101 results on '"Lauber C"'
Search Results
2. Taxonomy of Viruses
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Gorbalenya, A.E., primary, Lauber, C., additional, and Siddell, S., additional
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- 2019
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3. Phylogeny of Viruses ☆
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Gorbalenya, Alexander E., primary and Lauber, C., additional
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- 2017
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4. Biopsychosocial correlates of persistent somatic symptoms in patients with chronic kidney disease – results of the Hamburg City Health Study (HCHS)
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Jessen, B., primary, Schmidt-Lauber, C., additional, Huber, T., additional, Löwe, B., additional, and Shedden Mora, M., additional
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- 2022
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5. Predictors of somatic symptom persistence in patients with chronic kidney disease (SOMA.CK). Project 3 of the SOMACROSS research unit
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Shedden-Mora, M., primary, Jessen, B., additional, Schmidt-Lauber, C., additional, Löwe, B., additional, and Huber, T., additional
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- 2022
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6. Effectiveness of group body psychotherapy for negative symptoms of schizophrenia: multicentre randomised controlled trial
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Priebe, S., Savill, M., Wykes, T., Bentall, R. P., Reininghaus, U., Lauber, C, Bremner, S., Eldridge, S., and Röhricht, F.
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- 2016
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7. Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells
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Lauber, C, Vieyres, G, Terczyńska-Dyla, E, Anggakusuma, Dijkman, R, Gad, H H, Akhtar, H, Geffers, R, Vondran, F W R, Thiel, V, Kaderali, L, Pietschmann, T, and Hartmann, R
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- 2015
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8. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2
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Gorbalenya, A.E., Baker, S.C., Baric, R.S., Groot, R.J. de, Drosten, C., Gulyaeva, A.A., Haagmans, B.L., Lauber, C., Leontovich, A.M., Neuman, B.W., Penzar, D., Perlman, S., Poon, L.L.M., Samborskiy, D.V., Sidorov, I.A., Sola, I., Ziebuhr, J., Coronaviridae Study Grp, European Commission, German Research Foundation, and Virology
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Microbiology (medical) ,Coronaviridae ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,Immunology ,Diseases ,Nidovirales ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Microbiology ,Applied microbiology ,03 medical and health sciences ,0302 clinical medicine ,Virology ,medicine ,Genetics ,Respiratory system ,Taxonomy ,030304 developmental biology ,Coronavirus ,0303 health sciences ,biology ,fungi ,virus diseases ,Biodiversity ,Cell Biology ,biology.organism_classification ,3. Good health ,030220 oncology & carcinogenesis ,Viruses - Abstract
Versión preprint diponible en BioRxiv (doi: 10.1101/2020.02.07.937862) http://hdl.handle.net/10261/212994, The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks., Work on DEmARC advancement and coronavirus and nidovirus taxonomies was supported by the EU Horizon 2020 EVAg 653316 project and the LUMC MoBiLe program (to A.E.G.), and on coronavirus and nidovirus taxonomies by a Mercator Fellowship by the Deutsche Forschungsgemeinschaft (to A.E.G.) in the context of the SFB1021 (A01 to J.Z.).
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- 2020
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9. Heterologe Expression und Charakterisierung einer GDS(L)‐ähnlichen Hydrolase aus Pleurotus sapidus mit einem ungewöhnlichen SGNH‐Motiv im aktiven Zentrum.
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Fingerhut, M.A., Henrich, L., Lauber, C., Broel, N., Ghezellou, P., Karrer, D., Spengler, B., Langfelder, K., Stressler, T., Zorn, H., and Gand, M.
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- 2024
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10. Are there any lessons to be learnt from psychiatric epidemiology?
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Lauber, C.
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- 2015
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11. Uncovering the Horseshoe Effect in Microbial Analyses (vol 2, e00166-16, 2017)
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Morton, JT, Toran, L, Edlund, A, Metcalf, JL, Lauber, C, and Knight, R
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- 2018
12. ICTV Virus Taxonomy Profile: Polyomaviridae
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Moens, U., Calvignac-Spencer, S., Lauber, C., Ramgvist, T., Feltkamp, M.C.W., Daugherty, M.D., Verschoor, E.J., Ehlers, B., and ICTV Report Consortium
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taxonomy ,Merkel cell polyomavirus ,budgerigar fledgling disease polyomavirus ,BK polyomavirus ,JC polyomavirus ,Polyomaviridae ,ICTV report ,simian virus 40 - Published
- 2017
13. Phylogeny of Viruses☆
- Author
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Gorbalenya, Alexander E. and Lauber, C.
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Distance-based inference ,Maximum likelihood reasoning ,Epidemiology ,Evolution ,Molecular clock ,Bayesian reasoning ,Phylogenomics ,Evolutionary rate ,Character-based inference ,Article ,Recombination ,Tree of Life ,Phylogeography ,Mutation ,Phylogenetic tree ,Taxonomy - Abstract
Biological species, including viruses, change through generations and over time in the process known as evolution. Viruses may evolve at high, uneven, and fluctuating rates among genome sites. The accumulated changes, through either mutation or recombination with other species, are first fixed in the genome of successful individuals that give rise to genetic lineages. The relationship between biological lineages related by common descent is called ‘phylogeny’. For inferring phylogeny, the differences between aligned sequences of genomes and proteins are quantified and depicted in the form of a tree, in which contemporary species and their intermediate and common ancestors occupy, respectively, the terminal nodes, internal nodes, and the root. The tree is characterized by a topology, length of branches, shape, and the root position. A complex mathematical apparatus has been developed for phylogeny inference that can evaluate inter-species differences, facilitate tree building and comparison of trees, and assess the fit between data and tree through, typically, computationally intensive calculations. A reconstructed tree is an approximation of the true phylogeny that practically remains unknown. The phylogenetic analysis is used in applied and fundamental virus research, including epidemiology, diagnostics, forensic studies, phylogeography, evolutionary studies, and virus taxonomy. It can provide an evolutionary perspective on variation of any trait that can be measured for a group of viruses.
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- 2017
14. MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients
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Harrach, S, primary, Schmidt-Lauber, C, additional, Pap, T, additional, Pavenstädt, H, additional, Schlatter, E, additional, Schmidt, E, additional, Berdel, W E, additional, Schulze, U, additional, Edemir, B, additional, Jeromin, S, additional, Haferlach, T, additional, Ciarimboli, G, additional, and Bertrand, J, additional
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- 2016
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15. Are there any lessons to be learnt from psychiatric epidemiology?
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Lauber, C., primary
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- 2014
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16. 8903: Are Athletic Training Preceptors Using Patient-Reported Outcome Measures? A Pilot Study.
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Lauber, C. A., Cleveland, A., Davis, R., and Olivas, A.
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CONFERENCES & conventions ,MEDICAL preceptorship ,HEALTH outcome assessment ,TRAINING of athletic trainers - Abstract
Context: Patient-reported outcome measures (PROMs) provide information regarding impairments, function, health, and overall quality of life from the patient's perspective. Typically, questionnaires are used to capture experiences, perceptions, and values from patients. Information gained from PROMs assist clinicians in developing a treatment plan based on the patient's goals. Current literature exists in physical therapy, athletic training, nursing, and physiotherapy regarding the use of PROMs as well as the benefits of and barriers to their use. However, the use of PROMs by health care professionals who serve as both a clinician and a preceptor to athletic training students is absent from the literature. Objective: To determine whether athletic training preceptors in a Midwestern state use PROMs, and to determine the perceived benefits and problems with PROM use. Design: Cross-sectional. Setting: Online questionnaire. Patients or Other Participants: Seventy-five preceptors (M/F:32/43; age = 32.41 ± 9.44 years), recruited from 9 professional athletic training programs in a Midwestern state, completed the questionnaire. Data Collection and Analysis: Participants completed a previously validated online questionnaire consisting of 86 items split into 2 question sets. Participants who identified using PROMs completed 54 questions regarding the benefits, problems, policies, procedures, and selection requirements of PROM use. Participants not using PROMs completed 32 questions regarding problems with PROM use. Questions regarding benefits and problems were rated on a 5-point scale ranging from 1 (strongly disagree) to 5 (strongly agree). The data did not demonstrate normal distribution and represented categorical data. Chi-square tests were used to analyze the data. The α level was P ≤ .05. Results: The majority of responding preceptors (70.7%) do not use PROMs. For those preceptors who use PROMs, there were no significant differences between sex, health care profession, practice setting, or highest degree earned regarding the benefits of or the problems with PROM use (P ≥ .05). Descriptive analysis of preceptors who use PROMs and those who do not indicates perceived differences regarding problems with PROM use. Conclusions: Our results indicate that the majority of athletic training preceptors do not use PROMs in the clinical setting when providing care for patients. Interestingly, the problems with PROM use identified by those preceptors who do not use PROMs are not identified as problems by preceptors who do use PROMs. There seems to be a disconnect between what is perceived as problems with PROM use versus the actual problems of PROMs that were reported by preceptors who use PROMs. Because it appears preceptors are not using PROMs, students are unable to gain experience with PROM use with actual patients. Health care professionals should implement PROMs into their specific clinical setting and identify problems of PROM use. Each health care professional can work toward finding the solution to the most common problems of PROM use related to their clinical setting. [ABSTRACT FROM AUTHOR]
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- 2018
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17. The triglyceride-synthesizing enzyme diacylglycerol acyltransferase 2 modulates the formation of the hepatitis C virus replication organelle.
