👤 Uwe Zimmermann

Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p < 0.001), likelihood ratio test 236.3, df: 1, p < 0.001, showing a higher net benefit across almost all threshold probabilities. Adding the CAC score to CCTA findings in patients with stable chest pain improves the diagnostic performance in detecting CAD and the net benefit compared with CCTA alone. CAC scoring CT performed before coronary CTA and included in the diagnostic model can improve obstructive CAD diagnosis, especially when CCTA is non-diagnostic. • The combination of coronary artery calcium with coronary computed tomography angiography showed significantly higher AUC (87%, 95% confidence interval [CI]: 86 to 89%) for diagnosis of coronary artery disease compared to coronary computed tomography angiography alone (80%, 95% CI: 78 to 82%, p < 0.001). • Diagnostic improvement was mostly seen in patients with non-diagnostic C. • The improvement in diagnostic performance and the net benefit was consistent across age groups, chest pain types, and genders. Show less

For a drive unit for axes of robots and robot-like systems (RLS) usually a motor-gearbox arrangement is chosen due to its high-power density. The combination of a high-ratio gearbox and a high-speed electric motor ensures a very compact and efficient design of the drive train. The transmission properties primarily determine the properties of the axes and the whole robot system. Robots and RLS use various types of high-ratio precision gearboxes based on different operating principles. Due to the different operating principles, it is difficult to describe comparable properties across all different types. In addition, there are many influences on the properties which significantly determine their shapes and values. These influencing parameters are insufficiently documented and are often poorly accessible for profound comparability and further consideration. In this paper, an overview of the properties of robot gearboxes is given. Based on these properties, different robot gearboxes can be systematically evaluated and compared to one another. The properties are influenced by various design, operating or manufacturing factors such as the gearbox size, the operating torque and speed or the manufacturing process. In a further step, these influences on the most relevant properties, efficiency and stiffness, are determined and systematically evaluated. This evaluation is based on the specification data of various robot gearbox manufacturers. The properties efficiency and stiffness show a dependency on the gearbox size, the operating torque, speed as well as the ambient temperature and on the transmission ratio. The shown procedure can also be adapted to other properties. Show less

Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn's disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, and the number keeps increasing over time. IBD has a multifactorial etiology, from genetic to environmental factors. Most of the IBD treatments revolve around disease management, by reducing the inflammatory signals. We previously identified the surface layer protein A (SlpA) of Show less

Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10 Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD. Show less

HP1 is a structural component of heterochromatin. Mammalian HP1 isoforms HP1α, HP1β, and HP1γ play different roles in genome stability, but their precise role in heterochromatin structure is unclear. Analysis of Hp1α Show less

Histone H3 trimethylation of lysine 9 (H3K9me3) and proteins of the heterochromatin protein 1 (HP1) family are hallmarks of heterochromatin, a state of compacted DNA essential for genome stability and long-term transcriptional silencing. The mechanisms by which H3K9me3 and HP1 contribute to chromatin condensation have been speculative and controversial. Here we demonstrate that human HP1β is a prototypic HP1 protein exemplifying most basal chromatin binding and effects. These are caused by dimeric and dynamic interaction with highly enriched H3K9me3 and are modulated by various electrostatic interfaces. HP1β bridges condensed chromatin, which we postulate stabilizes the compacted state. In agreement, HP1β genome-wide localization follows H3K9me3-enrichment and artificial bridging of chromatin fibres is sufficient for maintaining cellular heterochromatic conformation. Overall, our findings define a fundamental mechanism for chromatin higher order structural changes caused by HP1 proteins, which might contribute to the plastic nature of condensed chromatin. Show less

The cationic, water-soluble quaternary trospium chloride (TC) is incompletely absorbed from the gut and undergoes wide distribution but does not pass the blood-brain barrier. It is secreted by the kidneys, liver, and intestine. To evaluate potential transport mechanisms for TC, we measured affinity of the drug to the human uptake and efflux transporters known to be of pharmacokinetic relevance. Affinity of TC to the uptake transporters OATP1A2, -1B1, -1B3, -2B1, OCT1, -2, -3, OCTN2, NTCP, and ASBT and the efflux carriers P-gp, MRP2 and MRP3 transfected in HEK293 and MDCK2 cells was measured. To identify relevant pharmacokinetic mechanisms in the bladder urothelium, mRNA expression of multidrug transporters, drug metabolizing enzymes, and nuclear receptors, and the uptake of TC into primary human bladder urothelium (HBU) cells were measured. TC was shown to be a substrate of OATP1A2 (Km = 6.9 ± 1.3 μmol/L; Vmax = 41.6 ± 1.8 pmol/mg·min), OCT1 (Km = 106 ± 16 μmol/L; Vmax = 269 ± 18 pmol/mg·min), and P-gp (Km = 34.9 ± 7.5 μmol/L; Vmax = 105 ± 9.1 pmol/mg·min, lipovesicle assay). The genetic OATP1A2 variants *2 and *3 were loss-of-function transporters for TC. The mRNA expression analysis identified the following transporter proteins in the human urothelium: ABCB1 (P-gp), ABCC1-5 (MRP1-5), ABCG2 (BCRP), SLCO2B1 (OATP2B1), SLCO4A1 (OATP4A1), SLC22A1 (OCT1), SLC22A3 (OCT3), SLC22A4 (OCTN1), SLC22A5 (OCTN2), and SLC47A1 (MATE1). Immuno-reactive P-gp and OATP1A2 were localized to the apical cell layers. Drug metabolizing enzymes CYP3A5, -2B6, -2B7 -2E1, SULT1A1-4, UGT1A1-10, and UGT2B15, and nuclear receptors NR1H3 and NR1H4 were also expressed on mRNA level. TC was taken up into HBU cells (Km = 18.5 ± 4.8 μmol/L; Vmax = 106 ± 11.3 pmol/mg·min) by mechanisms that could be synergistically inhibited by naringin (IC50 = 10.8 (8.4; 13.8) μmol/L) and verapamil (IC50 = 4.6 (2.8; 7.5) μmol/L), inhibitors of OATP1A2 and OCT1, respectively. Affinity of TC to OCT1 and P-glycoprotein may be the reason for incomplete oral absorption, wide distribution into liver and kidneys, and substantial intestinal and renal secretions. Absence of brain distribution may result from affinity to P-gp and a low affinity to OATP1A2. The human urothelium expresses many drug transporters and drug metabolizing enzymes that may interact with TC and other drugs eliminated into the urine. Show less