a diagnosis. This pain was the worst ever experienced and debilitating, leaving people unable to cope and desperate for relief. 12/14 were advised to attend the ED following identification of red flags by: GPs (n=9); physiotherapists (n=2); surgical colleague (n=1); and 111 (n=1). Factors such as guilt, previous experience of being disregarded, and symptom misattribution were seen to cause delays in seeking care. Conclusion. This paper revealed a disconnect between the priorities of patients and clinicians prior to attending the ED. Clinicians need to validate the pain experience, communicate clearly why signs and symptoms are concerning, and convey the urgency and potential impact of CES. Conflicts of interest. None. Sources of funding. Funding for primary data: Health Education England & National. Institute of Health and Care Research (ICA-CDRF-2018-04-ST2-040)

Specific and rapid detection methods for spinal tuberculosis, with sufficient sensitivity in HIV-1 co-infected individuals, are needed, to ensure early initiation of appropriate treatment to prevent physical disability and neurological fallout. In addition, understanding the systemic and local pathophysiology of spinal tuberculosis, and its interaction with HIV-1 infection, is crucial to guide future therapeutic interventions. We prospectively enrolled adult patients presenting with signs and symptoms of suspected spinal tuberculosis, at Groote Schuur Hospital, between November 2020 and December 2021. TB diagnostic testing was performed on open and CT-guided spinal biopsies using Xpert MTB/RIF Ultra compared to gold standards TB culture and histology. A highly sensitive droplet digital PCR assay for detecting and quantifying Mycobacterium tuberculosis complex (MTBC) and HIV-1 DNA was tested. Plasma inflammatory proteins were measured to assess systemic inflammation. Xpert Ultra had a high sensitivity of 94.7% and specificity of 100% for STB against TB culture and histology in both open and CT-guided biopsy samples. The ddPCR assay confirmed TB detection in 94% of patients with positive Xpert Ultra results. Four patients with negative TB diagnostic results had MTBC DNA detected by ddPCR. HIV-1 DNA was detected in the spinal tissues from all HIV-1-infected patients. MTBC DNA levels were significantly higher in HIV-1-co-infected spinal tissue samples (p< 0.01). We identified four biomarkers significantly associated with higher bacterial burden at the disease site (p< 0.01). Xpert Ultra and MTBC ddPCR improve the detection of STB. DdPCR can be utilized as an additional, highly sensitive tool for detecting and quantifying Mtb, in pathological samples that may be paucibacillary. These findings provide novel diagnostic and pathophysiologic insight into STB, in the context of HIV-1 infection, and provide rationale to include these tests in hospital and research settings for patients from communities burdened by TB and HIV-1

Introduction. Recent studies suggested that the progression of osteoarthritis (OA), a chronic degenerative joint disease, may be affected by the autonomic nervous system (ANS). Under healthy conditions, the sympathetic (SNS) and parasympathetic (PNS) branches of the ANS are well coordinated to maintain homeostasis. However, pathological conditions are frequently associated with a disturbance of this fine-tuned balance. Therefore, we analyzed whether an autonomic dysfunction occurs in OA patients. Method. 225 participants with early- or late-stage knee OA as well as 40 healthy age-matched probands were included in this study. Autonomic activity was investigated by analyzing heart rate variability (HRV), which decreases under chronic sympathetic overactivity. Time- and frequency-domain HRV indices SDRR, RMSSD, pRR50 and LF were examined. Linear regression analysis was performed to adjust for clinical characteristics, such as age, sex, BMI, or medication. Moreover, perceived chronic stress (PSQ) and pain (WOMAC) were assessed via questionnaires. In addition, the serum stress hormones cortisol, DHEA-S and IL-6 were analyzed via ELISA. Result. SDRR, RMSSD, and pRR50 were slightly reduced in the early stage of OA and showed significant decrease in the later stage of the disease. Also LF decreased significantly with OA progression. HRV was significantly influenced by the grade of OA, but not other patient characteristics. Moreover, late-stage OA patients demonstrated significantly higher PSQ and WOMAC levels compared to healthy controls. In addition, cortisol/DHEA-S ratio and IL-6 serum concentrations were significantly higher in late-stage than in early-stage OA patients and healthy controls. Conclusion. Reduced HRV, increased cortisol/DHEA-S ratio and PSQ level as well as elevated systemic IL-6 concentration indicated an autonomic shift towards a more pronounced SNS activity due to PNS deficiency in OA patients, particularly in the late-stage of the disease. Therefore, modulation of the ANS, for example by vagus nerve stimulation, might be a potential treatment strategy for of knee OA patients

