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Abstract Background Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1–40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance. Methods We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation, and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5 to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000 Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR. Results UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity, and precision (0.977 ± 0.018; 1.000 ± 0.0005; 0.993 ± 0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R 2 = 0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40 quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and explored KIV-2 SNP haplotype patterns across five ancestries. Conclusions UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale.

Thermoplastic (TP) composites, known for their ease of handling, suitability for high production rates, and recyclability, are emerging as a promising alternative to thermoset-based composites. The expected growth in TP-based composites in automotive, sports, and aerospace industries may result in increased post industrial waste. To address this, we repurposed our in-house process scrapped carbon fibre-reinforced polycarbonate tapes into sheet moulding compounds (SMCs) and Hybridised SMCs (Hy-SMCs) using compression moulding. In Hy-SMCs, the top and bottom layers were unidirectional tapes, while the core section had randomly oriented platelets in a 50:50 ratio. Our evaluation included qualitative and thermo-mechanical standard tests. The incorporation of unidirectional tapes in Hy-SMCs significantly improved the tensile and flexural properties of SMCs. Specifically, these enhancements resulted in an impressive 81 to 85% increase in mechanical strength compared to the standard aluminium grade. Additionally, Hy-SMCs exhibited a 120 to 130% increase in tensile and flexural properties compared to SMCs. Fractography revealed a complex relation between fractured surfaces, with multimode failures in both SMCs and Hy-SMCs. Also, the non-destructive evaluation showed platelet reorientation during consolidation and localised voids with increased specimen thickness.

Abstract The alarming increase in global rates of metabolic diseases (MetDs) and their association with cancer risk renders them a considerable burden on our society. The interplay of environmental and genetic factors in causing MetDs may be reflected in DNA methylation patterns, particularly at non-canonical (non-B) DNA structures, such as G-quadruplexes (G4s) or R-loops. To gain insight into the mechanisms of MetD progression, we focused on DNA methylation and functional analyses on intragenic regions of two MetD risk genes, the glucokinase (GCK) exon 7 and the transmembrane 6 superfamily 2 (TM6SF2) intron 2-exon 3 boundary, which harbor non-B DNA motifs for G4s and R-loops. Pyrosequencing of 148 blood samples from a nested cohort study revealed significant differential methylation in GCK and TM6SF2 in MetD patients versus healthy controls. Furthermore, these regions harbor hypervariable and differentially methylated CpGs also in hepatocellular carcinoma versus normal tissue samples from The Cancer Genome Atlas (TCGA). Permanganate/S1 nuclease footprinting with direct adapter ligation (PDAL-Seq), native polyacrylamide DNA gel electrophoresis and circular dichroism (CD) spectroscopy revealed the formation of G4 structures in these regions and demonstrated that their topology and stability is affected by DNA methylation. Detailed analyses including histone marks, chromatin conformation capture data, and luciferase reporter assays, highlighted the cell-type specific regulatory function of the target regions. Based on our analyses, we hypothesize that changes in DNA methylation lead to topological changes, especially in GCK exon 7, and cause the activation of alternative regulatory elements or potentially play a role in alternative splicing. Our analyses provide a new view on the mechanisms underlying the progression of MetDs and their link to hepatocellular carcinomas, unveiling non-B DNA structures as important key players already in early disease stages.

Abstract Background Variable number tandem repeats (VNTRs) are highly polymorphic DNA regions harboring many potentially disease-causing variants. However, VNTRs often appear unresolved (“dark”) in variation databases due to their repetitive nature. One particularly complex and medically relevant VNTR is the KIV-2 VNTR located in the cardiovascular disease gene LPA which encompasses up to 70% of the coding sequence. Results Using the highly complex LPA gene as a model, we develop a computational approach to resolve intra-repeat variation in VNTRs from largely available short-read sequencing data. We apply the approach to six protein-coding VNTRs in 2504 samples from the 1000 Genomes Project and developed an optimized method for the LPA KIV-2 VNTR that discriminates the confounding KIV-2 subtypes upfront. This results in an F1-score improvement of up to 2.1-fold compared to previously published strategies. Finally, we analyze the LPA VNTR in > 199,000 UK Biobank samples, detecting > 700 KIV-2 mutations. This approach successfully reveals new strong Lp(a)-lowering effects for KIV-2 variants, with protective effect against coronary artery disease, and also validated previous findings based on tagging SNPs. Conclusions Our approach paves the way for reliable variant detection in VNTRs at scale and we show that it is transferable to other dark regions, which will help unlock medical information hidden in VNTRs.

BackgroundThe association between education and atherosclerotic cardiovascular disease (ASCVD) has been well described for decades. Nevertheless, most cardiovascular risk models, including SCORE2, still do not take educational status into account even if this factor is easily assessed and costs nothing to acquire. Using carotid plaques as a proxy for ASCVD, we analysed educational status as associated with carotid plaque development, to determine if the relationship remains, how it relates to traditional risk factors and, how it impacts the European cardiovascular risk model, SCORE2. Our study also provides further data on plaque development in a well-characterised population nearly equally weighted by gender.Methods9,083 subjects (51% female, 49% male) from the Paracelsus 10,000 cohort, underwent a carotid doppler duplex as part of thorough screening for subclinical ASCVD. Well over 90% of carotid doppler duplex examinations were performed by the same experienced clinician. Subjects were then classified by educational status using the Generalized International Standard Classification of Education. Plaque absence or presence was dichotomised and variables analysed using regression modelling to examine educational status relative to cardiovascular risk factors and with respect to the SCORE2 model.ResultsUsing medium educational status as a reference, subjects in our cohort with low educational status had higher odds, while subjects with high educational status had lower odds for carotid plaques compared to subjects with medium education (aOR 1.76 95%CI 1.50–2.06; and 0.0.63 95%CI 0.57–0.70, respectively). Even after adjusting for common risk factors including metabolic syndrome and SCORE2, the relationship was maintained. Furthermore, when comparing the potential predictive power of SCORE2 alone and plus educational status using the Akaike information criterion, we showed a ‘better fit’ when educational status was added.ConclusionsMeasuring educational status is cost-free and easy for clinicians to obtain. We believe cardiovascular risk prediction models such as SCORE2 may more accurately reflect individual risk if educational status is also taken into account. Additionally, we believe clinicians need to understand and appropriately address educational status as a risk factor, to better quantify individual risk and take appropriate measures to reduce risk so that the association may finally be broken.

