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1. Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

Author

Julia Dietz, Christiana Graf, Christoph P. Berg, Kerstin Port, Katja Deterding, Peter Buggisch, Kai-Henrik Peiffer, Johannes Vermehren, Georg Dultz, Andreas Geier, Florian P. Reiter, Tony Bruns, Jörn M. Schattenberg, Elena Durmashkina, Thierry Gustot, Christophe Moreno, Janina Trauth, Thomas Discher, Janett Fischer, Thomas Berg, Andreas E. Kremer, Beat Müllhaupt, Stefan Zeuzem, Christoph Sarrazin, C. Antoni, A. Teufel, R. Vogelmann, M. Ebert, J. Balavoine, E. Giostra, M. Berning, J. Hampe, T. Boettler, C. Neumann-Haefelin, R. Thimme, A. De Gottardi, A. Rauch, N. Semmo, V. Ellenrieder, M. Gress, A. Herrmann, A. Stallmach, D. Hoffmann, U. Protzer, A. Kodal, M. Löbermann, T. Götze, V. Keitel-Anselmino, C.M. Lange, R. Zachoval, J. Mayerle, A. Maieron, P. Michl, U. Merle, D. Moradpour, J.-P. Chave, M. Muche, H.-J. Epple, M. Müller-Schilling, F. Kocheise, T. Müller, F. Tacke, E. Roeb, J. Rissland, M. Krawczyk, P. Schulze, D. Semela, U. Spengler, J. Rockstroh, C.P. Strassburg, J. Siebler, J. Schulze zur Wiesch, F. Piecha, J. von Felden, S. Jordan, A. Lohse, M. Sprinzl, P. Galle, R. Stauber, B. Strey, W. Steckstor, W. Schmiegel, N.H. Brockmeyer, A. Canbay, C. Trautwein, F. Uschner, J. Trebicka, T. Weber, H. Wedemeyer, M. Cornberg, M. Manns, P. Wietzke-Braun, R. Günther, K. Willuweit, G. Hilgard, H. Schmidt, E. Zizer, J. Backhus, T. Seufferlein, O. Al-Taie, W. Angeli, S. Beckebaum, A. Erhardt, A. Garrido-Lüneburg, H. Gattringer, D. Genné, M. Gschwantler, F. Gundling, S. Hametner, R. Schöfl, S. Haag, H. Heinzow, T. Heyer, C. Hirschi, A. Jussios, S. Kanzler, N. Kordecki, M. Kraus, U. Kullig, S. Wollschläger, L. Magenta, B. Terziroli Beretta-Piccoli, M. Menges, L. Mohr, K. Muehlenberg, C. Niederau, B. Paulweber, A. Petrides, M. Pinkernell, R. Piso, W. Rambach, L. Reinhardt, M. Reiser, B. Riecken, A. Rieke, J. Roth, M. Schelling, P. Schlee, A. Schneider, D. Scholz, E. Schott, M. Schuchmann, U. Schulten-Baumer, A. Seelhoff, A. Stich, F. Stickel, J. Ungemach, E. Walter, A. Weber, H. Wege, T. Winzer, W. Abels, M. Adler, F. Audebert, C. Baermann, E. Bästlein, R. Barth, K. Barthel, W. Becker, J. Behrends, J. Benninger, F. Berger, D. Berzow, T. Beyer, M. Bierbaum, O. Blaukat, A. Bodtländer, G. Böhm, N. Börner, U. Bohr, B. Bokemeyer, H.R. Bruch, D. Bucholz, P. Buggisch, K. Matschenz, J. Petersen, O. Burkhard, N. Busch, C. Chirca, R. Delker, J. Diedrich, M. Frank, M. Diehl, A.O. Tal, M. Schneider, A. Dienethal, P. Dietel, N. Dikopoulos, M. Dreck, F. Dreher, L. Drude, K. Ende, U. Ehrle, K. Baumgartl, F. Emke, R. Glosemeyer, G. Felten, D. Hüppe, J. Fischer, U. Fischer, D. Frederking, B. Frick, G. Friese, B. Gantke, P. Geyer, H.R. Schwind, M. Glas, T. Glaunsinger, F. Goebel, U. Göbel, B. Görlitz, R. Graf, H. Gruber, C. Hartmann, C. Klag, G. Härter, M. Herder, T. Heuchel, S. Heuer, H. Hinrichsen, B. Seegers, K.-H. Höffl, H. Hörster, J.-U. Sonne, W.P. Hofmann, F. Holst, M. Hunstiger, A. Hurst, E. Jägel-Guedes, C. John, M. Jung, B. Kallinowski, B. Kapzan, W. Kerzel, P. Khaykin, M. Klarhof, U. Klüppelberg, Wolfratshausen, K. Klugewitz, B. Knapp, U. Knevels, T. Kochsiek, A. Körfer, A. Köster, M. Kuhn, A. Langekamp, B. Künzig, R. Link, M. Littman, H. Löhr, T. Lutz, P. Gute, G. Knecht, U. Lutz, D. Mainz, I. Mahle, P. Maurer, S. Mauss, C. Mayer, H. Möller, R. Heyne, D. Moritzen, M. Mroß, M. Mundlos, U. Naumann, O. Nehls, K, R. Ningel, A. Oelmann, H. Olejnik, K. Gadow, E. Pascher, A. Philipp, M. Pichler, F. Polzien, R. Raddant, M. Riedel, S. Rietzler, M. Rössle, W. Rufle, A. Rump, C. Schewe, C. Hoffmann, D. Schleehauf, W. Schmidt, G. Schmidt-Heinevetter, J. Schmidtler-von Fabris, L. Schneider, A. Schober, S. Niehaus-Hahn, J. Schwenzer, T. Seidel, G. Seitel, C. Sick, K. Simon, D. Stähler, F. Stenschke, H. Steffens, K. Stein, M. Steinmüller, T. Sternfeld, K. Svensson, W. Tacke, G. Teuber, K. Teubner, J. Thieringer, A. Tomesch, U. Trappe, J. Ullrich, G. Urban, S. Usadel, A. von Lucadou, F. Weinberger, M. Werheid-Dobers, P. Werner, T. Winter, E. Zehnter, and A. Zipf

Subjects
Direct-acting antivirals, Hepatitis C Virus, rare HCV genotypes, resistance-associated substitutions, treatment response, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Published
2024
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2. Acute liver injury following acetaminophen administration does not activate atrophic pathways in the mouse diaphragm

Author

C. S. Bruells, P. Duschner, G. Marx, G. Gayan-Ramirez, N. Frank, T. Breuer, O. Krenkel, F. Tacke, and J. C. Mossanen

Subjects
Medicine, Science
Abstract

Abstract N-acetyl-para-amino phenol (APAP, usually named paracetamol), which is commonly used for its analgesic and antipyretic properties may lead to hepatotoxicity and acute liver damage in case of overdoses. Released cytokines and oxidative stress following acute liver damage may affect other organs’ function notably the diaphragm, which is particularly sensitive to oxidative stress and circulating cytokines. We addressed this issue in a mouse model of acute liver injury induced by administration of APAP. C57BL/6J mice (each n = 8) were treated with N-acetyl-para-amino phenol (APAP) to induce acute drug caused liver injury and sacrificed 12 or 24 h afterwards. An untreated group served as controls. Key markers of inflammation, proteolysis, autophagy and oxidative stress were measured in diaphragm samples. In APAP treated animals, liver damage was proven by the enhanced serum levels of alanine aminotransferase and aspartate aminotransferase. In the diaphragm, besides a significant increase in IL 6 and lipid peroxidation, no changes were observed in key markers of the proteolytic, and autophagy signaling pathways, other inflammatory markers and fiber dimensions. The first 24 h of acute liver damage did not impair diaphragm atrophic pathways although it slightly enhanced IL-6 and lipid peroxidation. Whether longer exposure might affect the diaphragm needs to be addressed in future experiments.

Published
2021
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5. GLP-2 as an indicator and modulator of acute inflammation improves cardiac function and survival in sepsis

Author

F Kahles, R Mertens, S Diebold, M C Arrivas, J Moellmann, J Steitz, Y Mirzaei, D Sandoval, L Martin, T Schuerholz, A Koch, F Tacke, D J Drucker, N Marx, and M Lehrke

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Purpose GLP-1 and GLP-2 (glucagon-like peptide-1/2) are gut hormones secreted in response to food. While GLP-1 controls glucose metabolism, GLP-2 is a local gut growth factor regulating intestinal nutrient absorption. GLP-2 has been found to be upregulated in patients with colitis. We hypothesize that beyond its local intestinal function GLP-2 might be involved in systemic immune responses. Methods and results To analyze whether GLP-2 secretion is modulated by the immune system, we measured circulating GLP-2 levels in 2 clinical cohorts. In the first cohort (n=34) GLP-2 levels increased over time following cardiac surgery as an inflammatory stimulus. In the second cohort 223 patients with sepsis had a 3.9 fold increase of GLP-2 plasma levels vs. 53 healthy controls (3.0 ng/mL vs. 11.4 ng/mL; p Conclusions Here we identified a counter-regulatory control system in which IL-6 derived upregulation of GLP-2 secretion limits excessive innate immune responses and protects against sepsis. These findings might open new avenues for the treatment of patients with inflammatory diseases. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): European Foundation for the Study of Diabetes, European Research Area Network on Cardiovascular Diseases (ERA-CVD and BMBF), Deutsche Forschungsgemeinschaft (DFG)

Published
2022

10. Neonatal Peyer’s patch cDC activation as a pacemaker of postnatal immune maturation

Author

N. Torow, R. Li, T. Hitch, C. Mingels, S. al Bounny, N. van Best, E.-L. Stange, A. Benabid, L. Rüttger, M. Gadermayr, S. Runge, N. Treichel, D. Merhof, S. Rosshart, N. Jehmlich, M. von Bergen, F. Heymann, T. Clavel, F. Tacke, H. Lelouard, I. Costa, and M. W. Hornef

Abstract

Marked differences exist between the mucosal immune system of the neonate and adult host. The pronounced influence of the enteric microbiota in adults suggests a causal relationship between postnatal colonization and immune maturation. However, using metagenomic, metaproteomic, and functional immunological analyses we demonstrate an early presence of bacteria and immunogenic microbial antigens preceding immune maturation in the small intestine, the primary inductive site of intestinal immunity. Instead, transcriptomic, flow cytometric and histological analysis indicated neonatal Peyer’s patch (PP) mononuclear phagocytes (MNP) as rate limiting factor of postnatal immune maturation. Despite the early presence of MNPs, conventional dendritic cells (cDC) of type 1, 2a and 2b exhibited significant age-dependent differences in tissue distribution and cellular composition. Single cell transcriptional profiling and functional assays revealed decreased antimicrobial and antigen processing/presentation capacity, an overall retarded cell maturation and reduced antigen uptake. In cDC2a this resulted in a reduced proportion of CCR7+migratory cells and a consequent defect in CD4 T cell priming. Interestingly, transcriptional profiling of neonatal DC subsets identified reduced expression of type I interferon (IFN)-stimulated genes (ISG). Type I IFN induction by oral administration of the TLR7 agonist R848 accelerated MNP maturation and enhanced cognate antigen CD4 T cell priming. However, humoral responses to oral vaccination in the presence of R848 were significantly reduced. Together, our results identify PP MNP maturation as pacemaker of postnatal mucosal immune priming, indicate the biological role of delayed maturation and demonstrate that targeted interventional strategies allow manipulation of mucosal responses in early life.

