Large deviations in boundary-driven systems: Numerical evaluation and effective large-scale behavior

We study rare events in systems of diffusive fields driven out of equilibrium by the boundaries. We present a numerical technique and use it to calculate the probabilities of rare events in one and two dimensions. Using this technique, we show that the probability density of a slowly varying configuration can be captured with a small number of long wave-length modes. For a configuration which varies rapidly in space this description can be complemented by a local equilibrium assumption

Structural results on convexity relative to cost functions

Mass transportation problems appear in various areas of mathematics, their solutions involving cost convex potentials. Fenchel duality also represents an important concept for a wide variety of optimization problems, both from the theoretical and the computational viewpoints. We drew a parallel to the classical theory of convex functions by investigating the cost convexity and its connections with the usual convexity. We give a generalization of Jensen's inequality for cost convex functions.Comment: 10 page

A first step towards translating evidence into practice: heart failure in a community practice-based research network

Objective To determine the validity of an electronic health record (EHR) in the identification of patients with left ventricular dysfunction in a primary care setting. Design A cross-sectional study. Setting Nine clinics participating from the Providence Research Network (PRN) comprising 75 physicians serving approximately 200 000 patients. All clinics utilise the Logician™ EHR for all patient care activities. Patients The study included all PRN patients with an active chart. Interventions All patients with a heart failure diagnosis in the problem list were identified by database query. Left ventricular ejection fraction (LVEF) data were identified through query of local cardiology and hospital echocardiography databases. Additional LVEF data were sought in a manual search of paper charts. Measurements and main results To determine the problem list coding accuracy for a heart failure (HF) diagnosis we evaluated sensitivity, positive predictive value and related derived statistical measures using documented LVEF as the ‘gold standard’.Of 205 755 active PRN patients, 1731 were identified with a problem list entry of HF. Based on comparison with documented LVEF, the sensitivity for problem list entry was 43.9% and 54.4% when HF was defined as an LVEF ≤55% and ≤40%, respectively. Conclusion The validity of an EHR problem list entry of HF was poor. The problem list validity could be enhanced through reconciliation with other data sources. Inaccurate EHR problem lists may have clinical consequences, including underprescribing of beneficial therapies

Non differentiable large-deviation functionals in boundary-driven diffusive systems

We study the probability of arbitrary density profiles in conserving diffusive fields which are driven by the boundaries. We demonstrate the existence of singularities in the large-deviation functional, the direct analog of the free-energy in non-equilibrium systems. These singularities are unique to non-equilibrium systems and are a direct consequence of the breaking of time-reversal symmetry. This is demonstrated in an exactly-solvable model and also in numerical simulations on a boundary-driven Ising model. We argue that this singular behavior is expected to occur in models where the compressibility has a deep enough minimum. The mechanism is explained using a simple model.Comment: 5 pages, 3 figure

Preclinical Pharmacokinetic Evaluation to Facilitate Repurposing of Tyrosine Kinase Inhibitors Nilotinib and Imatinib as Antiviral Agents

Background Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for “repurposing” as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the “Animal Rule” to facilitate use of validated animal models for conducting anti-viral efficacy studies. Methods To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. Results Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1–3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. Conclusions Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models

A Prescription for Improving Drug Formulary Decision Making

Gordon Schiff and colleagues present a new tool and checklist to help formularies make decisions about drug inclusion and to guide rational drug use

Perception-action loops of multiple agents : informational aspects and the impact of coordination

Copyright 2011 Elsevier B.V., All rights reserved.Embodied agents can be conceived as entities perceiving and acting upon an external environment. Probabilistic models of this perception-action loop have paved the way to the investigation of information-theoretic aspects of embodied cognition. This formalism allows (i) to identify information flows and their limits under various scenarios and constraints, and (ii) to use informational quantities in order to induce the self-organization of the agent's behavior without any externally specified drives. This article extends the perception-action loop formalism to multiple agents. The multiple-access channel model is presented and used to identify the relationships between informational quantities of two agents interacting in the same environment. The central question investigated in this article is the impact of coordination. Information-theoretic limits on what can be achieved with and without coordination are identified. For this purpose, different abstract channels are studied, along with a concrete example of agents interacting in space. It is shown that, under some conditions, self-organizing systems based on information-theoretic quantities have a tendency to spontaneously generate coordinated behavior. Moreover, in the perspective of engineering such systems to achieve specific tasks, these information-theoretic limits put constraints on the amount of coordination that is required to perform the task, and consequently on the mechanisms that underlie self-organization in the systemPeer reviewe

Anomalous scaling of dynamical large deviations

CITATION: Nickelsen, D. & Touchette, H. 2018. Anomalous scaling of dynamical large deviations. Physical Review Letters, 121(9):090602, doi:10.1103/PhysRevLett.121.090602.The original publication is available at https://journals.aps.org/prlThe typical values and fluctuations of time-integrated observables of nonequilibrium processes driven in steady states are known to be characterized by large deviation functions, generalizing the entropy and free energy to nonequilibrium systems. The definition of these functions involves a scaling limit, similar to the thermodynamic limit, in which the integration time τ appears linearly, unless the process considered has long-range correlations, in which case τ is generally replaced by τξ with ξ≠1. Here, we show that such an anomalous power-law scaling in time of large deviations can also arise without long-range correlations in Markovian processes as simple as the Langevin equation. We describe the mechanism underlying this scaling using path integrals and discuss its physical consequences for more general processes.https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.121.090602Publisher's versio