Off-the-Shelf Synthetic Biodegradable Grafts Transform In Situ into a Living Arteriovenous Fistula in a Large Animal Model

Current vascular access options require frequent interventions. In situ tissue engineering (TE) may overcome these limitations by combining the initial success of synthetic grafts with long-term advantages of autologous vessels by using biodegradable grafts that transform into autologous vascular tissue at the site of implantation. Scaffolds (6 mm-Ø) made of supramolecular polycarbonate-bisurea (PC-BU), with a polycaprolactone (PCL) anti-kinking-coil, are implanted between the carotid artery and jugular vein in goats. A subset is bio-functionalized using bisurea-modified-Stromal cell-derived factor-1α (SDF1α) derived peptides and ePTFE grafts as controls. Grafts are explanted after 1 and 3 months, and evaluated for material degradation, tissue formation, compliance, and patency. At 3 months, the scaffold is resorbed and replaced by vascular neo-tissue, including elastin, contractile markers, and endothelial lining. No dilations, ruptures, or aneurysms are observed and grafts are successfully cannulated at termination. SDF-1α-peptide-biofunctionalization does not influence outcomes. Patency is lower in TE grafts (50%) compared to controls (100% patency), predominantly caused by intimal hyperplasia. Rapid remodeling of a synthetic, biodegradable vascular scaffold into a living, compliant arteriovenous fistula is demonstrated in a large animal model. Despite lower patency compared to ePTFE, transformation into autologous and compliant living tissue with self-healing capacity may have long-term advantages

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress

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

Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review

Contains fulltext : 110141.pdf (publisher's version ) (Open Access)BACKGROUND: Loss of arm-hand performance due to a hemiparesis as a result of stroke or cerebral palsy (CP), leads to large problems in daily life of these patients. Assessment of arm-hand performance is important in both clinical practice and research. To gain more insight in e.g. effectiveness of common therapies for different patient populations with similar clinical characteristics, consensus regarding the choice and use of outcome measures is paramount. To guide this choice, an overview of available instruments is necessary. The aim of this systematic review is to identify, evaluate and categorize instruments, reported to be valid and reliable, assessing arm-hand performance at the ICF activity level in patients with stroke or cerebral palsy. METHODS: A systematic literature search was performed to identify articles containing instruments assessing arm-hand skilled performance in patients with stroke or cerebral palsy. Instruments were identified and divided into the categories capacity, perceived performance and actual performance. A second search was performed to obtain information on their content and psychometrics. RESULTS: Regarding capacity, perceived performance and actual performance, 18, 9 and 3 instruments were included respectively. Only 3 of all included instruments were used and tested in both patient populations. The content of the instruments differed widely regarding the ICF levels measured, assessment of the amount of use versus the quality of use, the inclusion of unimanual and/or bimanual tasks and the inclusion of basic and/or extended tasks. CONCLUSIONS: Although many instruments assess capacity and perceived performance, a dearth exists of instruments assessing actual performance. In addition, instruments appropriate for more than one patient population are sparse. For actual performance, new instruments have to be developed, with specific focus on the usability in different patient populations and the assessment of quality of use as well as amount of use. Also, consensus about the choice and use of instruments within and across populations is needed

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Minimum Information about a Biosynthetic Gene cluster

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.Chemistry and Chemical Biolog

Clinical diagnoses vs. autopsy findings in early deceased septic patients in the intensive care:a retrospective cohort study

Early death in sepsis occurs frequently; however, specific causes are largely unknown. An autopsy can contribute to ascertain causes of death. The objective of the study was to determine discrepancies in clinical diagnosis and postmortem findings in septic intensive care unit (ICU) patients deceased within 48 h after ICU admission. All septic ICU patients who deceased within 48 h after ICU admission were identified and included. Four intensivists determined the clinical cause of death by medical record review. An autopsy was performed within 24 h of death. Clinical diagnosis and postmortem findings were compared and classified as autopsy-identified missed clinical diagnoses and autopsy-refuted diagnoses. Class I and II missed major diagnoses using the Goldman criteria were scored. Between 2012 and 2017, 1107 septic patients were admitted to ICU. Of these, 344 patients (31%) died, of which 97 patients (28%) deceased within 48 h. In 32 (33%) early deceased patients, an autopsy was agreed. There were 26 autopsy-identified missed clinical diagnoses found, mostly myocardial infarction (n = 4) and pneumonia (n = 4). In four patients (13%), a class I discrepancy was found. In fourteen patients (42%), a class II discrepancy was found. In conclusion, an autopsy is an important diagnostic tool that can identify definite causes of death. These diagnoses deviate from diagnoses established during admission in early deceased sepsis patients

