Publications by authors named "Andreas Koch"

184 Publications

An Updated Narrative Review on Ergometric Systems Applied to Date in Assessing Divers' Fitness.

Healthcare (Basel) 2021 Aug 13;9(8). Epub 2021 Aug 13.

Forschungsgruppe Experimentelle Chirurgie, Universitäts-Klinikum Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.

Many recreational divers suffer medical conditions, potentially jeopardizing their safety. To scale down risks, medical examinations are mandatory and overwhelmingly performed using bicycle ergometry, which overlooks some important aspects of diving. Searching ergometric systems that better address the underwater environment, a systematic literature search was conducted using the keywords 'diving', 'fitness', 'ergometry', and 'exertion'. All presented alternative systems found convincingly describe a greatly reduced underwater physical performance. Thus, if a diver's workload in air should already be limited, he/she will suffer early from fatigue, risking a diving incident. How to assess fitness? Performance diagnostics in sports is always specific for a modality or movement. Therefore, professional scuba divers should be tested when fin-swimming underwater. For the vast number of recreational divers, the current screening can likely not be replaced. However, to prevent accidents, divers need to understand and be able to improve factors that limit their physical performance underwater. Other systems, presented here, will continue to be important tools in underwater research.
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http://dx.doi.org/10.3390/healthcare9081044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394438PMC
August 2021

Quantification of σ-Acceptor and π-Donor Stabilization in , and Hal Analogues of -Heterocyclic Carbenes (NHCs) on the Magnetic Criterion.

J Phys Chem A 2021 Aug 13;125(33):7235-7245. Epub 2021 Aug 13.

Department of Chemistry of the University of Potsdam, Karl-Liebknecht-Str. 24-25, Potsdam(Golm) D-14476, Germany.

The spatial magnetic properties, through-space NMR shieldings (TSNMRSs), of stable , and Hal analogues of -heterocyclic carbenes (NHCs) have been calculated using the GIAO perturbation method employing the nucleus-independent chemical shift (NICS) concept and the results visualized as iso-chemical-shielding surfaces (ICSSs) of various sizes and directions. The TSNMRS values (actually the anisotropy effects measurable in H NMR spectroscopy) are employed to qualify and quantify the position of the present mesomeric equilibria (carbenes ↔ ylides). The results are confirmed by geometry (bond angles and bond lengths), IR spectra, UV spectra, and C chemical shifts of the electron-deficient carbon centers.
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http://dx.doi.org/10.1021/acs.jpca.1c05257DOI Listing
August 2021

Accelerating AutoDock4 with GPUs and Gradient-Based Local Search.

J Chem Theory Comput 2021 Feb 6;17(2):1060-1073. Epub 2021 Jan 6.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United States.

AutoDock4 is a widely used program for docking small molecules to macromolecular targets. It describes ligand-receptor interactions using a physics-inspired scoring function that has been proven useful in a variety of drug discovery projects. However, compared to more modern and recent software, AutoDock4 has longer execution times, limiting its applicability to large scale dockings. To address this problem, we describe an OpenCL implementation of AutoDock4, called AutoDock-GPU, that leverages the highly parallel architecture of GPU hardware to reduce docking runtime by up to 350-fold with respect to a single-threaded process. Moreover, we introduce the gradient-based local search method ADADELTA, as well as an improved version of the Solis-Wets random optimizer from AutoDock4. These efficient local search algorithms significantly reduce the number of calls to the scoring function that are needed to produce good results. The improvements reported here, both in terms of docking throughput and search efficiency, facilitate the use of the AutoDock4 scoring function in large scale virtual screening.
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http://dx.doi.org/10.1021/acs.jctc.0c01006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063785PMC
February 2021

Hard x-ray single-shot spectrometer at the European X-ray Free-Electron Laser.

Rev Sci Instrum 2020 Oct;91(10):103101

European X-Ray Free-Electron Laser Facility GmbH, Holzkoppel 4, 22869 Schenefeld, Germany.

The European X-ray Free-Electron Laser Facility in Germany delivers x-ray pulses with femtosecond pulse duration at a repetition rate of up to 4.5 MHz. The free-electron laser radiation is created by the self-amplified spontaneous emission (SASE) process, whose stochastic nature gives rise to shot-to-shot fluctuations in most beam properties, including spectrum, pulse energy, spatial profile, wavefront, and temporal profile. Each spectrum consisting of many spikes varies in width and amplitude that appear differently within the envelope of the SASE spectrum. In order to measure and study the SASE spectrum, the HIgh REsolution hard X-ray single-shot (HIREX) spectrometer was installed in the photon tunnel of the SASE1 undulator beamline. It is based on diamond gratings, bent crystals as a dispersive element, and a MHz-repetition-rate strip detector. It covers a photon energy range of 3 keV-25 keV and a bandwidth of 0.5% of the SASE beam. The SASE spikes are resolved with 0.15 eV separation using the Si 440 reflection, providing a resolving power of 60 000 at a photon energy of 9.3 keV. The measured SASE bandwidth is 25 eV. In this paper, we discuss the design specifications, installation, and commissioning of the HIREX spectrometer. The spectral results using Si (110), Si (111), and C (110) crystals are presented.
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http://dx.doi.org/10.1063/5.0019935DOI Listing
October 2020

Expansion of CD161 expressing CD8+ single-positive and CD4+CD8+ double-positive PR3-specific T-cells in granulomatosis with polyangiitis.

