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959 Publications visible to you, out of a total of 959
Copy number variants in lipid metabolism genes are associated with gallstones disease in men
Genetical Statistics and Systems Biology

Abstract (Expand)

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian … ancestry (10-20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size \textgreater 100 kb, frequency \textless 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 \times 10-4; OR = 2.76; CI 95% = 1.53-4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.

Authors: Eduardo Pérez-Palma, Bernabé I. Bustos, Dennis Lal, Stephan Buch, Lorena Azocar, Mohammad Reza Toliat, Wolfgang Lieb, Andre Franke, Sebastian Hinz, Greta Burmeister, Witigo von Shönfels, Clemens Schafmayer, Peter Ahnert, Henry Völzke, Uwe Völker, Georg Homuth, Markus M. Lerch, Klaus Puschel, Rodrigo A. Gutiérrez, Jochen Hampe, Peter Nürnberg, Juan Francisco Miquel, Giancarlo V. de Ferrari

Date Published: 1st Feb 2020

Publication Type: Journal article

Markov State Modelling of Disease Courses and Mortality Risks of Patients with Community-Acquired Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

Community-acquired pneumonia (CAP) is one of the most frequent infectious diseases worldwide, with high lethality. Risk evaluation is well established at hospital admission, and re-evaluation is advised … for patients at higher risk. However, severe disease courses may develop from all levels of severity. We propose a stochastic continuous-time Markov model describing daily development of time courses of CAP severity. Disease states were defined based on the Sequential Organ Failure Assessment (SOFA) score. Model calibration was based on longitudinal data from 2838 patients with a primary diagnosis of CAP from four clinical studies (PROGRESS, MAXSEP, SISPCT, VISEP). We categorized CAP severity into five disease states and estimated transition probabilities for CAP progression between these states and corresponding sojourn times. Good agreement between model predictions and clinical data was observed. Time courses of mortality were correctly predicted for up to 28 days, including validation with patient data not used for model calibration. We conclude that CAP disease course follows a Markov process, suggesting the necessity of daily monitoring and re-evaluation of patient’s risk. Our model can be used for regular updates of risk assessments of patients and could improve the design of clinical trials by estimating transition rates for different risk groups.

Authors: Jens Przybilla, Peter Ahnert, Holger Bogatsch, Frank Bloos, Frank M. Brunkhorst, Critical Care Trials Group SepNet, Study Group Progress, Michael Bauer, Markus Loeffler, Martin Witzenrath, Norbert Suttorp, Markus Scholz

Date Published: 1st Feb 2020

Publication Type: Journal article

Prognostic Factors for Iatrogenic Tracheal Rupture: A Single-Center Retrospective Cohort Study
Genetical Statistics and Systems Biology

Abstract (Expand)

Iatrogenic tracheal ruptures are rare but severe complications of medical interventions. The main goal of this study was to explore prognostic factors for all-cause mortality and rupture-related … (adjusted) mortality. We retrospectively analyzed patients admitted to an academic referral center over a 15-year period (2004-2018). Fifty-four patients met the inclusion criteria, of whom 36 patients underwent surgical repair and 18 patients were treated conservatively. In a 90-day follow-up, the all-cause mortality was 50%, while the adjusted mortality was 13%. Rupture length was identified as a predictor for all-cause mortality (area under the curve, 0.84; 95% confidence interval (CI) 0.74-0.94) with a cutoff rupture length of 4.5 cm (sensitivity, 0.70; specificity, 0.81). Multivariate analysis confirmed rupture length as a prognostic factor for all-cause mortality (adjusted hazard ratio (HR) 1.5; 95% CI 1.2-1.9; p = 0.001), but not for adjusted mortality (HR 1.5; 95% CI 0.97-2.3; p = 0.068), while mediastinitis predicted adjusted mortality (HR 5.8; 95% CI 1.1-31.7; p = 0.042), but not all-cause mortality (HR 1.6; 95% CI 0.7-3.5; p = 0.243). The extent of iatrogenic tracheal rupture and mediastinitis might be relevant prognostic factors for all-cause mortality and adjusted mortality, respectively.

