Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3-4-part proximal humerus fractures in older patients (NITEP): An open-label randomized trial.

BACKGROUND: Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking. METHODS AND FINDINGS: The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [-9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [-7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [-5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely. CONCLUSIONS: In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.

Novel pathogenic variants in SPARC as cause of osteogenesis imperfecta: Two case reports.

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.

Synovial Fluid in Knee Osteoarthritis Extends Proinflammatory Niche for Macrophage Polarization.

Macrophage polarization is a steering factor of osteoarthritis (OA) progression. Synovial fluid (SF) obtained from OA patients with different Kellgren-Lawrence grades (KL grades) holds several proinflammatory factors and was hypothesized to induce macrophage differentiation and polarization by providing the needed microenvironment. U937 cells and peripheral-blood-mononuclear-cell-derived monocytes (PBMC-derived CD14+ cells) were induced with SFs of progressive KL grades for 48 h, and the status of the differentiated cells was evaluated by cell surface markers representing M1 and M2 macrophage phenotypes. Functional viability assessment of the differentiated cells was performed by cytokine estimation. The fraction of macrophages and their phenotypes were estimated by immunophenotyping of SF-isolated cells of different KL grades. A grade-wise proteome analysis of SFs was performed in search of the factors which are influential in macrophage differentiation and polarization. In the assay on U937 cells, induction with SF of KL grade III and IV showed a significant increase in M1 type (CD86+). The percentage of M2 phenotype (CD163+) was significantly higher after the induction with SF of KL grade II. A Significantly higher M1/M2 ratio was estimated in the cells induced with KL grade III and IV. The cell differentiation pattern in the assay on PBMC-derived CD14+ cells showed a grade-wise decline in both M1 (CD11C+, CD86+) and M2 phenotype (CD163+). Cytokine estimation specific to M1 (TNF-α, IL-6, IL-1ß, IFN-γ) and M2 (IL-4 and IL-10) macrophages corelated with the differentiation pattern in the U937 cell assay, while it did not reveal any significant changes in the PBMC-derived CD14+ cells assay. SF cells' immunophenotyping showed the highest percentage of CD14+ macrophages in KL grade II; CD86+ and CD163+ cells were minimal in all KL grades' SFs. The proteome analysis revealed significantly expressed MIF, CAPG/MCP, osteopontin, and RAS-related RAB proteins in KL grade III and IV samples, which are linked with macrophages' movement, polarization, and migration-behavior. In conclusion, this study demonstrated that SF in OA joints acts as a niche and facilitates M1 phenotype polarization by providing a proinflammatory microenvironment.

Isolated greater trochanter fracture may impose a comparable risk on older patients' survival as a conventional hip fracture: a population-wide cohort study.

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.

Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant.

Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic variants in prolyl 3-hydroxylase 1 (P3H1) are known to cause severe OI by affecting the competence of the prolyl 3-hydroxylation­cartilage associated protein­peptidyl-prolyl cis-trans isomerase B (P3H1-CRTAP-CyPB) complex, which acts on the Pro986 residue of collagen type I α 1 (COL1A1) and Pro707 collagen type I α 2 (COL1A2) chains. The investigation of an OI cohort of 146 patients in Vietnam identified 14 families with P3H1 variants. The c.1170+5G>C variant was found to be very prevalent (12/14) and accounted for 10.3% of the Vietnamese OI cohort. New P3H1 variants were also identified in this population. Interestingly, the c.1170+5G>C variants were found in families with the severe clinical Sillence types 2 and 3 but also the milder types 1 and 4. This is the first time that OI type 1 is reported in patients with P3H1 variants expanding the clinical spectrum. Patients with a homozygous c.1170+5G>C variant shared severe progressively deforming OI type 3: bowed long bones, deformities of ribcage, long phalanges and hands, bluish sclera, brachycephaly, and early intrauterine fractures. Although it remains unclear if the c.1170+5G>C variant constitutes a founder mutation in the Vietnamese population, its prevalence makes it valuable for the molecular diagnosis of OI in patients of the Kinh ethnicity. Our study provides insight into the clinical and genetic variation of P3H1-related OI in the Vietnamese population.