Published
2022

11. Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure

Author

Julia Dietz, Beat Müllhaupt, Peter Buggisch, Christiana Graf, Kai-Henrik Peiffer, Katrin Matschenz, Jörn M. Schattenberg, Christoph Antoni, Stefan Mauss, Claus Niederau, Thomas Discher, Janina Trauth, Georg Dultz, Julian Schulze zur Wiesch, Felix Piecha, Hartwig Klinker, Tobias Müller, Thomas Berg, Christoph Neumann-Haefelin, Christoph P. Berg, Stefan Zeuzem, Christoph Sarrazin, J. Balavoine, E. Giostra, M. Berning, J. Hampe, A. Canbay, W. Steckstor, W. Schmiegel, N.H. Brockmeyer, A. De Gottardi, A. Rauch, N. Semmo, J. Fischer, M. Gress, H. Heinzow, G. Hilgard, H. Schmidt, A. Herrmann, A. Stallmach, D. Hoffmann, U. Protzer, H. Klinker, P. Schulze, A. Kodal, A. Kremer, J. Siebler, M. Löbermann, T. Götze, J. Weigt, A. Lohse, J. Von Felden, S. Jordan, C.M. Lange, R. Zachoval, J. Mayerle, A. Maieron, D. Moradpour, J.-P. Chave, C. Moreno, M. Muche, H.-J. Epple, M. Müller-Schilling, F. Kocheise, B. Müllhaupt, K. Port, K. Deterding, H. Wedemeyer, M. Cornberg, M. Manns, L. Reinhardt, V. Ellenrieder, J. Rissland, D. Semela, U. Spengler, J. Rockstroh, E. Roeb, M. Sprinzl, P. Galle, R. Stauber, W. Stremmel, B. Strey, R. Thimme, T. Boettler, F. Tacke, A. Teufel, R. Vogelmann, M. Ebert, K. Tomasiewicz, C. Trautwein, T. Koenen, T. Weber, P. Wietzke-Braun, R. Günther, E. Zizer, J. Backhus, T. Seufferlein, W. Angeli, S. Beckebaum, C. Doberauer, E. Durmashkina, A. Hackelsberger, A. Erhardt, A. Garrido-Lüneburg, H. Gattringer, D. Genné, M. Gschwantler, F. Gundling, S. Hametner, R. Schöfl, C. Hartmann, T. Heyer, C. Hirschi, A. Jussios, S. Kanzler, N. Kordecki, M. Kraus, U. Kullig, S. Wollschläger, L. Magenta, B. Terziroli Beretta-Piccoli, M. Menges, L. Mohr, K. Muehlenberg, C. Niederau, B. Paulweber, A. Petrides, M. Pinkernell, R. Piso, W. Rambach, M. Reiser, B. Riecken, A. Rieke, J. Roth, M. Schelling, P. Schlee, A. Schneider, D. Scholz, E. Schott, M. Schuchmann, U. Schulten-Baumer, A. Seelhoff, A. Stich, F. Stickel, J. Ungemach, E. Walter, A. Weber, T. Winzer, W. Abels, M. Adler, F. Audebert, C. Baermann, E. Bästlein, R. Barth, K. Barthel, W. Becker, J. Behrends, J. Benninger, F. Berger, D. Berzow, T. Beyer, M. Bierbaum, O. Blaukat, A. Bodtländer, G. Böhm, N. Börner, U. Bohr, B. Bokemeyer, H.R. Bruch, D. Bucholz, O. Burkhard, N. Busch, C. Chirca, R. Delker, J. Diedrich, M. Frank, M. Diehl, A. Dienethal, P. Dietel, N. Dikopoulos, M. Dreck, F. Dreher, L. Drude, K. Ende, U. Ehrle, K. Baumgartl, F. Emke, R. Glosemeyer, G. Felten, D. Hüppe, U. Fischer, D. Frederking, B. Frick, G. Friese, B. Gantke, P. Geyer, H.R. Schwind, M. Glas, T. Glaunsinger, F. Goebel, U. Göbel, B. Görlitz, R. Graf, H. Gruber, G. Härter, M. Herder, T. Heuchel, S. Heuer, K.-H. Höffl, H. Hörster, J.-U. Sonne, W.P. Hofmann, F. Holst, M. Hunstiger, A. Hurst, E. Jägel-Guedes, C. John, M. Jung, B. Kallinowski, B. Kapzan, W. Kerzel, P. Khaykin, M. Klarhof, U. Klüppelberg, null Wolfratshausen, K. Klugewitz, B. Knapp, U. Knevels, T. Kochsiek, A. Körfer, A. Köster, M. Kuhn, A. Langekamp, B. Künzig, R. Link, M. Littman, H. Löhr, T. Lutz, G. Knecht, U. Lutz, D. Mainz, I. Mahle, P. Maurer, C. Mayer, V. Meister, H. Möller, R. Heyne, D. Moritzen, M. Mroß, M. Mundlos, U. Naumann, O. Nehls, K.R. Ningel, A. Oelmann, H. Olejnik, K. Gadow, E. Pascher, J. Petersen, A. Philipp, M. Pichler, F. Polzien, R. Raddant, M. Riedel, S. Rietzler, M. Rössle, W. Rufle, A. Rump, C. Schewe, C. Hoffmann, D. Schleehauf, W. Schmidt, G. Schmidt-Heinevetter, J. Schmidtler-von Fabris, L. Schneider, A. Schober, S. Niehaus-Hahn, J. Schwenzer, B. Seegers, T. Seidel, G. Seitel, C. Sick, K. Simon, D. Stähler, F. Stenschke, H. Steffens, K. Stein, M. Steinmüller, T. Sternfeld, K. Svensson, W. Tacke, G. Teuber, K. Teubner, J. Thieringer, A. Tomesch, U. Trappe, J. Ullrich, G. Urban, S. Usadel, A. Von Lucadou, F. Weinberger, M. Werheid-Dobers, P. Werner, T. Winter, E. Zehnter, and A. Zipf

Subjects
Hepatology, Genotype, Drug Resistance, Viral, Humans, Hepacivirus, Treatment Failure, Viral Nonstructural Proteins, Hepatitis C, Chronic, Antiviral Agents
Abstract

