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In patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.

The importance of mitral valve therapies is rising due to an aging population. Visualization and quantification of the valve anatomy from image acquisitions is an essential component of surgical and interventional planning. The segmentation of the mitral valve from computed tomography (CT) acquisitions is challenging due to high variation in appearance and visibility across subjects. We present a novel semi-automatic approach to segment the open-state valve in 3D CT volumes that combines user-defined landmarks to an initial valve model which is automatically adapted to the image information, even if the image data provide only partial visibility of the valve. Context information and automatic view initialization are derived from segmentation of the left heart lumina, which incorporates topological, shape and regional information. The valve model is initialized with user-defined landmarks in views generated from the context segmentation and then adapted to the image data in an active surface approach guided by landmarks derived from sheetness analysis. The resulting model is refined by user landmarks. For evaluation, three clinicians segmented the open valve in 10 CT volumes of patients with mitral valve insufficiency. Despite notable differences in landmark definition, the resulting valve meshes were overall similar in appearance, with a mean surface distance of $$1.62 \pm 2.10$$ mm. Each volume could be segmented in 5–22 min. Our approach enables an expert user to easily segment the open mitral valve in CT data, even when image noise or low contrast limits the visibility of the valve.

Severe mitral valve regurgitation can either be treated by a replacement or a repair of the valve. The latter is recommended due to lower perioperative mortality and better long-term survival. On the other hand, recurrence rates after mitral valve repair are high compared to those after replacements and the repair intervention can cause induced mitral valve stenosis. So far, there are no methods to predict the hemodynamic outcome of a chosen treatment or to compare different treatment options in advance. To overcome this, diastolic mitral valve hemodynamics are simulated using computational fluid dynamics after different virtual treatments of the valve. The left ventricular geometry of one patient was reconstructed using trans-esophageal echocardiography and computed tomography data. Pre-op hemodynamics are simulated using a referenced wall model to avoid expansive modeling of wall motion. Subsequently, the flow structures are compared to in vivo measurements. After manipulating the patient-specific geometry in order to mimic a restrictive mitral annuloplasty as well as a MitraClip intervention, hemodynamics results are calculated. Good agreements exist between calculated pre-op hemodynamics and in vivo measurements. The virtual annuloplasty did not result in any remarkable change of hemodynamics. Neither the pressure drop nor the velocity field showed strong differences. In contrast, the virtual MitraClip intervention led to a complete change in blood flow structures as well as an elevated pressure drop across the valve. The presented approach allows fast simulation of the diastolic hemodynamic situation before and after treatment of a mitral valve insufficiency. However, this approach is limited to the early diastolic phase of the cardiac cycle and needs to be validated using a larger sample size.

Background Endomyocardial biopsies (EMB) are the gold standard for the diagnosis of myocarditis in children and adults. The existing WHO/ISFC criteria for lymphocytic cell infiltrates by are based on the myocardium of adults. The aim of this study was to present a paediatric control cohort for the evaluation of inflammation in EMB of children. Methods In this study endomyocardial tissue from 62 children under 4 years of age was investigated, being collected during a planned open heart surgery with routine resection from ventricular site. Patients had no history of infection or myocardial inflammation. The heart tissue was formalin fixed and embedded in paraffin. Four μm thick tissue sections were stained with haematoxylin and eosin, Masson's trichrome, and Giemsa. Immunohistochemical stainings included quantitative evaluation of CD3+ T cells, CD20+ B cells, CD68+ macrophages and MHCII expression. Results The myocardium was obtained in 96.8% (n = 60) of the cases from the right and in 3.2% (n = 2) from the left ventricle. The median age (interquartile range) at biopsy was 0.5 years (0.3–0.9), 66.1% male. Within this cohort, a median of 2.5/mm2 (1.0–4.0) CD3+ T cells, 0.5/mm2 (0.0–0.6) CD20+ B cells and 4.0/mm2 (2.5–6.0) CD68+ macrophages were detected. The MHC II grade was 0 in 71.0% (n = 44) and 1 in 29.0% (n = 18). Conclusion This is the first paediatric control cohort being relevant for the correct interpretation of inflammatory heart diseases in EMB. The lymphocytic cell numbers in children needing congenital heart surgery without myocardial inflammation are below the existing values in adults.