Aims. Current diagnostic tools are not always able to effectively identify periprosthetic joint infections (PJIs). Recent studies suggest that circulating microRNAs (miRNAs) undergo changes under pathological conditions such as infection. The aim of this study was to analyze miRNA expression in hip arthroplasty PJI patients. Methods. This was a prospective pilot study, including 24 patients divided into three groups, with eight patients each undergoing revision of their hip arthroplasty due to aseptic reasons, and low- and high-grade PJI, respectively. The number of intraoperative samples and the incidence of positive cultures were recorded for each patient. Additionally, venous blood samples and periarticular tissue samples were collected from each patient to determine miRNA expressions between the groups. MiRNA screening was performed by small RNA-sequencing using the miRNA next generation sequencing (NGS) discovery (miND) pipeline. Results. Overall, several miRNAs in plasma and tissue were identified to be progressively deregulated according to ongoing PJI. When comparing the plasma samples, patients with a high-grade infection showed significantly higher expression levels for hsa-miR-21-3p, hsa-miR-1290, and hsa-miR-4488, and lower expression levels for hsa-miR-130a-3p and hsa-miR-451a compared to the aseptic group. Furthermore, the high-grade group showed a significantly higher regulated expression level of hsa-miR-1260a and lower expression levels for hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-148b-5p, hsa-miR-301a-3p, hsa-miR-451a, and hsa-miR-454-3p compared to the low-grade group. No significant differences were found between the low-grade and aseptic groups. When comparing the tissue samples, the high-grade group showed significantly higher expression levels for 23 different miRNAs and lower expression levels for hsa-miR-2110 and hsa-miR-3200-3p compared to the aseptic group. No significant differences were found in miRNA expression between the high- and low-grade groups, as well as between the low-grade and aseptic groups. Conclusion. With this prospective pilot study, we were able to identify a circulating miRNA signature correlating with high-grade PJI compared to aseptic patients undergoing hip arthroplasty revision. Our data contribute to establishing miRNA signatures as potential novel diagnostic and prognostic biomarkers for PJI. Cite this article: Bone Jt Open 2024;5(6):479–488

