In silico trials for treatment of acute ischemic stroke: Design and implementation

An in silico trial simulates a disease and its corresponding therapies on a cohort of virtual patients to support the development and evaluation of medical devices, drugs, and treatment. In silico trials have the potential to refine, reduce cost, and partially replace current in vivo studies, n

A simplified mesoscale 3D model for characterizing fibrinolysis under flow conditions

One of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conducted in vitro flow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.</p

In silico trials for treatment of acute ischemic stroke: Design and implementation

An in silico trial simulates a disease and its corresponding therapies on a cohort of virtual patients to support the development and evaluation of medical devices, drugs, and treatment. In silico trials have the potential to refine, reduce cost, and partially replace current in vivo studies, namely clinical trials and animal testing. We present the design and implementation of an in silico trial for treatment of acute ischemic stroke. We propose an event-based modelling approach for the simulation of a disease and injury, where changes to the state of the system (the events) are assumed to be instantaneous. Using this approach we are able to combine a diverse set of models, spanning multiple time scales, to model acute ischemic stroke, treatment, and resulting brain tissue injury. The in silico trial is designed to be modular to aid development and reproducibility. It provides a comprehensive framework for application to any potential in silico trial. A statistical population model is used to generate cohorts of virtual patients. Patient functional outcomes are also predicted with a statistical model, using treatment and injury results and the patient's clinical parameters. We demonstrate the functionality of the event-based modelling approach and trial framework by running proof of concept in silico trials. The proof of concept trials simulate the same cohort of patients twice: once with successful treatment (successful recanalisation) and once with unsuccessful treatment (unsuccessful treatment). Ways to overcome some of the challenges and difficulties in setting up such an in silico trial are discussed, such as validation and computational limitations

EasyVVUQ: Covidsim version

Version of EasyVVUQ used to generate the results of: W. Edeling. H. Arabnejad, R. Sinclair et al, The Impact of Uncertainty on Predictions of the CovidSim Epidemiological Code, Nat Comp Sci, 2021

Mediating war: hot diaries, liquid letters and vivid remembrances

Introductions to life-writing anthologies often allude to the ‘immediacy’ of their contents. The term has been attached to diaries and letters, the life stories of so-called ordinary people, oral as opposed to written remembrances, and, most particularly, accounts of difficult or distressing experiences—memories of war, for instance. This article considers what implications the privileging of unmediated experience might have for the work of life writing. It will do so through readings of epistolary responses, written between 1963–4, to a BBC call for ‘vivi[d]’ remembrances of the First World War; these would be used to produce an ambitious documentary series, The Great War. The article explores how dreams of immediacy shaped these responses, and draws attention to the stylistic means and metaphors by which experiential proximity was performed. It raises the question of whether assumptions about the virtues of immediacy risk discouraging the production of valuable forms of life writing: sustained, critical and reflective

Quantitative 3D analysis of tissue damage in a rat model of microembolization

There is a discrepancy between successful recanalization and good clinical outcome after endovascular treatment (EVT) in acute ischemic stroke patients. During removal of a thrombus, a shower of microemboli may release and lodge to the distal circulation. The objective of this study was to determine the extent of damage on brain tissue caused by microemboli. In a rat model of microembolization, a mixture of microsphere (MS) sizes (15, 25 and 50 µm diameter) was injected via the left internal carotid artery. A 3D image of the left hemisphere was reconstructed and a point-pattern spatial analysis was applied based on G- and K-functions to unravel the spatial correlation between MS and the induced hypoxia or infarction. We show a spatial correlation between MS and hypoxia or infarction spreading up to a distance of 1000–1500 µm. These results imply that microemboli, which individually may not always be harmful, can interact and result in local areas of hypoxia or even infarction when lodged in large numbers