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The sustainability of vascular access for hemodialysis is limited by frequent interventions and the inability of synthetic grafts to self-heal. Tissue engineering offers a solution through biodegradable grafts that remodel into autologous tissue. Here we assess electrospun polycarbonate-bis urea (PC-BU) vascular scaffolds (6mm-inner-Ø), reinforced with 3D-printed polycaprolactone coils, in a goat model, and compared them to expanded polytetrafluoroethylene (ePTFE) controls. The tissue-engineered grafts were repeatedly cannulated starting two weeks after implantation and were evaluated using computed tomography and histological analyses. By 12 weeks, the PC-BU grafts remodel into autologous tissue while maintaining structural integrity, maintaining integrity without dilations, ruptures, or aneurysms. Cannulation does not interfere with scaffold degradation or neo-tissue formation. Although the patency rate is lower for the PC-BU grafts (50%) compared to ePTFE (100%), the engineered grafts exhibit a self-healing response not seen in ePTFE. These findings demonstrate the potential of PC-BU tissue-engineered grafts as healing, functional vascular access solutions for hemodialysis, supporting cannulation during tissue transformation. Vascular access for hemodialysis is often compromised by synthetic grafts that lack self-healing capabilities. Here, electrospun polycarbonate-bis urea grafts, reinforced with 3D-printed polycaprolactone coils, are shown to remodel into autologous tissue in goats.

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo . Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall.

The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically-driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a non-canonical role for the Notch ligand Jagged1 in regulating the activity of mechanosensitive kinases in endothelial cells. We show that stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence and peaks at 0.8-1Pa without impacting Jagged1s Notch-activation potential. On the contrary Jagged1 regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of VEGFR2 and ERK in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, the direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induces Src activation. Taken together, we demonstrate a novel non-canonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.

Fluid shear stress (FSS) from the blood flow is a crucial regulator of vascular physiology and is associated with major cardiovascular pathologies. Endothelial cells are the primary mechanotransducers of FSS. Here, we show that Jagged1, a canonical ligand of the Notch pathway, modulates biomechanical signaling in endothelial cells in response to FSS. We found that changes in FSS magnitude alter the expression and localization of Jagged1 independently of its effect on Notch expression or activation. Deletion of Jagged1 decreases FSS-induced VEGFR2 and ERK activity in vitro and causes attenuated kinase activity and cardiac defects in zebrafish embryos without significant changes in canonical Notch activity. We show that direct physical stimulation of Jagged1 induces mechanosignaling through the VEGFR2 pathway, independently of Notch signaling but mediated by Jagged1-induced Src activation. Our findings suggest a novel non-canonical role for Jagged1 as a mechanotransducer in endothelial cells with implications for cardiovascular morphogenesis and disease.Competing Interest StatementThe authors have declared no competing interest.

Data-driven decision support tools have been increasingly recognized to transform health care. However, such tools are often developed on predefined research datasets without adequate knowledge of the origin of this data and how it was selected. How a dataset is extracted from a clinical database can profoundly impact the validity, interpretability and interoperability of the dataset, and downstream analyses, yet is rarely reported. Therefore, we present a case study illustrating how a definitive patient list was extracted from a clinical source database and how this can be reported. A single-center observational study was performed at an academic hospital in the Netherlands to illustrate the impact of selecting a definitive patient list for research from a clinical source database, and the importance of documenting this process. All admissions from the critical care database admitted between January 1, 2013, and January 1, 2023, were used. An interdisciplinary team collaborated to identify and address potential sources of data insufficiency and uncertainty. We demonstrate a stepwise data preparation process, reducing the clinical source database of 54,218 admissions to a definitive patient list of 21,553 admissions. Transparent documentation of the data preparation process improves the quality of the definitive patient list before analysis of the corresponding patient data. This study generated seven important recommendations for preparing observational health-care data for research purposes. Documenting data preparation is essential for understanding a research dataset originating from a clinical source database before analyzing health-care data. The findings contribute to establishing data standards and offer insights into the complexities of preparing health-care data for scientific investigation. Meticulous data preparation and documentation thereof will improve research validity and advance critical care.