Spinal surgery deals with the treatment of different pathological conditions of the spine such as tumors, deformities, degenerative disease, infections and traumas. Research in the field of vertebral surgery can be divided into two main areas: 1) research lines transversal to the different branches; 2) specific research lines for the different branches. The transversal lines of research are represented by strategies for the reduction of complications, by the development of minimally invasive surgical techniques, by the development of surgical navigation systems and by the development of increasingly reliable systems for the control of intra-operative monitoring. Instead, specific lines of research are developed within the different branches. In the field of oncological pathology, the current research concerns the development of in vitro models for the study of metastases and research for the study of targeted treatment methods such as electrochemotherapy and mesenchymal stem cells for the treatment of aneurysmal bone cysts. Research in the field of spinal deformities is focused on the development of increasingly minimally invasive methods and systems which, combined with appropriate pharmacological treatments, help reduce trauma, stress and post-operative pain. Scaffolds based on blood clots are also being developed to promote vertebral fusion, a fundamental requirement for improving the outcome of vertebral arthrodesis performed for the treatment of degenerative disc disease. To improve the management and the medical and surgical treatment of vertebral infections, research has focused on the definition of multidisciplinary strategies aimed at identifying the best possible treatment path. Thus, flow-charts have been created which allow to manage the patient suffering from vertebral infection. In addition, dedicated silver-coated surgical instrumentation and bone substitutes have been developed that simultaneously guarantee mechanical stability and reduce the risk of further local infection. In the field of vertebral traumatology, the most recent research studies have focused on the development of methods for the biostimulation of the bone growth in order to obtain, when possible, healing without surgery. Methods have also been developed that allow the minimally invasive percutaneous treatment of fractures by means of vertebral augmentation with PMMA, or more recently with the use of silicone which from a biomechanical point of view has an elastic modulus more similar to that of bone. It is clear that scientific research has changed clinical practice both in terms of medical and surgical management of patients with spinal pathologies. The results obtained stimulate the basic research to achieve even more. For this reason, new lines of research have been undertaken which, in the oncology field, aim at developing increasingly specific therapies against target receptors. Research efforts are also being multiplied to achieve regeneration of the degenerated intervertebral disc and to develop implants with characteristics increasingly similar to those of bone in order to improve mechanical stability and durability over time. Photodynamic therapies are being developed for the treatment of infections in order to reduce the use of antibiotic therapies. Finally, innovative lines of research are being launched to treat and regenerate damaged nerve structures with the goal, still far from today, of making patients with spinal cord injuries to walk

Aim. Infection is one of the worst complications following total joint arthroplasty, which is often associated with significant morbidity. Currently, due to the global burden of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections, few multicentre studies have described a microbiological shift from Gram-positive cocci (GPC) towards MDR-GNB PJI (prosthetic joint infection). Additionally, the emergence of MDR-GNB impacts the therapeutic options and may increase the rate of PJI treatment failure. The purpose of the present study was to describe the predisposing factors associated to failure of treatment in an orthopaedic reference hospital in Brazil from 2014 through 2019. Method. Retrospective case-control analysis of patients treated for MDR-GNB PJI over a five-year period. Data were collected from medical, surgical and laboratory records. PJI were defined according the current MSIS criteria. MDR was defined as non-susceptibility to at least one agent in three or more antimicrobial categories. Patients with PJI with at least two positive tissue cultures for MDR-GNB were selected. The control group was patient with PJI caused by multisensitive organism (GNB or GPC). Absence of signs and symptoms of infection during the follow-up period was defined as cure. Definition of failure: death, need for another course of antibiotic, or the need for another surgical procedure to control the infectious site (relapse). Results. A total of 104 patients were selected, 59 patients in the MDR-GNB PJI group and 44 in the control group. Two outcomes were compared: cure or failure. The overall 1-year survival rate was 65.3% with the median survival time being 207.08 days. In the MDR-BGN infection group the 1-year survival rate was 59.3% and the average time of survival was 141.14 days. In contrast, in the Control group the 1-year survival rate was 73.8% with an average survival time of 230.29 days (p = 0.023). HR: 2.447, IC 1.099–5.448. The independent variables in the multivariate analysis associated to treatment failure were MDR-BGN infection (p = 0.023) HR 2,447 IC 1,099 –5,448, revision surgery (p = 0.042) HR 2,027 IC: 2,027–4,061, presence of comorbidities (p = 0.048) HR 2,508 IC: 0,972- 6,469 and previous antimicrobial use in the last 3 months (p = 0.022). HR 2,132 IC: 1,096- 4,149. Conclusions. GNB-MDR PJI increases approximately 2.5 times the chance of unfavourable outcome such as death and infectious relapse compared to infections with other multisensitive microorganism

