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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).
- ItemOcean warming and acidification may drag down the commercial Arctic cod fishery by 2100(San Francisco, California, US : PLOS, 2020) Hänsel, Martin C.; Schmidt, Jörn O.; Stiasny, Martina H.; Stöven, Max T.; Voss, Rudi; Quaas, Martin F.The Arctic Ocean is an early warning system for indicators and effects of climate change. We use a novel combination of experimental and time-series data on effects of ocean warming and acidification on the commercially important Northeast Arctic cod (Gadus morhua) to incorporate these physiological processes into the recruitment model of the fish population. By running an ecological-economic optimization model, we investigate how the interaction of ocean warming, acidification and fishing pressure affects the sustainability of the fishery in terms of ecological, economic, social and consumer-related indicators, ranging from present day conditions up to future climate change scenarios. We find that near-term climate change will benefit the fishery, but under likely future warming and acidification this large fishery is at risk of collapse by the end of the century, even with the best adaptation effort in terms of reduced fishing pressure.
- 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.
- ItemMaternal mycotoxin exposure and adverse pregnancy outcomes: a systematic review(Berlin ; Heidelberg : Springer, 2020) Kyei, Nicholas N.A.; Boakye, Daniel; Gabrysch, SabineMycotoxin exposure from food occurs globally but is more common in hot humid environments, especially in low-income settings, and might affect pregnancy outcomes. This study aimed to synthesize the evidence from epidemiological studies on the relationship between maternal or fetal exposure to different mycotoxins and the occurrence of adverse pregnancy outcomes. Multiple databases were systematically searched up to December 2018 to identify studies that assessed the association between mycotoxin exposure in pregnant women or fetuses and at least one pregnancy outcome. Studies were appraised and results were synthesized using standard methods for conducting systematic reviews. This review identified and included 17 relevant studies. There is some evidence to suggest that exposure to various Aspergillus mycotoxins (e.g., aflatoxin) during pregnancy may impair intrauterine fetal growth and promote neonatal jaundice. Findings were inconclusive concerning the influence of aflatoxin exposure on perinatal death and preterm birth. Only two studies assessed effects of maternal exposure to Fusarium mycotoxins (e.g., fumonisin) on adverse pregnancy outcomes. These studies found that maternal fumonisin exposure may be associated with hypertensive emergencies in pregnancy and with neural tube defects. Studies using grain farming and weather conditions as a proxy measure for mycotoxin exposure found that such exposure was associated with an increased risk of preterm birth and late-term miscarriage. In conclusion, there is already some evidence to suggest that exposure to mycotoxins during pregnancy may have detrimental effects on pregnancy outcomes. However, given the limited number of studies, especially on effects of Fusarium mycotoxins, more studies are needed for a more comprehensive understanding of the effects of different mycotoxins on maternal and fetal health and to guide public health policies and interventions. © 2020, The Author(s).
- ItemMolecular mechanisms of the efficacy of cold atmospheric pressure plasma (CAP) in cancer treatment(Basel : MDPI AG, 2020) Semmler, Marie Luise; Bekeschus, Sander; Schäfer, Mirijam; Bernhardt, Thoralf; Fischer, Tobias; Witzke, Katharina; Seebauer, Christian; Rebl, Henrike; Grambow, Eberhard; Vollmar, Brigitte; Nebe, J. Barbara; Metelmann, Hans-Robert; Woedtke, Thomas von; Emmert, Steffen; Boeckmann, LarsRecently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemIMAGE-IN: Interactive web-based multidimensional 3D visualizer for multi-modal microscopy images(San Francisco, California, US : PLOS, 2022) Gupta, Yubraj; Costa, Carlos; Pinho, Eduardo; A. Bastião Silva, Luís; Heintzmann, RainerAdvances in microscopy hardware and storage capabilities lead to increasingly larger multidimensional datasets. The multiple dimensions are commonly associated with space, time, and color channels. Since “seeing is believing”, it is important to have easy access to user-friendly visualization software. Here we present IMAGE-IN, an interactive web-based multidimensional (N-D) viewer designed specifically for confocal laser scanning microscopy (CLSM) and focused ion beam scanning electron microscopy (FIB-SEM) data, with the goal of assisting biologists in their visualization and analysis tasks and promoting digital work-flows. This new visualization platform includes intuitive multidimensional opacity fine-tuning, shading on/off, multiple blending modes for volume viewers, and the ability to handle multichannel volumetric data in volume and surface views. The software accepts a sequence of image files or stacked 3D images as input and offers a variety of viewing options ranging from 3D volume/surface rendering to multiplanar reconstruction approaches. We evaluate the performance by comparing the loading and rendering timings of a heterogeneous dataset of multichannel CLSM and FIB-SEM images on two devices with installed graphic cards, as well as comparing rendered image quality between ClearVolume (the ImageJ open-source desktop viewer), Napari (the Python desktop viewer), Imaris (the closed-source desktop viewer), and our proposed IMAGE-IN web viewer.