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Reichert I, Lee JY, Weber L, Fuh MM, Schlaeger L, Rößler S, Kinast V, Schlienkamp S, Conradi J, Vondran FWR, Pfaender S, Scaturro P, Steinmann E, Bartenschlager R, Pietschmann T, Heeren J, Lauber C, and Vieyres G
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- Humans, Hepatitis C metabolism, Hepatitis C virology, Lipid Droplets metabolism, Lipid Droplets virology, Diacylglycerol O-Acyltransferase metabolism, Diacylglycerol O-Acyltransferase genetics, Hepacivirus physiology, Virus Replication physiology, Triglycerides metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum virology
- Abstract
The replication organelle of hepatitis C virus (HCV), called membranous web, is derived from the endoplasmic reticulum (ER) and mainly comprises double membrane vesicles (DMVs) that concentrate the viral replication complexes. It also tightly associates with lipid droplets (LDs), which are essential for virion morphogenesis. In particular acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a rate-limiting enzyme in triglyceride synthesis, promotes early steps of virus assembly. The close proximity between ER membranes, DMVs and LDs therefore permits the efficient coordination of the HCV replication cycle. Here, we demonstrate that exaggerated LD accumulation due to the excessive expression of the DGAT1 isozyme, DGAT2, dramatically impairs the formation of the HCV membranous web. This effect depended on the enzymatic activity and ER association of DGAT2, whereas the mere LD accumulation was not sufficient to hamper HCV RNA replication. Our lipidomics data indicate that both HCV infection and DGAT2 overexpression induced membrane lipid biogenesis and markedly increased phospholipids with long chain polyunsaturated fatty acids, suggesting a dual use of these lipids and their possible competition for LD and DMV biogenesis. On the other hand, overexpression of DGAT2 depleted specific phospholipids, particularly oleyl fatty acyl chain-containing phosphatidylcholines, which, in contrast, are increased in HCV-infected cells and likely essential for viral infection. In conclusion, our results indicate that lipid exchanges occurring during LD biogenesis regulate the composition of intracellular membranes and thereby affect the formation of the HCV replication organelle. The potent antiviral effect observed in our DGAT2 overexpression system unveils lipid flux that may be relevant in the context of steatohepatitis, a hallmark of HCV infection, but also in physiological conditions, locally in specific subdomains of the ER membrane. Thus, LD formation mediated by DGAT1 and DGAT2 might participate in the spatial compartmentalization of HCV replication and assembly factories within the membranous web., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Reichert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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18. Characterization of a GDS(L)-like hydrolase from Pleurotus sapidus with an unusual SGNH motif.
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Fingerhut MA, Henrich L, Lauber C, Broel N, Ghezellou P, Karrer D, Spengler B, Langfelder K, Stressler T, Zorn H, and Gand M
- Abstract
The GDS(L)-like lipase from the Basidiomycota Pleurotus sapidus (PSA_Lip) was heterologously expressed using Trichoderma reesei with an activity of 350 U L
-1 . The isoelectric point of 5.0 was determined by isoelectric focusing. The novel PSA_Lip showed only 23.8-25.1%, 25.5%, 26.6% and 28.4% identity to the previously characterized GDSL-like enzymes phospholipase, plant lipase, acetylcholinesterase and acetylxylan esterase, from the carbohydrate esterase family 16, respectively. Therefore, the enzyme was purified from the culture supernatant and the catalytic properties and the substrate specificity of the enzyme were investigated using different assays to reveal its potential function. While no phospholipase, acetylcholinesterase and acetylxylan esterase activities were detected, studies on the hydrolysis of ferulic acid methyl ester (~ 8.3%) and feruloylated carbohydrate 5-O-transferuloyl-arabino-furanose (~ 0.8%) showed low conversions of these substrates. By investigating the hydrolytic activity towards p-nitrophenyl-(pNP)-esters with various chain-lengths, the highest activity was determined for medium chain-length pNP-octanoate at 65 °C and a pH value of 8, while almost no activity was detected for pNP-hexanoate. The enzyme is highly stable when stored at pH 10 and 4 °C for at least 7 days. Moreover, using consensus sequence analysis and homology modeling, we could demonstrate that the PSA_Lip does not contain the usual SGNH residues in the actives site, which are usually present in GDS(L)-like enzymes., (© 2024. The Author(s).)- Published
- 2024
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19. Acute kidney injury predicts mortality in very elderly critically-ill patients.
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Alba Schmidt E, De Rosa S, Müller J, Hüsing P, Daniels R, Theile P, Schweingruber N, Kluge S, Huber TB, Roedl K, and Schmidt-Lauber C
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- Humans, Male, Female, Retrospective Studies, Aged, 80 and over, Germany epidemiology, Incidence, Length of Stay statistics & numerical data, Risk Factors, Acute Kidney Injury mortality, Acute Kidney Injury epidemiology, Critical Illness mortality, Hospital Mortality, Intensive Care Units, Creatinine blood
- Abstract
Background: The increasing admissions of very elderly patients to intensive care units (ICUs) over recent decades highlight a growing need for understanding acute kidney injury (AKI) in this population. Although these individuals are potentially at high risk for AKI and adverse outcomes, data on AKI in this population is scarce. This study investigates the AKI incidence and outcomes of critically-ill patients aging at least 90 years., Methods: This retrospective cohort study conducted at the Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Germany (2008-2020), investigates AKI incidence and outcomes between 2008 and 2020 in critically-ill patients aged ≥ 90 years. AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria using creatinine dynamics and/or urine output. Primary endpoint was overall mortality after 1 year. Secondary endpoints were in-hospital mortality, length of ICU and hospital stay., Results: During the study period 92,958 critically-ill patients were treated and 1108 were ≥ 90 years. Of these, 1054 patients had available creatinine values and were included in the present study. AKI occurred in 24.4%, mostly classified as mild (17.5%). AKI was independently associated with a significant increase in overall mortality (HR 1.21, 95 %-CI: 1.01-1.46), in-hospital mortality (OR 2, 1.41-2.85), length of ICU (+2.8 days, 2.3-3.3) and hospital stay (+2.3 days, 0.9-3.7). Severity escalated these effects, but even mild AKI showed significance. Introducing urine-based criteria increased incidence but compromised mortality prediction., Conclusions: AKI is a frequent complication in very elderly critically-ill patients. Occurrence of AKI at any stage was associated with increased mortality. Predictive ability applied to AKI defined by creatinine but not urine output. Careful attention of creatinine dynamics is essential in very elderly ICU-patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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20. Pathogen dynamics and discovery of novel viruses and enzymes by deep nucleic acid sequencing of wastewater.
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Wyler E, Lauber C, Manukyan A, Deter A, Quedenau C, Teixeira Alves LG, Wylezich C, Borodina T, Seitz S, Altmüller J, and Landthaler M
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- Sewage virology, Viruses genetics, Wastewater virology, High-Throughput Nucleotide Sequencing
- Abstract
Wastewater contains an extensive reservoir of genetic information, yet largely unexplored. Here, we analyzed by high-throughput sequencing total nucleic acids extracted from wastewater samples collected during a 17 month-period in Berlin, Germany. By integrating global wastewater datasets and applying a novel computational approach to accurately identify viral strains within sewage RNA-sequencing data, we demonstrated the emergence and global dissemination of a specific astrovirus strain. Astrovirus abundance and sequence variation mirrored temporal and spatial patterns of infection, potentially serving as footprints of specific timeframes and geographical locations. Additionally, we revealed more than 100,000 sequence contigs likely originating from novel viral species, exhibiting distinct profiles in total RNA and DNA datasets and including undescribed bunyaviruses and parvoviruses. Finally, we identified thousands of new CRISPR-associated protein sequences, including Transposase B (TnpB), a class of compact, RNA-guided DNA editing enzymes. Collectively, our findings underscore the potential of high-throughput sequencing of total nucleic acids derived from wastewater for a broad range of applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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21. Effect of periprocedural furosemide-induced diuresis with matched isotonic intravenous hydration in patients with chronic kidney disease undergoing transcatheter aortic valve implantation.