Purpose: ‘Red flags’ are patient responses and findings on history taking and physical examination that are associated with an increased risk of serious spinal disorders. The purpose of this paper is to identify red flags reported in the low back pain literature, establish consensus on whether (or not) they are considered red flags, and review the evidence for these signs and symptoms. Methods: The following databases were searched using key words ‘red flag’ and ‘low back pain’:. MEDLINE (1951→). EMBASE (1974→). CINAHL (1982→). PsycINFO (1806→). AMED (1985→). PEDro. In addition, national guidelines and key texts were hand-searched. Each red flag identified in the literature was classified using The Guidelines Development Group’s format (where 100% coverage = ‘unanimity’; 75–99% = ‘consensus’; 51–74% = ‘majority view’; and 0–50% = ‘no consensus’), and the findings summarized. Results: The electronic searches revealed 54 papers, with the resultant ‘red flags’ ranging from ‘no consensus’ to ‘unanimity’. Evidence for these signs and symptoms is variable. Case reports and series justify labelling some features ‘red flags’, whilst others owe their label to clinical experience and expert opinion. Conclusion: Case reports and series should be reported/ published to help identify those signs and symptoms suggestive of serious spinal disorders and those more likely to be ‘red herrings’. Despite their importance, there is inconsistency within the literature in identifying true red flags and, an ability to identify these signs and symptoms is essential for all who practise spinal assessments

Introduction: Pathological conditions, which determine human atrophy, are numerouses and heterogeneous. Experimental studies prove that these different pathological conditions use common enzymatic pathways leading muscle atrophy. In every catabolic conditions where there is proteolyses’s increase, this one happens in association with up-regulation of two specific genes of skeletal muscle atrophy. These genes, MuRf1 (muscle ring finger-1) and MAFbx (muscle atrophy F-box), encode ubiquitin ligases. These ligases bind and mediate ubiquitination of myofibrillar proteins for subsequent degradation during muscle atrophy. The aim of our study is to obtain a better understanding of human muscle physiopathology in atrophy by use of histochemistry and immunolocalisation of MuRF-1 and MAFbx. Patients and Methods: 15 patients, amputated at third distal or proximal leg because of different acute or chronic pathology, were divided in two group. Group A: 12 elderly patients (mean age 72 years) amputated for vascular diseases (8) and complication of a diabetic foot (4). Group B: 3 young patients involved in car accident (mean age 25) amputated for limb’s acute arterial insufficiency. Gastrocnemius muscle biopsy specimens were obtained for all the patients, after that the informed consent was obtain, for histochemical (haematossilineosin), and immunohistochemical (anti- MuRf1, anti- MAFbx) analysis. Results: Histochemistry: Group A: skeletal muscle showed a decrease in fiber size in cross-sectional area and fiber length with adipose tissue. Group B: light skeletal muscle structural alteration. Immuno-histochemistry: in group A, in muscular drawings, polyclonal antibodies direct against MuRf1 and MAFbx had stained muscle biopsy specimens. Muscle fiber cells showed MuRf1 and MAFbx subsarcolemmatic immunoreactivity and weakly immunoreactivity of the extracellular matrix. We noticed no positivity to anti- MuRf1 and anti- MAFbx less in sections from group B muscle biopsy specimens and in sections in which were present tissue muscle degeneration with replacement of adipose tissue. Conclusion: The pathological results supported the concept that MuRf1 and MAFbx appeared to be regulatory peptide in cellular pathology that conduce to muscular atrophy. Our data support the hypothesis that different pathological conditions use common enzymatic pathways leading muscle atrophy. The demonstration that the muscle-specific proteins MAFbx and MuRF1 are upregulated in multiple pathological conditions of skeletal muscle atrophy it is critical to continue studying the cellular pathways to discover promising targets for the development of effective new treatments for skeletal muscle disease

