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The stroke field is inevitably connected with imaging in which radiologists fulfill a central role. Our landmark MR CLEAN trial led to the implementation of baseline computed tomography angiography or magnetic resonance angiography in the acute stroke workup and subsequent endovascular treatment (EVT) for ischemic stroke patients with a large vessel occlusion in the anterior circulation, resulting in numerous patients worldwide currently being treated often successfully. A reversal of the pathophysiologic process behind an acute cerebrovascular event was made possible. Subsequently, in the MR CLEAN II trials, the clinical impact of both diagnostic and interventional radiologists remained a cornerstone of our research, which means value-based radiology. Within these MR CLEAN II trials, we proved that aspirin and heparin during EVT should be avoided due to increased symptomatic intracranial hemorrhage risk (MR CLEAN-MED). We concluded there is additional benefit of EVT in the 6-to-24-h window after stroke in the presence of good collaterals on baseline CTA (MR CLEAN-LATE). The impactful success of our stroke trials that changed many guidelines was mainly attributable to (1) the societal burden of the disease, with two thirds of patients dying or being independent at 3 months; (2) the fact that stroke is a common disease, (3) the relatively simple and pragmatic approach of the trials resembling real-world setting; (4) the acceleration of implementation in clinical practice facilitated by a structured approach to guideline development and conditional funding; and foremost (5) the excellent collaboration on a professional level between-disciplines, i.e., diagnostic radiologists, interventionalists, and neurologists. Critical relevance statement The MR CLEAN and MR CLEAN II trials have had tremendous impact on clinical practice, directly by more patients being treated with an effective intervention and indirectly through adoption of evidence-based guidelines. It is in

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.

Despite the overall treatment effect of EVT is highly effective, there are many targets to further improve patient outcomes. In this thesis, we identified factors influencing outcome after EVT and evaluated alternative approaches for study design to accelerate research on new therapeutic strategies. Based on our findings, we recommend to perform EVT under local anesthesia instead of conscious sedation if this is considered safe. Besides, large drops in periprocedural blood pressure should be avoided as these are associated with worse outcomes. Blood pressure on hospital admission is not an argument to withhold or delay EVT for ischemic stroke as blood pressure does not negate the effect of EVT. Furthermore, prevention of post-procedural adverse events has a great potential to further improve outcomes in successfully reperfused patients. A reduced infarct volume after EVT explains one third of treatment benefit in terms of neurological deficit. Development of new imaging techniques for accurate, reliable assessment of brain tissue viability is of importance to further improve both stroke research and clinical practice. Another future direction for EVT research is the use of cohorts of synthetic stroke patients for the development and validation of prediction tools, decision model analysis, and in-silico trials, as we demonstrated statistical methods to generate realistic cohorts of synthetic stroke patients.

The advancement of ischaemic stroke treatment relies on resource-intensive experiments and clinical trials. In order to improve ischaemic stroke treatments, such as thrombolysis and thrombectomy, we target the development of computational tools for in silico trials which can partially replace these animal and human experiments with fast simulations. This study proposes a model that will serve as part of a predictive unit within an in silico clinical trial estimating patient outcome as a function of treatment. In particular, the present work aims at the development and evaluation of an organ-scale microcirculation model of the human brain for perfusion prediction. The model relies on a three-compartment porous continuum approach. Firstly, a fast and robust method is established to compute the anisotropic permeability tensors representing arterioles and venules. Secondly, vessel encoded arterial spin labelling magnetic resonance imaging and clustering are employed to create an anatomically accurate mapping between the microcirculation and large arteries by identifying superficial perfusion territories. Thirdly, the parameter space of the problem is reduced by analysing the governing equations and experimental data. Fourthly, a parameter optimization is conducted. Finally, simulations are performed with the tuned model to obtain perfusion maps corresponding to an open and an occluded (ischaemic stroke) scenario. The perfusion map in the occluded vessel scenario shows promising qualitative agreement with computed tomography images of a patient with ischaemic stroke caused by large vessel occlusion. The results highlight that in the case of vessel occlusion (i) identifying perfusion territories is essential to capture the location and extent of underperfused regions and (ii) anisotropic permeability tensors are required to give quantitatively realistic estimation of perfusion change. In the future, the model will be thoroughly validated against experiments.

Objective The effect of anesthetic management (general anesthesia [GA], conscious sedation, or local anesthesia) on functional outcome and the role of blood pressure management during endovascular treatment (EVT) for acute ischemic stroke is under debate. We aimed to determine whether hypotension during EVT under GA is associated with functional outcome at 90 days. Methods We retrospectively collected data from patients with a proximal intracranial occlusion of the anterior circulation treated with EVT under GA. The primary outcome was the distribution on the modified Rankin Scale at 90 days. Hypotension was defined using two thresholds: a mean arterial pressure (MAP) of 70 mm Hg and a MAP 30% below baseline MAP. To quantify the extent and duration of hypotension, the area under the threshold (AUT) was calculated using both thresholds. Results Of the 366 patients included, procedural hypotension was observed in approximately half of them. The occurrence of hypotension was associated with poor functional outcome (MAP >70 mm Hg: adjusted common odds ratio [acOR], 0.57; 95% confidence interval [CI], 0.35-\ 0.94; MAP decrease ≥30%: acOR, 0.76; 95% CI, 0.48-1.21). In addition, an association was found between the number of hypotensive periods and poor functional outcome (MAP <70 mm Hg: acOR, 0.85 per period increase; 95% CI, 0.73-0.99; MAP decrease ≥30%: acOR, 0.90 per period; 95% CI, 0.78-1.04). No association existed between AUT and functional outcome (MAP <70 mm Hg: acOR, 1.000 per 10 mm Hg∗min increase; 95% CI, 0.998-1.001; MAP decrease ≥30%: acOR, 1.000 per 10 mm Hg∗min; 95% CI, 0.999- 1.000). Conclusions Occurrence of procedural hypotension and an increase in number of procedural hypotensive periods were associated with poor functional outcome, whereas the extent and duration of hypotension were not. Randomized clinical trials are needed to confirm our hypothesis that hypotension during EVT under GA has detrimental effects.

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.

Evidence on the clinical effectiveness of probiotics in the prevention of necrotising enterocolitis (NEC) in preterm infants is conflicting and cohort studies lacked adjustment for time trend and feeding type. This study investigated the association between the introduction of routine probiotics (Lactobacillus acidophilus and Bifidobacterium bifidum; Infloran (R)) on the primary outcome 'NEC or death'. Preterm infants (gestational age