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Assessing a Formal Model of Reflective Equilibrium
Get PDFBeisbart, Betz, and Brun (2021) have introduced a formal model of reflective equilibrium based on the theory of dialectical structures Betz (2013), which they use as a methodological tool to understand the method of reflective equilibrium better. This report summarizes the findings of assessing the model thoroughly by numerical investigation. We simulate RE processes for a broad spectrum of model parameters and initial conditions and use four different model variants (including the original model). We analyze the dependence of simulation results on different parameters and assess the models’ consistency conduciveness and ability to reach global optima and full RE states. The results show that the models’ behaviour depends crucially on the specifics of the simulation setup (e.g., the sentence pool size and weights). We can, therefore, not draw any general conclusions about the overall performance of the model variants. Rather, the specifics of the context in which an RE model is used must be considered to choose a specific model. Finally, we identify some critical knowledge gaps we cannot close with this report that call for further research into RE modelling
Simple blood tests to diagnose compensated advanced chronic liver disease and stratify risk of clinically significant portal hypertension.
No full textBACKGROUND AIMS
Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. Limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by FIB-4 and CSPH by von Willebrand factor/platelet count ratio (VITRO).
APPROACH RESULTS
Patients with (suspected) compensated chronic liver disease undergoing FIB4+LSM were included in the LSM/FIB-4-cohorts from Vienna&Salzburg. The HVPG/VITRO-cohorts included patients undergoing hepatic venous pressure gradient (HVPG)-measurement+VITRO from Vienna&Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients of whom 211 (3.4%) developed hepatic decompensation. 1724 (28.1%) had LSM ≥10 kPa, which corresponded to FIB-4≥1.75. Importantly, both LSM (AUROC:0.897 [95%CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95%CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4≥1.75 identified patients at risk for first hepatic decompensation (5y-cumulative incidence:7.6%), while in those <1.75, risk was negligible (0.3%).HVPG/VITRO-derivation-cohort: 247 patients of whom 202 had cACLD/FIB-4≥1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95%CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95%CI:0.801-0.910], p=0.351) and the ANTICIPATE model (AUROC:0.910 [95%CI:0.869-0.952], p=0.498). VITRO<1.0/≥2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to Baveno-VII criteria.LSM/FIB-4-derivation-cohort findings were externally validated in n=1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n=133) and externally (n=55) validated.
CONCLUSION
Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention
Correction: Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life.
Get PDFPersonen, Wissen, Karrieren. Bildung und Professionalisierung zwischen Stadt und Hof (1470-1540/50)
No full textDen Jahrzehnten um 1500, die geprägt waren von politischer Verdichtung und veränderten Herrschaftskonzepten, von wirtschaftlicher Hochkonjunktur, neuen Technologien und kulturellen Wandlungen, nähert sich der Band aus einer spezifischen wissensgeschichtlichen Perspektive. Seine Beiträge thematisieren die Rolle von Stadt und Hof für Produktion und Organisation, Vermittlung und Transfer von Wissen sowie für die Karrieren von Wissensträgern. Der personengeschichtlich akzentuierte Blick trifft dabei auf unterschiedliche Wissensbereiche: Neben Universitätsgelehrten geht es ebenso um Spezialisten und Praktiker, deren Profession nur in Teilen oder auch gar nicht von akademischer Bildung bestimmt wurde. Behandelt werden gelehrte Räte und Amtsträger in fürstlichen wie gräflichen Diensten, Ärzte, Astrologen und Kartographen, Herolde und Handwerker, Bergmeister und Kaufleute
Strategies to improve AV synchrony in patients with a Micra AV leadless pacemaker.