Purpose: To investigate whether patients who present with Lumbar radicular signs and symptoms and who have MRI scans reported as showing no nerve root compression, improve following Nerve Root Injection (NRI). Methods: The clinic notes and MRI results of 127 patients who underwent NRI under the care of two spinal surgeons were reviewed retrospectively. Those patients with radicular pain and MRI scans reported as showing no nerve root compression were evaluated further. All patients had a selective NRI using a standard image intensifier guided oblique approach with 40 mg Kenalog and 1 ml 0.25% bupivacaine injected around the nerve root. The patients’ symptoms and signs were noted at the follow up appointment six weeks later. Results: 43 of the 127 patients who underwent selective NRI had MRI scan reports suggesting no nerve root compression. Of the 47 patients 30 (69%) reported a significant improvement (p=0.0009) in their leg pain following the NRI, the remaining 13 patients reported no relief. Conclusions: Clinicians treating patients presenting with lumbar radicular signs and symptoms should not rely on MRI report alone in the diagnosis and management of the patient. The results show that patients who exhibit lumbar radicular signs and symptoms who have non-concordant MRI results may still benefit from treatment (NRI). Ethics approval: None required. Statement of interest: None

Cancer is a major health problem for teenagers and young adults (TYA’s). However, many young people are often late to receive a cancer diagnosis. Young people may not recognize symptoms as serious and delay seeking help. Furthermore, there is evidence to suggest that once a young person does seek help from a general practitioner (GP), significant delay can still occur. During the annual Find Your Sense of Tumour (FYSOT) conference 2007; a group of 200 TYA’s with cancer participated in a survey regarding their diagnostic experience; the cohort included 22 patients with bone tumours. Following the onset of symptoms; nearly half of the TYA’s with a bone tumour (46%) reported 4 or more visits to their G.P before being referred to a specialist. However, 91% of bone tumour patients had multiple, ‘classic’ cancer symptoms and the majority (77%) sought help from the G.P within 4 weeks of noticing symptoms. The ‘Christie Crew’ (CC) are a group of TYA’s who have been treated for cancer and work on various projects to improve cancer services. The Christie Crew wanted to empower young people with the knowledge that TYA’s do get cancer and to raise awareness of the signs and symptoms of cancer and have produced a DVD and education pack that has been launched across 80 schools and throughout the North West. The DVD is highlights individual’s stories of diagnosis. There is also a poster campaign highlighting signs and symptoms of cancer being displayed in large public venues across the Manchester area. The aim is to roll out the project nationally as part of the health awareness (Healthy Schools) initiative. By highlighting that young people get cancer it is hoped that more young people will recognise the signs and symptoms and be empowered to go to their GP if they have persistent problems

Prosthetic joint infections (PJI) are caused by a variety of microorganisms but most frequently by staphylococci. The results of treatment of PJI due to organisms other than staphylococci are less known. The aim of this study is to evaluate the outcomes after streptococcal PJI. The data of 26 streptococcal (13 hip and 13 knee PJI from 24 patients) were retrieved from hospital based PJI register, and analyzed. There were 15 female and 11 male patients (mean age 66 y). Most (13) PJI were hematogenous. 15 PJI had been treated with debridement and retention (D&R) of the infected joint, 1 with permanent resection arthroplasty, 9 had two stage revision and 1 patient had one stage partial replacement. After the microbiological diagnosis was established most patients received 2–3 weeks of penicillin G or ceftriaxone followed by 2–6 months of oral amoxicillin. All patients had regular follow-ups after the procedure at least at 1 month, three months and one year. The results were classified as: PJI cure (in absence of clinical signs and symptoms of infection and with negative CRP), probable failure (in absence of clinical signs and symptoms of infection but with elevated CRP), definite failure (if a new treatment was necessary), and mechanical failure (aseptic loosening, periprosthetic fracture, quadriceps rupture). One foreign patient was lost to follow up. The mean follow up time for the rest was 60 months (from 16 to 167) months. There was probable prosthesis failure in 1 case, definite prosthesis failure in 7 cases and mechanical failure in 3 cases. The mean survival time of the failed prostheses was 28 (range from 2 to 83) months. 6 failures (40 %) occurred in group of cases that had undergone D&R, and 1 (6 %) in the two stage revision group. Among the 7 definite failures in 4 patients antibiotic treatment was empirically started after the symptoms reappeared resulting in long remission periods. Comparing to the published results of staphylococcal PJI it seems that D&R of the prosthesis for streptococcal PJI is considerably less successful. Rifampicin as a proven treatment of choice for staphylococcal infections is probably the main reason for the difference. An unexpected feature of streptococcal PJI is that definite failures are easily suppressed for long time with a short course of oral antibiotics

