Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation.

Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well.

Preventive health examinations: protocol for a prospective cross-sectional study of German employees aged 45 to 59 years (Ü45-check).

Objective: Early identification of health-related risk factors is of great importance for maintaining workability. Screening examinations can help to detect diseases at an early stage and provide more needs-based recommendations. This study aims (1) to assess the individual need for prevention or rehabilitation based on preventive health examinations compared to a questionnaire survey, (2) to assess the results of the preventive health examinations compared to the Risk Index - Disability Pension (RI-DP), (3) to assess the results of the questionnaire survey compared to the RI-DP, (4) to assess the general health status of the sample (target population > 1,000) in German employees aged 45-59, (5) to identify the most common medical conditions. A further study question aims, and (6) to investigate the general health status of the specific occupational groups. Methods: Comprehensive diagnostics including medical examination, anamnesis, anthropometric measurements, bioelectrical impedance analysis (BIA), handgrip strength, resting electrocardiogram (ECG), resting blood pressure, pulse wave velocity (PWV), and laboratory blood analyses added by a questionnaire are conducted. The research questions are analyzed in an exploratory manner. Results and conclusion: We expect that the results will allow us to formulate recommendations regarding screening for prevention and rehabilitation needs on a more evidence-based level.Clinical Trial Registration: DRKS ID: DRKS00030982.

Topography stitching in the spatial frequency domain for the representation of mid-spatial frequency errors.

Sub-aperture fabrication techniques such as diamond turning, ion beam figuring, and bonnet polishing are indispensable tools in today's optical fabrication chain. Each of these tools addresses different figure and roughness imperfections corresponding to a broad spatial frequency range. Their individual effects, however, cannot be regarded as completely independent from each other due to the concurrent formation of form and finish errors, particularly in the mid-spatial frequency (MSF) region. Deterministic Zernike polynomials and statistical power spectral density (PSD) functions are often used to represent form and finish errors, respectively. Typically, both types of surface errors are treated separately when their impact on optical performance is considered: (i) wave aberrations caused by figure errors and (ii) stray light resulting from surface roughness. To fill the gap between deterministic and statistical descriptions, a generalized surface description is of great importance for bringing versatility to the entire optical fabrication chain by enabling easy and quick exchange of surface topography data between three disciplines: optical design, manufacturing, and characterization. In this work, we present a surface description by stitching the amplitude and unwrapped phase spectra of several surface topography measurements at different magnifications. An alternative representation of surface errors at different regimes is proposed, allowing us to bridge the gap between figure and finish as well as to describe the well-known MSF errors.

Rapid Inflammasome Activation Is Attenuated in Post-Myocardial Infarction Monocytes.

Inflammasomes are crucial gatekeepers of the immune response, but their maladaptive activation associates with inflammatory pathologies. Besides canonical activation, monocytes can trigger non-transcriptional or rapid inflammasome activation that has not been well defined in the context of acute myocardial infarction (AMI). Rapid transcription-independent inflammasome activation induced by simultaneous TLR priming and triggering stimulus was measured by caspase-1 (CASP1) activity and interleukin release. Both classical and intermediate monocytes from healthy donors exhibited robust CASP1 activation, but only classical monocytes produced high mature interleukin-18 (IL18) release. We also recruited a limited number of coronary artery disease (CAD, n=31) and AMI (n=29) patients to evaluate their inflammasome function and expression profiles. Surprisingly, monocyte subpopulations isolated from blood collected during percutaneous coronary intervention (PCI) from AMI patients presented diminished CASP1 activity and abrogated IL18 release despite increased NLRP3 gene expression. This unexpected attenuated rapid inflammasome activation was accompanied by a significant increase of TNFAIP3 and IRAKM expression. Moreover, TNFAIP3 protein levels of circulating monocytes showed positive correlation with high sensitive troponin T (hsTnT), implying an association between TNFAIP3 upregulation and the severity of tissue injury. We suggest this monocyte attenuation to be a protective phenotype aftermath following a very early inflammatory wave in the ischemic area. Damage-associated molecular patterns (DAMPs) or other signals trigger a transitory negative feedback loop within newly recruited circulating monocytes as a mechanism to reduce post-injury tissue damage.

Preclinical assessment of a modified Occlutech left atrial appendage closure device in a porcine model.

Left atrial appendage (LAA) closure is being developed as an alternative for stroke prevention in patients with atrial fibrillation that cannot tolerate long-term oral anticoagulation. To assess the feasibility, safety, and performance of a novel modified Occlutech LAA closure device in a preclinical porcine model, the modified Occlutech modified Occlutech Plus LAA closure device was implanted in 12 female pigs (25-39 kg body weight) under fluoroscopic and transesophageal echocardiography (TEE) guidance. Procedural and technical success, as well as safety of LAA closure, were evaluated peri-procedurally and after 4, 8, and 12 weeks. Moreover, after 4, 8 and, 12 weeks animals were sacrificed for pathological analysis (e.g., thrombus formation, device ingrowth, endothelialization, and inflammation). All LAA closure devices were successfully implanted. On follow-up, no serious adverse events such as device-associated thrombus or translocalization/embolization were observed. A clinically non-significant pericarditis was observed in 4 animals at the time of autopsy. Endothelialization of the device was visible after 4 weeks, advanced after 8 weeks and completed after 12 weeks. Immunohistochemistry showed low amounts of inflammatory infiltration on the edges of the device. The results of this study indicate that implantation of a modified Occlutech LAA closure device is feasible with rapid endothelialization and low inflammatory infiltration in a porcine model. Human data are needed to further characterize safety and efficacy.