- ItemEffectiveness of myAirCoach: A mHealth Self-Management System in Asthma(Amsterdam [u.a.] : Elsevier, 2020) Khusial, Rishi J.; Honkoop, Persijn J.; Usmani, Omar; Soares, Marcia; Simpson, Andrew; Biddiscombe, Martyn; Meah, Sally; Bonini, Matteo; Lalas, Antonios; Polychronidou, Eleftheria; Koopmans, Julia G.; Moustakas, Konstantinos; Snoeck-Stroband, Jiska B.; Ortmann, Steffen; Votis, Konstantinos; Tzovaras, Dimitrios; Chung, Kian Fan; Fowler, Stephen; Sont, Jacob K.Background: Self-management programs have beneficial effects on asthma control, but their implementation in clinical practice is poor. Mobile health (mHealth) could play an important role in enhancing self-management. Objective: To assess the clinical effectiveness and technology acceptance of myAirCoach-supported self-management on top of usual care in patients with asthma using inhalation medication. Methods: Patients were recruited in 2 separate studies. The myAirCoach system consisted of an inhaler adapter, an indoor air-quality monitor, a physical activity tracker, a portable spirometer, a fraction exhaled nitric oxide device, and an app. The primary outcome was asthma control; secondary outcomes were exacerbations, quality of life, and technology acceptance. In study 1, 30 participants were randomized to either usual care or myAirCoach support for 3 to 6 months; in study 2, 12 participants were provided with the myAirCoach system in a 3-month before-after study. Results: In study 1, asthma control improved in the intervention group compared with controls (Asthma Control Questionnaire difference, 0.70; P = .006). A total of 6 exacerbations occurred in the intervention group compared with 12 in the control group (hazard ratio, 0.31; P = .06). Asthma-related quality of life improved (mini Asthma-related Quality of Life Questionnaire difference, 0.53; P = .04), but forced expiratory volume in 1 second was unchanged. In study 2, asthma control improved by 0.86 compared with baseline (P = .007) and quality of life by 0.16 (P = .64). Participants reported positive attitudes toward the system. Discussion: Using the myAirCoach support system improves asthma control and quality of life, with a reduction in severe asthma exacerbations. Well-validated mHealth technologies should therefore be further studied. © 2020 The Authors
- ItemSpatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder(New York, NY : Nature Publishing Group, 2020) Bottek, Jenny; Soun, Camille; Lill, Julia K.; Dixit, Akanksha; Thiebes, Stephanie; Beerlage, Anna-Lena; Horstmann, Marius; Urbanek, Annett; Heuer, Heike; Uszkoreit, Julian; Eisenacher, Martin; Bracht, Thilo; Sitek, Barbara; Hoffmann, Franziska; Vijitha, Nirojah; von Eggeling, Ferdinand; Engel, Daniel R.The urothelium of the urinary bladder represents the first line of defense. However, uropathogenic E. coli (UPEC) damage the urothelium and cause acute bacterial infection. Here, we demonstrate the crosstalk between macrophages and the urothelium stimulating macrophage migration into the urothelium. Using spatial proteomics by MALDI-MSI and LC-MS/MS, a novel algorithm revealed the spatial activation and migration of macrophages. Analysis of the spatial proteome unravelled the coexpression of Myo9b and F4/80 in the infected urothelium, indicating that macrophages have entered the urothelium upon infection. Immunofluorescence microscopy additionally indicated that intraurothelial macrophages phagocytosed UPEC and eliminated neutrophils. Further analysis of the spatial proteome by MALDI-MSI showed strong expression of IL-6 in the urothelium and local inhibition of this molecule reduced macrophage migration into the urothelium and aggravated the infection. After IL-6 inhibition, the expression of matrix metalloproteinases and chemokines, such as CX3CL1 was reduced in the urothelium. Accordingly, macrophage migration into the urothelium was diminished in the absence of CX3CL1 signaling in Cx3cr1gfp/gfp mice. Conclusively, this study describes the crosstalk between the infected urothelium and macrophages through IL-6-induced CX3CL1 expression. Such crosstalk facilitates the relocation of macrophages into the urothelium and reduces bacterial burden in the urinary bladder. © 2020, The Author(s).