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Voigtländer-Buschmann L, Schäfer S, Schmidt-Lauber C, Weimann J, Shenas M, Giraldo Cortes J, Kuta PM, Zeller T, Twerenbold R, Seiffert M, Schofer N, Schneeberger Y, Schäfer A, Schirmer J, Reichenspurner H, Blankenberg S, Conradi L, and Schäfer U
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- Humans, Female, Male, Aged, 80 and over, Aged, Fluid Therapy methods, Treatment Outcome, Diuresis drug effects, Diuretics administration & dosage, Diuretics therapeutic use, Contrast Media adverse effects, Contrast Media administration & dosage, Postoperative Complications prevention & control, Postoperative Complications epidemiology, Risk Factors, Transcatheter Aortic Valve Replacement adverse effects, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic physiopathology, Aortic Valve Stenosis surgery, Furosemide administration & dosage, Acute Kidney Injury prevention & control, Acute Kidney Injury chemically induced, Acute Kidney Injury etiology
- Abstract
Background: Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) is a serious complication which is associated with increased mortality. The RenalGuard system was developed to reduce the risk of AKI after contrast media exposition by furosemide-induced diuresis with matched isotonic intravenous hydration. The aim of this study was to examine the effect of the RenalGuard system on the occurrence of AKI after TAVI in patients with chronic kidney disease., Methods: The present study is a single-center randomized trial including patients with severe aortic valve stenosis undergoing TAVI. Overall, a total of 100 patients treated by TAVI between January 2017 and August 2018 were randomly assigned to a periprocedural treatment with the RenalGuard system or standard treatment by pre- and postprocedural intravenous hydration. Primary endpoint was the occurrence of AKI after TAVI, and secondary endpoints were assessed according to valve academic research consortium 2 criteria., Results: Overall, the prevalence of AKI was 18.4% (n = 18). The majority of these patients developed mild AKI according to stage 1. Comparing RenalGuard to standard therapy, no significant differences were observed in the occurrence of AKI (RenalGuard: 21.3%; control group: 15.7%; p = 0.651). In addition, there were no differences between the groups with regard to 30-day and 12-month mortality and procedure-associated complication rates., Conclusion: In this randomized trial, we did not detect a reduction in AKI after TAVI by using the RenalGuard system. A substantial number of patients with chronic kidney disease developed AKI after TAVI, whereas the majority presented with mild AKI according to stage 1 (ClinicalTrials.gov number NCT04537325)., (© 2023. The Author(s).)
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- 2024
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22. Kidney dysfunction predicts 90 days mortality after stroke thrombectomy independent of cardiovascular risk factors and chronic kidney disease.
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Heinze M, Schell M, Nägele FL, Cheng B, Flottmann F, Fiehler J, Schmidt-Lauber C, and Thomalla G
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- Humans, Female, Male, Aged, Cross-Sectional Studies, Aged, 80 and over, Middle Aged, Risk Factors, Glomerular Filtration Rate, Ischemic Stroke mortality, Ischemic Stroke complications, Stroke mortality, Heart Disease Risk Factors, Renal Insufficiency, Chronic mortality, Renal Insufficiency, Chronic complications, Thrombectomy
- Abstract
Introduction: Kidney dysfunction (KD) is a risk factor for cerebrovascular events and has been shown to have a detrimental effect on outcome after stroke. We evaluated the influence of KD at admission and pre-existing diagnosis of chronic kidney disease (CKD) before thrombectomy for anterior circulation stroke on functional independence and mortality 90 days after stroke in this cross-sectional study., Patients and Methods: We included patients with acute ischemic stroke in the anterior circulation treated with thrombectomy at our hospital between June 2015 and May 2022. We analyzed clinical characteristics, laboratory values and pre-existing diagnosis of CKD. KD at admission was defined as glomerular filtration rate (GFR) <60 ml/min/1.73 m
2 . Outcomes were defined as a modified Rankin Scale Score of 0-2 for functional independence and mortality at 90 days. We fitted multivariate regression analysis to examine the influence of pre-treatment KD and pre-diagnosed CKD on outcome., Results: Nine hundred fifty-three patients were included in this analysis (mean age 73.8 years, 54.2% female). KD was present in 31.8%, and patients with KD were older and more often female, presented more often with comorbidities such as arterial hypertension, diabetes, and atrial fibrillation, and were less often independent before the index stroke. In multivariate analysis adjusted for age, independence before the index stroke, diabetes, hypertension, atrial fibrillation, initial NIHSS, thrombolysis treatment, and recanalization outcome, KD on admission had no significant influence on functional independence 90 days after stroke, but predicted mortality with an odds ratio of 1.80 (95% CI 1.23-2.63, p = 0.003). This influence also persisted when controlling for pre-diagnosed CKD (OR 1.60, 95% CI 1.05-2.43, p = 0.027)., Discussion: KD might function as a surrogate parameter for comorbidity burden and thus increased risk of mortality in this cohort., Conclusions: KD on admission is associated with an 80% higher risk of mortality at 90 days after stroke thrombectomy independent of cardiovascular risk factors and CKD awareness. KD on admission should not exclude patients from thrombectomy but might support prognostic evaluation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.- Published
- 2024
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23. Analysis of Replication, Cell Division-Mediated Spread, and HBV Envelope Protein-Dependent Pseudotyping of Three Mammalian Delta-like Agents.
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Gnouamozi GE, Zhang Z, Prasad V, Lauber C, Seitz S, and Urban S
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- Animals, Humans, Cell Division, Chiroptera virology, Viral Envelope Proteins genetics, Viral Envelope Proteins metabolism, Cell Line, Hepatitis B virology, Hepatitis B Surface Antigens genetics, Hepatitis B Surface Antigens metabolism, Genotype, HEK293 Cells, Hepatitis D virology, RNA, Viral genetics, RNA, Viral metabolism, Virus Replication, Hepatitis Delta Virus genetics, Hepatitis Delta Virus physiology, Hepatitis B virus genetics, Hepatitis B virus physiology, Marmota virology
- Abstract
The human hepatitis delta virus (HDV) is a satellite RNA virus that depends on hepatitis B virus (HBV) surface proteins (HBsAg) to assemble into infectious virions targeting the same organ (liver) as HBV. Until recently, the evolutionary origin of HDV remained largely unknown. The application of bioinformatics on whole sequence databases lead to discoveries of HDV-like agents (DLA) and shed light on HDV's evolution, expanding our understanding of HDV biology. DLA were identified in heterogeneous groups of vertebrates and invertebrates, highlighting that the evolution of HDV, represented by eight distinct genotypes, is broader and more complex than previously foreseen. In this study, we focused on the characterization of three mammalian DLA discovered in woodchuck ( Marmota monax ), white-tailed deer ( Odocoileus virginianus ), and lesser dog-like bat ( Peropteryx macrotis ) in terms of replication, cell-type permissiveness, and spreading pathways. We generated replication-competent constructs expressing 1.1-fold over-length antigenomic RNA of each DLA. Replication was initiated by transfecting the cDNAs into human (HuH7, HeLa, HEK293T, A549) and non-human (Vero E6, CHO, PaKi, LMH) cell lines. Upon transfection and replication establishment, none of the DLA expressed a large delta antigen. A cell division-mediated viral amplification assay demonstrated the capability of non-human DLA to replicate and propagate in hepatic and non-hepatic tissues, without the requirement of envelope proteins from a helper virus. Remarkably L-HDAg but not S-HDAg from HDV can artificially mediate envelopment of WoDV and DeDV ribonucleoproteins (RNPs) by HBsAg to form infectious particles, as demonstrated by co-transfection of HuH7 cells with the respective DLA expression constructs and a plasmid encoding HBV envelope proteins. These chimeric viruses are sensitive to HDV entry inhibitors and allow synchronized infections for comparative replication studies. Our results provide a more detailed understanding of the molecular biology, evolution, and virus-host interaction of this unique group of animal viroid-like agents in relation to HDV.
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- 2024
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24. Deep mining of the Sequence Read Archive reveals major genetic innovations in coronaviruses and other nidoviruses of aquatic vertebrates.
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Lauber C, Zhang X, Vaas J, Klingler F, Mutz P, Dubin A, Pietschmann T, Roth O, Neuman BW, Gorbalenya AE, Bartenschlager R, and Seitz S
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- Animals, Vertebrates virology, Vertebrates genetics, Fishes virology, Evolution, Molecular, Data Mining, Nidovirales Infections virology, Nidovirales Infections genetics, Nidovirales genetics, Genome, Viral, Coronavirus genetics, Coronavirus classification, Phylogeny
- Abstract
Virus discovery by genomics and metagenomics empowered studies of viromes, facilitated characterization of pathogen epidemiology, and redefined our understanding of the natural genetic diversity of viruses with profound functional and structural implications. Here we employed a data-driven virus discovery approach that directly queries unprocessed sequencing data in a highly parallelized way and involves a targeted viral genome assembly strategy in a wide range of sequence similarity. By screening more than 269,000 datasets of numerous authors from the Sequence Read Archive and using two metrics that quantitatively assess assembly quality, we discovered 40 nidoviruses from six virus families whose members infect vertebrate hosts. They form 13 and 32 putative viral subfamilies and genera, respectively, and include 11 coronaviruses with bisegmented genomes from fishes and amphibians, a giant 36.1 kilobase coronavirus genome with a duplicated spike glycoprotein (S) gene, 11 tobaniviruses and 17 additional corona-, arteri-, cremega-, nanhypo- and nangoshaviruses. Genome segmentation emerged in a single evolutionary event in the monophyletic lineage encompassing the subfamily Pitovirinae. We recovered the bisegmented genome sequences of two coronaviruses from RNA samples of 69 infected fishes and validated the presence of poly(A) tails at both segments using 3'RACE PCR and subsequent Sanger sequencing. We report a genetic linkage between accessory and structural proteins whose phylogenetic relationships and evolutionary distances are incongruent with the phylogeny of replicase proteins. We rationalize these observations in a model of inter-family S recombination involving at least five ancestral corona- and tobaniviruses of aquatic hosts. In support of this model, we describe an individual fish co-infected with members from the families Coronaviridae and Tobaniviridae. Our results expand the scale of the known extraordinary evolutionary plasticity in nidoviral genome architecture and call for revisiting fundamentals of genome expression, virus particle biology, host range and ecology of vertebrate nidoviruses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lauber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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25. Daratumumab as rescue therapy in life-threatening granulomatosis with polyangiitis.