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):182-183. Epub 2020 Sep 16.

University of Lübeck, Department of Rheumatology and Clinical Immunology, Lübeck, Germany.

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July 2021

Outcomes of a new slowly resorbable biosynthetic mesh (Phasix™) in potentially contaminated incisional hernias: A prospective, multi-center, single-arm trial.

Int J Surg 2020 Nov 12;83:31-36. Epub 2020 Sep 12.

Erasmus University Medical Centre Rotterdam, Department of Surgery, Rotterdam, The Netherlands.

Background: Resorbable biomaterials have been developed to reduce the amount of foreign material remaining in the body after hernia repair over the long-term. However, on the short-term, these resorbable materials should render acceptable results with regard to complications, infections, and reoperations to be considered for repair. Additionally, the rate of resorption should not be any faster than collagen deposition and maturation; leading to early hernia recurrence. Therefore, the objective of this study was to collect data on the short-term performance of a new resorbable biosynthetic mesh (Phasix™) in patients requiring Ventral Hernia Working Group (VHWG) Grade 3 midline incisional hernia repair.

Materials And Methods: A prospective, multi-center, single-arm trial was conducted at surgical departments in 15 hospitals across Europe. Patients aged ≥18, scheduled to undergo elective Ventral Hernia Working Group Grade 3 hernia repair of a hernia larger than 10 cm were included. Hernia repair was performed with Phasix™ Mesh in sublay position when achievable. The primary outcome was the rate of surgical site occurrence (SSO), including infections, that required intervention until 3 months after repair.

Results: In total, 84 patients were treated with Phasix™ Mesh. Twenty-two patients (26.2%) developed 32 surgical site occurrences. These included 11 surgical site infections, 9 wound dehiscences, 7 seromas, 2 hematomas, 2 skin necroses, and 1 fistula. No significant differences in surgical site occurrence development were found between groups repaired with or without component separation technique, and between clean-contaminated or contaminated wound sites. At three months, there were no hernia recurrences.

Conclusion: Phasix™ Mesh demonstrated acceptable postoperative surgical site occurrence rates in patients with a Ventral Hernia Working Group Grade 3 hernia. Longer follow-up is needed to evaluate the recurrence rate and the effects on quality of life. This study is ongoing through 24 months of follow-up.
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http://dx.doi.org/10.1016/j.ijsu.2020.08.053DOI Listing
November 2020

GPU-Accelerated Drug Discovery with Docking on the Summit Supercomputer: Porting, Optimization, and Application to COVID-19 Research.

ArXiv 2020 Jul 6. Epub 2020 Jul 6.

Protein-ligand docking is an in silico tool used to screen potential drug compounds for their ability to bind to a given protein receptor within a drug-discovery campaign. Experimental drug screening is expensive and time consuming, and it is desirable to carry out large scale docking calculations in a high-throughput manner to narrow the experimental search space. Few of the existing computational docking tools were designed with high performance computing in mind. Therefore, optimizations to maximize use of high-performance computational resources available at leadership-class computing facilities enables these facilities to be leveraged for drug discovery. Here we present the porting, optimization, and validation of the AutoDock-GPU program for the Summit supercomputer, and its application to initial compound screening efforts to target proteins of the SARS-CoV-2 virus responsible for the current COVID-19 pandemic.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359529PMC
July 2020

Assessment of a dive incident using heart rate variability.

Diving Hyperb Med 2020 Jun;50(2):157-163

Forschungsgruppe Experimentelle Chirurgie, Universitäts-Klinikum, Düsseldorf, Germany.

Introduction: Scuba diving likely has an impact on the autonomic nervous system (ANS). In the course of conducting trials of underwater ECG recording for measurement of heart rate variability, there was an unexpected stressful event; one participant's regulator iced and began to free-flow.

Methods: A custom-made, water- and pressure-tight aluminum housing was used to protect a portable Holter monitor. ECGs were recorded in three experienced divers who witnessed an unplanned moderately stressful incident during diving. The ECG signals were analysed for measures of heart rate variability (HRV).

Results: Analysis for different short-term HRV measures provided consistent results if periods of interest were appropriately time-aligned. There was improvement in sympatho-vagal balance. One diver unexpectedly exhibited an increase in both sympathetic and vagal activity shortly after the incident.

