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

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Influenza vaccination in Brazil: rationale and caveats.

Mass vaccination campaigns against influenza in the elderly have been conducted in Brazil since 1999. A search of the literature on influenza in Brazil indicated that data on disease burden are still scarce and inaccurate. Published data seem to indicate that vaccination has produced some impact in the southern and southeastern regions but not in other regions of Brazil. A discussion of the technical and scientific rationale for mass immunization against influenza is presented and it is argued that the current strategy has not taken into account potential differences in disease occurrence in different areas. It is suggested some epidemiological surveillance actions needed to address major concerns regarding mass influenza vaccination and its impact in Brazil

Control of gene expression in Trypanosomatidae

The study of mechanisms which control gene expression in trypanosomatids has developed at an increasing rate since 1989 when the first successful DNA transfection experiments were reported. Using primarily Trypanosoma brucei as a model, several groups have begun to elucidate the basic control mechanisms and to define the cellular factors involved in mRNA transcription, processing and translation in these parasites. This review focuses on the most recent studies regarding a subset of genes that are expressed differentially during the life cycle of three groups of parasites. In addition to T. brucei, I will address studies on gene regulation in a few species of Leishmania and the results obtained by a much more limited group of laboratories studying gene expression in Trypanosoma cruzi. It is becoming evident that the regulatory strategies chosen by different species of trypanosomatids are not similar, and that for these very successful parasites it is probably advantageous to employ multiple mechanisms simultaneously. In addition, with the increasing numbers of parasite genes that have now been submitted to molecular dissection, it is also becoming evident that, among the various strategies for gene expression control, there is a predominance of regulatory pathways acting at the post-transcriptional level

An Improved Coarse-Grained Model to Accurately Predict Red Blood Cell Morphology and Deformability

Accurate modelling of red blood cells (RBCs) has greater potential over experiments, as it can be more robust and significantly cheaper than equivalent experimental procedures to investigate the mechanical properties, rheology and dynamics of RBCs. The recent advances in numerical modelling techniques for RBC studies are reviewed in this study, and in particular, the discrete models for a triangulated surface to represent the in-plane stretching energy and out-of-plane bending energy of the RBC membrane are discussed. In addition, an improved RBC membrane model is presented based on coarse-grained (CG) technique that accurately and efficiently predicts the morphology and deformability of a RBC. The CG-RBC membrane model predicts the minimum energy configuration of the RBC from the competition between the in-plane stretching energy of the cytoskeleton and the out-of-plane bending energy of the lipid-bilayer under the given reference states of the cell surface area and volume. A quantitative evaluation of several cellular measurements including length, thickness and shape factor, is presented between the CG-RBC membrane model and three-dimensional (3D) confocal microscopy imaging generated RBC shapes at equivalent reference states. The CG-RBC membrane model predicts agreeable deformation characteristics of a healthy RBC with the analogous experimental observations corresponding to optical tweezers stretching deformations. The numerical approach presented here forms the foundation for investigations into RBC morphology and deformability under diverse shape-transforming scenarios, in vitro RBC storage, microvascular circulation and flow through microfluidic devices

The Phylum Spirochaetaceae

Spirochaetaceae is a family of spirochetes that cause syphilis, Lyme disease, epidemic and endemic relapsing fever, leptospirosis, swine dysentery, and periodontal disease. The spirochetes are presently classified as members of class Spirochaetes in the order Spirochaetales and are divided into three major phylogenetic groupings or families. The first family, Spirochaetaceae, contains species in the genera Borrelia, Brevinema, Cristispira, Spirochaeta, Spironema, and Treponema. The second family, Brachyspiraceae, contains the genus Brachyspira (Serpulina). The third family, Leptospiraceae, contains species of the genera Leptonema and Leptospira. One of the unique features of spirochetes is motility mediated by axial flagella with a rapid drifting rotation. The DNA of the Spirochaeta species contains guanine (G) + cytosine (C) ranging from 51 % to 65 mol %. The presence of several linear plasmids seems to cause the segmentation of Borrelia DNA into several linear pieces. This has led to the suggestion that the relatively small linear chromosome and the linear plasmids actually are minichromosomes. Various molecular and immunological detection methods have been developed for detection and identification of spirochetes