Mast Cells Differentiated in Synovial Fluid and Resident in Osteophytes Exalt the Inflammatory Pathology of Osteoarthritis.

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.

Simple Excel and ICD-10 based dataset calculator for the Charlson and Elixhauser comorbidity indices.

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.

Causal variation modelling identifies large inter- and intra-regional disparities in physical therapy offered to hip fracture patients in Estonia.

PURPOSE: An essential measure of hip fracture (HF) rehabilitation, the amount of physical therapy (PT) used per patient, has been severely understudied. This study (1) evaluates post-acute PT use after HF in Estonia, (2) presents causal variation modelling for examining inter- and intra-regional disparities, and (3) analyses its temporal trends. MATERIALS AND METHODS: This retrospective cohort study used validated population-wide health data, including patients aged ≥50 years, with an index HF diagnosed between January 2009 and September 2017. Patients' 6-month PT use was analysed and reported separately for acute and post-acute phases. RESULTS: While most of the included 11,461 patients received acute rehabilitation, only 40% of them received post-acute PT by a median of 6 h. Analyses based on measures of central tendency revealed 2.5 to 2.6-fold inter-regional differences in HF post-acute rehabilitation. Variation modelling additionally detected intra-regional disparities, showing imbalances in the fairness of allocating local rehabilitation resources between a county's patients. CONCLUSIONS: This study demonstrates the advantages of causal variation modelling for identifying inter- and intra-regional disparities in rehabilitation. The analyses revealed persisting large multi-level disparities and accompanying overall inaccessibility of PT in HF rehabilitation in Estonia, showing an urgent need for system-wide improvements.Implications for rehabilitationThis study demonstrates the advantages of causal variation modelling for identifying inter- and intra-regional disparities in rehabilitation, using an essential outcome measure - used physical therapy hours.The study revealed large multi-level disparities and overall inaccessibility of physical therapy in hip fracture rehabilitation in Estonia, showing an urgent need for system-wide improvements.This study expands our knowledge on unstudied topics - hip fracture post-acute care and long-term physical therapy use.This regional analysis provides the first evidence-based regional-level basis for improving the rehabilitation system in Estonia.

Upregulation of 15 Antisense Long Non-Coding RNAs in Osteosarcoma.

The human genome encodes thousands of natural antisense long noncoding RNAs (lncRNAs); they play the essential role in regulation of gene expression at multiple levels, including replication, transcription and translation. Dysregulation of antisense lncRNAs plays indispensable roles in numerous biological progress, such as tumour progression, metastasis and resistance to therapeutic agents. To date, there have been several studies analysing antisense lncRNAs expression profiles in cancer, but not enough to highlight the complexity of the disease. In this study, we investigated the expression patterns of antisense lncRNAs from osteosarcoma and healthy bone samples (24 tumour-16 bone samples) using RNA sequencing. We identified 15 antisense lncRNAs (RUSC1-AS1, TBX2-AS1, PTOV1-AS1, UBE2D3-AS1, ERCC8-AS1, ZMIZ1-AS1, RNF144A-AS1, RDH10-AS1, TRG-AS1, GSN-AS1, HMGA2-AS1, ZNF528-AS1, OTUD6B-AS1, COX10-AS1 and SLC16A1-AS1) that were upregulated in tumour samples compared to bone sample controls. Further, we performed real-time polymerase chain reaction (RT-qPCR) to validate the expressions of the antisense lncRNAs in 8 different osteosarcoma cell lines (SaOS-2, G-292, HOS, U2-OS, 143B, SJSA-1, MG-63, and MNNG/HOS) compared to hFOB (human osteoblast cell line). These differentially expressed IncRNAs can be considered biomarkers and potential therapeutic targets for osteosarcoma.

Synovium-Synovial Fluid Axis in Osteoarthritis Pathology: A Key Regulator of the Cartilage Degradation Process.