Conclusions: A conventional open-water dive affected the ANS of experienced recreational divers as measured by HRV which provides a global evaluation of the ANS and alterations in its two branches. The heart rate variability data gathered from several participating divers around the time of this event illustrate the potential utility of this variable in quantifying stress during diving. HRV data may be useful in addressing relevant diving related questions such as effects of cold, exercise or different breathing gases on ANS function.
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http://dx.doi.org/10.28920/dhm50.2.157-163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481106PMC
June 2020

Synthesis and Conformational Analysis of Naphthoxazine-Fused Phenanthrene Derivatives.

Molecules 2020 May 28;25(11). Epub 2020 May 28.

Institute of Pharmaceutical Chemistry and MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.

The synthesis of new phenanthr[9,10-][1,3]oxazines was achieved by the direct coupling of 9-phenanthrol with cyclic imines in the modified -Friedel-Crafts reaction followed by the ring closure of the resulting bifunctional aminophenanthrols with formaldehyde. Aminophenanthrol-type Mannich bases were synthesised and transformed to phenanthr[9,10-][1,3]oxazines via [4 + 2] cycloaddition. Detailed NMR structural analyses of the new polyheterocycles as well as conformational studies including Density Functional Theory (DFT) modelling were performed. The relative stability of -quinone methides (-QMs) was calculated, the geometries obtained were compared with the experimentally determined NMR structures, and thereby, the regioselectivity of the reactions has been assigned.
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http://dx.doi.org/10.3390/molecules25112524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321197PMC
May 2020

Magnetic-Based Enrichment of Rare Cells from High Concentrated Blood Samples.

Cancers (Basel) 2020 Apr 10;12(4). Epub 2020 Apr 10.

Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.

Here, we tested two magnetic-bead based systems for the enrichment and detection of rare tumor cells in concentrated blood products. For that, the defined numbers of cells from three pancreatic cancer cell lines were spiked in 10 peripheral blood mononuclear cells (PBMNCs) concentrated in 1 mL, mimicking diagnostic leukapheresis (DLA) samples, and samples were processed for circulating tumor cells (CTC) enrichment with the IsoFlux or the KingFisher systems, using different types of magnetic beads from the respective technology providers. Beads were conjugated with different anti-EpCAM and MUC-1 antibodies. Recovered cells were enumerated and documented by fluorescent microscopy. For the IsoFlux system, best performance was obtained with IsoFlux CTC enrichment kit, but these beads compromised the subsequent immunofluorescence staining. For the KingFisher system, best recoveries were obtained using Dynabeads Biotin Binder beads. These beads also allowed one to capture CTCs with different antibodies and the subsequent immunofluorescence staining. KingFisher instrument allowed a single and streamlined protocol for the enrichment and staining of CTCs that further prevented cell loss at the enrichment/staining interface. Both IsoFlux and KingFisher systems allowed the enrichment of cell line cells from the mimicked-DLA samples. However, in this particular experimental setting, the recovery rates obtained with the KingFisher system were globally higher, the system was more cost-effective, and it allowed higher throughput.
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http://dx.doi.org/10.3390/cancers12040933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225976PMC
April 2020

Bent Allenes or Di-1,3-betaines-An Answer Given on the Magnetic Criterion.

J Phys Chem A 2020 Apr 9;124(16):3180-3190. Epub 2020 Apr 9.

Institut für Chemie, Universität Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam (Golm), Germany.

The spatial magnetic properties, through-space NMR shieldings (TSNMRS), of bent allene , the corresponding C-extended 1,3-butadiene derivative , and a number of related compounds have been calculated using the gauge-independent atomic orbital perturbation method, employing the nucleus-independent chemical shift concept and visualized as isochemical shielding surfaces of various sizes and directions. Prior to that, both structures and C chemical shifts were calculated and compared with available experimental bond lengths and δ(C)/ppm values (also, as a quality criterion for the computed structures). Bond lengths, the δ(C)/ppm, and the TSNMRS values are employed to qualify and quantify the electronic structure of the studied compounds in terms of dative or classical electron-sharing bonds.
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http://dx.doi.org/10.1021/acs.jpca.0c01392DOI Listing
April 2020

The C chemical shift and the anisotropy effect of the carbene electron-deficient centre: Simple means to characterize the electron distribution of carbenes.

Magn Reson Chem 2020 03 6;58(3):280-292. Epub 2020 Jan 6.

Institut für Chemie, Universität Potsdam, Potsdam, Germany.

Both the C chemical shift and the calculated anisotropy effect (spatial magnetic properties) of the electron-deficient centre of stable, crystalline, and structurally characterized carbenes have been employed to unequivocally characterize potential resonance contributors to the present mesomerism (carbene, ylide, betaine, and zwitter ion) and to determine quantitatively the electron deficiency of the corresponding carbene carbon atom. Prior to that, both structures and C chemical shifts were calculated and compared with the experimental δ( C)/ppm values and geometry parameters (as a quality criterion for obtained structures).
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http://dx.doi.org/10.1002/mrc.4979DOI Listing
March 2020

Characterization of glycolysis-related gene expression in malignant melanoma.