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Published
2022

14. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Author

D. KLIONSKY, A. ABDEL-AZIZ, S. ABDELFATAH, M. ABDELLATIF, A. ABDOLI, S. ABEL, H. ABELIOVICH, M. ABILDGAARD, Y. ABUDU, A. ACEVEDO-AROZENA, I. ADAMOPOULOS, K. ADELI, T. ADOLPH, A. ADORNETTO, E. AFLAKI, G. AGAM, A. AGARWAL, B. AGGARWAL, M. AGNELLO, P. AGOSTINIS, J. AGREWALA, A. AGROTIS, P. AGUILAR, S. AHMAD, Z. AHMED, U. AHUMADA-CASTRO, S. AITS, S. AIZAWA, Y. AKKOC, T. AKOUMIANAKI, H. AKPINAR, A. AL-ABD, L. AL-AKRA, A. AL-GHARAIBEH, M. ALAOUI-JAMALI, S. ALBERTI, E. ALCOCER-GOMEZ, C. ALESSANDRI, M. ALI, M. AL-BARI, S. ALIWAINI, J. ALIZADEH, E. ALMACELLAS, A. ALMASAN, A. ALONSO, G. ALONSO, N. ALTAN-BONNET, D. ALTIERI, S. ALVES, C. DA COSTA, M. ALZAHARNA, M. AMADIO, C. AMANTINI, C. AMARAL, S. AMBROSIO, A. AMER, V. AMMANATHAN, Z. AN, S. ANDERSEN, S. ANDRABI, M. ANDRADE-SILVA, A. ANDRES, S. ANGELINI, D. ANN, U. ANOZIE, M. ANSARI, P. ANTAS, A. ANTEBI, Z. ANTON, T. ANWAR, L. APETOH, N. APOSTOLOVA, T. ARAKI, Y. ARAKI, K. ARASAKI, W. ARAUJO, J. ARAYA, C. ARDEN, M. AREVALO, S. ARGUELLES, E. ARIAS, J. ARIKKATH, H. ARIMOTO, A. ARIOSA, D. ARMSTRONG-JAMES, L. ARNAUNE-PELLOQUIN, A. AROCA, D. ARROYO, I. ARSOV, R. ARTERO, D. ASARO, M. ASCHNER, M. ASHRAFIZADEH, O. ASHUR-FABIAN, A. ATANASOV, A. AU, P. AUBERGER, H. AUNER, L. AURELIAN, R. AUTELLI, L. AVAGLIANO, Y. AVALOS, S. AVEIC, C. AVELEIRA, T. AVINWITTENBERG, Y. AYDIN, S. AYTON, S. AYYADEVARA, M. AZZOPARDI, M. BABA, J. BACKER, S. BACKUES, D. BAE, O. BAE, S. BAE, E. BAEHRECKE, A. BAEK, S. BAEK, G. BAGETTA, A. BAGNIEWSKA-ZADWORNA, H. BAI, J. BAI, X. BAI, Y. BAI, N. BAIRAGI, S. BAKSI, T. BALBI, C. BALDARI, W. BALDUINI, A. BALLABIO, M. BALLESTER, S. BALAZADEH, R. BALZAN, R. BANDOPADHYAY, S. BANERJEE, Y. BAO, M. BAPTISTA, A. BARACCA, C. BARBATI, A. BARGIELA, D. BARILA, P. BARLOW, S. BARMADA, E. BARREIRO, G. BARRETO, J. BARTEK, B. BARTEL, A. BARTOLOME, G. BARVE, S. BASAGOUDANAVAR, D. BASSHAM, R. JR, A. BASU, H. BATOKO, I. BATTEN, E. BAULIEU, B. BAUMGARNER, J. BAYRY, R. BEALE, I. BEAU, F. BEAUMATIN, L. BECHARA, G. BECK, M. BEERS, J. BEGUN, C. BEHRENDS, G. BEHRENS, R. BEI, E. BEJARANO, S. BEL, C. BEHL, A. BELAID, N. BELGAREH-TOUZE, C. BELLAROSA, F. BELLEUDI, M. PEREZ, R. BELLO-MORALES, J. BELTRAN, S. BELTRAN, D. BENBROOK, M. BENDORIUS, B. BENITEZ, I. BENITO-CUESTA, J. BENSALEM, M. BERCHTOLD, S. BEREZOWSKA, D. BERGAMASCHI, M. BERGAMI, A. BERGMANN, L. BERLIOCCHI, C. BERLIOZ-TORRENT, A. BERNARD, L. BERTHOUX, C. BESIRLI, S. BESTEIRO, V. BETIN, R. BEYAERT, J. BEZBRADICA, K. BHASKAR, I. BHATIA-KISSOVA, R. BHATTACHARYA, S. BHATTACHARYA, S. BHATTACHARYYA, M. BHUIYAN, S. BHUTIA, L. BI, X. BI, T. BIDEN, K. BIJIAN, V. BILLES, N. BINART, C. BINCOLETTO, A. BIRGISDOTTIR, G. BJORKOY, G. BLANCO, A. BLAS-GARCIA, J. BLASIAK, R. BLOMGRAN, K. BLOMGREN, J. BLUM, E. BOADA-ROMERO, M. BOBAN, K. BOESZEBATTAGLIA, P. BOEUF, B. BOLAND, P. BOMONT, P. BONALDO, S. BONAM, L. BONFILI, J. BONIFACINO, B. BOONE, M. BOOTMAN, M. BORDI, C. BORNER, B. BORNHAUSER, G. BORTHAKUR, J. BOSCH, S. BOSE, L. BOTANA, J. BOTAS, C. BOULANGER, M. BOULTON, M. 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SCOTT, K. SCOTTO, A. SCOVASSI, A. SCRIMA, A. SCRIVO, D. SEBASTIAN, S. SEBTI, S. SEDEJ, L. SEGATORI, N. SEGEV, P. SEGLEN, I. SEILIEZ, E. SEKI, S. SELLECK, F. SELLKE, A. PEREZ-LARA, J. SELSBY, M. SENDTNER, S. SENTURK, E. SERANOVA, C. SERGI, R. SERRA-MORENO, H. SESAKI, C. SETTEMBRE, S. SETTY, G. SGARBI, O. SHA, J. SHACKA, J. SHAH, D. SHANG, C. SHAO, F. SHAO, S. SHARBATI, L. SHARKEY, D. SHARMA, G. SHARMA, K. SHARMA, P. SHARMA, S. SHARMA, H. SHEN, J. SHEN, M. SHEN, W. SHEN, Z. SHEN, R. SHENG, Z. SHENG, J. SHI, X. SHI, Y. SHI, K. SHIBA-FUKUSHIMA, J. SHIEH, Y. SHIMADA, S. SHIMIZU, M. SHIMOZAWA, T. SHINTANI, C. SHOEMAKER, S. SHOJAEI, I. SHOJI, B. SHRAVAGE, V. SHRIDHAR, C. SHU, H. SHU, K. SHUI, A. SHUKLA, T. SHUTT, V. SICA, A. SIDDIQUI, A. SIERRA, V. SIERRA-TORRE, S. SIGNORELLI, P. SIL, B. SILVA, J. SILVA, E. SILVA-PAVEZ, S. SILVENTE-POIROT, R. SIMMONDS, A. SIMON, H. SIMON, M. SIMONS, A. SINGH, L. SINGH, R. SINGH, S. SINGH, D. SINHA, R. SINHA, S. SINHA, A. SIRKO, K. SIROHI, E. SIVRIDIS, P. SKENDROS, A. SKIRYCZ, I. SLANINOVA, S. SMAILI, A. SMERTENKO, M. SMITH, S. SOENEN, E. SOHN, S. SOK, G. SOLAINI, T. SOLDATI, S. SOLEIMANPOUR, R. SOLER, A. SOLOVCHENKO, J. SOMARELLI, A. SONAWANE, F. SONG, H. SONG, J. SONG, K. SONG, Z. SONG, L. SORIA, M. SORICE, A. SOUKAS, S. SOUKUP, D. SOUSA, N. SOUSA, P. SPAGNUOLO, S. SPECTOR, M. BHARATH, D. ST CLAIR, V. STAGNI, L. STAIANO, C. STALNECKER, M. STANKOV, P. STATHOPULOS, K. STEFAN, S. STEFAN, L. STEFANIS, J. STEFFAN, A. STEINKASSERER, H. STENMARK, J. STERNECKERT, C. STEVENS, V. STOKA, S. STORCH, B. STORK, F. STRAPPAZZON, A. STROHECKER, D. STUPACK, H. SU, L. SU, A. SUAREZFONTES, C. SUBAUSTE, S. SUBBIAN, P. SUBIRADA, G. SUDHANDIRAN, C. SUE, X. SUI, C. SUMMERS, G. SUN, J. SUN, K. SUN, M. SUN, Q. SUN, Y. SUN, Z. SUN, K. SUNAHARA, E. SUNDBERG, K. SUSZTAK, P. SUTOVSKY, H. SUZUKI, G. SWEENEY, J. SYMONS, S. SZE, N. SZEWCZYK, C. TABOLACCI, F. TACKE, H. TAEGTMEYER, M. TAFANI, M. TAGAYA, H. TAI, S. TAIT, Y. TAKAHASHI, S. TAKATS, P. TALWAR, C. TAM, S. TAM, D. TAMPELLINI, A. TAMURA, C. TAN, E. TAN, Y. TAN, M. TANAKA, D. TANG, J. TANG, T. TANG, I. TANIDA, Z. TAO, M. TAOUIS, L. TATENHORST, N. TAVERNARAKIS, A. TAYLOR, G. TAYLOR, J. TAYLOR, E. TCHETINA, A. TEE, I. TEGEDER, D. TEIS, N. TEIXEIRA, F. TEIXEIRA-CLERC, K. TEKIRDAG, T. TENCOMNAO, S. TENREIRO, A. TEPIKIN, P. TESTILLANO, G. TETTAMANTI, P. THARAUX, K. THEDIECK, A. THEKKINGHAT, S. THELLUNG, J. THINWA, V. THIRUMALAIKUMAR, S. THOMAS, P. THOMES, A. THORBURN, L. THUKRAL, T. THUM, M. THUMM, L. TIAN, A. TICHY, A. TILL, V. TIMMERMAN, V. TITORENKO, S. TODI, K. TODOROVA, J. TOIVONEN, L. TOMAIPITINCA, D. TOMAR, C. TOMAS-ZAPICO, B. TONG, C. TONG, X. TONG, S. TOOZE, M. TORGERSEN, S. TORII, L. TORRES-LOPEZ, A. TORRIGLIA, C. TOWERS, R. TOWNS, S. TOYOKUNI, V. TRAJKOVIC, D. TRAMONTANO, Q. TRAN, L. TRAVASSOS, C. TRELFORD, S. TREMEL, I. TROUGAKOS, B. TSAO, M. TSCHAN, H. TSE, T. TSE, H. TSUGAWA, A. TSVETKOV, D. TUMBARELLO, Y. TUMTAS, M. TUNON, S. TURCOTTE, B. TURK, V. TURK, B. TURNER, R. TUXWORTH, J. TYLER, E. TYUTEREVA, Y. UCHIYAMA, A. UGUNKLUSEK, H. UHLIG, I. ULASOV, M. UMEKAWA, C. UNGERMANN, R. UNNO, S. URBE, E. URIBE-CARRETERO, S. USTUN, V. UVERSKY, T. VACCARI, M. VACCARO, B. VAHSEN, H. VAKIFAHMETOGLU-NORBERG, R. VALDOR, M. VALENTE, A. VALKO, R. VALLEE, A. VALVERDE, G. VAN DEN BERGHE, S. VAN DER VEEN, L. VAN KAER, J. VAN LOOSDREGT, S. VAN WIJK, W. VANDENBERGHE, I. VANHOREBEEK, M. VANNIER-SANTOS, N. VANNINI, M. VANRELL, C. VANTAGGIATO, G. VARANO, I. VARELA-NIETO, M. VARGA, M. VASCONCELOS, S. VATS, D. VAVVAS, I. VEGANAREDO, S. VEGA-RUBIN-DE-CELIS, G. VELASCO, A. VELAZQUEZ, T. VELLAI, E. VELLENGA, F. VELOTTI, M. VERDIER, P. VERGINIS, I. VERGNE, P. VERKADE, M. VERMA, P. VERSTREKEN, T. VERVLIET, J. VERVOORTS, A. VESSONI, V. VICTOR, M. VIDAL, C. VIDONI, O. VIEIRA, R. VIERSTRA, S. VIGANO, H. VIHINEN, V. VIJAYAN, M. VILA, M. VILAR, J. VILLALBA, A. VILLALOBO, B. VILLAREJO-ZORI, F. VILLARROYA, J. VILLARROYA, O. VINCENT, C. VINDIS, C. VIRET, M. VISCOMI, D. VISNJIC, I. VITALE, D. VOCADLO, O. VOITSEKHOVSKAJA, C. VOLONTE, M. VOLTA, M. VOMERO, C. VON HAEFEN, M. VOOIJS, W. VOOS, L. VUCICEVIC, R. WADE-MARTINS, S. WAGURI, K. WAITE, S. WAKATSUKI, D. WALKER, M. WALKER, S. WALKER, J. WALTER, F. WANDOSELL, B. WANG, C. WANG, D. WANG, F. WANG, G. WANG, H. WANG, J. WANG, K. WANG, L. WANG, M. WANG, N. WANG, P. WANG, Q. WANG, W. WANG, X. WANG, Y. WANG, Z. WANG, G. WARNES, V. WARNSMANN, H. WATADA, E. WATANABE, M. WATCHON, T. WEAVER, G. WEGRZYN, A. WEHMAN, H. WEI, L. WEI, T. WEI, Y. WEI, O. WEIERGRABER, C. WEIHL, G. WEINDL, R. WEISKIRCHEN, A. WELLS, R. WEN, X. WEN, A. WERNER, B. WEYKOPF, S. WHEATLEY, J. WHITTON, A. WHITWORTH, K. WIKTORSKA, M. WILDENBERG, T. WILEMAN, S. WILKINSON, D. WILLBOLD, B. WILLIAMS, R. WILLIAMS, P. WILLIAMSON, R. WILSON, B. WINNER, N. WINSOR, S. WITKIN, H. WODRICH, U. WOEHLBIER, T. WOLLERT, E. WONG, J. WONG, R. WONG, V. WONG, W. WONG, A. WU, C. WU, J. WU, K. WU, M. WU, S. WU, W. WU, X. WU, Y. WU, R. XAVIER, H. XIA, L. XIA, Z. XIA, G. XIANG, J. XIANG, M. XIANG, W. XIANG, B. XIAO, G. XIAO, H. XIAO, J. XIAO, L. XIAO, S. XIAO, Y. XIAO, B. XIE, C. XIE, M. XIE, Y. XIE, Z. XIE, M. XILOURI, C. XU, E. XU, H. XU, J. XU, L. XU, W. XU, X. XU, Y. XUE, S. YAKHINE-DIOP, M. YAMAGUCHI, O. YAMAGUCHI, A. YAMAMOTO, S. YAMASHINA, S. YAN, Z. YAN, Y. YANAGI, C. YANG, D. YANG, H. YANG, J. YANG, L. YANG, M. YANG, P. YANG, Q. YANG, S. YANG, W. YANG, X. YANG, Y. YANG, H. YAO, S. YAO, X. YAO, Y. YAO, T. YASUI, M. YAZDANKHAH, P. YEN, C. YI, X. YIN, Y. YIN, Z. YIN, M. YING, Z. YING, C. YIP, S. YIU, Y. YOO, K. YOSHIDA, S. YOSHII, T. YOSHIMORI, B. YOUSEFI, B. YU, H. YU, J. YU, L. YU, M. YU, S. YU, V. YU, W. YU, Z. YU, J. YUAN, L. YUAN, S. YUAN, Y. YUAN, Z. YUAN, J. YUE, Z. YUE, J. YUN, R. YUNG, D. ZACKS, G. ZAFFAGNINI, V. ZAMBELLI, I. ZANELLA, Q. ZANG, S. ZANIVAN, S. ZAPPAVIGNA, P. ZARAGOZA, K. ZARBALIS, A. ZAREBKOHAN, A. ZARROUK, S. ZEITLIN, J. ZENG, E. ZEROVNIK, L. ZHAN, B. ZHANG, D. ZHANG, H. ZHANG, J. ZHANG, K. ZHANG, L. ZHANG, M. ZHANG, P. ZHANG, S. ZHANG, W. ZHANG, X. ZHANG, Y. ZHANG, Z. ZHANG, H. ZHAO, L. ZHAO, S. ZHAO, T. ZHAO, X. ZHAO, Y. ZHAO, G. ZHENG, K. ZHENG, L. ZHENG, S. ZHENG, X. ZHENG, Y. ZHENG, Z. ZHENG, B. ZHIVOTOVSKY, Q. ZHONG, A. ZHOU, B. ZHOU, C. ZHOU, G. ZHOU, H. ZHOU, J. ZHOU, K. ZHOU, R. ZHOU, X. ZHOU, Y. ZHOU, Z. ZHOU, B. ZHU, C. ZHU, G. ZHU, H. ZHU, W. ZHU, Y. ZHU, H. ZHUANG, X. ZHUANG, K. ZIENTARA-RYTTER, C. ZIMMERMANN, E. ZIVIANI, T. ZOLADEK, W. ZONG, D. ZOROV, A. ZORZANO, W. ZOU, Z. ZOU, S. ZURYN, W. ZWERSCHKE, B. BRAND-SABERI, C. KENCHAPPA, S. OSHIMA, Y. RONG, J. SLUIMER, and C. STALLINGS

Subjects
flux, macroautophagy, phagophore, stress, vacuole, Autophagosome, LC3, lysosome, neurodegeneration, cancer
Abstract