This article presents results from an explorative comparative study on ‘double standard’ constellations in French, German and (Brazilian) Portuguese. The concept of 'double' or even ‘multiple standards’ is based on the observation that many current standard languages are not homogeneous. Rather, the divergence of written and spoken standards, the emergence of informal standards and pluricentric/pluriareal situations have often resulted in the coexistence of different standard varieties/standard language registers. The aim of our study is to identify and discuss ‘double standard’ situations in three major languages against the background of the respective standardisation histories and current developments. Despite their different standardisation ages, ‘double standard’ constellations have emerged in all three languages, firstly, between written and spoken standard varieties, and, secondly, between different spoken registers – albeit with very different manifestations, ranging from a continuum between formal and informal registers (French) and the emergence of a ‘Neo-standard’ (with regional features) parallel to a conservative spoken standard (German) to the increasing integration of informal registers into a post-colonial standard variety (Portuguese in Brazil). In all three cases, the developments in the spoken standard can be seen as a process of demotisation. Although informal registers have become increasingly prevalent, the popular idea of a ‘best language’ remains unchallenged.

Introduction & Purpose Cardiovascular diseases (CVD) are a common cause of declining physical performance and quality of life. Despite the recommendation of physical activity as class 1A in the American Heart Association’s guidelines for cardiac rehabilitation (Pelliccia et al., 2021) and the clear need for innovative rehabilitation programs, no tele-medical exercise program has been adopted into standard care (Scherrenberg et al., 2021; Snoswell et al., 2020). Classic CVD exercise therapy typically includes group ergometer and strength training. The primary aim of this project was to integrate exercise as a pillar of therapy in the HerzMobil Tirol project, leading to the implementation of a telemedicine-assisted exercise program. Methods Patients enrolled in the CHD project had the opportunity to participate in TAEP. The initial and final therapeutic examinations included a medical history interview, the 1-minute sit-to-stand test (STS; Strassmann et al., 2013) and standardized EQ-5D-5L to assess the quality of life. Based on the guidelines and the classic CVD therapy the TAEP participants completed a twelve-week home-based exercise program. It included endurance training (5 days/week for 30 minutes) and video-guided strength, mobility and coordination training (2-3 times/week), where the focus was on strength training. The program was analysed and adapted individually by an exercise therapist. The intensity was controlled using the Borg scale and the talk test (Bok et al., 2022). Results 22 patients completed the TAEP, 77% (n = 17) were male and 23% (n = 5) were female and the median age was 61 (53-71) years. During the twelve weeks, the patients completed a median of 257 (213-351) minutes per week of endurance-oriented exercise training (e.g. walking or cycling) and performed video-guided home-based strength training with a median of twice (1-2) per week. 95% of patients fulfilled the recommendations for endurance training and 64% for strength training. The TAEP participants showed a significant (p < 0.001) increase in STS with a median of 37% (18-24). There was a significant improvement in quality of life according to the EQ-5D-5L health scale with a median from 70 (60-85) to 83 (79-95; p < 0.001). Discussion The current literature on cardiovascular diseases and exercise as therapy continues to underline the importance of physical activity for the prevention and treatment of these conditions. Studies indicate that regular exercise can reduce the risk of cardiovascular diseases and serves as an effective complement to pharmacological therapy. The results of the present project show that the integration of exercise therapy into a telemedical care program is feasible and effective. However, the lack of a control group and the small sample size made it difficult to compare the results directly and if the observed changes are actually attributable to the TAEP. Conclusion In our programme, we have learned that (1) a doctor’s recommendation for exercise therapy and (2) personal contact between the exercise therapist and the patient are key to patients’ adherence to exercise therapy. The TAEP was well received by the patients and feasible irrespective of the patients’ age. In the age of digitalisation, telemedicine-supported training therapy is an option in cardiac rehabilitation, even for people in remote catchment areas. References Bok, D., Rakovac, M., & Foster, C. (2022). An examination and critique of subjective methods to determine exercise intensity: The talk test, feeling scale, and rating of perceived exertion. Sports Medicine, 52(9), 2085–2109. https://doi.org/10.1007/s40279-022-01690-3 Pelliccia, A., Sharma, S., Gati, S., Bäck, M., Börjesson, M., Caselli, S., Collet, J.-P., Corrado, D., Drezner, J. A., Halle, M., Hansen, D., Heidbuchel, H., Myers, J., Niebauer, J., Papadakis, M., Piepoli, M. F., Prescott, E., Roos-Hesselink, J. W., Graham Stuart, A., … Rakhit, D. (2021). 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease. European Heart Journal, 42(1), 17–96. https://doi.org/10.1093/eurheartj/ehaa605 Scherrenberg, M., Wilhelm, M., Hansen, D., Völler, H., Cornelissen, V., Frederix, I., Kemps, H., & Dendale, P. (2021). The future is now: A call for action for cardiac telerehabilitation in the COVID-19 pandemic from the secondary prevention and rehabilitation section of the European Association of Preventive Cardiology. European Journal of Preventive Cardiology, 28(5), 524–540. https://doi.org/10.1177/2047487320939671 Strassmann, A., Steurer-Stey, C., Lana, K. D., Zoller, M., Turk, A. J., Suter, P., & Puhan, M. (2013). Population-based reference values for the 1-min sit-to-stand test. International Journal of Public Health, 58(6), 949–953. https://doi.org/10.1007/s00038-013-0504-z Snoswell, C. L., Taylor, M. L., Comans, T. A., Smith, A. C., Gray, L. C., & Caffery, L. J. (2020). Determining if telehealth can reduce health system costs: Scoping review. Journal of Medical Internet Research, 22(10), Article e17298. https://doi.org/10.2196/17298

Purpose: To compare suprapubic access (SPA) and transurethral catheterization (TUC) in voiding cystourethrogram (VCUG). Methods: Retrospective single-center evaluation of 311 VCUG performed in male patients under 12 years of age. Two study groups were built based on the bladder access method. TUC was performed in 213 patients, whereas 98 received SPA. The groups were compared regarding the procedural switch rate, the complication rate, radiation parameters, the amount of contrast media applied and the examination quality. Complications were graded in minor (contrast leakage, premature termination of the examination) and major (fever, urinary tract infection, bladder perforation). Fluoroscopy time and radiation parameters were compared. Examination quality was assessed based on the satisfactory acquisition of fluoroscopic images using a four-point Likert scale. Results: In 9% of the SPA examinations a method switch to TUC was necessary. The minor complication rate was 1.9% for TUC and 35.7% for SPA (p < 0.001). The major complication rate was 0.9% for TUC and 2% for SPA (p > 0.05). Mean fluoroscopy time and radiation dose were significantly lower in TUC (TUC, 26 ± 19 s, 0.6 ± 1.2 µGy·m2; SPA, 38 ± 33 s, 1.7 ± 2.9 µGy·m2; p = 0.01/0.001). There was no significant difference regarding the amount of contrast media applied (TUC, 62 ± 40 mL; SPA, 66 ± 41 mL; p > 0.05) and the examination quality with full diagnostic quality achieved in 88% of TUC and 89% of SPA examinations (p > 0.05). Conclusions: As TUC provides significantly lower radiation exposure and less periprocedural complications, it should be the primary bladder access route for VCUG in pediatric male patients.

