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1. NMR metabolomics-guided DNA methylation mortality predictorsResearch in context

Author

Daniele Bizzarri, Marcel J.T. Reinders, Lieke Kuiper, Marian Beekman, Joris Deelen, Joyce B.J. van Meurs, Jenny van Dongen, René Pool, Dorret I. Boomsma, Mohsen Ghanbari, Lude Franke, Pieternella E. Slagboom, Erik B. van den Akker, J.M. Geleijnse, E. Boersma, W.E. van Spil, M.M.J. van Greevenbroek, C.D.A. Stehouwer, C.J.H. van der Kallen, I.C.W. Arts, F. Rutters, J.W.J. Beulens, M. Muilwijk, P.J.M. Elders, L.M. 't Hart, M. Ghanbari, M.A. Ikram, M.G. Netea, M. Kloppenburg, Y.F.M. Ramos, N. Bomer, I. Meulenbelt, K. Stronks, M.B. Snijder, A.H. Zwinderman, B.T. Heijmans, L.H. Lumey, C. Wijmenga, J. Fu, A. Zhernakova, J. Deelen, S.P. Mooijaart, M. Beekman, P.E. Slagboom, G.L.J. Onderwater, A.M.J.M. van den Maagdenberg, G.M. Terwindt, C. Thesing, M. Bot, B.W.J.H. Penninx, S. Trompet, J.W. Jukema, N. Sattar, I.C.C. van der Horst, P. van der Harst, C. So-Osman, J.A. van Hilten, R.G.H.H. Nelissen, I.E. Höfer, F.W. Asselbergs, P. Scheltens, C.E. Teunissen, W.M. van der Flier, J. van Dongen, R. Pool, A.H.M. Willemsen, D.I. Boomsma, H.E.D. Suchiman, J.J.H. Barkey Wolf, D. Cats, H. Mei, M. Slofstra, M. Swertz, M.J.T. Reinders, and E.B. van den Akker

Subjects
DNA methylation predictors, NMR metabolomics, Ageing biomarkers, Epigenetic clock, Metabolic risk score, Epidemiology, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

Published
2024
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2. Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

