Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

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

Custom designing therapeutic cancer vaccines. Delivery of immunostimulatory molecule adjuvants by protein transfer

Attempts to create vaccines for humans against invading pathogens such as viruses and bacteria have met with tremendous success. The process of developing vaccines against these pathogens is greatly aided by the fact that they contain antigens that are entirely foreign to humans. Although the knowledge and strategies developed for designing vaccines against these microbes may be of use in developing cancer vaccines, the poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Established tumors have not only withstood immune screening and selection pressure, making them poor stimulators of an immune response, but have also adapted mechanisms to continue evading immune surveillance by creating an immunosuppressive environment. Also, genetic differences in immune responses to an antigen among individuals result in an antigenic profile that varies from patient to patient. Cancers bear such great similarities to normal cells in the body that, on a molecular level, the differences between cancerous and non-cancerous cells are minor. Therefore, developing vaccines which use the host\u27s own tumor tissues carries the risk of breaking tolerance to self-antigens that are present in the tumor tissue. Vaccination strategies that will optimally stimulate the immune system against tumor specific antigens under immunosuppressive conditions need to be developed. In practical terms, this calls for a method by which therapeutic vaccines may be custom-designed to treat cancers case by case. Ex vivo manipulation of dendritic cells and gene transfer of immunostimulatory molecules in ex vivo expanded tumors are being tested in both experimental models and also in human clinical trials. Some of them have met with limited success. Emerging technologies such as protein transfer, which make it possible to express immunostimulatory molecules on tumor cell membranes, offer the means to develop efficient tumor vaccines that are simple and fast, while being easy to store and administer in human patients. Progress in these techniques will move the cancer vaccine field a step closer towards realizing custom designed cancer vaccines in human clinical settings. © 2008 Landes Bioscience

Primary Breast Cancer in Aberrant Breast Tissue in the Axilla

Primary breast cancer in aberrant axillary breast tissue is rare. Breast cancer in the axilla is most often due to lymph node metastases from an ipsilateral breast tumor or from an occult primary lesion. We describe two patients with primary breast cancer in aberrant breast tissue in the axilla, and review the literature to define guidelines for diagnosis and treatment

A review and survey of policies utilized for interventional pain procedures: a need for consensus

Lynn Kohan,1 Reza Salajegheh,1 Robin J Hamill-Ruth,1 Sandeep Yerra,1 John Butz,2 1Department of Anesthesiology, University of Virginia, Charlottesville, VA, 2West River Anesthesiology Consultants, Rapid City, SD, USA Background: Other than the newly published anticoagulation guidelines, there are currently few recommendations to assist pain medicine physicians in determining the safety parameters to follow when performing interventional pain procedures. Little information exists regarding policies for oral intake, cumulative steroid dose limits, driving restrictions with and without sedation, and routine medication use for interventional procedures.Methods: A 16-question survey was developed on common policies currently in use for interventional pain procedures. The questionnaire was distributed through the &shy;American Society of Regional Anesthesia and Pain Medicine and American Academy of Pain Medicine. We sought to statistically analyze the range of policies being used by pain medicine physicians and to determine if there are any commonly accepted standards.Results: A total of 337 physicians out of 4037 members responded to our survey with a response rate of 8.4%. A total of 82% of these respondents used a sedative agent while performing an interventional pain procedure. The majority of respondents required drivers after procedures, except after trigger points. A total of 47% indicated that they have an nil per os (NPO) policy for procedures without sedation. A total of 98% reported that they had an anticoagulation policy before an interventional procedure. A total of 17% indicated that the interval between steroid doses was &lt;2&nbsp;weeks, while 53% indicated that they waited 2&ndash;4&nbsp;weeks between steroid doses.Conclusion: Our study has clearly demonstrated a wide variation in the current practice among physicians regarding sedation, NPO status, steroid administration, and the need for designated drivers. There was much higher endorsement of policies regarding anticoagulation. There is an obvious need for evidence-based guidelines for these aspects of interventional pain care to improve patient safety and minimize the risk of adverse events. Keywords: interventional pain procedures policies, steroids in pain procedures, driver policy in interventional pain procedures, NSAIDs and anticoagulants in interventional pain procedure

Void growth and coalescence in single crystals

Void growth and coalescence in single crystals are investigated using crystal plasticity based 3D finite element calculations. A unit cell involving a single spherical void and fully periodic boundary conditions is deformed under constant macroscopic stress triaxiality. Simulations are performed for different values of the stress triaxiality, for different crystal orientations, and for low and high work-hardening capacity. Under low stress triaxiality, the void shape evolution, void growth, and strain at the onset of coalescence are strongly dependent on the crystal orientation, while under high stress triaxiality, only the void growth rate is affected by the crystal orientation. These effects lead to significant variations in the ductility defined as the strain at the onset of coalescence. An attempt is made to predict the onset of coalescence using two different versions of the Thomason void coalescence criterion, initially developed in the framework of isotropic perfect plasticity. The first version is based on a mean effective yield stress of the matrix and involves a fitting parameter to properly take into account material strain hardening. The second version of the Thomason criterion is based on a local value of the effective yield stress in the ligament between the voids, with no fitting parameter. The first version is accurate to within 20% relative error for most cases, and often more accurate. The second version provides the same level of accuracy except for one crystal orientation. Such a predictive coalescence criterion constitutes an important ingredient towards the development of a full constitutive model for porous single crystals. (C) 2009 Elsevier Ltd. All rights reserved.status: publishe

The Facet-Gurson model for ductile damage process

An attempt is made to incorporate the effect of texture-induced plastic anisotropy in Gursontype porous plasticity theory. The plastic anisotropy is modelled by using the recently developed Facet method in stress space. The Facet method relies on the theory of dualplastic potentials and proposes an expression for a yield surface. The parameters of such yield surfaces are determined by fitting to the results of virtual mechanical tests. These virtual tests can be performed using any of the existing micromechanical models, such as Taylor theory, provided that the crystallographic texture of the material is known. The coupling of anisotropy and damage is implemented by replacing the effective stress of the Gurson matrix by the anisotropic effective stress calculated by the Facet method, as well as by adjusting one anisotropy-related parameter in the flow potential. The coupled model is applied on mono-And poly-crystalline materials that have an initially spherical void, with 1% void volume fraction. The capability of the coupled model is assessed with the results obtained from crystal plasticity based FE cell calculations.status: publishe

Simulation based Analysis of Transformerless Photovoltaic Inverter Topologies for Reactive Power handling Capability

This study investigates the reactive power generation capability of the existing transformerless Photovoltaic Inverter Topologies (PVIT) with their conventional switching strategies. The topologies such as H5, families of H6 (H6, H6-I, H6-II, H6-III and H6-IV), HERIC, and clamped topologies (optimized H5, passive clamped H6 and HBZVR) have been selected for analysis. Matlab/Simulink simulation platform is employed for the analysis of PVIT. It has been observed that transformer-less PVIT with their conventional switching strategies are not suitable for reactive power injection. These topologies are generating highly distorted current at zero crossings during the reactive power flow. The improved switching strategies are needed to make these topologies suitable for the reactive power applications without any modification in the structure of the inverter.Accepted author manuscriptPhotovoltaic Materials and DevicesIntelligent Electrical Power Grid