Abstract Photon-counting detector (PCD)-CT allows for reconstruction of virtual non-iodine (VNI) images from contrast-enhanced datasets. This study assesses the diagnostic performance of aortic valve calcification scoring (AVCS) derived from VNI datasets generated with a 1st generation clinical dual-source PCD-CT. AVCS was evaluated in 123 patients (statistical analysis only comprising patients with aortic valve calcifications [n = 56; 63.2 ± 11.6 years]), who underwent contrast enhanced electrocardiogram-gated (either prospective or retrospective or both) cardiac CT on a clinical PCD system. Patient data was reconstructed at 70 keV employing a VNI reconstruction algorithm. True non-contrast (TNC) scans at 70 keV without quantum iterative reconstruction served as reference in all individuals. Subgroup analysis was performed in 17 patients who received both, prospectively and retrospectively gated contrast enhanced scans (n = 8 with aortic valve calcifications). VNI images with prospective/retrospective gating had an overall sensitivity of 69.2%/56.0%, specificity of 100%/100%, accuracy of 85.4%/81.0%, positive predictive value of 100%/100%, and a negative predictive value of 78.2%/75.0%. VNI images with retrospective gating achieved similar results. For both gating approaches, AVCSVNI showed high correlation (r = 0.983, P

Abstract Objectives The aim of the present study was to follow the daily course of patients with olfactory dysfunction and healthy controls and to assess (i) how many times a day, (ii) at which time, and (iii) in which aspect of daily life participants are conscious about their sense of smell. Methods In this longitudinal study, 49 patients with smell loss and 30 healthy participants were enrolled. Olfactory function was assessed using the Sniffin’ Sticks. All participants received paper diaries designed for a 14‐day period, featuring 12 rows representing 12 daily hours and six columns for various daily life aspects. They were instructed to mark their awareness of smell by indicating the relevant row and column in the diary. Following the return of the diaries, a second olfactory test was conducted within the patient group. Results On average, patients were consciously aware of their sense of smell around 8 times daily, while healthy participants noted it about 6.5 times a day. Both groups primarily focused on their sense of smell during activities related to “eating,” followed by considerations in “social life” and “personal hygiene.” Interestingly, distinct patterns emerged: patients peaked in awareness at 8 a.m. and 7 p.m., whereas healthy individuals showed peaks at 6 a.m., 12 p.m., and 7 p.m. Despite regular diary use, we observed no improvement in patients' olfactory function or related quality of life. Conclusion The olfactory diary is a valuable tool unveiling individual smell awareness patterns in patients with smell loss, aiding in counseling and patient management. Level of Evidence 4

Fluid-particle-structure interactions (FPSI) govern a wide range of natural and engineering phenomena, from landslides to erosion in abrasive water jet cutting nozzles. Despite the importance of studying FPSI, existing numerical frameworks often simplify or neglect certain physics, limiting their applicability. This work introduces a novel 6-way CFD-DEM-FEM momentum coupling for FPSI using a partitioned coupling approach, providing a flexible and adaptable solution.Our prototype uses the preCICE coupling library to couple three numerical solvers: OpenFOAM for fluid dynamics, eXtended Discrete Element Method (XDEM) for particle motion, and CalculiX for structural mechanics. The coupling approach extends existing adapters and introduces a novel XDEM preCICE adapter, allowing data exchange over surface and volumetric meshes.Numerical experiments successfully demonstrate the 6-way coupling, showcasing fluid-structure interactions and particle dynamics. The versatility of the partitioned coupling approach is highlighted, allowing the interchangeability of different single-physics solvers and facilitating the study of complex FPSI phenomena.This article offers a thorough description of the methodology, coupling strategies, and detailed results, offering insights into the advantages and disadvantages of the proposed approach. This work lays the groundwork for a scalable and customizable FPSI simulation framework with a wide range of applications.

Abstract Habitat loss and degradation are key drivers of the current biodiversity crisis. Most research focuses on the question of which traits allow species to persist in degraded habitats. We asked whether a species' trophic position or niche width influences the resilience of species in degraded habitats and to what extent habitat degradation affects trophic interactions between species. We used nitrogen isotope ratios (15N:14N, expressed as δ15N value) to quantify and compare trophic positions and niche widths of understory birds inhabiting old‐growth and young secondary forests in the Pacific lowlands of Costa Rica. We found that a species' trophic position rather than its trophic niche width determined its persistence in secondary forests. Species feeding at lower trophic levels in old‐growth forests were less likely to persist in secondary forests than those occupying a higher trophic position in old‐growth forests. This pattern is likely induced by the occurrence of relatively large‐bodied habitat specialists with a flexible and high‐trophic level diet in secondary forests. These habitat specialists likely caused generalist bird species to lower their trophic position relative to conspecifics in old‐growth forests. Regarding trophic niche widths, species in secondary forests tend to have larger niche widths than old‐growth forest species. However, as old‐growth forest specialists and generalists did not differ in their niche widths, no systematic effect of trophic niche width on species persistence after forest disturbance was found. This is the first study that shows a systematic effect of trophic position on the persistence of a wide range of bird species in a disturbed forest ecosystem. It therefore provides important insights into species' responses to habitat degradation and the conservation value of secondary forests. To improve habitat quality for old‐growth forest birds and facilitate avian seed dispersal, the creation of large contiguous forest patches should be prioritised when implementing reforestation measures.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating “avatars” (herein defined as an extension of “digital twins”) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

Abstract The beneficial effect of sleep on memory consolidation relies on the precise interplay of slow oscillations and spindles. However, whether these rhythms are orchestrated by an underlying pacemaker has remained elusive. Here, we tested the relationship between respiration, which has been shown to impact brain rhythms and cognition during wake, sleep-related oscillations and memory reactivation in humans. We re-analysed an existing dataset, where scalp electroencephalography and respiration were recorded throughout an experiment in which participants (N = 20) acquired associative memories before taking a nap. Our results reveal that respiration modulates the emergence of sleep oscillations. Specifically, slow oscillations, spindles as well as their interplay (i.e., slow-oscillation_spindle complexes) systematically increase towards inhalation peaks. Moreover, the strength of respiration - slow-oscillation_spindle coupling is linked to the extent of memory reactivation (i.e., classifier evidence in favour of the previously learned stimulus category) during slow-oscillation_spindles. Our results identify a clear association between respiration and memory consolidation in humans and highlight the role of brain-body interactions during sleep.

