New Insights and Methods in the Treatment of Scar Related Arrhythmias

This thesis contains research on the outcome of catheter ablation on scar related arrhythmias. Specifically, the role of remote magnetic navigation, contact force, a substrate approach and image-integration on ablation for scar related arrhythmias was investigated

Comparison of long-term outcome between patients aged < 65 years vs. ≥ 65 years after atrial fibrillation ablation

Background Atrial fibrillation (AF) is the most frequent arrhythmia, and its prevalence is increasing with aging. We aimed to compare the long-term outcome data of patients < 65 years vs. ≥ 65 years who underwent ca

Ventricular tachycardia in ischemic cardiomyopathy; a combined endo-epicardial ablation as the first procedure versus a stepwise approach (EPILOGUE) - study protocol for a randomized controlled trial

Background: The role of epicardial substrate ablation of ventricular tachycardia (VT) as a first-line approach in patients with ischemic heart disease is not clearly defined. Epicardial ablation as a first-line option is standard for patients with nonischemic dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Several nonrandomized studies, including studies on patients with ischemic heart disease, have shown that epicardial VT ablation improves outcome but this approach was often used after a failed endocardial approach. The aim of this study is to determine whether a combined endo-epicardial scar homogenization as a first-line approach will improve the outcome of VT ablation. Methods/Design: The EPILOGUE study is a multicenter, two-armed, nonblinded, randomized controlled trial. Patients with ischemic heart disease who are referred for VT ablation will be randomly assigned to combined endo-epicardial scar homogenization or endocardial scar homogenization only (control group). The primary outcome is recurrence of sustained VT during a 2-year follow-up. Secondary outcomes include procedural success and safety. Discussion: This study is the first randomized trial that evaluates the role of a combined endo-epicardial scar homogenization versus endocardial scar homogenization for the treatment of ischemic scar-related VT. Trial registration:NL4816807814v0

Contact feedback improves 1-year outcomes of remote magnetic navigation-guided ischemic ventricular tachycardia ablation

Introduction: Remote magnetic navigation (RMN)-guided catheter ablation (CA) is a feasible treatment option for patients presenting with ischemic ventricular tachycardia (VT). Catheter-tissue contact feedback, enhances lesion formation and may consequently improve CA outcomes. Until recently, contact feedback was unavailable for RMN-guided CA. The novel e-Contact Module (ECM) was developed to continuously monitor and ensure catheter-tissue contact during RMN-guided CA. Objective: The present study aims to evaluate the effect of ECM implementation on acute and long-term outcomes in RMN-guided ischemic VT ablation. Method: This retrospective, two-center study included consecutive ischemic VT patients undergoing RMN-guided CA from 2010 to 2017. Baseline clinical data, procedural data, including radiation times, and acute success rates were compared between CA procedures performed with ECM (ECM+) and without ECM (ECM−). One-year VT-free survival was analyzed using Cox-proportional hazards models, adjusting for potential confounders: age, left ventricular function, VT inducibility at baseli

Killer cell proteases can target viral immediate-early proteins to control human cytomegalovirus infection in a noncytotoxic manner.

Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital defects and can trigger devastating disease in immune-suppressed patients. Cytotoxic lymphocytes (CD8+ T cells and NK cells) control HCMV infection by releasing interferon-γ and five granzymes (GrA, GrB, GrH, GrK, GrM), which are believed to kill infected host cells through cleavage of intracellular death substrates. However, it has recently been demonstrated that the in vivo killing capacity of cytotoxic T cells is limited and multiple T cell hits are required to kill a single virus-infected cell. This raises the question whether cytotoxic lymphocytes can use granzymes to control HCMV infection in a noncytotoxic manner. Here, we demonstrate that (primary) cytotoxic lymphocytes can block HCMV dissemination independent of host cell death, and interferon-α/β/γ. Prior to killing, cytotoxic lymphocytes induce the degradation of viral immediate-early (IE) proteins IE1 and IE2 in HCMV-infected cells. Intriguingly, both IE1 and/or IE2 are directly proteolyzed by all human granzymes, with GrB and GrM being most efficient. GrB and GrM cleave IE1 after Asp398 and Leu414, respectively, likely resulting in IE1 aberrant cellular localization, IE1 instability, and functional impairment of IE1 to interfere with the JAK-STAT signaling pathway. Furthermore, GrB and GrM cleave IE2 after Asp184 and Leu173, respectively, resulting in IE2 aberrant cellular localization and functional abolishment of IE2 to transactivate the HCMV UL112 early promoter. Taken together, our data indicate that cytotoxic lymphocytes can also employ noncytotoxic ways to control HCMV infection, which may be explained by granzyme-mediated targeting of indispensable viral proteins during lytic infection