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Krusche M, Oqueka T, Wichmann D, Kluge S, Huber TB, Kötter I, and Schmidt-Lauber C
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- Humans, Antibodies, Monoclonal therapeutic use, Granulomatosis with Polyangiitis drug therapy
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- 2024
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26. Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.
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Sake SM, Zhang X, Rajak MK, Urbanek-Quaing M, Carpentier A, Gunesch AP, Grethe C, Matthaei A, Rückert J, Galloux M, Larcher T, Le Goffic R, Hontonnou F, Chatterjee AK, Johnson K, Morwood K, Rox K, Elgaher WAM, Huang J, Wetzke M, Hansen G, Fischer N, Eléouët JF, Rameix-Welti MA, Hirsch AKH, Herold E, Empting M, Lauber C, Schulz TF, Krey T, Haid S, and Pietschmann T
- Subjects
- Animals, Female, Mice, Drug Repositioning, Piperidines pharmacology, Piperidines therapeutic use, Viral Fusion Proteins genetics, Viral Fusion Proteins chemistry, Dibenzocycloheptenes, Pyridines, Respiratory Syncytial Virus Infections drug therapy
- Abstract
Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC
50 : 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor., (© 2024. The Author(s).)- Published
- 2024
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27. Early acute kidney injury and transition to renal replacement therapy in critically ill patients with SARS-CoV-2 requiring veno-venous extracorporeal membrane oxygenation.
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Roedl K, De Rosa S, Fischer M, Braunsteiner J, Schmidt-Lauber C, Jarczak D, Huber TB, Kluge S, and Wichmann D
- Abstract
Background: Critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requiring veno-venous extracorporeal membrane oxygenation (vv-ECMO) are at risk for acute kidney injury (AKI). Currently, the incidence of AKI and progression to kidney replacement therapy (RRT) in critically ill patients with vv-ECMO for severe COVID-19 and implications on outcome are still unclear., Methods: Retrospective analysis at the University Medical Center Hamburg-Eppendorf (Germany) between March 1st, 2020 and July 31st, 2021. Demographics, clinical parameters, AKI, type of organ support, length of ICU stay, mortality and severity scores were assessed., Results: Ninety-one critically ill patients with SARS-CoV-2 requiring ECMO were included. The median age of the study population was 57 (IQR 49-64) years and 67% (n = 61) were male. The median SAPS II and SOFA Score on admission were 40 (34-46) and 12 (10-14) points, respectively. We observed that 45% (n = 41) developed early-AKI, 38% (n = 35) late-AKI and 16% (n = 15) no AKI during the ICU stay. Overall, 70% (n = 64) of patients required RRT during the ICU stay, 93% with early-AKI and 74% with late-AKI. Risk factors for early-AKI were younger age (OR 0.94, 95% CI 0.90-0.99, p = 0.02) and SAPS II (OR 1.12, 95% CI 1.06-1.19, p < 0.001). Patients with and without RRT were comparable regarding baseline characteristics. SAPS II (41 vs. 37 points, p < 0.05) and SOFA score (13 vs. 12 points, p < 0.05) on admission were significantly higher in patients receiving RRT. The median duration of ICU (36 vs. 28 days, p = 0.27) stay was longer in patients with RRT. An ICU mortality rate in patients with RRT in 69% (n = 44) and in patients without RRT of 56% (n = 27) was observed (p = 0.23)., Conclusion: Critically ill patients with severe SARS-CoV-2 related ARDS requiring vv-ECMO are at high risk of early acute kidney injury. Early-AKI is associated with age and severity of illness, and presents with high need for RRT. Mortality in patients with RRT was comparable to patients without RRT., (© 2023. The Author(s).)
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- 2023
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28. Evolutionary Insight into the Association between New Jersey Polyomavirus and Humans.
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Aghebatrafat AA, Lauber C, Merkel K, Fruth B, Langergraber K, Robbins MM, Wittig RM, Leendertz FH, and Calvignac-Spencer S
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- Animals, Humans, New Jersey epidemiology, Biological Evolution, Phylogeny, Polyomavirus genetics, Hominidae, Polyomavirus Infections epidemiology
- Abstract
Advances in viral discovery techniques have led to the identification of numerous novel viruses in human samples. However, the low prevalence of certain viruses in humans raises doubts about their association with our species. To ascertain the authenticity of a virus as a genuine human-infecting agent, it can be useful to investigate the diversification of its lineage within hominines, the group encompassing humans and African great apes. Building upon this rationale, we examined the case of the New Jersey polyomavirus (NJPyV; Alphapolyomavirus terdecihominis ), which has only been detected in a single patient thus far. In this study, we obtained and analyzed sequences from closely related viruses infecting all African great ape species. We show that NJPyV nests within the diversity of these viruses and that its lineage placement is compatible with an ancient origin in humans, despite its apparent rarity in human populations.
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- 2023
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29. Increased blood pressure after nonsevere COVID-19.
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Schmidt-Lauber C, Alba Schmidt E, Hänzelmann S, Petersen EL, Behrendt CA, Twerenbold R, Blankenberg S, Huber TB, and Wenzel UO
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- Humans, Middle Aged, Blood Pressure physiology, Cross-Sectional Studies, Prospective Studies, COVID-19 complications, Hypertension
- Abstract
Background: Various sequelae have been described after nonsevere coronavirus disease 2019 (COVID-19), but knowledge on postacute effects on blood pressure is limited., Methods: This is a cross-sectional analysis of blood pressure profiles in individuals after nonsevere COVID-19 compared with matched population-based individuals without prior COVID-19. Data were derived from the ongoing and prospective Hamburg City Health Study, a population-based study in Hamburg, Germany, and its associated COVID-19 program, which included individuals at least 4 months after COVID-19. Matching was performed by age, sex, education, and preexisting hypertension in a 1 : 4 ratio., Results: Four hundred and thirty-two individuals after COVID-19 (mean age 56.1 years) were matched to 1728 controls without prior COVID-19 (56.2 years). About 92.8% of COVID-19 courses were mild or moderate, only 7.2% were hospitalized, and no individual had been treated on an intensive care unit. Even after adjustment for relevant competing risk factors, DBP [+4.7 mmHg, 95% confidence interval (95% CI) 3.97-5.7, P < 0.001] was significantly higher in individuals after COVID-19. For SBP, a trend towards increased values was observed (+1.4 mmHg, 95% CI -0.4 to 3.2, P = 0.120). Hypertensive blood pressures at least 130/80 mmHg (according to the ACC/AHA guideline) and at least 140/90 mmHg (ESC/ESH guideline) occurred significantly more often in individuals after COVID-19 than matched controls (odds ratio 2.0, 95% CI 1.5-2.7, P < 0.001 and odds ratio 1.6, 95% CI 1.3-2.0, P < 0.001, respectively), mainly driven by changes in DBP., Conclusion: Blood pressure is higher in individuals after nonsevere COVID-19 compared with uninfected individuals suggesting a significant hypertensive sequela., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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30. Kidney outcome after mild to moderate COVID-19.
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Schmidt-Lauber C, Hänzelmann S, Schunk S, Petersen EL, Alabdo A, Lindenmeyer M, Hausmann F, Kuta P, Renné T, Twerenbold R, Zeller T, Blankenberg S, Fliser D, and Huber TB
- Subjects
- Humans, SARS-CoV-2, Albuminuria, Cohort Studies, Prospective Studies, Pandemics, Hematuria, Cross-Sectional Studies, Kidney, Disease Progression, COVID-19 complications, COVID-19 epidemiology, Pyuria
- Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela., Methods: This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction-confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria., Results: A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {β = -1.84 [95% confidence interval (CI) -3.16 to -0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48-1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49-1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [β = -72.19 (95% CI -130.0 to -14.4)]., Conclusion: While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
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- 2023
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31. Viroid-like RNA-dependent RNA polymerase-encoding ambiviruses are abundant in complex fungi.