Pathol Res Pract 2020 Jan 18;216(1):152752. Epub 2019 Nov 18.

Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, Germany; Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany. Electronic address:

Malignant melanoma exhibits a distinct metabolic phenotype with high glycolytic activity. Previously, we have shown that glucose transporter isoform 1 (GLUT1) favors growth and metastasis of malignant melanoma. In this study, we investigated the expression of GLUT1 and the further glycolysis-related genes hexokinase 1 and 2 (HK1, HK2), lactate dehydrogenase A (LDH-A) and monocarboxylate transporters 1 and 4 (MCT1, MCT4) in eleven human melanoma cell lines under normoxic and hypoxic conditions. Furthermore, a set of 25 human malignant melanoma tissue samples was analyzed. Under hypoxic conditions, we could observe a significant upregulation of hypoxia-inducible factor 1 alpha (HIF-1a) target genes GLUT1, HK2 and LDH-A, but not MCT4. While under normoxic conditions the expression of glycolysis-related genes showed no correlation with origin or BRAF mutation status, GLUT1 expression was significantly elevated in metastatic and BRAF-V600E mutated melanoma cell lines under hypoxic conditions. Furthermore, GLUT1 expression in human melanoma tissue samples correlated significantly with HK1, LDH-A and MCT1 expression, confirming a glycolytic phenotype. Notably, Cyclin D1 expression, which is used as a prognostic marker for the outcome of melanoma patients, as it is associated with proliferation and invasiveness of melanoma, significantly correlated with GLUT1, HK1, LDH-A and MCT1 expression. In summary, our findings provide further evidence that enhanced glycolytic activity in melanoma favors disease progression and is an attractive therapeutic target for this highly aggressive tumor.
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http://dx.doi.org/10.1016/j.prp.2019.152752DOI Listing
January 2020

Does oxygen-enriched air better than normal air improve sympathovagal balance in recreational divers?An open-water study.

Res Sports Med 2020 Jul-Sep;28(3):397-412. Epub 2019 Nov 24.

Forschungsgruppe Experimentelle Chirurgie, Universitäts-Klinikum Düsseldorf , Düsseldorf, Germany.

Effects of the hyperbaric environment on the autonomic nervous system (ANS) in recreational divers are not firmly settled. Aim of this exploratory study was to (1) assess ANS changes during scuba diving via recordings of electrocardiograms (ECG) and to (2) study whether nitrox40 better improves sympathovagal balance over air. 13 experienced divers (~40yrs) performed two open-water dives each breathing either air or nitrox40 (25m/39min). 3-channel ECGs were recorded using a custom-made underwater Holter-monitor. The underwater Holter system proved to be safe. Air consumption exceeded nitrox40 consumption by 12% (n = 13; p < 0.05). Both air and nitrox40 dives reduced HR (10 vs 13%; p < 0.05). The overall HRV (pNN50: 82 vs 126%; p < 0.05) and its vagal proportion (RMSSD: 33 vs 50%; p < 0.05) increased during the dive. Moreover, low (LF: 61 vs 47%) and high (HF: 71 vs 140%) frequency power were increased (all p < 0.05), decreasing the ratio of LF to HF (22 vs 34%). : Conventional open-water dives distinctly affect the ANS in experienced recreational divers, with sympathetic activation less pronounced than vagal activation thereby improving the sympathovagal balance. Nitrox40 delivered two positive results: nitrox40 consumption was lower than air consumption, and nitrox40 better improved the sympathovagal balance over air.
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http://dx.doi.org/10.1080/15438627.2019.1694930DOI Listing
December 2020

D3R Grand Challenge 4: prospective pose prediction of BACE1 ligands with AutoDock-GPU.

J Comput Aided Mol Des 2019 12 6;33(12):1071-1081. Epub 2019 Nov 6.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, USA.

In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of AutoDock4 implemented in OpenCL, which features a gradient-based local search. The pose prediction challenge was organized in two stages. In Stage 1a, the protein conformations associated with each of the ligands were undisclosed, so we docked each ligand to a set of eleven receptor conformations, chosen to maximize the diversity of binding pocket topography. Protein conformations were made available in Stage 1b, making it a re-docking task. For all calculations, macrocyclic conformations were sampled on the fly during docking, taking the target structure into account. To leverage information from existing structures containing BACE1 bound to ligands available in the PDB, we tested biased docking and pose filter protocols to facilitate poses resembling those experimentally determined. Both pose filters and biased docking resulted in more accurate docked poses, enabling us to predict for both Stages 1a and 1b ligand poses within 2 Å RMSD from the crystallographic pose. Nevertheless, many of the ligands could be correctly docked without using existing structural information, demonstrating the usefulness of physics-based scoring functions, such as the one used in AutoDock4, for structure based drug design.
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http://dx.doi.org/10.1007/s10822-019-00241-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325737PMC
December 2019

Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4.