Nature-based solutions are increasingly used in domestic wastewater treatment, because of their potential to remove contaminants and pathogens from water (e.g., stormwater, river water, wastewater) as well as their provided co-benefits, such as mitigation of the heat island effect or enhanced biodiversity. The transition from traditional grey technologies towards nature-based solutions in domestic wastewater treatment might yield multiple benefits for local communities while enhancing biodiversity. Although some nature-based solutions such as treatment wetlands have been used for decades in domestic wastewater treatment, this is not the case for others such as green walls or roofs, which lack implementation guidelines and design criteria. Aiming to support implementation of nature-based solutions in domestic wastewater treatment, we have developed an online decision-support system for the pre-selection of the best nature-based solution to use in each socio-environmental context and adapted to the needs, as well as an estimate of the required area. Our decision-support system's recommendations are based on an expert knowledge-driven approach, building on two complementary expert knowledge elicitation workshops. We hope the developed online decision-support system will support the transition towards integrating nature-based solutions into urban water and wastewater treatment systems. HIGHLIGHTS We lack implementation guidelines and design criteria for nature-based solutions (NBS) in water sanitation.; We have developed an online decision-support system to facilitate NBS implementation.; NBS implementation in domestic wastewater treatment will support SDG6 achievement.;

Abstract Understanding how cells dynamically adapt to their environment is a primary focus of biology research. Temporal information about cellular behavior is often limited by both small numbers of data time-points and the methods used to analyze this data. Here, we apply unsupervised machine learning to a data set containing the activity of 1805 native promoters in E. coli measured every 10 minutes in a high-throughput microfluidic device via fluorescence time-lapse microscopy. Specifically, this data set reveals E. coli transcriptome dynamics when exposed to different heavy metal ions. We use a bioinformatics pipeline based on Independent Component Analysis (ICA) to generate insights and hypotheses from this data. We discovered three primary, time-dependent stages of promoter activation to heavy metal stress (fast, intermediate, and steady). Furthermore, we uncovered a global strategy E. coli uses to reallocate resources from stress-related promoters to growth-related promoters following exposure to heavy metal stress.

Abstract Background Parameters of body composition have prognostic potential in patients with oncologic diseases. The aim of the present study was to analyse the prognostic potential of radiomics‐based parameters of the skeletal musculature and adipose tissues in patients with advanced hepatocellular carcinoma (HCC). Methods Radiomics features were extracted from a cohort of 297 HCC patients as post hoc sub‐study of the SORAMIC randomized controlled trial. Patients were treated with selective internal radiation therapy (SIRT) in combination with sorafenib or with sorafenib alone yielding two groups: (1) sorafenib monotherapy (n = 147) and (2) sorafenib and SIRT (n = 150). The main outcome was 1‐year survival. Segmentation of muscle tissue and adipose tissue was used to retrieve 881 features. Correlation analysis and feature cleansing yielded 292 features for each patient group and each tissue type. We combined 9 feature selection methods with 10 feature set compositions to build 90 feature sets. We used 11 classifiers to build 990 models. We subdivided the patient groups into a train and validation cohort and a test cohort, that is, one third of the patient groups. Results We used the train and validation set to identify the best feature selection and classification model and applied it to the test set for each patient group. Classification yields for patients who underwent sorafenib monotherapy an accuracy of 75.51% and area under the curve (AUC) of 0.7576 (95% confidence interval [CI]: 0.6376–0.8776). For patients who underwent treatment with SIRT and sorafenib, results are accuracy = 78.00% and AUC = 0.8032 (95% CI: 0.6930–0.9134). Conclusions Parameters of radiomics‐based analysis of the skeletal musculature and adipose tissue predict 1‐year survival in patients with advanced HCC. The prognostic value of radiomics‐based parameters was higher in patients who were treated with SIRT and sorafenib.

IntroductionThe potential for secondary use of health data to improve healthcare is currently not fully exploited. Health data is largely kept in isolated data silos and key infrastructure to aggregate these silos into standardized bodies of knowledge is underdeveloped. We describe the development, implementation, and evaluation of a federated infrastructure to facilitate versatile secondary use of health data based on Health Data Space nodes.Materials and methodsOur proposed nodes are self-contained units that digest data through an extract-transform-load framework that pseudonymizes and links data with privacy-preserving record linkage and harmonizes into a common data model (OMOP CDM). To support collaborative analyses a multi-level feature store is also implemented. A feasibility experiment was conducted to test the infrastructures potential for machine learning operations and deployment of other apps (e.g., visualization). Nodes can be operated in a network at different levels of sharing according to the level of trust within the network.ResultsIn a proof-of-concept study, a privacy-preserving registry for heart failure patients has been implemented as a real-world showcase for Health Data Space nodes at the highest trust level, linking multiple data sources including (a) electronical medical records from hospitals, (b) patient data from a telemonitoring system, and (c) data from Austria’s national register of deaths. The registry is deployed at the tirol kliniken, a hospital carrier in the Austrian state of Tyrol, and currently includes 5,004 patients, with over 2.9 million measurements, over 574,000 observations, more than 63,000 clinical free text notes, and in total over 5.2 million data points. Data curation and harmonization processes are executed semi-automatically at each individual node according to data sharing policies to ensure data sovereignty, scalability, and privacy. As a feasibility test, a natural language processing model for classification of clinical notes was deployed and tested.DiscussionThe presented Health Data Space node infrastructure has proven to be practicable in a real-world implementation in a live and productive registry for heart failure. The present work was inspired by the European Health Data Space initiative and its spirit to interconnect health data silos for versatile secondary use of health data.

Abstract Most invasive lobular breast carcinomas (ILBCs) are luminal‐type carcinomas with an HER2‐negative phenotype (ERBB2 or HER2 un‐amplified) and CDH1 mutations. Rare variants include ERBB2‐amplified subtypes associated with an unfavorable prognosis and less response to anti‐HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2‐amplified ILBC and compared these characteristics with ERBB2‐unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin‐embedded formalin‐fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast‐specific markers was tested by immunohistochemistry (IHC). Hybrid capture‐based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2‐amplified ILBC had higher tumor stage (p

Abstract This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall’s concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p

Abstract Allantoin is a good source of ammonium for many organisms, and in Escherichia coli it is utilized under anaerobic conditions. We provide evidence that allantoinase (AllB) is allosterically activated by direct binding of the allantoin catabolic enzyme, glycerate 2-kinase (GlxK) in the presence of glyoxylate. Glyoxylate is known to be an effector of the AllR repressor which regulates the allantoin utilization operons in E. coli. AllB has low affinity for allantoin, but its activation by GlxK leads to increased affinity for its substrate. We also show that the predicted allantoin transporter YbbW (re-named AllW) has allantoin specificity and the protein–protein interaction with AllB. Our results show that the AllB-dependent allantoin degradative pathway is subject to previously unrecognized regulatory mechanisms involving direct protein–protein interactions.

An extended hybrid method for the analysis of the symmetric structural behavior of segmental tunnel linings is proposed. Their deformations cannot be determined by the traditional hybrid methods when the convergences are close to the serviceability limit states (SLSs). Two real-scale tests are employed for the validation of the proposed method. It involves structural analysis that is based on transfer relations. They represent analytical solutions of the linear theory of thin circular arches, and they contain the symmetric mode of rigid-body displacements. The method is termed hybrid because it is based on two types of input, namely the external loading and experimental data of displacements monitored during the test. It is termed extended because, additionally, the vertical and horizontal convergences are employed to produce more accurate structural deformations than obtained by the traditional hybrid method. The latter is found to be unsuitable for structural analysis after sudden failure has occurred in the vicinity of segmental interfaces. At the respective load steps, the structures were in convergence-related serviceability class C, referring to endangered serviceability. The local failures occurring at these load steps resulted in a rapid increase in the structural deformations and fast attainment of the SLS. If, in convergence-related serviceability class C, local failures at segmental interfaces are detected, the strengthening of the structure is necessary. This cannot be delayed to the attainment of serviceability class D, i.e., to reaching the SLS.