Author

Astrid Marchal, Elizabeth T. Cirulli, Iva Neveux, Evangelos Bellos, Ryan S. Thwaites, Kelly M. Schiabor Barrett, Yu Zhang, Ivana Nemes-Bokun, Mariya Kalinova, Andrew Catchpole, Stuart G. Tangye, András N. Spaan, Justin B. Lack, Jade Ghosn, Charles Burdet, Guy Gorochov, Florence Tubach, Pierre Hausfater, Clifton L. Dalgard, Shen-Ying Zhang, Qian Zhang, Christopher Chiu, Jacques Fellay, Joseph J. Grzymski, Vanessa Sancho-Shimizu, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, Alexandre Bolze, Alessandro Aiuti, Saleh Al-Muhsen, Fahd Al-Mulla, Ali Amara, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Lisa M. Arkin, Hagit Baris Feldman, Paul Bastard, Alexandre Belot, Catherine M. Biggs, Dusan Bogunovic, Anastasiia Bondarenko, Alessandro Borghesi, Ahmed A. Bousfiha, Petter Brodin, Yenan Bryceson, Manish J. Butte, Giorgio Casari, John Christodoulou, Roger Colobran, Antonio Condino-Neto, Stefan N. Constantinescu, Megan A. Cooper, Murkesh Desai, Beth A. Drolet, Xavier Duval, Jamila El Baghdadi, Philippine Eloy, Sara Espinosa-Padilla, Carlos Flores, José Luis Franco, Antoine Froidure, Peter K. Gregersen, Bodo Grimbacher, Filomeen Haerynck, David Hagin, Rabih Halwani, Lennart Hammarström, James R. Heath, Elena W.Y. Hsieh, Eystein Husebye, Kohsuke Imai, Yuval Itan, Emmanuelle Jouanguy, Elżbieta Kaja, Timokratis Karamitros, Kai Kisand, Cheng-Lung Ku, Yu-Lung Lau, Yun Ling, Carrie L. Lucas, Tom Maniatis, Davood Mansouri, László Maródi, France Mentré, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Trine H. Mogensen, Tomohiro Morio, Lisa F.P. Ng, Luigi D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona O'Farrelly, Satoshi Okada, Keisuke Okamoto, Tayfun Ozcelik, Qiang Pan-Hammarström, Jean W. Pape, Rebeca Perez de Diego, Jordi Perez-Tur, David S. Perlin, Graziano Pesole, Anna M. Planas, Carolina Prando, Aurora Pujol, Anne Puel, Lluis Quintana-Murci, Sathishkumar Ramaswamy, Laurent Renia, Igor Resnick, Carlos Rodríguez-Gallego, Anna Sediva, Mikko R.J. Seppänen, Mohammad Shahrooei, Anna Shcherbina, Ondrej Slaby, Andrew L. Snow, Pere Soler-Palacín, Vassili Soumelis, Ivan Tancevski, Ahmad Abou Tayoun, Şehime Gülsün Temel, Christian Thorball, Pierre Tiberghien, Sophie Trouillet-Assant, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed J. Uddin, Diederik van de Beek, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Pawel Zawadzki, Serge Bureau, Yannick Vacher, Anne Gysembergh-Houal, Lauren Demerville, Abla Benleulmi-Chaachoua, Sebastien Abad, Radhiya Abassi, Abdelrafie Abdellaoui, Abdelkrim Abdelmalek, Hendy Abdoul, Helene Abergel, Fariza Abeud, Sophie Abgrall, Noemie Abisror, Marylise Adechian, Nordine Aderdour, Hakeem Farid Admane, Frederic Adnet, Sara Afritt, Helene Agostini, Claire Aguilar, Sophie Agut, Tommaso Francesco Aiello, Marc Ait Kaci, Hafid Ait Oufella, Gokula Ajeenthiravasan, Virginie Alauzy, Fanny Alby-Laurent, Lucie Allard, Marie-Alexandra Alyanakian, Blanca Amador Borrero, Sabrina Amam, Lucile Amrouche, Marc Andronikof, Dany Anglicheau, Nadia Anguel, Djillali Annane, Mohammed Aounzou, Caroline Aparicio, Gladys Aratus, Jean-Benoit Arlet, Jeremy Arzoine, Elisabeth Aslangul, Mona Assefi, Adeline Aubry, Laetitia Audiffred, Etienne Audureau, Christelle Nathalie Auger, Jean-Charles Auregan, Celine Awotar, Sonia Ayllon Milla, Delphine Azan, Laurene Azemar, Billal Azzouguen, Marwa Bachir Elrufaai, Aïda Badsi, Prissile Bakouboula, Coline Balcerowiak, Fanta Balde, Elodie Baldivia, Eliane-Flore Bangamingo, Amandine Baptiste, Fanny Baran-Marszak, Caroline Barau, Nathalie Barget, Flore Baronnet, Romain Barthelemy, Jean-Luc Baudel, Camille Baudry, Elodie Baudry, Laurent Beaugerie, Adel Belamri, Nicolas Belaube, Rhida Belilita, Pierre Bellassen, Rawan Belmokhtar, Isabel Beltran, Ruben Benainous, Mourad Benallaoua, Robert Benamouzig, Amélie Benbara, Jaouad Benhida, Anis Benkhelouf, Jihene Benlagha, Chahinez Benmostafa, Skander Benothmane, Miassa Bentifraouine, Laurence Berard, Quentin Bernier, Enora Berti, Astrid Bertier, Laure Berton, Simon Bessis, Alexandra Beurton, Celine Bianco, Clara Bianquis, Frank Bidar, Philippe Blanche, Clarisse Blayau, Alexandre Bleibtreu, Emmanuelle Blin, Coralie Bloch-Queyrat, Marie-Christophe Boissier, Diane Bollens, Marion Bolzoni, Rudy pierre Bompard, Nicolas Bonnet, Justine Bonnouvrier, Shirmonecrystal Botha, Wissam Boucenna, Fatiha Bouchama, Olivier Bouchaud, Hanane Bouchghoul, Taoueslylia Boudjebla, Noel Boudjema, Catherine Bouffard, Adrien Bougle, Meriem Bouguerra, Leila Bouras, Agnes Bourcier, Anne Bourgarit Durand, Anne Bourrier, Fabrice Bouscarat, Diane Bouvry, Nesrine Bouziri, Ons Bouzrara, Sarah Bribier, Delphine Brugier, Melanie Brunel, Eida Bui, Anne Buisson, Iryna Bukreyeva, Côme Bureau, Jacques Cadranel, Johann Cailhol, Ruxandra Calin, Clara Campos Vega, Pauline Canavaggio, Marta Cancella, Delphine Cantin, Albert Cao, Lionel Carbillon, Nicolas Carlier, Clementine Cassard, Guylaine Castor, Marion Cauchy, Olivier Cha, Benjamin Chaigne, Salima Challal, Karine