A Model of the Cellular Iron Homeostasis Network Using Semi-Formal Methods for Parameter Space Exploration

This paper presents a novel framework for the modeling of biological networks. It makes use of recent tools analyzing the robust satisfaction of properties of (hybrid) dynamical systems. The main challenge of this approach as applied to biological systems is to get access to the relevant parameter sets despite gaps in the available knowledge. An initial estimate of useful parameters was sought by formalizing the known behavior of the biological network in the STL logic using the tool Breach. Then, once a set of parameter values consistent with known biological properties was found, we tried to locally expand it into the largest possible valid region. We applied this methodology in an effort to model and better understand the complex network regulating iron homeostasis in mammalian cells. This system plays an important role in many biological functions, including erythropoiesis, resistance against infections, and proliferation of cancer cells.Comment: In Proceedings HSB 2012, arXiv:1208.315

Model Predictive Control for Signal Temporal Logic Specification

We present a mathematical programming-based method for model predictive control of cyber-physical systems subject to signal temporal logic (STL) specifications. We describe the use of STL to specify a wide range of properties of these systems, including safety, response and bounded liveness. For synthesis, we encode STL specifications as mixed integer-linear constraints on the system variables in the optimization problem at each step of a receding horizon control framework. We prove correctness of our algorithms, and present experimental results for controller synthesis for building energy and climate control

Signal Convolution Logic

We introduce a new logic called Signal Convolution Logic (SCL) that combines temporal logic with convolutional filters from digital signal processing. SCL enables to reason about the percentage of time a formula is satisfied in a bounded interval. We demonstrate that this new logic is a suitable formalism to effectively express non-functional requirements in Cyber-Physical Systems displaying noisy and irregular behaviours. We define both a qualitative and quantitative semantics for it, providing an efficient monitoring procedure. Finally, we prove SCL at work to monitor the artificial pancreas controllers that are employed to automate the delivery of insulin for patients with type-1 diabetes

Effects of a Multimodal Transitional Care Intervention in Patients at High Risk of Readmission: The TARGET-READ Randomized Clinical Trial.

IMPORTANCE Hospital readmissions are frequent, costly, and sometimes preventable. Although these issues have been well publicized and incentives to reduce them introduced, the best interventions for reducing readmissions remain unclear. OBJECTIVES To evaluate the effects of a multimodal transitional care intervention targeting patients at high risk of hospital readmission on the composite outcome of 30-day unplanned readmission or death. DESIGN, SETTING, AND PARTICIPANTS A single-blinded, multicenter randomized clinical trial was conducted from April 2018 to January 2020, with a 30-day follow-up in 4 medium-to-large-sized teaching hospitals in Switzerland. Participants were consecutive patients discharged from general internal medicine wards and at higher risk of unplanned readmission based on their simplified HOSPITAL score (≥4 points). Data were analyzed between April and September 2022. INTERVENTIONS The intervention group underwent systematic medication reconciliation, a 15-minute patient education session with teach-back, a planned first follow-up visit with their primary care physician, and postdischarge follow-up telephone calls from the study team at 3 and 14 days. The control group received usual care from their hospitalist, plus a 1-page standard study information sheet. MAIN OUTCOMES AND MEASURES Thirty-day postdischarge unplanned readmission or death. RESULTS A total of 1386 patients were included with a mean (SD) age of 72 (14) years; 712 (51%) were male. The composite outcome of 30-day unplanned readmission or death was 21% (95% CI, 18% to 24%) in the intervention group and 19% (95% CI, 17% to 22%) in the control group. The intention-to-treat analysis risk difference was 1.7% (95% CI, -2.5% to 5.9%; P = .44). There was no evidence of any intervention effects on time to unplanned readmission or death, postdischarge health care use, patient satisfaction with the quality of their care transition, or readmission costs. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, use of a standardized multimodal care transition intervention targeting higher-risk patients did not significantly decrease the risks of 30-day postdischarge unplanned readmission or death; it demonstrated the difficulties in preventing hospital readmissions, even when multimodal interventions specifically target higher-risk patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03496896

Effectiveness of Transition Care Intervention Targeted to High-Risk Patients to Reduce Readmissions: Study Protocol for the TARGET-READ Multicenter Randomized-Controlled Trial.