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Chong LC and Lauber C
- Abstract
Ambiviruses are hybrid infectious elements encoding the hallmark gene of RNA viruses, the RNA-dependent RNA polymerase, and self-cleaving RNA ribozymes found in many viroids. Ambiviruses are thought to be pathogens of fungi, although the majority of reported genomes have been identified in metatranscriptomes. Here, we present a comprehensive screen for ambiviruses in more than 46,500 fungal transcriptomes from the Sequence Read Archive (SRA). Our data-driven virus discovery approach identified more than 2,500 ambiviral sequences across the kingdom Fungi with a striking expansion in members of the phylum Basidiomycota representing the most complex fungal organisms. Our study unveils a large diversity of unknown ambiviruses with as little as 27% protein sequence identity to known members and sheds new light on the evolution of this distinct class of infectious agents with RNA genomes. No evidence for the presence of ambiviruses in human microbiomes was obtained from a comprehensive screen of respective metatranscriptomes available in the SRA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chong and Lauber.)
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- 2023
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32. Editor's Choice - Prevalence of Peripheral Arterial Disease, Abdominal Aortic Aneurysm, and Risk Factors in the Hamburg City Health Study: A Cross Sectional Analysis.
- Author
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Behrendt CA, Thomalla G, Rimmele DL, Petersen EL, Twerenbold R, Debus ES, Kölbel T, Blankenberg S, Schmidt-Lauber C, Peters F, and Zyriax BC
- Abstract
Objective: There is a paucity of current figures on the prevalence of carotid and lower extremity peripheral arterial disease (PAD) and abdominal aortic aneurysm (AAA) as well as the associated cardiovascular risk factors to support considerations on screening programmes., Methods: In the population based Hamburg City Health Study, participants between 45 and 74 years were randomly recruited. In the current cross sectional analysis of the first 10 000 participants enrolled between February 2016 and November 2018, the prevalence of carotid artery disease (intima-media thickness ≥ 1 mm), lower extremity PAD (ankle brachial index ≤ 0.9), and AAA (aortic diameter ≥ 30 mm) was determined. Multivariable logistic regression models were applied to determine the association between vascular diseases and risk factors. To account for missing values, multiple imputation was performed., Results: A total of 10 000 participants were analysed (51.1% females, median age 63 years, median body mass index 26.1 kg/m
2 ). In medians, the intima media thickness was 0.74 mm (interquartile range [IQR] 0.65 - 0.84), the ankle brachial index 1.04 (IQR 0.95 - 1.13), and the aortic diameter 17.8 mm (IQR 16.1 - 19.6). Concerning risk factors, 64% self reported any smoking, 39% hypertension, 5% coronary artery disease, 3% congestive heart failure, 5% atrial fibrillation, and 3% history of stroke or myocardial infarction, respectively. In males, the prevalence of carotid artery disease, lower extremity PAD, and AAA were 35.3%, 22.7%, and 1.3%, respectively, and in females, 23.4%, 24.8%, and 0.2%, respectively. Higher age and current smoking were likewise associated with higher prevalence while the impact of variables varied widely., Conclusion: In this large population based cohort study of 10 000 subjects from Hamburg, Germany, a strikingly high prevalence of PAD was revealed. Almost 45% suffered from any index disease, while AAA was only diagnosed in 1.3% of males and 0.2% of females. The high prevalence of atherosclerotic disease and associated cardiovascular risk factors underline that it is essential to increase awareness and fuel efforts for secondary prevention., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2023
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33. Predictors of somatic symptom persistence in patients with chronic kidney disease (SOMA.CK): study protocol for a mixed-methods cohort study.
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Shedden-Mora MC, Jessen B, Schmidt-Lauber C, Löwe B, Rösch M, Dannemeyer H, Gloy J, Van den Bergh O, and Huber TB
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- Humans, Cohort Studies, Quality of Life psychology, Qualitative Research, Medically Unexplained Symptoms, Renal Insufficiency, Chronic complications
- Abstract
Introduction: Seven of 10 patients with non-dialysis chronic kidney disease (CKD) experience burdensome persistent somatic symptoms (PSS). Despite the high prevalence and relevance for quality of life, disease progression and mortality, the pathogenesis of PSS in CKD remains poorly understood. The SOMA.CK study aims to investigate biopsychosocial predictors and their interactions for PSS in non-dialysis CKD and to develop a multivariate prognostic prediction model for PSS in CKD., Methods and Analysis: The study is a mixed-methods cohort study with assessments at baseline, 6 and 12 months. It aims to include 330 patients with CKD stages G2-4 (eGFR=15-89 mL/min/1.73 m
2 ). Primary outcome is the CKD-specific somatic symptom burden assessed with the CKD Symptom Burden Index. Secondary outcomes include quality of life, general somatic symptom burden and functioning. The interplay of biomedical (eg, biomarkers, epigenetics), treatment-related (eg, therapies and medication) and psychosocial variables (eg, negative affectivity, expectations) will be investigated to develop a prognostic prediction model for PSS. In an embedded mixed-methods approach, an experimental study in 100 patients using an affective picture paradigm will test the effect of negative affect induction on symptom perception. An embedded longitudinal qualitative study in 40-50 newly diagnosed patients will use thematic analysis to explore mechanisms of symptom development after receiving a CKD diagnosis. SOMA.CK is part of the interdisciplinary research unit 'Persistent SOMAtic Symptoms ACROSS Diseases'., Ethics and Dissemination: The study was approved by the Ethics Committee of the Hamburg Medical Association (2020-10195-BO-ff). Findings will be disseminated through peer-reviewed publications, scientific conferences, the involvement of our patient advisory board and the lay public. Focusing on subjective symptom burden instead of objective disease markers will fundamentally broaden the understanding of PSS in CKD and pave the path for the development of mechanism-based tailored interventions., Trial Registration Number: ISRCTN16137374., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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34. Outcomes of critically ill coronavirus disease 2019 patients requiring kidney replacement therapy: A retrospective cohort study.
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Braunsteiner J, Jarczak D, Schmidt-Lauber C, Boenisch O, de Heer G, Burdelski C, Frings D, Sensen B, Nierhaus A, Hoxha E, Huber TB, Wichmann D, Kluge S, Fischer M, and Roedl K
- Abstract
Background: Coronavirus disease 2019 (COVID-19) has resulted in high hospitalization rates worldwide. Acute kidney injury (AKI) in patients hospitalized for COVID-19 is frequent and associated with disease severity and poor outcome. The aim of this study was to investigate the incidence of kidney replacement therapy (KRT) in critically ill patients with COVID-19 and its implication on outcome., Methods: We retrospectively analyzed all COVID-19 patients admitted to the Department of Intensive Care Medicine at the University Medical Center Hamburg-Eppendorf (Germany) between 1 March 2020 and 31 July 2021. Demographics, clinical parameters, type of organ support, length of intensive care unit (ICU) stay, mortality and severity scores were assessed., Results: Three-hundred critically ill patients with COVID-19 were included. The median age of the study population was 61 (IQR 51-71) years and 66% ( n = 198) were male. 73% ( n = 219) of patients required invasive mechanical ventilation. Overall, 68% ( n = 204) of patients suffered from acute respiratory distress syndrome and 30% ( n = 91) required extracorporeal membrane oxygenation (ECMO). We found that 46% ( n = 139) of patients required KRT. Septic shock (OR 11.818, 95% CI: 5.941-23.506, p < 0.001), higher simplified acute physiology scores (SAPS II) (OR 1.048, 95% CI: 1.014-1.084, p = 0.006) and vasopressor therapy (OR 5.475, 95% CI: 1.127-26.589, p = 0.035) were independently associated with the initiation of KRT. 61% ( n = 85) of patients with and 18% ( n = 29) without KRT died in the ICU ( p < 0.001). Cox regression found that KRT was independently associated with mortality (HR 2.075, 95% CI: 1.342-3.208, p = 0.001) after adjusting for confounders., Conclusion: Critically ill patients with COVID-19 are at high risk of acute kidney injury with about half of patients requiring KRT. The initiation of KRT was associated with high mortality., Competing Interests: Author SK received research support by Ambu, E.T.View Ltd., Fisher & Paykel, Pfizer, and Xenios, lecture honorarium from ArjoHuntleigh, Astellas, Astra, Basilea, Bard, Baxter, Biotest, CSL Behring, Cytosorbents, Fresenius, Gilead, MSD, Orion, Pfizer, Philips, Sedana, Sorin, Xenios, and Zoll, and consultant honorarium from AMOMED, Astellas, Baxter, Bayer, Fresenius, Gilead, MSD, Pfizer, and Xenios. Author DW received lecture honorarium from 3M, ADVANZ (previously Correvio), AMEOS, Gilead, Kite, Lilly, MSD, Pfizer, and Shionogi and consultation honorarium from Eumedica, EUSA-Pharm, Gilead, Kite, MSD, Novartis, Pfizer, and Shionogi. No other potential conflict of interest relevant to this article was reported. Author AN received research funds, lecture honoraria and travel reimbursement within the last 5 years from CytoSorbents Europe, Biotest AG, and Thermo Fisher Scientific. Author DF reports lecture honoraria within the last 5 years from Xenios AG. Author KR received travel reimbursement from Gilead within the last 5 years. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Braunsteiner, Jarczak, Schmidt-Lauber, Boenisch, de Heer, Burdelski, Frings, Sensen, Nierhaus, Hoxha, Huber, Wichmann, Kluge, Fischer and Roedl.)
