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Concurrent multiscale techniques such as Adaptive Resolution Scheme (AdResS) can offer ample computational advantages over conventional atomistic (AT) molecular dynamics simulations. However, they typically rely on aphysical hybrid regions to maintain numerical stability when high-resolution degrees of freedom (DOFs) are randomly re-inserted at the resolution interface. We propose an Energy Minimized AT (DOF) Insertion (EMATI) method that uses an informed rather than random AT DOF insertion to tackle the root cause of the issue, i.e., overlapping AT potentials. EMATI enables us to directly couple AT and coarse-grained resolutions without any modifications of the interaction potentials. We exemplify AdResS-EMATI in a system of liquid butane and show that it yields improved structural and thermodynamic properties at the interface compared to competing AdResS approaches. Furthermore, our approach extends the applicability of the AdResS without a hybrid region to systems for which force capping is inadequate. [ABSTRACT FROM AUTHOR]

PurposeTo investigate the biocompatibility of the new cyanine dye: 3,3′-Di-(4-sulfobutyl)-1,1,1′,1′-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function.MethodsDSS at a concentration of 0.5% was applied via intravitreal injections to adult Brown Norway rats with BSS serving as a control. Retinal toxicity was assessed 7 days later by means of retinal ganglion cell (RGC) counts, light microscopy, optical coherence tomography (OCT), and electroretinography (ERG).ResultsNo significant decrease in RGC numbers was observed. No structural changes of the central retina were observed either in vivo (OCT) or under light microscopy. ERGs detected a temporary reduction of retinal function 7 days after injection; this was no longer evident 14 days after injection.ConclusionsDSS showed good biocompatibility in a well-established experimental in vivo setting and may be usable for intraocular surgery as an alternative to other cyanine dyes. In contrast to indocyanine green, it additionally offers fluorescence in the visual spectrum. Further studies with other animal models are needed before translation into clinical application. [ABSTRACT FROM AUTHOR]

Purpose: The postoperative occurrence of corneal guttae (CG) in patients after Descemet membrane endothelial keratoplasty (DMEK) can lead to a significant reduction in visual acuity (VA) with the subsequent need for repeat DMEK. Therefore, the aim of this study was to analyze the prevalence and clinical significance of CG in transplanted corneas after DMEK., Methods: The prevalence and progression of CG after DMEK of 1657 patients were examined using endothelial specular microscopy images. The severity grade of CG was classified into 3 grades (G1 <40%, G2 40-80%, G3 >80%). Central corneal thickness, VA, and endothelial cell density (ECD) were examined during a postoperative follow-up time of 19.5 ± 17.6 months (range 6-84 months)., Results: The prevalence of CG postoperatively was 1.3% (22/1657 eyes) after 4-6 weeks. We could classify 15/22 (68%) as G1, 5/22 (23%) as G2, and 2/22 (9%) as G3. In 12/22 (55%), either preparation and/or implantation was conspicuously difficult. None of the eyes showed an increase in CG during follow-up. 21/22 were stable in VA, central corneal thickness, and ECD during the entire follow-up. One patient with G3 required a repeat DMEK after 12 months (secondary graft failure)., Conclusions: The prevalence of CG in our study population was notably lower than previously described and was mainly characterized by mild, low-grade findings without clinical significance and were stable during the follow-up. Preoperative overlook of CG in the tissue bank cannot be completely excluded, but the remarkable proportion of intraoperative complications in this group may have led to the occurrence of these CG., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: N. Ferrand, S. Thaler, D. Süsskind und J.M. Rohrbach geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patient/-innen zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern/Vertreterinnen eine schriftliche Einwilligung vor. Eine Einwilligung in die Erstellung und Veröffentlichung eines Fallberichts gemäß Art. 7 Datenschutzgrundverordnung (DSGVO) liegt vor.

