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Eosinophilic cholangitis is a potentially underdiagnosed etiology in indeterminate biliary stricture
(2017)
Walter, Dirk Henning ; Hartmann, Sylvia ; Herrmann, Eva ; Peveling-Oberhag, Jan Franz-Josef ; Bechstein, Wolf Otto ; Zeuzem, Stefan ; Hansmann, Martin-Leo ; Friedrich-Rust, Mireen ; Albert, Jörg Gerhard
AIM: To investigate presence and extent of eosinophilic cholangitis (EC) as well as IgG4-related disease in patients with indeterminate biliary stricture (IBS).
METHODS: All patients with diagnosis of sclerosing cholangitis (SC) and histopathological samples such as biopsies or surgical specimens at University Hospital Frankfurt from 2005-2015 were included. Histopathological diagnoses as well as further clinical course were reviewed. Tissue samples of patients without definite diagnosis after complete diagnostic work-up were reviewed regarding presence of eosinophilic infiltration and IgG4 positive plasma cells. Eosinophilic infiltration was as well assessed in a control group of liver transplant donors and patients with primary sclerosing cholangitis.
RESULTS: one hundred and thirty-five patients with SC were included. In 10/135 (13.5%) patients, no potential cause of IBS could be identified after complete diagnostic work-up and further clinical course. After histopathological review, a post-hoc diagnosis of EC was established in three patients resulting in a prevalence of 2.2% (3/135) of all patients with SC as well as 30% (3/10) of patients, where no cause of IBS was identified. 2/3 patients with post-hoc diagnosis of EC underwent surgical resection with suspicion for malignancy. Diagnosis of IgG4-related cholangitis was observed in 7/135 patients (5.1%), whereas 3 cases were discovered in post-hoc analysis. 6/7 cases with IgG4-related cholangitis (85.7%) presented with eosinophilic infiltration in addition to IgG4 positive plasma cells. There was no patient with eosinophilic infiltration in the control group of liver transplant donors (n = 27) and patients with primary sclerosing cholangitis (n = 14).
CONCLUSION: EC is an underdiagnosed benign etiology of SC and IBS, which has to be considered in differential diagnosis of IBS.
Koch, Christine ; Schwing, Anna M. ; Herrmann, Eva ; Borner, Markus ; Díaz-Rubio, Eduardo ; Dotan, Efrat ; Feliu, Jaime ; Okita, Natsuko ; Souglakos, John ; Arkenau, Hendrik-Tobias ; Porschen, Rainer ; Koopman, Miriam ; Punt, Cornelis J. A. ; Gramont, Aimery de ; Tournigand, Christophe ; Zeuzem, Stefan ; Trojan, Jörg
Background: The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients ( ≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials.
Results: Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70–88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials.
Materials and Methods: PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age.
Conclusions: This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.
Acharya, Shreyasi ; Adam, Jaroslav ; Adamová, Dagmar ; Adler, Clemens ; Adolfsson, Jonatan ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahn, Sang Un ; Aiola, Salvatore ; Akindinov, Alexander ; Al-Turany, Mohammad ; Alam, Sk Noor ; Antonczyk, Dariusz ; Arend, Andreas ; Bazo Alba, José Luis ; Albuquerque, Danilo Silva de ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfaro Molina, Jose Ruben ; Alici, Andrea ; Alkin, Anton ; Alme, Johan ; Alt, Torsten ; Altenkämper, Lucas ; Altsybeev, Igor ; Prado, Caio Alves Garcia ; Andrei, Cristian ; Andreou, Dimitra ; Andrews, Harry Arthur ; Andronic, Anton ; Anguelov, Venelin ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Anwar, Rafay ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arnaldi, Roberta ; Arnold, Oliver Werner ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Audurier, Benjamin ; Augustinus, Andre ; Averbeck, Ralf Peter ; Azmi, Mohd Danish ; Badalà, Angela ; Baek, Yong Wook ; Bagnasco, Stefano ; Bailhache, Raphaëlle ; Bala, Renu ; Baldisseri, Alberto ; Ball, Markus ; Baral, Rama Chandra ; Barbano, Anastasia Maria ; Barbera, Roberto ; Barile, Francesco ; Barioglio, Luca ; Barnaföldi, Gergely Gábor ; Barnby, Lee Stuart ; Ramillien Barret, Valerie ; Bartalini, Paolo ; Barth, Klaus ; Bartos, D ; Bartsch, Esther ; Basile, Maurizio ; Bastid, Nicole ; Basu, Sumit ; Bathen, Bastian ; Batigne, Guillaume ; Batyunya, Boris ; Bätzing, Paul Christoph ; Baumann, Christoph ; Bearden, Ian Gardner ; Beck, Hans ; Bedda, Cristina ; Behera, Nirbhay Kumar ; Belikov, Iouri ; Bellini, Francesca ; Bello Martinez, Hector ; Bellwied, Rene ; Espinoza Beltran, Lucina Gabriela ; Belyaev, Vladimir ; Bencédi, Gyula ; Beolè, Stefania ; Berceanu, Ionela ; Bercuci, Alexandru ; Berdnikov, Yaroslav ; Berényi, Dániel ; Bertens, Redmer Alexander ; Berzano, Dario ; Betev, Latchezar ; Bhasin, Anju ; Bhat, Inayat Rasool ; Bhati, Ashok Kumar ; Bhattacharjee, Buddhadeb ; Bhom, Jihyun ; Bianchi, Antonio ; Bianchi, Livio ; Bianchi, Nicola ; Bianchin, Chiara ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Biro, Gabor ; Biswas, Rathijit ; Biswas, Saikat ; Blair, Justin Thomas ; Blau, Dmitry S. ; Blume, Christoph ; Boca, Gianluigi ; Bock, Friederike ; Bogdanov, Alexey A. ; Boldizsar, Laszlo ; Bombara, Marek ; Bonomi, Germano ; Bonora, Matthias ; Book, Julian ; Borel, Herve ; Borissov, Alexander ; Borri, Marcello ; Botta, Elena ; Bourjau, Christian ; Bratrud, Lars ; Braun-Munzinger, Peter ; Bregant, Marco ; Broker, Theo Alexander ; Broz, Michal ; Brücken, Erik Jens ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Bucher, Damian ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bühler, Paul ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Bashir Butt, Jamila ; Buxton, Jesse Thomas ; Cabala, Jan ; Caffarri, Davide ; Caines, Helen Louise ; Caliva, Alberto ; Calvo Villar, Ernesto ; Camerini, Paolo ; Capon, Aaron Allan ; Caragheorgheopol, G ; Carena, Francesco ; Carena, Wisla ; Carnesecchi, Francesca ; Castillo Castellanos, Javier Ernesto ; Castro, Andrew John ; Casula, Ester Anna Rita ; Catanescu, V ; Ceballos Sanchez, Cesar ; Cerello, Piergiorgio ; Chandra, Sinjini ; Chang, Beomsu ; Chapeland, Sylvain ; Chartier, Marielle ; Chattopadhyay, Subhasis ; Chattopadhyay, Sukalyan ; Chauvin, Alex Henri Jean ; Chernenko, Sergey P. ; Cherney, Michael Gerard ; Cheshkov, Cvetan Valeriev ; Cheynis, Brigitte ; Chibante Barroso, Vasco Miguel ; Chinellato, David Dobrigkeit ; Cho, Soyeon ; Chochula, Peter ; Chojnacki, Marek ; Choudhury, Subikash ; Chowdhury, Tasnuva ; Christakoglou, Panagiotis ; Christensen, Christian Holm ; Christiansen, Peter L. ; Chujo, Tatsuya ; Chung, Suh-Urk ; Cicalò, Corrado ; Cifarelli, Luisa ; Cindolo, Federico ; Ciobanu, M ; Cleymans, Jean Willy Andre ; Colamaria, Fabio Filippo ; Colella, Domenico ; Collu, Alberto ; Colocci, Manuel ; Concas, Matteo ; Conesa Balbastre, Gustavo ; Conesa Del Valle, Zaida ; Connors, Megan Elizabeth ; Contreras Nuno, Jesus Guillermo ; Cormier, Thomas Michael ; Corrales Morales, Yasser ; Cortes Maldonado, Ismael ; Cortese, Pietro ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Costanza, Susanna ; Crkovská, Jana ; Crochet, Philippe ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Dahms, Torsten ; Dainese, Andrea ; Danisch, Meike Charlotte ; Danu, Andrea ; Das, Debasish ; Das, Indranil ; Das, Supriya ; Dash, Ajay Kumar ; Dash, Sadhana ; Daues, Heinz ; De, Sudipan ; De Caro, Annalisa ; De Cataldo, Giacinto ; Conti, Camila de ; Cuveland, Jan de ; De Falco, Alessandro ; De Gruttola, Daniele ; De Marco, Nora ; De Pasquale, Salvatore ; Souza, Rafael Derradi de ; Degenhardt, Hermann Franz ; Deisting, Alexander ; Deloff, Andrzej ; Deplano, Caterina ; Devismes, A ; Dhankher, Preeti ; Di Bari, Domenico ; Di Mauro, Antonio ; Di Nezza, Pasquale ; Di Ruzza, Benedetto ; Dietel, Thomas ; Dillenseger, Pascal ; Divià, Roberto ; Djuvsland, Øystein ; Dobrin, Alexandru Florin ; Domenicis Gimenez, Diogenes ; Donigus, Benjamin ; Dordic, Olja ; Doremalen, Lennart Vincent Rogier van ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Duggal, Ashpreet Kaur ; Dupieux, Pascal ; Duta, V ; Ehlers Iii, Raymond James ; Elia, Domenico ; Emschermann, David ; Endress, Eric ; Engel, Heiko ; Epple, Eliane ; Erazmus, Barbara Ewa ; Erhardt, Filip ; Espagnon, Bruno ; Esumi, ShinIchi ; Eulisse, Giulio ; Eum, Jongsik ; Evans, David ; Evdokimov, Sergey ; Fabbietti, Laura ; Faivre, Julien ; Fantoni, Alessandra ; Fasel, Markus ; Fateev, O ; Feldkamp, Linus ; Feliciello, Alessandro ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Feuillard, Victor Jose Gaston ; Figiel, Jan ; Figueredo, Marcel Araujo Silva ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fleck, M ; Floris, Michele ; Foertsch, Siegfried Valentin ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; 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Marin, Ana Maria ; Markert, Christina ; Marquard, Marco ; Martin, Nicole Alice ; Martinengo, Paolo ; Lucio Martinez, Jose Antonio ; Martínez Hernández, Mario Iván ; García Martínez, Ginés ; Martinez Pedreira, Miguel ; Masciocchi, Silvia ; Masera, Massimo ; Masoni, Alberto ; Masson, Erwann ; Mastroserio, Annalisa ; Mathis, Andreas Michael ; Matyja, Adam Tomasz ; Mayer, Christoph ; Mazer, Joel Anthony ; Mazzilli, Marianna ; Mazzoni, Alessandra Maria ; Meddi, Franco ; Melikyan, Yuri ; Menchaca-rocha, Arturo Alejandro ; Meninno, Elisa ; Mercado Pérez, Jorge ; Meres, Michal ; Mhlanga, Sibaliso ; Miake, Yasuo ; Mieskolainen, Matti Mikael ; Mihaylov, Dimitar Lubomirov ; Mikhaylov, Konstantin ; Milošević, Jovan ; Mischke, André ; Mishra, Aditya Nath ; Miśkowiec, Dariusz Czesław ; Mitra, Jubin ; Mitu, Ciprian Mihai ; Mohammadi, Naghmeh ; Mohanty, Bedangadas ; Khan, Mohammed Mohisin ; Godoy, Denise Aparecida Moreira de ; Perez Moreno, Luis Alberto ; Moretto, Sandra ; Morino, Yuhei ; Morreale, Astrid ; Morsch, Andreas ; Muccifora, Valeria ; Mudnic, Eugen ; Muhlheim, Daniel ; Muhuri, Sanjib ; Mukherjee, Maitreyee ; Mulligan, James Declan ; Gameiro Munhoz, Marcelo ; Munning, Konstantin ; Munzer, Robert Helmut ; Murakami, Hikari ; Murray, Sean ; Musa, Luciano ; Musinsky, Jan ; Myers, Corey James ; Myrcha, Julian Wojciech ; Mycke, Jan Felix ; Nag, Dipanjan ; Naik, Bharati ; Nair, Rahul Ramachandran ; Nandi, Basanta Kumar ; Nania, Rosario ; Nappi, Eugenio ; Narayan, Amrendra ; Naru, Muhammad Umair ; Luz, Pedro Hugo Ferreira Natal da ; Nattrass, Christine ; Rosado Navarro, Sebastian ; Nayak, Kishora ; Nayak, Ranjit ; Nayak, Tapan Kumar ; Nazarenko, Sergey ; Nedosekin, Alexander ; Oliveira, Renato Aparecido Negrao de ; Neher, Michael ; Nellen, Lukas ; Nesbo, Simon Voigt ; Ng, Fabian ; Nicassio, Maria ; Niculescu, Mihai ; Niedziela, Jeremi ; Nielsen, Borge Svane ; Nikolaev, Sergey ; Nikulin, Sergey ; Nikulin, Vladimir ; Noferini, Francesco ; Nomokonov, Petr V. ; Nooren, Gerardus ; Cabanillas Noris, Juan Carlos ; Norman, Jaime ; Nyanin, Alexander ; Nystrand, Joakim Ingemar ; Oeschler, Helmut ; Oh, Saehanseul ; Ohlson, Alice ; Okubo, Tsubasa ; Oláh, László ; Oleniacz, Janusz ; Silva, Antonio Carlos Oliveira da ; Oliver, Michael Henry ; Onderwaater, Jacobus ; Oppedisano, Chiara ; Orava, Risto ; Oravec, Matej ; Ortiz Velasquez, Antonio ; Oskarsson, Anders Nils Erik ; Otwinowski, Jacek Tomasz ; Oyama, Ken ; Pachmayer, Yvonne C. ; Pacik, Vojtech ; Pagano, Davide ; Pagano, Paola ; Paic, Guy ; Panebratsev, Yu ; Palni, Prabhakar ; Pan, Jinjin ; Pandey, Ashutosh Kumar ; Panebianco, Stefano Matthias ; Papikyan, Vardanush ; Pappalardo, Giuseppe Salvatore ; Pareek, Pooja ; Park, Jonghan ; Park, WooJin ; Parmar, Sonia ; Passfeld, Annika ; Pathak, Surya Prakash ; Patra, Rajendra Nath ; Paul, Biswarup ; Pei, Hua ; Peitzmann, Thomas ; Peng, Xinye ; Pereira, Luis Gustavo ; Pereira da Costa, Hugo Denis Antonio ; Peresunko, Dmitry Yurevich ; Pérez Lezama, Edgar ; Peskov, Vladimir ; Pestov, Yury N. ; Petráček, Vojtech ; Petris, M ; Petrov, Viacheslav ; Petrovici, Mihai A. ; Petta, Catia ; Pezzi, Rafael Peretti ; Piano, Stefano ; Pikna, Miroslav ; Pillot, Philippe ; Ozelin de Lima Pimentel, Laís ; Pinazza, Ombretta ; Pinsky, Lawrence ; Pitz, Nora ; Piyarathna, Danthasinghe ; Płoskoń, Mateusz ; Planinic, Mirko ; Pliquett, Fabian ; Pluta, Jan Marian ; Pochybova, Sona ; Podesta Lerma, Pedro Luis Manuel ; Poghosyan, Martin G. ; Polishchuk, Boris ; Poljak, Nikola ; Poonsawat, Wanchaloem ; Pop, Amalia ; Poppenborg, Hendrik ; Porteboeuf, Sarah Julie ; Pozdniakov, Valeriy ; Prasad, Sidharth Kumar ; Preghenella, Roberto ; Prino, Francesco ; Pruneau, Claude A. ; Pshenichnov, Igor