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Abstract Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA’s remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP – 95.2 (− 554.1; 156.0) vs 231.3 (− 59.7; 388.1) p

Abstract Background To validate pulmonary computed tomography (CT) perfusion in a porcine model by invasive monitoring of cardiac output (CO) using thermodilution method. Methods Animals were studied at a single center, using a Swan-Ganz catheter for invasive CO monitoring as a reference. Fifteen pigs were included. Contrast-enhanced CT perfusion of the descending aorta and right and left pulmonary artery was performed. For variation purposes, a balloon catheter was inserted to block the contralateral pulmonary vascular bed; additionally, two increased CO settings were created by intravenous administration of catecholamines. Finally, stepwise capillary occlusion was performed by intrapulmonary arterial injection of 75-μm microspheres in four stages. A semiautomatic selection of AFs and a recirculation-aware tracer-kinetics model to extract the first-pass of AFs, estimating blood flow with the Stewart-Hamilton method, was implemented. Linear mixed models (LMM) were developed to calibrate blood flow calculations accounting with individual- and cohort-level effects. Results Nine of 15 pigs had complete datasets. Strong correlations were observed between calibrated pulmonary (0.73, 95% confidence interval [CI] 0.6–0.82) and aortic blood flow measurements (0.82, 95% CI, 0.73–0.88) and the reference as well as agreements (± 2.24 L/min and ± 1.86 L/min, respectively) comparable to the state of the art, on a relatively wide range of right ventricle-CO measurements. Conclusions CT perfusion validly measures CO using LMMs at both individual and cohort levels, as demonstrated by referencing the invasive CO. Relevance statement Possible clinical applications of CT perfusion for measuring CO could be in acute pulmonary thromboembolism or to assess right ventricular function to show impairment or mismatch to the left ventricle. Key points • CT perfusion measures flow in vessels. • CT perfusion measures cumulative cardiac output in the aorta and pulmonary vessels. • CT perfusion validly measures CO using LMMs at both individual and cohort levels, as demonstrated by using the invasive CO as a reference standard. Graphical Abstract

Abstract Decision making frequently depends on monitoring the duration of sensory events. To determine whether, and how, the perception of elapsed time derives from the neuronal representation of the stimulus itself, we recorded and optogenetically modulated vibrissal somatosensory cortical activity as male rats judged vibration duration. Perceived duration was dilated by optogenetic excitation. A second set of rats judged vibration intensity; here, optogenetic excitation amplified the intensity percept, demonstrating sensory cortex to be the common gateway both to time and to stimulus feature processing. A model beginning with the membrane currents evoked by vibrissal and optogenetic drive and culminating in the representation of perceived time successfully replicated rats’ choices. Time perception is thus as deeply intermeshed within the sensory processing pathway as is the sense of touch itself, suggesting that the experience of time may be further investigated with the toolbox of sensory coding.

Removing occluding objects such as vehicles from drivable areas allows precise extraction of road boundaries and related semantic objects such as lane-markings, which is crucial for several applications such as generating high-definition maps for autonomous driving. Conventionally, multiple images of the same area taken at different times or from various perspectives are used to remove occlusions and to reconstruct the occluded areas. Nevertheless, these approaches require large amounts of data, which are not always available. Furthermore, they do not work for static occlusions caused by, among others, parked vehicles. In this paper, we address occlusion removal based on single aerial images using generative adversarial networks (GANs), which are able to deal with the mentioned challenges. To this end, we adapt several state-of-the-art GAN-based image inpainting algorithms to reconstruct the missing information. Results indicate that the StructureFlow algorithm outperforms the competitors and the restorations obtained are robust, with high visual fidelity in real-world applications. Furthermore, due to the lack of annotated aerial vehicle removal datasets, we generate a new dataset for training and validating the algorithms, the Aerial Vehicle Occlusion Removal (AVOR) dataset. To the best of our knowledge, our work is the first to address vehicle removal using deep learning algorithms to enhance maps.

Alarm flood due to abnormality propagation is the most difficult alarm overloading problem in nuclear power plants (NPPs). Root-cause analysis is suggested to help operators in understand emergency events and plant status. Multilevel Flow Modeling (MFM) has been extensively applied in alarm management by virtue of the capability of explaining causal dependencies among alarms. However, there has never been a technique that can identify the actual root cause for complex alarm situations. This paper presents an automated root-cause analysis system based on MFM. The causal reasoning algorithm is first applied to identify several possible root causes that can lead to massive alarms. A novel root-cause ranking algorithm can subsequently be used to isolate the most likely faults from the other root-cause candidates. The proposed method is validated on a pressurized water reactor (PWR) simulator at HAMMLAB. The results show that the actual root cause is accurately identified for every tested operating scenario. The automation of root-cause identification and ranking affords the opportunity of real-time alarm analysis. It is believed that the study can further improve the situation awareness of operators in the alarm flooding situation.