Background: Intraoperative 2D quantitative angiography (QA) for intracranial aneurysms (IAs) has accuracy challenges due to the variability of hand injections. Despite the success of singular value decomposition (SVD) algorithms in reducing biases in computed tomography perfusion (CTP), their application in 2D QA has not been extensively explored. This study seeks to bridge this gap by investigating the potential of SVD-based deconvolution methods in 2D QA, particularly in addressing the variability of injection durations., Purpose: Building on the identified limitations in QA, the study aims to adapt SVD-based deconvolution techniques from CTP to QA for IAs. This adaptation seeks to capitalize on the high temporal resolution of QA, despite its two-dimensional nature, to enhance the consistency and accuracy of hemodynamic parameter assessment. The goal is to develop a method that can reliably assess hemodynamic conditions in IAs, independent of injection variables, for improved neurovascular diagnostics., Materials and Methods: The study included three internal carotid aneurysm (ICA) cases. Virtual angiograms were generated using computational fluid dynamics (CFD) for three physiologically relevant inlet velocities to simulate contrast media injection durations. Time-density curves (TDCs) were produced for both the inlet and aneurysm dome. Various SVD variants, including standard SVD (sSVD) with and without classical Tikhonov regularization, block-circulant SVD (bSVD), and oscillation index SVD (oSVD), were applied to virtual angiograms. The method was applied on virtual angiograms to recover the aneurysmal dome impulse response function (IRF) and extract flow related parameters such as Peak Height PH IRF , Area Under the Curve AUC IRF , and Mean transit time MTT. Next, correlations between QA parameters, injection duration, and inlet velocity were assessed for unconvolved and deconvolved data for all SVD methods. Additionally, we performed an in vitro study, to complement our in silico investigation. We generated a 2D DSA using a flow circuit design for a patient-specific internal carotid artery phantom. The DSA showcases factors like x-ray artifacts, noise, and patient motion. We evaluated QA parameters for the in vitro phantoms using different SVD variants and established correlations between QA parameters, injection duration, and velocity for unconvolved and deconvolved data., Results: The different SVD algorithm variants showed strong correlations between flow and deconvolution-adjusted QA parameters. Furthermore, we found that SVD can effectively reduce QA parameter variability across various injection durations, enhancing the potential of QA analysis parameters in neurovascular disease diagnosis and treatment., Conclusion: Implementing SVD-based deconvolution techniques in QA analysis can enhance the precision and reliability of neurovascular diagnostics by effectively reducing the impact of injection duration on hemodynamic parameters., (© 2024 American Association of Physicists in Medicine.)