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Published
2021

19. Autoren

Author

R.P. Andrié, J. Angenendt, H. Aubin, S. Baldus, J. Balzer, J. Baltzer, J. Behr, Marcus Benz, M. Berger, N. Blank, E. Blind, M. Buchfelder, A. Burk, C. Detter, R. Diel, H.-C. Diener, W. Domschke, K. Doppler, J. Ellinger, H.-J. Epple, R. Erbel, S. Fichtner-Feigl, M. Fischereder, M. Forsting, M. Friedrich, U. Frommberger, B.C. Frye, F.-D. Goebel, K. Grabitz, A. Groeneveld, F. Gundling, C.N. Gutt, G. Haidl, U. Hartmann, C. Hausteiner-Wiehle, B. Herpertz-Dahlmann, D. Heuß, P. Heußner, E. Hiller, U. Hohenfellner, J. Honegger, T. Hornung, F. Jansen, T. Jelinek, B. Jordan, C. Keck, M. Kelm, A. Kilian, A. Kleindienst, H. Kölbl, M.E. Kreis, B. Kroener-Herwig, A.K. Külz, F. Lammert, A. Lichtenberg, V. Limmroth, K. Lindner, R. Loddenkemper, H.-M. Lorenz, N. Lügering, P. Mallmann, R. Max, U. Merle, F. Mellert, G. Michels, R.-U. Müller, S.C. Müller, S. Müller-Lissner, J. Müller-Quernheim, C. Neuhof, K.G. Parhofer, E. Petri, T. Pfeiffer, Adrian Pilatz, C. Pizarro, C. Probst, W. Rascher, F. Raue, C. Reindl, C. Riedner, D. Riemann, V. Röckelein, W. Sandmann, T. Sauerbruch, N. Schahab, A. Schaper, W. Schepp, S. Schliep, H.-G. Schnürch, J. Schölmerich, Ulf Schönermarck, J. Schopohl, A. Schuchert, H. Schulze-Koops, J. Schupp, S.E. Segerer, N. Senninger, U. Seybold, B. Siegmund, D. Skowasch, C. Sommer, M. Stahl, A. Stallmach, M. Sticherling, W. Stremmel, U. Sure, F. Tacke, T. Vloet, U. Voderholzer, Y. von Kodolitsch, F. Wagenlehner, T. Wahlers, L.T. Weber, W. Weidner, B.T. Weis-Müller, N. Werner, U. Wintergerst, Gunter Wolf, D. Ziegler, S. Zierz, and Th. Zimmermann

Published
2019

20. Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1–3 Infections

Author

Julia Dietz, Ulrich Spengler, Beat Müllhaupt, Julian Schulze zur Wiesch, Felix Piecha, Stefan Mauss, Barbara Seegers, Holger Hinrichsen, Christoph Antoni, Perdita Wietzke-Braun, Kai-Henrik Peiffer, Annemarie Berger, Katrin Matschenz, Peter Buggisch, Johanna Backhus, Eugen Zizer, Tobias Boettler, Christoph Neumann-Haefelin, David Semela, Rudolf Stauber, Thomas Berg, Christoph Berg, Stefan Zeuzem, Johannes Vermehren, Christoph Sarrazin, J. Balavoine, E. Giostra, M. Berning, J. Hampe, A. De Gottardi, A. Rauch, N. Semmo, T. Discher, J. Trauth, J. Fischer, M. Gress, R. Günther, H. Heinzow, J. Schmidt, A. Herrmann, A. Stallmach, G. Hilgard, K. Deterding, C.M. Lange, S. Ciesek, H. Wedemeyer, D. Hoffmann, H. Klinker, P. Schulze, F. Kocheise, M. Müller-Schilling, A. Kodal, A. Kremer, M. Ganslmayer, J. Siebler, F. Lammert, J. Rissland, M. Löbermann, T. Götze, A. Canbay, A. Lohse, J. von Felden, S. Jordan, A. Maieron, D. Moradpour, J.-P. Chave, C. Moreno, T. Müller, M. Muche, H.-J. Epple, K. Port, T. von Hahn, M. Cornberg, M. Manns, L. Reinhardt, V. Ellenrieder, J. Rockstroh, J. Schattenberg, M. Sprinzl, P. Galle, E. Roeb, M. Steckstor, W. Schmiegel, N.H. Brockmeyer, T. Seufferlein, W. Stremmel, B. Strey, R. Thimme, A. Teufel, R. Vogelmann, M. Ebert, K. Tomasiewicz, C. Trautwein, F. Tacke, T. Koenen, T. Weber, R. Zachoval, J. Mayerle, B. Raziorrouh, W. Angeli, S. Beckebaum, C. Doberauer, E. Durmashkina, A. Hackelsberger, A. Erhardt, A. Garrido-Lüneburg, H. Gattringer, D. Genné, M. Gschwantler, F. Gundling, S. Hametner, R. Schöfl, C. Hartmann, T. Heyer, C. Hirschi, A. Jussios, S. Kanzler, N. Kordecki, M. Kraus, U. Kullig, S. Wollschläger, L. Magenta, B. Terziroli Beretta-Piccoli, M. Menges, L. Mohr, K. Muehlenberg, C. Niederau, B. Paulweber, A. Petrides, M. Pinkernell, R. Piso, W. Rambach, M. Reiser, B. Riecken, A. Rieke, J. Roth, M. Schelling, P. Schlee, A. Schneider, D. Scholz, E. Schott, M. Schuchmann, U. Schulten-Baumer, A. Seelhoff, A. Stich, F. Stickel, J. Ungemach, E. Walter, A. Weber, T. Winzer, W. Abels, M. Adler, F. Audebert, C. Baermann, E. Bästlein, R. Barth, K. Barthel, W. Becker, J. Behrends, J. Benninger, F. Berger, D. Berzow, T. Beyer, M. Bierbaum, O. Blaukat, A. Bodtländer, G. Böhm, N. Börner, U. Bohr, B. Bokemeyer, H.R. Bruch, D. Bucholz, O. Burkhard, N. Busch, C. Chirca, R. Delker, J. Diedrich, M. Frank, M. Diehl, A. Dienethal, P. Dietel, N. Dikopoulos, M. Dreck, F. Dreher, L. Drude, K. Ende, U. Ehrle, K. Baumgartl, F. Emke, R. Glosemeyer, G. Felten, D. Hüppe, U. Fischer, D. Frederking, B. Frick, G. Friese, B. Gantke, P. Geyer, H.R. Schwind, M. Glas, T. Glaunsinger, F. Goebel, U. Göbel, B. Görlitz, R. Graf, H. Gruber, G. Härter, M. Herder, T. Heuchel, S. Heuer, K.-H. Höffl, H. Hörster, J.-U. Sonne, W.P. Hofmann, F. Holst, M. Hunstiger, A. Hurst, E. Jägel-Guedes, C. John, M. Jung, B. Kallinowski, B. Kapzan, W. Kerzel, P. Khaykin, M. Klarhof, U. Klüppelberg, K. Klugewitz, B. Knapp, U. Knevels, T. Kochsiek, A. Körfer, A. Köster, M. Kuhn, A. Langekamp, B. Künzig, R. Link, M. Littman, H. Löhr, T. Lutz, G. Knecht, U. Lutz, D. Mainz, I. Mahle, P. Maurer, C. Mayer, V. Meister, H. Möller, R. Heyne, D. Moritzen, M. Mroß, M. Mundlos, U. Naumann, O. Nehls, K.&R. Ningel, A. Oelmann, H. Olejnik, K. Gadow, E. Pascher, J. Petersen, A. Philipp, M. Pichler, F. Polzien, R. Raddant, M. Riedel, S. Rietzler, M. Rössle, W. Rufle, A. Rump, C. Schewe, C. Hoffmann, D. Schleehauf, K.J. Schmidt, W. Schmidt, G. Schmidt-Heinevetter, J. Schmidtler-von Fabris, E. Schnaitmann, L. Schneider, A. Schober, S. Niehaus-Hahn, J. Schwenzer, T. Seidel, G. Seitel, C. Sick, K.G. Simon, D. Stähler, F. Stenschke, H. Steffens, K. Stein, M. Steinmüller, T. Sternfeld, K. Svensson, W. Tacke, G. Teuber, K. Teubner, J. Thieringer, A. Tomesch, U. Trappe, J. Ullrich, G. Urban, S. Usadel, A. von Lucadou, F. Weinberger, M. Werheid-Dobers, P. Werner, T. Winter, E. Zehnter, and A. Zipf

Subjects
medicine.medical_specialty, Elbasvir, Daclatasvir, Genotype, Sustained Virologic Response, Sofosbuvir, Combination therapy, Voxilaprevir, Hepacivirus, Viral Nonstructural Proteins, Chronic liver disease, Antiviral Agents, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Drug Resistance, Viral, medicine, Humans, Hepatology, business.industry, Ribavirin, Liver Neoplasms, Gastroenterology, Hepatitis C, Chronic, medicine.disease, Hepatitis C, chemistry, Grazoprevir, 030220 oncology & carcinogenesis, Retreatment, Drug Therapy, Combination, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Published
2021

21. Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit

Author

Sakr Y., Rubatto Birri P. N., Kotfis K., Nanchal R., Shah B., Kluge S., Schroeder M. E., Marshall J. C., Vincent J. -L, E Tomas, E Amisi Bibonge, B Charra, M Faroudy, L Doedens, Z Farina, D Adler, C Balkema, A Kok, S Alaya, H Gharsallah, D Muzha, A Temelkov, G Georgiev, G Simeonov, G Tsaryanski, S Georgiev, A Seliman, S Vrankovic, Z Vucicevic, I Gornik, B Barsic, I Husedzinovic, P Pavlik, J Manak, E Kieslichova, R Turek, M Fischer, R Valkova, L Dadak, P Dostal, J Malaska, R Hajek, A Židková, P Lavicka, J Starkopf, Z Kheladze, M Chkhaidze, V Kaloiani, L Medve, A Sarkany, I Kremer, Z Marjanek, P Tamasi, I Krupnova, I Vanags, V Liguts, V Pilvinis, S Vosylius, G Kekstas, M Balciunas, J Kolbusz, A Kübler, B Mielczarek, M Mikaszewska-Sokolewicz, K Kotfis, B Tamowicz, W Sulkowski, P Smuszkiewicz, A Pihowicz, E Trejnowska, N Hagau, D Filipescu, G Droc, M Lupu, A Nica, R Stoica, D Tomescu, D Constantinescu, G Valcoreanu Zbaganu, A Slavcovici, V Bagin, D Belsky, S Palyutin, S Shlyapnikov, D Bikkulova, A Gritsan, G Natalia, E Makarenko, V Kokhno, A Tolkach, E Kokarev, B Belotserkovskiy, K Zolotukhin, V Kulabukhov, L Soskic, I Palibrk, R Jankovic, B Jovanovic, M Pandurovic, V Bumbasirevic, B Uljarevic, M Surbatovic, N Ladjevic, G Slobodianiuk, V Sobona, A Cikova, A Gebhardtova, C Jun, S Yunbo, J Dong, S Feng, M Duan, Y Xu, X Xue, T Gao, X Xing, X Zhao, C Li, G Gengxihua, H Tan, J Xu, L Jiang, Q Tiehe, Q Bingyu, Q Shi, Z Lv, L Zhang, L Jingtao, Z Zhen, Z Wang, T Wang, L Yuhong, Q Zhai, Y Chen, C Wang, W Jiang, W Ruilan, Y Chenv, H Xiaobo, H Ge, T Yan, C Yuhui, J Zhang, F Jian-Hong, H Zhu, F Huo, Y Wang, M Zhuang, Z Ma, J Sun, L Liuqingyue, M Yang, J Meng, S Ma, Y Kang, L Yu, Q Peng, Y Wei, W Zhang, R Sun, A Yeung, W Wan, K Sin, K Lee, M Wijanti, U Widodo, H Samsirun, T Sugiman, C Wisudarti, T Maskoen, N Hata, Y Kobe, O Nishida, D Miyazaki, S Nunomiya, S Uchino, N Kitamura, K Yamashita, S Hashimoto, H Fukushima, N Nik Adib, L Tai, B Tony, R Bigornia, J Palo, S Chatterjee, B Tan, A Kong, S Goh, C Lee, C Pothirat, B Khwannimit, P Theerawit, P Pornsuriyasak, A Piriyapatsom, A 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Davies, E Vickers, B Agarwal, T Szakmany, S Wimbush, I Welters, R Pearse, R Hollands, J Kirk-Bayley, N Fletcher, B Bray, D Brealey, Sakr, Y, Rubatto Birri, P, Kotfis, K, Nanchal, R, Shah, B, Kluge, S, Schroeder, M, Marshall, J, Vincent, J, Citerio, G, Sakr Y., Rubatto Birri P.N., Kotfis K., Nanchal R., Shah B., Kluge S., Schroeder M.E., Marshall J.C., and Vincent J.-L, E Tomas, E Amisi Bibonge, B Charra, M Faroudy, L Doedens, Z Farina, D Adler, C Balkema, A Kok, S Alaya, H Gharsallah, D Muzha, A Temelkov, G Georgiev, G Simeonov, G Tsaryanski, S Georgiev, A Seliman, S Vrankovic, Z Vucicevic, I Gornik, B Barsic, I Husedzinovic, P Pavlik, J Manak, E Kieslichova, R Turek, M Fischer, R Valkova, L Dadak, P Dostal, J Malaska, R Hajek, A Židková, P Lavicka, J Starkopf, Z Kheladze, M Chkhaidze, V Kaloiani, L Medve, A Sarkany, I Kremer, Z Marjanek, P Tamasi, I Krupnova, I Vanags, V Liguts, V Pilvinis, S Vosylius, G Kekstas, M Balciunas, J Kolbusz, A Kübler, B Mielczarek, M Mikaszewska-Sokolewicz, K Kotfis, B Tamowicz, W Sulkowski, P Smuszkiewicz, A Pihowicz, E Trejnowska, N Hagau, D Filipescu, G Droc, M Lupu, A Nica, R Stoica, D Tomescu, D Constantinescu, G Valcoreanu Zbaganu, A Slavcovici, V Bagin, D Belsky, S Palyutin, S Shlyapnikov, D Bikkulova, A Gritsan, G Natalia, E Makarenko, V Kokhno, A Tolkach, E Kokarev, B Belotserkovskiy, K Zolotukhin, V Kulabukhov, L Soskic, I Palibrk, R Jankovic, B Jovanovic, M Pandurovic, V Bumbasirevic, B Uljarevic, M Surbatovic, N Ladjevic, G Slobodianiuk, V Sobona, A Cikova, A Gebhardtova, C Jun, S Yunbo, J Dong, S Feng, M Duan, Y Xu, X Xue, T Gao, X Xing, X Zhao, C Li, G Gengxihua, H Tan, J Xu, L Jiang, Q Tiehe, Q Bingyu, Q Shi, Z Lv, L Zhang, L Jingtao, Z Zhen, Z Wang, T Wang, L Yuhong, Q Zhai, Y Chen, C Wang, W Jiang, W Ruilan, Y Chenv, H Xiaobo, H Ge, T Yan, C Yuhui, J Zhang, F Jian-Hong, H Zhu, F Huo, Y Wang, C Li, M Zhuang, Z Ma, J Sun, L Liuqingyue, M Yang, J Meng, S Ma, Y Kang, L Yu, Q Peng, Y Wei, W Zhang, R Sun, A Yeung, W Wan, K Sin, K Lee, M Wijanti, U Widodo, H Samsirun, T Sugiman, C Wisudarti, T Maskoen, N Hata, Y Kobe, O Nishida, D Miyazaki, S Nunomiya, S Uchino, N Kitamura, K Yamashita, S Hashimoto, H Fukushima, N Nik Adib, L Tai, B Tony, R Bigornia, R Bigornia, R Bigornia, J Palo, S Chatterjee, B Tan, A Kong, S Goh, C Lee, C Pothirat, B Khwannimit, P Theerawit, P Pornsuriyasak, A Piriyapatsom, A Mukhtar, A Nabil Hamdy, H Hosny, A Ashraf, M Mokhtari, S Nowruzinia, A Lotfi, F Zand, R Nikandish, O Moradi Moghaddam, J Cohen, O Sold, T Sfeir, A Hasan, D Abugaber, H Ahmad, T Tantawy, S Baharoom, H Algethamy, A Amr, G Almekhlafi, R Coskun, M Sungur, A Cosar, B Güçyetmez, O Demirkiran, E Senturk, H Ulusoy, H Atalan, S Serin, I Kati, Z Alnassrawi, A Almemari, K Krishnareddy, S Kashef, A Alsabbah, G Poirier, J Marshall, M Herridge, M Herridge, R Fernandez-Medero, G Fulda, S Banschbach, J Quintero, E Schroeder, C Sicoutris, R Gueret, R Kashyap, P Bauer, R Nanchal, R Wunderink, E Jimenez, A Ryan, D Prince, J Edington, F Van Haren, A Bersten, D J Hawkins, M Kilminster, D Sturgess, M Ziegenfuss, S O' Connor, J Lipman, L Campbell, R Mcallister, B Roberts, P Williams, R Parke, P Seigne, R Freebairn, D Nistor, C Oxley, P Young, R Valentini, N Wainsztein, P Comignani, M Casaretto, G Sutton, P Villegas, C Galletti, J Neira, D Rovira, J Hidalgo, F Sandi, E Caser, M Thompson, M D'agostino Dias, L Fontes, M Lunardi, N Youssef, S Lobo, R Silva, J Sales Jr, L Madeira Campos Melo, M Oliveira, M Fonte, C Grion, C Feijo, V Rezende, M Assuncao, A Neves, P Gusman, D Dalcomune, C Teixeira, K Kaefer, I Maia, V Souza Dantas, R Costa Filho, F Amorim, M Assef, P Schiavetto, J Houly, F Bianchi, F Dias, C Avila, J Gomez, L Rego, P Castro, J Passos, C Mendes, C Grion, G Colozza Mecatti, M Ferrreira, V Irineu, M Guerreiro, S Ugarte, V Tomicic, C Godoy, W Samaniego, I Escamilla, L Castro Castro, G Libreros Duque, D Diaz-Guio, F Benítez, A Guerra Urrego, R Buitrago, G Ortiz, M Villalba Gaviria, D Salas, J Ramirez-Arce, E Salgado, D Morocho, J Vergara, M Chung Sang, C Orellana-Jimenez, L Garrido, O Diaz, D Resiere, C Osorio, A De La Vega, R Carrillo, V Sanchez, A Villagomez, R Martinez Zubieta, M Sandia, M Zalatiel, M Poblano, D Rodriguez Gonzalez, F Arrazola, L Juan Francisco, S A Ñamendys-Silva, M Hernandez, D Rodriguez Cadena, I Lopez Islas, C Ballesteros Zarzavilla, A Matos, I Oyanguren, J Cerna, R Quispe Sierra, R Jimenez, L Castillo, R Ocal, A Sencan, S Mareque Gianoni, A Deicas, J Hurtado, G Burghi, A Martinelli, I Von Der Osten, C Du Maine, M Bhattacharyya, S Bandyopadhyay, S Yanamala, P Gopal, S Sahu, M Ibrahim, D Rathod, N Mukundan, A Dewan, P Amin, S Samavedam, B Shah, D Gurupal, B Lahkar, A Mandal, M Sircar, S Ghosh, V Balasubramani, F Kapadia, S Vadi, K Nair, S Tripathy, S Nandakumar, J Sharma, A Kar, S Jha, K Zirpe-Gurav, M Patel, A Bhavsar, D Samaddar, A Kulkarni, M Hashmi, W Ali, S Nadeem, K Indraratna, A Margarit, P Urbanek, J Schlieber, J Reisinger, J Auer, A Hartjes, A Lerche, T Janous, E Kink, W Krahulec, K Smolle, M Van Der Schueren, P Thibo, M Vanhoof, I Ahmet, G Philippe, P Dufaye, O Jacobs, V Fraipont, P Biston, A Dive, Y Bouckaert, E Gilbert, B Gressens, E Pinck, V Collin, J L Vincent, J De Waele, R Rimachi, D Gusu, K De Decker, K Mandianga, L Heytens, X Wittebole, S Herbert, V Olivier, W Vandenheede, P Rogiers, P Kolodzeike, M Kruse, T Andersen, V Harjola, K Saarinen, M Leone, A Durocher, S Moulront, A Lepape, M Losser, P Cabaret, E Kalaitzis, E Zogheib, P Charve, B Francois, J Y Lefrant, B Beilouny, X Forceville, B Misset, F Jacobs, F Bernard, D Payen, A Wynckel, V Castelain, A Faure, P Lavagne, L Thierry, M Moussa, A Vieillard-Baron, M Durand, M Gainnier, C Ichai, S Arens, C Hoffmann, M Kaffarnik, C Scharnofske, I Voigt, C Peckelsen, M Weber, J Gille, A Lange, G Schoser, A Sablotzki, U Jaschinski, A Bluethgen, F Vogel, A Tscheu, T Fuchs, M Wattenberg, T Helmes, S Scieszka, M Heintz, S Sakka, J Kohler, F Fiedler, M Danz, Y Sakr, R Riessen, T Kerz, A Kersten, F Tacke, G Marx, T Volkert, A Schmutz, A Nierhaus, S Kluge, P Abel, R Janosi, S Utzolino, H Bracht, S Toussaint, M Giannakou Peftoulidou, P Myrianthefs, A Armaganidis, C Routsi, A Xini, E Mouloudi, I Kokoris, G Kyriazopoulos, S Vlachos, A Lavrentieva, P Partala, G Nakos, A Moller, S Stefansson, J Barry, R O'Leary, C Motherway, M Faheem, E Dunne, M Donnelly, T Konrad, E Bonora, C Achilli, S Rossi, G Castiglione, A Peris, D Albanese, N Stocchetti, G Citerio, L Mozzoni, E Sisillo, P De Negri, M Savioli, P Vecchiarelli, F Puflea, V Stankovic, G Minoja, S Montibeller, P Calligaro, R Sorrentino, M Feri, M Zambon, E Colombaroli, A Giarratano, T Pellis, C Capra, M Antonelli, A Gullo, C Chelazzi, A De Capraris, N Patroniti, M Girardis, F Franchi, G Berlot, M Buttigieg, H Ponssen, J Ten Cate, L Bormans, S Husada, M Buise, B Van Der Hoven, A Reidinga, M Kuiper, P Pickkers, G Kluge, S Den Boer, J Kesecioglu, H Van Leeuwen, H Flaatten, S Mo, V Branco, F Rua, E Lafuente, M Sousa, N Catorze, M Barros, L Pereira, A Vintém De Oliveira, J Gomes, I Gaspar, M Pereira, M Cymbron, A Dias, E Almeida, S Beirao, I Serra, R Ribeiro, P Povoa, F Faria, Z Costa-E-Silva, J Nóbrega, F Fernandes, J Gabriel, G Voga, E Rupnik, L Kosec, M Kerin Povšic, I Osojnik, V Tomic, A Sinkovic, J González, E Zavala, J Pérez Valenzuela, L Marina, P Vidal-Cortés, P Posada, A Ignacio Martin-Loeches, N Muñoz Guillén, M Palomar, J Sole-Violan, A Torres, M Gonzalez Gallego, G Aguilar, R Montoiro Alluév, M Argüeso, M Parejo, M Palomo Navarro, A Jose, N Nin, F Alvarez Lerma, O Martinez, E Tenza Lozano, S Arenal López, M Perez Granda, S Moreno, C Llubia, C De La Fuente Martos, P Gonzalez-Arenas, N Llamas Fernández, B Gil Rueda, I Estruch Pons, N Cruza, F Maroto, A Estella, A Ferrer, L Iglesias Fraile, B Quindos, A Quintano, M Tebar, P Cardinal, A Reyes, A Rodríguez, A Abella, S García Del Valle, S Yus, E Maseda, J Berezo, A Tejero Pedregosa, C Laplaza, R Ferrer, J Rico-Feijoo, M Rodríguez, P Monedero, K Eriksson, D Lind, D Chabanel, H Zender, K Heer, B Frankenberger, S Jakob, A Haller, S Mathew, R Downes, C Barrera Groba, A Johnston, R Meacher, R Keays, P Haji-Michael, C Tyler, A Ferguson, S Jones, D Tyl, A Ball, J Vogel, M Booth, P Downie, M Watters, S Brett, M Garfield, L Everett, S Heenen, S Dhir, Z Beardow, M Mostert, S Brosnan, N Pinto, S Harris, A Summors, N Andrew, A Rose, R Appelboam, O Davies, E Vickers, B Agarwal, T Szakmany, S Wimbush, I Welters, R Pearse, R Hollands, J Kirk-Bayley, N Fletcher, B Bray, D Brealey