J Comput Aided Mol Des 2019 12 6;33(12):1011-1020. Epub 2019 Nov 6.

Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, USA.

Molecular docking has been successfully used in computer-aided molecular design projects for the identification of ligand poses within protein binding sites. However, relying on docking scores to rank different ligands with respect to their experimental affinities might not be sufficient. It is believed that the binding scores calculated using molecular mechanics combined with the Poisson-Boltzman surface area (MM-PBSA) or generalized Born surface area (MM-GBSA) can predict binding affinities more accurately. In this perspective, we decided to take part in Stage 2 of the Drug Design Data Resource (D3R) Grand Challenge 4 (GC4) to compare the performance of a quick scoring function, AutoDock4, to that of MM-GBSA in predicting the binding affinities of a set of [Formula: see text]-Amyloid Cleaving Enzyme 1 (BACE-1) ligands. Our results show that re-scoring docking poses using MM-GBSA did not improve the correlation with experimental affinities. We further did a retrospective analysis of the results and found that our MM-GBSA protocol is sensitive to details in the protein-ligand system: (i) neutral ligands are more adapted to MM-GBSA calculations than charged ligands, (ii) predicted binding affinities depend on the initial conformation of the BACE-1 receptor, (iii) protonating the aspartyl dyad of BACE-1 correctly results in more accurate binding affinity predictions.
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http://dx.doi.org/10.1007/s10822-019-00240-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027993PMC
December 2019

Identification of strontium in the merger of two neutron stars.

Nature 2019 10 23;574(7779):497-500. Epub 2019 Oct 23.

INAF, Astrophysics and Space Science Observatory, Bologna, Italy.

Half of all of the elements in the Universe that are heavier than iron were created by rapid neutron capture. The theory underlying this astrophysical r-process was worked out six decades ago, and requires an enormous neutron flux to make the bulk of the elements. Where this happens is still debated. A key piece of evidence would be the discovery of freshly synthesized r-process elements in an astrophysical site. Existing models and circumstantial evidence point to neutron-star mergers as a probable r-process site; the optical/infrared transient known as a 'kilonova' that emerges in the days after a merger is a likely place to detect the spectral signatures of newly created neutron-capture elements. The kilonova AT2017gfo-which was found following the discovery of the neutron-star merger GW170817 by gravitational-wave detectors-was the first kilonova for which detailed spectra were recorded. When these spectra were first reported, it was argued that they were broadly consistent with an outflow of radioactive heavy elements; however, there was no robust identification of any one element. Here we report the identification of the neutron-capture element strontium in a reanalysis of these spectra. The detection of a neutron-capture element associated with the collision of two extreme-density stars establishes the origin of r-process elements in neutron-star mergers, and shows that neutron stars are made of neutron-rich matter.
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http://dx.doi.org/10.1038/s41586-019-1676-3DOI Listing
October 2019

[Diagnostic algorithm "FAI and sports hernia" : Results of the consensus meeting for groin pain in athletes].

Orthopade 2020 Mar;49(3):211-217

Hernienzentrum 3+CHIRURGEN, Klosterstraße 34/35, 13581, Berlin, Deutschland.

As a result of the complexity and diversity of diseases in the region of the groin, differentiation of the various soft-tissue and bone pathologies remains a challenge for differential diagnosis in routine clinical practice. In the case of athletes with pain localized in the area of the groin, femoroacetabular impingement (FAI) and athlete's groin must be considered as important causes of the groin pain, whereby the common occurrence of double pathologies further complicates diagnosis. Despite the importance of groin pain and its differential diagnoses in everyday clinical practice, there has been a lack of recognized recommendations for diagnostic procedure to date. To this end, a consensus meeting was held in February 2017, in which a group composed equally of groin and hip surgeons took part. With the formulation of recommendations and the establishment of a practicable diagnostic path, colleagues that are involved in treating such patients should be sensitized to this issue and the quality of the diagnosis of groin pain improved in routine clinical practice.
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http://dx.doi.org/10.1007/s00132-019-03775-wDOI Listing
March 2020

Operation of photon diagnostic imagers for beam commissioning at the European XFEL.

J Synchrotron Radiat 2019 Sep 19;26(Pt 5):1489-1495. Epub 2019 Aug 19.

European XFEL, 22869 Schenefeld, Germany.