We validated a Deep Embedded Clustering (DEC) model and its adaptation for integrating mixed datatypes (in this study, numerical and categorical variables). Deep Embedded Clustering (DEC) is a promising technique capable of managing extensive sets of variables and non-linear relationships. Nevertheless, DEC cannot adequately handle mixed datatypes. Therefore, we adapted DEC by replacing the autoencoder with an X-shaped variational autoencoder (XVAE) and optimising hyperparameters for cluster stability. We call this model “X-DEC”. We compared DEC and X-DEC by reproducing a previous study that used DEC to identify clusters in a population of intensive care patients. We assessed internal validity based on cluster stability on the development dataset. Since generalisability of clustering models has insufficiently been validated on external populations, we assessed external validity by investigating cluster generalisability onto an external validation dataset. We concluded that both DEC and X-DEC resulted in clinically recognisable and generalisable clusters, but X-DEC produced much more stable clusters.

Myocardial injury in COVID-19 is associated with in-hospital mortality. However, the development of myocardial injury over time and whether myocardial injury in patients with COVID-19 at the intensive care unit is associated with outcome is unclear. This study prospectively investigates myocardial injury with serial measurements over the full course of intensive care unit admission in mechanically ventilated patients with COVID-19. As part of the prospective Maastricht Intensive Care COVID cohort, predefined myocardial injury markers, including high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and electrocardiographic characteristics were serially collected in mechanically ventilated patients with COVID-19. Linear mixed-effects regression was used to compare survivors with nonsurvivors, adjusting for gender, age, APACHE-II score, daily creatinine concentration, hypertension, diabetes mellitus, and obesity. In 90 patients, 57 (63%) were survivors and 33 (37%) nonsurvivors, and a total of 628 serial electrocardiograms, 1,565 hs-cTnT, and 1,559 NT-proBNP concentrations were assessed. Log-hs-cTnT was lower in survivors compared with nonsurvivors at day 1 (β −0.93 [−1.37; −0.49], p <0.001) and did not change over time. Log-NT-proBNP did not differ at day 1 between both groups but decreased over time in the survivor group (β −0.08 [−0.11; −0.04] p <0.001) compared with nonsurvivors. Many electrocardiographic abnormalities were present in the whole population, without significant differences between both groups. In conclusion, baseline hs-cTnT and change in NT-proBNP were strongly associated with mortality. Two-thirds of patients with COVID-19 showed electrocardiographic abnormalities. Our serial assessment suggests that myocardial injury is common in mechanically ventilated patients with COVID-19 and is associated with outcome.

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo. Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80–85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially. Results: Glyoxalase-1 mRNA expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (P<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (P=0.003). D-Lactate was increased in all four groups. L-Lactate was increased in all groups, except in the control group. Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention.

BackgroundCoronary artery calcification (CAC) is associated with poor outcome in critically ill patients. A deterioration in cardiac conduction and loss of myocardial tissue could be an underlying cause. Vectorcardiography (VCG) and cardiac biomarkers provide insight into these underlying causes. The aim of this study was to investigate whether a high degree of CAC is associated with VCG-derived variables and biomarkers, including high-sensitivity troponin-T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP).MethodsMechanically ventilated coronavirus-19 (COVID-19) patients with an available chest computed tomography (CT) and 12-lead electrocardiogram (ECG) were studied. CAC scores were determined using chest CT scans. Patients were categorized into 3 sex-specific tertiles: low, intermediate, and high CAC. Daily 12 leads-ECGs were converted to VCGs. Daily hs-cTnT and NT-proBNP levels were determined. Linear mixed-effects regression models examined the associations between CAC tertiles and VCG variables, and between CAC tertiles and hs-cTnT or NT-proBNP levels.ResultsIn this study, 205 patients (73.2% men, median age 65 years [IQR 57.0; 71.0]) were included. Compared to the lowest CAC tertile, the highest CAC tertile had a larger QRS area at baseline (6.65 µVs larger [1.50; 11.81], p = 0.012), which decreased during admission (− 0.27 µVs per day [− 0.43; − 0.11], p = 0.001). Patients with the highest CAC tertile also had a longer QRS duration (12.02 ms longer [4.74; 19.30], p = 0.001), higher levels of log hs-cTnT (0.79 ng/L higher [0.40; 1.19], p < 0.001) and log NT-proBNP (0.83 pmol/L higher [0.30; 1.37], p = 0.002).ConclusionPatients with a high degree of CAC had the largest QRS area and higher QRS amplitude, which decreased more over time when compared to patients with a low degree of CAC. These results suggest that CAC might contribute to loss of myocardial tissue during critical illness. These insights could improve risk stratification and prognostication of patients with critical illness.