Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Ultrasonic techniques for improving inspection of sodium-cooled systems

International audienceIn 2007, the CEA, EDF, AREVA launched a coordinated research program for the development of Generation IV sodium-cooled fast reactors (SFR). A R&D program has been defined for the development of ultrasonic (US) techniques in sodium which are required for periodic inspections and continuous monitoring. This program involves both experimentation and modeling of the associated phenomenon. Within the scope of the future ASTRID prototype design, the main milestones until 2012 include validating the ultrasonic transducers, the qualification of in-sodium or out-of-sodium inspection techniques

Recent modelling advances in NDT to improve safety and sustainability for the next generation of nuclear reactor

International audienceIn the frame of Generation 4 Nuclear Reactor developments, the French LMA Laboratory and the French CEA nuclear institute undertake a joint work for improving monitoring and inspection of future Sodium Fast Reactors.The goal is to properly test and monitor, with non-destructive acoustic methods, structures and materials at different scales (from micrometric to metric) and at different operating states (nominal, partial, shutdown, incidental or even accidental). Indeed, acoustic signatures can be recorded (reflected signals, vibrations, noise), and, after treatment, allow checking the good health or state of components and structures immersed in liquid sodium (detection of displacements, flaws, leaks, bubbles, buckling).This is a real challenge as the media are rather complex, due to their geometry (shapes and access), their physical properties (multiphase, heterogeneous, anisotropic, flowing fluid, thermal gradients), high temperature, irradiation and sodium. This leads to use active acoustic methods (volumetric and guided waves) or passive ones (acoustic emission), and linear and non-linear acoustic methods.A number of experiments are performed at full scale or less, mainly in simulating water fluid (in conventional water test vessels, on water loops, with Schlieren bench) but also in sodium facilities.Numerical simulations are performed with available or tuned codes (multi-physics, ray tracing and finite elements, spectral finite elements ) in order to predict wave propagation within materials and structures. In addition, among other inverse methods used, defect detection can be done with time reversal techniques coupling with adjoint method.The future MISTRAL common lab will allow to ease this joint work between CEA Cadarache and LMA

Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands

The accumulation of unfolded proteins under endoplasmic reticulum (ER) stress leads to the activation of the multidomain protein sensor IRE1α as part of the unfolded protein response (UPR). Clustering of IRE1α lumenal domains in the presence of unfolded proteins promotes kinase <i>trans</i>-autophosphorylation in the cytosol and subsequent RNase domain activation. Interestingly, there is an allosteric relationship between the kinase and RNase domains of IRE1α, which allows ATP-competitive inhibitors to modulate the activity of the RNase domain. Here, we use kinase inhibitors to study how ATP-binding site conformation affects the activity of the RNase domain of IRE1α. We find that diverse ATP-competitive inhibitors of IRE1α promote dimerization and activation of RNase activity despite blocking kinase autophosphorylation. In contrast, a subset of ATP-competitive ligands, which we call KIRAs, allosterically inactivate the RNase domain through the kinase domain by stabilizing monomeric IRE1α. Further insight into how ATP-competitive inhibitors are able to divergently modulate the RNase domain through the kinase domain was gained by obtaining the first structure of <i>apo</i> human IRE1α in the RNase active back-to-back dimer conformation. Comparison of this structure with other existing structures of IRE1α and integration of our extensive structure activity relationship (SAR) data has led us to formulate a model to rationalize how ATP-binding site ligands are able to control the IRE1α oligomeric state and subsequent RNase domain activity