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Introduction: Osteophytes are a prominent feature of osteoarthritis (OA) joints and one of the clinical hallmarks of the disease progression. Research on osteophytes is fragmentary and modes of its contribution to OA pathology are obscure. Aim: To elucidate the role of osteophytes in OA pathology from a perspective of molecular and cellular events. Methods: RNA-seq of fully grown osteophytes, collected from tibial plateau of six OA patients revealed patterns corresponding to active extracellular matrix re-modulation and prominent participation of mast cells. Presence of mast cells was further confirmed by immunohistochemistry, performed on the sections of the osteophytes using anti-tryptase alpha/beta-1 and anti-FC epsilon RI antibodies and the related key up-regulated genes were validated by qRT-PCR. To test the role of OA synovial fluid (SF) in mast cell maturation as proposed by the authors, hematopoietic stem cells (HSCs) and ThP1 cells were cultured in a media supplemented with 10% SF samples, obtained from various grades of OA patients and were monitored using specific cell surface markers by flow cytometry. Proteomics analysis of SF samples was performed to detect additional markers specific to mast cells and inflammation that drive the cell differentiation and maturation. Results: Transcriptomics of osteophytes revealed a significant upregulation of mast cells specific genes such as chymase 1 (CMA1; 5-fold) carboxypeptidase A3 (CPA3; 4-fold), MS4A2/FCERI (FCERI; 4.2-fold) and interleukin 1 receptor-like 1 (IL1RL1; 2.5-fold) indicating their prominent involvement. (In IHC, anti-tryptase alpha/beta-1 and anti- FC epsilon RI-stained active mast cells were seen populated in cartilage, subchondral bone, and trabecular bone.) Based on these outcomes and previous learnings, the authors claim a possibility of mast cells invasion into osteophytes is mediated by SF and present in vitro cell differentiation assay results, wherein ThP1 and HSCs showed differentiation into HLA-DR+/CD206+ and FCERI+ phenotype, respectively, after exposing them to medium containing 10% SF for 9 days. Proteomics analysis of these SF samples showed an accumulation of mast cell-specific inflammatory proteins. Conclusions: RNA-seq analysis followed by IHC study on osteophyte samples showed a population of mast cells resident in them and may further accentuate inflammatory pathology of OA. Besides subchondral bone, the authors propose an alternative passage of mast cells invasion in osteophytes, wherein OA SF was found to be necessary and sufficient for maturation of mast cell precursor into effector cells.

Background The Charlson and Elixhauser Comorbidity Indices are the most widely used comorbidity assessment methods in medical research. Both methods are adapted for use with the International Classification of Diseases, which 10th revision (ICD-10) is used by over a hundred countries in the world. Available Charlson and Elixhauser Comorbidity Index calculating methods are limited to a few applications with command-line user interfaces, all requiring specific programming language skills. This study aims to use Microsoft Excel to develop a non-programming and ICD-10 based dataset calculator for Charlson and Elixhauser Comorbidity Index and to validate its results with R- and SAS-based methods. Methods The Excel-based dataset calculator was developed using the program’s formulae, ICD-10 coding algorithms, and different weights of the Charlson and Elixhauser Comorbidity Index. Real, population-wide, nine-year spanning, index hip fracture data from the Estonian Health Insurance Fund was used for validating the calculator. The Excel-based calculator’s output values and processing speed were compared to R- and SAS-based methods. Results A total of 11,491 hip fracture patients’ comorbidities were used for validating the Excel-based calculator. The Excel-based calculator’s results were consistent, revealing no discrepancies, with R- and SAS-based methods while comparing 192,690 and 353,265 output values of Charlson and Elixhauser Comorbidity Index, respectively. The Excel-based calculator’s processing speed was slower but differing only from a few seconds up to four minutes with datasets including 6250–200,000 patients. Conclusions This study proposes a novel, validated, and non-programming-based method for calculating Charlson and Elixhauser Comorbidity Index scores. As the comorbidity calculations can be conducted in Microsoft Excel’s simple graphical point-and-click interface, the new method lowers the threshold for calculating these two widely used indices. Trial registration retrospectively registered.

This study investigated the effect of total joint arthroplasty (TJA) on arterial stiffness in patients with severe osteoarthritis (OA) compared to non-OA controls. A prospective cohort of 70 severe OA patients undergoing TJA (mean age 62 ± 7) and 82 age- and sex-matched controls without OA was followed over seven years. Aortic pulse wave velocity (aPWV), augmentation index (AIx), and central and peripheral haemodynamic parameters were measured using applanation tonometry (Sphygmocor) at baseline and follow-up. At baseline, the aPWV was significantly higher in the TJA group ( p  = 0.023). Over seven years, aPWV increased significantly in the control group, eliminating the between-group difference (9.3 ± 0.3 m/s in TJA vs. 9.3 ± 0.2 m/s in controls, p  = 0.939). AIx was initially similar between groups, but was significantly lower in the TJA group at follow-up ( p  = 0.005). The increase in central diastolic blood pressure was also significantly smaller in the TJA group ( p  = 0.008). These results indicate that TJA may slow the progression of arterial stiffness and reduce central haemodynamic changes in severe OA patients compared to the general population.