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- 2022
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35. The Impact of Chronic Kidney Disease on Mid-Term Outcomes after Revascularisation of Peripheral Arterial Occlusive Disease: Results from a Prospective Cohort Study.
- Author
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Kotov A, Blasche DA, Peters F, Pospiech P, Rother U, Stavroulakis K, Remig J, Schmidt-Lauber C, Zeller T, Görtz H, Teßarek J, and Behrendt CA
- Abstract
Objective: The current study aimed to determine the relationship between chronic kidney disease (CKD) and major 12-month outcomes for patients with in-hospital treatment for symptomatic peripheral arterial occlusive disease (PAOD)., Methods: An analysis of the prospective longitudinal multicentric cohort study with 12-month follow-up was conducted including patients who underwent endovascular or open surgery for symptomatic PAOD at 35 German vascular centres (initial study protocol: NCT03098290). Severity of CKD was grouped into four stages combining information about the estimated glomerular filtration rate (eGFR) at baseline and dialysis dependency. Outcomes included overall mortality as well as the two composite endpoints of amputation or death, and of major cardiovascular events (MACE). 12-month incidences and adjusted hazard ratios were estimated using the Kaplan-Meier function and Cox proportional hazard models., Results: A total of 4354 patients (32% female, 69 years mean age, 68% intermittent claudication, 69% percutaneous endovascular revascularisation) were included and followed for 244 days in median. Thereof, 22% had any CKD and 5% had end stage kidney disease (ESKD) at baseline. The 12-month overall mortality rate was 3.6% (95% CI 2.3-4.9) with 96 events in the entire cohort: 147 were amputated or died (5.3%, 95% CI 5.2-5.3), and 277 had a MACE (9.5%, 95% CI 9.4-9.5). When compared with patients without kidney disease, ESKD was significantly associated with overall mortality (HR 1.9; 95% CI 1.1-3.5), amputation or death (HR 2.4; 95% CI 1.4-4.1), and MACE (HR 2.0; 95% CI 1.3-3.2)., Conclusions: In the current study on mid-term outcomes after invasive revascularisation for symptomatic PAOD, one out of five patients suffered from any CKD while those few with ESKD had twice the odds of death, of amputation or death, and of major adverse cardiovascular events after twelve months. These results emphasise that concomitant CKD and its impact on outcomes should be considered by severity while mild and moderate grades should not lead to ineffectual treatment strategies.
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- 2022
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36. Opportunities and Challenges of Data-Driven Virus Discovery.
- Author
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Lauber C and Seitz S
- Subjects
- Molecular Biology, Sequence Analysis, Viruses genetics
- Abstract
Virus discovery has been fueled by new technologies ever since the first viruses were discovered at the end of the 19th century. Starting with mechanical devices that provided evidence for virus presence in sick hosts, virus discovery gradually transitioned into a sequence-based scientific discipline, which, nowadays, can characterize virus identity and explore viral diversity at an unprecedented resolution and depth. Sequencing technologies are now being used routinely and at ever-increasing scales, producing an avalanche of novel viral sequences found in a multitude of organisms and environments. In this perspective article, we argue that virus discovery has started to undergo another transformation prompted by the emergence of new approaches that are sequence data-centered and primarily computational, setting them apart from previous technology-driven innovations. The data-driven virus discovery approach is largely uncoupled from the collection and processing of biological samples, and exploits the availability of massive amounts of publicly and freely accessible data from sequencing archives. We discuss open challenges to be solved in order to unlock the full potential of data-driven virus discovery, and we highlight the benefits it can bring to classical (mostly molecular) virology and molecular biology in general.
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- 2022
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37. A set of gene knockouts as a resource for global lipidomic changes.
- Author
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Spiegel A, Lauber C, Bachmann M, Heninger AK, Klose C, Simons K, Sarov M, and Gerl MJ
- Subjects
- Animals, Fatty Acids genetics, Gene Knockout Techniques, Lipids genetics, Mammals, Lipid Metabolism genetics, Lipidomics
- Abstract
Enzyme specificity in lipid metabolic pathways often remains unresolved at the lipid species level, which is needed to link lipidomic molecular phenotypes with their protein counterparts to construct functional pathway maps. We created lipidomic profiles of 23 gene knockouts in a proof-of-concept study based on a CRISPR/Cas9 knockout screen in mammalian cells. This results in a lipidomic resource across 24 lipid classes. We highlight lipid species phenotypes of multiple knockout cell lines compared to a control, created by targeting the human safe-harbor locus AAVS1 using up to 1228 lipid species and subspecies, charting lipid metabolism at the molecular level. Lipid species changes are found in all knockout cell lines, however, some are most apparent on the lipid class level (e.g., SGMS1 and CEPT1), while others are most apparent on the fatty acid level (e.g., DECR2 and ACOT7). We find lipidomic phenotypes to be reproducible across different clones of the same knockout and we observed similar phenotypes when two enzymes that catalyze subsequent steps of the long-chain fatty acid elongation cycle were targeted., (© 2022. The Author(s).)
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- 2022
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38. The Human Liver-Expressed Lectin CD302 Restricts Hepatitis C Virus Infection.
- Author
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Reinecke B, Frericks N, Lauber C, Dinkelborg K, Matthaei A, Vondran FWR, Behrendt P, Haid S, Brown RJP, and Pietschmann T
- Subjects
- Antiviral Agents metabolism, Hepatocytes immunology, Hepatocytes virology, Humans, Virus Replication, Hepacivirus physiology, Hepatitis C immunology, Lectins, C-Type genetics, Lectins, C-Type metabolism, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism
- Abstract
C-type lectin domain-containing proteins (CTLDcps) shape host responses to pathogens and infectious disease outcomes. Previously, we identified the murine CTLDcp Cd302 as restriction factor, limiting hepatitis C virus (HCV) infection of murine hepatocytes. In this study, we investigated in detail the human orthologue's ability to restrict HCV infection in human liver cells. CD302 overexpression in Huh-7.5 cells potently inhibited infection of diverse HCV chimeras representing seven genotypes. Transcriptional profiling revealed abundant CD302 mRNA expression in human hepatocytes, the natural cellular target of HCV. Knockdown of endogenously expressed CD302 modestly enhanced HCV infection of Huh-7.5 cells and primary human hepatocytes. Functional analysis of naturally occurring CD302 transcript variants and engineered CD302 mutants showed that the C-type lectin-like domain (CTLD) is essential for HCV restriction, whereas the cytoplasmic domain (CPD) is dispensable. Coding single nucleotide polymorphisms occurring in human populations and mapping to different domains of CD302 did not influence the capacity of CD302 to restrict HCV. Assessment of the anti-HCV phenotype at different life cycle stages indicated that CD302 preferentially targets the viral entry step. In contrast to the murine orthologue, overexpression of human CD302 did not modulate downstream expression of nuclear receptor-controlled genes. Ectopic CD302 expression restricted infection of liver tropic hepatitis E virus (HEV), while it did not affect infection rates of two respiratory viruses, including respiratory syncytial virus (RSV) and the alpha coronavirus HVCoV-229E. Together, these findings suggest that CD302 contributes to liver cell-intrinsic defense against HCV and might mediate broader antiviral defenses against additional hepatotropic viruses. IMPORTANCE The liver represents an immunoprivileged organ characterized by enhanced resistance to immune responses. However, the importance of liver cell-endogenous, noncytolytic innate immune responses in pathogen control is not well defined. Although the role of myeloid cell-expressed CTLDcps in host responses to viruses has been characterized in detail, we have little information about their potential functions in the liver and their relevance for immune responses in this organ. Human hepatocytes endogenously express the CTLDcp CD302. Here, we provide evidence that CD302 limits HCV infection of human liver cells, likely by inhibiting a viral cell entry step. We confirm that the dominant liver-expressed transcript variant, as well as naturally occurring coding variants of CD302, maintain the capacity to restrict HCV. We further show that the CTLD of the protein is critical for the anti-HCV activity and that overexpressed CD302 limits HEV infection. Thus, CD302 likely contributes to human liver-intrinsic antiviral defenses.
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- 2022
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39. Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme.
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Petersen EL, Goßling A, Adam G, Aepfelbacher M, Behrendt CA, Cavus E, Cheng B, Fischer N, Gallinat J, Kühn S, Gerloff C, Koch-Gromus U, Härter M, Hanning U, Huber TB, Kluge S, Knobloch JK, Kuta P, Schmidt-Lauber C, Lütgehetmann M, Magnussen C, Mayer C, Muellerleile K, Münch J, Nägele FL, Petersen M, Renné T, Riedl KA, Rimmele DL, Schäfer I, Schulz H, Tahir E, Waschki B, Wenzel JP, Zeller T, Ziegler A, Thomalla G, Twerenbold R, and Blankenberg S
- Subjects
- Cohort Studies, Humans, SARS-CoV-2, Stroke Volume, Ventricular Function, Left, COVID-19 diagnosis, COVID-19 epidemiology
- Abstract
Aims: Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population., Methods and Results: Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient -3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography -0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient -2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ., Conclusion: Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)
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- 2022
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40. Lipidomic risk scores are independent of polygenic risk scores and can predict incidence of diabetes and cardiovascular disease in a large population cohort.