- ItemMolecular characterisation of extended-spectrum ß-lactamase producing Escherichia coli in wild birds and cattle, Ibadan, Nigeria(London : BioMed Central, 2021) Fashae, Kayode; Engelmann, Ines; Monecke, Stefan; Braun, Sascha D.; Ehricht, RalfBackground: Antimicrobial resistance (AMR) is an increasing global health concern reducing options for therapy of infections and also for perioperative prophylaxis. Many Enterobacteriaceae cannot be treated anymore with third generation cephalosporins (3GC) due to the production of certain 3GC hydrolysing enzymes (extended spectrum beta-lactamases, ESBLs). The role of animals as carriers and vectors of multi-resistant bacteria in different geographical regions is poorly understood. Therefore, we investigated the occurrence and molecular characteristics of ESBL-producing Escherichia coli (E. coli) in wild birds and slaughtered cattle in Ibadan, Nigeria. Cattle faecal samples (n = 250) and wild bird pooled faecal samples (cattle egrets, Bubulcus ibis, n = 28; white-faced whistling duck, Dendrocygna viduata, n = 24) were collected and cultured on cefotaxime-eosin methylene blue agar. Antimicrobial susceptibility was determined by agar diffusion assays and all 3GC resistant isolates were genotypically characterised for AMR genes, virulence associated genes (VAGs) and serotypes using DNA microarray-based assays. Results: All 3GC resistant isolates were E. coli: cattle (n = 53), egrets (n = 87) and whistling duck (n = 4); cultured from 32/250 (12.8%), 26/28 (92.9%), 2/24(8.3%), cattle, egrets and whistling duck faecal samples, respectively. blaCTX-M gene family was prevalent; blaCTX-M15 (83.3%) predominated over blaCTX-M9 (11.8%). All were susceptible to carbapenems. The majority of isolates were resistant to at least one of the other tested antimicrobials; multidrug resistance was highest in the isolates recovered from egrets. The isolates harboured diverse repositories of other AMR genes (including strB and sul2), integrons (predominantly class 1) and VAGs. The isolates recovered from egrets harboured more AMR genes; eight were unique to these isolates including tetG, gepA, and floR. The prevalent VAGs included hemL and iss; while 14 (including sepA) were unique to certain animal isolates. E. coli serotypes O9:H9, O9:H30 and O9:H4 predominated. An identical phenotypic microarray profile was detected in three isolates from egrets and cattle, indicative of a clonal relationship amongst these isolates. Conclusion: Wild birds and cattle harbour diverse ESBL-producing E. coli populations with potential of inter-species dissemination and virulence. Recommended guidelines to balance public health and habitat conservation should be implemented with continuous surveillance. © 2021, The Author(s).
- ItemMultiple distinct outbreaks of Panton-Valentine leucocidin-positive community-associated meticillin-resistant Staphylococcus aureus in Ireland investigated by whole-genome sequencing(Kidlington [u.a.] : Elsevier, 2021) McManus, B.A.; Aloba, B.K.; Earls, M.R.; Brennan, G.I.; O'Connell, B.; Monecke, S.; Ehricht, R.; Shore, A.C.; Coleman, D.C.Background Panton–Valentine leucocidin (PVL)-positive community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) is increasingly associated with infection outbreaks. Aim To investigate multiple suspected PVL-positive CA-MRSA outbreaks using whole-genome sequencing (WGS). Methods Forty-six suspected outbreak-associated isolates from 36 individuals at three separate Irish hospitals (H1–H3) and from separate incidents involving separate families associated with H2 were investigated by whole-genome multi-locus sequence typing (wgMLST). Findings Two clusters (CH1 and CH2) consisting of 8/10 and 6/6 PVL-positive t008 ST8-MRSA-IVa isolates from H1 and H2, respectively, were identified. Within each cluster, neighbouring isolates were separated by ≤5 allelic differences; however, ≥73 allelic differences were identified between the clusters, indicating two independent outbreaks. Isolates from the H3 maternity unit formed two clusters (CH3–SCI and CH3–SCII) composed of four PVL-negative t4667 ST5-MRSA-V and 14 PVL-positive t002 ST5-MRSA-IVc isolates, respectively. Within clusters, neighbouring isolates were separated by ≤24 allelic differences, whereas both clusters were separated by 1822 allelic differences, indicating two distinct H3 outbreaks. Eight PVL-positive t127 ST1-MRSA-V+fus and three PVL-negative t267 ST97-MRSA-V+fus isolates from two distinct H2-associated families FC1 (N = 4) and FC2 (N = 7) formed three separate clusters (FC1 (t127), FC2 (t127) and FC2 (t267)). Neighbouring isolates within clusters were closely related and exhibited ≤7 allelic differences. Intrafamilial transmission was apparent, but the detection of ≥48 allelic differences between clusters indicated no interfamilial transmission. Conclusion The frequent importation of PVL-positive CA-MRSA into healthcare settings, transmission and association with outbreaks is a serious ongoing concern. WGS is a highly discriminatory, informative method for deciphering such outbreaks conclusively.