Subjects
Internationality, Time Factors, Databases, Factual, medicine.medical_treatment, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Settore MED/41 - Anestesiologia, Critical Care and Intensive Care Medicine, law.invention, 0302 clinical medicine, law, Risk Factors, 80 and over, 030212 general & internal medicine, Hospital Mortality, 610 Medicine & health, Aged, 80 and over, Medical Audit, fluid output, Middle Aged, Water-Electrolyte Balance, fluid administration, Intensive care unit, outcome, septic shock, Adult, Aged, Humans, Intensive Care Units, Sepsis, Fluid Therapy, Cohort, Human, Cohort study, medicine.medical_specialty, Time Factor, Sepsi, Intensive Care Unit, Observational Study, 03 medical and health sciences, Databases, Hemofiltration, medicine, Journal Article, Risk factor, Intensive care medicine, Factual, Hetastarch, business.industry, Septic shock, Risk Factor, 030208 emergency & critical care medicine, fluid administration, fluid output, outcome, septic shock, medicine.disease, business
Abstract

Contains fulltext : 177598.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis. DESIGN: Observational cohort study. SETTING: Seven hundred and thirty ICUs in 84 countries. PATIENTS: All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission. MEASUREMENTS AND MAIN RESULTS: ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock. CONCLUSIONS: In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.

Published
2017

22. [Diagnosis and stage-adapted treatment of acute pancreatitis]

Author

U, Herbers, C, Trautwein, F, Tacke, and A, Koch

Subjects
Enteral Nutrition, Pancreatitis, Acute Necrotizing, Drainage, Humans, Endoscopy
Abstract

Acute pancreatitis is a potentially life-threatening disease, which is morphologically classified into interstitial edematous or necrotizing pancreatitis. According to the revised Atlanta classification, mild, moderate and severe clinical courses are differentiated regarding local and systemic complications as well as concomitant organ failure. In the initial disease phase, the therapeutic measures are focused on (aggressive) volume replacement, early enteral nutrition and adequate analgesia. Characteristic in the course of severe acute pancreatitis are abdominal necroses, which require individualized and interdisciplinary treatment with antibiotic therapy, drainage and definitive necrosectomy. Necrosectomy should be planned as a "step-up approach" using interventional-radiological, endoscopic and minimally invasive surgical procedures.

Published
2018

23. Autoren

Author

P. Albers, R.P. Andrié, J. Angenendt, B. Appenrodt, A. Arkudas, H. Aubin, R. Autschbach, S. Baldus, J. Balzer, J. Baltzer, J. Behr, A. Behrens, Marcus Benz, M. Berger, F. Berr, S.C. Bischoff, A. Böhm, M. Böhm, D. Bokemeyer, F. Borowitzka, M. Brüwer, M. Buchfelder, A. Burk, K. Caca, S. Daum, C. Detter, H.-C. Diener, W. Domschke, K. Doppler, C.E. Elger, C. Ell, J. Ellinger, H.-J. Epple, B. Esser, Sebastian Ewen, C. Fibbe, S. Fichtner-Feigl, P. Fiegel, W. Fischbach, M. Fischereder, U.R. Fölsch, M. Forsting, N. Frey, S.M. Freys, M. Friedrich, T. Frieling, U. Frommberger, P. Frühmorgen, S. Geidel, C.-T. Germer, F.-D. Goebel, A. Goetzenich, K. Grabitz, M. Greetfeld, A. Groeneveld, P.K. Groha, F. Gundling, C.N. Gutt, T. Haak, U. Hartmann, H. Hauner, C. Hausteiner-Wiehle, P. Henningsen, B. Herpertz-Dahlmann, D. Heuß, P. Heußner, J. Hoffmann, U. Hohenfellner, R.E. Horch, M. Hüll, S. John, B. Jordan, C. Jurowich, A. Käberich, H. Katus, C. Keck, M. Kelm, K. Kiehne, Adrienne Kilian, I. Kindermann, A. Kleindienst, K. Klingel, Y. von Kodolitsch, H. Kölbl, S. Koletzko, O. Kollmar, S. Konstantinidis, H.J. Kramer, M.E. Kreis, B. Kroener-Herwig, C. Kurschat, F. Lammert, G. Lamprecht, J.M. Langosch, P. Layer, L. Leifeld, A. Lichtenberg, K. Lindner, A. Link, N. Lügering, Achim Lusch, T. Marth, U. Merle, F. Mellert, M. Meyer-Marcotty, G. Michels, J.M. Middeke, G. Möddel, J. Mössner, A. Müller, J.L. Müller, R.-U. Müller, S.C. Müller, S. Müller-Lissner, U. Müller-Werdan, M. Neubrand, C. Neuhof, K.G. Parhofer, E. Petri, T. Pfeiffer, Adrian Pilatz, C. Pizarro, T. Pohle, E. Polykandriotis, C. Probst, W. Rascher, B. Rauch, M. Reuss-Borst, C. Riedner, E. Rietschel, V. Röckelein, Ch. Rüster, M. Ruß, M. Sailer, W. Sandmann, T. Sauerbruch, B. Schaaf, C.A. Schaefer, N. Schahab, A. Schaper, J. Schetelig, M. Schmitz, H.-G. Schnürch, J. Schölmerich, Ulf Schönermarck, J.W. Schrickel, A. Schuchert, H. Schunkert, S.E. Segerer, N. Senninger, U. Seybold, B. Siegmund, D. Skowasch, C. Sommer, U. Spengler, M. Stahl, A. Stallmach, G. Stolpmann, W. Stremmel, U. Sure, F. Tacke, B.T. te Wildt, P. Trinkler, H. Tröger, M. Unnewehr, T. Vloet, U. Voderholzer, P.M. Vogt, W. von Scheidt, F. Wagenlehner, T. Wahlers, L.T. Weber, T. Wehrmann, B.T. Weis-Müller, K. Werdan, U. Wintergerst, T. Wittwer, Gunter Wolf, K. Wölfling, G. Wolkersdörfer, D. Ziegler, and S. Zierz

Published
2018

25. Socio-economic Status (SES) Affects Infants' Selective Exploration

Author

Nicholas F. Tacke, Lillian S. Bailey, and Melissa W. Clearfield

Subjects
Physical context, Behavior change, Developmental and Educational Psychology, Task analysis, Cognition, Cognitive skill, Psychology, Affordance, Socioeconomic status, Developmental psychology
Abstract

Infants change their behaviours in accordance with the objects they are exploring. They also tailor their exploratory actions to the physical context. This selectivity of exploratory actions represents a foundational cognitive skill that underlies higher-level cognitive processes. The present study compared the development of selective exploratory behaviours in high and low socio-economic status (SES) infants. Sixty-one 6‐8- and 10‐12-month-old infants were presented with rigid andflexible cubes on a tray that was half rigid and halfflexible. There were SES effects for each category of exploratory behaviours: object only, surface only and object‐ surface interactions. Low-SES infants engaged in comparable amounts of exploratory behaviours with high-SES infants, but they exhibited behaviours less conducive to information uptake, compared with high-SES infants. The results suggest difficulty for low-SES infants in transitioning to more mature exploration strategies. Copyright © 2015 John Wiley & Sons, Ltd.

Published
2015

28. List of Contributors

Author

L. Abenavoli, J.G. Abraldes, N.E. Aguilar-Olivos, J. Aguirre-García, P. Almeda-Valdés, J. Arauz, R.N. Aravalli, J. Arellanes-Robledo, A. Ascensão, A. Bardia, J. Beleza, T.R. Billiar, L.D. Buendía-Montaño, J. Camacho, S. Casas-Grajales, A. Casillas-Ramírez, G. Castañeda-Hernández, A.I. Cederbaum, V. Chagoya de Sánchez, E. Chávez, I. Colle, L. Cruz-Antonio, A. Cruz-Baquero, A.J. Czaja, L. Dara, M. del Pilar Cabrales-Romero, M. Dhayal, M. Espinosa-Cantellano, V.M. Factor, P. Ferenci, E. Fernández-Martínez, M. Fernandez, N.A. Fierro, R.E. Flores-Beltrán, S.W. French, P. Fu, H. Fukui, M. Galicia-Moreno, A. Galli, P. García-López, G. Garcia-Tsao, M.C. García de León, P. Ginès, C. Girish, L.E. Gómez-Quiroz, I.O. Gonçalves, K. Gonzalez-Aldaco, J. Gracia-Sancho, I. Grattagliano, I. Graupera, O.A. Gressner, A.M. Gressner, R.J. Groszmann, G. Guízar-Sahagún, D.G. Gutiérrez-Reyes, M.C. Gutiérrez-Ruiz, M.A. Habeeb, H. Hai, L. Hammerich, E. Hernández-Aquino, C. Hernández, H. Jaeschke, M.B. Jiménez-Castro, N. Kaplowitz, A. Katoonizadeh, N. Kawada, D. Kershenobich, A.A. Khan, S.H. Ki, K.M. Kim, M.R. Lakshman, W. Li, X. Liang, X. Liu, Z.-X. Liu, P.A. Loughran, S.C. Lu, S. Maeda, J. Magalhães, J. Mann, J.U. Marquardt, M. Martínez-Castillo, M.L. Martínez-Chantar, H.Y. Martínez-Padrón, A. Martínez-Palomo, M.J. Martins, J.M. Mato, N. Méndez-Sánchez, N. Milic, G. Montes-Páez, S. Montes, P. Muriel, T. Nakamura, M. Noureddin, P.J. Oliveira, R. Pacheco-Rivera, J. Pacheco-Yépez, A. Panduro, C. Peralta, J.I. Pérez-Carreón, P. Portincasa, S.C. Pradhan, S. Raevens, A. Ramachandran, E. Ramos-Tovar, K. Reyes-Gordillo, S. Rivera-Mancía, M.S. Roberts, A.Y. Rocha-Sánchez, S. Roman, J. Serrano-Luna, R. Shah, W. Shibata, M. Shibayama, Y. Shimizu, G. Shiota, E. Solà, F. Tacke, K. Tajiri, A. Takaki, M. Tarocchi, S.S. Thorgeirsson, T.T.V. Thuy, T.T. Thuy le, T. Torimura, L.A. Tristán-López, V. Tsutsumi, G.R. Tsutsumi, D. Uchida, T. Ueno, M. Uribe, E.E. Vargas-Pozada, L.F. Vázquez-Flores, G. Velasco-Loyden, L. Vergani, S.K. Vishwakarma, J.D. Vorobioff, J.-Y. Wang, H. Wang, S.-D. Wu, F. Xia, W. Xu, L. Xu, K. Yamamoto, X.R. Yao, J. Yu, L. Zeng, and B.J. Zhou

Published
2017

29. Cytokines in Steatohepatitis

Author

F. Tacke and L. Hammerich

Subjects
business.industry, Fatty liver, Inflammasome, Inflammation, medicine.disease, Systemic inflammation, Proinflammatory cytokine, Immunology, Nonalcoholic fatty liver disease, medicine, Tumor necrosis factor alpha, Steatohepatitis, medicine.symptom, business, medicine.drug
Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver diseases in Western countries and becoming a major health and economic burden. The progression of NAFLD from steatosis to steatohepatitis is causally linked to a massive inflammatory response in the liver, but also associated with signs of systemic inflammation. Cytokines are critically involved in the regulation of immune responses during the progression of NAFLD, and the interplay between systemic and hepatic inflammatory signals is considered as a critical factor in the pathogenesis. Proinflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin (IL) 6, IL8, or IL17 contribute to disease progression, while the anti-inflammatory IL10 is associated with protection. In addition, stimulation of toll-like receptors leads to activation of the inflammasome and release of IL1β, contributing to fibrogenesis and inflammation in the liver. This chapter summarizes the major findings regarding the functional role of cytokines in the development of steatohepatitis.