Champion, Patrick Chariot, Julie Chas, Simon Chauveau, Anthony Chauvin, Clement Chauvin, Nathalie Chavarot, Kamélia Chebbout, Mustapha Cherai, Ilaria Cherubini, Amelie Chevalier, Thibault Chiarabini, Thierry Chinet, Richard Chocron, Pascaline Choinier, Juliette Chommeloux, Christophe Choquet, Laure Choupeaux, Benjamin Chousterman, Dragosmarius Ciocan, Ada Clarke, Gaëlle Clavere, Florian Clavier, Karine Clement, Sebastien Clerc, Yves Cohen, Fleur Cohen, Adrien Cohen, Audrey Coilly, Hester Colboc, Pauline Colin, Magalie Collet, Chloé Comarmond, Emeline Combacon, Alain Combes, Celine Comparon, Jean-Michel Constantin, Hugues Cordel, Anne-Gael Cordier, Adrien Costantini, Nathalie Costedoat Chalumeau, Camille Couffignal, Doriane Coupeau, Alain Creange, Yannie Cuvillier Lamarre, Charlène Da Silveira, Sandrine Dautheville Guibal El Kayani, Nathalie De Castro, Yann De Rycke, Lucie Del Pozo, Quentin Delannoy, Mathieu Delay, Robin Deleris, Juliette Delforge, Laëtitia Delphine, Noemie Demare, Sophie Demeret, Alexandre Demoule, Aurore Deniau, François Depret, Sophie Derolez, Ouda Derradji, Nawal Derridj, Vincent Descamps, Lydia Deschamps, Celine Desconclois, Cyrielle Desnos, Karine Desongins, Robin Dhote, Benjamin Diallo, Morgane Didier, Myriam Diemer, Stephane Diez, Juliette Djadi-Prat, Fatima-Zohra Djamouri Monnory, Siham Djebara, Naoual Djebra, Minette Djietcheu, Hadjer Djillali, Nouara Djouadi, Severine Donneger, Catarina Dos Santos, Nathalie Dournon, Martin Dres, Laura Droctove, Marie Drogrey, Margot Dropy, Elodie Drouet, Valérie Dubosq, Evelyne Dubreucq, Estelle Dubus, Boris Duchemann, Thibault Duchenoy, Emmanuel Dudoignon, Romain Dufau, Florence Dumas, Clara Duran, Emmanuelle Duron, Antoine Durrbach, Claudine Duvivier, Nathan Ebstein, Jihane El Khalifa, Alexandre Elabbadi, Caroline Elie, Gabriel Ernotte, Anne Esling, Martin Etienne, Xavier Eyer, Muriel Sarah Fartoukh, Takoua Fayali, Marion Fermaut, Arianna Fiorentino, Souha Fliss, Marie-Céline Fournier, Benjamin Fournier, Hélène Francois, Olivia Freynet, Yvann Frigout, Isaure Fromont, Axelle Fuentes, Thomas Furet, Joris Galand, Marc Garnier, Agnes Gaubert, Stéphane Gaudry, Samuel Gaugain, Damien Gauthier, Maxime Gautier, Sophie Georgin-Lavialle, Daniela Geromin, Mohamed Ghalayini, Bijan Ghaleh, Myriam Ghezal, Aude Gibelin, Linda Gimeno, Benoit Girard, Bénédicte Giroux Leprieur, Doryan Gomes, Elisabete Gomes-Pires, Anne Gouge, Amel Gouja, Helene Goulet, Sylvain Goupil, Jeanne Goupil De Bouille, Julien Gras, Segolene Greffe, Lamiae Grimaldi, Paul Guedeney, Bertrand Guidet, Matthias Guillo, Mariechristelle Gulczynski, Tassadit Hadjam, Didier Haguenauer, Soumeya Hammal, Nadjib Hammoudi, Olivier Hanon, Anarole Harrois, Coraline Hautem, Guillaume Hekimian, Nicholas Heming, Olivier Hermine, Sylvie Ho, Marie Houllier, Benjamin Huot, Tessa Huscenot, Wafa Ibn Saied, Ghilas Ikherbane, Meriem Imarazene, Patrick Ingiliz, Lina Iratni, Stephane Jaureguiberry, Jean-Francois Jean-Marc, Deleena Jeyarajasingham, Pauline Jouany, Veronique Jouis, Clement Jourdaine, Ouifiya Kafif, Rim Kallala, Sandrine Katsahian, Lilit Kelesyan, Vixra Keo, Flora Ketz, Warda Khamis, Enfel Khelili, Mehdi Khellaf, Christy Gaëlla Kotokpo Youkou, Ilias Kounis, Gaelle Kpalma, Jessica Krause, Vincent Labbe, Karine Lacombe, Jean-Marc Lacorte, Anne Gaelle Lafont, Emmanuel Lafont, Lynda Lagha, Lionel Lamhaut, Aymeric Lancelot, Cecilia Landman, Fanny Lanternier, Cecile Larcheveque, Caroline Lascoux Combe, Ludovic Lassel, Benjamin Laverdant, Christophe Lavergne, Jean-Rémi Lavillegrand, Pompilia Lazureanu, Loïc Le Guennec, Lamia Leberre, Claire Leblanc, Marion Leboyer, Francois Lecomte, Marine Lecorre, Romain Leenhardt, Marylou Lefebvre, Bénédicte Lefebvre, Paul Legendre, Anne Leger, Laurence Legros, Justyna Legrosse, Sébastien Lehuunghia, Julien Lemarec, Jeremie Leporrier-Ext, Manon Lesein, Hubert Lesur, Vincent Levy, Albert Levy, Edwige Lopes, Amanda Lopes, Vanessa Lopez, Julien Lopinto, Olivier Lortholary, Badr Louadah, Bénédicte Loze, Marie-Laure Lucas, Axelle Lucasamichi, Liem Binh Luong, Arouna Magazimama-Ext, David Maingret, Lakhdar Mameri, Philippe Manivet, Cylia Mansouri, Estelle Marcault, Jonathan Marey, Nathalie Marin, Clémence Marois, Olivier Martin, Lou Martineau, Cannelle Martinez-Lopez, Pierre Martyniuck, Pauline Mary De Farcy, Nessrine Marzouk, Rafik Masmoudi, Alexandre Mebazaa, Frédéric Mechai, Fabio Mecozzi, Chamseddine Mediouni, Bruno Megarbane, Mohamed Meghadecha, Élodie Mejean, Arsene Mekinian, Nour Mekki Abdelhadi, Rania Mekni, Thinhinan Sabrina Meliti, Breno Melo Lima, Paris Meng, Soraya Merbah, Fadhila Messani, Yasmine Messaoudi, Baboo-Irwinsingh Mewasing, Lydia Meziane, Carole Michelot-Burger, Françoise Mignot, Fadi Hillary Minka, Makoto Miyara, Pierre Moine, Jean-Michel Molina, Anaïs Montegnies-Boulet, Alexandra Monti, Claire Montlahuc, Anne-Lise Montout, Alexandre Moores, Caroline Morbieu, Helene Mortelette, Stéphane Mouly, Rosita Muzaffar, Cherifa Iness Nacerddine, Marine Nadal, Hajer