We report on a 66-year-old neuro-urological female patient who, three years after implantation of a neurostimulator, experienced cecal necrosis due to strangulation caused by the cable of the device., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The integration of alternative data extraction approaches for multimodal data, can significantly reduce modeling difficulties for the automatic location assessment. We develop a method for assessing the quality of the immediate living environment by incorporating human judgments as ground truth into a neural network for generating new synthetic data and testing the effects in surrogate hedonic models. We expect that the quality of the data will be less biased if the annotation is performed by multiple independent persons applying repeated trials which should reduce the overall error variance and lead to more robust results. Experimental results show that linking repeated subjective judgements and Deep Learning can reliably determine the quality scores and thus expand the range of information for the quality assessment. The presented method is not computationally intensive, can be performed repetitively and can also be easily adapted to machine learning approaches in a broader sense or be transferred to other use cases. Following aspects are essential for the implementation of the method:•Sufficient amount of representative data for human assessment.•Repeated assessment trials by individuals.•Confident derivation of the effect of human judgments on property price as an approbation for further generation of synthetic data., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Environmental and socio-economic developments induce land-use changes with potentially negative impacts on human well-being. To counteract undesired developments, a profound understanding of the complex relationships between drivers, land use, and ecosystem services is needed. Yet, national studies examining extended time periods are still rare. Based on the Special Report on land use, land management and climate change by the Austrian Panel on Climate Change (APCC), we use the Driver-Pressure-State-Impact-Response (DPSIR) framework to (1) identify the main drivers of land-use change, (2) describe past and future land-use changes in Austria between 1950 and 2100, (3) report related impacts on ecosystem services, and (4) discuss management responses. Our findings indicate that socio-economic drivers (e.g., economic growth, political systems, and technological developments) have influenced past land-use changes the most. The intensification of agricultural land use and urban sprawl have primarily led to declining ecosystem services in the lowlands. In mountain regions, the abandonment of mountain grassland has prompted a shift from provisioning to regulating services. However, simulations indicate that accelerating climate change will surpass socio-economic drivers in significance towards the end of this century, particularly in intensively used agricultural areas. Although climate change-induced impacts on ecosystem services remain uncertain, it can be expected that the range of land-use management options will be restricted in the future. Consequently, policymaking should prioritize the development of integrated land-use planning to safeguard ecosystem services, accounting for future environmental and socio-economic uncertainties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Covid-19 disease causes an immense burden on the healthcare system. It has not yet been finally clarified which patients will suffer from a severe course and which will not. Coagulation disorders can be detected in many of these patients. The aim of the present study was therefore to identify variables of the coagulation system including standard and viscoelastometric tests as well as components of glycocalyx damage that predict admission to the intensive care unit., Methods: Adult patients were included within 24 h of admission. Blood samples were analyzed at hospital admission and at ICU admission if applicable. We analyzed group differences and furthermore performed receiver operator characteristics (ROC)., Results: This study included 60 adult COVID-19 patients. During their hospital stay, 14 patients required ICU treatment. Comparing ICU and non-ICU patients at time of hospital admission, D-dimer (1450 µg/ml (675/2850) vs. 600 µg/ml (500/900); p  = 0.0022; cut-off 1050 µg/ml, sensitivity 71%, specificity 89%) and IL-6 (47.6 pg/ml (24.9/85.4 l) vs. 16.1 pg/ml (5.5/34.4); p  = 0.0003; cut-off 21.25 pg/ml, sensitivity 86%, specificity 65%) as well as c-reactive protein (92 mg/dl (66.8/131.5) vs. 43.5 mg/dl (26.8/83.3); p  = 0.0029; cutoff 54.5 mg/dl, sensitivity 86%, specificity 65%) were higher in patients who required ICU admission. Thromboelastometric variables and markers of glycocalyx damage (heparan sulfate, hyaluronic acid, syndecan-1) at the time of hospital admission did not differ between groups., Conclusion: General inflammatory variables continue to be the most robust predictors of a severe course of a COVID-19 infection. Viscoelastometric variables and markers of glycocalyx damage are significantly increased upon admission to the ICU without being predictors of ICU admission.

A 21-year-old athletic woman had been suffering from flank pain during fluid intake after sports for some time. Urological work-up revealed hydronephrosis with a "fishhook" shape and medial displacement of the ureter. This ureteral narrowing was studied ureterorenoscopically, bioptically and endoscopic-radiologically without the correct diagnosis of a retrocaval ureter being made. Therapeutically, a DJ stent was inserted several times, a balloon dilatation was performed under anaesthesia three times and finally a permanent DJ catheter was inserted. Due to the patient's dissatisfaction, an endoscopic endopyelotomy using Acucise was offered., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Neural network (NN) potentials promise highly accurate molecular dynamics (MD) simulations within the computational complexity of classical MD force fields. However, when applied outside their training domain, NN potential predictions can be inaccurate, increasing the need for Uncertainty Quantification (UQ). Bayesian modeling provides the mathematical framework for UQ, but classical Bayesian methods based on Markov chain Monte Carlo (MCMC) are computationally intractable for NN potentials. By training graph NN potentials for coarse-grained systems of liquid water and alanine dipeptide, we demonstrate here that scalable Bayesian UQ via stochastic gradient MCMC (SG-MCMC) yields reliable uncertainty estimates for MD observables. We show that cold posteriors can reduce the required training data size and that for reliable UQ, multiple Markov chains are needed. Additionally, we find that SG-MCMC and the Deep Ensemble method achieve comparable results, despite shorter training and less hyperparameter tuning of the latter. We show that both methods can capture aleatoric and epistemic uncertainty reliably, but not systematic uncertainty, which needs to be minimized by adequate modeling to obtain accurate credible intervals for MD observables. Our results represent a step toward accurate UQ that is of vital importance for trustworthy NN potential-based MD simulations required for decision-making in practice.

