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Bousquet, J. ; Farrell, J. ; Crooks, G. ; Hellings, P. ; Bel, E. H. ; Bewick, M. ; Chavannes, N. H. ; Correia de Sousa, J. ; Cruz, A. A. ; Haahtela, T. ; Joos, G. ; Khaltaev, N. ; Malva, J. ; Muraro, A. ; Nogues, M. ; Palkonen, S. ; Pedersen, S. ; Robalo-Cordeiro, C. ; Samolinski, B. ; Strandberg, T. ; Valiulis, A. ; Yorgancioglu, A. ; Zuberbier, T. ; Bedbrook, A. ; Aberer, W. ; Adachi, M. ; Agusti, A. ; Akdis, C. A. ; Akdis, M. ; Ankri, J. ; Alonso, A. ; Annesi-Maesano, I. ; Ansotegui, I. J. ; Anto, J. M. ; Arnavielhe, S. ; Arshad, H. ; Bai, C. ; Baiardini, I. ; Bachert, C. ; Baigenzhin, A. K. ; Barbara, C. ; Bateman, E. D. ; Beghé, B. ; Ben Kheder, A. ; Bennoor, K. S. ; Benson, M. ; Bergmann, K. C. ; Bieber, T. ; Bindslev-Jensen, C. ; Bjermer, L. ; Blain, H. ; Blasi, F. ; Boner, A. L. ; Bonini, M. ; Bonini, S. ; Bosnic-Anticevitch, S. ; Boulet, L. P. ; Bourret, R. ; Bousquet, P. J. ; Braido, F. ; Briggs, A. H. ; Brightling, C. E. ; Brozek, J. ; Buhl, R. ; Burney, P. G. ; Bush, A. ; Caballero-Fonseca, F. ; Caimmi, D. ; Calderon, M. A. ; Calverley, P. M. ; Camargos, P. A. M. ; Canonica, G. W. ; Camuzat, T. ; Carlsen, K. H. ; Carr, W. ; Carriazo, A. ; Casale, T. ; Cepeda Sarabia, A. M. ; Chatzi, L. ; Chen, Y. Z. ; Chiron, R. ; Chkhartishvili, E. ; Chuchalin, A. G. ; Chung, K. F. ; Ciprandi, G. ; Cirule, I. ; Cox, L. ; Costa, D. J. ; Custovic, A. ; Dahl, R. ; Dahlen, S. E. ; Darsow, U. ; De Carlo, G. ; De Blay, F. ; Dedeu, T. ; Deleanu, D. ; De Manuel Keenoy, E. ; Demoly, P. ; Denburg, J. A. ; Devillier, P. ; Didier, A. ; Dinh-Xuan, A. T. ; Djukanovic, R. ; Dokic, D. ; Douagui, H. ; Dray, G. ; Dubakiene, R. ; Durham, S. R. ; Dykewicz, M. S. ; El-Gamal, Y. ; Emuzyte, R. ; Fabbri, L. M. ; Fletcher, M. ; Fiocchi, A. ; Fink Wagner, A. ; Fonseca, J. ; Fokkens, W. J. ; Forastiere, F. ; Frith, P. ; Gaga, M. ; Gamkrelidze, A. ; Garces, J. ; Garcia-Aymerich, J. ; Gemicioğlu, B. ; Gereda, J. E. ; González Diaz, S. ; Gotua, M. ; Grisle, I. ; Grouse, L. ; Gutter, Z. ; Guzmán, M. A. ; Heaney, L. G. ; Hellquist-Dahl, B. ; Henderson, D. ; Hendry, A. ; Heinrich, J. ; Heve, D. ; Horak, F. ; Hourihane, J. O’. B. ; Howarth, P. ; Humbert, M. ; Hyland, M. E. ; Illario, M. ; Ivancevich, J. C. ; Jardim, J. R. ; Jares, E. J. ; Jeandel, C. ; Jenkins, C. ; Johnston, S. L. ; Jonquet, O. ; Julge, K. ; Jung, K. S. ; Just, J. ; Kaidashev, I. ; Kaitov, M. R. ; Kalayci, O. ; Kalyoncu, A. F. ; Keil, T. ; Keith, P. K. ; Klimek, L. ; Koffi