The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ���18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation-not only in adult-but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

This research paper introduces an adaptive algorithm to reconstruct the left ventricle from computer tomographic images (CT). Often, manual image segmentation gives the right geometry but produces too smooth shapes while automatic segmentation algorithms incorporate too much details including unwanted noise with complicated topology. The correct topology is most important in the ventricle motion approximation gained for example from 4D computed tomography and applied in computational fluid dynamics (CFD) of the heart. We propose to bridge the two extremes i.e. producing models with common spherical topologies and smoothness level while preserving important details as much as possible. We propose a controlled shrinkwrap algorithm together with a framework where level of details can be chosen based on a single parameter. We demonstrate the results on a patient specific left ventricle to understand the effect of papillary muscles in computational fluid dynamic progressively from a smooth to a detailed surface.

Purpose: While novel tools for segmentation of the mitral valve are often based on automatic image processing, they mostly require manual interaction by a proficient user. Those segmentations are essential for numerical support of mitral valve treatment using computational fluid dynamics, where the reconstructed geometry is incorporated into a simulation domain. To quantify the uncertainty and reliability of hemodynamic simulations, it is crucial to examine the influence of user-dependent variability in valve segmentation. Methods: Previously, the inter-user variability of landmarks in mitral valve segmentation was investigated. Here, the inter-user variability of geometric parameters of the mitral valve, projected orifice area (OA) and projected annulus area (AA), is investigated for 10 mitral valve geometries, each segmented by three users. Furthermore, the propagation of those variations into numerically calculated hemodynamics, i.e., the blood flow velocity, was investigated. Results: Among the three geometric valve parameters, AA was least user-dependent. Almost all deviations to the mean were below 10%. Larger variations were observed for OA. Variations observed for the numerically calculated hemodynamics were in the same order of magnitude as those of geometric parameters. No correlation between variation of geometric parameters and variation of calculated hemodynamic parameters was found. Conclusion: Errors introduced due to the user-dependency were of the same size as the variations of calculated hemodynamics. The variation was thereby of the same scale as deviations in clinical measurements of blood flow velocity using Doppler echocardiography. Since no correlation between geometric and hemodynamic uncertainty was found, further investigation of the complex relationship between anatomy, leaflet shape and flow is necessary.

Purpose Myocarditis is one major cause for the development of acute or chronic heart failure where immunosuppressive therapies are still divergently discussed. The aim of this study was to analyze cytokines in children with suspected myocarditis to describe their immunologic patterns and to reveal potential therapeutic targets. Methods Sera of children hospitalized with suspected myocarditis and sera from a pediatric control cohort collected during April 2017 and July 2019 were analyzed. Sera were taken after admission and before further intensive care treatment. The cytokines Interleukin (IL)-1 beta, IL-2, IL-6, IL-10 and IL-1 receptor antagonist (IL-1RA) were analyzed by enzyme-linked immunosorbent assay (ELISA) kits of Meso Scale Discovery Inc. and RD p Conclusion In children with suspected myocarditis cytokines as IL-2, IL-6 and IL-10 correlate with myocardial damage and dysfunction as potential markers for heart failure. The higher levels of IL-1RA in children with severe disease course may represent the immunologic reaction of a more fulminant myocarditis pointing towards potential therapeutic targets in children with an inappropriate elevation of IL-1RA.

Various options are available for the treatment of mitral valve insufficiency, including reconstructive approaches such as annulus correction through ring implants. The correct choice of general therapy and implant is relevant for an optimal outcome. Additional to guidelines, decision support systems (DSS) can provide decision aid by means of virtual intervention planning and predictive simulations. Our approach on virtual downsizing is one of the virtual intervention tools that are part of the DSS workflow. It allows for emulating a ring implantation based on patient-specific lumen geometry and vendor-specific implants. Our approach is fully automatic and relies on a lumen mask and an annulus contour as inputs. Both are acquired from previous DSS workflow steps. A virtual surface- and contour-based model of a vendor-specific ring design (26–40 mm) is generated. For each case, the ring geometry is positioned with respect to the original, patient-specific annulus and additional anatomical landmarks. The lumen mesh is parameterized to allow for a vertex-based deformation with respect to the user-defined annulus. Derived from post-interventional observations, specific deformation schemes are applied to atrium and ventricle and the lumen mesh is altered with respect to the ring location. For quantitative evaluation, the surface distance between the deformed lumen mesh and segmented post-operative echo lumen close to the annulus was computed for 11 datasets. The results indicate a good agreement. An arbitrary subset of six datasets was used for a qualitative evaluation of the complete lumen. Two domain experts compared the deformed lumen mesh with post-interventional echo images. All deformations were deemed plausible. Our approach on virtual downsizing allows for an automatic creation of plausible lumen deformations. As it takes only a few seconds to generate results, it can be added to a virtual intervention toolset without unnecessarily increasing the pipeline complexity.

