Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial)

Aims Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. Methods and results The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74–1.08 vs. HR 0.80, 95% CI 0.72–0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72–1.01 vs. HR 0.80, 95% CI 0.71–0.90, P interaction = 0.53), and NYHA III–IV and II (HR 0.83, 95% CI 0.74–0.94 vs. HR 0.81, 95% CI 0.69–0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68–0.85 vs. HR 0.97, 95% CI 0.81–0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. Conclusions Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern

Contributions of the anterolateral complex and the anterolateral ligament to rotatory knee stability in the setting of ACL Injury: a roundtable discussion

Persistent rotatory knee laxity is increasingly recognized as a common finding after anterior cruciate ligament (ACL) reconstruction. While the reasons behind rotator knee laxity are multifactorial, the impact of the anterolateral knee structures is significant. As such, substantial focus has been directed toward better understanding these structures, including their anatomy, biomechanics, in vivo function, injury patterns, and the ideal procedures with which to address any rotatory knee laxity that results from damage to these structures. However, the complexity of lateral knee anatomy, varying dissection techniques, differing specimen preparation methods, inconsistent sectioning techniques in biomechanical studies, and confusing terminology have led to discrepancies in published studies on the topic. Furthermore, anatomical and functional descriptions have varied widely. As such, we have assembled a panel of expert surgeons and scientists to discuss the roles of the anterolateral structures in rotatory knee laxity, the healing potential of these structures, the most appropriate procedures to address rotatory knee laxity, and the indications for these procedures. In this round table discussion, KSSTA Editor-in-Chief Professor Jón Karlsson poses a variety of relevant and timely questions, and experts from around the world provide answers based on their personal experiences, scientific study, and interpretations of the literature. Level of evidence V

Combination of a High Residual Varus and Joint-Line Lowering Strongly Increases the Risk of Early Implant Failure in Medial Unicompartmental Knee Arthroplasty

Background: Outliers in implant positioning, malalignment, and joint line height change are risk factors for unicompartmental knee arthroplasty (UKA) failure. However, their relationships and patterns in large datasets remain unexplored. This study assessed medial UKA survival in a large cohort and explored associated risk factors. Methods: This was a retrospective cohort study on medial UKA patients (2011 to 2019). Radiological outcomes included tibial implant positioning in the coronal plane, posterior tibial slope, residual knee deformity, and joint line restitution. Survival rate at last follow-up was recorded. Multinomial logistic regression analyzed risk factors, incorporating demographic and univariate analysis data. Results: Three hundred and sixty-six knees met inclusion criteria, with 10 lost to follow-up (2.7%). Mean follow-up was 61.3 months [24.1 to 135.1]. 5- and 10-year implant survival rates were 92% ± 1.6 and 88.4% ± 3.8, respectively. Multivariate analysis identified post-operative hip-knee-ankle angle (HKA) ≤ 175° (OR = 5.30 [1.64 to 17.13], P = .005) and joint line lowering ≥2 mm (OR = 8.86 [2.06 to 38.06]) as significant risk factors for tibial implant failure. Their combination carried a significantly high risk of failure (OR = 10.3 [3.1 to 34.3]). Post-operative HKA 175° was common in knees with pre-operative HKA 172°. Conclusion: This study reports encouraging 5- and 10-year survival outcomes for medial UKA. Tibial loosening was the main reason for revision. Patients with joint line lowering ≥ 2 mm and post-operative HKA ≤ 175° were at high risk of tibial implant failure. Surgeons should carefully restore the joint line in cases of pre-operative HKA 172°. © 2023 Elsevier Inc

Characterisation of Agomelatine-Induced Increase in Liver Enzymes: Frequency and Risk Factors Determined from a Pooled Analysis of 7605 Treated Patients

International audienceBackground: Antidepressant-induced liver injury is a major concern and a liver monitoring scheme has been recommended by the European Medicines Agency for agomelatine. Objective: The objective of this study was to assess the liver safety and identify the characteristics of patients who developed a significant increase in transaminases whilst taking agomelatine. Method: A retrospective pooled analysis of changes in transaminase levels in 9234 patients treated with agomelatine (25 or 50 mg/day; n = 7605) or placebo (n = 1629) from 49 phase II and III studies was undertaken. A significant increase in transaminase levels was defined as an increase to >3 times the upper limit of normal (ULN) (>3 × ULN). Final causality was determined in a case-by-case review by five academic experts. Results: Serum transaminases increased to >3 × ULN in 1.3 and 2.5 % of patients treated with 25 and 50 mg of agomelatine, respectively, compared with 0.5 % for placebo. The onset of increased transaminases occurred before 12 weeks in 64 % of patients. The median time to recovery (to ≤2 × ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1 % of patients despite continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. No cases of acute liver failure or fatal outcome occurred. Patients with elevated transaminases at baseline, secondary to obesity/fatty liver disease, had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. Conclusion: Incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. Overall, in clinical trials, the liver profile of agomelatine seems safe when serum transaminases are monitored. © 2016, Springer International Publishing Switzerland

Gender does not influence outcomes and complications in medial unicompartmental knee arthroplasty.