Nadif, Kladoum Nassarmadji, Pierre Natella, Sandrine Ndingamondze, Stefan Neraal, Caroline Nguyen, Bao N'Guyen, Isabelle Nion Larmurier, Luc Nlomenyengue, Nicolas Noel, Hilario Nunes, Edris Omar, Zineb Ouazene, Elise Ouedraogo, Wassila Ouelaa, Anissa Oukhedouma, Yasmina Ould Amara, Herve Oya, Johanna Oziel, Thomas Padilla, Elena Paillaud, Solenne Paiva, Beatrice Parfait, Perrine Parize, Christophe Parizot, Antoine Parrot, Arthur Pavot, Laetitia Peaudecerf, Frédéric Pene, Marion Pepin, Julie Pernet, Claire Pernin, Mylène Petit, Olivier Peyrony, Marie-Pierre Pietri, Olivia Pietri, Marc Pineton De Chambrun, Michelle Pinson, Claire Pintado, Valentine Piquard, Christine Pires, Benjamin Planquette, Sandrine Poirier, Anne-Laure Pomel, Stéphanie Pons, Diane Ponscarme, Annegaelle Pourcelot, Valérie Pourcher, Anne Pouvaret, Florian Prever, Miresta Previlon, Margot Prevost, Marie-Julie Provoost, Cyril Quemeneur, Cédric Rafat, Agathe Rami, Brigitte Ranque, Maurice Raphael, Jean Herle Raphalen, Anna Rastoin, Mathieu Raux, Amani Rebai, Michael Reby, Alexis Regent, Asma Regrag, Matthieu Resche-Rigon, Quentin Ressaire, Christian Richard, Mariecaroline Richard, Maxence Robert, Benjamin Rohaut, Camille Rolland-Debord, Jacques Ropers, Anne-Marie Roque-Afonso, Charlotte Rosso, Mélanie Rousseaux, Nabila Rousseaux, Swasti Roux, Lorène Roux, Claire Rouzaud, Antoine Rozes, Emma Rubenstein, Jean-Marc Sabate, Sheila Sabet, Sophie-Caroline Sacleux, Nathalie Saidenberg Kermanach, Faouzi Saliba, Dominique Salmon, Laurent Savale, Guillaume Savary, Rebecca Sberro, Anne Scemla, Frederic Schlemmer, Mathieu Schwartz, Saïd Sedfi, Samia Sefir-Kribel, Philippe Seksik, Pierre Sellier, Agathe Selves, Nicole Sembach, Luca Semerano, Marie-Victoire Senat, Damien Sene, Alexandra Serris, Lucile Sese, Naima Sghiouar, Johanna Sigaux, Martin Siguier, Johanne Silvain, Noémie Simon, Tabassome Simon, Lina Innes Skandri, Miassa Slimani, Aurélie Snauwaert, Harry Sokol, Heithem Soliman, Nisrine Soltani, Benjamin Soyer, Gabriel Steg, Lydia Suarez, Tali-Anne Szwebel, Kossi Taffame, Yacine Tandjaoui-Lambiotte, Claire Tantet, Mariagrazia Tateo, Igor Theodose, Pierre clement Thiebaud, Caroline Thomas, Kelly Tiercelet, Julie Tisserand, Carole Tomczak, Krystel Torelino, Fatima Touam-Ext, Lilia Toumi, Gustave Toury, Mireille Toy-Miou, Olivia Tran Dinh Thanh Lien, Alexy Trandinh, Jean-Marc Treluyer, Baptiste Trinque, Jennifer Truchot, Sarah Tubiana, Simone Tunesi, Matthieu Turpin, Agathe Turpin, Tomas Urbina, Rafael Usubillaga Narvaez, Yurdagul Uzunhan, Prabakar Vaittinadaayar, Arnaud Valent, Maelle Valentian, Nadia Valin, Hélène Vallet, Marina Vaz, Miguel-Alejandro Vazquezibarra, Benoit Vedie, Laetitia Velly, Celine Verstuyft, Cedric Viallette, Eric Vicaut, Dorothee Vignes, Damien Vimpere, Myriam Virlouvet, Guillaume Voiriot, Lena Voisot, Emmanuel Weiss, Nicolas Weiss, Anaïs Winchenne, Youri Yordanov, Lara Zafrani, Mohamad Zaidan, Wissem Zaidi, Cathia Zak, Aida Zarhrate-Ghoul, Ouassila Zatout, Suzanne Zeino, Michel Zeitouni, Naïma Zemirli, Lorene Zerah, Ounsa Zia, Marianne Ziol, Oceane Zolario, Julien Zuber, Claire Andrejak, François Angoulvant, Delphine Bachelet, Marie Bartoli, Romain Basmaci, Sylvie Behillil, Marine Beluze, Dehbia Benkerrou, Krishna Bhavsar, Lila Bouadma, Sabelline Bouchez, Maude Bouscambert, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chirouze, Alexandra Coelho, Sandrine Couffin-Cadiergues, Eric d’Ortenzio, Marie-Pierre Debray, Laurene Deconinck, Dominique Deplanque, Diane Descamps, Mathilde Desvallée, Alpha Diallo, Alphonsine Diouf, Céline Dorival, François Dubos, Brigitte Elharrar, Vincent Enouf, Hélène Esperou, Marina Esposito-Farese, Manuel Etienne, Eglantine Ferrand Devouge, Nathalie Gault, Alexandre Gaymard, Tristan Gigante, Morgane Gilg, Jérémie Guedj, Alexandre Hoctin, Isabelle Hoffmann, Ikram Houas, Jean-Sébastien Hulot, Salma Jaafoura, Florentia Kaguelidou, Sabrina Kali, Antoine Khalil, Coralie Khan, Cédric Laouénan, Samira Laribi, Minh Le, Quentin Le Hingrat, Soizic Le Mestre, Hervé Le Nagard, François-Xavier Lescure, Sophie Letrou, Yves Levy, Bruno Lina, Guillaume Lingas, Jean-Christophe Lucet, Denis Malvy, Marina Mambert, Amina Meziane, Hugo Mouquet, Jimmy Mullaert, Nadège Neant, Duc Nguyen, Marion Noret, Saad Nseir, Aurélie Papadopoulos, Christelle Paul, Nathan Peiffer-Smadja, Thomas Perpoint, Ventzislava Petrov-Sanchez, Gilles Peytavin, Huong Pham, Olivier Picone, Oriane Puéchal, Christian Rabaud, Manuel Rosa-Calatrava, Bénédicte Rossignol, Patrick Rossignol, Carine Roy, Marion Schneider, Richa Su, Coralie Tardivon, Marie-Capucine Tellier, François Téoulé, Olivier Terrier, Jean-François Timsit, Christelle Tual, Sylvie Van Der Werf, Noémie Vanel, Aurélie Veislinger, Benoit Visseaux, Aurélie Wiedemann, Yazdan Yazdanpanah, Loubna Alavoine, Charlotte Charpentier, Aline Dechanet, Jean-Luc Ecobichon, Wahiba Frezouls, Nadhira Houhou, Jonathan Lehacaut, Pauline Manchon, Mariama Nouroudine, Caroline Quintin, Michael Thy, Sylvie van der