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- ItemLaboratory-Developed Tests: Design of a Regulatory Strategy in Compliance with the International State-of-the-Art and the Regulation (EU) 2017/746 (EU IVDR [In Vitro Diagnostic Medical Device Regulation])([New York] : Springer Nature, 2022) Spitzenberger, Folker; Patel, Jaimin; Gebuhr, Inga; Kruttwig, Klaus; Safi, Abdulrahim; Meisel, ChristianPurpose: This study aimed at the development of a regulatory strategy for compliance of laboratory-developed tests (LDTs) with requirements of the Regulation (EU) 2017/746 (“EU-IVDR”) under consideration of international requirements for LDTs as established in major regulatory regions. Furthermore, it was analysed in how far elements of current LDT regulation could qualify for an internationally harmonised concept ensuring quality, safety and performance of LDTs. Methods: A review of regulatory literature including legislation as well as guidance documents was performed. The regulatory strategy was adapted from international guidance concepts used for commercially marketed IVD. It was then applied to the example of a large medical laboratory in the EU. A high-level comparison was conducted to identify gaps and matches between the different international regulatory requirements for LDTs. Results: A four-step strategy for compliance of LDTs with the EU IVDR was implemented in an exemplary medical laboratory. On the basis of an internationally used LDT definition, LDTs constitute nearly 50% of the total IVD devices used in the laboratory. While an ISO 15189-compliant QMS is a major component, it should be accompanied by the application of appropriate processes for risk management, performance evaluation and continuous monitoring of LDTs. At least six criteria represent common characteristics of a potential, internationally convergent concept for the regulation/standardization of LDTs. Conclusions: This study confirms the impact of LDTs for individualized and innovative medical laboratory testing. Prerequisites for LDT use as especially given by the IVDR and missing interpretation in the EU with regard to the scope of LDT definition, the application of standards and the extent of documentation for LDTs currently lead to uncertainties for both laboratories and regulatory bodies responsible for LDT oversight. The characteristics identified as common criteria for ensuring quality, safety and performance of LDTs may be considered as central elements of future international consensus guidance. © 2021, The Author(s).
- ItemNanoscopic tip sensors fabricated by gas phase etching of optical glass fibers(Heidelberg : Springer, 2012) Bierlich, J.; Kobelke, J.; Brand, D.; Kirsch, K.; Dellith, J.; Bartelt, H.Silica-based fiber tips are used in a variety of spectroscopic, micro- or nano-scopic optical sensor applications and photonic micro-devices. The miniaturization of optical sensor systems and the technical implementation using optical fibers can provide new sensor designs with improved properties and functionality for new applications. The selective-etching of specifically doped silica fibers is a promising method in order to form complex photonic micro structures at the end or within fibers such as tips and cavities in various shapes useful for the all-fiber sensor and imaging applications. In the present study, we investigated the preparation of geometrically predefined, nanoscaled fiber tips by taking advantage of the dopant concentration profiles of highly doped step-index fibers. For this purpose, a gas phase etching process using hydrofluoric acid (HF) vapor was applied. The shaping of the fiber tips was based on very different etching rates as a result of the doping characteristics of specific optical fibers. Technological studies on the influence of the etching gas atmosphere on the temporal tip shaping and the final geometry were performed using undoped and doped silica fibers. The influence of the doping characteristics was investigated in phosphorus-, germanium-, fluorine- and boron-doped glass fibers. Narrow exposed as well as protected internal fiber tips in various shapes and tip radiuses down to less than 15 nm were achieved and characterized geometrically and topologically. For investigations into surface plasmon resonance effects, the fiber tips were coated with nanometer-sized silver layers by means of vapour deposition and finally subjected to an annealing treatment.