Bone is a connective tissue that undergoes constant remodeling. Any disturbances during this process may result in undesired pathological conditions. A single nucleotide substitution (596T-A) in exon eight which leads to a M199K mutation in human RANKL was found to cause osteoclast-poor autosomal recessive osteopetrosis (ARO). Patients with ARO cannot be cured by hematopoietic stem cell transplantation and, without proper treatments, will die in their early age. To date, how this mutation alters RANKL function has not been characterized. We thus hypothesized that hRANKL M199 residue is a structural determinant for normal RANKL-RANK interaction and osteoclast differentiation. By sharing our findings, we aim to achieve an improved clinical outcome in treating bone-related diseases such as osteoporosis, ARO and osteoarthritis. Site-directed mutagenesis was employed to create three rat RANKL mutants, replacing the methionine 200 (human M199 equivalent residue) with either lysine (M200K), alanine (M200A) or glutamic acid (M200E). Recombinant proteins were subsequently purified through affinity chromatography and visualized by Coomassie blue staining and western blot. MTS was carried out before osteoclastogenesis assay in vitro to measure the cellular toxicity. Bone resorption pit assay, immuno-fluorescent staining, luciferase reporter assay, RT-PCR, western blot and calcium oscillation detection were also conducted to explore the biological effect of rRANKL mutants. Computational modeling, thermal Shift Assay, western blot and protein binding affinity experiments were later carried out for structural analyses. rRANKL mutants M200K/A/E showed a drastically reduced ability to induce osteoclast formation and did not demonstrate features of competitive inhibition against wild-type rRANKL. These mutants are all incapable of supporting osteoclastic polarization and bone resorption or activating RANKL-induced osteoclast marker gene transcription. Consistently, they were unable to induce calcium flux, and also showed a diminished induction of IκBa degradation and activation of NF-kB and NFATc1 transcriptional activity. Furthermore, the transcriptional activation of the antioxidant response element (ARE) crucial in modulating oxidative stress and providing cytoprotection was also unresponsive to stimulation with rM200s. Structural analyses showed that rM200 is located in a hydrophobic pocket critical for protein folding. Thermal shift and western blot assays suggested that rM200 mutants formed unstructured proteins, with disturbed trimerisation and the loss of affinity to its intrinsic receptors RANK and OPG. Taken together, we first demonstrates the underlying cause of M199-meidated ARO in a cellular and molecular level by establishing a phenotype in BMMs similar to observed in human samples. Further investigation hints the structural significance of a hydrophobic pocket within the TNF-like region. Combined with pharmaceutical studies on small-molecule drugs, this finding may represent a therapeutic target motif for future development of anti-resorptive treatments