X-ray photon beam diagnostic imagers are located at 24 positions in the European XFEL beam transport system to characterize the X-ray beam properties, and to give feedback for tuning and optimization of the electron acceleration and orbit, the undulators, and the X-ray optics. One year of commissioning allowed experience to be gained with these imagers, which will be reported here. The sensitive Spontaneous Radiation imager is useful for various investigations in spontaneous radiation mode: for undulator adjustments and for low-signal imaging applications. The high-resolution Free-Electron Laser imager, 10 µm spatial resolution, is extensively used for the monitoring of beam position, spot size and shape, gain curve measurements, and also for beam-intensity monitoring. The wide field-of-view pop-in monitors (up to 200 mm) are regularly used for alignment and tuning of the various X-ray optical components like mirrors, slits and monochromators, and also for on-line beam control of a stable beam position at the instruments. The Exit Slit imager after the soft X-ray monochromator provides spectral information of the beam together with multi-channel plate based single-pulse gating. For particular use cases, these special features of the imagers are described. Some radiation-induced degradation of scintillators took place in this initial commissioning phase, providing useful information for better understanding of damage thresholds. Visible-light radiation in the beam pipe generated by upstream bending magnets caused spurious reflections in the optical system of some of the imagers which can be suppressed by aluminium-coated scintillating screens.
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http://dx.doi.org/10.1107/S1600577519008737DOI Listing
September 2019

X-ray photon diagnostics at the European XFEL.

J Synchrotron Radiat 2019 Sep 2;26(Pt 5):1422-1431. Epub 2019 Aug 2.

Joint Institute for Nuclear Research (JINR), Joliot-Curie Straße 6, Dubna, Moscow Region 141980, Russian Federation.

The European X-ray Free-Electron Laser (European XFEL) (Altarelli et al., 2006; Tschentscher et al., 2017), the world's largest and brightest X-ray free-electron laser (Saldin et al., 1999; Pellegrini et al., 2016), went into operation in 2017. This article describes the as-built realization of photon diagnostics for this facility, the diagnostics commissioning and their application for commissioning of the facility, and results from the first year of operation, focusing on the SASE1 beamline, which was the first to be commissioned. The commissioning consisted of pre-beam checkout, first light from the bending magnets, X-rays from single undulator segments, SASE tuning with many undulator segments, first lasing, optics alignment for FEL beam transport through the tunnel up to the experiment hutches, and finally beam delivery to first users. The beam properties assessed by photon diagnostics throughout these phases included per-pulse intensity, beam position, shape, lateral dimensions and spectral properties. During this time period, the machine provided users with up to 14 keV photon energy, 1.5 mJ pulse energy, 300 FEL pulses per train and 4.5 MHz intra-bunch train repetition rate at a 10 Hz train repetition rate. Finally, an outlook is given into the diagnostic prospects for the future.
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http://dx.doi.org/10.1107/S1600577519006611DOI Listing
September 2019

Transdermal Delivery of Sumatriptan Succinate Using Iontophoresis and Dissolving Microneedles.

J Pharm Sci 2019 11 30;108(11):3649-3656. Epub 2019 Jul 30.

LTS Lohmann Therapie-Systeme AG, Lohmannstraβe 2, 56626 Andernach, Germany.

This study focuses on the in vitro transdermal transport of sumatriptan succinate using combined iontophoresis and dissolving polymeric microneedle arrays. Permeation experiments were performed to evaluate the effects of formulation parameters on drug release from polyvinylpyrrolidone systems under mild electrical current (≤500 μA/cm). The preparations consisted of hydrophilic, positively charged molecules encapsulated in a water-soluble and biocompatible polymeric material. Current densities of 100, 300, and 500 μA/cm were applied during a 6-h period using silver/silver chloride electrodes. The circular array consisted of 600 needles and occupied a 0.785 cm area. Tests, carried out with Franz diffusion cells and skin of Göttingen minipigs, showed that small decreases in the polymer concentration led to negligible lag times and marked increases in the cumulative amount of drug permeated in 6 h (Q) and in the flux (J). At 500 μA/cm, Q and J nearly doubled for a microneedle loaded with 5% (w/w) sumatriptan and 20% (w/w) PVP (lag time = 0 min; Q = 2888 μg/cm; J = 490 μg/cm/h) relative to a system loaded with 5% (w/w) drug and 30% (w/w) PVP (lag time = 36 min; Q = 1437 μg/cm; J = 266 μg/cm/h).
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http://dx.doi.org/10.1016/j.xphs.2019.07.020DOI Listing
November 2019

-Quinone Methide Driven Synthesis of New ,- or ,-Heterocycles.

ChemistryOpen 2019 Jul 16;8(7):961-971. Epub 2019 Jul 16.

Institute of Pharmaceutical Chemistry and MTA-SZTE Stereochemistry Research Group University of Szeged H-6720 Szeged, Eötvös u. 6 Hungary.