- ItemThe Superconducting Gravimeter CD-034 at Moxa Observatory: More than 20 Years of Scientific Experience and a Reanimation(Basel : Birkhäuser, 2022) Jahr, T.; Stolz, R.In this work, advanced methods and processing schemes for the analysis of data from a Superconducting Gravimeter (SG) will be introduced and their relevance on acquired data proved. The SG CD-034 was installed on Easter of 1999 in the Geodynamic Observatory Moxa of the Friedrich Schiller University Jena, Germany. Initially, the quality of the recorded data was examined, spectra for the detection of the parasitic modes were calculated and the calibration values for the two sensors were determined. Ever since very high-quality gravity data of this SG and most of the other worldwide SGs were made available through the storage archive of the Global Geodynamics Project (GGP later changed to IGETS, International Geodynamics and Earth Tide Service) for global scientific investigations at that time. SG’s such as the one in Moxa (Germany) still deliver significant scientific value for global gravitational field studies as well as for regional/local studies which will be shortly reviewed. Examples are the detection of polar motion, the influence of continental water loading in general and in particular river basin loads, the gravimetric effect of North Sea storm surges and the study of hydro-gravimetric signals, which could be compared with satellite observations and global hydraulic models. The long-term, low-noise operation of complex SG’s requires some effort on maintenance. In order to evaluate the correct operation of the SG, new data processing steps were introduced to assist in the analysis of the data in case of issues with the instrumentation. For example, in 2012/2013 and 2020/2021 severe interference in the gravimeter electronics in Moxa led to a significant loss of data. In both cases, however, the cause could be determined, and the corresponding electronic components renewed. Since July 2021, the SG in Moxa registers again with high data quality comparable or slightly better than before the incident. Initial tests and tidal analyses confirm the validity of the old calibration factors, and the authors now look forward to the re-established long-term recording with excitement and confidence.
- ItemGermania and alumina dopant diffusion and viscous flow effects at preparation of doped optical fibers(Ostrava : VSB - Technical University of Ostrava and University of Zilina Faculty of Electrical Engineering, 2017) Kobelke, Jens; Schuster, Kay; Bierlich, Jörg; Unger, Sonja; Schwuchow, Anka; Elsmann, Tino; Dellith, Jan; Aichele, Claudia; Fatobene Ando, Ron; Bartelt, HartmutWe report on germania and alumina dopant profile shift effects at preparation of compact optical fibers using packaging methods (Stack-and-Draw method, Rod-in-Tube (RiT) technique). The sintering of package hollow volume by viscous flow results in a shift of the core-pitch ratio in all-solid microstructured fibers. The ratio is increased by about 5% in the case of a hexagonal package. The shift by diffusion effects of both dopants is simulated for typical slow speed drawing parameters. Thermodynamic approximations of surface dissociation of germania doped silica suggest the need of an adequate undoped silica barrier layer to prevent an undesired bubble formation at fiber drawing. In contrast, alumina doping does not estimate critical dissociation effects with vaporous aluminium oxide components. We report guide values of diffusion length of germania and alumina for the drawing process by kinetic approximation. The germania diffusion involves a small core enlargement, typically in the sub-micrometer scale. Though, the alumina diffusion enlarges it by a few micrometers. A drawn pure alumina preform core rod transforms to an amorphous aluminosilicate core with a molar alumina concentration of only about 50% and a non-gaussian concentration profile.
- ItemCharacterisation of a novel composite SCCmec-SCCfus element in an emerging Staphylococcus aureus strain from the Arabian Gulf region(San Francisco : Public Library of Science, 2019) Senok, Abiola; Slickers, Peter; Hotzel, Helmut; Boswihi, Samar; Braun, Sascha D.; Gawlik, Darius; Müller, Elke; Nabi, Anju; Nassar, Rania; Nitschke, Hedda; Reißig, Annett; Ruppelt-Lorz, Antje; Mafofo, Joseph; Somili, Ali M.; Udo, Edet; Ehricht, Ralf; Monecke, StefanFusidic acid is a steroid antibiotic known since the 1960s. It is frequently used in topical preparations, i.e., ointments, for the treatment of skin and soft tissue infections caused by Staphylococcus aureus. There is an increasing number of methicillin-resistant S. aureus (MRSA) strains that harbour plasmid-borne fusB/far1 or fusC that is localised on SCC elements. In this study we examined a series of related CC30-MRSA isolates from the Arabian Gulf countries that presented with SCCmec elements and fusC, including a variant that—to the best of our knowledge—has not yet formally been described. It consisted of a class B mec complex and ccrA/B-4 genes. The