Failure of conventional anti-inflammatory therapies in osteoarthritis (OA) underlines the insufficient knowledge about inflammatory mechanisms, patterns and their relationship with cartilage degradation. Considering non-linear nature of cartilage loss in OA, a better understanding of inflammatory milieu and MMP status at different stages of OA is required to design early-stage therapies or personalized disease management. For this, an investigation based on a synovium-synovial fluid (SF) axis was planned to study OA associated changes in synovium and SF along the progressive grades of OA. Gene expressions in synovial-biopsies from different grades OA patients (N = 26) revealed a peak of IL-1ß, IL-15, PGE2 and NGF in early OA (Kellgren-Lawrence (KL) grade-I and II); the highest MMP levels were found in advanced stages (KL grade-III and IV). MMPs (MMP-1, 13, 2 and 9) abundance and FALGPA activity estimated in forty SFs of progressive grades showed the maximum protein levels and activity in KL grade-II and III. In an SF challenge test, SW982 and THP1 cells were treated with progressive grade SFs to study the dynamics of MMPs modulation in inflammatory microenvironment; the test yielded a result pattern, which matched with FALGPA and the protein-levels estimation. Inflammatory mediators in SFs served as steering factor for MMP up-regulation. A correlation-matrix of IL-1ß and MMPs revealed expressional negative correlation.

Nonoperative hip fracture management practices and patient survival compared to surgical care: an analysis of Estonian population-wide data.

A notable proportion of hip fracture patients receive nonoperative management, but such practice is seldom analysed. Although highly variable reasons underpin hip fracture nonoperative management, none of these practices conclusively outweigh the superiority of operative management. Nonoperative management should be only considered when surgery is not an option. PURPOSE: Reasons underpinning hip fracture (HF) nonoperative management (NOM) are seldom analysed. This study aims to identify the reasons behind NOM and assess the accuracy of these decisions using these patients' survival compared with those treated with operative management (OM). METHODS: This is a retrospective cohort study based on population-wide administrative health data, including patients aged ≥ 50 with an index HF diagnosis between January 2009 and September 2017. NOM patients were subgrouped according to their expected prognoses, and their survival up to 36 months was compared with those treated surgically. RESULTS: From a total of 11,210 included patients, 6.8% (766) received NOM. Varying reasons lead to NOM, dividing them further into five distinct subgroups: (I) 46% NOM decision due to poor expected prognosis with OM; (II) 29% NOM decision due to poor expected prognosis for mixed reasons; (III) 15% NOM decision due to good expected prognosis with NOM; (IV) 8.0% NOM decision due to patient's refusal of OM; and (V) 1.3% NOM decision due to occult HF. Only poor prognosis and patients who refused OM (I, II, IV) had worse survival than OM patients. However, a relatively high proportion of the poor prognosis patients survived 1 year (29%). CONCLUSION: Although there was high variability in reasons underpinning HF NOM, none of these practices conclusively outweigh OM's superiority. NOM should be considered with utmost care and only for patients for whom OM is out of the question - well-defined medical unfitness or carefully considered refusal by understanding the increased mortality risk.

Pathophysiological landscape of osteoarthritis.

A sharp rise in osteoarthritis (OA) incidence is expected as over 25% of world population ages in the coming decade. Although OA is considered a degenerative disease, mounting evidence suggests a strong connection with chronic metabolic conditions and low-grade inflammation. OA pathology is increasingly understood as a complex interplay of multiple pathological events including oxidative stress, synovitis and immune responses revealing its intricate nature. Cellular, biochemical and molecular aspects of these pathological events along with major outcomes of the relevant research studies in this area are discussed in the present review. With reference to their published and unpublished work, the authors strongly propose synovitis as a central OA pathology and the key OA pathological events are described in connection with it. Recent research outcomes also have succeeded to establish a linkage between metabolic syndrome and OA, which has been precisely included in the present review. Impact of aging process cannot be neglected in OA. Cell senescence is an important mechanism of aging through which it facilitates development of OA like other degenerative disorders, also discussed within a frame of OA. Conclusively, the reviewers urge low-grade inflammation linked to aging and derailed immune function as a pathological platform for OA development and progression. Thus, interventions targeted to prevent inflammaging hold a promising potential in effective OA management and efforts should be invested in this direction.