Werf, Valérie Vignali, Abir Chahine, Nawal Waucquier, Maria-Claire Migaud, Félix Djossou, Mayka Mergeay-Fabre, Aude Lucarelli, Magalie Demar, Léa Bruneau, Patrick Gérardin, Adrien Maillot, Christine Payet, Bruno Laviolle, Fabrice Laine, Christophe Paris, Mireille Desille-Dugast, Julie Fouchard, Thierry Pistone, Pauline Perreau, Valérie Gissot, Carole L.E. Goas, Samatha Montagne, Lucie Richard, Kévin Bouiller, Maxime Desmarets, Alexandre Meunier, Marilou Bourgeon, Benjamin Lefévre, Hélène Jeulin, Karine Legrand, Sandra Lomazzi, Bernard Tardy, Amandine Gagneux-Brunon, Frédérique Bertholon, Elisabeth Botelho-Nevers, Christelle Kouakam, Leturque Nicolas, Layidé Roufai, Karine Amat, Hélène Espérou, Samia Hendou, Giuseppe Foti, Giuseppe Citerio, Ernesto Contro, Alberto Pesci, Maria Grazia Valsecchi, Marina Cazzaniga, Giacomo Bellani, Jorge Abad, Giulia Accordino, Micol Angelini, Sergio Aguilera-Albesa, Aina Aguiló-Cucurull, Esra Akyüz Özkan, Ilad Alavi Darazam, Jonathan Antonio Roblero Albisures, Juan C. Aldave, Miquel Alfonso Ramos, Taj Ali Khan, Anna Aliberti, Seyed Alireza Nadji, Gulsum Alkan, Suzan A. AlKhater, Jerome Allardet-Servent, Luis M. Allende, Rebeca Alonso-Arias, Mohammed S. Alshahrani, Laia Alsina, Zahir Amoura, Arnau Antolí, Romain Arrestier, Mélodie Aubart, Teresa Auguet, Iryna Avramenko, Gökhan Aytekin, Axelle Azot, Seiamak Bahram, Fanny Bajolle, Fausto Baldanti, Aurélie Baldolli, Maite Ballester, Benoit Barrou, Federica Barzaghi, Sabrina Basso, Gulsum Iclal Bayhan, Liliana Bezrodnik, Agurtzane Bilbao, Geraldine Blanchard-Rohner, Ignacio Blanco, Adeline Blandinières, Daniel Blázquez-Gamero, Marketa Bloomfield, Mireia Bolivar-Prados, Raphael Borie, Elisabeth Botdhlo-Nevers, Aurore Bousquet, David Boutolleau, Claire Bouvattier, Oksana Boyarchuk, Juliette Bravais, M. Luisa Briones, Marie-Eve Brunner, Raffaele Bruno, Maria Rita P. Bueno, Huda Bukhari, Jacinta Bustamante, Juan José Cáceres Agra, Ruggero Capra, Raphael Carapito, Maria Carrabba, Carlos Casasnovas, Marion Caseris, Irene Cassaniti, Martin Castelle, Francesco Castelli, Martín Castillo de Vera, Mateus V. Castro, Emilie Catherinot, Jale Bengi Celik, Alessandro Ceschi, Martin Chalumeau, Bruno Charbit, Cécile Boulanger, Père Clavé, Bonaventura Clotet, Anna Codina, Cloé Comarmond, Patrizia Comoli, Angelo G. Corsico, Taner Coşkuner, Aleksandar Cvetkovski, Cyril Cyrus, David Dalmau, François Danion, David Ross Darley, Vincent Das, Nicolas Dauby, Stéphane Dauger, Paul De Munte, Loic de Pontual, Amin Dehban, Geoffroy Delplancq, Isabelle Desguerre, Antonio Di Sabatino, Jean-Luc Diehl, Stephanie Dobbelaere, Elena Domínguez-Garrido, Clément Dubost, Olov Ekwall, Şefika Elmas Bozdemir, Marwa H. Elnagdy, Melike Emiroglu, Akifumi Endo, Emine Hafize Erdeniz, Selma Erol Aytekin, Maria Pilar Etxart Lasa, Romain Euvrard, Giovanna Fabio, Laurence Faivre, Antonin Falck, Muriel Fartoukh, Morgane Faure, Miguel Fernandez Arquero, Ricard Ferrer, Jose Ferreres, Bruno Francois, Victoria Fumadó, Kitty S.C. Fung, Francesca Fusco, Alenka Gagro, Blanca Garcia Solis, Pierre Garçon, Pascale Gaussem, Zeynep Gayretli, Juana Gil-Herrera, Laurent Gilardin, Audrey Giraud Gatineau, Mònica Girona-Alarcón, Karen Alejandra Cifuentes Godínez, Jean-Christophe Goffard, Nacho Gonzales, Luis I. Gonzalez-Granado, Rafaela González-Montelongo, Antoine Guerder, Belgin Gülhan, Victor Daniel Gumucio, Leif Gunnar Hanitsch, Jan Gunst, Marta Gut, Jérôme Hadjadj, Selda Hancerli, Tetyana Hariyan, Nevin Hatipoglu, Deniz Heppekcan, Elisa Hernandez-Brito, Po-ki Ho, María Soledad Holanda-Peña, Juan P. Horcajada, Sami Hraiech, Linda Humbert, Ivan F.N. Hung, Alejandro D. Iglesias, Antonio Íñigo-Campos, Matthieu Jamme, María Jesús Arranz, Marie-Thérèse Jimeno, Iolanda Jordan, Saliha Kanık-Yüksek, Yalcin Kara, Aydın Karahan, Adem Karbuz, Kadriye Kart Yasar, Ozgur Kasapcopur, Kenichi Kashimada, Sevgi Keles, Yasemin Kendir Demirkol, Yasutoshi Kido, Can Kizil, Ahmet Osman Kılıç, Adam Klocperk, Antonia Koutsoukou, Zbigniew J. Król, Hatem Ksouri, Paul Kuentz, Arthur M.C. Kwan, Yat Wah M. Kwan, Janette S.Y. Kwok, Jean-Christophe Lagier, David S.Y. Lam, Vicky Lampropoulou, Fleur Le Bourgeois, Yee-Sin Leo, Rafael Leon Lopez, Daniel Leung, Michael Levin, Michael Levy, Romain Lévy, Zhi Li, Daniele Lilleri, Edson Jose Adrian Bolanos Lima, Agnes Linglart, Eduardo López-Collazo, José M. Lorenzo-Salazar, Céline Louapre, Catherine Lubetzki, Kwok-Cheung Lung, Charles-Edouard Luyt, David C. Lye, Cinthia Magnone, Enrico Marchioni, Carola Marioli, Majid Marjani, Laura Marques, Jesus Marquez Pereira, Andrea Martín-Nalda, David Martínez Pueyo, Javier Martinez-Picado, Iciar Marzana, Carmen Mata-Martínez, Alexis Mathian, Larissa R.B. Matos, Gail V. Matthews, Julien Mayaux, Raquel McLaughlin-Garcia, Philippe Meersseman, Jean-Louis Mège, Armand Mekontso-Dessap, Isabelle Melki, Federica Meloni, Jean-François Meritet, Paolo Merlani, Özge Metin Akcan, Mehdi Mezidi, Isabelle Migeotte, Maude Millereux, Matthieu Million, Tristan Mirault, Clotilde