Oncogene-induced senescence is thought to constitute a barrier to carcinogenesis by arresting cells at risk of malignant transformation. However, numerous findings suggest that senescent cells may conversely promote tumor growth and metastatic progression, for example, through the senescence-associated secretory phenotype (SASP) they produce. Here, we investigated the degree to which senescent tumor cells exist within untreated human primary breast carcinomas and whether the presence of senescent cancer cells in primary tumors is recapitulated in their matched lymph node metastases. For the detection of senescence, we used SA-β-galactosidase (SA-β-gal) staining and other senescence markers such as Ki67, p21, p53, and p16. In patients with invasive luminal A and B breast carcinomas, we found broad similarities in the appearance of cancer cells between primary tumors and their corresponding metastases. Analysis of lymph nodes from patients with other breast cancer subtypes also revealed senescent tumor cells within metastatic lesions. Collectively, our findings show that senescent tumor cells exist within primary breast carcinomas and metastatic lesions. These results suggest a potential role for senescent breast tumor cells during metastatic progression and raise the question as to whether the targeting of senescent tumor cells with anti-senescent drugs might represent a novel avenue for improved treatment of breast and other cancers.

Purpose: Descemet membrane endothelial keratoplasty (DMEK) accounts for >50% of all corneal transplants in Germany. So far, no data from such a large multicenter study have been published., Methods: This retrospective study included 3200 DMEKs at seven departments performed for Fuchs endothelial corneal dystrophy (FECD) or bullous keratopathy (BK). We evaluated best corrected visual acuity (BCVA, logMAR), endothelial cell density (ECD, cells/mm 2 ), minimal corneal thickness (CT, μm), rebubbling-, primary transplant failure- and immune reaction-rate. Changes over time were evaluated by linear mixed models for repeated measures and correlation with case number by center by weighted linear regression., Results: For patients without vision-limiting comorbidities (74% of all analysed eyes, n = 2270), mean BCVA improved from 0.6 ± 0.4 logMAR to 0.2 ± 0.2 logMAR 6 months (p < 0.001, n = 1441) and 0.1 ± 0.2 logMAR 12 months (p = 0.001, n = 1402) postoperatively. BK- had a worse BCVA compared to FECD-patients (0.3 ± 0.5 vs. 0.1 ± 0.2 logMAR [p < 0.001] at 1 year). ECD declined from 2465 ± 259 cells/mm 2 (n = 2876 preoperatively) to 1587 ± 433 cells/mm 2 after 12 months (p < 0.001, n = 1237). Mean rebubbling rate was 0.4 ± 0.7/eye. 784 eyes (25%) received at least one rebubbling. More rebubblings correlated with a lower ECD, a worse BCVA, a higher CT, and higher transplant failure and rejection rates (p < 0.001, p = 0.013 for BCVA at 12 months). A single rebubbling did not influence the BCVA (p = 0.785). Graft failure rate was 3% (n = 67), rejection rate 1.5% (n = 48)., Conclusion: Descemet membrane endothelial keratoplasty increases visual acuity with low transplant failure- and rejection-rates. FECD has a better outcome than BK. Since a quarter of all patients need a rebubbling, this should be included in the informed consent. Remarkably, one rebubbling has no influence on the outcome., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To study the possibility of SARS-CoV-2 to infect human corneal cells and tissues under standard corneal culture conditions using explants of COVID-19 donors and primary cornea-derived epithelial cells., Methods: Cornea isolated from deceased COVID-19 donors was cultured for 4 weeks, and SARS-CoV-2 replication was monitored by qRT-PCR. Furthermore, primary corneal epithelial cells from healthy donors were cultured ex vivo and infected with SARS-CoV-2 and human cytomegalovirus (HCMV) as a control. Infection status was assessed by western blotting and reporter gene expression using green fluorescent protein-expressing viral strains. ACE2 and TMPRSS2 receptor expression levels in cornea and epithelial cells were assessed by qRT-PCR., Results: We did not detect SARS-CoV-2 replication in 10 corneas isolated from deceased COVID-19 patients and cultured for 4 weeks, indicating absence of infection under natural conditions. Furthermore, high-titer SARS-CoV-2 infection of ex vivo cultured cornea-derived epithelial cells did not result in productive virus replication. In contrast, the same cells were highly permissive for HCMV. This phenotype could potentially be explained by low ACE2 and TMPRSS2 transcriptional activity in cornea and cornea-derived epithelial cells., Conclusions: Our data suggest that cornea and limbal epithelial cells are refractory to productive SARS-CoV-2 infection. This could be due to the absence of robust receptor expression levels necessary for viral entry. This study adds further evidence to support the very low possibility of transmission of SARS-CoV-2 from an infected corneal transplant donor to a recipient in corneal organ cultures., (© 2022. The Author(s).)