RNA sequencing analysis reveals increased expression of interferon signaling genes and dysregulation of bone metabolism affecting pathways in the whole blood of patients with osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disorder in which the patients suffer from numerous fractures, skeletal deformities and bluish sclera. The disorder ranges from a mild form to severe and lethal cases. The main objective of this pilot study was to compare the blood transcriptional landscape of OI patients with COL1A1 pathogenic variants and their healthy relatives, in order to find out different gene expression and dysregulated molecular pathways in OI. METHODS: We performed RNA sequencing analysis of whole blood in seven individuals affected with different OI severity and their five unaffected relatives from the three families. The data was analyzed using edgeR package of R Bioconductor. Functional profiling and pathway analysis of the identified differently expressed genes was performed with g:GOSt and MinePath web-based tools. RESULTS: We identified 114 differently expressed genes. The expression of 79 genes was up-regulated, while 35 genes were down-regulated. The functional analysis identified a presence of dysregulated interferon signaling pathways (IFI27, IFITM3, RSAD12, GBP7). Additionally, the expressions of the genes related to extracellular matrix organization, Wnt signaling, vitamin D metabolism and MAPK-ERK 1/2 pathways were also altered. CONCLUSIONS: The current pilot study successfully captured the differential expression of inflammation and bone metabolism pathways in OI patients. This work can contribute to future research of transcriptional bloodomics in OI. Transcriptional bloodomics has a strong potential to become a major contributor to the understanding of OI pathological mechanisms, the discovery of phenotype modifying factors, and the identification of new therapeutic targets. However, further studies in bigger cohorts of OI patients are needed to confirm the findings of the current work.

Metabolomic Signature of Amino Acids, Biogenic Amines and Lipids in Blood Serum of Patients with Severe Osteoarthritis.

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.

Alternative splicing of leptin receptor overlapping transcript in osteosarcoma.

IMPACT STATEMENT: Osteosarcoma (OS, also known as osteogenic sarcoma) is the most common primary malignancy of bone in children and adolescents. The molecular mechanisms of OS are extremely complicated and its molecular mediators remain to be elucidated. We sequenced total RNA from 18 OS bone samples (paired normal-tumor biopsies). We found statistically significant (FDR <0.05) 26 differentially expressed transcript variants of LEPROT gene with different expressions in normal and tumor samples. These findings contribute to the understanding of molecular mechanisms of OS development and provide encouragement to pursue further research.

High variability in hip fracture post-acute care and dementia patients having worse chances of receiving rehabilitation: an analysis of population-based data from Estonia.

PURPOSE: Rehabilitation is a fundamental part of hip fracture (HF) care; however, the best strategies are unclear. This study maps index HF patients' post-acute care (PAC) in Estonia and compares the PAC of patients with and without a diagnosis of dementia. METHODS: A retrospective cohort study was conducted using validated population-based data from the Estonian Health Insurance Fund using inclusion criteria: age ≥ 50 years, International Classification of Diseases code (S72.0-2) indicating HF between 1 January 2009 and 30 September 2017, and the survival of PAC. The presence of dementia diagnosis was based on the 10th revision of the International Classification of Diseases codes. RESULTS: A total of 8729 patients were included in the study, 11% of whom had a dementia diagnosis. The PAC of HF patients varied from extensive to no care: 8.7% received combined inpatient and outpatient care; 59% received hospital care (13% had a length of stay (LOS) > 6 weeks; 33% had LOS between 2-4 weeks, 14% had LOS < 2 weeks); 4% received only community-based care; 28% received no PAC. Physical therapy (PT) was received by 56% of patients and by 35% of those with dementia diagnosis. Dementia patients had 1.5-fold higher odds of not receiving PT. CONCLUSION: In Estonia, the PAC after index HF varies from extensive to no care, and the provision of PT is limited and unequal, affecting dementia patients in particular. Thus, there is an urgent need to standardise index HF PAC by reviewing the resources of PT and developing effective rehabilitation practices.