Finger vein recognition is gaining popularity in the field of biometrics, yet the inter-operability of finger vein patterns has received limited attention. This study aims to fill this gap by introducing a cross-device finger vein dataset and evaluating the performance of finger vein recognition across devices using a classical method, a convolutional neural network, and our proposed patch-based convolutional auto-encoder (CAE). The findings emphasise the importance of standardisation of finger vein recognition, similar to that of fingerprints or irises, crucial for achieving inter-operability. Despite the inherent challenges of cross-device recognition, the proposed CAE architecture in this study demonstrates promising results in finger vein recognition, particularly in the context of cross-device comparisons.

Purpose: Post acute sequelae of SARS-CoV-2 infection are defined by persistence or re-occurrence of symptoms six to 12 weeks after SARS-CoV-2 infections. Methods: Twice vaccinated hospital employees after mild to moderate post-vaccination SARS-CoV-2 infection completed a questionnaire on the incidence of general, respiratory, neuropsychiatric, dermatological and gastrointestinal symptoms, experienced during their acute infection and eight weeks after recovery. Post acute sequelae of SARS-CoV-2 infection were analysed in relation to socio-demographic-, health-, virus- and acute infection-related characteristics. Results: 73 participants, 25 women and 48 men with a mean age of 40.9 years, with a post-vaccination SARS-CoV-2 infection completed the survey. Out of these 93 % reported at least one symptom at time of initial SARS-CoV-2 infection, 31.5 %, predominantly women, reported post acute sequelae at least eight weeks after the acute infection stage. Fatigue, dysgeusia and dysosmia, headache or difficulty concentrating and shortness of breath during acute infection, BMI> 25 and pre-existing pulmonary disorders were associated with post acute sequelae of SARS-CoV-2 infection. Participants with initially more than five symptoms were four times more likely to report post acute sequelae. Conclusion: It is suggested that the multiplicity of symptoms during acute SARS-CoV-2 infections increases the risk for post acute symptoms.

Abstract The severity of coronavirus disease 2019 (COVID-19) is related to the presence of comorbidities including metabolic diseases. We herein present data from the longitudinal prospective CovILD trial, and investigate the recovery from COVID-19 in individuals with dysglycemia and dyslipidemia. A total of 145 COVID-19 patients were prospectively followed and a comprehensive clinical, laboratory and imaging assessment was performed at 60, 100, 180, and 360 days after the onset of COVID-19. The severity of acute COVID-19 and outcome at early post-acute follow-up were significantly related to the presence of dysglycemia and dyslipidemia. Still, at long-term follow-up, metabolic disorders were not associated with an adverse pulmonary outcome, as reflected by a good recovery of structural lung abnormalities in both, patients with and without metabolic diseases. To conclude, dyslipidemia and dysglycemia are associated with a more severe course of acute COVID-19 as well as delayed early recovery but do not impair long-term pulmonary recovery.

This study demonstrates the utilization of deep learning techniques for binary semantic segmentation of pores in carbon fiber reinforced polymers (CFRP) using X-ray computed tomography (XCT) datasets. The proposed workflow is designed to generate efficient segmentation models with reasonable execution time, applicable even for users using consumer-grade GPU systems. First, U-Net, a convolutional neural network, is modified to handle the segmentation of XCT datasets. In the second step, suitable hyperparameters are determined through a parameter analysis (hyperparameter tuning), and the parameter set with the best result was used for the final training. In the final step, we report on our efforts of implementing the testing stage in open_iA, which allows users to segment datasets with the fully trained model within reasonable time. The model performs well on datasets with both high and low resolution, and even works reasonably for barely visible pores with different shapes and size. In our experiments, we could show that U-Net is suitable for pore segmentation. Despite being trained on a limited number of datasets, it exhibits a satisfactory level of prediction accuracy.

Objective: Standard nerve excitability testing (NET) predominantly assesses Aα- and Aβ-fiber function, but a method examining small afferents would be of great interest in pain studies. Here, we examined the properties of a novel perception threshold tracking (PTT) method that preferentially activates Aδ-fibers using weak currents delivered by a novel multipin electrode and compared its reliability with NET. Methods: Eighteen healthy subjects (mean age:34.06 ± 2.0) were examined three times with motor and sensory NET and PTT in morning and afternoon sessions on the same day (intra-day reliability) and after a week (inter-day reliability). NET was performed on the median nerve, while PTT stimuli were delivered through a multipin electrode located on the forearm. During PTT, subjects indicated stimulus perception via a button press and the intensity of the current was automatically increased or decreased accordingly by Qtrac software. This allowed changes in the perception threshold to be tracked during strength-duration time constant (SDTC) and threshold electrotonus protocols. Results: The coefficient of variation (CoV) and interclass coefficient of variation (ICC) showed good–excellent reliability for most NET parameters. PTT showed poor reliability for both SDTC and threshold electrotonus parameters. There was a significant correlation between large (sensory NET) and small (PTT) fiber SDTC when all sessions were pooled (r = 0.29, p = 0.03). Conclusions: Threshold tracking technique can be applied directly to small fibers via a psychophysical readout, but with the current technique, the reliability is poor. Significance: Further studies are needed to examine whether Aβ-fiber SDTC may be a surrogate biomarker for peripheral nociceptive signalling.

Adaptive laboratory evolution (ALE) has long been used as the tool of choice for microbial engineering applications, ranging from the production of commodity chemicals to the innovation of complex phenotypes. With the advent of systems and synthetic biology, the ALE experimental design has become increasingly sophisticated. For instance, implementation of in silico metabolic model reconstruction and advanced synthetic biology tools have facilitated the effective coupling of desired traits to adaptive phenotypes. Furthermore, various multi-omic tools now enable in-depth analysis of cellular states, providing a comprehensive understanding of the biology of even the most genomically perturbed systems. Emerging machine learning approaches would assist in streamlining the interpretation of massive and multiplexed datasets and promoting our understanding of complexity in biology. This review covers some of the representative case studies among the 700 independent ALE studies reported to date, outlining key ideas, principles, and important mechanisms underlying ALE designs in bioproduction and synthetic cell engineering, with evidence from literatures to aid comprehension.