Neural network (NN) potentials are a natural choice for coarse-grained (CG) models. Their many-body capacity allows highly accurate approximations of the potential of mean force, promising CG simulations of unprecedented accuracy. CG NN potentials trained bottom-up via force matching (FM), however, suffer from finite data effects: They rely on prior potentials for physically sound predictions outside the training data domain, and the corresponding free energy surface is sensitive to errors in the transition regions. The standard alternative to FM for classical potentials is relative entropy (RE) minimization, which has not yet been applied to NN potentials. In this work, we demonstrate, for benchmark problems of liquid water and alanine dipeptide, that RE training is more data efficient, due to accessing the CG distribution during training, resulting in improved free energy surfaces and reduced sensitivity to prior potentials. In addition, RE learns to correct time integration errors, allowing larger time steps in CG molecular dynamics simulation, while maintaining accuracy. Thus, our findings support the use of training objectives beyond FM, as a promising direction for improving CG NN potential's accuracy and reliability.

Background: The detection of direct oral anticoagulants (DOACs) is still challenging but important in emergency patients. We recently demonstrated that modified thromboelastometry can detect rivaroxaban and dabigatran. Data on the detection rates of modified compared to standard thromboelastometric tests of apixaban and edoxaban, are missing. The aim of this in-vitro dose-effect-study was to add data on these DOACs and to evaluate thromboelastometric tests in-vitro using data of both studies., Methods: The study was approved by the Ludwig-Maximilians-University ethics committee (No 17-525-2). Written informed consent was obtained from all individuals. Blood samples of healthy volunteers and samples of 10 volunteers for each DOAC were used. Blood samples were spiked with six different concentrations of edoxaban and apixaban (0ng/ml; 31.25ng/ml; 62.5ng/ml; 125ng/ml; 250 ng/ml; 500ng/ml). Modified tests (low-tissue-factor test TFTEM and ecarin-based test ECATEM) as well as standard tests (e.g. FIBTEM) analyzing extrinsic pathway of coagulation were used. Receiver operating characteristics analyzes were performed as well as regression analyzes., Results: TFTEM CT correlated well with anti-Xa levels of apixaban and edoxaban (apixaban: r 2  = 0.8064 p < 0.0001; edoxaban: r 2  = 0.8603; p < 0.0001). The detection of direct FXa inhibitors (> 30 ng/mL) was successful with FIBTEM CT with a sensitivity and specificity of 81% and 90%, respectively. As expected, ECATEM CT was not prolonged by direct FXa-inhibitors due to its specificity for direct thrombin inhibitors. Again, TFTEM CT provided the highest sensitivity and specificity for the detection of direct FXa inhibitors with 96% and 95%, respectively. ECATEM test showed 100% sensitivity and 100% specificity for the detection of dabigatran., Conclusions: Our study presents modified thromboelastometric tests with improved detection of even low DOAC concentrations > 30 ng/mL, including apixaban in-vitro. The study thus complements the previously published data on dabigatran and rivaroxaban. Validation studies must confirm the results due to the explanatory design of this study., (© 2022. The Author(s).)

Background: Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME., Methods: TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell-cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model., Results: Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro., Conclusions: Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa., (© 2022. The Author(s).)