To synthesize functionalized Mannich bases that can serve two different types of -quinone methide (-QM) intermediates, 2-naphthol and 6-hydroxyquinoline were reacted with salicylic aldehyde in the presence of morpholine. The Mannich bases that can form -QM and --QM were also synthesized by mixing 2-naphthol, 2-nitrobenzaldehyde, and morpholine followed by reduction of the nitro group. The highly functionalized aminonaphthol derivatives were then tested in [4+2] cycloaddition with different cyclic imines. The reaction proved to be both regio- and diastereoselective. In all cases, only one reaction product was obtained. Detailed structural analyses of the new polyheterocycles as well as conformational studies including DFT modelling were performed. The relative stability of -QMs/-QM were also calculated, and the regioselectivity of the reactions could be explained only when the cycloaddition started from aminodiol . It was summarized that starting from diaminonaphthol , the regioselectivity of the reaction is driven by the higher nucleophilicity of the amino group compared with the hydroxy group. 12H-benzo[a]xanthen-12-one (), formed via -QM formation, was isolated as a side product. The proton NMR spectrum of proved to be very unique from NMR point of view. The reason for the extreme low-field position of proton H-1 could be accounted for by theoretical calculation of structure and spatial magnetic properties of the compound in combination of ring current effects of the aromatic moieties and steric compression within the heavily hindered H(1)-C(1)-C(12b)-C(12a)-C(12)=O structural fragment.
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http://dx.doi.org/10.1002/open.201900150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632948PMC
July 2019

Validation of a palliative care outcome measurement tool supplemented by neurological symptoms (HOPE+): Identification of palliative concerns of neurological patients.

Palliat Med 2019 10 8;33(9):1221-1231. Epub 2019 Jul 8.

Department of Palliative Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.

Background: There is growing interest to integrate palliative care and its structures into the care of neurological patients. However, in Germany there is no comprehensive assessment tool capturing the symptoms of patients with advanced neurological diseases.

Aim: To validate a newly developed palliative care measurement tool based on an extension of the validated core documentation system Hospice and Palliative Care Evaluation considering additional neurological issues (HOPE+).

Design: Prospective, observational study using HOPE+ and as external criteria, the Eastern Cooperative Oncology Group (ECOG) performance status and the 12 months "surprise" question (12-SQ) in a neurological population, and assessment for its construct validity and diagnostic accuracy.

Setting/participants: All newly admitted patients to the Department of Neurorehabilitation, Dr. Becker Rhein-Sieg-Clinic aged 18-100 years (#DRKS00010947).

Results: Data from 263 patients (63 ± 14 years of age) were analyzed. HOPE+ revealed a moderately correlated six-factor structure ( = -0.543-0.525). Correlation analysis to evaluate discriminant validity using ECOG as external criterion was high (s(261) = 0.724,  < 0.001) and confirmed for severely affected patients by adding the 12-SQ ("No"-group: 48.00 ± 14.92 vs "Yes"-group: 18.67 ± 7.57,  < 0.009). Operating characteristics show satisfactory diagnostic accuracy (area under the curve: 0.746 ± 0.049, 95% confidence interval = 0.650-0.842).

Conclusion: HOPE+ demonstrates promising psychometric properties. It helps to assess palliative care issues of patients in neurological settings and, in combination with the 12-SQ, conceivably conditions when to initiate the palliative care approach in a population underrepresented in palliative care structures so far.
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http://dx.doi.org/10.1177/0269216319861927DOI Listing
October 2019

Operation of X-ray gas monitors at the European XFEL.

J Synchrotron Radiat 2019 Jul 4;26(Pt 4):1045-1051. Epub 2019 Jun 4.

X-ray Photon Diagnostics Group, European XFEL, Holzkoppel 4, 22869 Schenefeld, Germany.

X-ray gas monitors (XGMs) are operated at the European XFEL for non-invasive single-shot pulse energy measurements and average beam position monitoring. They are used for tuning and maintaining the self-amplified spontaneous emission (SASE) operation and for sorting single-shot experimental data according to the pulse-resolved energy monitor data. The XGMs were developed at DESY based on the specific requirements for the European XFEL. In total, six XGM units are continuously in operation. Here, the main principle and experimental setup of an XGM are summarized, and the locations of the six XGMs at the facility are shown. Pulse energy measurements at 0.134 nm wavelength are presented, exceeding 1 mJ obtained with an absolute measurement uncertainty of 7-10%; correlations between different XGMs are shown, from which a SASE1 beamline transmission of 97% is deduced. Additionally, simultaneous position measurements close to the undulator and at the end of the tunnel are shown, along with the correlation of beam position data simultaneously acquired by an XGM and an imager.
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http://dx.doi.org/10.1107/S1600577519003795DOI Listing
July 2019

First measurements with the K-monochromator at the European XFEL.

J Synchrotron Radiat 2019 Jul 4;26(Pt 4):1037-1044. Epub 2019 Jun 4.