Published
2017

30. SOCIOECONOMIC STATUS AFFECTS ORAL AND MANUAL EXPLORATION ACROSS THE FIRST YEAR

Author

Sarah B. Stanger, Nicholas F. Tacke, Lillian S. Bailey, Melissa W. Clearfield, and Helen K. Jenne

Subjects
education.field_of_study, Population, Cognition, language.human_language, Developmental psychology, German, Psychiatry and Mental health, Developmental trajectory, Pediatrics, Perinatology and Child Health, Developmental and Educational Psychology, language, Psychology, Mouthing, education, Socioeconomic status
Abstract

Oral and manual exploration are part of the foundation of problem solving and cognition in infancy. How these develop in an at-risk population, infants in poverty, is unknown. The current study tested exploratory behaviors longitudinally at 6, 9, and 12 months in infants from high- and low-socioeconomic (SES) families. Oral exploration consisted of passive and active mouthing and looks after active mouthing. Manual exploration consisted of frequency of fingering, rotating, and transferring the object. High-SES infants replicated the trajectory previously reported in the literature, showing a decrease in mouthing and fingering and an increase in rotating and transferring (e.g., Palmer, 1989). In contrast, low-SES infants showed no change in any of the manual exploratory behaviors over the first year, thus demonstrating reduced overall levels of exploration as well as a different developmental trajectory. Results are discussed in terms of attention, potential physiological mechanisms, and implications for later problem solving. Abstracts translated in Spanish, French, German, and Japanese can be found on the abstract page of each article on Wiley Online Library at http://wileyonlinelibrary.com/journal/imhj.

Published
2013

31. Invasive Candida-Infektionen bei Leberzirrhose

Author

F Tacke and A Koch

Subjects
medicine.medical_specialty, Cirrhosis, business.industry, MEDLINE, Emergency Nursing, Critical Care and Intensive Care Medicine, medicine.disease, Candida infections, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Emergency Medicine, Internal Medicine, medicine, 030211 gastroenterology & hepatology, 030212 general & internal medicine, business
Published
2017

33. Pathophysiologie der Leberfibrose

Author

F. Tacke and R. Weiskirchen

Subjects
Gynecology, medicine.medical_specialty, business.industry, Liver fibrosis, Internal Medicine, medicine, business
Abstract

Die chronische Schadigung der Leber, z. B. durch Hepatitisviren, Alkohol, metabolisches Syndrom oder andere Noxen, fuhrt neben dem Untergang von Hepatozyten zu einer Entzundungsreaktion mit Einwanderung und Aktivierung von Immunzellen sowie zu einer Proliferation und Transdifferenzierung mesenchymaler Zellen innerhalb der Leber, insbesondere der hepatischen Sternzellen. Letztere sind fur die massive Zunahme extrazellularer Matrixproteine und die damit einhergehende Fibrosierung des Organs verantwortlich. Unbehandelt kann die Leberfibrose zur Zirrhose und hepatischen Insuffizienz fuhren. Das Ziel dieses Ubersichtsartikels ist, das aktuelle Wissen uber die pathophysiologische Sequenz der Fibrosierung systematisch darzustellen und den entscheidenden Einfluss von Zytokinen und Chemokinen in diesem Prozess zu diskutieren. Das Verstandnis der komplexen zellularen Interaktionen in der Leberfibrose lasst fur die Zukunft neue antifibrotische Therapiestrategien erwarten.

Published
2010

34. [IL-6 dependent GLP-1 secretion during acute inflammation]

Author

F, Kahles, C, Meyer, J, Möllmann, S, Diebold, H M, Findeisen, C, Lebherz, C, Trautwein, A, Koch, F, Tacke, N, Marx, and M, Lehrke

Subjects
Blood Glucose, Mice, Glucagon-Like Peptide 1, Interleukin-6, Critical Illness, Hyperglycemia, Sepsis, Awards and Prizes, Animals, Humans, Insulin, Signal Transduction
Published
2015

35. [S2k Guideline non-alcoholic fatty liver disease]

Author

E, Roeb, H M, Steffen, H, Bantel, U, Baumann, A, Canbay, M, Demir, U, Drebber, A, Geier, J, Hampe, C, Hellerbrand, A, Pathil-Warth, J M, Schattenberg, C, Schramm, H K, Seitz, N, Stefan, F, Tacke, A, Tannapfel, P, Lynen Jansen, and J, Bojunga

Subjects
Non-alcoholic Fatty Liver Disease, Germany, Practice Guidelines as Topic, Gastroenterology, Humans, Obesity
Published
2015

36. [First data concerning the medical supply of patients with non-alcoholic fatty liver disease in Germany - a survey in university hospital centers of hepatology]

Author

J, Weiss, M, Rau, H, Bantel, H, Bock, M, Demir, J, Kluwe, M, Krawczyk, A, Pathil-Warth, J M, Schattenberg, F, Tacke, E, Roeb, A, Geier, and A, Zipprich

Subjects
Hospitals, University, Patients, Non-alcoholic Fatty Liver Disease, Germany, Health Care Surveys, Utilization Review, Gastroenterology, Prevalence, Humans, Workload, Referral and Consultation
Abstract

Non-alcoholic fatty liver disease (NAFLD) currently is one oft the most common reasons for chronic liver injury in the western world. In the European and American population the prevalence is up to 30 %. The medical supply of German patients with NAFLD is variable and has not been analyzed to date.We sent questionnaires to all university liver centers in Germany (11 questions) concerning the medical supply of patients with NAFLD. Questions included the rate of patients with fatty liver disease in the outpatient clinics, metabolic comorbidities and the kind of assignment. Besides that, individual clinical standards were documented. We compared longitudinal changes between 2008 and 2013.The return rate of questionnaires was 65 % (n = 20). Analysis showed that the portion of NAFLD patients in the university outpatient clinics had increased between 2008 and 2013 with the predominant part of patients being assigned from external practitioners and not from internal departments of the hospital. Only few patients were assigned by diabetologists or endocrinologists, but on the other hand most liver outpatient clinics investigated their NAFLD patients for metabolic disorders. Cooperation between liver outpatient clinics and other medical services was moderate and was rated average, joint conferences were held rarely. Follow-up visits of patients with NAFLD take place regularly in all centers, however based on different criterions. A consistent algorithm concerning risk assessment and invasive workup does not exist.The awareness concerning patients with NAFLD seems to have grown in recent years. Nevertheless, the medical supply of these patients is quite heterogenous and consistent standards do not exist. Therefore, a common guidline is urgently required.

Published
2015

39. The PDE-4 Inhibitor Roflumilast reduces weight gain, enhances insulin sensitivity and prevents hepatic steatosis in mice by increasing mitochondrogenesis

Author

S Krüger, C Bäck, Hannes M. Findeisen, F Tacke, A Liberman, Florian Kahles, Michael Lehrke, Julia Möllmann, K Hess, Corinna Lebherz, and Nikolaus Marx

Subjects
medicine.medical_specialty, Endocrinology, Chemistry, Endocrinology, Diabetes and Metabolism, Internal medicine, medicine, Insulin sensitivity, medicine.symptom, Steatosis, medicine.disease, Weight gain, Roflumilast, medicine.drug
Published
2014

40. GLP-1 regulates the metabolic response during acute inflammation and predicts outcome in critically ill patients: central role of IL-6

Author

Hannes M. Findeisen, Christina Meyer, Julia Möllmann, A. Koch, Nikolaus Marx, Corinna Lebherz, Florian Kahles, Michael Lehrke, F Tacke, and S. Diebold

Subjects
medicine.medical_specialty, biology, business.industry, Critically ill, Endocrinology, Diabetes and Metabolism, medicine, biology.protein, Inflammation, medicine.symptom, Intensive care medicine, Interleukin 6, business, Outcome (game theory)
Published
2014

41. [Abnormal liver function tests in the intensive care unit]

Author

A, Koch, K, Streetz, J, Tischendorf, C, Trautwein, and F, Tacke

Subjects
Heart Failure, Critical Illness, Cholangitis, Sclerosing, Shock, Cardiogenic, Liver Failure, Acute, Prognosis, Diagnosis, Differential, Intensive Care Units, Liver Function Tests, Sepsis, Humans, Female, Hospital Mortality, Chemical and Drug Induced Liver Injury, Aged, Ultrasonography
Abstract

Abnormal liver biochemical and function tests are found in the majority of critically ill patients and are associated with increased mortality. Frequent causes for elevated liver function tests in the intensive care unit (ICU) are acute hepatic dysfunction due to acute hepatitis, acute liver failure (ALF), and drug-induced liver injury (DILI). Furthermore, exacerbations of pre-existing liver diseases (acute on chronic) and secondary liver injury during critical diseases such as sepsis, right heart failure, or cardiogenic shock, resulting in ischemic or hypoxic hepatitis, need to be considered. Elevated liver enzymes may also reflect a complication of ICU treatment measures like drug-related hepatotoxicity, secondary sclerosing cholangitis in critically ill patients (SC-CIP), or related to parenteral nutrition. Comprehensive diagnostic evaluation is essential to identify the underlying etiology of abnormal liver function tests and to initiate the appropriate therapeutic strategies.

Published
2013

42. [Management of decompensated liver cirrhosis in the intensive care unit]

Author

O, Lerschmacher, A, Koch, K, Streetz, C, Trautwein, and F, Tacke

Subjects
Diagnosis, Differential, Liver Cirrhosis, Intensive Care Units, Hepatorenal Syndrome, Hepatic Encephalopathy, Humans, Esophageal and Gastric Varices, Gastrointestinal Hemorrhage, Prognosis, Algorithms, Liver Transplantation
Abstract

Liver cirrhosis is the end-stage of long-standing chronic liver diseases. The occurrence of complications from liver cirrhosis increases the mortality risk, but the prognosis can be improved by optimal management in the intensive care unit (ICU). Defined diagnostic algorithms allow the etiology and presence of typical complications upon presentation to the ICU to be identified. Acute variceal bleeding requires endoscopic intervention, vasoactive drugs, antibiotics, supportive intensive care measures and, where necessary, urgent transjugular intrahepatic portosystemic shunt (TIPS) procedure. Spontaneous bacterial peritonitis needs to be diagnosed and immediately treated in patients with ascites. Hepatorenal syndrome should be treated by albumin and terlipressin. In case of respiratory failure, differential diagnosis should not only consider pneumonia, pulmonary embolism and cardiac failure, but also hepatic hydrothorax, portopulmonary hypertension and hepatopulmonary syndrome. The feasibility of liver transplantation should be always discussed in patients with decompensated cirrhosis. Artificial liver support devices may only serve as a bridging procedure until transplant.

Published
2013

43. [Gastrointestinal bleeding in liver cirrhosis at the ICU]

Author

A, Koch, L, Buendgens, H, Dückers, J, Bruensing, M, Matthes, J, Kunze, U, Herbers, H H, Lutz, T, Luedde, J J W, Tischendorf, C, Trautwein, and F, Tacke

Subjects
Adult, Aged, 80 and over, Liver Cirrhosis, Male, Adolescent, Critical Care, Incidence, Comorbidity, Middle Aged, Survival Analysis, Causality, Survival Rate, Intensive Care Units, Young Adult, Treatment Outcome, Risk Factors, Germany, Humans, Female, Gastrointestinal Hemorrhage, Aged, Retrospective Studies
Abstract

Due to portal hypertension and bleeding disorders, patients with liver cirrhosis are at increased risk for severe gastrointestinal bleedings (GIB), commonly requiring therapy at the intensive care unit (ICU). In order to identify epidemiological and prognostic factors for GIB in cirrhotic patients, we retrospectively analysed patients from our medical ICU from 1999 to 2010. Among 7376 critically ill patients, 650 (8.8 %) were diagnosed with liver cirrhosis. Hepatic cirrhosis was frequently found in ICU patients admitted due to severe GIB (23.2 % of 711 patients had cirrhosis). Moreover, patients with cirrhosis were at increased risk to develop severe GIB during intensive care treatment (40.9 % of 44 patients with GIB during ICU stay had cirrhosis). Besides the high rate of variceal bleedings (64.4 %) in cirrhotic patients, non-variceal haemorrhages were also common (28.5 %). We identified the MELD score and necessity of mechanical ventilation as independent risk factors for mortality in cirrhotic patients with severe GIB. Patients with liver cirrhosis and severe GIB had significantly impaired prognosis (case-related fatality rate of 26.1 % with cirrhosis vs. 6.8 % without cirrhosis), especially in cases of newly developed GIB during ICU therapy. Advanced therapeutic approaches and novel strategies are warranted to improve the critical prognosis of these high-risk patients.