Abstract In the present study, we investigate arc plasma expansion in an industrial vacuum arc remelting (VAR) process using experimental and numerical tools. Stainless steel is the alloy of interest for the electrode (cathode) and ingot (anode). During the operation of the VAR process, behaviors of cathode spots and plasma arc were captured using the high-speed camera (Phantom v2512). We found that spots prefer to onset and remain within the partially melted surface at the center of the electrode tip. Existing spots outside the melting zone accelerate toward the edge of the electrode to extinguish. We observed a fairly symmetrical and centric plasma column during the operation. For further investigation of the observed arc column in our experiment, we used the two-fluid magnetohydrodynamics (MHD) model of plasma proposed by Braginskii. Thus, we modeled the arc column as a mixture of two continuous interpenetrating compressible fluids involving ions and electrons. Through numerical simulations, we calculated plasma parameters such as number density of ions/electrons, electric current density, flow of ions/electrons, temperature of ions/electrons, and light intensity for the observed arc column in our experiment. The calculated light intensity of plasma was compared with images captured by the camera to verify the model. The distribution of electric current density along the surface of the anode, namely ingot, is a decisive parameter that impacts the quality of the final product (ingot) in VAR process. Herein, we confirm that the traditionally used Gaussian distribution of electric current density along the surface of the ingot is viable.

Abstract When facing particular combinations of stimuli and responses, people create temporary event-files integrating the corresponding stimulus and response features. Subsequent repetition of one or more of these features retrieves the entire event-file, which impairs performance if not all features are repeated (partial-repetition costs). In the literature, different decay functions have been reported presumably dependent on the type of feature that is repeated (e.g. target vs. distractor features). Here, we use a variant of the S1R1-S2R2 and distractor-response binding task and analyze for the first time target-based and distractor-based event-file decay functions within the same task and sample. While we found evidence for decay functions and also stronger retrieval due to target than distractor repetitions, slopes of the decay functions were comparable suggesting that the decay process itself is equal irrespective of the type of stimulus feature that is repeated. Our study thereby confirms overarching approaches that summarize paradigm specific findings with the same set of core processes.

Joseph Weizenbaum fled from the Nazis to the USA, later studying mathematics and becoming a professor of computer science at the Massachusetts Institute of Technology (MIT). He became famous for the Eliza program, which simulates a psychotherapist who—apparently at least—tries to understand its client psychologically, and which became a very early example of chatbots simulating human language. His research led Weizenbaum to a critical attitude toward the possibilities, limits and uses of computers. His main work, “The Power of Computers and the Powerlessness of Reason”, dealt with the effects of computers on the world of human experience—at that time a new and, in its explosiveness, still largely unknown topic. This text makes available in English for the first time an interview with Joseph Weizenbaum conducted in 1998. The interview focuses on the development of artificial intelligence, arguments about analogies between human and artificial intelligence, and perspectives on critical thinking about the relationship between humans and computers.

Making judgments of learning (JOLs) can reactively alter memory itself, a phenomenon termed the reactivity effect. The current study recorded electroencephalography (EEG) signals during the encoding phase of a word list learning task to explore the neurocognitive features associated with JOL reactivity. The behavioral results show that making JOLs reactively enhances recognition performance. The EEG results reveal that, compared with not making JOLs, making JOLs increases P200 and LPC amplitudes and decreases alpha and beta power. Additionally, the signals of event-related potentials (ERPs) and event-related desynchronizations (ERDs) partially mediate the reactivity effect. These findings support the enhanced learning engagement theory and the elaborative processing explanation to account for the JOL reactivity effect.

Background: To provide updated estimates on SARS-CoV-2 antibody seroprevalence and average antibody titres for Central Europe. Methods: In repeat cross-sectional investigations (1 May 2022 to 9 March 2023) involving 28,768 blood donors in the Federal State of Tyrol, Austria (participation rate: 87.0%), we measured Spike receptor-binding domain (RBD) and Nucleocapsid IgG antibodies (37,065 and 12,645 samples), and estimated monthly seroprevalences and geometric mean titres. Results: Median age of participants was 45.4 years (range 18–70); 43.2% were female. Spike RBD IgG antibody seroprevalence was 96.3% (95% CI: 95.6–96.9%) in May 2022, 97.4% (96.7–98.0%) in December 2022, and 97.9% (96.4–98.8%) in March 2023. Among seropositive participants, geometric mean titres increased from 1400 BAU/mL (95% CI: 1333–1471) in May 2022 to 1821 BAU/mL (1717–1932) in December 2022, and dropped to 1559 BAU/mL (1405–1729) by March 2023. Furthermore, titres differed markedly by vaccination status and history of infection, with being the highest in participants with booster vaccination and prior infection. In autumn 2022, Nucleocapsid IgG antibody seroprevalence ranged from 36.5% (35.0–38.1) in September to 39.2% (37.2–41.2) in December 2022. Conclusion: Seroprevalence of SARS-CoV-2 antibodies in blood donors from Tyrol, Austria, was remarkably stable from May 2022 to March 2023. In contrast, average Spike RBD IgG antibody titres peaked in December 2022.

Protein adulteration is a common fraud in the food industry due to the high price of protein sources and their limited availability. Total nitrogen determination is the standard analytical technique for quality control, which is incapable of distinguishing between protein nitrogen and nitrogen from non-protein sources. Three benchtops and one handheld near-infrared spectrometer (NIRS) with different signal processing techniques (grating, Fourier transform, and MEM—micro-electro-mechanical system) were compared with detect adulteration in protein powders at low concentration levels. Whey, beef, and pea protein powders were mixed with a different combination and concentration of high nitrogen content compounds—namely melamine, urea, taurine, and glycine—resulting in a total of 819 samples. NIRS, combined with chemometric tools and various spectral preprocessing techniques, was used to predict adulterant concentrations, while the limit of detection (LOD) and limit of quantification (LOQ) were also assessed to further evaluate instrument performance. Out of all devices and measurement methods compared, the most accurate predictive models were built based on the dataset acquired with a grating benchtop spectrophotometer, reaching R2P values of 0.96 and proximating the 0.1% LOD for melamine and urea. Results imply the possibility of using NIRS combined with chemometrics as a generalized quality control tool for protein powders.

Introduction: Alzheimer’s disease (AD) and aging are associated with platelet hyperactivity. However, the mechanisms underlying abnormal platelet function in AD and aging are yet poorly understood.Methods: To explore the molecular profile of AD and aged platelets, we investigated platelet activation (i.e., CD62P expression), proteome and transcriptome in AD patients, non-demented elderly, and young individuals as controls.Results: AD, aged and young individuals showed similar levels of platelet activation based on CD62P expression. However, AD and aged individuals had a proteomic signature suggestive of increased platelet activation compared with young controls. Transcriptomic profiling suggested the dysregulation of proteolytic machinery involved in regulating platelet function, particularly the ubiquitin-proteasome system in AD and autophagy in aging. The functional implication of these transcriptomic alterations remains unclear and requires further investigation.Discussion: Our data strengthen the evidence of enhanced platelet activation in aging and provide a first glimpse of the platelet transcriptomic changes occurring in AD.

