Web-based database for the management of tissue specimens in a transregional histological research facility

BACKGROUND: In the setting of a histological research core facility sample tracking and project specific archiving of tissue specimens and communication of related data is of central importance. DESCRIPTION: Over a 24-month period 10 laboratories from two transregional research centers submitted in excess of 3000 tissue samples for histological processing and evaluation to our core facility. A web based database was set up to overcome the logistical problem of managing samples with inconsistent, duplicate and missing labels and to allow for efficient sample tracking, archiving and communication with the collaborating research laboratories. The database allows the users to remotely generate unique sample identifiers and enter sample annotation prior to sample processing. Furthermore the database facilitates communication about experimental set-up results and media files such as histological images. CONCLUSION: Our newly constructed web based portal is an important tool for the management of research samples of our histological core facility and facilitates significantly interdisciplinary and transregional research. It is freely available for scientific use

Limit-point / limit-circle classification of second-order differential operators arising in PT quantum mechanics

We consider a second-order dierential equation −y′′+q(x)y(x) = y(x) with complex-valued potential q and eigenvalue parameter ∈ C. In PT quantum mechanics the potential has the form q(x) = −(ix)N+2 and is dened on a contour ⊂ C. Via a parametrization we obtain two dierential equations on [0;∞) and (−∞; 0]. With a WKB-analysis we classify this problem according to the limit-point/ limit-circle scheme

A novel molecular signature identifies mixed subtypes in renal cell carcinoma with poor prognosis and independent response to immunotherapy

BACKGROUND Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes. METHODS Individual RCC samples were modeled as linear combination of the main subtypes (clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC)) using computational gene expression deconvolution. The new molecular subtyping was compared with histological classification of RCC using the Cancer Genome Atlas (TCGA) cohort (n = 864; ccRCC: 512; pRCC: 287; chRCC: 65) as well as 92 independent histopathologically well-characterized RCC. Predicted continuous subtypes were correlated to cancer-specific survival (CSS) in the TCGA cohort and validated in 242 independent RCC. Association with treatment-related progression-free survival (PFS) was studied in the JAVELIN Renal 101 (n = 726) and IMmotion151 trials (n = 823). CSS and PFS were analyzed using the Kaplan-Meier and Cox regression analysis. RESULTS One hundred seventy-four signature genes enabled reference-free molecular classification of individual RCC. We unambiguously assign tumors to either ccRCC, pRCC, or chRCC and uncover molecularly heterogeneous tumors (e.g., with ccRCC and pRCC features), which are at risk of worse outcome. Assigned proportions of molecular subtype-features significantly correlated with CSS (ccRCC (P = 4.1E - 10), pRCC (P = 6.5E - 10), chRCC (P = 8.6E - 06)) in TCGA. Translation into a numerical RCC-R(isk) score enabled prognosis in TCGA (P = 9.5E - 11). Survival modeling based on the RCC-R score compared to pathological categories was significantly improved (P = 3.6E - 11). The RCC-R score was validated in univariate (P = 3.2E - 05; HR = 3.02, 95% CI: 1.8-5.08) and multivariate analyses including clinicopathological factors (P = 0.018; HR = 2.14, 95% CI: 1.14-4.04). Heterogeneous PD-L1-positive RCC determined by molecular subtyping showed increased PFS with checkpoint inhibition versus sunitinib in the JAVELIN Renal 101 (P = 3.3E - 04; HR = 0.52, 95% CI: 0.36 - 0.75) and IMmotion151 trials (P = 0.047; HR = 0.69, 95% CI: 0.48 - 1). The prediction of PFS significantly benefits from classification into heterogeneous and unambiguous subtypes in both cohorts (P = 0.013 and P = 0.032). CONCLUSION Switching from categorical to continuous subtype classification across most frequent RCC subtypes enables outcome prediction and fosters personalized treatment strategies

A Research Program on Innovations in Prehistory and Antiquity

The authors discuss the simultaneous appearance of technological innovations in three key technologies (metallurgy, wheeled vehicles, weighing systems) in the second half of the 4th millennium. This is done from a source-critical perspective because the innova- tions are discussed with the help of dynamic maps from the Topoi project Digital Atlas of Innovations. Besides indications of diffusion gradients influenced by special research conditions, exceptional waves of innovation can be detected for all three technologies in the discussed period. These waves of innovation cannot, however, be generalized but have to be understood on the basis of the respective technology traditions and lines of devel- opment specific to local areas. Monocentric diffusion theories can be clearly disproven, local technology developments and their converging in certain centrally situated regions have to be assumed instead. Similarly, the transfer of objects and their châine opératoire can only be detected rather infrequently, while the adaptation to local socio-economic and environmental factors can be demonstrated

Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD

25 years of experience with transjugular intrahepatic portosystemic shunt (TIPS): changes in patient selection and procedural aspects

Background: TIPS is an established treatment for portal hypertension. The aim was to analyze how patient selection for TIPS implantation and procedural aspects have changed over 25 years. Routinely collected demographic, clinical, laboratory, and procedural data of 835 patients treated with TIPS in a single center were used. Time trends over the observational period from 1993 to 2018 were retrospectively analyzed. Descriptive statistical analysis was performed. Results: The most common indication for TIPS implantation has changed significantly from secondary prevention of variceal hemorrhage in the early years to treatment of recurrent ascites. During the observation period, increasingly more severely ill patients became TIPS candidates. There was little change in MELD scores over this period (in total median 13.00; IQR 10.00-18.00). The proportion of patients with Child-Pugh C cirrhosis increased. The most frequent underlying diseases in total were alcohol-related liver disease (66.5%) and viral hepatitis (11.9%). However, shares of cryptogenic liver cirrhosis, autoimmune hepatitis, and NASH increased over time. The proportion of patients post liver transplant also increased. While bare metal stents were standard in the past, use of covered stents increased. The success rate of TIPS (defined by successful implantation and a decrease in the portosystemic pressure gradient <= 12 mmHg) increased significantly over time. The total success rate according to this definition was 84.9%. Conclusion: The results of our analysis reflect technical developments in TIPS, especially in terms of stent material and gains in clinical experience, particularly regarding indications and patient selection for TIPS implantation

Validation of the network of relationship inventory in female and male adolescents

Friendships and their different qualities have been shown to be important for adolescents\u27 socio-emotional development and psychological adjustment. In empirical research on such friendship qualities, the Network of Relationship Inventory-Relationship Quality Version (NRI-RQV) is a widely used questionnaire. Here, we conduct an extensive validation of a German version of the NRI-RQV, investigating its factor structure, reliability, and concurrent validity, in a sample of N= 679 adolescents aged 13-18 years. Applying multigroup confirmatory factor analysis, we further test whether the factor structure of the friendship quality construct holds across groups of males and females. Results showed that a structure with nine correlated first-order factors fit the data well, indicating nine distinct friendship qualities in males and females. Measurement invariance testing suggested the same underlying friendship quality construct, albeit differences in mean scores per gender. As evidence for concurrent validity, closeness and discordant friendship qualities showed expected correlations with empathy and social problems, respectively, but not with aggressive behavior. Overall, results indicate good psychometric properties for the German version of the NRI-RQV as a measure of friendship qualities in both males and females. (DIPF/Orig.

Diagnostic Value of Initial Chest CT Findings for the Need of ICU Treatment/Intubation in Patients with COVID-19

Computed tomography (CT) plays an important role in the diagnosis of COVID-19. The aim of this study was to evaluate a simple, semi-quantitative method that can be used for identifying patients in need of subsequent intensive care unit (ICU) treatment and intubation. We retrospectively analyzed the initial CT scans of 28 patients who tested positive for SARS-CoV-2 at our Level-I center. The extent of lung involvement on CT was classified both subjectively and with a simple semi-quantitative method measuring the affected area at three lung levels. Competing risks Cox regression was used to identify factors associated with the time to ICU admission and intubation. Their potential diagnostic ability was assessed with receiver operating characteristic (ROC)/area under the ROC curves (AUC) analysis. A 10% increase in the affected lung parenchyma area increased the instantaneous risk of intubation (hazard ratio (HR) = 2.00) and the instantaneous risk of ICU admission (HR 1.73). The semi-quantitative measurement outperformed the subjective assessment diagnostic ability (AUC = 85.6% for ICU treatment, 71.9% for intubation). This simple measurement of the involved lung area in initial CT scans of COVID-19 patients may allow early identification of patients in need of ICU treatment/intubation and thus help make optimal use of limited ICU/ventilation resources in hospitals