Invasive aspergillosis mimicking metastatic lung cancer

In a patient with a medical history of cancer, the most probable diagnosis of an (18)FDG-avid pulmonary mass combined with intracranial abnormalities on brain imaging is metastasized cancer. However, sometimes a differential diagnosis with an infectious cause such as aspergillosis can be very challenging as both cancer and infection are sometimes difficult to distinguish. Pulmonary aspergillosis can present as an infectious pseudotumour with clinical and imaging characteristics mimicking lung cancer. Even in the presence of cerebral lesions, radiological appearance of abscesses can look like brain metastasis. These similarities can cause significant diagnostic difficulties with a subsequent therapeutic delay and a potential adverse outcome. Awareness of this infectious disease that can mimic lung cancer, even in an immunocompetent patient, is important. We report a case of a 65-year-old woman with pulmonary aspergillosis disseminated to the brain mimicking metastatic lung cancer

Curriculum vitae of the LOTOS-EUROS (v2.0) chemistry transport model

The development and application of chemistry transport models has a long tradition. Within the Netherlands the LOTOS–EUROS model has been developed by a consortium of institutes, after combining its independently developed predecessors in 2005. Recently, version 2.0 of the model was released as an open-source version. This paper presents the curriculum vitae of the model system, describing the model's history, model philosophy, basic features and a validation with EMEP stations for the new benchmark year 2012, and presents cases with the model's most recent and key developments. By setting the model developments in context and providing an outlook for directions for further development, the paper goes beyond the common model description. With an origin in ozone and sulfur modelling for the models LOTOS and EUROS, the application areas were gradually extended with persistent organic pollutants, reactive nitrogen, and primary and secondary particulate matter. After the combination of the models to LOTOS–EUROS in 2005, the model was further developed to include new source parametrizations (e.g. road resuspension, desert dust, wildfires), applied for operational smog forecasts in the Netherlands and Europe, and has been used for emission scenarios, source apportionment, and long-term hindcast and climate change scenarios. LOTOS–EUROS has been a front-runner in data assimilation of ground-based and satellite observations and has participated in many model intercomparison studies. The model is no longer confined to applications over Europe but is also applied to other regions of the world, e.g. China. The increasing interaction with emission experts has also contributed to the improvement of the model's performance. The philosophy for model development has always been to use knowledge that is state of the art and proven, to keep a good balance in the level of detail of process description and accuracy of input and output, and to keep a good record on the effect of model changes using benchmarking and validation. The performance of v2.0 with respect to EMEP observations is good, with spatial correlations around 0.8 or higher for concentrations and wet deposition. Temporal correlations are around 0.5 or higher. Recent innovative applications include source apportionment and data assimilation, particle number modelling, and energy transition scenarios including corresponding land use changes as well as Saharan dust forecasting. Future developments would enable more flexibility with respect to model horizontal and vertical resolution and further detailing of model input data. This includes the use of different sources of land use characterization (roughness length and vegetation), detailing of emissions in space and time, and efficient coupling to meteorology from different meteorological models

Comprehensive routine diagnostic screening to identify predictive mutations, gene amplifications, and microsatellite instability in FFPE tumor material

Background: Sensitive and reliable molecular diagnostics is needed to guide therapeutic decisions for cancer patients. Although less material becomes available for testing, genetic markers are rapidly expanding. Simultaneous detection of predictive markers, including mutations, gene amplifications and MSI, will save valuable material, time and costs. Methods: Using a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach, we developed an NGS panel allowing detection of predictive mutations in 33 genes, gene amplifications of 13 genes and microsatellite instability (MSI) by the evaluation of 55 microsatellite markers. The panel was designed to target all clinically relevant single and multiple nucleotide mutations in routinely available lung cancer, colorectal cancer, melanoma, and gastro-intestinal stromal tumor samples, but is useful for a broader set of tumor types. Results: The smMIP-based NGS panel was successfully validated and cut-off values were established for reliable gene amplification analysis (i.e. relative coverage ≥3) and MSI detection (≥30% unstable loci). After validation, 728 routine diagnostic tumor samples including a broad range of tumor types were sequenced with sufficient sensitivity (2.4% drop-out), including samples with low DNA input (< 10 ng; 88% successful), low tumor purity (5-10%; 77% successful), and cytological material (90% successful). 75% of these tumor samples showed ≥1 (likely) pathogenic mutation, including targetable mutations (e.g. EGFR, BRAF, MET, ERBB2, KIT, PDGFRA). Amplifications were observed in 5.5% of the samples, comprising clinically relevant amplifications (e.g. MET, ERBB2, FGFR1). 1.5% of the tumor samples were classified as MSI-high, including both MSI-prone and non-MSI-prone tumors. Conclusions: We developed a comprehensive workflow for predictive analysis of diagnostic tumor samples. The smMIP-based NGS analysis was shown suitable for limited amounts of histological and cytological material. As smMIP technology allows easy adaptation of panels, this approach can comply with the rapidly expanding molecular markers