Get PDFThe second generation of transcatheter pacing systems, called Micra AV, can provide atrio-ventricular (AV) synchronous pacing via a new pacing algorithm relying on sensing mechanical atrial contraction. Several novel programming parameters were introduced to enable AV synchronous pacing, including an A3 and A4 window as well as a conduction and an activity mode switch. In addition to several automated features, manual programming optimization of some of the novel parameters is key to improving AV synchrony. A solid knowledge of the features and their programming is essential for electrophysiologists implanting or following patients with Micra AV devices. Differences in programming optimization might partially explain the high variability of AV synchrony published in real-world data reports. This article reviews the key programming parameters of Micra AV. Subsequently, optimal programming recommendations for defined patient profiles are presented. Those were established by consensus within an Experts Panel comprised of 11 European electrophysiologists from high-volume Micra AV centers. The patient profiles were 1) high degree AV block and slow sinus rhythm; 2) high degree AV block and fast sinus rhythm; and 3) intermittent AV block. The panel recommended to evaluate the mechanical atrial activity on transthoracic echocardiography prior to implant. It was also agreed that Auto A3 Threshold and Tracking Check should be turned off in all patients, AV Conduction Mode Switch should be turned off in all patients with high degree AV block, and the lower rate should be programmed to 50 bpm with exceptions based on individual clinical assessment. Future studies will be useful to evaluate the strength of those recommendations to improve the AV synchrony
Zehenerkrankungen bei Rindern auf Alpweiden
Get PDFIn der Schweiz werden viele Rinder und Kühe auf Alpweiden zusammen mit Tieren aus anderen Betrieben gesömmert. Erfahrungsgemäss treten auf grösseren Rinderalpen häufig Zehenerkrankungen bei Rindern auf, was zu einem hohen Arbeitsaufwand für das Alppersonal und zum Einsatz grosser Mengen an Antibiotika führt. Um diese Situation langfristig zu verbessern, wurden durch die Wiederkäuerklinik der Vetsuisse-Fakultät der Universität Bern zwei wissenschaftliche Studien durchgeführt. Diese hatten zum Ziel, die Ursachen für die beschriebenen Zehenerkrankungen zu eruieren und gleichzeitig Risikofaktoren für deren Auftreten zu beschreiben, um deren Vorkommen in Zukunft vorzubeugen. Insbesondere war von Interesse, ob Dermatitis digitalis (DD; Mortellaro'sche Krankheit) eine relevante Rolle spielt. Projekt 1 wurde auf zwei grossen Alpen im Kanton Uri und Projekt 2 auf 11 Alpen im Unterengadin (Kanton Graubünden) durchgeführt
Multi-phase quantitative compositional mapping by LA-ICP-MS: Analytical approach and data reduction protocol implemented in XMapTools
Get PDFMapping of trace element signatures is an expanding tool in geoscience and material sciences, which allows the study of solid materials, and processes that may not be captured by major elements. Developments in laserablation inductively-coupled-plasma mass-spectrometry (LA-ICP-MS) capabilities in the last decade now provide the necessary spatial resolution for in situ element mapping. The acquisition of two-dimensional, fully quantitative and geologically meaningful data with LA-ICP-MS is still a challenging task, and a particular obstacle is the calibration of inhomogeneous phases, such as chemically zoned minerals. This work presents a novel approach to data reduction and image generation for multi-element mapping employing LA-ICP- quadrupole MS (LA-ICP-QMS), implemented in the free and open-source software XMapTools. Three geological applications are presented to illustrate the benefits of the procedures. Garnet from an eclogitic sample (Lato Hills, Togo) and plagioclase, K-feldspar, biotite from a migmatite sample (El Oro Complex, Ecuador) were mapped multiple times at different spatial resolutions to test the calibration quality and chemical detection capabilities. Rutile in a metapelite sample (Val Malenco, Italian Alps) was mapped, and Zr-in-rutile thermometry shows a temperature range of 510 to 550 ◦C within a single grain. The accuracy of the LA-ICP-MS method was verified by comparison with zoned major and minor element maps (garnet, plagioclase) and Ti-in-biotite geothermometry maps obtained by electron probe microanalysis (EPMA). A spatial resolution of up to 5 μm is achieved with LAICP-QMS, which is similar to the resolution reported for LA-ICP time-of-flight mass spectrometry (LA-ICPTOFMS), albeit at significantly lower acquisition speed. Maps with lower spatial resolution offer better chemical detection power as demonstrated by lower per-pixel limit of detection (LOD) map calculation. Moreover, such maps are also recorded faster. The pixel allocation strategy and the instrumental conditions also have a direct impact on map quality. We recommend that maps are interpolated to square pixels, where a pixel consists of multiple sweeps to gain an improved detection power. Benchmarks using an emulated LA-ICP-MS mapping show that the spot size, together with scan direction, can lead to a shift in composition depending on the feature size of chemical patterns. This is verified by mapping a thin 10 μm annulus in garnet visible in REE and such compositional shifts can have a significant impact on e.g., diffusion modelling. The new software solution provides a multi-standard and variable composition calibration of LA-ICP-MS maps with single pixel LOD filtering at 95% confidence, allowing the user to quantify inhomogeneous materials of major and trace elements simultaneously with improved accuracy
Role of calcium integrin-binding protein 1 in the mechanobiology of the liver endothelium.