The aim of this registry is to provide data on age-related clinical features of suspected myocarditis and to create a study platform allowing for deriving diagnostic criteria and, at a later stage, testing therapeutic interventions in patients with myocarditis.After an initial 6-month pilot phase, MYKKE was opened in June 2014 as a prospective multicenter registry for patients from pediatric heart centers, university hospitals, and community hospitals with pediatric cardiology wards in Germany. Inclusion criteria consisted of age18 years and hospitalization for suspected myocarditis as leading diagnosis at the discretion of the treating physician. By December 31, 2015, fifteen centers across Germany were actively participating and had enrolled 149 patients. Baseline data reveal 2 age peaks (2 years,12 years), show higher proportions of males, and document a high prevalence of severe disease courses in pediatric patients with suspected myocarditis. Severe clinical courses and early adverse events were more prevalent in younger patients and were related to severely impaired leftventricular ejection fraction at initial presentation.MYKKE represents a multicenter registry and research platform for children and adolescents with suspected myocarditis that achieve steady recruitment and generate a wide range of real-world data on clinical course, diagnostic workup, and treatment of this group of patients. The baseline data reveal the presence of 2 age peaks and provide important insights into the severity of disease in children with suspected myocarditis. In the future, MYKKE might facilitate interventional substudies by providing an established collaborating network using common diagnostic approaches.

The onset of wheals and/or angioedema following the exposure to cold may be associated with a number of different diseases. Most frequently this occurs in cold contact urticaria, a type of physical urticaria, which is characterized by a positive cold stimulation test. The clinical symptoms are based on cold-dependent mast cell activation with subsequent release of proinflammatory mediators. In cases of negative or atypical reaction to cold stimulation testing rare acquired atypical or familiar cold urticaria forms may be suspected. Strict avoidance of cold should be recommended as far as possible. As the underlying causes of cold contact urticaria are widely unknown, the symptomatic use of non-sedating antihistamines is the treatment of first choice. The very rare familiar cold auto-inflammatory syndrome (FCAS) is based on CIAS1/NLRP3 mutations and may be treated effectively by neutralization of pathogenic interleukin 1β.

Background Increased dosing of nonsedating antihistamines is recommended by the current European Academy of Allergology and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum guidelines on patients with acquired cold urticaria (ACU) who do not respond satisfactorily to the standard dose. Prospective data supporting this recommendation are scant. Objective We sought to assess the effects of 5 and 20 mg of desloratadine and placebo on cold-induced urticarial reactions in patients with ACU. Methods In this prospective, randomized, double-blind, 3-way crossover trial, patients with ACU (n = 30) received placebo, 5 mg of desloratadine, and 20 mg of desloratadine every day each for 7 days separated by 14-day washout periods. At the end of each treatment, patients underwent cold provocation with the TempTest 2.0/2.1 system, and urticarial reactions were assessed by using digital 3-dimensional time-lapse photography and thermography; the critical temperature threshold (CTT) and critical stimulation time threshold (CSTT) were measured. Adverse events (AEs) reported during the study were assessed. Results Compared with placebo, 7 days of desloratadine at 5 and 20 mg/d significantly reduced the volume of cold-induced wheals and areas of hyperthermic skin and improved CTT and CSTT results. Desloratadine at 20 mg/d significantly reduced cold-induced wheal volume and CTT and CSTT values versus desloratadine at 5 mg/d. Desloratadine was well tolerated, with no increased rate of somnolence or other AEs with 20 mg of desloratadine. Conclusions Desloratadine at standard and high doses significantly improved objective signs of ACU provoked by cold exposure. Desloratadine at 4 times the standard dose significantly reduced ACU lesion severity versus 5 mg of desloratadine without an increase in AEs. This study supports current guidelines that increased desloratadine dosing might benefit patients with urticaria who do not respond to standard doses.

TARA is an object-oriented program written in C++, which allows in an easy way a partial wave analysis of complicated multi-body final states as occurring in today's particle physics experiments. The main features are: full automatic generation of amplitudes at run time, unlimited spin of the resonances and initial states, decays with and without parity conservation, arbitrary dynamics, full LATEX-documentation of any function implemented, parameter documentation and control throughout the whole fit and visualization of the results.