fusidic acid resistance gene fusC was present, but contrary to the previously sequenced element of HDE288, it was not accompanied by tirS. This element was identified in CC30 MRSA from Kuwait, Saudi Arabia and the United Arab Emirates that usually also harbour the Panton-Valentin leukocidin (PVL) genes. It was also identified in CC8 and ST834 isolates. In addition, further CC30 MRSA strains with other SCCmec VI elements harbouring fusC were found to circulate in the Arabian Gulf region. It can be assumed that MRSA strains with SCCmec elements that include fusC have a selective advantage in both hospital and community settings warranting a review of the use of topical antibiotics and indicating the necessity of reducing over-the-counter sale of antibiotics, including fusidic acid, without prescription.Fusidic acid is a steroid antibiotic known since the 1960s. It is frequently used in topical preparations, i.e., ointments, for the treatment of skin and soft tissue infections caused by Staphylococcus aureus. There is an increasing number of methicillin-resistant S. aureus (MRSA) strains that harbour plasmid-borne fusB/far1 or fusC that is localised on SCC elements. In this study we examined a series of related CC30-MRSA isolates from the Arabian Gulf countries that presented with SCCmec elements and fusC, including a variant that—to the best of our knowledge—has not yet formally been described. It consisted of a class B mec complex and ccrA/B-4 genes. The fusidic acid resistance gene fusC was present, but contrary to the previously sequenced element of HDE288, it was not accompanied by tirS. This element was identified in CC30 MRSA from Kuwait, Saudi Arabia and the United Arab Emirates that usually also harbour the Panton-Valentin leukocidin (PVL) genes. It was also identified in CC8 and ST834 isolates. In addition, further CC30 MRSA strains with other SCCmec VI elements harbouring fusC were found to circulate in the Arabian Gulf region. It can be assumed that MRSA strains with SCCmec elements that include fusC have a selective advantage in both hospital and community settings warranting a review of the use of topical antibiotics and indicating the necessity of reducing over-the-counter sale of antibiotics, including fusidic acid, without prescription.
- ItemConsensusPrime—A Bioinformatic Pipeline for Ideal Consensus Primer Design(Basel : MDPI, 2022) Collatz, Maximilian; Braun, Sascha D.; Monecke, Stefan; Ehricht, RalfBackground: High-quality oligonucleotides for molecular amplification and detection procedures of diverse target sequences depend on sequence homology. Processing input sequences and identifying homogeneous regions in alignments can be carried out by hand only if they are small and contain sequences of high similarity. Finding the best regions for large and inhomogeneous alignments needs to be automated. Results: The ConsensusPrime pipeline was developed to sort out redundant and technical interfering data in multiple sequence alignments and detect the most homologous regions from multiple sequences. It automates the prediction of optimal consensus primers for molecular analytical and sequence-based procedures/assays. Conclusion: ConsensusPrime is a fast and easy-to-use pipeline for predicting optimal consensus primers that is executable on local systems without depending on external resources and web services. An implementation in a Docker image ensures platform-independent executability and installability despite the combination of multiple programs. The source code and installation instructions are publicly available on GitHub.
- ItemA manual and an automatic TERS based virus discrimination(Cambridge : RSC Publ., 2015) Olschewski, Konstanze; Kämmer, Evelyn; Stöckel, Stephan; Bocklitz, Thomas; Deckert-Gaudig, Tanja; Zell, Roland; Cialla-May, Dana; Weber, Karina; Deckert, Volker; Popp, JürgenRapid techniques for virus identification are more relevant today than ever. Conventional virus detection and identification strategies generally rest upon various microbiological methods and genomic approaches, which are not suited for the analysis of single virus particles. In contrast, the highly sensitive spectroscopic technique tip-enhanced Raman spectroscopy (TERS) allows the characterisation of biological nano-structures like virions on a single-particle level. In this study, the feasibility of TERS in combination with chemometrics to discriminate two pathogenic viruses, Varicella-zoster virus (VZV) and Porcine teschovirus (PTV), was investigated. In a first step, chemometric methods transformed the spectral data in such a way that a rapid visual discrimination of the two examined viruses was enabled. In a further step, these methods were utilised to perform an automatic quality rating of the measured spectra. Spectra that passed this test were eventually used to calculate a classification model, through which a successful discrimination of the two viral species based on TERS spectra of single virus particles was also realised with a classification accuracy of 91%.