This study addresses a crucial gap in the knowledge of normative spinal growth in children. The objective of this study is to provide detailed and accurate 3D reference values for global and segmental spinal dimensions in healthy children under the age of 11. Radiographic spine examinations of healthy children conducted to rule out scoliosis were reviewed in four scoliosis referral centers in North America. All consecutive children aged three to eleven years old with EOS biplanar good quality x-rays, but without diagnosed growth-affecting pathologies, were included. Postero-Anterior and Lateral calibrated x-rays were used for spine 3D reconstruction and computation of vertebral body height and spine length. Median and interquartile range were calculated from cross-sectional data. Smooth centiles growth curves for 3D True Spinal Length (3DTSL) between T1 and S1, as well as for mid-vertebral heights of T5, T12 and L3, where fit and calibrated from data using the Lambda-Mu-Sigma method (GAMLSS package for R). This method automatically selects the best performing distribution from a familly of choices. Tables of centiles were then predicted from the computed models for selected ages. A total of 638 full spine examinations from asymptomatic patients were reconstructed in 3D, 397 in girls and 241 in boys. Medians and interquartile ranges were calculated for 3DTSL (T1-S1): 285 (24) mm, 314 (26) mm and 349 (31) mm, and for selected vertebral heights T5: 10 (1) mm, 11 (1) mm and 12 (1) mm, T12: 13 (2) mm, 14 (1) mm and 16 (2) mm, and L3: 14 (1) mm, 16 (2) mm and 18 (2) mm, respectively for the 3–6, 6–8 and 8–11 age groups. Centile curves ready for clinical use of the 3DTSL (T1-S1) and of the vertebral heights of T5, T12 and L3 as a function of age were derived for the 5, 10, 25, 50, 75, 90 and 95th centiles. In general, boys presented linear relationships between spinal dimensions and age, and girls presented more diverging trends with increased variance for older ages. Accordingly curves for boys follow the Normal distribution whereas those for girls follow the original Box-Cox-Cole-Green distribution. Model diagnostic tests (normally distributed residuals, adequate wormplots and |Z statistics| < 2) confirmed adequacy of the models and the absence of significant misfit. Accurate reference values were derived for spinal dimensions in healthy children. Spinal dimension charts showed that the spinal lengths and vertebral heights changed relatively constantly across the age groups closely resembling WHO total body height charts. The reference values will help physicians better assess their patients' growth potential. It could also be used to predict expected spinal dimensions at maturity or changes in pathologic conditions as well as to assess the impact of growth friendly interventions in the correction of spinal deformities

Necrotizing Fasciitis (NF) is a life-threatening infectious condition which requires expedient diagnosis to proceed with urgent surgical debridement. However, it can be difficult to establish an early diagnosis and expedite operative management as signs and symptoms are often non-specific and may mimic other pathology. Scoring systems such as The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) have been proposed to incorporate laboratory findings to predict whether a soft tissue infection is likely to be NF. Recent studies have found the sensitivity and specificity of the LRINEC tool to be lower than originally cited by the LRINEC authors in a validation cohort. Furthermore, there seems to be a predilection for certain geographic locations of patients with NF transferred to our tertiary care center for management, however, to our knowledge, geographic risk factors for NF have not been reported. This study also aims to determine the morbidity and mortality rate of NF at our Canadian tertiary hospital in recent years. Comorbidities such as smoking, diabetes, and steroid use will be analyzed for any correlation with developing NF. Identification of patient factors in correlation with laboratory values may help identify patients at higher risk for having NF upon their presentation to the emergency department. A resultant earlier diagnosis of necrotizing soft tissue infections would allow for earlier surgical debridement and positively influence patient outcomes. A retrospective chart review of 125 cases of NF at Kingston Health Sciences Centre from 2005 to 2017 was carried out to assess the validity of the LRINEC in our population and to examine the effect of comorbid factors such as smoking, diabetes, and corticosteroid use on the development of NF. The study cohort included patients treated by all surgical disciplines at our institution over twelve years. A separate cohort of 125 cellulitis or abscess cases was analyzed to assess the validity of the LRINEC tool in differentiating necrotizing fasciitis from non-necrotizing infections such as cellulitis and soft tissue abscess. The 30-day mortality rate of NF treated at our institution during the study period was 21%. Advanced age was found to be a significant risk factor for death within 30 days of diagnosis (p=0.001). Smoking and steroid use were both found to increase risk for developing NF (p=0.01 and p=0.03, respectively). Diabetes did not appear to increase risk NF. There was no statistical difference in mortality rates between males and females with NF. The sensitivity of LRINEC in detecting NF was only 47% with a specificity of 74%. The mortality rate of NF at our center is similar to that of other countries in recent years. Males and females have nearly equal mortality rates from NF. Smoking and steroid use appear to increase risk for developing NF, while diabetes may not. The LRINEC assessment tool alone may underestimate risk for developing NF, however, use of other clinical factors such as comorbidity analysis will further aide in the diagnosis of NF allowing for earlier surgical debridement