Background Osteogenesis Imperfecta (OI) is a rare genetic disorder involving bone fragility. OI patients typically suffer from numerous fractures, skeletal deformities, shortness of stature and hearing loss. The disorder is characterised by genetic and clinical heterogeneity. Pathogenic variants in more than 20 different genes can lead to OI, and phenotypes can range from mild to lethal forms. As a genetic disorder which undoubtedly affects quality of life, OI significantly alters the reproductive confidence of families at risk. The current review describes a selection of the latest reproductive approaches which may be suitable for prospective parents faced with a risk of OI. The aim of the review is to alleviate suffering in relation to family planning around OI, by enabling prospective parents to make informed and independent decisions. Main body The current review provides a comprehensive overview of possible reproductive options for people with OI and for unaffected carriers of OI pathogenic genetic variants. The review considers reproductive options across all phases of family planning, including pre-pregnancy, fertilisation, pregnancy, and post-pregnancy. Special attention is given to the more modern techniques of assisted reproduction, such as preconception carrier screening, preimplantation genetic testing for monogenic diseases and non-invasive prenatal testing. The review outlines the methodologies of the different reproductive approaches available to OI families and highlights their advantages and disadvantages. These are presented as a decision tree, which takes into account the autosomal dominant and autosomal recessive nature of the OI variants, and the OI-related risks of people without OI. The complex process of decision-making around OI reproductive options is also discussed from an ethical perspective. Conclusion The rapid development of molecular techniques has led to the availability of a wide variety of reproductive options for prospective parents faced with a risk of OI. However, such options may raise ethical concerns in terms of methodologies, choice management and good clinical practice in reproductive care, which are yet to be fully addressed.

BackgroundConsidering the excellent results already achieved in total hip arthroplasty (THA), new implants must be at least as safe as currently used implants and lead to longer survival. A new cementless femoral stem, SP-CL®, has been introduced. The aim of this study is to evaluate intraoperative complications and assess the risk factors of THA with the SP-CL® implant.Materials and methodsAll THA patients who were operated on using the SP-CL® (LINK, Hamburg, Germany) implant between 2015 and 2018 were included in the analysis. Data were collected from medical records from national and hospital electronic databases. Radiological measurements were made from standard pre- and postoperative radiographs.ResultsA total of 222 THA were performed using the SP-CL® implant. The average age of the patients was 56 years (14–77 years). There were 1 transient sciatic nerve injury, 1 acetabular fracture, and 11 (5.0%) intraoperative femoral fractures (IFF), of which 7 were treated with cerclage wire or titanium band during the operation while the other fractures were treated conservatively. None of the IFF patients were revised due to fracture during the follow-up period (one revision due to infection). The radiographic morphology of proximal femur was associated with increased risk of IFF (p = 0.02).ConclusionsThe results of the current study demonstrate a 5% incidence of IFF when using the LINK SP-CL® femoral stem in THA. The radiographic morphology of the proximal femur was an important predictor of IFF and should be assessed when using SP-CL®.Level of evidenceLevel 4.

Metabolomic analysis is an emerging new diagnostic tool, which holds great potential for improving the understanding of osteoarthritis (OA)-caused metabolomic shifts associated with systemic inflammation and oxidative stress. The main aim of the study was to map the changes of amino acid, biogenic amine and complex lipid profiles in severe OA, where the shifts should be more eminent compared with early stages. The fasting serum of 70 knee and hip OA patients and 82 controls was assessed via a targeted approach using the AbsoluteIDQ™ p180 kit. Changes in the serum levels of amino acids, sphingomyelins, phoshatidylcholines and lysophosphatidylcholines of the OA patients compared with controls suggest systemic inflammation in severe OA patients. Furthermore, the decreased spermine to spermidine ratio indicates excessive oxidative stress to be associated with OA. Serum arginine level was positively correlated with radiographic severity of OA, potentially linking inflammation through NO synthesis to OA. Further, the level of glycine was negatively associated with the severity of OA, which might refer to glycine deficiency in severe OA. The current study demonstrates significant changes in the amino acid, biogenic amine and low-molecular weight lipid profiles of severe OA and provides new insights into the complex interplay between chronic inflammation, oxidative stress and OA.

Atopic dermatitis is a chronic inflammatory disease which usually starts in the early childhood and ends before adulthood. However up to 3% of adults remain affected by the disease. The onset and course of the disease is influenced by various genetic and environmental factors. Although the immune system has a great effect on the outcome of the disease, metabolic markers can also try to explain the background of atopic dermatitis. In this study we analyzed the serum of patients with atopic dermatitis using both targeted and untargeted metabolomics approaches. We found the most significant changes to be related to phosphatidylcholines, acylcarnitines and their ratios and a cleavage peptide of Fibrinogen A-α. These findings that have not been reported before will further help to understand this complex disease.