The impact of gender on the outcomes of unicompartmental knee arthroplasty (UKA) remains a topic of active discussion with limited exploration thus far. The study aims to elucidate the gender effect on clinical outcomes, complications, pre- and postoperative radiological outcomes following the implantation of a medial UKA at mid-term follow-up in a large section of patients. This was a single-centre, retrospective cohort study encompassing patients undergoing medial UKA between 2011 and 2019. The International Knee Society (IKS) Knee and Function score, patient satisfaction, complications, revisions, pre- and postoperative radiological outcomes (coronal plane alignment, femoral and tibial component positioning, posterior tibial slope) were evaluated. Survival rate at the time of the last follow-up was also recorded. Of the 366 knees that met the inclusion criteria, 10 were lost to follow-up, accounting for a 2.7% loss. Mean follow-up was 5.2 ± 2 years [2.1-11.3]. Out of the total population, 205 patients were females (57.6%, 205/356) and 151 were males (42.4%, 151/356). Men exhibited superior pre- and postoperative IKS function scores (p = 0.017). However, no significant differences were observed between women and men regarding improvements of IKS Knee and Function scores, radiographic outcomes and implant survivorship. At a mean follow-up of 5 years, this study revealed no significant impact of gender on clinical outcomes and complications in patients undergoing medial UKA. Furthermore, no significant differences were evident in radiographic outcomes, implant positioning and knee phenotype. Level III

Characterization of agomelatine-induced liver injury, incidence and risk factors: A pooled analysis of 7605 treated patients

International audienceIntroduction/objective The hepatic safety of agomelatine was assessed in 49 phase II and III studies. The aim was to analyze the characteristics of patients who developed an increase in transaminases whilst taking agomelatine. Method A retrospective pooled analysis of changes in serum transaminase in 7605 patients treated with agomelatine (25 mg or 50 mg/day) from 49 completed studies was undertaken. A significant increase in serum transaminase was defined as &gt; 3-fold the upper limit of normal (&gt; 3 ULN). Final causality was determined in a case-by-case review by five academic experts. Results Transaminase increased to &gt; 3 ULN in 1.3% and 2.5% of patients treated with 25 mg and 50 mg of agomelatine respectively, compared to 0.5% for placebo. The onset of increased transaminases occurred at &lt; 12 weeks in 64% of patients. The median time to recovery (to ≤ 2ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1% patients despite the continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. Patients with elevated transaminases at baseline, secondary to obesity and fatty liver disease (NAFLD), had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. This reflects the widespread fluctuations of serum transaminases in patients with NAFLD. Conclusions The overall incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. The liver profile of agomelatine seems safe when serum transaminases are monitore

Differential effects of oxytocin on olfactory, hippocampal and hypothalamic neurogenesis in adult sheep

International audienceNew neurons are continuously added in the dentate gyrus of the hippocampus, the olfactory bulb and the hypothalamus of mammalian brain. In sheep, while the control of adult neurogenesis by the social environment or the photoperiod has been the subject of several studies, its regulation by intrinsic factors, like hormones or neurotransmitters is less documented. We addressed this question by investigating the effects of central oxytocin administration on hippocampal, olfactory and hypothalamic neurogenesis. Endogenous markers, Ki67, Sox2 and DCX were used to assess cell proliferation, progenitor cells density and cell survival respectively in non-gestant ewes receiving a steroid treatment followed by intracerebroventricular injections of either oxytocin or saline. The results showed that oxytocin treatment significantly decreases the density of neuroblasts in the olfactory bulb, increases the density of neuroblasts in the ventromedian nucleus of the hypothalamus while no change is observed in both ventral and dorsal dentate gyms. In addition, no change in the density of progenitor cells is found in the three neurogenic niches. These findings show for the first time that in females, oxytocin can regulate adult neurogenesis by acting on neuroblasts but not on progenitor cells and that this regulation is region specific

New Bio-tribo-mineralogical Expertise Protocol for Joint Implant Wear Particles. Application: Medical Diagnostic and Articular Implants Optimisation

International audienceThe evaluation of the wear of hip prostheses is regulated by international standards, however, the results of in vitro tests do not allow to predict the effective lifetime once the implants are in place. Our study aims to develop a new method of in vitro testing of implants, more representative of their wear in physiological conditions. We also want to develop a questionnaire that can detect the particular sensitivities of each patient to the constituent materials of the prostheses and thus guide the choice of one's implant to limit the risk of aseptic loosening