Mircher, Mehdi Mirsaeidi, Yoko Mizoguchi, Bhavi P. Modi, Francesco Mojoli, Elsa Moncomble, Abián Montesdeoca Melián, Antonio Morales Martinez, Francisco Morandeira, Pierre-Emmanuel Morange, Clémence Mordacq, Guillaume Morelle, Stéphane J. Mouly, Adrián Muñoz-Barrera, Cyril Nafati, Shintaro Nagashima, Yu Nakagama, Bénédicte Neven, João Farela Neves, Yuk-Yung Ng, Hubert Nielly, Yeray Novoa Medina, Esmeralda Nuñez Cuadros, Semsi Nur Karabela, J. Gonzalo Ocejo-Vinyals, Mehdi Oualha, Amani Ouedrani, Tayfun Özçelik, Aslinur Ozkaya-Parlakay, Michele Pagani, Maria Papadaki, Philippe Parola, Tiffany Pascreau, Stéphane Paul, Estela Paz-Artal, Sigifredo Pedraza, Nancy Carolina González Pellecer, Silvia Pellegrini, Rebeca Pérez de Diego, Xosé Luis Pérez-Fernández, Aurélien Philippe, Quentin Philippot, Adrien Picod, Marc Pineton de Chambrun, Antonio Piralla, Laura Planas-Serra, Dominique Ploin, Julien Poissy, Géraldine Poncelet, Garyphallia Poulakou, Marie S. Pouletty, Persia Pourshahnazari, Jia Li Qiu-Chen, Paul Quentric, Thomas Rambaud, Didier Raoult, Violette Raoult, Anne-Sophie Rebillat, Claire Redin, Léa Resmini, Pilar Ricart, Jean-Christophe Richard, Raúl Rigo-Bonnin, Nadia Rivet, Jacques G. Rivière, Gemma Rocamora-Blanch, Mathieu P. Rodero, Carlos Rodrigo, Luis Antonio Rodriguez, Carlos Rodriguez-Gallego, Agustí Rodriguez-Palmero, Carolina Soledad Romero, Anya Rothenbuhler, Damien Roux, Nikoletta Rovina, Flore Rozenberg, Yvon Ruch, Montse Ruiz, Maria Yolanda Ruiz del Prado, Juan Carlos Ruiz-Rodriguez, Joan Sabater-Riera, Kai Saks, Maria Salagianni, Oliver Sanchez, Adrián Sánchez-Montalvá, Silvia Sánchez-Ramón, Laire Schidlowski, Agatha Schluter, Julien Schmidt, Matthieu Schmidt, Catharina Schuetz, Cyril E. Schweitzer, Francesco Scolari, Luis Seijo, Analia Gisela Seminario, Piseth Seng, Sevtap Senoglu, Mikko Seppänen, Alex Serra Llovich, Virginie Siguret, Eleni Siouti, David M. Smadja, Nikaia Smith, Ali Sobh, Xavier Solanich, Jordi Solé-Violán, Catherine Soler, Betül Sözeri, Giulia Maria Stella, Yuriy Stepanovskiy, Annabelle Stoclin, Fabio Taccone, Jean-Luc Taupin, Simon J. Tavernier, Loreto Vidaur Tello, Benjamin Terrier, Guillaume Thiery, Karolina Thorn, Caroline Thumerelle, Imran Tipu, Martin Tolstrup, Gabriele Tomasoni, Julie Toubiana, Josep Trenado Alvarez, Vasiliki Triantafyllia, Jesús Troya, Owen T.Y. Tsang, Liina Tserel, Eugene Y.K. Tso, Alessandra Tucci, Şadiye Kübra Tüter Öz, Matilde Valeria Ursini, Takanori Utsumi, Pierre Vabres, Juan Valencia-Ramos, Ana Maria Van Den Rym, Isabelle Vandernoot, Valentina Velez-Santamaria, Silvia Patricia Zuniga Veliz, Mateus C. Vidigal, Sébastien Viel, Cédric Villain, Marie E. Vilaire-Meunier, Judit Villar-García, Audrey Vincent, Dimitri Van der Linden, Alla Volokha, Fanny Vuotto, Els Wauters, Alan K.L. Wu, Tak-Chiu Wu, Aysun Yahşi, Osman Yesilbas, Mehmet Yildiz, Barnaby E. Young, Ufuk Yükselmiş, Marco Zecca, Valentina Zuccaro, Jens Van Praet, Bart N. Lambrecht, Eva Van Braeckel, Cédric Bosteels, Levi Hoste, Eric Hoste, Fré Bauters, Jozefien De Clercq, Catherine Heijmans, Hans Slabbynck, Leslie Naesens, Benoit Florkin, Mary-Anne Young, Amanda Willis, Paloma Lapuente-Suanzes, Ana de Andrés-Martín, Matilda Berkell, Valerio Carelli, Alessia Fiorentino, Surbhi Malhotra, Alessandro Mattiaccio, Tommaso Pippucci, Marco Seri, Evelina Tacconelli, Michiel van Agtmael, Anne Geke Algera, Brent Appelman, Frank van Baarle, Diane Bax, Martijn Beudel, Harm Jan Bogaard, Marije Bomers, Peter Bonta, Lieuwe Bos, Michela Botta, Justin de Brabander, Godelieve de Bree, Sanne de Bruin, David T.P. Buis, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Mirjam Dijkstra, Dave A. Dongelmans, Romein W.G. Dujardin, Paul Elbers, Lucas Fleuren, Suzanne Geerlings, Theo Geijtenbeek, Armand Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura Hagens, Jorg Hamann, Vanessa Harris, Robert Hemke, Sabine M. Hermans, Leo Heunks, Markus Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H.T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Frederique Paulus, Edgar Peters, Dan A.I. Pina-Fuentes, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Reijnders, Maurits C.F. J. de Rotte, Michiel Schinkel, Marcus J. Schultz, Femke A.P. Schrauwen, Alex Schuurmans, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry Smit, Cornelis S. Stijnis, Willemke Stilma, Charlotte Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Carolien Volleman, Heder de Vries, Lonneke A. Vught, Michèle van Vugt, Dorien Wouters, A.H. Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P.J. Vlaar, Miranda F. Tompkins, Camille Alba, Daniel N. Hupalo, John Rosenberger, Gauthaman Sukumar, Matthew D. Wilkerson, Xijun Zhang, Justin Lack, Andrew J. Oler, Kerry Dobbs, Ottavia M. Delmonte, Jeffrey J. Danielson, Andrea Biondi, Laura Rachele Bettini, Mariella D’Angiò, Ilaria Beretta, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Eugenia Quiros-Roldan, Camillo Rossi, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, and Gian Luigi Marseglia