Intraoperative complications in total hip arthroplasty using a new cementless femoral implant (SP-CL®).

BACKGROUND: Considering 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 METHODS: All 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. RESULTS: A 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). CONCLUSIONS: The 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 EVIDENCE: Level 4.

Reproductive options for families at risk of Osteogenesis Imperfecta: a review.

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.

Inter- and Intrafamilial Phenotypic Variability in Individuals with Collagen-Related Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a rare genetic disorder also known as a "brittle bone disease." Around 90% of patients with OI harbor loss-of-function or dominant negative pathogenic variants in the COL1A1 and COL1A2 genes, which code for collagen type I α1 and α2 chains. Collagen-related forms of the disorder are classified as Sillence OI types I-IV. OI phenotype expression ranges from mild to lethal. The current study aims to evaluate associations between interfamilial and intrafamilial phenotypic variability and genotype characteristics of patients with collagen-related OI. The study was based on a systematic review of collagen-related OI cases from the University of Tartu OI database (n = 137 individuals from 81 families) and the Dalgleish database (n = 479 individuals). Interfamilial variability analysis has shown that 17.74% of all studied OI-related variants were associated with the same phenotype. The remaining 82.26% of pathogenic variants were associated with variable phenotypes. Additionally, higher interfamilial variability correlated with the COL1A1 gene (P value = 0.001) and dominant-negative variants (P value = 0.0007). Within intrafamilial variability, 32.81% families had increasing or decreasing OI phenotype severity across generations. Higher intrafamilial variability of phenotypes correlated with the collagen I dominant negative variants (P value = 0.0246). The current study shows that, in line with other phenotype modification factors, OI interfamilial and intrafamilial diversity potential is associated with the genotype characteristics of the OI-causing pathogenic variants. The results of the current study may advance knowledge of OI phenotype modification as well as assist family planning and the evaluation of disease progression in subsequent generations.

The Genetic Variations Associated With Time to Aseptic Loosening After Total Joint Arthroplasty.

BACKGROUND: Total joint arthroplasty (TJA) is one of the most frequent surgical procedures performed in modern hospitals, and aseptic loosening is the most common indication for revision surgeries. We conducted a systemic exploration of potential genetic determinants for early aseptic loosening. METHODS: Data from 423 patients undergoing TJA were collected and analyzed. Three analytical groups were formed based on joint arthroplasty status. Group 1 were TJA patients without symptoms of aseptic loosening of at least 1 year, group 2 were patients with primary TJA, and group 3 were patients receiving revision surgery because of aseptic loosening. Genome-wide genotyping comparing genotype frequencies between patients with and without aseptic loosening (group 3 vs groups 1 and 2) was conducted. A case-control association analysis and linear modeling were applied to identify the impact of the identified genes on implant survival with time to the revision as an outcome measure. RESULTS: We identified 52 single-nucleotide polymorphisms (SNPs) with a genome-wide suggestive P value less than 10-5 to be associated with the implant loosening. The most remarkable odds ratios (OR) were found with the variations in the IFIT2/IFIT3 (OR, 21.6), CERK (OR, 12.6), and PAPPA (OR, 14.0) genes. Variations in the genotypes of 4 SNPs-rs115871127, rs16823835, rs13275667, and rs2514486-predicted variability in the time to aseptic loosening. The time to aseptic loosening varied from 8 to 16 years depending on the genotype, indicating a substantial effect of genetic variance. CONCLUSION: Development of the aseptic loosening is associated with several genetic variations and we identified at least 4 SNPs with a significant effect on the time for loosening. These data could help to develop a personalized approach for TJA and loosening management.