- ItemBackground Reduction in STED-FCS Using a Bivortex Phase Mask(Washington, DC : ACS Publications, 2020) Barbotin, Aurélien; Urbančič, Iztok; Galiani, Silvia; Eggeling, Christian; Booth, MartinFluorescence correlation spectroscopy (FCS) is a valuable tool to study the molecular dynamics in living cells. When used together with a super-resolution stimulated emission depletion (STED) microscope, STED-FCS can measure diffusion processes on the nanoscale in living cells. In two-dimensional (2D) systems like the cellular plasma membrane, a ring-shaped depletion focus is most commonly used to increase the lateral resolution, leading to more than 25-fold decrease in the observation volume, reaching the relevant scale of supramolecular arrangements. However, STED-FCS faces severe limitations when measuring diffusion in three dimensions (3D), largely due to the spurious background contributions from undepleted areas of the excitation focus that reduce the signal quality and ultimately limit the resolution. In this paper, we investigate how different STED confinement modes can mitigate this issue. By simulations as well as experiments with fluorescent probes in solution and in cells, we demonstrate that the coherent-hybrid (CH) depletion pattern created by a bivortex phase mask reduces background most efficiently and thus provides superior signal quality under comparable reduction of the observation volume. Featuring also the highest robustness to common optical aberrations, CH-STED can be considered the method of choice for reliable STED-FCS-based investigations of 3D diffusion on the subdiffraction scale. Copyright © 2020 American Chemical Society.
- ItemOptical properties of silicon nanowire arrays formed by metal-assisted chemical etching: Evidences for light localization effect(New York, NY [u.a.] : Springer, 2012) Osminkina, L.A.; Gonchar, K.A.; Marshov, V.S.; Bunkov, K.V.; Petrov, D.V.; Golovan, L.A.; Talkenberg, F.; Sivakov, V.A.; Timoshenko, V.Y.We study the structure and optical properties of arrays of silicon nanowires (SiNWs) with a mean diameter of approximately 100 nm and length of about 1-25 μm formed on crystalline silicon (c-Si) substrates by using metal-assisted chemical etching in hydrofluoric acid solutions. In the middle infrared spectral region, the reflectance and transmittance of the formed SiNW arrays can be described in the framework of an effective medium with the effective refractive index of about 1.3 (porosity, approximately 75%), while a strong light scattering for wavelength of 0.3 ÷ 1 μm results in a decrease of the total reflectance of 1%-5%, which cannot be described in the effective medium approximation. The Raman scattering intensity under excitation at approximately 1 μm increases strongly in the sample with SiNWs in comparison with that in c-Si substrate. This effect is related to an increase of the light-matter interaction time due to the strong scattering of the excitation light in SiNW array. The prepared SiNWs are discussed as a kind of 'black silicon', which can be formed in a large scale and can be used for photonic applications as well as in molecular sensing.
- ItemGiant refractometric sensitivity by combining extreme optical Vernier effect and modal interference([London] : Macmillan Publishers Limited, part of Springer Nature, 2020) Gomes, André D.; Kobelke, Jens; Bierlich, Jörg; Dellith, Jan; Rothhardt, Manfred; Bartelt, Hartmut; Frazão, OrlandoThe optical Vernier effect consists of overlapping responses of a sensing and a reference interferometer with slightly shifted interferometric frequencies. The beating modulation thus generated presents high magnified sensitivity and resolution compared to the sensing interferometer, if the two interferometers are slightly out of tune with each other. However, the outcome of such a condition is a large beating modulation, immeasurable by conventional detection systems due to practical limitations of the usable spectral range. We propose a method to surpass this limitation by using a few-mode sensing interferometer instead of a single-mode one. The overlap response of the different modes produces a measurable envelope, whilst preserving an extremely high magnification factor, an order of magnification higher than current state-of-the-art performances. Furthermore, we demonstrate the application of that method in the development of a giant sensitivity fibre refractometer with a sensitivity of around 500 µm/RIU (refractive index unit) and with a magnification factor over 850.