Impact of Incomplete Revascularization After PCI in Left Main Disease: The EXCEL Trial.

BACKGROUND: The importance of complete revascularization after percutaneous coronary intervention (PCI) in patients with left main coronary artery disease is uncertain. We investigated the clinical impact of complete revascularization in patients with left main coronary artery disease undergoing PCI in the EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization). METHODS: Composite rates of death or myocardial infarction (MI) following PCI during 5-year follow-up were examined in 903 patients based on core laboratory definitions of anatomic and functional complete revascularization, residual SYNTAX score (The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery), and residual Jeopardy Score (rJS). RESULTS: The risk of death or MI did not vary based on anatomic, functional, or residual SYNTAX score complete revascularization but did differ according to the rJS (5-year rates 17.6%, 19.5%, and 38.9% with rJS 0, 2, and ≥4, respectively; P=0.006). The higher rate of death or MI with rJS≥4 versus rJS≤2 was driven conjointly by increased mortality (adjusted hazard ratio, 2.29 [95% CI, 1.11-4.71]; P=0.02) and spontaneous MI (adjusted hazard ratio, 2.89 [95% CI, 1.17-7.17]; P=0.02). The most common location for untreated severe stenoses in the rJS≥4 group was the left circumflex artery (LCX), and the post-PCI absence, compared with the presence, of any untreated lesion with diameter stenosis ≥70% in the LCX was associated with reduced 5-year rates of death or MI (18.9% versus 35.2%; hazard ratio, 0.48 [95% CI, 0.32-0.74]; P<0.001). The risk was the highest for residual ostial/proximal LCX lesions. CONCLUSIONS: Among patients undergoing PCI in EXCEL trial, incomplete revascularization according to the rJS was associated with increased rates of death and spontaneous MI. Post-PCI untreated high-grade lesions in the LCX (especially the ostial/proximal LCX) drove these outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01205776.

Modelling uniaxial non-uniform yeast colony growth: Comparing an agent-based model and continuum approximations.

Biological experiments have shown that yeast can be restricted to grow in a uniaxial direction, vertically upwards from an agar plate to form a colony. The growth occurs as a consequence of cell proliferation driven by a nutrient supply at the base of the colony, and the height of the colony has been observed to increase linearly with time. Within the colony the nutrient concentration is non-constant and yeast cells throughout the colony will therefore not have equal access to nutrient, resulting in non-uniform growth. In this work, an agent based model is developed to predict the microscopic spatial distribution of labelled cells within the colony when the probability of cell proliferation can vary in space and time. We also describe a method for determining the average trajectories or pathlines of labelled cells within a colony growing in a uniaxial direction, enabling us to connect the microscopic and macroscopic behaviours of the system. We present results for six cases, which involve different assumptions for the presence or absence of a quiescent region (where no cell proliferation occurs), the size of the proliferative region, and the spatial variation of proliferation rates within the proliferative region. These six cases are designed to provide qualitative insight into likely growth scenarios whilst remaining amenable to analysis. We compare our macroscopic results to experimental observations of uniaxial colony growth for two cases where only a fixed number of cells at the base of the colony can proliferate. The model predicts that the height of the colony will increase linearly with time in both these cases, which is consistent with experimental observations. However, our model shows how different functional forms for the spatial dependence of the proliferation rate can be distinguished by tracking the pathlines of cells at different positions in the colony. More generally, our methodology can be applied to other biological systems exhibiting uniaxial growth, providing a framework for classifying or determining regions of uniform and non-uniform growth.

From gene list to gene network: Recognizing functional connections that regulate behavioral traits.

The study of social breeding systems is often gene focused, and the field of insect sociobiology has been successful at assimilating tools and techniques from molecular biology. One common output from sociogenomic studies is a gene list. Gene lists are readily generated from microarray, RNA sequencing, or other molecular screens that typically aim to prioritize genes based on the differences in their expression. Gene lists, however, are often unsatisfying because the information they provide is simply tabular and does not explain how genes interact with each other, or how genetic interactions change in real time under social or environmental circumstances. Here, we promote a view that is relatively common to molecular systems biology, where gene lists are converted into gene networks that better describe the functional connections that regulate behavioral traits. We present a narrative related to honeybee worker sterility to show how network analysis can be used to reprioritize candidate genes based on connectivity rather than their freestanding expression values. Networks can also reveal multigene modules, motifs, clusters or other system-wide properties that might not be apparent from an ab initio list. We argue that because network analyses are not restricted to "genes" as nodes, their implementation can potentially connect multiple levels of biological organization into a single, progressively complex study system.

Andexanet alfa for the reversal of anticoagulant activity in patients treated with direct and indirect factor Xa inhibitors.

INTRODUCTION: Andexanet alfa is a recombinant factor Xa decoy molecule that inhibits direct and indirect factor Xa inhibitors to allow the normal coagulation process to resume. Its development arises in a space where novel oral anticoagulants are receiving expanded indications yet their use is limited by the lack of an effective reversal agent. Areas covered: This article reviews the biochemical properties, mechanism of action and the preclinical and clinical trials on andexanet alfa. It additionally aims to provide expert commentary and future perspectives on the efficacy, safety and challenges facing andexanet alfa as a universal antidote for direct and indirect factor Xa inhibitors. Expert commentary: Andexanet alfa shows promise to become a highly effective, novel antidote for factor Xa anticoagulation. Its biochemical profile and mechanism of action are immediately more attractive than other drugs on the market and under development due to its inert nature within the normal coagulation cascade, with minimal intrinsic procoagulant or anticoagulant properties. The anticoagulant antidote space will continue to develop as more specific and universal options become available for reversal of the effect of DOACs. Preliminary results of a pivotal phase 3b/4 trial demonstrate a favorable efficacy and safety profile in patients with acute hemorrhage.