Oral Thromboprophylaxis Following Total Hip or Knee Replacement: Review and Multicentre Experience with Dabigatran Etexilate

The risk of venous thromboembolism (VTE) in patients undergoing total knee or hip replacement surgery is high. As a result, thromboprophylaxis is highly recommended. While current thromboprophylactic agents, such as low molecular weight heparins (LMWH) and vitamin K antagonists, are safe and effective their use can be problematic. Therefore, there is a need for alternative anticoagulants that are as safe and effective as conventional agents, but are more convenient and easier to use. Dabigatran etexilate, a direct thrombin inhibitor, is one such anticoagulant. For VTE prevention following major orthopaedic surgery, dabigatran etexilate shows similar efficacy and safety to the LMWH enoxaparin, and is approved for use in more than 75 countries, including Europe and Canada. Here, we summarize and discuss the experiences of four German clinics that have recently introduced dabigatran etexilate into clinical practice. Overall, dabigatran etexilate was well received by patients, surgeons and nurses, and compared favourably with enoxaparin. Staff appreciated the oral, single-dose administration of dabigatran etexilate. Patient satisfaction was high, especially in those individuals who had previously used LMWHs. In this review, we also address a number of questions that were asked by patients or staff; this will be of relevance to orthopaedic surgeons and nurses. We conclude that, in these four German clinics, dabigatran etexilate offered an effective oral alternative to existing thromboprophylactic agents in patients undergoing major orthopaedic surgery

The effect of type of femoral component fixation on mortality and morbidity after hip hemiarthroplasty:A systematic review and meta-analysis

Background: Hip hemiarthroplasty is a well-established treatment of displaced femoral neck fracture, although debate exists over whether cemented or uncemented fixation is superior. Uncemented prostheses have typically been used in younger, healthier patients and cemented prostheses in older patients with less-stable bone. Also, earlier research has suggested that bone cement has cytotoxic effects and may trigger cardiovascular and respiratory adverse events. Questions/Purposes: The aim of this systematic review and meta-analysis was to compare morbidity and mortality rates after cemented and uncemented hemiarthroplasty for the treatment of displaced femoral neck fractures in elderly patients. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched seven medical databases for randomized clinical trials and observational studies. We compared cemented and uncemented hemiarthroplasty using the Harris Hip Score (HHS), as well as measures of postoperative pain, mortality, and complications. Data were extracted and pooled as risk ratios or standardized mean difference with their corresponding 95% confidence intervals in a meta-analysis model. Results: The meta-analysis included 34 studies (12 randomized trials and 22 observational studies), with a total of 42,411 patients. In the pooled estimate, cemented hemiarthroplasty was associated with less risk of postoperative pain than uncemented hemiarthroplasty. There were no significant differences between groups regarding HHS or rates of postoperative mortality, pulmonary embolism, cardiac arrest, myocardial infarction, acute cardiac arrhythmia, or deep venous thrombosis. Conclusions: While we found that cemented hemiarthroplasty results in less postoperative pain than uncemented hemiarthroplasty in older patients with femoral neck fracture, the lack of significant differences in functional hip scores, mortality, and complications was surprising. Further high-level research is needed

Chlamydia trachomatis Co-opts the FGF2 Signaling Pathway to Enhance Infection

The molecular details of Chlamydia trachomatis binding, entry, and spread are incompletely understood, but heparan sulfate proteoglycans (HSPGs) play a role in the initial binding steps. As cell surface HSPGs facilitate the interactions of many growth factors with their receptors, we investigated the role of HSPG-dependent growth factors in C. trachomatis infection. Here, we report a novel finding that Fibroblast Growth Factor 2 (FGF2) is necessary and sufficient to enhance C. trachomatis binding to host cells in an HSPG-dependent manner. FGF2 binds directly to elementary bodies (EBs) where it may function as a bridging molecule to facilitate interactions of EBs with the FGF receptor (FGFR) on the cell surface. Upon EB binding, FGFR is activated locally and contributes to bacterial uptake into non-phagocytic cells. We further show that C. trachomatis infection stimulates fgf2 transcription and enhances production and release of FGF2 through a pathway that requires bacterial protein synthesis and activation of the Erk1/2 signaling pathway but that is independent of FGFR activation. Intracellular replication of the bacteria results in host proteosome-mediated degradation of the high molecular weight (HMW) isoforms of FGF2 and increased amounts of the low molecular weight (LMW) isoforms, which are released upon host cell death. Finally, we demonstrate the in vivo relevance of these findings by showing that conditioned medium from C. trachomatis infected cells is enriched for LMW FGF2, accounting for its ability to enhance C. trachomatis infectivity in additional rounds of infection. Together, these results demonstrate that C. trachomatis utilizes multiple mechanisms to co-opt the host cell FGF2 pathway to enhance bacterial infection and spread

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council