Combined [18F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [18F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2

Abstract Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms. Here we evaluated reactivation of parvovirus B19 and several viruses of the herpes family in patients with long-COVID syndrome, how vaccination affected viral interference, and how virus reactivation influenced clinical conditions. Clinical and laboratory data on 252 consecutive patients (97 vaccinated and 155 non-vaccinated) were recorded between April 2021–May 2022 (median 243 days post-COVID-19 infection). Viral IgG and IgM titers were compared between vaccinated or non-vaccinated patients, and age and sex-matched healthy controls. Vaccination was associated with significantly less frequent fatigue and multiorgan symptoms (P < 0.001), significantly less cumulative IgM positivity of the investigated viruses, significantly lower plasma levels of IgG subfractions 2 and 4, and significantly lower quantitative Cytomegalovirus (CMV) IgG, CMV IgM, and EBV IgM titers. These results indicate that anti-SARS-CoV2 vaccination interrupts viral crosstalk in patients with long-COVID syndrome. (ClinicalTrials.gov Identifier: NCT05398952)

Epstein–Barr virus (EBV) reactivation may be involved in long-COVID symptoms, but reactivation of other viruses as a factor has received less attention. Here we evaluated the reactivation of parvovirus-B19 and several members of the Herpesviridae family (DNA viruses) in patients with long-COVID syndrome. We hypothesized that monovalent COVID-19 vaccines inhibit viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome, thereby reducing clinical symptoms. Clinical and laboratory data for 252 consecutive patients with PCR-verified past SARS-CoV-2 infection and long-COVID syndrome (155 vaccinated and 97 non-vaccinated) were recorded during April 2021–May 2022 (median 243 days post-COVID-19 infection). DNA virus–related IgG and IgM titers were compared between vaccinated and non-vaccinated long-COVID patients and with age- and sex-matched non-infected, unvaccinated (pan-negative for spike-antibody) controls. Vaccination with monovalent COVID-19 vaccines was associated with significantly less frequent fatigue and multiorgan symptoms ( p < 0.001), significantly less cumulative DNA virus–related IgM positivity, significantly lower levels of plasma IgG subfractions 2 and 4, and significantly lower quantitative cytomegalovirus IgG and IgM and EBV IgM titers. These results indicate that anti-SARS-CoV-2 vaccination may interrupt viral cross-talk in patients with long-COVID syndrome (ClinicalTrials.gov Identifier: NCT05398952).

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA–miRNA–mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA–miRNA–mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA–miRNA–mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.

Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.

Clusterin exerts anti-inflammatory, cytoprotective and anti-apoptotic effects. Both an increase and decrease of clusterin in acute myocardial infarction (AMI) has been reported. We aimed to clarify the role of clusterin as a systemic biomarker in AMI. AMI was induced by percutaneous left anterior artery (LAD) occlusion for 90 min followed by reperfusion in 24 pigs. Contrast ventriculography was performed after reperfusion to assess left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) and additional cMRI + late enhancement to measure infarct size and LV functions at day 3 and week 6 post-MI. Blood samples were collected at prespecified timepoints. Plasma clusterin and other biomarkers (cTnT, NT-proBNP, neprilysin, NGAL, ET-1, osteopontin, miR21, miR29) were measured by ELISA and qPCR. Gene expression profiles of infarcted and remote region 3 h (n = 5) and 3 days (n = 5) after AMI onset were analysed by RNA-sequencing. AMI led to an increase in LVEDV and LVESV during 6-week, with concomitant elevation of NT-proBNP 3-weeks after AMI. Plasma clusterin levels were increased immediately after AMI and returned to normal levels until 3-weeks. Plasma NGAL, ET-1 and miR29 was significantly elevated at 3 weeks follow-up, miR21 increased after reperfusion and at 3 weeks post-AMI, while circulating neprilysin levels did not change. Elevated plasma clusterin levels 120 min after AMI onset suggest that clusterin might be an additional early biomarker of myocardial ischemia.

Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7–21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF.

Circular RNAs (circRNAs) are classified as long non-coding RNAs (lncRNAs) that are characterized by a covalent closed-loop structure.This closed-loop shape is the result of a backsplicing event in which the 3' and 5' splice sites are ligated.Through the lack of 3' poly(A) tails and 5' cap structures, circRNAs are more stable than linear RNAs because these adjustments make the circular loop less susceptible to exonucleases.The majority of identified circRNAs possess cell-and tissue-specific expression patterns.In addition, high-throughput RNA-sequencing combined with novel bioinformatics algorithms revealed that circRNA sequences are often conserved across different species suggesting a positive evolutionary pressure.Implicated as regulators of protein turnover, micro RNA (miRNA) sponges, or broad effectors in cell differentiation, proliferation, and senescence, research of circRNA has increased in recent years.Particularly in cardiovascular research, circRNArelated discoveries have opened the door for the development of potential diagnostic and therapeutic tools.Increasing evidence links deviating circRNA expression patterns to various cardiovascular diseases including ischemic heart failure.In this mini-review, we summarize the current state of knowledge on circRNAs in cardiac regeneration with a focus on cardiac cell proliferation, differentiation, cardiomyocyte survival, and cardiac reprogramming.