Published
2013

44. Hepatitis B e antigen-suppressing mutations enhance the replication efficiency of adefovir-resistant hepatitis B virus strains

Author

U, Herbers, S, Amini-Bavil-Olyaee, A, Mueller, T, Luedde, C, Trautwein, and F, Tacke

Subjects
Hepatitis B virus, Telbivudine, Adenine, Organophosphonates, Gene Products, pol, Virus Replication, Antiviral Agents, Cell Line, Tumor, Drug Resistance, Viral, Mutation, Humans, Hepatitis B e Antigens, Promoter Regions, Genetic, Tenofovir, Thymidine
Abstract

Hepatitis B e antigen (HBeAg) negative hepatitis B virus (HBV) infections caused by precore (PC) or basal core promoter (BCP) mutations are associated with disease progression and complications. PC or BCP mutations may enhance the replication capacity of distinct drug-resistance-associated polymerase mutations, but their effect on adefovir-resistant HBV mutants is unclear. Importantly, BCP mutations were an independent risk factor for virological breakthrough in lamivudine-resistant patients treated with adefovir. We aimed at addressing the functional consequences of PC and BCP mutations on the replication and drug susceptibility of adefovir-resistant HBV mutants. Therefore, HBV constructs with wild type (WT) or adefovir-resistant rtN236T, rtA181V and rtA181T mutations, with or without concomitant PC or BCP mutations, were analysed in vitro using molecular assays. The adefovir-resistant polymerase mutations rtN236T, rtA181V and rtA181T showed a drastically reduced viral replication compared with WT. Interestingly, additional PC or BCP mutations enhanced the reduced replication efficacy of adefovir-resistant constructs and restored HBV replication to WT level. HBV rtA181T mutants displayed abolished hepatitis B surface antigen (HBsAg) secretion, owing to a sW172* stop codon in the overlapping envelope gene. All rtN236T- or rtA181V/T-containing constructs, regardless of concomitant PC or BCP mutations, were resistant to adefovir, but remained susceptible to telbivudine, entecavir and tenofovir. In conclusion, adefovir drug resistance mutations reduced viral replication, which can be significantly increased by additional HBeAg-suppressing PC or BCP mutations. Because increased HBV replication in HBeAg-negative patients has been associated with an unfavourable clinical course, close monitoring appears indispensable during adefovir treatment in HBeAg-negative patients.

Published
2013

45. [Bleeding origin, patient-related risk factors, and prognostic indicators in patients with acute gastrointestinal hemorrhages requiring intensive care treatment. A retrospective analysis from 1999 to 2010]

Author

A, Koch, L, Buendgens, H, Dückers, J, Bruensing, M, Matthes, J, Kunze, H H, Lutz, T, Luedde, J J W, Tischendorf, C, Trautwein, and F, Tacke

Subjects
Adult, Aged, 80 and over, Male, Adolescent, Critical Care, Anticoagulants, Comorbidity, Middle Aged, Prognosis, Endoscopy, Gastrointestinal, Hospitals, University, Survival Rate, Young Adult, Risk Factors, Cause of Death, Germany, Acute Disease, Humans, Female, Gastrointestinal Hemorrhage, Platelet Aggregation Inhibitors, Aged, Retrospective Studies
Abstract

Gastrointestinal bleeding (GIB) is a common problem in elderly patients involving severe comorbidities and concomitant antiplatelet or anticoagulatory therapy. The risk factors and prognostic indicators of patients with severe GIB requiring intensive care medical treatment have not been well evaluated.A retrospective analysis of 7,376 patients from the medical intensive care unit (ICU) at the University Hospital Aachen was carried out between 1999 and 2010.Of 614 patients admitted to the ICU because of acute GIB, 463 (75%) presented with upper GIB (UGIB) and 151 (25%) with lower GIB (LGIB). Despite early endoscopic intervention and ICU treatment, UGIB had a mortality rate of 16%, whereas LGIB showed a significantly better prognosis (mortality5%) in the ICU setting. Risk factors for OGIB-related mortality were hemodynamic instability, organ failure, comorbidities (especially liver cirrhosis), and rebleeding. In total, 218 patients (36%) were treated with antiplatelet or anticoagulatory drugs, which were associated with a favorable prognosis in the UGIB group. Elevated serum lactate levels upon admission were superior in predicting mortality than established indicators of prognosis such as the Rockall or the Glasgow-Blatchford score.Despite successful endoscopic intervention, severe acute UGIB is associated with a significant mortality rate of 16% in the ICU setting, determined by hemodynamic failure, organ dysfunction, and comorbidities. The serum lactate levels of patients with GIB on the day of admission to the ICU are prognostic.

Published
2012

46. [Treatment of inflammatory bowel disease in intensive care medicine]

Author

A, Koch, F, Tacke, K L, Streetz, and C, Trautwein

Subjects
Abdominal Abscess, Critical Care, Middle Aged, Combined Modality Therapy, Fever of Unknown Origin, Nephrectomy, Shock, Septic, Abscess, Abdominal Pain, Anti-Bacterial Agents, Megacolon, Toxic, Crohn Disease, Drainage, Humans, Rectal Fistula, Colitis, Ulcerative, Female, Kidney Diseases, Tomography, X-Ray Computed, Immunosuppressive Agents, Ultrasonography
Abstract

In patients with inflammatory bowel disease (IBD) complications of both IBD and immunosuppressive therapy may be life-threatening conditions requiring intensive care therapy. These patients oftentimes present themselves with severe bloody diarrhoea, and infectious colitis, pseudomembranous colitis or intestinal ischemia must be included in the differential diagnosis. Steroids, immunosuppressants such as azathioprine, 6-mercaptopurine, methotraxate or ciclosporine, as well as biologicals, which act as TNF-alpha antagonists, are commonly used for maintenance therapy and treatment of acute exacerbations of IBD. Due to immunosuppressive therapy potentially life-threatening infections and reactivations of latent infections like tuberculosis or cytomegalovirus (CMV) can occur. Fistulas, abscesses, perforations and intestinal obstructions are typical complications of Crohn's disease in the intensive care setting, whereas clinical presentation in ulcerative colitis is characterised by its acute exacerbation and the toxic dilatation of the colon, potentially resulting in toxic megacolon with high risk of perforation or severe bleeding. Most important for an effective therapy in the critically ill patient with inflammatory bowel disease are the control of the underlying disease, the empiric antibiotic therapy in case of infectious complications, transcutaneous drainage of abscesses, bowel decompression in toxic megacolon and the early interdisciplinary assessment of the abdomen.

Published
2012

48. Neuer Biomarker bei Sepsis-Patienten?

Author

C Roderburg, Fabian Benz, and F Tacke

Abstract

Bei einer Sepsis konnen eine fruhzeitige Diagnose und entsprechende therapeutische Masnahmen die Sterblichkeit erheblich senken. Derzeit existiert eine Reihe von Laborwerten und klinischen Parametern, an denen sich die Behandlung orientieren kann. Die Biomarker der nachsten Generation sind aber moglicherweise Mikro-RNAs (miRNAs), und eine Arbeitsgruppe aus Aachen hat den prognostischen Wert einer solchen miRNA getestet.

Published
2014

49. Impact of hepatitis B e antigen-suppressing mutations on the replication efficiency of entecavir-resistant hepatitis B virus strains

Author

S, Amini-Bavil-Olyaee, U, Herbers, T, Luedde, C, Trautwein, and F, Tacke

Subjects
Hepatitis B virus, Guanine, Adenine, Organophosphonates, Viral Load, Virus Replication, Antiviral Agents, Polymorphism, Single Nucleotide, Viral Proteins, Hepatitis B, Chronic, Lamivudine, Cell Line, Tumor, Drug Resistance, Viral, Mutation, Humans, Hepatitis B e Antigens, Tenofovir
Abstract

Hepatitis B e antigen (HBeAg)-negative hepatitis B commonly requires long-term treatment with nucleos(t)ide analogues aiming at persistently suppressing hepatitis B virus (HBV) replication to halt progression of liver disease and prevent complications. Entecavir (ETV) is widely used in HBeAg-negative hepatitis B, but distinct HBV polymerase mutations can confer resistance against ETV, in conjunction with lamivudine resistance. Precore (PC) and basal core promoter (BCP) mutations that underlie HBeAg-negativity enhance replication of lamivudine-resistant mutants. To comprehensively analyse the impact of PC or BCP mutations on viral replication of ETV-resistant HBV mutants, replication-competent HBV constructs were generated harbouring lamivudine resistance (rtM204V/rtL180M, rtM204I) plus ETV resistance (rtS202G, rtS202I or rtT184G) on wild-type (WT)-, PC- and BCP-backgrounds. Functional consequences on viral fitness and susceptibility to antivirals were assessed in vitro. The presence of any ETV resistance drastically reduced viral replication when compared to WT HBV. In rtS202G mutants (plus lamivudine resistance), addition of either PC or BCP mutations moderately enhanced the reduced replication, without reaching WT HBV levels. In rtS202I or rtT184G mutants, PC and BCP mutations did not significantly improve viral fitness. All ETV-resistant constructs, independently of PC or BCP mutations, showed resistance towards ETV and lamivudine, but remained susceptible to tenofovir. Our data demonstrate that HBeAg-suppressing PC or BCP mutations cannot restore the strongly reduced replicative capacity of ETV-resistant HBV mutants to WT level, although they moderately increase replication of rtS202G combination mutants. ETV resistance thereby differs from lamivudine resistance alone, corroborating that ETV is in short term a safe option for HBeAg-negative patients.

Published
2010

50. [ALT screening for chronic liver diseases: scrutinizing the evidence]

Author

H, Wedemeyer, W P, Hofmann, S, Lueth, P, Malinski, R, Thimme, F, Tacke, and J, Wiegand

Subjects
Evidence-Based Medicine, Hepatitis, Viral, Human, National Health Programs, Cost-Benefit Analysis, Liver Diseases, Alanine Transaminase, Comorbidity, Prognosis, Hepatitis, Autoimmune, Cross-Sectional Studies, Liver Function Tests, Predictive Value of Tests, Germany, Chronic Disease, Humans, Mass Screening, Aspartate Aminotransferases
Abstract

Elevated serum amino-transferase levels may be associated with liver injury. Testing for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is part of many routine screening approaches. The aim of this manuscript was to scrutinize the evidence for using ALT testing as a primary screening parameter for liver diseases. We conclude that (i) elevated serum ALT levels indicate a high specificity and a reasonable sensitivity liver injury, (ii) 10 - 25 % of German adults have elevated ALT levels, (iii) ALT values are increased in the majority but not all patients with acute and chronic liver disease (iv) elevated ALT-values are associated with an increased risk of liver-specific mortality, (v) elevated ALT values are also a risk factor for non-hepatic diseases including diabetes mellitus type 2, metabolic syndrome, cardiovascular diseases and malignancies, (vi) many liver diseases identified by an ALT screening can be treated successfully including prevention of development of clinical endpoints, (vii) an ALT-screening is very likely to be cost-effective although studies are needed for Germany to support this conclusion.

Published
2010

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