Objectives: During the years, acute bacterial skin and skin structure infections (ABSSSIs) have seen an increase in incidence in many parts of the western world. Additionally, the treatment of ABSSSIs, generally consisting of surgical debridement or drainage and empiric antibiotics in the hospital, can be further complicated by emerging multi drug resistant bacteria, most notably methicillin-resistant Staphylococcus aureus (MRSA). As the incidence rates increase alongside with rising antibiotic resistance, ABSSSIs are becoming a significant burden for healthcare systems. This study aims to collect evidence on the healthcare resource utilization of ABSSSI and the economic implications of different treatment modalities for the management of these diseases. Methods: A systematic literature search in MEDLINE, Cochane and ISPOR abstract databases with predefined inclusion criteria and subsequent quality assessment was performed. Results: The search identified 1,799 unique publications of which 26 contained relevant economic data on ABSSSIs treatment and were therefore included in this manuscript. There were six healthcare resource utilization studies, 11 cost analyses, three cost-minimization and six cost-effectiveness analyses, of which only a single study reported quality adjusted life years. Vancomycin was evaluated in most studies (21), followed by linezolid (15), daptomycin (8) and others (7). Conclusions: This review provides an in-depth overview of the economic implications of current ABSSSI management. Major cost drivers of ABSSSI treatment were length of hospital stay and the overall cost associated with frequent intravenous antibiotics administration. While most studies (20) applied a hospital perspective, there was a substantial disparity on the specific costs in- or excluded in the analysis, and on the unit prices. This led to significant variations of the final cost outcomes. Notably, over 10-fold differences were found. The overall quality and comparability of the literature reviewed was sub-optimal, elevating the need for more high-quality and reproducible economic evaluations in the area of ABSSSIs.

The analysis of a particle physics experiment requires the correct selection of the desired multiplicity of charged (pions or kaons) and neutral (photons) particles. Due to fluctuations in hadronic and electromagnetic showers often too many photons are reconstructed by the analysis software. The combination of a feed forward neural network and a genetic algorithm is used to separate photons and fluctuations.

The onset of wheals and/or angioedema following the exposure to cold may be associated with a number of different diseases. Most frequently this occurs in cold contact urticaria, a type of physical urticaria, which is characterized by a positive cold stimulation test. The clinical symptoms are based on cold-dependent mast cell activation with subsequent release of proinflammatory mediators. In cases of negative or atypical reaction to cold stimulation testing rare acquired atypical or familiar cold urticaria forms may be suspected. Strict avoidance of cold should be recommended as far as possible. As the underlying causes of cold contact urticaria are widely unknown, the symptomatic use of non-sedating antihistamines is the treatment of first choice. The very rare familiar cold auto-inflammatory syndrome (FCAS) is based on CIAS1/NLRP3 mutations and may be treated effectively by neutralization of pathogenic interleukin 1beta.

OBJECTIVES: Erythropoietin has been widely adapted into clinical practice in orthopedic surgery to prevent anemia and ultimately lower the use of allogeneic blood transfusions. Its safety and efficacy has been shown in various randomized clinical trials. Questions regarding the cost-effectiveness of this treatment, however, have yet to be answered conclusively. Notably, current indication guidelines are based on preoperative hemoglobin levels, but do not differentiate between total hip arthroplasty (THA) and total knee arthroplasty (TKA). This literature review aims at analyzing the cost-effectiveness of preoperative erythropoietin as blood sparing measure in patients undergoing elective orthopedic surgery, specifically THA and TKA. Additionally, patient inclusion criteria are analyzed in order to identify the potentially most cost-effective patient subgroups, e.g. based on preoperative hemoglobin levels, primary or revisional surgery and THA versus TKA. METHODS: Systematic literature review. RESULTS: A MEDLINE database search and subsequent exclusion of irrelevant or inaccessible papers resulted in the inclusion of 8 research articles that at least partially performed a cost-effectiveness or cost-benefit analysis of erythropoietin in orthopedic surgery. Four of the studies concluded erythropoietin is not cost-effective, three studies were not able to draw a conclusion based on their data, and one study found erythropoietin cost-effective. CONCLUSIONS: We found that studies were difficult to compare, with inclusion criteria and comparators varying among studies. Notably, most economic evaluations were substantially lacking depth and did not comply with common guidelines for pharmacoeconomic research. Although some articles found erythropoietin generally not cost-effective, their data did suggest otherwise within certain patient subgroups. Patients with lower preoperative hemoglobin levels, primary surgery and THA benefitted the most from erythropoietin. Additionally, most studies seemed to overestimate treatment costs, using outdated prices or neglecting competitively priced biosimilars. Therefore, a more differentiated approach is required to elucidate the costeffectiveness of erythropoietin in orthopedic surgery, discriminating between total hip and knee arthroplasty.