Authors: Sebastian Krämer, Johannes Broschewitz, Holger Kirsten, Carolin Sell, Uwe Eichfeld, Manuel Florian Struck

Date Published: 1st Feb 2020

Publication Type: Journal article

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining … association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Authors: Laura Fachal, Hugues Aschard, Jonathan Beesley, Daniel R. Barnes, Jamie Allen, Siddhartha Kar, Karen A. Pooley, Joe Dennis, Kyriaki Michailidou, Constance Turman, Penny Soucy, Audrey Lemaçon, Michael Lush, Jonathan P. Tyrer, Maya Ghoussaini, Mahdi Moradi Marjaneh, Xia Jiang, Simona Agata, Kristiina Aittomäki, M. Rosario Alonso, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Bernd Auber, Paul L. Auer, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Amie M. Blanco, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ake Borg, Kristin Bosse, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Ian W. Brock, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Nicola J. Camp, Ian Campbell, Federico Canzian, Jason S. Carroll, Brian D. Carter, Jose E. Castelao, Jocelyne Chiquette, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, J. Margriet Collée, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de La Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Susan M. Domchek, Thilo Dörk, Isabel Dos-Santos-Silva, Arnaud Droit, Stéphane Dubois, Martine Dumont, Mercedes Duran, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Giuseppe Floris, Henrik Flyger, Lenka Foretova, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Gaetana Gambino, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Maria Grazia Tibiletti, Mark H. Greene, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Wei He, Catherine S. Healey, Bernadette A. M. Heemskerk-Gerritsen, Jane Heyworth, Peter Hillemanns, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, John L. Hopper, Anthony Howell, Guanmengqian Huang, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Judy Kirk, Cari M. Kitahara, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Stella Koutros, Katerina Kubelka-Sabit, Ava Kwong, Kyriacos Kyriacou, Yael Laitman, Diether Lambrechts, Eunjung Lee, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annika Lindblom, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Jan Lubiński, Robert J. MacInnis, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Keitaro Matsuo, Tabea Maurer, Dimitrios Mavroudis, Rebecca Mayes, Lesley McGuffog, Catriona McLean, Noura Mebirouk, Alfons Meindl, Austin Miller, Nicola Miller, Marco Montagna, Fernando Moreno, Kenneth Muir, Anna Marie Mulligan, Victor M. Muñoz-Garzon, Taru A. Muranen, Steven A. Narod, Rami Nassir, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Finn C. Nielsen, Liene Nikitina-Zake, Aaron Norman, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Nick Orr, Ana Osorio, V. Shane Pankratz, Janos Papp, Sue K. Park, Tjoung-Won Park-Simon, Michael T. Parsons, James Paul, Inge Sokilde Pedersen, Bernard Peissel, Beth Peshkin, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Miquel Angel Pujana, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Johanna Rantala, Rohini Rau-Murthy, Gad Rennert, Harvey A. Risch, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Estela Sánchez-Herrero, Dale P. Sandler, Marta Santamariña, Christobel Saunders, Elinor J. Sawyer, Maren T. Scheuner, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Ben Schöttker, Peter Schürmann, Christopher Scott, Rodney J. Scott, Leigha Senter, Caroline M. Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Christian F. Singer, Thomas P. Slavin, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony J. Swerdlow, Rulla M. Tamimi, Yen Yen Tan, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Maria Tengström, Soo Hwang Teo, Mary Beth Terry, Alex Teulé, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Nadine Tung, Maria Tzardi, Hans-Ulrich Ulmer, Celine M. Vachon, Christi J. van Asperen, Lizet E. van der Kolk, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Joseph Vijai, Maartje J. Vogel, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Hans Wildiers, Robert Winqvist, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, David Hunter, Paul D. P. Pharoah, Jenny Chang-Claude, Montserrat García-Closas, Marjanka K. Schmidt, Roger L. Milne, Vessela N. Kristensen, Juliet D. French, Stacey L. Edwards, Antonis C. Antoniou, Georgia Chenevix-Trench, Jacques Simard, Douglas F. Easton, Peter Kraft, Alison M. Dunning

