Out of the core: the impact of focal ischemia in regions beyond the penumbra.

The changes in the necrotic core and the penumbra following induction of focal ischemia have been the focus of attention for some time. However, evidence shows, that ischemic injury is not confined to the primarily affected structures and may influence the remote areas as well. Yet many studies fail to probe into the structures beyond the penumbra, and possibly do not even find any significant results due to their short-term design, as secondary damage occurs later. This slower reaction can be perceived as a therapeutic opportunity, in contrast to the ischemic core defined as irreversibly damaged tissue, where the window for salvation is comparatively short. The pathologies in remote structures occur relatively frequently and are clearly linked to the post-stroke neurological outcome. In order to develop efficient therapies, a deeper understanding of what exactly happens in the exo-focal regions is necessary. The mechanisms of glia contribution to the ischemic damage in core/penumbra are relatively well described and include impaired ion homeostasis, excessive cell swelling, glutamate excitotoxic mechanism, release of pro-inflammatory cytokines and phagocytosis or damage propagation via astrocytic syncytia. However, little is known about glia involvement in post-ischemic processes in remote areas. In this literature review, we discuss the definitions of the terms "ischemic core", "penumbra" and "remote areas." Furthermore, we present evidence showing the array of structural and functional changes in the more remote regions from the primary site of focal ischemia, with a special focus on glia and the extracellular matrix. The collected information is compared with the processes commonly occurring in the ischemic core or in the penumbra. Moreover, the possible causes of this phenomenon and the approaches for investigation are described, and finally, we evaluate the efficacy of therapies, which have been studied for their anti-ischemic effect in remote areas in recent years.

An in vitro model that mimics the foreign body response in the peritoneum: Study of the bioadhesive properties of HA-based materials.

A cascade of reactions known as the foreign body response (FBR) follows the implantation of biomaterials leading to the formation of a fibrotic capsule around the implant and subsequent health complications. The severity of the FBR is driven mostly by the physicochemical characteristics of implanted material, the method and place of implantation, and the degree of immune system activation. Here we present an in vitro model for assessing new materials with respect to their potential to induce a FBR in the peritoneum. The model is based on evaluating protein sorption and cell adhesion on the implanted material. We tested our model on the free-standing films prepared from hyaluronan derivatives with different hydrophobicity, swelling ratio, and rate of solubilization. The proteomic analysis of films incubated in the mouse peritoneum showed that the presence of fibrinogen was driving the cell adhesion. Neither the film surface hydrophobicity/hydrophilicity nor the quantity of adsorbed proteins were decisive for the induction of the long-term cell adhesion leading to the FBR, while the dissolution rate of the material proved to be a crucial factor. Our model thus helps determine the probability of a FBR to materials implanted in the peritoneum while limiting the need for in vivo animal testing.

The Role of Adherence Thresholds for Development and Performance Aspects of a Prediction Model for Direct Oral Anticoagulation Adherence.

Patients who do not sufficiently adhere to their dosing regimens will, ultimately, do not get the full benefit of their medication. For example, if direct oral anticoagulants (DOAC) are not taken continuously, an intervention to improve adherence or maintain persistence will show direct effects on clinical outcomes. Usually, adherent patients are defined by taking ≥80% of their medication. The resulting binary adherence status from this threshold can as well be used for predictive classification. Thus, the threshold can determine the prediction model's performance to identify patients at risk for poor adherence by this binary adherence status. In this perspective, we propose a plan for model development and performance considering the threshold's role. Concerning development demands, we extracted predictors from a systematic literature search on DOAC adherence to be used as a core set of candidate predictors. Independently, we investigated how well a future model would technically have to perform by modeling drug intake and thromboembolic events based on a rivaroxaban pharmacokinetic-pharmacodynamic model. Using this simulation framework for different thresholds, we projected the impact of an imperfectly predicted adherence status on the event risk, and how imperfect sensitivity and specificity affect the cost balance if a supporting intervention was offered to patients classified as non-adherent. Our simulation results suggest applying a rather high threshold (90%) for discrimination between patients at low or high risk for non-adherence by a prediction model in order to assure cost-efficient implementation.