Dynamic Influence Networks for Rule-based Models

We introduce the Dynamic Influence Network (DIN), a novel visual analytics technique for representing and analyzing rule-based models of protein-protein interaction networks. Rule-based modeling has proved instrumental in developing biological models that are concise, comprehensible, easily extensible, and that mitigate the combinatorial complexity of multi-state and multi-component biological molecules. Our technique visualizes the dynamics of these rules as they evolve over time. Using the data produced by KaSim, an open source stochastic simulator of rule-based models written in the Kappa language, DINs provide a node-link diagram that represents the influence that each rule has on the other rules. That is, rather than representing individual biological components or types, we instead represent the rules about them (as nodes) and the current influence of these rules (as links). Using our interactive DIN-Viz software tool, researchers are able to query this dynamic network to find meaningful patterns about biological processes, and to identify salient aspects of complex rule-based models. To evaluate the effectiveness of our approach, we investigate a simulation of a circadian clock model that illustrates the oscillatory behavior of the KaiC protein phosphorylation cycle.Comment: Accepted to TVCG, in pres

Direct oral anticoagulants in the treatment and long-term prevention of venous thrombo-embolism

Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE). They are at least as effective and as safe as conventional therapy (heparins and vitamin-K inhibitors) and have practical advantages, such as fixed dosing and no need for laboratory monitoring. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. Direct oral anticoagulants should streamline the management of most patients with VTE and will facilitate care in the outpatient setting. Nevertheless, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolvin

Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants.

Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention

Exciton Footprint of Self-assembled AlGaAs Quantum Dots in Core-Shell Nanowires

Quantum-dot-in-nanowire systems constitute building blocks for advanced photonics and sensing applications. The electronic symmetry of the emitters impacts their function capabilities. Here, we study the fine structure of gallium-rich quantum dots nested in the shell of GaAs-AlGaAs core-shell nanowires. We used optical spectroscopy to resolve the splitting resulting from the exchange terms and extract the main parameters of the emitters. Our results indicate that the quantum dots can host neutral as well as charges excitonic complexes and that the excitons exhibit a slightly elongated footprint, with the main axis tilted with respect to the growth axis. GaAs-AlGaAs emitters in a nanowire are particularly promising for overcoming the limitations set by strain in other systems, with the benefit of being integrated in a versatile photonic structure

Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data.

Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. The role and usefulness of PR with regard to levels of cardiovascular risk are unclear. We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischaemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20 µM ADP. Thirteen prospective studies totaled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5 %) during a median follow-up of 12 months. The strength of the association between the risk of MACE and PR increased significantly (p=0.04) with the number of risk factors present (age> 75 years, ACS at inclusion, diabetes, and hypertension). No association was detected in patients with no risk factor (p=0.48). In patients presenting one risk factor, only high-PR was associated with an increased risk of MACE (HR 3.2, p=0.001). In patients presenting ≥ 2 risk factors, the increase of risk started from medium-PR (medium-PR: HR=2.9, p=0.0004; high-PR: HR=3.7, p=0.0003). PR allowed the reclassification of 44 % of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high risk patients. In conclusion, the magnitude of the association between PR and MACE risk is strongly dependent on the level of cardiovascular risk faced by patients on clopidogrel

Comparative Long-Term Effect of Three Anti-P2Y12 Drugs after Percutaneous Angioplasty: An Observational Study Based on Electronic Drug Adherence Monitoring

Aims: Dual platelet inhibition using anti-P2Y12 drugs and aspirin is the standard of care in patients after percutaneous coronary interventions (PCI). Prasugrel and ticagrelor have been shown to be more potent than clopidogrel with less high on-treatment platelet reactivity. Whether differences in long-term adherence to these drugs can partly explain different antiplatelet efficacy has not been studied so far. The objective was to compare the long-term P2Y12 receptor inhibition and drug adherence to different anti-P2Y12 drugs, and to assess the impact of adherence on the pharmacodynamic effect.Methods: Monocentric, prospective, observational study. Stable outpatients treated with clopidogrel 75 mg once daily, prasugrel 10 mg once daily or ticagrelor 90 mg twice daily after PCI with stent implantation were included. Drug adherence was recorded during 6 months using electronic monitoring. Platelet responsiveness was assessed with the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI) at inclusion, 3 and 6 months.Results: 120 patients had VASP-PRI and adherence data available. At 6-months, mean VASP-PRI (±SD) was 17.7 ± 11.0% with ticagrelor, 29.2 ± 15.5% with prasugrel and 47.2 ± 17.6% with clopidogrel (ANOVA, P < 0.0001).Median [IQR] taking adherence was 96 [82–100]% with ticagrelor, 100 [97–101]% with prasugrel and 100 [99–101]% with clopidogrel (p = 0.0001). Median [IQR] correct dosing was 88 [73–95]% with ticagrelor, 97 [92.5–98]% with prasugrel and 98 [96–99]% with clopidogrel (p = 0.0001).Anti-P2Y12 drug (p ≤ 0.001) and diabetes (p = 0.014) emerged as predictors of poor antiplatelet response after adjusting for age, BMI, sex, and CYP2C19∗2 carriers status.Conclusion: Drug adherence to anti-P2Y12 drugs assessed with electronic monitoring was very high. However, anti-P2Y12 drugs showed significant differences in antiplatelet activity, with newer anti-P2Y12 drugs ticagrelor and prasugrel exerting a stronger P2Y12 receptor inhibition.These data suggest that pharmacokinetic-pharmacodynamic differences between oral anti-P2Y12 drugs are more important than adherence in determining antiplatelet efficacy when adherence to prescription is high.The study was registered (Current Controlled Trials ISRCTN85949729)

RuleVis: Constructing Patterns and Rules for Rule-Based Models

We introduce RuleVis, a web-based application for defining and editing "correct-by-construction" executable rules that model biochemical functionality, which can be used to simulate the behavior of protein-protein interaction networks and other complex systems. Rule-based models involve emergent effects based on the interactions between rules, which can vary considerably with regard to the scale of a model, requiring the user to inspect and edit individual rules. RuleVis bridges the graph rewriting and systems biology research communities by providing an external visual representation of salient patterns that experts can use to determine the appropriate level of detail for a particular modeling context. We describe the visualization and interaction features available in RuleVisand provide a detailed example demonstrating how RuleVis can be used to reason about intracellular interactions