While the contribution of sharp wave ripples in memory consolidation and decision-making is established in rodent models, our understanding of their role in human memory is incomplete. Here, the authors discuss common methodological challenges in detecting, analyzing, and reporting sharp wave ripples, then they suggest practical solutions to distinguish them from other high-frequency events

Abstract Background IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements. Methods This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory. Discussion The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. Trial registration This trial was registered on 02 February 2019 in EudraCT ( 2019-000755-14 ).

Abstract This work is devoted to the efficient simulation of large multi-physical networks stemming from automated modelling processes in system simulation software. The simulation of hybrid, battery and fuel cell electric vehicle applications requires the coupling of electrical, mechanical, fluid, and thermal networks. Each network is established by combining the connection structure of a graph with physical equations of elementary components and resulting in a DAE (differential algebraic equation). To speed up the simulation a non-iterative multirate time integration co-simulation method for the system of coupled DAEs is established. The power of the multirate method is shown via two representative examples of battery powered electric vehicle with a cooling system for the battery pack and a three phase inverter with a cooling system. This work is an extended version of (Kolmbauer et al. in Scientific Computing in Electrical Engineering (SCEE 2020), Springer, Cham, pp. 231–240, 2021).

Background: Hyperferritinemia (HF) is a common finding and can be considered as metabolic HF (MHF) in combination with metabolic diseases. The definition of MHF was heterogenous until a consensus statement was published recently. Our aim was to apply the definition of MHF to provide data on the prevalence and characteristics of MHF in a Central-European cohort. Methods: This study was a retrospective analysis of the Paracelsus 10,000 study, a population-based cohort study from the region of Salzburg, Austria. We included 8408 participants, aged 40–77. Participants with HF were divided into three categories according to their level of HF and evaluated for metabolic co-morbidities defined by the proposed criteria for MHF. Results: HF was present in 13% (n = 1111) with a clear male preponderance (n = 771, 69% of HF). Within the HF group, 81% (n = 901) of subjects fulfilled the metabolic criteria and were defined as MHF, of which 75% (n = 674) were characterized by a major criterion. In the remaining HF cohort, 52% (n = 227 of 437) of subjects were classified as MHF after application of the minor criteria. Conclusion: HF is a common finding in the general middle-aged population and the majority of cases are classified as MHF. The new classification provides useful criteria for defining MHF.

Summary: Background: After an initial stroke, current clinical practice is aimed at preventing recurrent stroke. Thus far, population-based estimates on the risk of recurrent stroke remain scarce. Here we describe the risk of recurrent stroke in a population-based cohort study. Methods: We included Rotterdam Study participants who developed a first-ever incident stroke during follow-up between 1990 until 2020. During further follow-up, these participants were monitored for the occurrence of a recurrent stroke. We determined stroke subtypes based on clinical and imaging information. We calculated ten-year overall and sex-specific cumulative incidences of first recurrent stroke. To reflect changing secondary preventive strategies employed in recent decades, we then calculated the risk of recurrent stroke within ten-year epochs based on first-ever stroke date (1990–2000, 2000–2010 and 2010–2020). Findings: In total, 1701 participants (mean age 80.3 years, 59.8% women) from 14,163 community-living individuals suffered a first stroke between 1990 and 2020. Of these strokes, 1111 (65.3%) were ischaemic, 141 (8.3%) haemorrhagic, and 449 (26.4%) unspecified. During 6585.3 person-years of follow-up, 331 (19.5%) suffered a recurrent stroke, of which 178 (53.8%) were ischaemic, 34 (10.3%) haemorrhagic and 119 (36.0%) unspecified. Median time between first and recurrent stroke was 1.8 (interquartile range 0.5–4.6) years. Overall ten-year recurrence risk following first-ever stroke was 18.0% (95% CI 16.2%–19.8%), 19.3% (16.3%–22.3%) in men and 17.1% (14.8%–19.4%) in women. Recurrent stroke risk declined over time, with a ten-year risk of 21.4% (17.9%–24.9%) between 1990 and 2000 and 11.0% (8.3%–13.8%) between 2010 and 2020. Interpretation: In this population-based study, almost one in five people with first-ever stroke suffered a recurrence within ten years of the initial stroke. Furthermore, recurrence risk declined between 2010 and 2020. Funding: Netherlands Organization for Health Research and Development, EU’s Horizon 2020 research programme and the Erasmus Medical Centre MRACE grant.

Clouds and precipitation over mountainous terrain are a challenge for models and observations alike. In this study, we exploit a unique, nearly one decade long dataset of collocated microwave radiometer, radar, ceilometer, and auxiliary observations collected at the Environmental Research Station Schneefernerhaus (UFS). Located at 2650 m a.s.l. just 300 m below the summit of Zugspitze, Germany's highest mountain, this dataset allows a combined view on water vapor, clouds, and precipitation. Annual and diurnal cycles of water vapor, cloud liquid water, cloud ice, rainfall, and snowfall rate are investigated. Strong diurnal cycles during summer in several observables indicate a strong coupling with the surface and convective transport of air from the surrounding valleys to the level of UFS resulting in maximum amounts in integrated water vapor (IWV), cloud liquid water path (LWP) and rain during the afternoon. In contrast, no diurnal cycle is found during winter, which points to the predominance of advection of cloud systems associated with large scale dynamics during winter. Daily precipitation estimates for snowfall and rainfall derived from a vertically pointing, low-cost micro rain radar (MRR) are found to be in good agreement with manual observations from the German Weather Service at the summit. Exploiting the synergy of MRR and microwave radiometer measurements revealed that almost 90 % of the snow clouds contained significant amounts of super-cooled LWP but only a weak correlation between snowfall rate and LWP is found. The still growing data set at this very particular location, also in combination with further observations, such as trace gases and aerosols, has a unique potential for many applications, e.g. to investigate cloud processes, evaluate high resolution models, and to validate satellite products.

This retrospective study aims to provide an intra-individual comparison of aortic CT angiographies (CTAs) using first-generation photon-counting-detector CT (PCD-CT) and third-generation energy-integrating-detector CT (EID-CT). High-pitch CTAs were performed with both scanners and equal contrast-agent protocols. EID-CT employed automatic tube voltage selection (90/100 kVp) with reference tube current of 434/350 mAs, whereas multi-energy PCD-CT scans were generated with fixed tube voltage (120 kVp), image quality level of 64, and reconstructed as 55 keV monoenergetic images. For image quality assessment, contrast-to-noise ratios (CNRs) were calculated, and subjective evaluation (overall quality, luminal contrast, vessel sharpness, blooming, and beam hardening) was performed independently by three radiologists. Fifty-seven patients (12 women, 45 men) were included with a median interval between examinations of 12.7 months (interquartile range 11.1 months). Using manufacturer-recommended scan protocols resulted in a substantially lower radiation dose in PCD-CT (size-specific dose estimate: 4.88 ± 0.48 versus 6.28 ± 0.50 mGy, p < 0.001), while CNR was approximately 50% higher (41.11 ± 8.68 versus 27.05 ± 6.73, p < 0.001). Overall image quality and luminal contrast were deemed superior in PCD-CT (p < 0.001). Notably, EID-CT allowed for comparable vessel sharpness (p = 0.439) and less pronounced blooming and beam hardening (p < 0.001). Inter-rater agreement was good to excellent (0.58–0.87). Concluding, aortic PCD-CTAs facilitate increased image quality with significantly lower radiation dose compared to EID-CTAs.