IntroductionTotal hip arthroplasty (THA) is an effective treatment for severe osteoarthritis. However, THA has a high surgical risk for patients with concomitant diseases and is associated with several serious complications, such as myocardial infarction, acute kidney injury and cognitive dysfunction. This study will explore the potential protective effects of remote ischaemic preconditioning (RIPC) in cemented THA patients.Methods and analysisThe PRINCIPAL study is designed as a randomised, controlled, parallel-group, blinded trial to assess the impact of RIPC in cemented THA patients. The study will compare two patient groups—one group will have the RIPC procedure, and the second will have the sham procedure. The primary outcome is the peak troponin T concentration during the three postoperative days. Secondary outcomes include markers of arterial stiffness (augmentation index (AIx), carotid-femoral pulse wave velocity, central blood pressures), neural (neuron-specific enolase, S100B) and renal injury biomarkers (estimated glomerular filtration rate, creatinine, cystatin C), markers of systemic inflammation (hypoxia-inducible factor 1-alpha, interleukin (IL)-6, IL-1β, tumour necrosis factor-alpha, IL-10) and oxidative stress (total peroxide concentration, total antioxidant capacity), as well as clinical outcome measures such as major adverse cardiovascular events and all-cause mortality.Ethics and disseminationThe ethical board of the University of Tartu has granted approval for the study (no. 384T-26). The results of this study will be disseminated in international peer-reviewed journals.Trial registration numberNCT06323018.

Background: Besides conventional norms that recognize synovial fluid (SF) as a joint lubricant, nutritional channel, and a diagnostic tool in knee osteoarthritis (kOA), based on the authors previous studies, this study aims to define functional role of SF in kOA. Methods: U937, a monocytic, human myeloid cell line, was induced with progressive grades of kOA SF, and the induction response was assessed on various pro-inflammatory parameters. This ‘SF challenge test model’ was further extended to determine the impact of SF on U937 differentiation using macrophage-specific markers and associated transcription factor genes. Mitochondrial membrane potential changes in SF-treated cells were evaluated with fluorescent JC-1 probe. Results: a significant increase in nitric oxide, matrix metalloproteinase (MMP) 1, 13, and vascular endothelial growth factor (VEGF)-1 was noted in the induced cells. A marked increase was seen in CD68, CD86, and the transcription factors –activator protein (AP)-1, interferon regulatory factor (IRF)-1, and signal transducer and activator of transcription (STAT)-6 in the SF-treated cells indicating active monocytes to macrophage differentiation. Reduced mitochondrial membrane potential was reflected by a reduced red-to-green ratio in JC-1 staining. Conclusions: these results underline the active role of OA SF in stimulating and maintaining inflammation in joint cells, fostering monocyte differentiation into pro-inflammatory macrophages. The decline in the membrane potential suggestive of additional inflammatory pathway in OA via the release of pro-apoptotic factors and damaged associated molecular patterns (DAMPs) within the cells. Overall, biochemical modulation of SF warrants a potential approach to intervene inflammatory cascade in OA and mitigate its progression.

Background Isolated greater trochanter fracture (IGT) and conventional hip fracture (HF) affect the same anatomical area but are usually researched separately. HF is associated with high mortality, and its management is well established. In contrast, IGT’s effect on mortality is unknown, and its best management strategies are unclear. This study aims to compare these patient populations, their acute- and post-acute care, physical and occupational therapy use, and up to three-year mortality. Methods This retrospective cohort study is based on population-wide data of Estonia, where routine IGT management is non-operative and includes immediate weight-bearing as tolerated. The study included patients aged ≥ 50 years with a validated index HF or IGT diagnosis between 2009–2017. The fracture populations’ acute- and post-acute care, one-year physical and occupational therapy use and three-year mortality were compared. Results A total of 0.4% (50/11,541) of included patients had an IGT. The baseline characteristics of the fracture cohorts showed a close resemblance, but the IGT patients received substantially less care. Adjusted analyses showed that the IGT patients’ acute care was 4.5 days [3.4; 5.3] shorter they had 39.2 percentage points [25.5; 52.8] lower probability for receiving post-acute care, and they had 50 percentage points [5.5: 36]] lower probability for receiving physical and occupational therapy. The IGT and HF patients’ mortality rates were comparable, being 4% and 9% for one month, 28% and 31% for one year, and 46% and 49% for three years, respectively. Crude and adjusted analyses could not find significant differences in their three-year mortality, showing a p -value of 0.6 and a hazard ratio of 0.9 [0.6; 1.3] for the IGT patients, retrospectively. Conclusions Despite IGT being a relatively minor injury, the evidence from this study suggests that it may impose a comparable risk on older patients’ survival, as does HF due to the close resemblance of the two fracture populations. Therefore, IGT in older patients may signify an underlying need for broad-based medical attention, ensuring need-based, ongoing, coordinated care. Trial registration Retrospectively registered.