The stem cell fraction of a cell population is finely tuned by stimuli from the external microenvironment. Among these stimuli, a decrease of extracellular pH (pHe) may occur in a variety of physiological and pathological conditions, including hypoxia and inflammation. Also in bone, the maintenance of acid-base balance is fundamental for skeleton homeostasis. Bone cells are extremely sensitive to the effects of interstitial pH. Acidosis inhibits mineral deposition by osteoblasts and activates osteoclast-mediated bone resorption. Moreover, acidosis is associated with inflammation, and in case of bone injury, local short-term acidosis is a crucial regulator of the healing process. Evidence of the role of acidosis as an enhancer of MSC stemness and for their activation as sensors and switcher of inflammation will be discussed

Tendinopathy is one of the most common orthopaedic pathological conditions characterized by tendon degenerative changes. Excessive mechanical loading is considered as a major causative factor in the development of tendinopathy, but the mechanisms of pathogenesis remain unclear. High mobility group box-1 (HMGB1), a potent inflammatory mediator when released into the matrix, has been identified in the early stage tendinopathy patients. Since the release and contribution of HMGB1 in tendinopathy development due to mechanical overloading is unknown, we investigated the role of HMGB1 in tendinopathy using a mouse intensive treadmill running (ITR) model and injection of glycyrrhizin (GL), a specific inhibitor of HMGB1. A total of 48 mice were divided into four groups, Cage Control group: The animals were allowed to move freely in their cage, GL group: The animals were received daily IP injection of GL (50 mg/kg body weight) for 24 weeks, ITR group: The animals ran on treadmill at 15 meters/min for three h/ day, five days a week for 12 or 24 weeks, GL+ITR group: The animals ran the same protocol as that of ITR group plus daily IP injection of GL for 12 or 24 weeks. Six mice/group were sacrificed at 12 or 24 weeks and the Achilles and patellar tendon tissues were harvested and used for histochemical staining and immunostaining. Mechanical overloading induced HMGB1 released from the cell nuclei to the matrix (Fig. 1a, b) caused tendon inflammation (Fig. 1c, d) and led to tendon degenerative changes (Fig. 1e-j). After 12 weeks of ITR, the tendon tissue near the bone insertion site showed typical tendinopathic changes in cell shape, accumulation of glycosaminoglycans (GAG) (Fig. 1e, f), and increase in SOX-9 staining (Fig. 1g-j). After 24 weeks ITR, the distal site of Achilles tendon showed considerable changes in cell shape (Fig. 2A, g, arrows), which is round compared to more elongated in the control and GL groups (Fig. 2A, e, f). However, daily treatment with GL prior to ITR blocked the cell shape change (Fig. 2A, h) and, ITR induced extensive GAG accumulation in ITR group (Fig. 2B, bottom panel). Furthermore, GL inhibited ITR-induced expression of chondrogenic markers (SOX-9 and collagen II) in the tendons (Fig. 3). Our results showed that mechanical overloading-induced HMGB1 plays a critical role in the development of tendinopathy by initiating tendon inflammation and eventual degeneration characterized by the presence of chondrocyte-like cells, accumulation of proteoglycans, high levels of collagen type II production, and chondrogenic marker SOX-9 expression. These results provide the first evidence for the role of HMGB1 as a therapeutic target to prevent tendinopathy before its onset and block further development at its early inflammation stages. The inhibition of tendinopathy development by GL administration in this study also suggests the putative therapeutic potential of this natural triterpene that is already in clinical use to treat other inflammation-related diseases. For any figures or tables, please contact authors directly