A. ; Puccio, Maximiliano ; Puddu, Giovanna ; Pujahari, Prabhat Ranjan ; Punin, Valery ; Putschke, Jörn H. ; Radomski, Sylwester ; Rachevski, Alexandre ; Raha, Sibaji ; Rajput, Sonia ; Rak, Jan ; Rakotozafindrabe, Andry Malala ; Ramello, Luciano ; Rami, Fouad ; Rana, Dhan Bahadur ; Raniwala, Rashmi ; Raniwala, Sudhir ; Räsänen, Sami Sakari ; Rascanu, Bogdan Theodor ; Rathee, Deepika ; Ratza, Viktor ; Ravasenga, Ivan ; Read, Kenneth Francis ; Redlich, Krzysztof ; Rehman, Attiq ur ; Reichelt, Patrick ; Reidt, Felix ; Reischl, A ; Ren, Xiaowen ; Renfordt, Rainer Arno Ernst ; Reolon, Anna Rita ; Reshetin, Andrey ; Reygers, Klaus ; Riabov, Viktor ; Ricci, Renato Angelo ; Richert, Tuva Ora Herenui ; Richter, Matthias Rudolph ; Riedler, Petra ; Riegler, Werner ; Riggi, Francesco ; Ristea, Cătălin-Lucian ; Rodrı́guez Cahuantzi, Mario ; Røed, Ketil ; Rogochaya, Elena ; Rohr, David ; Röhrich, Dieter ; Rokita, Przemyslaw Stefan ; Ronchetti, Federico ; Dominguez Rosas, Edgar ; Rosnet, Philippe ; Rossi, Andrea ; Rotondi, Alberto ; Roukoutakis, Filimon ; Roy, Ankhi ; Roy, Christelle Sophie ; Roy, Pradip Kumar ; Vazquez Rueda, Omar ; Rui, Rinaldo ; Rumyantsev, Boris ; Rusanov, Ivan ; Rustamov, Anar ; Ryabinkin, Evgeny ; Ryabov, Yury ; Rybicki, Andrzej ; Saarinen, Sampo ; Sadhu, Samrangy ; Sadovskiy, Sergey ; Šafařík, Karel ; Saha, Sumit Kumar ; SahlmÜller, Baldo ; Sahoo, Baidyanath ; Sahoo, Pragati ; Sahoo, Raghunath ; Sahoo, Sarita ; Sahu, Pradip Kumar ; Saini, Jogender ; Sakai, Shingo ; Sakata, Dousatsu ; Saleh, Mohammad Ahmad ; Salzwedel, Jai ; Sambyal, Sanjeev Singh ; Samsonov, Vladimir ; Sandoval, Andres ; Sann, Hans ; Sano, Masato ; Santo, Rainer ; Sarkar, Debojit ; Sarkar, Nachiketa ; Sarma, Pranjal ; Sas, Mike Henry Petrus ; Scapparone, Eugenio ; Scarlassara, Fernando ; Schaefer, Brennan ; Scharenberg, Rolf Paul ; Scheid, Horst Sebastian ; Schiaua, Claudiu Cornel ; Schicker, Rainer ; Schmidt, Christian Joachim ; Schmidt, Hans Rudolf ; Schmidt, Marten Ole ; Schmidt, Martin ; Schmidt, Nicolas ; Schmiederer, Stefan ; Schneider, R ; Schukraft, Jürgen ; Schulze, R ; Schutz, Yves Roland ; Schwarz, Kilian Eberhard ; Schweda, Kai Oliver ; Scioli, Gilda ; Scomparin, Enrico ; Scott, Rebecca Michelle ; Sedykh, S ; Šefčík, Michal ; Seger, Janet Elizabeth ; Sekiguchi, Yuko ; Sekihata, Daiki ; Selyuzhenkov, Ilya ; Senosi, Kgotlaesele ; Senyukov, Serhiy ; Serradilla Rodriguez, Eulogio ; Sett, Priyanka ; Sevcenco, Adrian ; Shabanov, Arseniy ; Shabetai, Alexandre ; Shahoyan, Ruben ; Shaikh, Wadut ; Shangaraev, Artem ; Sharma, Anjali ; Sharma, Ankita ; Sharma, Mona ; Sharma, Monika ; Sharma, Natasha ; Sheikh, Ashik Ikbal ; Shigaki, Kenta ; Shimansky, S ; Shou, Qiye ; Shtejer Diaz, Katherin ; Shukla, P ; Sibiryak, Yury ; Sicking, Eva ; Siddhanta, Sabyasachi ; Sielewicz, Krzysztof Marek ; Siemiarczuk, Teodor ; Silaeva, Svetlana ; Silvermyr, David Olle Rickard ; Silvestre, Catherine Micaela ; Simatovic, Goran ; Simon, Reinhard S ; Simonetti, Giuseppe ; Singaraju, Rama Narayana ; Singh, Ranbir ; Singhal, Vikas ; Sarkar - Sinha, Tinku ; Sitar, Branislav ; Sitta, Mario ; Skaali, Toralf Bernhard ; Slupecki, Maciej ; Smirnov, Nikolai ; Smykov, L ; Snellings, Raimond ; Snellman, Tomas Wilhelm ; Solveit, Hans Kristian ; Sommer, Wolfgang ; Song, Jihye ; Song, Myunggeun ; Soramel, Francesca ; Sorensen, Soren Pontoppidan ; Sozzi, Federica ; Spiriti, Eleuterio ; Sputowska, Iwona Anna ; Srivastava, Brijesh Kumar ; Stachel, Johanna ; Stan, Ionel ; Stankus, Paul William ; Stelzer, Herbert ; Stenlund, Evert Anders ; Stiller, Johannes ; Stocco, Diego ; Stockmeyer, M.R. ; Storetvedt, Maksim Melnik ; Strmen, Peter ; Suaide, Alexandre Alarcon do Passo ; Sugitate, Toru ; Suire, Christophe Pierre ; Suleymanov, Mais Kazim Oglu ; Šuljić, Miljenko ; Sultanov, Rishat ; Šumbera, Michal ; Sumowidagdo, Suharyo ; Suzuki, Ken ; Swain, Sagarika ; Szabo, Alexander ; Szarka, Imrich ; Tabassam, Uzma ; Takahashi, Jun ; Tambave, Ganesh Jagannath ; Tanaka, Naoto ; Tarhini, Mohamad ; Tariq, Mohammad ; Tarzila, Madalina-Gabriela ; Tauro, Arturo ; Tejeda Muñoz, Guillermo ; Telesca, Adriana ; Terasaki, Kohei ; Terrevoli, Cristina ; Teyssier, Boris ; Thakur, Dhananjaya ; Thakur, Sanchari ; Thomas, Deepa ; Thoresen, Freja ; Tieulent, Raphael Noel ; Tikhonov, Anatoly ; Tilsner, Heinz ; Timmins, Anthony Robert ; Toia, Alberica ; Rojas Torres, Solangel ; Tripathy, Sushanta ; 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Crispin S. ; Willsher, Emily ; Windelband, Bernd Stefan ; Winn, Michael ; Witt, William Edward ; Xu, C ; Yalcin, Serpil ; Yamakawa, Kosei ; Yang, Ping ; Yano, Satoshi ; Yin, Zhongbao ; Yokoyama, Hiroki ; Yoo, In-kwon ; Yoon, Jin Hee ; Yurchenko, Volodymyr ; Yurevich, Vladimir ; Zaccolo, Valentina ; Zaman, Ali ; Zampolli, Chiara ; Correia Zanoli, Henrique Jose ; Zanevski, Yuri ; Zardoshti, Nima ; Zarochentsev, Andrey ; Závada, Petr ; Zavyalov, Nikolay ; Zbroszczyk, Hanna Paulina ; Zhalov, Mikhail ; Zhang, Haitao ; Zhang, Xiaoming ; Zhang, Yonghong ; Chunhui, Zhang ; Zhang, Zuman ; Zhao, Chengxin ; Zhigareva, Natalia ; Zhou, Daicui ; Zhou, You ; Zhou, Zhuo ; Zhu, Hongsheng ; Zhu, Jianhui ; Zichichi, Antonino ; Zimmer, Stefan ; Zimmermann, Alice ; Zimmermann, Markus ; Zinovjev, Gennady M. ; Zmeskal, Johann ; Zou, Shuguang
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Acharya, Shreyasi ; Adam, Jaroslav ; Adamová, Dagmar ; Adler, Clemens ; Adolfsson, Jonatan ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Nazeer ; Ahn, Sang Un ; Aiola, Salvatore ; Akindinov, Alexander ; Al-Turany, Mohammad ; Alam, Sk Noor ; Antonczyk, Dariusz ; Arend, Andreas ; Bazo Alba, José Luis ; Albuquerque, Danilo Silva de ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfaro Molina, Jose Ruben ; Alici, Andrea ; Alkin, Anton ; Alme, Johan ; Alt, Torsten ; Altenkämper, Lucas ; Altsybeev, Igor ; Prado, Caio Alves Garcia ; Andrei, Cristian ; Andreou, Dimitra ; Andrews, Harry Arthur ; Andronic, Anton ; Anguelov, Venelin ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antonioli, Pietro ; Anwar, Rafay ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arnaldi, Roberta ; Arnold, Oliver Werner ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Audurier, Benjamin ; Augustinus, Andre ; 