European X-ray Free Electron Laser Facility GmbH, 22869 Schenefeld, Germany.

Hard X-ray free-electron lasers (XFELs) generate intense coherent X-ray beams by passing electrons through undulators, i.e. very long periodic magnet structures, which extend over hundreds of meters. The SASE1 and SASE2 undulator systems of the European XFEL consist of 35 segments with variable-gap planar undulators which are initially tuned to precise on-axis magnetic field strengths in a magnetic measurement laboratory to keep an important quality parameter - the K-value variation from segment to segment - below a certain limit (3 × 10 for 12 keV photon energy). After tunnel installation only photon-based methods can determine the K-values of undulator segments with a similar accuracy. The synchrotron radiation from a single or a few segments can be spectrally filtered by a dedicated crystal monochromator (K-monochromator) and recorded with a photodiode or with an imager that provides 2D information, tuned for high sensitivity to detect low photon densities from distant single undulator segments. This instrumentation is applied for electron orbit analysis and optimization, and adjustment of individual undulators in terms of their central magnetic axis with respect to the electron beam. Single undulator segments were analysed by scanning the monochromator crystal angle and detecting the steepest slope of a photodiode signal. Alternatively, in the imaging method, an imager recorded the radiation cone of electrons passing through the undulator segment. From the spatial distribution of the radiation, the K-parameter was determined with a sufficiently high relative accuracy.
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http://dx.doi.org/10.1107/S1600577519005307DOI Listing
July 2019

Effect of hyperoxia on the immune status of oxygen divers and endurance athletes.

Free Radic Res 2019 May 23;53(5):522-534. Epub 2019 May 23.

a Naval Institute for Maritime Medicine , Kronshagen , Germany.

Physical activity, particularly that, exerted by endurance athletes, impacts the immune status of the human body. Prolonged duration and high-intensity endurance training lead to increased production of reactive oxygen species (ROS) and thereby to oxidative stress. Military combat swimmers (O-divers) are regularly exposed to hyperbaric hyperoxia (HBO) in addition to intensive endurance training intervals. They are, therefore, exposed to extreme levels of oxidative stress. Several studies support that the intensity of oxidative stress essentially determines the effect on immune status. The aim of this study was to comparatively characterise peripheral blood mononuclear cells (PBMCs) of O-divers (military combat swimmers), endurance athletes (amateur triathletes), and healthy control volunteers with respect to DNA fragmentation, immune status and signs of inflammation. Furthermore, it was investigated how PBMCs from these groups responded acutely to exposure to HBO. We showed that DNA fragmentation was comparable in PBMCs of all three groups under basal conditions directly after HBO exposure. However, significantly higher DNA fragmentation was observed in O-divers 18 hours after HBO, possibly indicating a slower recovery. O-divers also exhibited a proinflammatory immune status exemplified by an elevated number of CD4CD25 T cells, elevated expression of proinflammatory cytokine IL-12, and diminished expression of anti-inflammatory TGF-β1 compared to controls. Supported by a decreased basal gene expression and prolonged upregulation of anti-oxidative HO-1, these data suggest that higher oxidative stress levels, as present under intermitted hyperbaric hyperoxia, e.g. through oxygen diving, promote a higher inflammatory immune status than oxidative stress through endurance training alone.
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http://dx.doi.org/10.1080/10715762.2019.1612890DOI Listing
May 2019

Benzenium Ion: Aromatic as the π-Complex or Antiaromatic as the σ-Complex Being Somewhat Similar to the Cyclopentadienyl Cation.

J Phys Chem A 2019 May 14;123(20):4443-4451. Epub 2019 May 14.

Institut für Chemie , Universität Potsdam , Karl-Liebknecht-Str. 24-25 , D-14476 Potsdam (Golm), Germany.

The spatial magnetic properties, through-space NMR shieldings (TSNMRSs), of the benzenium cation (CH) 1 and of ±I/M-substituted analogues CHX 3-8 [X = -Me, -CF, -NH, -NO, -NO, -SiH] have been calculated using the gauge-independent atomic orbital perturbation method employing the nucleus-independent chemical shift concept, and iso-chemical-shielding surfaces of various sizes and directions have been observed. The TSNMRS values were employed to compare the spatial magnetic properties (TSNMRS) of benzene and the benzenium ion 1 and then further compared with analogues 3-8, to answer the question whether the electronic structures of 1 and 3-8 are still similar to those of aromatic species or somewhat similar to the antiaromatic cyclopentadienyl cation 2, supported by structural data and δ(C)/ppm values.
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http://dx.doi.org/10.1021/acs.jpca.9b03121DOI Listing
May 2019

In Reply.

Authors:
Andreas Koch

Dtsch Arztebl Int 2019 03;116(10):175-176

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http://dx.doi.org/10.3238/arztebl.2019.0175cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482371PMC
March 2019
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