N’Goran, B. ; Kolek, V. ; Koppelman, G. H. ; Kowalski, M. L. ; Kull, I. ; Kuna, P. ; Kvedariene, V. ; Lambrecht, B. ; Lau, S. ; Larenas‑Linnemann, D. ; Laune, D. ; Le, L. T. T. ; Lieberman, P. ; Lipworth, B. ; Li, J. ; Lodrup Carlsen, K. ; Louis, R. ; MacNee, W. ; Magard, Y. ; Magnan, A. ; Mahboub, B. ; Mair, A. ; Majer, I. ; Makela, M. J. ; Manning, P. ; Mara, S. ; Marshall, G. D. ; Masjedi, M. R. ; Matignon, P. ; Maurer, M. ; Mavale‑Manuel, S. ; Melén, E. ; Melo‑Gomes, E. ; Meltzer, E. O. ; Menzies‑Gow, A. ; Merk, H. ; Michel, J. P. ; Miculinic, N. ; Mihaltan, F. ; Milenkovic, B. ; Mohammad, G. M. Y. ; Molimard, M. ; Momas, I. ; Montilla‑Santana, A. ; Morais‑Almeida, M. ; Morgan, M. ; Mösges, R. ; Mullol, J. ; Nafti, S. ; Namazova‑Baranova, L. ; Naclerio, R. ; Neou, A. ; Neffen, H. ; Nekam, K. ; Niggemann, B. ; Ninot, G. ; Nyembue, T. D. ; O’Hehir, R. E. ; Ohta, K. ; Okamoto, Y. ; Okubo, K. ; Ouedraogo, S. ; Paggiaro, P. ; Pali‑Schöll, I. ; Panzner, P. ; Papadopoulos, N. ; Papi, A. ; Park, H. S. ; Passalacqua, G. ; Pavord, I. ; Pawankar, R. ; Pengelly, R. ; Pfaar, O. ; Picard, R. ; Pigearias, B. ; Pin, I. ; Plavec, D. ; Poethig, D. ; Pohl, W. ; Popov, T. A. ; Portejoie, F. ; Potter, P. ; Postma, D. ; Price, D. ; Rabe, K. F. ; Raciborski, F. ; Radier Pontal, F. ; Repka‑Ramirez, S. ; Reitamo, S. ; Rennard, S. ; Rodenas, F. ; Roberts, J. ; Roca, J. ; Rodriguez Mañas, L. ; et al
Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.
Fruchart, Jean-Charles ; Davignon, Jean ; Hermans, Michael P. ; Al-Rubeaan, Khalid ; Amarenco, Pierre ; Assmann, Gerd ; Barter, Philip ; Betteridge, John ; Bruckert, Eric ; Cuevas, Ada ; Farnier, Michel ; Ferrannini, Ele ; Fioretto, Paola ; Genest, Jacques ; Ginsberg, Henry N. ; Gotto Jr., Antonio M. ; Hu, Dayi ; Kadowaki, Takashi ; Kodama, Tatsuhiko ; Krempf, Michel ; Matsuzawa, Yuji ; Núñez-Cortés, Jesús Millán ; Monfil, Calos Calvo ; Ogawa, Hisao ; Plutzky, Jorge ; Rader, Daniel J. ; Sadikot, Shaukat ; Santos, Raul D. ; Shlyakhto, Evgeny ; Sritara, Piyamitr ; Sy, Rody ; Tall, Alan ; Tan, Chee Eng ; Tokgözoğlu, Lale ; Toth, Peter P. ; Valensi, Paul ; Wanner, Christoph ; Zambon, Albertro ; Zhu, Junren ; Zimmet, Paul
Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R(3)i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R(3)i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R(3)i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptor alpha agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R(3)i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.