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Bhati, Ashok Kumar ; Bhattacharjee, Buddhadeb ; Bhom, Jihyun ; Bianchi, Antonio ; Bianchi, Livio ; Bianchi, Nicola ; Bianchin, Chiara ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Biro, Gabor ; Biswas, Rathijit ; Biswas, Saikat ; Blair, Justin Thomas ; Blau, Dmitry S. ; Blume, Christoph ; Boca, Gianluigi ; Bock, Friederike ; Bogdanov, Alexey A. ; Boldizsar, Laszlo ; Bombara, Marek ; Bonomi, Germano ; Bonora, Matthias ; Book, Julian ; Borel, Herve ; Borissov, Alexander ; Borri, Marcello ; Botta, Elena ; Bourjau, Christian ; Bratrud, Lars ; Braun-Munzinger, Peter ; Bregant, Marco ; Broker, Theo Alexander ; Broz, Michal ; Brücken, Erik Jens ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Bucher, Damian ; Budnikov, Dmitry ; Büsching, Henner ; Bufalino, Stefania ; Bühler, Paul ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Bashir Butt, Jamila ; Buxton, Jesse Thomas ; Cabala, Jan ; Caffarri, Davide ; Caines, Helen Louise ; Caliva, Alberto ; Calvo Villar, Ernesto ; Camerini, Paolo ; Capon, Aaron Allan ; Caragheorgheopol, G ; Carena, Francesco ; Carena, Wisla ; Carnesecchi, Francesca ; Castillo Castellanos, Javier Ernesto ; Castro, Andrew John ; Casula, Ester Anna Rita ; Catanescu, V ; Ceballos Sanchez, Cesar ; Cerello, Piergiorgio ; Chandra, Sinjini ; Chang, Beomsu ; Chapeland, Sylvain ; Chartier, Marielle ; Chattopadhyay, Subhasis ; Chattopadhyay, Sukalyan ; Chauvin, Alex Henri Jean ; Chernenko, Sergey P. ; Cherney, Michael Gerard ; Cheshkov, Cvetan Valeriev ; Cheynis, Brigitte ; Chibante Barroso, Vasco Miguel ; Chinellato, David Dobrigkeit ; Cho, Soyeon ; Chochula, Peter ; Chojnacki, Marek ; Choudhury, Subikash ; Chowdhury, Tasnuva ; Christakoglou, Panagiotis ; Christensen, Christian Holm ; Christiansen, Peter L. ; Chujo, Tatsuya ; Chung, Suh-Urk ; Cicalò, Corrado ; Cifarelli, Luisa ; Cindolo, Federico ; Ciobanu, M ; Cleymans, Jean Willy Andre ; Colamaria, Fabio Filippo ; Colella, Domenico ; Collu, Alberto ; Colocci, Manuel ; Concas, Matteo ; Conesa Balbastre, Gustavo ; Conesa Del Valle, Zaida ; Connors, Megan Elizabeth ; Contreras Nuno, Jesus Guillermo ; Cormier, Thomas Michael ; Corrales Morales, Yasser ; Cortes Maldonado, Ismael ; Cortese, Pietro ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Costanza, Susanna ; Crkovská, Jana ; Crochet, Philippe ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Dahms, Torsten ; Dainese, Andrea ; Danisch, Meike Charlotte ; Danu, Andrea ; Das, Debasish ; Das, Indranil ; Das, Supriya ; Dash, Ajay Kumar ; Dash, Sadhana ; Daues, Heinz ; De, Sudipan ; De Caro, Annalisa ; De Cataldo, Giacinto ; Conti, Camila de ; Cuveland, Jan de ; De Falco, Alessandro ; De Gruttola, Daniele ; De Marco, Nora ; De Pasquale, Salvatore ; Souza, Rafael Derradi de ; Degenhardt, Hermann Franz ; Deisting, Alexander ; Deloff, Andrzej ; Deplano, Caterina ; Devismes, A ; Dhankher, Preeti ; Di Bari, Domenico ; Di Mauro, Antonio ; Di Nezza, Pasquale ; Di Ruzza, Benedetto ; Dietel, Thomas ; Dillenseger, Pascal ; Divià, Roberto ; Djuvsland, Øystein ; Dobrin, Alexandru Florin ; Domenicis Gimenez, Diogenes ; Donigus, Benjamin ; Dordic, Olja ; Doremalen, Lennart Vincent Rogier van ; Dubey, Anand Kumar ; Dubla, Andrea ; Ducroux, Laurent ; Duggal, Ashpreet Kaur ; Dupieux, Pascal ; Duta, V ; Ehlers Iii, Raymond James ; Elia, Domenico ; Emschermann, David ; Endress, Eric ; Engel, Heiko ; Epple, Eliane ; Erazmus, Barbara Ewa ; Erhardt, Filip ; Espagnon, Bruno ; Esumi, ShinIchi ; Eulisse, Giulio ; Eum, Jongsik ; Evans, David ; Evdokimov, Sergey ; Fabbietti, Laura ; Faivre, Julien ; Fantoni, Alessandra ; Fasel, Markus ; Fateev, O ; Feldkamp, Linus ; Feliciello, Alessandro ; Feofilov, Grigori A. ; Ferencei, Jozef ; Fernández Téllez, Arturo ; Ferretti, Alessandro ; Festanti, Andrea ; Feuillard, Victor Jose Gaston ; Figiel, Jan ; Figueredo, Marcel Araujo Silva ; Filchagin, Sergey ; Finogeev, Dmitry ; Fionda, Fiorella Maria Celeste ; Fleck, M ; Floris, Michele ; Foertsch, Siegfried Valentin ; Foka, Panagiota ; Fokin, Sergey ; Fragiacomo, Enrico ; Francescon, Andrea ; Francisco, Audrey ; Frankenfeld, Ulrich ; Freuen, S ; Fronzé, Gabriele Gaetano ; Fuchs, Ulrich ; Furget, Christophe ; Furs, Artur ; Fusco Girard, Mario ; Gaardhoeje, Jens Joergen ; Gagliardi, Martino ; Gago Medina, Alberto Martín ; Gajdosova, Katarina ; Gallio, Mauro ; Duarte Galvan, Carlos ; Ganoti, Paraskevi ; Garabatos Cuadrado, Jose ; Garcia-Solis, Edmundo Javier ; Garg, Kunal ; Gargiulo, Corrado ; Gasik, Piotr ; Gatz, Henriette ; Gauger, Erin Frances ; Ducati, Maria Beatriz de Leone Gay ; Germain, Marie ; Ghosh, Jhuma ; Ghosh, Premomoy ; Ghosh, Sanjay Kumar ; Gianotti, Paola ; Giolu, G ; Giubellino, Paolo ; Giubilato, Piero ; Gładysz-Dziaduś, Ewa ; Glasow, Richard ; Glässel, Peter ; Gremmler, Svenja ; Gómez Coral, Diego Mauricio ; Gómez Ramírez, Andrés ; Sanchez Gonzalez, Andres ; Gorbunov, Sergey ; Görlich, Lidia Maria ; Gotovac, Sven ; Gottschalk, Dirk ; Gottschlag, Holger ; Grabski, Varlen ; Graczykowski, Łukasz Kamil ; Graham, Katie Leanne ; Grajcarek, Robert ; Greiner, Leo Clifford ; Grelli, Alessandro ; Grigoraș, Costin ; Grigoryev, Vladislav ; Grigoryan, Ara ; Grigoryan, Smbat ; Grimm, Helge ; Grion, Nevio ; Gronefeld, Julius Maximilian ; Grosa, Fabrizio ; Große-Oetringhaus, Jan Fiete ; Grosso, Raffaele ; Gruber, Lukas ; Guber, Fedor ; Guernane, Rachid ; Guerzoni, Barbara ; Gulbrandsen, Kristjan Herlache ; Gunji, Taku ; Gupta, Anik ; Gupta, Ramni ; Gutfleisch, M ; Bautista Guzman, Irais ; Haake, Rüdiger ; Hadjidakis, Cynthia Marie ; Hamagaki, Hideki ; Hamar, Gergö ; Hamon, Julien Charles ; Haque, Md Rihan ; Harris, John William ; Hartig, Matthias ; Harton, Austin Vincent ; Hassan, Hadi ; Hatzifotiadou, Despina ; Hayashi, Shinichi ; Heckel, Stefan Thomas ; Hehner, Joerg ; Heide, Markus ; Hellbär, Ernst ; Helstrup, Håvard ; Herghelegiu, Andrei Ionut ; Herrera Corral, Gerardo Antonio ; Herrmann, Florian ; Herrmann, Norbert ; Hess, Benjamin Andreas ; Hetland, Kristin Fanebust ; Hillemanns, Hartmut ; Hills, Christopher ; Hippolyte, Boris ; Hladkỳ, Jan ; Hohlweger, Bernhard ; Horak, David ; Hornung, Sebastian ; Hosokawa, Ritsuya ; Hristov, Peter ; Huber, Sebastian ; Hughes, Charles ; Humanic, Thomas J. ; Hussain, Nur ; Hussain, Tahir ; Hutter, Dirk ; Hwang, Dae Sung ; Iga Buitron, Sergio Arturo ; Ilkaev, Radiy ; Inaba, Motoi ; Ippolitov, Mikhail ; Irfan, Muhammad ; Islam, Md Samsul ; Ivanov, Marian ; Ivanov, Vladimir ; Izucheev, Vladimir ; Jacak, Barbara ; Jacazio, Nicolò ; Jacobs, Peter Martin ; Jadhav, Manoj Bhanudas ; Jadlovsky, Jan ; Jaelani, Syaefudin ; Jahnke, Cristiane ; Jakubowska, Monika Joanna ; Janik, Malgorzata Anna ; Pahula Hewage, Sandun ; Jena, Chitrasen ; Jena, Satyajit ; Jercic, Marko ; Jiménez Bustamante, Raúl Tonatiuh ; Jones, Peter Graham ; Jusko, Anton ; Kalinak, Peter ; Kalweit, Alexander Philipp ; Kang, Ju Hwan ; Kaplin, Vladimir ; Kar, Somnath ; Karasu Uysal, Ayben ; Karavichev, Oleg V. ; Karavicheva, Tatiana L. ; Karayan, Lilit ; Karczmarczyk, Przemyslaw ; Karpechev, Evgeny ; Kebschull, Udo ; Keidel, Ralf ; Keijdener, Darius Laurens D. ; Keil, Markus ; Ketzer, Bernhard ; Khabanova, Zhanna ; Khan, Palash ; Khan, Shuaib Ahmad ; Khanzadeev, Alexei ; Kharlov, Yury ; Khatun, Anisa ; Khuntia, Arvind ; Kielbowicz, Mirosław Marek ; Kileng, Bjarte ; Kim, Byungchul ; Kim, Daehyeok ; Kim, Dong Jo ; Kim, Hyeonjoong ; Kim, Jinsook ; Kim, Jiyoung ; Kim, Minjung ; Kim, Minwoo ; Kim, Se Yong ; Kim, Taesoo ; Kirsch, Stefan ; Kisel, Ivan ; Kiselev, Sergej N. ; Kisiel, Adam Ryszard ; Kislov, E ; Kiss, Gabor ; Klay, Jennifer Lynn ; Klein, Carsten ; Klein, Jochen ; Klein-Bösing, Christian ; Klein-Bösing, Melanie ; Kliemant, Michael ; Klingenmeyer, Hannah ; Klewin, Sebastian ; Kluge, Alexander ; Knichel, Michael Linus ; Knospe, Anders Garritt ; Kobdaj, Chinorat ; Varga-Kofarago, Monika ; Kohn, Martin ; Kollegger, Thorsten ; Kondratev, Valerii ; Kondratyeva, Natalia ; Kondratyuk, Evgeny ; Konevskikh, Artem ; Konno, Masahiro ; Konyushikhin, Maxim A. ; Kopcik, Michal ; Kour, Mandeep ; Kouzinopoulos, Charalampos ; Kovalenko, Oleksandr ; Kovalenko, Vladimir ; Kowalski, Marek ; Koyithatta Meethaleveedu, Greeshma ; Králik, Ivan ; Kramer, Frederick ; Kravčáková, Adela ; Krawutschke, Tobias ; Kreis, Lukas ; Krivda, Marian ; Krizek, Filip ; Krumbhorn, Dirk ; Kryshen, Evgeny ; Krzewicki, Mikolaj ; Kubera, Andrew Michael ; Kucera, Vit ; Kuhn, Christian Claude ; Kuijer, Paulus Gerardus ; Kumar, Ajay ; Kumar, Jitendra ; Kumar, Lokesh ; Kumar, Shyam ; Kundu, Sourav ; Kurashvili, Podist ; Kurepin, Alexander ; Kurepin, Alexey B. ; Kuryakin, Alexey ; Kushpil, Svetlana ; Kweon, Min Jung ; Kwon, Youngil ; La Pointe, Sarah Louise ; La Rocca, Paola ; Lagana Fernandes, Caio ; Lai, Yue Shi ; Lakomov, Igor ; Langoy, Rune ; Lapidus, Kirill ; Lara Martinez, Camilo Ernesto ; Lardeux, Antoine Xavier ; Lattuca, Alessandra ; Laudi, Elisa ; Lavicka, Roman ; Lea, Ramona ; Leardini, Lucia ; Lee, Seongjoo ; Lehas, Fatiha ; Lehmann, T ; Lehner, Jorg ; Lehner, Sebastian ; Lehrbach, Johannes ; Lemmon, Roy Crawford ; Lenti, Vito ; Leogrande, Emilia ; Leon Monzon, Ildefonso ; Lesser, F ; Lévai, Peter ; Li, Xiaomei ; Lien, Jørgen André ; Lietava, Roman ; Lim, Bong-Hwi ; Lindal, Svein ; Lindenstruth, Volker ; Lindsay, Scott William ; Lippmann, Christian ; Lisa, Michael A. ; Litichevskyi, Vladyslav ; Llope, William ; Lodato, Davide Francesco ; Lohner, Daniel ; Lønne, Per-Ivar ; Loginov, Vitaly ; Loizides, Constantinos ; Lončar, Petra ; Lopez, Xavier Bernard ; López Torres, Ernesto ; Lowe, Andrew John ; Lu, XianGuo ; Ludolphs, W ; Lüttig, Philipp ; Luhder, Jens Robert ; Lunardon, Marcello ; Luparello, Grazia ; Lupi, Matteo ; Lutz, Tyler Harrison ; Maevskaya, Alla ; Mager, Magnus ; Magureanu, C ; Mahajan, Sanjay ; Mahmoud, Tariq ; Mahmood, Sohail Musa ; Maire, Antonin ; Majka, Richard Daniel ; Malaev, Mikhail ; Malinina, Liudmila ; Mal’Kevich, Dmitry ; Malzacher, Peter ; Mamonov, Alexander ; Manko, Vladislav ; Manso, Franck ; Manzari, Vito ; Mao, Yaxian ; Marchisone, Massimiliano ; Mareš, Jiří ; Margagliotti, Giacomo Vito ; Margotti, Anselmo ; Margutti, Jacopo ; Marin, Ana Maria ; Markert, Christina ; Marquard, Marco ; Martin, Nicole Alice ; Martinengo, Paolo ; Lucio Martinez, Jose Antonio ; Martínez Hernández, Mario Iván ; García Martínez, Ginés ; Martinez Pedreira, Miguel ; Masciocchi, Silvia ; Masera, Massimo ; Masoni, Alberto ; Masson, Erwann ; Mastroserio, Annalisa ; Mathis, Andreas Michael ; Matyja, Adam Tomasz ; Mayer, Christoph ; Mazer, Joel Anthony ; Mazzilli, Marianna ; Mazzoni, Alessandra Maria ; Meddi, Franco ; Melikyan, Yuri ; Menchaca-rocha, Arturo Alejandro ; Meninno, Elisa ; Mercado Pérez, Jorge ; Meres, Michal ; Mhlanga, Sibaliso ; Miake, Yasuo ; Mieskolainen, Matti Mikael ; Mihaylov, Dimitar Lubomirov ; Mikhaylov, Konstantin ; Milošević, Jovan ; Mischke, André ; Mishra, Aditya Nath ; Miśkowiec, Dariusz Czesław ; Mitra, Jubin ; Mitu, Ciprian Mihai ; Mohammadi, Naghmeh ; Mohanty, Bedangadas ; Khan, Mohammed Mohisin ; Godoy, Denise Aparecida Moreira de ; Perez Moreno, Luis Alberto ; Moretto, Sandra ; Morino, Yuhei ; Morreale, Astrid ; Morsch, Andreas ; Muccifora, Valeria ; Mudnic, Eugen ; Muhlheim, Daniel ; Muhuri, Sanjib ; Mukherjee, Maitreyee ; Mulligan, James Declan ; Gameiro Munhoz, Marcelo ; Munning, Konstantin ; Munzer, Robert Helmut ; Murakami, Hikari ; Murray, Sean ; Musa, Luciano ; Musinsky, Jan ; Myers, Corey James ; Myrcha, Julian Wojciech ; Mycke, Jan Felix ; Nag, Dipanjan ; Naik, Bharati ; Nair, Rahul Ramachandran ; Nandi, Basanta Kumar ; Nania, Rosario ; Nappi, Eugenio ; Narayan, Amrendra ; Naru, Muhammad Umair ; Luz, Pedro Hugo Ferreira Natal da ; Nattrass, Christine ; Rosado Navarro, Sebastian ; Nayak, Kishora ; Nayak, Ranjit ; Nayak, Tapan Kumar ; Nazarenko, Sergey ; Nedosekin, Alexander ; Oliveira, Renato Aparecido Negrao de ; Neher, Michael ; Nellen, Lukas ; Nesbo, Simon Voigt ; Ng, Fabian ; Nicassio, Maria ; Niculescu, Mihai ; Niedziela, Jeremi ; Nielsen, Borge Svane ; Nikolaev, Sergey ; Nikulin, Sergey ; Nikulin, Vladimir ; Noferini, Francesco ; Nomokonov, Petr V. ; Nooren, Gerardus ; Cabanillas Noris, Juan Carlos ; Norman, Jaime ; Nyanin, Alexander ; Nystrand, Joakim Ingemar ; Oeschler, Helmut ; Oh, Saehanseul ; Ohlson, Alice ; Okubo, Tsubasa ; Oláh, László ; Oleniacz, Janusz ; Silva, Antonio Carlos Oliveira da ; Oliver, Michael Henry ; Onderwaater, Jacobus ; Oppedisano, Chiara ; Orava, Risto ; Oravec, Matej ; Ortiz Velasquez, Antonio ; Oskarsson, Anders Nils Erik ; Otwinowski, Jacek