Background: In 2014, Austrian health authorities implemented an organized breast cancer screening program. Until then, there has been a long-standing tradition of opportunistic screening. Objectives: To evaluate the cost-effectiveness of organized screening compared with opportunistic screening, as well as to identify factors influencing the clinical and economic outcomes. Methods: We developed and validated an individual-level state-transition model and assessed the health outcomes and costs of organized and opportunistic screening for 40-year-old asymptomatic women. The base-case analysis compared a scenario involving organized biennial screening with a scenario reflecting opportunistic screening practice for an average risk woman aged 45 to 69 years. We applied an annual discount rate of 3% and estimated the incremental cost-effectiveness ratio in terms of the cost (2012 euros) per life-year gained (LYG) from a health care perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainty. Results: Compared with opportunistic screening, an organized program yielded on average additional 0.0118 undiscounted life-years (i.e., 4.3 days) and cost savings of (sic)41 per woman. In the base-case analysis, the incremental cost-effectiveness ratio of organized screening was approximately (sic)20,000 per LYG compared with no screening. Assuming a willingness-to-pay threshold of (sic)50,000 per LYG, there was a 70% probability that organized screening would be considered cost-effective. The attendance rate, but not the test accuracy of mammography, was an influential factor for the cost-effectiveness. Conclusions: The decision to adopt organized screening is likely an efficient use of limited health care resources in Austria.

In Austria, especially among children, the prevalence of obesity has increased since 1999. Therefore, a System Dynamics model, simulating the prevalence of obesity, has been developed. The modular architecture allows separate analysis of the model parts and also adding and connecting different modules, like for example a cost module or a module for an obesityrelated disease to the existing population model and the disease model of obesity. Three interventions, treating obesity with an increase in caloric expenditure and/or a reduction of caloric intake, are tested, analysed and compared. The results show that a reduction of caloric intake reduces the prevalence of obesity and overweight until 2050 (intervention 1). Furthermore, a reduction for the doubled amount of kilocalories per day doesn’t have the doubled effect on the reduction of the prevalence (intervention 2 compared to 1). Last, but not least, intervention 3 compared to intervention 2 shows that physical activity together with a reduction of caloric intake reduces the prevalence much more than a single reduction of caloric intake in the amount of kilocalories due to physical activity and eating less together. Introduction Body Mass Index Classification BMI underweight < 18,50 normal weight 18,50 – 24,99 overweight 25,00 – 29,99 obese 30,00 Table 1. Classification of obesity and overweight according to the WHO [2] measured through the BMI. Simulation Notes Europe SNE 26(3), 2016, 161 166 DOI: 10.11128/sne.26.tn.10345 Received: September 9, 2015; Revised: December 3, 2015; Accepted: January 15, 2016; Glock et al. Treatment Strategies for Obesity in Austria Modelled with System Dynamics 162 SNE 26(3) – 9/2016 TN 1 Method: System Dynamics stocks flows t parameters auxiliaries Figure 1. A simple stock and flow diagram. The flow is dependent on the stock and a parameter, represented by the smaller arrows. Sources 2 Architecture of the Model population model disease model interface 2.1 Population model aging death migration births Figure 2. Structure of the population model. births (male births, female births r p age specific fertility rates total fertility average fertility age Glock et al. Treatment Strategies for Obesity in Austria Modelled with System Dynamics SNE 26(3) – 9/2016 163 T N 2.2 Disease model Figure 3. Flows between adjacent BMI categories in the disease model. caloric changes in energy balance changes of rates change of rates

System dynamics models are widely used for applications in health care. Modelling of different reimbursement systems is a comparatively new field of application. This paper tries to identify the core dynamic structures and feedback loops that drive such models. We created a simplified model of physician reimbursement that includes the interaction between patients, their disease state, and the pressures on physician behaviour from reimbursement and their workload. Several simulated scenarios show that its behaviour is plausible and in line with theories on the influence of different reimbursement systems. Introduction

Modeling techniques and the decision process for research question definition using PICO (Population, Intervention, Control/Comperator, Outcome) in HTA (Health Technology Assessment) problems are described briefly in the first part of the paper. The second part deals with some aspects of realized screening questions regarding cost effectiveness of organized breast cancer screening in Austria and a screening program for abdominal aortic aneurysm. In case of breast cancer a closer look on model calibration for natural history behavior of tumor growth/development is given.

Agent-based modeling is a method to model a system by autonomous entities. The proposed framework models single persons with personal behavior, different health states and ability to spread the disease. Upon simulation, the epidemic emerges automatically. This approach is clear and easily understandable but requires extensive knowledge of the epidemic’s background. Such real-world model structures produce realistic epidemics, allowing detailed examination of the transmission process or testing and analyzing the outcome of interventions like vaccinations. Due to changed epidemic propagation, effects like herd immunity or serotype shift arise automatically. Beyond that, a modular structure splits the model into parts, which can be developed and validated separately. This approach makes development more efficient, increases credibility of the results and allows reusability and exchangeability of existing modules. Thus, knowledge and models can be easily and efficiently transferred, for example to compute scenarios for different countries and similar diseases.