Hospital readmissions within 30 days represent a burden for the patients and the entire health care system. Improving the care around hospital discharge period could decrease the risk of avoidable readmissions. We describe the methods of a trial that aims to evaluate the effect of a structured multimodal transitional care intervention targeted to higher-risk medical patients on 30-day unplanned readmissions and death. The TARGET-READ study is an investigator-initiated, pragmatic single-blinded randomized multicenter controlled trial with two parallel groups. We include all adult patients at risk of hospital readmission based on a simplified HOSPITAL score of ≥4 who are discharged home or nursing home after a hospital stay of one day or more in the department of medicine of the four participating hospitals. The patients randomized to the intervention group will receive a pre-discharge intervention by a study nurse with patient education, medication reconciliation, and follow-up appointment with their referring physician. They will receive short follow-up phone calls at 3 and 14 days after discharge to ensure medication adherence and follow-up by the ambulatory care physician. A blind study nurse will collect outcomes at 1 month by phone call interview. The control group will receive usual care. The TARGET-READ study aims to increase the knowledge about the efficacy of a bundled intervention aimed at reducing 30-day hospital readmission or death in higher-risk medical patients

A Contract-Based Methodology for Aircraft Electric Power System Design

In an aircraft electric power system, one or more supervisory control units actuate a set of electromechanical switches to dynamically distribute power from generators to loads, while satisfying safety, reliability, and real-time performance requirements. To reduce expensive redesign steps, this control problem is generally addressed by minor incremental changes on top of consolidated solutions. A more systematic approach is hindered by a lack of rigorous design methodologies that allow estimating the impact of earlier design decisions on the final implementation. To achieve an optimal implementation that satisfies a set of requirements, we propose a platform-based methodology for electric power system design, which enables independent implementation of system topology (i.e., interconnection among elements) and control protocol by using a compositional approach. In our flow, design space exploration is carried out as a sequence of refinement steps from the initial specification toward a final implementation by mapping higher level behavioral and performance models into a set of either existing or virtual library components at the lower level of abstraction. Specifications are first expressed using the formalisms of linear temporal logic, signal temporal logic, and arithmetic constraints on Boolean variables. To reason about different requirements, we use specialized analysis and synthesis frameworks and formulate assume guarantee contracts at the articulation points in the design flow. We show the effectiveness of our approach on a proof-of-concept electric power system design

Reactive Synthesis from Signal Temporal Logic Specifications

We present a counterexample-guided inductive synthesis approach to controller synthesis for cyber-physical systems subject to signal temporal logic (STL) specifications, operating in potentially adversarial nondeterministic environments. We encode STL specifications as mixed integer-linear constraints on the variables of a discrete-time model of the system and environment dynamics, and solve a series of optimization problems to yield a satisfying control sequence. We demonstrate how the scheme can be used in a receding horizon fashion to fulfill properties over unbounded horizons, and present experimental results for reactive controller synthesis for case studies in building climate control and autonomous driving

Robustness Analysis and Behavior Discrimination in Enzymatic Reaction Networks

Characterizing the behavior and robustness of enzymatic networks with numerous variables and unknown parameter values is a major challenge in biology, especially when some enzymes have counter-intuitive properties or switch-like behavior between activation and inhibition. In this paper, we propose new methodological and tool-supported contributions, based on the intuitive formalism of temporal logic, to express in a rigorous manner arbitrarily complex dynamical properties. Our multi-step analysis allows efficient sampling of the parameter space in order to define feasible regions in which the model exhibits imposed or experimentally observed behaviors. In a first step, an algorithmic methodology involving sensitivity analysis is conducted to determine bifurcation thresholds for a limited number of model parameters or initial conditions. In a second step, this boundary detection is supplemented by a global robustness analysis, based on quasi-Monte Carlo approach that takes into account all model parameters. We apply this method to a well-documented enzymatic reaction network describing collagen proteolysis by matrix metalloproteinase MMP2 and membrane type 1 metalloproteinase (MT1-MMP) in the presence of tissue inhibitor of metalloproteinase TIMP2. For this model, our method provides an extended analysis and quantification of network robustness toward paradoxical TIMP2 switching activity between activation or inhibition of MMP2 production. Further implication of our approach is illustrated by demonstrating and analyzing the possible existence of oscillatory behaviors when considering an extended open configuration of the enzymatic network. Notably, we construct bifurcation diagrams that specify key parameters values controlling the co-existence of stable steady and non-steady oscillatory proteolytic dynamics