Marenholz, Ingo ; Esparza-Gordillo, Jorge ; Rüschendorf, Franz ; Bauerfeind, Anja ; Strachan, David P. ; Spycher, Ben D. ; Baurecht, Hansjörg ; Magaritte-Jeannin, Patricia ; Sääf, Annika ; Kerkhof, Marjan ; Ege, Markus ; Baltic, Svetlana ; Matheson, Melanie C. ; Li, Jin ; Michel, Sven ; Ang, Wei Q. ; McArdle, Wendy ; Arnold, Andreas ; Homuth, Georg ; Demenais, Florence ; Bouzigon, Emmanuelle ; Söderhäll, Cilla ; Pershagen, Göran ; de Jongste, Johan C. ; Postma, Dirkje S. ; Braun-Fahrländer, Charlotte ; Horak, Elisabeth ; Ogorodova, Ludmila M. ; Puzyrev, Valery P. ; Bragina, Elena Yu ; Hudson, Thomas J. ; Morin, Charles ; Duffy, David L. ; Marks, Guy B. ; Robertson, Colin F. ; Montgomery, Grant W. ; Musk, Bill ; Thompson, Philip J. ; Martin, Nicholas G. ; James, Alan ; Sleiman, Patrick ; Toskala, Elina ; Rodriguez, Elke ; Fölster-Holst, Regina ; Franke, Andre ; Lieb, Wolfgang ; Gieger, Christian ; Heinzmann, Andrea ; Rietschel, Ernst ; Keil, Thomas ; Cichon, Sven ; Nöthen, Markus M. ; Pennel, Craig E. ; Sly, Peter D. ; Schmidt, Carsten O. ; Matanovic, Anja ; Schneider, Valentin ; Heinig, Matthias ; Hübner, Norbert ; Holt, Patrick G. ; Lau, Susanne ; Kabesch, Michael ; Weidinger, Stefan ; Hakonarson, Hakon ; Ferreira, Manuel A. R. ; Laprise, Catherine ; Freidin, Maxim B. ; Genuneit, Jon ; Koppelman, Gerard H. ; Melén, Erik ; Dizier, Marie-Hélène ; Henderson, A. John ; Lee, Young Ae
Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Bousquet, Jean ; Anto, Josep M. ; Bachert, Claus ; Haahtela, Tari ; Zuberbier, Torsten ; Czarlewski, Wienczyslawa ; Bedbrook, Anna ; Bosnic‐Anticevich, Sinthia ; Walter Canonica, G. ; Cardona, Victoria ; Costa, Elisio ; Cruz, Alvaro A. ; Erhola, Marina ; Fokkens, Wytske J. ; Fonseca, Joao A. ; Illario, Maddalena ; Ivancevich, Juan‐Carlos ; Jutel, Marek ; Klimek, Ludger ; Kuna, Piotr ; Kvedariene, Violeta ; Le, LTT ; Larenas‐Linnemann, Désirée E. ; Laune, Daniel ; Lourenço, Olga M. ; Melén, Erik ; Mullol, Joaquim ; Niedoszytko, Marek ; Odemyr, Mikaëla ; Okamoto, Yoshitaka ; Papadopoulos, Nikos G. ; Patella, Vincenzo ; Pfaar, Oliver ; Pham‐Thi, Nhân ; Rolland, Christine ; Samolinski, Boleslaw ; Sheikh, Aziz ; Sofiev, Mikhail ; Suppli Ulrik, Charlotte ; Todo‐Bom, Ana ; Tomazic, Peter‐Valentin ; Toppila‐Salmi, Sanna ; Tsiligianni, Ioanna ; Valiulis, Arunas ; Valovirta, Erkka ; Ventura, Maria‐Teresa ; Walker, Samantha ; Williams, Sian ; Yorgancioglu, Arzu ; Agache, Ioana ; Akdis, Cezmi A. ; Almeida, Rute ; Ansotegui, Ignacio J. ; Annesi‐Maesano, Isabella ; Arnavielhe, Sylvie ; Basagaña, Xavier ; D. Bateman, Eric ; Bédard, Annabelle ; Bedolla‐Barajas, Martin ; Becker, Sven ; Bennoor, Kazi S. ; Benveniste, Samuel ; Bergmann, Karl C. ; Bewick, Michael ; Bialek, Slawomir ; E. Billo, Nils ; Bindslev‐Jensen, Carsten ; Bjermer, Leif ; Blain, Hubert ; Bonini, Matteo ; Bonniaud, Philippe ; Bosse, Isabelle ; Bouchard, Jacques ; Boulet, Louis‐Philippe ; Bourret, Rodolphe ; Boussery, Koen ; Braido, Fluvio ; Briedis, Vitalis ; Briggs, Andrew ; Brightling, Christopher E. ; Brozek, Jan ; Brusselle, Guy ; Brussino, Luisa ; Buhl, Roland ; Buonaiuto, Roland ; Calderon, Moises A. ; Camargos, Paulo ; Camuzat, Thierry ; Caraballo, Luis ; Carriazo, Ana‐Maria ; Carr, Warner ; Cartier, Christine ; Casale, Thomas ; Cecchi, Lorenzo ; Cepeda Sarabia, Alfonso M. ; H. Chavannes, Niels ; Chkhartishvili, Ekaterine ; Chu, Derek K. ; Cingi, Cemal ; Correia de Sousa, Jaime ; Costa, David J. ; Courbis, Anne‐Lise ; Custovic, Adnan ; Cvetkosvki, Biljana ; D'Amato, Gennaro ; da Silva, Jane ; Dantas, Carina ; Dokic, Dejan ; Dauvilliers, Yves ; De Feo, Giulia ; De Vries, Govert ; Devillier, Philippe ; Di Capua, Stefania ; Dray, Gerard ; Dubakiene, Ruta ; Durham, Stephen R. ; Dykewicz, Mark ; Ebisawa, Motohiro ; Gaga, Mina ; El‐Gamal, Yehia ; Heffler, Enrico ; Emuzyte, Regina ; Farrell, John ; Fauquert, Jean‐Luc ; Fiocchi, Alessandro ; Fink‐Wagner, Antje ; Fontaine, Jean‐François ; Fuentes Perez, José M. ; Gemicioğlu, Bilun ; Gamkrelidze, Amiran ; Garcia‐Aymerich, Judith ; Gevaert, Philippe ; Gomez, René Maximiliano ; González Diaz, Sandra ; Gotua, Maia ; Guldemond, Nick A. ; Guzmán, Maria‐Antonieta ; Hajjam, Jawad ; Huerta Villalobos, Yunuen R. ; Humbert, Marc ; Iaccarino, Guido ; Ierodiakonou, Despo ; Iinuma, Tomohisa ; Jassem, Ewa ; Joos, Guy ; Jung, Ki‐Suck ; Kaidashev, Igor ; Kalayci, Omer ; Kardas, Przemyslaw ; Keil, Thomas ; Khaitov, Musa ; Khaltaev, Nikolai ; Kleine‐Tebbe, Jorg ; Kouznetsov, Rostislav ; Kowalski, Marek L. ; Kritikos, Vicky ; Kull, Inger ; La Grutta, Stefania ; Leonardini, Lisa ; Ljungberg, Henrik ; Lieberman, Philip ; Lipworth, Brian ; Lodrup Carlsen, Karin C. ; Lopes‐Pereira, Catarina ; Loureiro, Claudia C. ; Louis, Renaud ; Mair, Alpana ; Mahboub, Bassam ; Makris, Michaël ; Malva, Joao ; Manning, Patrick ; Marshall, Gailen D. ; Masjedi, Mohamed R. ; Maspero, Jorge F. ; Carreiro‐Martins, Pedro ; Makela, Mika ; Mathieu‐Dupas, Eve ; Maurer, Marcus ; De Manuel Keenoy, Esteban ; Melo‐Gomes, Elisabete ; Meltzer, Eli O. ; Menditto, Enrica ; Mercier, Jacques ; Micheli, Yann ; Miculinic, Neven ; Mihaltan, Florin ; Milenkovic, Branislava ; Mitsias, Dimitirios I. ; Moda, Giuliana ; Mogica‐Martinez, Maria‐Dolores ; Mohammad, Yousser ; Montefort, Steve ; Monti, Ricardo ; Morais‐Almeida, Mario ; Mösges, Ralph ; Münter, Lars ; Muraro, Antonella ; Murray, Ruth ; Naclerio, Robert ; Napoli, Luigi ; Namazova‐Baranova, Leyla ; Neffen, Hugo ; Nekam, Kristoff ; Neou, Angelo ; Nordlund, Björn ; Novellino, Ettore ; Nyembue, Dieudonné ; O'Hehir, Robyn ; Ohta, Ken ; Okubo, Kimi ; Onorato, Gabrielle L. ; Orlando, Valentina ; Ouedraogo, Solange ; Palamarchuk, Julia ; Pali‐Schöll, Isabella ; Panzner, Peter ; Park, Hae‐Sim ; Passalacqua, Gianni ; Pépin, Jean‐Louis ; Paulino, Ema ; Pawankar, Ruby ; Phillips, Jim ; Picard, Robert ; Pinnock, Hilary ; Plavec, Davor ; Popov, Todor A. ; Portejoie, Fabienne ; Price, David ; Prokopakis, Emmanuel P. ; Psarros, Fotis ; Pugin, Benoit ; Puggioni, Francesca ; Quinones‐Delgado, Pablo ; Raciborski, Filip ; Rajabian‐Söderlund, Rojin ; Regateiro, Frederico S. ; Reitsma, Sietze ; Rivero‐Yeverino, Daniela ; Roberts, Graham ; Roche, Nicolas ; Rodriguez‐Zagal, Erendira ; Rolland, Christine ; Roller‐Wirnsberger, Regina E. ; Rosario, Nelson ; Romano, Antonino ; Rottem, Menachem ; Ryan, Dermot ; Salimäki, Johanna ; Sanchez‐Borges, Mario M. ; Sastre, Joaquin ; Scadding, Glenis K. ; Scheire, Sophie ; Schmid‐Grendelmeier, Peter ; Schünemann, Holger J. ; Sarquis Serpa, Faradiba ; Shamji, Mohamed ; Sisul, Juan‐Carlos ; Sofiev, Mikhail ; Solé, Dirceu ; Somekh, David ; Sooronbaev, Talant ; Sova, Milan ; Spertini, François ; Spranger, Otto ; Stellato, Cristiana ; Stelmach, Rafael ; Thibaudon, Michel ; To, Teresa ; Toumi, Mondher ; Usmani, Omar ; Valero, Antonio A. ; Valenta, Rudolph ; Valentin‐Rostan, Marylin ; Pereira, Marilyn Urrutia ; van der Kleij, Rianne ; Van Eerd, Michiel ; Vandenplas, Olivier ; Vasankari, Tuula ; Vaz Carneiro, Antonio ; Vezzani, Giorgio ; Viart, Frédéric ; Viegi, Giovanni ; Wallace, Dana ; Wagenmann, Martin ; Wang, De Yun ; Waserman, Susan ; Wickman, Magnus ; Williams, Dennis M. ; Wong, Gary ; Wroczynski, Piotr ; Yiallouros, Panayiotis K. ; Yusuf, Osman M. ; Zar, Heather J. ; Zeng, Stéphane ; Zernotti, Mario E. ; Zhang, Luo ; Shan Zhong, Nan ; Zidarn, Mihaela
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
Haake, Markus ; Haack, Beatrice ; Schäfer, Tina ; Harter, Patrick N. ; Mattavelli, Greta ; Eiring, Patrick ; Vashist, Neha ; Wedekink, Florian ; Genssler, Sabrina ; Fischer, Birgitt ; Dahlhoff, Julia ; Mokhtari, Fatemeh ; Kuzkina, Anastasia ; Welters, Marij J. P. ; Benz, Tamara M. ; Sorger, Lena ; Thiemann, Vincent ; Almanzar, Giovanni ; Selle, Martina ; Thein, Klara ; Späth, Jacob ; Gonzalez, Maria Cecilia ; Reitinger, Carmen ; Ipsen-Escobedo, Andrea ; Wistuba-Hamprecht, Kilian ; Eichler, Kristin ; Filipski, Katharina ; Zeiner, Pia S. ; Beschorner, Rudi ; Goedemans, Renske ; Gogolla, Falk Hagen ; Hackl, Hubert ; Rooswinkel, Rogier W. ; Thiem, Alexander ; Romer Roche, Paula ; Joshi, Hemant ; Pühringer, Dirk ; Wöckel, Achim ; Diessner, Joachim E. ; Rüdiger, Manfred ; Leo, Eugen ; Cheng, Phil F. ; Levesque, Mitchell P. ; Goebeler, Matthias ; Sauer, Markus ; Nimmerjahn, Falk ; Schuberth-Wagner, Christine ; Felten, Stefanie von ; Mittelbronn, Michel ; Mehling, Matthias ; Beilhack, Andreas ; van der Burg, Sjoerd H. ; Riedel, Angela ; Weide, Benjamin ; Dummer, Reinhard ; Wischhusen, Jörg
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
Manchia, Mirko ; Adli, Mazda ; Akula, Nirmala ; Arda, Raffaella ; Aubry, Jean-Michel ; Backlund, Lena ; Banzato, Claudio E. M. ; Baune, Bernhard T. ; Bellivier, Frank ; Bengesser, Susanne ; Biernacka, Joanna M. ; Brichant-Petitjean, Clara ; Bui, Elise ; Calkin, Cynthia V. ; Cheng, Andrew Tai Ann ; Chillotti, Caterina ; Cichon, Sven ; Clark, Scott ; Czerski, Piotr M. ; Dantas, Clarissa ; Del Zompo, Maria ; DePaulo, J. Raymond ; Detera-Wadleigh, Sevilla D. ; Etain, Bruno ; Falkai, Peter ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Jan ; Gard, Sébastien ; Garnham, Julie ; Goes, Fernando S. ; Grof, Paul ; Gruber, Oliver ; Hashimoto, Ryota ; Hauser, Joanna ; Heilbronner, Urs ; Hoban, Rebecca ; Hou, Liping ; Jamain, Stéphane ; Kahn, Jean-Pierre ; Kassem, Layla ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Kuo, Po-Hsiu ; Kusumi, Ichiro ; Laje, Gonzalo ; Lavebratt, Catharina ; Leboyer, Marion ; Leckband, Susan G. ; López Jaramillo, Carlos A. ; Maj, Mario ; Malafosse, Alain ; Martinsson, Lina ; Masui, Takuya ; Mitchell, Philip B. ; Mondimore, Frank ; Monteleone, Palmiero ; Nallet, Audrey ; Neuner, Maria ; Novák, Tomás ; O'Donovan, Claire ; Ösby, Urban ; Ozaki, Norio ; Perlis, Roy H. ; Pfennig, Andrea ; Potash, James B. ; Reich-Erkelenz, Daniela ; Reif, Andreas ; Reininghaus, Eva ; Richardson, Sara ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schubert, Oliver K. ; Schweizer, Barbara ; Seemüller, Florian ; Grigoroiu-Serbanescu, Maria ; Severino, Giovanni ; Seymour, Lisa R. ; Slaney, Claire ; Smoller, Jordan W. ; Squassina, Alessio ; Stamm, Thomas ; Steele, Jo ; Stopkova, Pavla ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Wray, Naomi R. ; Wright, Adam ; Zandi, Peter P. ; Zilles, David ; Bauer, Michael ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas G. ; Alda, Martin
Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
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