Resverlogix (Canada)

Secondary prevention of acute MI, both ST elevated and non-ST elevated is essential to reduce cardiovascular mortality and hospital readmission, ensuring patients return to normality with an improved quality of life. Thus far, professional associations and country-specific guidelines have provided guidance suited to their respective populations. The Asia Pacific Cardiometabolic Consortium has developed these consensus recommendations to unify the approach to long-term care of patients after MI, which can be applied across the Asia-Pacific region. The consensus statements, which were developed by an expert panel, took into account international and local guidelines and current evidence, along with the opinions and professional experience offered by regional experts. These statements were then put to an online vote to achieve a consensus. The resulting 13 statements discuss secondary prevention strategies encompassing pharmacotherapy, lifestyle modifications, cardiac rehabilitation and discharge management for the effective long-term care of patients with a history of type 1 MI, specifically relating to atherosclerotic plaque rupture and thrombosis.

[Deliverable pending final approval by the EC] This deliverable has the objective to provide the outcomes of the activities performed in Work Package (WP) 2 “Specifications”. The activities included the design of the 5G-IANA Automotive Open Experimentation Platform (AOEP) and the requirements specification of each architecture layer. The specified 5G-IANA architecture capitalizes on the 5G prospect of being a unified multi-service platform by orchestrating Vertical Services based on virtualized network slices and coordination of distributed edge-to-cloud deployment. The 5G-IANA AOEP aims to provide an open and flexible experimentation platform to third-parties developers (e.g., SMEs) that want to develop new 5G-based services devoted to the Automotive vertical. The availability of an easy-to-use experimentation environment can facilitate the launch of new services creating new market opportunities. Moreover, 5G-IANA will actively address the configuration of the 5G network (e.g., network slicing, edge resources, etc.) with the objective of supporting in the best way the requirements of the new services. In this way, it will be also possible to verify if the current 5G implementation can adequately satisfy the highly demanding performance requirements of Automotive services.

Background:Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders.Objective:To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE).Methods:The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group.Results:Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%).Conclusion:In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

Abstract Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infectionin vitroto levels comparable to antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.Graphical Abstract

We aim to provide a tool for independent system operators to detect the collusion and identify the colluding firms by using day-ahead data. In this paper, an approach based on supervised machine learning is presented for collusion detection in electricity markets. The possible scenarios of the collusion among generation firms are firstly identified. Then, for each scenario and possible load demand, market equilibrium is computed. Market equilibrium points under different collusions and their peripheral points are used to train the collusion detection machine using supervised learning approaches such as classification and regression tree (CART) and support vector machine (SVM) algorithms. By applying the proposed approach to a four-firm and ten-generator test system, the accuracy of the proposed approach is evaluated and the efficiency of SVM and CART algorithms in collusion detection are compared with other supervised learning and statistical techniques.

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Apabetalone (RVX-208) is a small molecule bromodomain &amp; extraterminal (BET) protein inhibitor that targets the second bromodomain (BD2) within BET proteins. In phase 2 trials, apabetalone treatment reduced relative risk of MACE events by 57% in patients with cardiovascular disease (CVD) and type II diabetes (T2DM). In both CVD and T2DM, elevated circulating glucose, inflammatory mediators, and cell surface adhesion molecules drive vascular inflammation (VI), resulting in the recruitment, adhesion, and infiltration of leukocytes to the atherosclerotic plaque. Continuous inflammation promotes cytokine production, immune cell infiltration, and plaque rupture, which accounts for 67% of fatal myocardial infarctions (MIs) and sudden cardiac deaths. Here we show in vitro that TNFα and high glucose treatment induced significant adhesion of THP-1 monocytes to endothelial cells, an outcome inhibited by apabetalone treatment. Apabetalone suppressed the transcription of critical drivers of pro-inflammatory signaling ( RELA ), immune cell activation and recruitment ( MCP-1 ), and plaque rupture ( IL-8 ) in endothelial cells. Ingenuity® Pathway Analysis (IPA®), GSEA, and GO analysis of human umbilical vein endothelial cell (HUVEC) gene expression data predicted that apabetalone would inhibit pro-atherogenic pathways, gene sets, and upstream regulators. These include cytokine and chemokine signalling, immune and inflammatory response, Toll-Like Receptor (TLR) signalling, and TNFα signalling. In addition, IPA® disease and biological function analysis predicted inhibition of immune cell recruitment and activation by apabetalone. These in vitro effects are consistent with plasma proteomic results (SOMAscan®) from apabetalone-treated CVD T2DM patients, which demonstrated inhibitory effects on TNFα signalling, acute phase response, intrinsic prothrombin activation, leukocyte extravasation signalling and coagulation. Amelioration of diabetes and inflammation driven atherogenesis by apabetalone treatment likely contributes to the reduction in MACE observed in phase 2. The ongoing phase 3 post-ACS clinical trial in T2DM patients, BETonMACE, is investigating the effect of apabetalone on MACE reduction and will report in 2019.