Compensation for general asymmetric static loads for a complete optical system of freeform mirrors.

Optical systems consisting of freeform metal mirrors are state of the art in optical engineering. The freeform shapes allow for more compact designs and offer more degrees of freedom for aberration correction. The metal components allow for the relocation of the effort from the integration to the fabrication stage. Metal mirrors for spaceborne optical systems experience several loads during orbital commissioning or operation. The present paper focuses on describing general static loads within the optical design to close the iteration loop between optical and mechanical design using this knowledge to investigate how to compensate for load-induced surface shape errors within the optical design. First, this analysis is performed for a two-mirror system with an asymmetric force load step. Second, the compensation for this load is discussed by performing another optical design step or a direct mechanical compensation step at mechanical design level. Since thermal loads usually introduce expansion effects, a third point of the paper is the discussion of thermal loads with some general results, to embed them into the shown formalism. The paper concludes by showing residual optical errors of the compensated optical system and comparing them with the nominal design.

Structure-function relationships of HDL in diabetes and coronary heart disease.

High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HDL, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function. Second, different cellular functions of HDL are weakly correlated with each other and determined by different structural components. Cholesterol efflux capacity (CEC) was no proxy of other functions. Third, 3 potentially novel determinants of HDL function were identified and validated by the use of artificially reconstituted HDL, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation-induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes.

Angular resolved power spectral density analysis for improving mirror manufacturing.

Ultra-precise diamond turning is the method of choice for manufacturing freeform optics. Analyzing surface errors in different spatial frequency ranges has mainly been performed in a one-dimensional representation of the power spectral density function. However, the advanced machine dynamics at the fabrication of freeform mirrors result in highly anisotropic surfaces with regular ripples in different orientations. To properly analyze the entire surface in the frequency regime, a new way of representing the two-dimensional power spectral density is introduced in this paper. This novel tool is utilized for the evaluation of an example freeform mirror.

Theoretical compensation of static deformations of freeform multimirror substrates.

Varying temperatures influence the figure errors of freeform metal mirrors by thermal expansion. Furthermore, different materials lead to thermo-elastic bending effects. The paper presents a derivation of a compensation approach for general static loads. Utilizing perturbation theory, this approach works for shape compensation of substrates that operate in various temperature environments. Verification is made using a finite element analysis, which is further used to produce manufacturable CAD models. The remaining low spatial frequency errors are deterministically correctable using diamond turning or polishing techniques.

[Recent and upcoming randomized trials for left atrial appendage occlusion : Need for a definite assessment of the situation]. / Aktuelle und zukünftige randomisierte Studien zum Vorhofohr-Okkluder : Notwendigkeit einer definitiven Standortbestimmung.

Atrial fibrillation (AF) is the most common arrhythmia affecting more than 1.6 million patients in Germany. Based on demographic developments, an the number is expected to increase. Embolic strokes in AF patients are particularly severe, and individualized new oral anticoagulant (NOAC) therapy reduces the incidence of stroke in these patients by approximately 70%. Besides vitamin K antagonists, the NOACs rivaroxaban, dabigatran, apixaban, and edoxaban have been introduced into clinical practice; however, major bleeding still occurs at a rate of 2-3% per year. Moreover, randomized studies and real-life registries suggest that >20% of patients with AF and an indication for anticoagulation cannot tolerate chronic oral anticoagulant therapy. Therefore, an alternative method for stroke prevention in AF patients has been developed, i. e., catheter-based exclusion of the left atrial appendage (LAA), a location that is prone for thrombus formation in these patients. The randomized trials of catheter-based LAA occlusion have compared this interventional therapy with vitamin K antagonists. In the future, however, LAA exclusion needs to be compared with NOAC therapy. Moreover, percutaneous LAA exclusion in clinical practice is mostly offered to patients ineligible for long-term oral anticoagulation or with high bleeding risk. However, no controlled, randomized trial data exist for this patient population. These data are needed for appropriate clinical judgment and optimal clinical management. Ongoing studies and scientific questions that are important to define the future for catheter-based LAA closure are discussed in this review.

Description and reimplementation of real freeform surfaces.

Freeform surfaces are becoming an increasingly exciting opportunity in optical design, in particular when correcting systems with off-axis geometries. Nevertheless, especially when coming to commercial use, the challenges for manufacturing are difficult to handle. The optical quality of a system is perturbed by typical deformations, such as localized figure errors and regular mid-spatial-frequency ripples, that come from the diamond-turning process. In this proposal, we investigated a workflow for analyzing the impact of real optical surfaces on the optical performance for even complex systems. Based on a simple and robust description, the surface is implemented back into the design. While the more localized deviations are analytically described by radial basis functions, the residual ripple structures are covered by a new approach based on the power spectral density. The reimport of optical surfaces back into the design software allows simple estimations for the requirements on manufacturing and the analysis of the realistic impact on system performance.