Date Published: 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving …g lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis. METHODS The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13). RESULTS In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 \pm 0.89 vs. 3.29 \pm 2.34, mean \pm SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 \pm 1.17 vs. 7.31 \pm 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury. CONCLUSIONS Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia. : WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Pneumonia, sepsis, and immune dysregulation cause morbidity and mortalityC5a is a component of the complement system and a proinflammatory mediator that modulates the innate immune response in critical illnessDisruption of the C5a receptor axis with antibodies or antagonists was previously protective in various animal sepsis models WHAT THIS ARTICLE TELLS US THAT IS NEW: In hospitalized patients with community-acquired pneumonia, serum C5a concentrations were 1.4-fold higher compared to healthy subjectsIn two mouse models of pneumonia and sepsis, NOX-D19, a C5a-neutralizing L-RNA aptamer, caused lower pulmonary hyperpermeability and sepsis-related acute liver injury.

Authors: Holger Müller-Redetzky, Ute Kellermann, Sandra-Maria Wienhold, Birgitt Gutbier, Jasmin Lienau, Katharina Hellwig, Katrin Reppe, Eleftheria Letsiou, Thomas Tschernig, Markus Scholz, Peter Ahnert, Christian Maasch, Kai Hoehlig, Sven Klussmann, Axel Vater, Theresa C. Firsching, Judith Hoppe, Norbert Suttorp, Martin Witzenrath

Date Published: 2020

Publication Type: Journal article

Professionalism of Information Management in Health Care: Development and Validation of the Construct and Its Measurement
Management of health information systems

Abstract (Expand)

BACKGROUND Against the background of a steadily increasing degree of digitalization in health care, a professional information management (IM) is required to successfully plan, implement, and evaluate …e information technology (IT). At its core, IM has to ensure a high quality of health data and health information systems to support patient care. OBJECTIVES The goal of the present study was to define what constitutes professional IM as a construct as well as to propose a reliable and valid measurement instrument. METHODS To develop and validate the construct of professionalism of information management (PIM) and its measurement, a stepwise approach followed an established procedure from information systems and behavioral research. The procedure included an analysis of the pertaining literature and expert rounds on the construct and the instrument, two consecutive and comprehensive surveys at the national and international level, exploratory and confirmatory factor analyses as well as reliability and validity testing. RESULTS Professionalism of information management was developed as a construct consisting of the three dimensions of strategic, tactical, and operational IM as well as of the regularity and cyclical phases of IM procedures as the two elements of professionalism. The PIM instrument operationalized the construct providing items that incorporated IM procedures along the three dimensions and cyclical phases. These procedures had to be evaluated against their degree of regularity in the instrument. The instrument proved to be reliable and valid in two consecutive measurement phases and across three countries. CONCLUSION It can be concluded that professionalism of information management is a meaningful construct that can be operationalized in a scientifically rigorous manner. Both science and practice can benefit from these developments in terms of improved self-assessment, benchmarking capabilities, and eventually, obtaining a better understanding of health IT maturity.

Authors: Johannes Thye, Moritz Esdar, Jan-David Liebe, Franziska Jahn, Alfred Winter, Ursula Hübner

Date Published: 2020

Publication Type: Journal article

Use of Natural Language Processing for Precise Retrieval of Key Elements of Health IT Evaluation Studies
Management of health information systems

Abstract (Expand)

Having precise information about health IT evaluation studies is important for evidence-based decisions in medical informatics. In a former feasibility study, we used a faceted search based on ontological … modeling of key elements of studies to retrieve precisely described health IT evaluation studies. However, extracting the key elements manually for the modeling of the ontology was time and resource-intensive. We now aimed at applying natural language processing to substitute manual data extraction by automatic data extraction. Four methods (Named Entity Recognition, Bag-of-Words, Term-Frequency-Inverse-Document-Frequency, and Latent Dirichlet Allocation Topic Modeling were applied to 24 health IT evaluation studies. We evaluated which of these methods was best suited for extracting key elements of each study. As gold standard, we used results from manual extraction. As a result, Named Entity Recognition is promising but needs to be adapted to the existing study context. After the adaption, key elements of studies could be collected in a more feasible, time- and resource-saving way.

Authors: Verena Dornauer, Franziska Jahn, Konrad Hoeffner, Alfred Winter, Elske Ammenwerth

Date Published: 2020

Publication Type: Journal article

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