- Author
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Lauber C, Gerl MJ, Klose C, Ottosson F, Melander O, and Simons K
- Subjects
- Cardiovascular Diseases epidemiology, Cardiovascular Diseases metabolism, Cohort Studies, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 metabolism, Female, Genomics methods, Humans, Incidence, Lipids blood, Male, Middle Aged, Proportional Hazards Models, Risk Assessment methods, Risk Factors, Sweden epidemiology, Cardiovascular Diseases genetics, Diabetes Mellitus, Type 2 genetics, Lipidomics methods, Multifactorial Inheritance genetics, Risk Assessment statistics & numerical data
- Abstract
Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to disease incidence. Here we integrated genetics, lipidomics, and standard clinical diagnostics to assess future T2D and CVD risk for 4,067 participants from a large prospective population-based cohort, the Malmö Diet and Cancer-Cardiovascular Cohort. By training Ridge regression-based machine learning models on the measurements obtained at baseline when the individuals were healthy, we computed several risk scores for T2D and CVD incidence during up to 23 years of follow-up. We used these scores to stratify the participants into risk groups and found that a lipidomics risk score based on the quantification of 184 plasma lipid concentrations resulted in a 168% and 84% increase of the incidence rate in the highest risk group and a 77% and 53% decrease of the incidence rate in lowest risk group for T2D and CVD, respectively, compared to the average case rates of 13.8% and 22.0%. Notably, lipidomic risk correlated only marginally with polygenic risk, indicating that the lipidome and genetic variants may constitute largely independent risk factors for T2D and CVD. Risk stratification was further improved by adding standard clinical variables to the model, resulting in a case rate of 51.0% and 53.3% in the highest risk group for T2D and CVD, respectively. The participants in the highest risk group showed significantly altered lipidome compositions affecting 167 and 157 lipid species for T2D and CVD, respectively. Our results demonstrated that a subset of individuals at high risk for developing T2D or CVD can be identified years before disease incidence. The lipidomic risk, which is derived from only one single mass spectrometric measurement that is cheap and fast, is informative and could extend traditional risk assessment based on clinical assays., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KS is CEO of Lipotype GmbH. KS and CK are shareholders of Lipotype GmbH. CL and MJG are employees of Lipotype GmbH.
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- 2022
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41. Molecular consequences of SARS-CoV-2 liver tropism.
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Wanner N, Andrieux G, Badia-I-Mompel P, Edler C, Pfefferle S, Lindenmeyer MT, Schmidt-Lauber C, Czogalla J, Wong MN, Okabayashi Y, Braun F, Lütgehetmann M, Meister E, Lu S, Noriega MLM, Günther T, Grundhoff A, Fischer N, Bräuninger H, Lindner D, Westermann D, Haas F, Roedl K, Kluge S, Addo MM, Huber S, Lohse AW, Reiser J, Ondruschka B, Sperhake JP, Saez-Rodriguez J, Boerries M, Hayek SS, Aepfelbacher M, Scaturro P, Puelles VG, and Huber TB
- Subjects
- Humans, Liver, Proteomics, Tropism, COVID-19, SARS-CoV-2
- Abstract
Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae
1 . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3 . Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets., (© 2022. The Author(s).)- Published
- 2022
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42. Bioinformatics of virus taxonomy: foundations and tools for developing sequence-based hierarchical classification.
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Gorbalenya AE and Lauber C
- Subjects
- Computational Biology, DNA Viruses genetics, Genome, Viral, Phylogeny, Viruses genetics, Viruses, Unclassified genetics
- Abstract
The genome sequence is the only characteristic readily obtainable for all known viruses, underlying the growing role of comparative genomics in organizing knowledge about viruses in a systematic evolution-aware way, known as virus taxonomy. Overseen by the International Committee on Taxonomy of Viruses (ICTV), development of virus taxonomy involves taxa demarcation at 15 ranks of a hierarchical classification, often in host-specific manner. Outside the ICTV remit, researchers assess fitting numerous unclassified viruses into the established taxa. They employ different metrics of virus clustering, basing on conserved domain(s), separation of viruses in rooted phylogenetic trees and pair-wise distance space. Computational approaches differ further in respect to methodology, number of ranks considered, sensitivity to uneven virus sampling, and visualization of results. Advancing and using computational tools will be critical for improving taxa demarcation across the virosphere and resolving rank origins in research that may also inform experimental virology., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2022
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43. Increased rejection rates in kidney transplantations during the COVID-19 pandemic.
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Schmidt-Lauber C, Spoden M, Huber TB, Günster C, and Grahammer F
- Subjects
- Graft Rejection, Humans, Pandemics, SARS-CoV-2, COVID-19, Kidney Transplantation
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- 2021
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44. Collateral Effects and Mortality of Kidney Transplant Recipients during the COVID-19 Pandemic.
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Schmidt-Lauber C, Günster C, Huber TB, Spoden M, and Grahammer F
- Subjects
- Communicable Disease Control, Humans, Pandemics, Renal Dialysis, Retrospective Studies, COVID-19, Kidney Transplantation adverse effects
- Abstract
Background: Collateral effects and consequences of the coronavirus disease 19 (COVID-19) pandemic on kidney transplant recipients remain widely unknown., Methods: This retrospective cohort study examined changes in admission rates, incidences of diseases leading to hospitalization, in-patient procedures, and maintenance medication in long-term kidney transplant recipients with functioning graft during the early COVID-19 pandemic in Germany. Data were derived from a nationwide health insurance database. Analysis was performed from March 15 to September 30 and compared the years 2019 and 2020. Effects on mortality and adverse allograft events were compared with COVID-19-attributed effects., Results: A total of 7725 patients were included in the final analysis. Admissions declined in 2020 by 17%, with the main dip during a 3-month lockdown (-31%) but without a subsequent rebound. Incidences for hospitalization did not increase for any investigated disease entities, whereas decreasing trends were noted for non-COVID-19 pulmonary and urogenital infections (incidence rate ratio 0.8, 95% CI, 0.62 to 1.03, and 0.82, 95% CI, 0.65 to 1.04, respectively). Non-COVID-19 hospital stays were 0.6 days shorter ( P =0.03) and not complicated by increased dialysis, ventilation, or intensive care treatment rates. In-hospital and 90-day mortality remained stable. Incidences of severe COVID-19 requiring hospitalization was 0.09 per 1000 patient-days, and in-hospital mortality was 9%. A third (31%) of patients with calcineurin-inhibitor medication and without being hospitalized for COVID-19 reduced doses by at least 25%, which was associated with an increased allograft rejection risk (adjusted hazard ratio 1.29, 95% CI, 1.02 to 1.63). COVID-19 caused 17% of all deaths but had no significant association with allograft rejections. All-cause mortality remained stable (incidence rate ratio 1.15, 95% CI, 0.91 to 1.46), also when restricting analysis to patients with no or outpatient-treated COVID-19 (0.97, 95% CI, 0.76 to 1.25)., Conclusion: Despite significant collateral effects, mortality remained unchanged during the early COVID-19 pandemic. Considerable temporary reductions in admissions are safe, whereas reducing immunosuppression results in increased allograft rejection risk., Competing Interests: T.B. Huber has consultancy agreements with Astrazeneca, Boehringer-Ingelheim, DaVita, Deerfield, Fresenius Medical Care, GoldfinchBio, MantraBio, Novartis, and Retrophin, and received research funding from Amicus and Fresenius Medical Care. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)
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- 2021
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45. Convalescent plasma treatment for early post-kidney transplant acquired COVID-19.
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Kluger MA, Czogalla J, Schmidt-Lauber C, Peine S, Schmiedel S, Bangert K, Kluge S, Huber S, Puelles VG, Fischer L, Huber TB, and Grahammer F
- Published
- 2021
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46. Shotgun mass spectrometry-based lipid profiling identifies and distinguishes between chronic inflammatory diseases.
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Matthiesen R, Lauber C, Sampaio JL, Domingues N, Alves L, Gerl MJ, Almeida MS, Rodrigues G, Araújo Gonçalves P, Ferreira J, Borbinha C, Pedro Marto J, Neves M, Batista F, Viana-Baptista M, Alves J, Simons K, Vaz WLC, and Vieira OV
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Female, Humans, Male, Mass Spectrometry methods, Middle Aged, Atherosclerosis blood, Ischemic Stroke blood, Lipidomics methods, Lipids blood, Lupus Erythematosus, Systemic blood
- Abstract
Background: Localized stress and cell death in chronic inflammatory diseases may release tissue-specific lipids into the circulation causing the blood plasma lipidome to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared., Methods: Plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related vascular disease, including cardiovascular (CVD) and ischemic stroke (IS), and systemic lupus erythematosus (SLE), were screened by a top-down shotgun mass spectrometry-based analysis without liquid chromatographic separation and compared to each other and to age-matched controls. Lipid profiling of 596 lipids was performed on a cohort of 427 individuals. Machine learning classifiers based on the plasma lipidomes were used to distinguish the two chronic inflammatory diseases from each other and from the controls., Findings: Analysis of the lipidomes enabled separation of the studied chronic inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control - Sensitivity: 0.94, Specificity: 0.88; IS vs control - Sensitivity: 1.0, Specificity: 1.0; SLE vs control - Sensitivity: 1, Specificity: 0.93) and from each other (SLE vs CVD ‒ Sensitivity: 0.91, Specificity: 1; IS vs SLE - Sensitivity: 1, Specificity: 0.82). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls, and partially separated CVD severities, as classified into five clinical groups. Dysregulated lipids are partially but not fully counterbalanced by statin treatment., Interpretation: Dysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes., Funding: Full list of funding sources at the end of the manuscript., Competing Interests: Declaration of Competing Interest KS is CEO and shareholder of Lipotype GmbH. CL and MG are employees of Lipotype GmbH. All other authors declare that they do not have any competing interests., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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47. Validation of a Prospective Urinalysis-Based Prediction Model for ICU Resources and Outcome of COVID-19 Disease: A Multicenter Cohort Study.