Abstract Background IL‐17A and TNF synergistically promote inflammation and tumorigenesis. Their interplay and impact on ovarian carcinoma (OC) progression are, however, poorly understood. We addressed this question focusing on mesothelial cells, whose interaction with tumor cells is known to play a pivotal role in transcoelomic metastasis formation. Methods Flow‐cytometry and immunohistochemistry experiments were employed to identify cellular sources of IL‐17A and TNF. Changes in transcriptomes and secretomes were determined by bulk and single cell RNA sequencing as well as affinity proteomics. Functional consequences were investigated by microscopic analyses and tumor cell adhesion assays. Potential clinical implications were assessed by immunohistochemistry and survival analyses. Results We identified Th17 cells as the main population of IL‐17A‐ and TNF producers in ascites and detected their accumulation in early omental metastases. Both IL‐17A and its receptor subunit IL‐17RC were associated with short survival of OC patients, pointing to a role in clinical progression. IL‐17A and TNF synergistically induced the reprogramming of mesothelial cells towards a pro‐inflammatory mesenchymal phenotype, concomitantly with a loss of tight junctions and an impairment of mesothelial monolayer integrity, thereby promoting cancer cell adhesion. IL‐17A and TNF synergistically induced the Th17‐promoting cytokines IL‐6 and IL‐1β as well as the Th17‐attracting chemokine CCL20 in mesothelial cells, indicating a reciprocal crosstalk that potentiates the tumor‐promoting role of Th17 cells in OC. Conclusions Our findings reveal a novel function for Th17 cells in the OC microenvironment, which entails the IL‐17A/TNF‐mediated induction of mesothelial‐mesenchymal transition, disruption of mesothelial layer integrity and consequently promotion of OC cell adhesion. These effects are potentiated by a positive feedback loop between mesothelial and Th17 cells. Together with the observed clinical associations and accumulation of Th17 cells in omental micrometastases, our observations point to a potential role in early metastases formation and thus to new therapeutic options.

BackgroundUnderstanding complex cardiac anatomy is essential for percutaneous left atrial appendage (LAA) closure. Conventional multi-slice computed tomography (MSCT) and transesophageal echocardiography (TEE) are now supported by advanced 3D printing and virtual reality (VR) techniques for three-dimensional visualization of volumetric data sets. This study aimed to investigate their added value for LAA closure procedures.MethodsTen patients scheduled for interventional LAA closure were evaluated with MSCT and TEE. Patient-specific 3D printings and VR models were fabricated based on MSCT data. Ten cardiologists then comparatively assessed LAA anatomy and its procedure relevant surrounding structures with all four imaging modalities and rated their procedural utility on a 5-point Likert scale questionnaire (from 1 = strongly agree to 5 = strongly disagree).ResultsDevice sizing was rated highest in MSCT (MSCT: 1.9 ± 0.8; TEE: 2.6 ± 0.9; 3D printing: 2.5 ± 1.0; VR: 2.5 ± 1.1; p

Abstract In view of the persisting tension between theoretical predictions and the LHC data for the pp → t t ¯ W $$ t\overline{t}W $$ ± production process, we present the state-of-the-art full off-shell NLO QCD result for pp → t t ¯ W $$ t\overline{t}W $$ + j + X. We concentrate on the multi-lepton decay channel at the LHC with s $$ \sqrt{s} $$ = 13 TeV. In our calculation off-shell top quarks and gauge bosons are described by Breit-Wigner propagators, furthermore, double-, single- as well as non-resonant top-quark contributions along with all interference effects are consistently incorporated at the matrix element level. We present results for both integrated and differential fiducial cross sections for various renormalisation and factorisation scale settings and different PDF sets. With a fairly inclusive choice of cuts and regardless of the scale and PDF choice, non-flat differential K $$ \mathcal{K} $$ -factors are obtained for many observables that we have examined. Since from an experimental point of view, both processes pp → t t ¯ W $$ t\overline{t}W $$ ± j + X and pp → t t ¯ W $$ t\overline{t}W $$ ± + X consist of similar final states we investigate the effect of additional jet activity on the integrated and differential fiducial cross sections. For this purpose, the normalised differential distributions for pp → e + ν e μ − ν ¯ $$ \overline{\nu} $$ μ τ + ν τ b b ¯ $$ b\overline{b} $$ j + X and pp → e + ν e μ − ν ¯ $$ \overline{\nu} $$ μ τ + ν τ b b ¯ $$ b\overline{b} $$ + X are compared. The theoretical results for the latter process are also recalculated.

Summary: A crucial requirement for metastasis formation in ovarian high-grade serous carcinoma (HGSC) is the disruption of the protective peritoneal mesothelium. Using co-culture systems of primary human cells, we discovered that tumor-associated NK cells induce TRAIL-dependent apoptosis in mesothelial cells via death receptors DR4 and DR5 upon encounter with activated T cells. Upregulation of TRAIL expression in NK cells concomitant with enhanced cytotoxicity toward mesothelial cells was driven predominantly by T-cell-derived TNFα, as shown by affinity proteomics-based analysis of the T cell secretome in conjunction with functional studies. Consistent with these findings, we detected apoptotic mesothelial cells in the peritoneal fluid of HGSC patients. In contrast to mesothelial cells, HGSC cells express negligible levels of both DR4 and DR5 and are TRAIL resistant, indicating cell-type-selective killing by NK cells. Our data point to a cooperative action of T and NK in breaching the mesothelial barrier in HGSC patients.

Abstract Background Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. fls485 coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze fls485 expression in human small intestinal mucosa. Methods fls485 expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several in situ techniques and usage of newly synthesized mouse monoclonal antibodies. Results fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c. Conclusions Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible.

The survival of chronic lymphocytic leukemia cells strongly depends on the presence of a supportive microenvironment. Here, the authors show that LYN kinase is essential for the reprogramming of stromal cells towards a leukemia-supportive phenotype that facilitates disease progression.