Tomasz ; Oyama, Ken ; Pachmayer, Yvonne C. ; Pacik, Vojtech ; Pagano, Davide ; Pagano, Paola ; Paic, Guy ; Panebratsev, Yu ; Palni, Prabhakar ; Pan, Jinjin ; Pandey, Ashutosh Kumar ; Panebianco, Stefano Matthias ; Papikyan, Vardanush ; Pappalardo, Giuseppe Salvatore ; Pareek, Pooja ; Park, Jonghan ; Park, WooJin ; Parmar, Sonia ; Passfeld, Annika ; Pathak, Surya Prakash ; Patra, Rajendra Nath ; Paul, Biswarup ; Pei, Hua ; Peitzmann, Thomas ; Peng, Xinye ; Pereira, Luis Gustavo ; Pereira da Costa, Hugo Denis Antonio ; Peresunko, Dmitry Yurevich ; Pérez Lezama, Edgar ; Peskov, Vladimir ; Pestov, Yury N. ; Petráček, Vojtech ; Petris, M ; Petrov, Viacheslav ; Petrovici, Mihai A. ; Petta, Catia ; Pezzi, Rafael Peretti ; Piano, Stefano ; Pikna, Miroslav ; Pillot, Philippe ; Ozelin de Lima Pimentel, Laís ; Pinazza, Ombretta ; Pinsky, Lawrence ; Pitz, Nora ; Piyarathna, Danthasinghe ; Płoskoń, Mateusz ; Planinic, Mirko ; Pliquett, Fabian ; Pluta, Jan Marian ; Pochybova, Sona ; Podesta Lerma, Pedro Luis Manuel ; Poghosyan, Martin G. ; Polishchuk, Boris ; Poljak, Nikola ; Poonsawat, Wanchaloem ; Pop, Amalia ; Poppenborg, Hendrik ; Porteboeuf, Sarah Julie ; Pozdniakov, Valeriy ; Prasad, Sidharth Kumar ; Preghenella, Roberto ; Prino, Francesco ; Pruneau, Claude A. ; Pshenichnov, Igor A. ; Puccio, Maximiliano ; Puddu, Giovanna ; Pujahari, Prabhat Ranjan ; Punin, Valery ; Putschke, Jörn H. ; Radomski, Sylwester ; Rachevski, Alexandre ; Raha, Sibaji ; Rajput, Sonia ; Rak, Jan ; Rakotozafindrabe, Andry Malala ; Ramello, Luciano ; Rami, Fouad ; Rana, Dhan Bahadur ; Raniwala, Rashmi ; Raniwala, Sudhir ; Räsänen, Sami Sakari ; Rascanu, Bogdan Theodor ; Rathee, Deepika ; Ratza, Viktor ; Ravasenga, Ivan ; Read, Kenneth Francis ; Redlich, Krzysztof ; Rehman, Attiq ur ; Reichelt, Patrick ; Reidt, Felix ; Reischl, A ; Ren, Xiaowen ; Renfordt, Rainer Arno Ernst ; Reolon, Anna Rita ; Reshetin, Andrey ; Reygers, Klaus ; Riabov, Viktor ; Ricci, Renato Angelo ; Richert, Tuva Ora Herenui ; Richter, Matthias Rudolph ; Riedler, Petra ; Riegler, Werner ; Riggi, Francesco ; Ristea, Cătălin-Lucian ; Rodrı́guez Cahuantzi, Mario ; Røed, Ketil ; Rogochaya, Elena ; Rohr, David ; Röhrich, Dieter ; Rokita, Przemyslaw Stefan ; Ronchetti, Federico ; Dominguez Rosas, Edgar ; Rosnet, Philippe ; Rossi, Andrea ; Rotondi, Alberto ; Roukoutakis, Filimon ; Roy, Ankhi ; Roy, Christelle Sophie ; Roy, Pradip Kumar ; Vazquez Rueda, Omar ; Rui, Rinaldo ; Rumyantsev, Boris ; Rusanov, Ivan ; Rustamov, Anar ; Ryabinkin, Evgeny ; Ryabov, Yury ; Rybicki, Andrzej ; Saarinen, Sampo ; Sadhu, Samrangy ; Sadovskiy, Sergey ; Šafařík, Karel ; Saha, Sumit Kumar ; SahlmÜller, Baldo ; Sahoo, Baidyanath ; Sahoo, Pragati ; Sahoo, Raghunath ; Sahoo, Sarita ; Sahu, Pradip Kumar ; Saini, Jogender ; Sakai, Shingo ; Sakata, Dousatsu ; Saleh, Mohammad Ahmad ; Salzwedel, Jai ; Sambyal, Sanjeev Singh ; Samsonov, Vladimir ; Sandoval, Andres ; Sann, Hans ; Sano, Masato ; Santo, Rainer ; Sarkar, Debojit ; Sarkar, Nachiketa ; Sarma, Pranjal ; Sas, Mike Henry Petrus ; Scapparone, Eugenio ; Scarlassara, Fernando ; Schaefer, Brennan ; Scharenberg, Rolf Paul ; Scheid, Horst Sebastian ; Schiaua, Claudiu Cornel ; Schicker, Rainer ; Schmidt, Christian Joachim ; Schmidt, Hans Rudolf ; Schmidt, Marten Ole ; Schmidt, Martin ; Schmidt, Nicolas ; Schmiederer, Stefan ; Schneider, R ; Schukraft, Jürgen ; Schulze, R ; Schutz, Yves Roland ; Schwarz, Kilian Eberhard ; Schweda, Kai ; Scioli, Gilda ; Scomparin, Enrico ; Scott, Rebecca Michelle ; Sedykh, S ; Šefčík, Michal ; Seger, Janet Elizabeth ; Sekiguchi, Yuko ; Sekihata, Daiki ; Selyuzhenkov, Ilya ; Senosi, Kgotlaesele ; Senyukov, Serhiy ; Serradilla Rodriguez, Eulogio ; Sett, Priyanka ; Sevcenco, Adrian ; Shabanov, Arseniy ; Shabetai, Alexandre ; Shahoyan, Ruben ; Shaikh, Wadut ; Shangaraev, Artem ; Sharma, Anjali ; Sharma, Ankita ; Sharma, Mona ; Sharma, Monika ; Sharma, Natasha ; Sheikh, Ashik Ikbal ; Shigaki, Kenta ; Shimansky, S ; Shou, Qiye ; Shtejer Diaz, Katherin ; Shukla, P ; Sibiryak, Yury ; Sicking, Eva ; Siddhanta, Sabyasachi ; Sielewicz, Krzysztof Marek ; Siemiarczuk, Teodor ; Silaeva, Svetlana ; Silvermyr, David Olle Rickard ; Silvestre, Catherine Micaela ; Simatovic, Goran ; Simon, Reinhard S ; Simonetti, Giuseppe ; Singaraju, Rama Narayana ; Singh, Ranbir ; Singhal, Vikas ; Sarkar - Sinha, Tinku ; Sitar, Branislav ; Sitta, Mario ; Skaali, Toralf Bernhard ; Slupecki, Maciej ; Smirnov, Nikolai ; Smykov, L ; Snellings, Raimond ; Snellman, Tomas Wilhelm ; Solveit, Hans Kristian ; Sommer, Wolfgang ; Song, Jihye ; Song, Myunggeun ; Soramel, Francesca ; Sorensen, Soren Pontoppidan ; Sozzi, Federica ; Spiriti, Eleuterio ; Sputowska, Iwona Anna ; Srivastava, Brijesh Kumar ; Stachel, Johanna ; Stan, Ionel ; Stankus, Paul William ; Stelzer, Herbert ; Stenlund, Evert Anders ; Stiller, Johannes ; Stocco, Diego ; Stockmeyer, M.R. ; Storetvedt, Maksim Melnik ; Strmen, Peter ; Suaide, Alexandre Alarcon do Passo ; Sugitate, Toru ; Suire, Christophe Pierre ; Suleymanov, Mais Kazim Oglu ; Šuljić, Miljenko ; Sultanov, Rishat ; Šumbera, Michal ; Sumowidagdo, Suharyo ; Suzuki, Ken ; Swain, Sagarika ; Szabo, Alexander ; Szarka, Imrich ; Tabassam, Uzma ; Takahashi, Jun ; Tambave, Ganesh Jagannath ; Tanaka, Naoto ; Tarhini, Mohamad ; Tariq, Mohammad ; Tarzila, Madalina-Gabriela ; Tauro, Arturo ; Tejeda Muñoz, Guillermo ; Telesca, Adriana ; Terasaki, Kohei ; Terrevoli, Cristina ; Teyssier, Boris ; Thakur, Dhananjaya ; Thakur, Sanchari ; Thomas, Deepa ; Thoresen, Freja ; Tieulent, Raphael Noel ; Tikhonov, Anatoly ; Tilsner, Heinz ; Timmins, Anthony Robert ; Toia, Alberica ; Rojas Torres, Solangel ; Tripathy, Sushanta ; Trogolo, Stefano ; Trombetta, Giuseppe ; Tropp, Lukas ; Trubnikov, Victor ; Trzaska, Wladyslaw Henryk ; Trzeciak, Barbara Antonina ; Tsiledakis, Georgios ; Tsuji, Tomoya ; Tumkin, Alexandr ; Turrisi, Rosario ; Tveter, Trine Spedstad ; Ullaland, Kjetil ; Umaka, Ejiro Naomi ; Uras, Antonio ; Usai, Gianluca ; Utrobicic, Antonija ; Vala, Martin ; Maarel, Jasper van der ; Hoorne, Jacobus Willem van ; Leeuwen, Marco van ; Vanat, Tomas ; Vargas, H ; Vyvre, Pierre vande ; Varga, Dezsö ; Vargas Treviño, Maria Aurora Diozcora ; Vargyas, Márton ; Varma, Raghava ; Vasileiou, Maria ; Vasiliev, Andrey ; Vauthier, Astrid ; Vazquez Doce, Oton ; Vechernin, Vladimir ; Veen, Annelies Marianne ; Velure, Arild ; Vercellin, Ermanno ; Vergara Limon, Sergio ; Vernet, Renaud ; Vértesi, Róbert ; Vicković, Linda ; Vigolo, Sonia ; Viinikainen, Jussi Samuli ; Vilakazi, Zabulon ; Villalobos Baillie, Orlando ; Villatoro Tello, Abraham ; Vinogradov, Alexander ; Vinogradov, Leonid ; Virgili, Tiziano ; Vislavicius, Vytautas ; Vodopyanov, Alexander ; Volkl, Martin Andreas ; Voloshin, Kirill ; Voloshin, Sergei ; Volpe, Giacomo ; Haller, Barthélémy von ; Vorobyev, Ivan ; Voscek, Dominik ; Vranić, Danilo ; Vrlakova, Janka ; Vulpescu, Bogdan ; Wagner, Boris ; Wang, Hongkai ; Wang, Mengliang ; Wang, Yifei ; Watanabe, Daisuke ; Watanabe, Kengo ; Watanabe, Yosuke ; Weber, Michael ; Weber, Steffen Georg ; Wegerle, Dominik ; Weiser, Dennis ; Wenzel, Sandro Christian ; Wessels, Johannes P. ; Westerhoff, Uwe ; Whitehead, Andile Mothegi ; Wiechula, Jens ; Wikne, Jon ; Wilk, Alexander ; Wilk, Grzegorz Andrzej ; Wilkinson, Jeremy John ; Willems, Guido Alexander ; Williams, M. Crispin S. ; Willsher, Emily ; Windelband, Bernd ; Winn, Michael ; Witt, William Edward ; Xu, C ; Yalcin, Serpil ; Yamakawa, Kosei ; Yang, Ping ; Yano, Satoshi ; Yin, Zhongbao ; Yokoyama, Hiroki ; Yoo, In-kwon ; Yoon, Jin Hee ; Yurchenko, Volodymyr ; Yurevich, Vladimir ; Zaccolo, Valentina ; Zaman, Ali ; Zampolli, Chiara ; Correia Zanoli, Henrique Jose ; Zanevski, Yuri ; Zardoshti, Nima ; Zarochentsev, Andrey ; Závada, Petr ; Zavyalov, Nikolay ; Zbroszczyk, Hanna Paulina ; Zhalov, Mikhail ; Zhang, Haitao ; Zhang, Xiaoming ; Zhang, Yonghong ; Chunhui, Zhang ; Zhang, Zuman ; Zhao, Chengxin ; Zhigareva, Natalia ; Zhou, Daicui ; Zhou, You ; Zhou, Zhuo ; Zhu, Hongsheng ; Zhu, Jianhui ; Zichichi, Antonino ; Zimmer, Stefan ; Zimmermann, Alice ; Zimmermann, Markus ; Zinovjev, Gennady M. ; Zmeskal, Johann ; Zou, Shuguang
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Grammatikos, Georgios ; Dietz, Julia ; Ferreirós Bouzas, Nerea ; Koch, Alexander ; Dultz, Georg ; Bon, Dimitra ; Karakasiliotis, Ioannis ; Lutz, Thomas ; Knecht, Gaby ; Gute, Peter ; Herrmann, Eva ; Zeuzem, Stefan ; Mavromara, Penelope ; Sarrazin, Christoph ; Pfeilschifter, Josef
Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.
Influence of antibiotic-regimens on intensive-care unit-mortality and liver-cirrhosis as risk factor
(2016)
Friedrich-Rust, Mireen ; Wanger, Beate ; Heupel, Florian ; Filmann, Natalie ; Brodt, Hans-Reinhard ; Kempf, Volkhard A. J. ; Kessel, Johanna ; Wichelhaus, Thomas Alexander ; Herrmann, Eva ; Zeuzem, Stefan ; Bojunga, Jörg
AIM: To assess the rate of infection, appropriateness of antimicrobial-therapy and mortality on intensive care unit (ICU). Special focus was drawn on patients with liver cirrhosis.
METHODS: The study was approved by the local ethical committee. All patients admitted to the Internal Medicine-ICU between April 1, 2007 and December 31, 2009 were included. Data were extracted retrospectively from all patients using patient charts and electronic documentations on infection, microbiological laboratory reports, diagnosis and therapy. Due to the large hepatology department and liver transplantation center, special interest was on the subgroup of patients with liver cirrhosis. The primary statistical-endpoint was the evaluation of the influence of appropriate versus inappropriate antimicrobial-therapy on in-hospital-mortality.
RESULTS: Charts of 1979 patients were available. The overall infection-rate was 53%. Multiresistant-bacteria were present in 23% of patients with infection and were associated with increased mortality (P < 0.000001). Patients with infection had significantly increased in-hospital-mortality (34% vs 17%, P < 0.000001). Only 9% of patients with infection received inappropriate initial antimicrobial-therapy, no influence on mortality was observed. Independent risk-factors for in-hospital-mortality were the presence of septic-shock, prior chemotherapy for malignoma and infection with Pseudomonas spp. Infection and mortality-rate among 175 patients with liver-cirrhosis was significantly higher than in patients without liver-cirrhosis. Infection increased mortality 2.24-fold in patients with cirrhosis. Patients with liver cirrhosis were at an increased risk to receive inappropriate initial antimicrobial therapy.
CONCLUSION: The results of the present study report the successful implementation of early-goal-directed therapy. Liver cirrhosis patients are at increased risk of infection, mortality and to receive inappropriate therapy. Increasing burden are multiresistant-bacteria.
Meybohm, Patrick ; Choorapoikayil, Suma ; Wessels, Anke ; Herrmann, Eva ; Zacharowski, Kai ; Spahn, Donat Rudolf
Background: Cell salvage is commonly used as part of a blood conservation strategy. However concerns among clinicians exist about the efficacy of transfusion of washed cell salvage.
Methods: We performed a meta-analysis of randomized controlled trials in which patients, scheduled for all types of surgery, were randomized to washed cell salvage or to a control group with no cell salvage. Data were independently extracted, risk ratio (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random effects model. The primary endpoint was the number of patients exposed to allogeneic red blood cell (RBC) transfusion.
Results: Out of 1140 search results, a total of 47 trials were included. Overall, the use of washed cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 39% (RR = 0.61; 95% CI 0.57 to 0.65; P < 0.001), resulting in an average saving of 0.20 units of allogeneic RBC per patient (weighted mean differences [WMD] = -0.20; 95% CI -0.22 to -0.18; P < 0.001), reduced risk of infection by 28% (RR = 0.72; 95% CI 0.54 to 0.97; P = 0.03), reduced length of hospital stay by 2.31 days (WMD = -2.31; 95% CI -2.50 to -2.11; P < 0.001), but did not significantly affect risk of mortality (RR = 0.92; 95% CI 0.63 to 1.34; P = 0.66). No statistical difference could be observed in the number of patients exposed to re-operation, plasma, platelets, or rate of myocardial infarction and stroke.
Conclusions: Washed cell salvage is efficacious in reducing the need for allogeneic RBC transfusion and risk of infection in surgery.
