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

Stable Spatially Localized Configurations in a Simple Structure—A Global Symmetry-Breaking Approach

We revisit the classic stability problem of the buckling of an inextensible, axially compressed beam on a nonlinear elastic foundation with a semi-analytical approach to understand how spatially localized deformation solutions emerge in many applications in mechanics. Instead of a numerical search for such solutions using arbitrary imperfections, we propose a systematic search using branch-following and bifurcation techniques along with group-theoretic methods to find all the bifurcated solution orbits (primary, secondary, etc.) of the system and to examine their stability and hence their observability. Unlike previously proposed methods that use multi-scale perturbation techniques near the critical load, we show that to obtain a spatially localized deformation equilibrium path for the perfect structure, one has to consider the secondary bifurcating path with the longest wavelength and follow it far away from the critical load. The novel use of group-theoretic methods here illustrates a general methodology for the systematic analysis of structures with a high degree of symmetry

Stable Spatially Localized Configurations in a Simple Structure—A Global Symmetry-Breaking Approach

We revisit the classic stability problem of the buckling of an inextensible, axially compressed beam on a nonlinear elastic foundation with a semi-analytical approach to understand how spatially localized deformation solutions emerge in many applications in mechanics. Instead of a numerical search for such solutions using arbitrary imperfections, we propose a systematic search using branch-following and bifurcation techniques along with group-theoretic methods to find all the bifurcated solution orbits (primary, secondary, etc.) of the system and to examine their stability and hence their observability. Unlike previously proposed methods that use multi-scale perturbation techniques near the critical load, we show that to obtain a spatially localized deformation equilibrium path for the perfect structure, one has to consider the secondary bifurcating path with the longest wavelength and follow it far away from the critical load. The novel use of group-theoretic methods here illustrates a general methodology for the systematic analysis of structures with a high degree of symmetry

A synaptic basis for paracrine interleukin-2 signaling during homotypic T cell interaction

T cells slow their motility, increase adherence, and arrest after encounters with antigen-presenting cells (APCs) bearing peptide-MHC complexes. Here, we analyzed the cell-cell communication among activating T cells. In vivo and in vitro, activating T cells associated in large clusters that collectively persisted for > 30 min, but they also engaged in more transient interactions, apparently distal to APCs. Homotypic aggregation was driven by LFA-1 integrin interactions. Ultrastructural analysis revealed that cell-cell contacts between activating T cells were organized as multifocal synapses, and T cells oriented both the microtubule-organizing complex and interleukin-2 (IL-2) secretion toward this synapse. T cells engaged in homotypic interactions more effectively captured IL-2 relative to free cells. T cells receiving paracrine synaptic IL-2 polarized their IL-2 signaling subunits into the synaptic region and more efficiently phosphorylated the transcription factor STAT5, likely through a synapse-associated signaling complex. Thus, synapse-mediated cytokine delivery accelerates responses in activating T cells.X117774sciescopu