Get PDFLiver sinusoidal endothelial cells (LSECs) dysfunction is a key process in the development of chronic liver disease (CLD). Progressive scarring increases liver stiffness in a winch-like loop stimulating a dysfunctional liver cell phenotype. Cellular stretching is supported by biomechanically modulated molecular factors (BMMFs) that can translocate into the cytoplasm to support mechanotransduction through cytoskeleton remodeling and gene transcription. Currently, the molecular mechanisms of stiffness-induced LSECs dysfunction remain largely unclear. Here we propose calcium- and integrin-binding protein 1 (CIB1) as BMMF with crucial role in LSECs mechanobiology in CLD. CIB1 expression and translocation was characterized in healthy and cirrhotic human livers and in LSECs cultured on polyacrylamide gels with healthy and cirrhotic-like stiffnesses. Following the modulation of CIB1 with siRNA, the transcriptome was scrutinized to understand downstream effects of CIB1 downregulation. CIB1 expression is increased in LSECs in human cirrhosis. In vitro, CIB1 emerges as an endothelial BMMF. In human umbilical vein endothelial cells and LSECs, CIB1 expression and localization are modulated by stiffness-induced trafficking across the nuclear membrane. LSECs from cirrhotic liver tissue both in animal model and human disease exhibit an increased amount of CIB1 in cytoplasm. Knockdown of CIB1 in LSECs exposed to high stiffness improves LSECs phenotype by regulating the intracellular tension as well as the inflammatory response. Our results demonstrate that CIB1 is a key factor in sustaining cellular tension and stretching in response to high stiffness. CIB1 downregulation ameliorates LSECs dysfunction, enhancing their redifferentiation, and reducing the inflammatory response
Defining the challenges and opportunities for using patient-derived models in prostate cancer research.
Get PDFBACKGROUND
There are relatively few widely used models of prostate cancer compared to other common malignancies. This impedes translational prostate cancer research because the range of models does not reflect the diversity of disease seen in clinical practice. In response to this challenge, research laboratories around the world have been developing new patient-derived models of prostate cancer, including xenografts, organoids, and tumor explants.
METHODS
In May 2023, we held a workshop at the Monash University Prato Campus for researchers with expertise in establishing and using a variety of patient-derived models of prostate cancer. This review summarizes our collective ideas on how patient-derived models are currently being used, the common challenges, and future opportunities for maximizing their usefulness in prostate cancer research.
RESULTS
An increasing number of patient-derived models for prostate cancer are being developed. Despite their individual limitations and varying success rates, these models are valuable resources for exploring new concepts in prostate cancer biology and for preclinical testing of potential treatments. Here we focus on the need for larger collections of models that represent the changing treatment landscape of prostate cancer, robust readouts for preclinical testing, improved in vitro culture conditions, and integration of the tumor microenvironment. Additional priorities include ensuring model reproducibility, standardization, and replication, and streamlining the exchange of models and data sets among research groups.
CONCLUSIONS
There are several opportunities to maximize the impact of patient-derived models on prostate cancer research. We must develop large, diverse and accessible cohorts of models and more sophisticated methods for emulating the intricacy of patient tumors. In this way, we can use the samples that are generously donated by patients to advance the outcomes of patients in the future
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