Rezende Felipe, Flávia Figueiredo de ; Schürmann, Christoph ; Schütz, Susanne ; Harenkamp, Sabine ; Herrmann, Eva ; Seimetz, Michael ; Weißmann, Norbert ; Schröder, Katrin
The free radical theory of aging suggests reactive oxygen species as a main reason for accumulation of damage events eventually leading to aging. Nox4, a member of the family of NADPH oxidases constitutively produces ROS and therefore has the potential to be a main driver of aging. Herein we analyzed the life span of Nox4 deficient mice and found no difference when compared to their wildtype littermates. Accordingly neither Tert expression nor telomere length was different in cells isolated from those animals. In fact, Nox4 mRNA expression in lungs of wildtype mice dropped with age. We conclude that Nox4 has no influence on lifespan of healthy mice.
Ullrich, Evelyn ; Salzmann-Manrique, Emilia ; Bakhtiar, Shahrzad ; Bremm, Melanie ; Gerstner, Stephanie ; Herrmann, Eva ; Bader, Peter ; Hoffmann, Petra ; Holler, Ernst ; Edinger, Matthias ; Wolff, Daniel
One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56high and mature cytotoxic CD56dim NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56high subset. Notably, the disturbed reconstitution of the CD56high NK cells also correlated with the severity of aGVHD.
Dietz, Julia ; Rupp, Daniel ; Susser, Simone ; Vermehren, Johannes ; Peiffer, Kai-Henrik ; Filmann, Natalie ; Bon, Dimitra ; Kuntzen, Thomas ; Mauß, Stefan ; Grammatikos, Georgios ; Perner, Dany ; Berkowski, Caterina ; Herrmann, Eva ; Zeuzem, Stefan ; Bartenschlager, Ralf ; Sarrazin, Christoph
Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR.
Solbach, Philipp ; Westhaus, Sandra ; Deest, Maximilian ; Herrmann, Eva ; Berg, Thomas ; Manns, Michael P. ; Ciesek, Sandra ; Sarrazin, Christoph ; Hahn, Thomas von
Background & Aims: Hepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C.
Methods: Baseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells.
Results: In the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment.
Conclusions: Oxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.
Augmenting LTP-like plasticity in human motor cortex by spaced paired associative stimulation
(2015)
Müller-Dahlhaus, Florian ; Lücke, Caroline ; Lu, Ming-Kuei ; Arai, Noritoshi ; Fuhl, Anna ; Herrmann, Eva ; Ziemann, Ulf
Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60min and 180min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60min and 180min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.
Grammatikos, Georgios ; Ferreirós Bouzas, Nerea ; Waidmann, Oliver ; Bon, Dimitra ; Schroeter, Sirkka ; Koch, Alexander ; Herrmann, Eva ; Zeuzem, Stefan ; Kronenberger, Bernd ; Pfeilschifter, Josef
Background: Sphingolipids constitute bioactive molecules with functional implications in liver homeostasis. Particularly, ablation of very long chain ceramides in a knockout mouse model has been shown to cause a severe hepatopathy.
Methods: We aimed to evaluate the serum sphingolipid profile of 244 patients with cirrhosis prospectively followed for a median period of 228±217 days via mass spectrometry.
Results: We thereby observed a significant decrease of long and very long chain ceramides, particularly of C24ceramide, in patients with increasing severity of cirrhosis (p<0.001). Additionally, hydropic decompensation, defined by clinical presentation of ascites formation, was significantly correlated to low C24ceramide levels (p<0.001) while a significant association to hepatic decompensation and poor overall survival was observed for low serum concentrations of C24ceramide (p<0.001) as well. Multivariate analysis further identified low serum C24ceramide to be independently associated to overall survival (standard beta = -0.001, p = 0.022).
Conclusions: In our current analysis serum levels of very long chain ceramides show a significant reciprocal correlation to disease severity and hepatic decompensation and are independently associated with overall survival in patients with cirrhosis. Serum sphingolipid metabolites and particularly C24ceramide may constitute novel molecular targets of disease severity, hepatic decompensation and overall prognosis in cirrhosis and should be further evaluated in basic research studies.
Casper, Markus ; Mengel, Martin ; Fuhrmann, Christine ; Herrmann, Eva ; Appenrodt, Beate ; Schiedermaier, Peter ; Reichert, Matthias ; Bruns, Tony ; Engelmann, Cornelius ; Grünhage, Frank ; Lammert, Frank
Background: Patients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP.
Methods/Design: The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014.
Discussion: Preventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms.
Trial registrations: German Clinical Trials Register DRKS00005616. Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26. Registered 26 January 2015.
Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia
(2014)
Eickmeier, Olaf ; Kim, Su Youn ; Herrmann, Eva ; Döring, Constanze ; Dücker, Ruth Pia ; Voss, Sandra ; Wehner, Sibylle ; Hölscher, Christoph ; Pietzner, Julia ; Zielen, Stefan ; Schubert, Ralf
Background: Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death.
Methods: We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm−/−).
Results: ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm−/− mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed.
Conclusions: Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.
Markova, Antoaneta A. ; Mihm, Ulrike ; Schlaphoff, Verena ; Lunemann, Sebastian ; Filmann, Natalie ; Bremer, Birgit ; Berg, Thomas ; Sarrazin, Christoph ; Zeuzem, Stefan ; Manns, Michael P. ; Cornberg, Markus ; Herrmann, Eva ; Wedemeyer, Heiner
Background: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown.
Methods: Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells.
Results: Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load.
Conclusions: PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.
Reinhard, Joscha ; Rösler, Roberta ; Yuan, Juping ; Schiermeier, Sven ; Herrmann, Eva ; Eichbaum, Michael H. R. ; Louwen, Frank
Aim. To compare the efficacy, safety, and patient’s perception of two prostaglandin E2 application methods for induction of labour.
Method. Above 36th weeks of gestation, all women, who were admitted to hospital for induction of labour, were prospectively randomised to intravaginal 1 mg or intracervical 0.5 mg irrespective of cervical Bishop score. The main outcome variables were induction-to-delivery interval, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, rate of vaginal delivery, and patient’s perception using semantic differential questionnaire.
Results. Thirty-nine patients were enrolled in this study. There was no statistical significant difference between the two groups in regard to perceptions of induction. The median induction delivery time using intravaginal versus intracervical administration was 29.9 versus 12.8 hours, respectively (). No statistically difference between the groups was detected in regard to parity, gestation age, cervical Bishop score, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, and mode of birth.
Summary. Irrespective of the cervical Bishop Score, intracervical gel had a shorter induction delivery time without impingement on the women’s perception of induction.
Susser, Simone ; Herrmann, Eva ; Lange, Christian ; Hamdi, Nabila ; Müller, Tobias ; Berg, Thomas ; Perner, Dany ; Zeuzem, Stefan ; Sarrazin, Christoph
Background: IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.
Methods: Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.
Results: Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.
Conclusion: IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.
Friedrich-Rust, Mireen ; Meyer, Gesine ; Dauth, Nina ; Berner, Christian ; Bogdanou, Dimitra ; Herrmann, Eva ; Zeuzem, Stefan ; Bojunga, Jörg
Background: Thyroid Imaging Reporting and Data System (TIRADS) was developed to improve patient management and cost-effectiveness by avoiding unnecessary fine needle aspiration biopsy (FNAB) in patients with thyroid nodules. However, its clinical use is still very limited. Strain elastography (SE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules.
Methods: The aim of the present study was to evaluate the interobserver agreement (IA) of TIRADS developed by Horvath et al. and SE. Three blinded observers independently scored stored images of TIRADS and SE in 114 thyroid nodules (114 patients). Cytology and/or histology was available for all benign (n = 99) and histology for all malignant nodules (n = 15).
Results: The IA between the 3 observers was only fair for TIRADS categories 2–5 (Coheńs kappa = 0.27,p = 0.000001) and TIRADS categories 2/3 versus 4/5 (ck = 0.25,p = 0.0020). The IA was substantial for SE scores 1–4 (ck = 0.66,p<0.000001) and very good for SE scores 1/2 versus 3/4 (ck = 0.81,p<0.000001). 92–100% of patients with TIRADS-2 had benign lesions, while 28–42% with TIRADS-5 had malignant cytology/histology. The negative-predictive-value (NPV) was 92–100% for TIRADS using TIRADS-categories 4&5 and 96–98% for SE using score ES-3&4 for the diagnosis of malignancy, respectively. However, only 11–42% of nodules were in TIRADS-categories 2&3, as compared to 58–60% with ES-1&2.
Conclusions: IA of TIRADS developed by Horvath et al. is only fair. TIRADS and SE have high NPV for excluding malignancy in the diagnostic work-up of thyroid nodules.
Background: To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and ε-aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery.
Methods and Findings: We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively.
Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13–2.21), p<0.001 in the low (n = 14,297) and in the intermediate risk subgroup (1.42 (1.09–1.84), p<0.001; n = 14,427), respectively. Contrarily, in the subgroup of high risk patients (n = 4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67–1.58), p = 0.90).
Conclusion: Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.