Discrete-Event-Simulation (DES) is a commonly used modeling tool to analyze the comparative effectiveness of alternative health technologies and to optimize resource allocation in health care settings. DES models are often rather complex and visualization is very important to improve transparency and acceptability. This study aims to illustrate and contrast alternative visualization techniques on a decision-analytic model for breast cancer. DES visualization methods and their applications in health care, engineering, and operations research were sought from a wide variety of sources, including literature databases (e. g., PubMed) and webpages of simulation conference (e. g., Winter Simulation Conference), academic societies etc. Based on this review, alternative visualization techniques for the conceptual model were selected, applied on a real world modeling example and compared. In health care, the recently published ISPOR-SMDM Modeling Good Research Practice guidelines recommend flow diagrams or state charts to represent the key elements of a model, including the possible pathways, and the presence of queues and decision points. For flow charts, we found an international standard (ISO 5807). The application of standards like this could support harmonization of process-oriented models. In general, flow charts may lack the information of health states and transitions between health states that are relevant for clinicians to review the model. The semantic for state charts invented by Harel provides a further development of the bubble diagrams of State-Transition (Markov) Models (e. g. one state containing other states, one state detects changes in another). In state charts, health states could explicitly be named but treatment processes and resources use are less explicit. For DES software implementation, state charts seem to be less intuitive. For both methods, the application of visualization standards and guidelines was not always straight forward for our breast cancer model. In the case example there was no superior visualization technique.

ARGESIM Benchmark C6 'Emergency Department -Follow-up Treatment' on the first glance is a classic discrete process system -with servers (treatment units) and entities (patients).But the different behaviour of doctors causes some modelling difficulties.This contribution presents an agent-based modelling approach, which is much more flexible than the classic DES approach, implemented in the Java-based simulator AnyLogic, which is capable of DES, agent-based, ODE, system dynamics and programming approach.

Markov cohort models are one of the standard methodologies for conducting cost-effectiveness analyses of health care interventions of chronic diseases. The system dynamics (SD) approach, where a model consists of stocks and their interconnecting flows, is rarely used, but in principle it can be used to conduct the same type of analysis. The authors show that a simple transformation from the transition probabilities of a Markov model to relative rates always leads to an equivalent system dynamics model. Here the stocks match the Markov states, because they store the same number of patients as in the corresponding state. The authors demonstrate an approach on an exemplary cost-effectiveness analysis for a smoking cessation programme for chronic obstructive pulmonary disease (COPD) with a simplified Markov model based on Menn (2009). Both the Markov model and the system dynamics model lead to nearly identical results. However, the latter offers more flexibility as it can incorporate interactions between different patient groups.

According to the Statistics Austria more than one third of the Austrian population suffers from at least one chronic disease. Therefore efficient tools for the evaluation of the prevalence of these diseases and possible treatment and/or prevention strategies are needed. When simulating a chronic disease usually a model part for population dynamics, for the disease and also for costs is needed. Since there are on the one hand a lot of different diseases and on the other hand a lot of countries with different demography in which these diseases occur, a modular architecture of the simulation tool may be useful. This means that the model, in this case implemented in System Dynamics, consists of independent model parts that are connected to each other on specifically defined interfaces. The proposed approach allows exchange of model parts and guarantees a high degree of reusability. In this paper an example of such a modular architecture together with its advantages and disadvantages will be given for the chronic disease of obesity and for the population of Austria.

In health care the reimbursement of medical providers is an important topic and can influence the overall outcome. We present the agent-based GAP-DRG model, which allows a comparison of reimbursement schemes in outpatient care. It models patients and medical providers as agents. In the simulation patients develop medical problems (i.e., diseases) and a need for medical services. This leads to utilization of medical providers. The reimbursement system receives information on the patients' visits via its generic interface, which facilitates an easy replacement. We describe the assumptions of the model in detail and show how it makes extensive use of available Austrian routine care data for its parameterization. The model design is optimized for utilizing as much of these data as possible. However, many assumptions have to be simplifications. Further work and detailed comparisons with health care data will provide insight on which assumptions are valid descriptions of the real process.

Simulator. The Ptolemy II project (from the Center for Hybrid and Embedded Software Systems in the Department of Electrical Engineering and Computer Sciences of the University of California in Berkeley) studies modelling and simulation of concurrent, real-time, embedded systems which combine the continuous dynamics of physical systems with discrete mode changes (for example from a digital controller). Models in Ptolemy II consist of so-called actors visually represented in block diagrams which are able to communicate with each other by sending messages over ports and channels. Actors and their connections describe an abstract syntax of the model; additionally one has to specify a ‘model of computation’ (like continuous time or discrete event) which gives operational rules for the execution of the model. Ptolemy II supports heterogeneous and hierarchical mixtures of different models of computation. It is constructed in Java and the source code is freely available (http://ptolemy.eecs.berkeley.edu/).