Coronary Artery Calcifications Are Associated With More Severe Multiorgan Failure in Patients With Severe Coronavirus Disease 2019 Infection: Longitudinal Results of the Maastricht Intensive Care COVID Cohort

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is regarded as a multisystemic disease. Patients with preexisting cardiovascular disease have an increased risk for a more severe disease course. This study aimed to investigate if a higher degree of coronary artery calcifications (CAC) on a standard chest computed tomography (CT) scan in mechanically ventilated patients was associated with a more severe multiorgan failure over time. MATERIALS AND METHODS: All mechanically ventilated intensive care unit patients with SARS-CoV-2 infection who underwent a chest CT were prospectively included. CT was used to establish the extent of CAC using a semiquantitative grading system. We categorized patients into 3 sex-specific tertiles of CAC: lowest, intermediate, and highest CAC score. Daily, the Sequential Organ Failure Assessment (SOFA) scores were collected to evaluate organ failure over time. Linear mixed-effects regression was used to investigate differences in SOFA scores between tertiles. The models were adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, cardiovascular risk factors, and chronic liver, lung, and renal disease. RESULTS: In all, 71 patients were included. Patients in the highest CAC tertile had, on average, over time, 1.8 (0.5-3.1) points higher SOFA score, compared with the lowest CAC tertile (P=0.005). This association remained significant after adjustment for age, sex, and APACHE II score (1.4 [0.1-2.7],P=0.042) and clinically relevant after adjustment for cardiovascular risk factors (1.3 [0.0-2.7],P=0.06) and chronic diseases (1.3 [-0.2 to 2.7],P=0.085). CONCLUSION: A greater extent of CAC is associated with a more severe multiorgan failure in mechanically ventilated coronavirus disease 2019 patients

Coronary Artery Calcifications Are Associated With More Severe Multiorgan Failure in Patients With Severe Coronavirus Disease 2019 Infection:Longitudinal Results of the Maastricht Intensive Care COVID Cohort

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is regarded as a multisystemic disease. Patients with preexisting cardiovascular disease have an increased risk for a more severe disease course. This study aimed to investigate if a higher degree of coronary artery calcifications (CAC) on a standard chest computed tomography (CT) scan in mechanically ventilated patients was associated with a more severe multiorgan failure over time. MATERIALS AND METHODS: All mechanically ventilated intensive care unit patients with SARS-CoV-2 infection who underwent a chest CT were prospectively included. CT was used to establish the extent of CAC using a semiquantitative grading system. We categorized patients into 3 sex-specific tertiles of CAC: lowest, intermediate, and highest CAC score. Daily, the Sequential Organ Failure Assessment (SOFA) scores were collected to evaluate organ failure over time. Linear mixed-effects regression was used to investigate differences in SOFA scores between tertiles. The models were adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, cardiovascular risk factors, and chronic liver, lung, and renal disease. RESULTS: In all, 71 patients were included. Patients in the highest CAC tertile had, on average, over time, 1.8 (0.5-3.1) points higher SOFA score, compared with the lowest CAC tertile (P=0.005). This association remained significant after adjustment for age, sex, and APACHE II score (1.4 [0.1-2.7], P=0.042) and clinically relevant after adjustment for cardiovascular risk factors (1.3 [0.0-2.7], P=0.06) and chronic diseases (1.3 [−0.2 to 2.7], P=0.085). CONCLUSION: A greater extent of CAC is associated with a more severe multiorgan failure in mechanically ventilated coronavirus disease 2019 patients