Submaximal ventilatory indices, i.e., point of optimal ventilatory efficiency (POE) and anaerobic threshold (AT), are valuable indicators to assess the metabolic and ventilatory response during cardiopulmonary exercise testing (CPET). The order in which the ventilatory indices occur (ventilatory indices sequencing pattern, VISP), may yield additional information for the interpretation of CPET results and for exercise intensity prescription. Therefore, we determined whether different VISP groups concerning POE and AT exist. Additionally, we analysed fat metabolism via the exercise intensity eliciting the highest fat oxidation rate (Fatmax) as a possible explanation for differences between VISP groups. 761 less trained adults (41–68 years) completed an incremental exercise test on a cycle ergometer until volitional exhaustion. The ventilatory indices were determined using automatic and visual detection methods, and Fatmax was determined using indirect calorimetry. Our study identified two VISP groups with a lower work rate at POE compared to AT in VISPPOE

Abstract Sepsis is a major reason for preventable hospital deaths. A cluster-randomized controlled trial on an educational intervention did not show improvements of sepsis management or outcome. We now aimed to test an improved implementation strategy in a second intervention phase in which new intervention hospitals (former controls) received a multifaceted educational intervention, while controls (former intervention hospitals) only received feedback of quality indicators. Changes in outcomes from the first to the second intervention phase were compared between groups using hierarchical generalized linear models controlling for possible confounders. During the two phases, 19 control hospitals included 4050 patients with sepsis and 21 intervention hospitals included 2526 patients. 28-day mortality did not show significant changes between study phases in both groups. The proportion of patients receiving antimicrobial therapy within one hour increased in intervention hospitals, but not in control hospitals. Taking at least two sets of blood cultures increased significantly in both groups. During phase 2, intervention hospitals showed higher proportion of adequate initial antimicrobial therapy and de-escalation within 5 days. A survey among involved clinicians indicated lacking resources for quality improvement. Therefore, quality improvement programs should include all elements of sepsis guidelines and provide hospitals with sufficient resources for quality improvement. Trial registration: ClinicalTrials.gov, NCT01187134. Registered 23 August 2010, https://www.clinicaltrials.gov/ct2/show/study/NCT01187134 .

Abstract Background Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. Methods This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. Discussion Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. Trial registration This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

Wastewater-based epidemiology (WBE) is an effective approach for tracking information on spatial distribution and temporal trends of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the community level. Herein, the development, implementation, and operation of the wastewater monitoring program serving Tyrol – a federal province of Austria – are described. The development of this program was initiated by Tyrolean health authorities at the end of the first phase of the Coronavirus disease 2019 (COVID-19) pandemic (May 2020). In close co-operation with the water sector and academic institutions, efficient and effective workflows and processes for wastewater surveillance were established. The monitoring program went into operation in November 2020. By the end of July 2021, a total of 5,270 wastewater influent samples collected at 43 sites were analyzed. The monitoring program provided valuable insights into the development of the pandemic situation in Tyrol and fulfilled several tasks that are of importance in different phases of the pandemic. It represented an early-warning system, provided independent confirmation of temporal trends in COVID-19 prevalence, enabled the assessment of the effectiveness of measures, alerted about bursts of disease activity, and provided evidence for the absence of COVID-19. These findings underline the importance of establishing national wastewater monitoring programs as a complementary source of information for efficient and effective pandemic management. HIGHLIGHTS The development, implementation, and operation of the Tyrolean SARS-CoV-2 wastewater monitoring program are described.; Health authorities are receiving regular updates on the pandemic situation in 43 Tyrolean regions.; Turnaround times are

Background Recovery trajectories from coronavirus disease 2019 (COVID-19) call for longitudinal investigation. We aimed to characterise the kinetics and status of clinical, cardiopulmonary and mental health recovery up to 1 year following COVID-19. Methods Clinical evaluation, lung function testing (LFT), chest computed tomography (CT) and transthoracic echocardiography were conducted at 2, 3, 6 and 12 months after disease onset. Submaximal exercise capacity, mental health status and quality of life were assessed at 12 months. Recovery kinetics and patterns were investigated by mixed-effect logistic modelling, correlation and clustering analyses. Risk of persistent symptoms and cardiopulmonary abnormalities at the 1-year follow-up were modelled by logistic regression. Findings Out of 145 CovILD study participants, 108 (74.5%) completed the 1-year follow-up (median age 56.5 years; 59.3% male; 24% intensive care unit patients). Comorbidities were present in 75% (n=81). Key outcome measures plateaued after 180 days. At 12 months, persistent symptoms were found in 65% of participants; 33% suffered from LFT impairment; 51% showed CT abnormalities; and 63% had low-grade diastolic dysfunction. Main risk factors for cardiopulmonary impairment included pro-inflammatory and immunological biomarkers at early visits. In addition, we deciphered three recovery clusters separating almost complete recovery from patients with post-acute inflammatory profile and an enrichment in cardiopulmonary residuals from a female-dominated post-COVID-19 syndrome with reduced mental health status. Conclusion 1 year after COVID-19, the burden of persistent symptoms, impaired lung function, radiological abnormalities remains high in our study population. Yet, three recovery trajectories are emerging, ranging from almost complete recovery to post-COVID-19 syndrome with impaired mental health.

The motion of particles in the moving grate combustion chamber is used as the case study. These problems are categorized as particle-fluid problems. They are typically solved using Lagrangian-Eulerian methods, one of which is the coupling between the discrete element method (DEM, which is applied to the particles phase) and the computational fluid dynamics method (CFD, which is applied to the fluid phase). The current study's objective is to avoid coupling and instead, focusing on using the CFD method only. There are dense piles of particles moving on the grates in the biomass combustion chamber. We assumed the dense particles' behaviors similar to the fluid, and then, applied the fluid governing equations to the particles phase. The virtual fields of the velocities, pressure, and density are specified for the particles' phase. Afterward, the physics-informed neural network (PINN) is used to reconstruct particles' fields and additionally to investigate the capability of the predicted fields to satisfy the fluid governing equations. This model has the benefit of reconstructing the particles' fields without the need for boundaries and initial conditions. The precision of the model is assessed by comparing the test data set with the exact data obtained from the eXtended discrete element method (XDEM is an in-house software). It is demonstrated that the trained neural network delivered high accuracy and is capable of predicting all outputs with an error value of less than 2 percent. Additionally, to choose the optimum architecture for the neural network, the effect of the number of hidden layers and neurons is studied.