- Author
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Gross O, Moerer O, Rauen T, Böckhaus J, Hoxha E, Jörres A, Kamm M, Elfanish A, Windisch W, Dreher M, Floege J, Kluge S, Schmidt-Lauber C, Turner JE, Huber S, Addo MM, Scheithauer S, Friede T, Braun GS, Huber TB, and Blaschke S
- Abstract
In COVID-19, guidelines recommend a urinalysis on hospital admission as SARS-CoV-2 renal tropism, post-mortem, was associated with disease severity and mortality. Following the hypothesis from our pilot study, we now validate an algorithm harnessing urinalysis to predict the outcome and the need for ICU resources on admission to hospital. Patients were screened for urinalysis, serum albumin (SA) and antithrombin III activity (AT-III) obtained prospectively on admission. The risk for an unfavorable course was categorized as (1) "low", (2) "intermediate" or (3) "high", depending on (1) normal urinalysis, (2) abnormal urinalysis with SA ≥ 2 g/dL and AT-III ≥ 70%, or (3) abnormal urinalysis with SA or AT-III abnormality. Time to ICU admission or death served as the primary endpoint. Among 223 screened patients, 145 were eligible for enrollment, 43 falling into the low, 84 intermediate, and 18 into high-risk categories. An abnormal urinalysis significantly elevated the risk for ICU admission or death (63.7% vs. 27.9%; HR 2.6; 95%-CI 1.4 to 4.9; p = 0.0020) and was 100% in the high-risk group. Having an abnormal urinalysis was associated with mortality, a need for mechanical ventilation, extra-corporeal membrane oxygenation or renal replacement therapy. In conclusion, our data confirm that COVID-19-associated urine abnormalities on admission predict disease aggravation and the need for ICU (ClinicalTrials.gov number NCT04347824).
- Published
- 2021
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48. Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements.
- Author
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Tegtmeyer B, Vieyres G, Todt D, Lauber C, Ginkel C, Engelmann M, Herrmann M, Pfaller CK, Vondran FWR, Broering R, Vafadarnejad E, Saliba AE, Puff C, Baumgärtner W, Miskey C, Ivics Z, Steinmann E, Pietschmann T, and Brown RJP
- Abstract
Transcriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Longitudinal sampling identified minimal gene dysregulation at six hours post infection (hpi). In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. We further find that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection, which can additionally reduce HCV RNA translation and replication. We also detected infection-induced downregulation of ∼90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits in PHHs, consistent with a signature of translational shutoff. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is likely pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity. IMPORTANCE Acute HCV infections are often asymptomatic and therefore frequently undiagnosed. We endeavored to recreate this understudied phase of HCV infection using explanted PHHs and monitored host responses to initial infection. We detected temporally distinct virus-induced perturbations in the transcriptional landscape, which were initially narrow but massively amplified in breadth and magnitude over time. At 72 hpi, we detected dysregulation of diverse gene programs, concurrently promoting both virus clearance and virus persistence. On the one hand, baseline expression of IRF1 combined with infection-induced upregulation of IFN-mediated effector genes suppresses virus propagation. On the other, we detect transcriptional signatures of host translational inhibition, which likely reduces processing of IFN-regulated gene transcripts and facilitates virus survival. Together, our data provide important insights into constitutive and virus-induced transcriptional programs in PHHs, and identifies simultaneous antagonistic dysregulation of pro-and anti-viral programs which may facilitate host tolerance and promote viral persistence., (Copyright © 2021 American Society for Microbiology.)
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- 2021
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49. Conservation of the HBV RNA element epsilon in nackednaviruses reveals ancient origin of protein-primed reverse transcription.
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Beck J, Seitz S, Lauber C, and Nassal M
- Subjects
- Conserved Sequence, Hepadnaviridae classification, Hepadnaviridae genetics, Hepatitis B virus classification, Hepatitis B virus genetics, Phylogeny, RNA, Viral genetics, Replication Origin, Viral Proteins genetics, DNA Replication, DNA, Viral biosynthesis, Evolution, Molecular, Hepadnaviridae physiology, Reverse Transcription, Viral Proteins metabolism, Virus Replication
- Abstract
Hepadnaviruses, with the human hepatitis B virus as prototype, are small, enveloped hepatotropic DNA viruses which replicate by reverse transcription of an RNA intermediate. Replication is initiated by a unique protein-priming mechanism whereby a hydroxy amino acid side chain of the terminal protein (TP) domain of the viral polymerase (P) is extended into a short DNA oligonucleotide, which subsequently serves as primer for first-strand synthesis. A key component in the priming of reverse transcription is the viral RNA element epsilon, which contains the replication origin and serves as a template for DNA primer synthesis. Here, we show that recently discovered non-enveloped fish viruses, termed nackednaviruses [C. Lauber et al. , Cell Host Microbe 22, 387-399 (2017)], employ a fundamentally similar replication mechanism despite their huge phylogenetic distance and major differences in genome organization and viral lifestyle. In vitro cross-priming studies revealed that few strategic nucleotide substitutions in epsilon enable site-specific protein priming by heterologous P proteins, demonstrating that epsilon is functionally conserved since the two virus families diverged more than 400 Mya. In addition, other cis elements crucial for the hepadnavirus-typical replication of pregenomic RNA into relaxed circular double-stranded DNA were identified at conserved positions in the nackednavirus genomes. Hence, the replication mode of both hepadnaviruses and nackednaviruses was already established in their Paleozoic common ancestor, making it a truly ancient and evolutionary robust principle of genome replication that is more widespread than previously thought., Competing Interests: The authors declare no competing interest.
- Published
- 2021
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50. HBV evolution and genetic variability: Impact on prevention, treatment and development of antivirals.
- Author
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Glebe D, Goldmann N, Lauber C, and Seitz S
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- Animals, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Chiroptera virology, Genome, Viral, Genotype, Hepatitis B virology, Hepatitis B Vaccines administration & dosage, Hepatitis B virus classification, Hepatitis B virus drug effects, Hepatocytes virology, Humans, Primates virology, Virus Internalization drug effects, Virus Replication drug effects, Antiviral Agents isolation & purification, Evolution, Molecular, Genetic Variation, Hepatitis B drug therapy, Hepatitis B prevention & control, Hepatitis B virus genetics
- Abstract
Hepatitis B virus (HBV) poses a major global health burden with 260 million people being chronically infected and 890,000 dying annually from complications in the course of the infection. HBV is a small enveloped virus with a reverse-transcribed DNA genome that infects hepatocytes and can cause acute and chronic infections of the liver. HBV is endemic in humans and apes representing the prototype member of the viral family Hepadnaviridae and can be divided into 10 genotypes. Hepadnaviruses have been found in all vertebrate classes and constitute an ancient viral family that descended from non-enveloped progenitors more than 360 million years ago. The de novo emergence of the envelope protein gene was accompanied with the liver-tropism and resulted in a tight virus-host association. The oldest HBV genomes so far have been isolated from human remains of the Bronze Age and the Neolithic (~7000 years before present). Despite the remarkable stability of the hepadnaviral genome over geological eras, HBV is able to rapidly evolve within an infected individual under pressure of the immune response or during antiviral treatment. Treatment with currently available antivirals blocking intracellular replication of HBV allows controlling of high viremia and improving liver health during long-term therapy of patients with chronic hepatitis B (CHB), but they are not sufficient to cure the disease. New therapy options that cover all HBV genotypes and emerging viral variants will have to be developed soon. In addition to the antiviral treatment of chronically infected patients, continued efforts to expand the global coverage of the currently available HBV vaccine will be one of the key factors for controlling the rising global spread of HBV. Certain improvements of the vaccine (e.g. inclusion of PreS domains) could counteract known problems such as low or no responsiveness of certain risk groups and waning anti-HBs titers leading to occult infections, especially with HBV genotypes E or F. But even with an optimal vaccine and a cure for hepatitis B, global eradication of HBV would be difficult to achieve because of an existing viral reservoir in primates and bats carrying closely related hepadnaviruses with zoonotic potential., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
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