Subjects
HLA, association, asymptomatic infection, COVID-19, population stratification, Genetics, QH426-470
Abstract

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Published
2024
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3. Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infectionResearch in context

Author

Lihui Guo, Brent Appelman, Kirsten Mooij-Kalverda, Riekelt H. Houtkooper, Michel van Weeghel, Frédéric M. Vaz, Annemiek Dijkhuis, Tamara Dekker, Barbara S. Smids, Jan Willem Duitman, Marianna Bugiani, Paul Brinkman, Jonne J. Sikkens, H.A. Ayesha Lavell, Rob C.I. Wüst, Michèle van Vugt, René Lutter, M.A. van Agtmael, A.G. Algera, B. Appelman, F.E.H.P. van Baarle, M. Beudel, H.J. Bogaard, M. Bomers, P.I. Bonta, L.D.J. Bos, M. Botta, J. de Brabander, G.J. de Bree, S. de Bruin, M. Bugiani, E.B. Bulle, O. Chouchane, A.P.M. Cloherty, D. Buis, M.C.F.J. de Rotte, M. Dijkstra, D.A. Dongelmans, R.W.G. Dujardin, P.E. Elbers, L.M. Fleuren, S.E. Geerlings, T.B.H. Geijtenbeek, A.R.J. Girbes, A. Goorhuis, M.P. Grobusch, L.A. Hagens, J. Hamann, V.C. Harris, R. Hemke, S.M. Hermans, L.M.A. Heunks, M.W. Hollmann, J. Horn, J.W. Hovius, M.D. de Jong, R. Koing, E.H.T. Lim, N. van Mourik, J.F. Nellen, E.J. Nossent, F. Paulus, E. Peters, D. Piña-Fuentes, T. van der Poll, B. Preckel, J.M. Prins, S.J. Raasveld, T.D.Y. Reijnders, M. Schinkel, F.A.P. Schrauwen, M.J. Schultz, A.R. Schuurman, J. Schuurmans, K. Sigaloff, M.A. Slim, P. Smeele, M.R. Smit, C. Stijnis, W. Stilma, C.E. Teunissen, P. Thoral, A.M. Tsonas, P.R. Tuinman, M. van der Valk, D.P. Veelo, C. Volleman, H. de Vries, L.A. van Vught, M. van Vugt, D. Wouters, A.H. Zwinderman, M.C. Brouwer, W.J. Wiersinga, A.P.J. Vlaar, and D. van de Beek

Subjects
IDO2, PASC, Autophagy, Apoptosis, Kynurenine, Mitochondrial_activity, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology. Methods: Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients. Findings: IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist. Interpretation: SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology. Funding: None.

Published
2023
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4. Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome

Author

Robert F. J. Kullberg, Justin de Brabander, Leonoor S. Boers, Jason J. Biemond, Esther J. Nossent, Leo M. A. Heunks, Alexander P. J. Vlaar, Peter I. Bonta, Tom van der Poll, JanWillem Duitman, Lieuwe D. J. Bos, W. Joost Wiersinga, Anno Saris, Heder De Vries, Lilian J. Meijboom, Siebe G. Blok, Alex R. Schuurman, Tom D.Y. Reijnders, Juan J. Garcia Vallejo, Hetty Bontkes, René Lutter, Harm Jan Bogaard, S. de Bruin, R. Koning, M.A. van Agtmael, A.G. Algera, F.E.H.P. van Baarle, D.J.C. Bax, M. Beudel, M. Bomers, M. Botta, G.J. de Bree, M. Bugiani, E.B. Bulle, O. Chouchane, A.P.M. Cloherty, P.E. Elbers, L.M. Fleuren, S.E. Geerlings, B.F. Geerts, T.B.H. Geijtenbeek, A.R.J. Girbes, A. Goorhuis, M.P. Grobusch, F.M.J. Hafkamp, L.A. Hagens, J. Hamann, V.C. Harris, R. Hemke, S.M. Hermans, M.W. Hollmann, J. Horn, J.W. Hovius, M.D. de Jong, N. van Mourik, J.F Nellen, F. Paulus, E. Peters, B. Preckel, S.J. Raasveld, M. Schinkel, M.J. Schultz, K. Sigaloff, M.R. Smit, C. Stijnis, W. Stilma, C.E. Teunissen, P. Thoral, A.M. Tsonas, M. van der Valk, D.P. Veelo, M. van Vugt, D. Wouters, A.H. Zwinderman, M.C. Brouwer, D. van de Beek, Internal medicine, Pulmonary medicine, CCA - Cancer Treatment and quality of life, VU University medical center, ACS - Heart failure & arrhythmias, ACS - Pulmonary hypertension & thrombosis, Center of Experimental and Molecular Medicine, Graduate School, Intensive Care Medicine, ACS - Microcirculation, AII - Inflammatory diseases, Pulmonology, Infectious diseases, and 01 Internal and external specialisms

Subjects
Pulmonary and Respiratory Medicine, Respiratory Distress Syndrome, Tumor Necrosis Factor-alpha, Critical Illness, Microbiota, host–microbial interactions, COVID-19, Critical Care and Intensive Care Medicine, Respiration, Artificial, RNA, Ribosomal, 16S, Humans, artificial respiration, lung microbiome, Lung
Abstract

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

Published
2022
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5. Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study

Author

Tessa M Kole, Elise Vanden Berghe, Monica Kraft, Judith M Vonk, Martijn C Nawijn, Salman Siddiqui, Kai Sun, Leonardo M Fabbri, Klaus F Rabe, Kian Fan Chung, Gabriele Nicolini, Alberto Papi, Chris Brightling, Dave Singh, Thys van der Molen, Sven-Erik Dahlén, Alvar Agusti, Rosa Faner, Jadwiga A Wedzicha, Gavin C Donaldson, Ian M Adcock, Lies Lahousse, Huib A M Kerstjens, Maarten van den Berge, P. Badorrek, M. Broeders, W.G. Boersma, A. Chetta, A. Cukier, M. D'Amato, R. Djukanovic, M.P. Foschino, C. Gessner, N. Hanania, R. Martin, S. Milleri, R. Olivenstein, P. Paggiaro, E. Pizzichini, V. Plaza Moral, D.S. Postma, N. Scichilone, R. Schilz, A. Spanevello, R. Stelmach, J.S. Vroegop, O.S. Usmani, Q. Zhang, H. Ahmed, D. Allen, S. Ballereau, M.K. Batuwitage, A. Bedding, A.F. Behndig, A. Berglind, A. Berton, J. Bigler, M.J. Boedigheimer, K. Bønnelykke, P. Brinkman, A. Bush, D. Campagna, C. Casaulta, A. Chaiboonchoe, T. Davison, B. De Meulder, I. Delin, P. Dennison, P. Dodson, L. El Hadjam, D. Erzen, C. Faulenbach, K. Fichtner, N. Fitch, E. Formaggio, M. Gahlemann, G. Galffy, D. Garissi, T. Garret, E. Guillmant-Farry, E. Henriksson, U. Hoda, J.M. Hohlfeld, X. Hu, A. James, K. Johnson, N. Jullian, G. Kerry, M. Klüglich, R. Knowles, J.R. Konradsen, K. Kretsos, L. Krueger, A-S. Lantz, C. Larminie, P. Latzin, D. Lefaudeux, N. Lemonnier, L.A. Lowe, R. Lutter, A. Manta, A. Mazein, L. McEvoy, A. Menzies-Gow, N. Mores, C.S. Murray, K. Nething, U. Nihlén, R. Niven, B. Nordlund, S. Nsubuga, J. Pellet, C. Pison, G. Praticò, M. Puig Valls, K. Riemann, J.P. Rocha, C. Rossios, G. Santini, M. Sagi, S. Scott, N. Sehgal, A. Selby, P. Söderman, A. Sogbesan, F. Spycher, S. Stephan, J. Stokholm, M. Sunther, M. Szentkereszty, L. Tamasi, K. Tariq, S Valente, W.M. Van Aalderen, C.M. Van Drunen, J. Van Eyll, A. Vyas, W. Yu, W. Zetterguist, Z. Zolkipli, A.H. Zwinderman, A. Agusti, J.A. Wedzicha, G.C. Donaldson, R. Faner, R. Breyer-Kohansal, A.H. Maitland-van der Zee, E. Melén, J.P. Allinson, L.E.G.W. Vanfleteren, J. Vestbo, I.M. Adcock, L. Lahousse, M. Van den Berge, P. Alter, F. Barbe, C.E. Brightling, M.K. Breyer, O.C. Burghuber, M. Casas, K.F. Chung, B.G. Cosío, F. Crispi, J. De Batlle, J.W. Fitting, J. Garcia, J. Hallberg, S. Hartl, D. Jarvis, A. Mathioudakis, L. Nicod, A. Papi, A. Ritchie, T. Sigsgaard, P.J. Sterk, A. Ullman, K. Vellvé, C. Vogelmeier, A.M. Wheelock, C.E. Wheelock, Pulmonology, AII - Infectious diseases, AII - Inflammatory diseases, Paediatric Pulmonology, Ear, Nose and Throat, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Pulmonary and Respiratory Medicine, SMALL AIRWAYS DYSFUNCTION, Medicine and Health Sciences, RISK-FACTORS, OBSTRUCTION
Abstract

BACKGROUND: Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study.METHODS: In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort.FINDINGS: Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43 years in non-PAL group), longer duration of asthma (24 years vs 12 years), male sex (51% vs 38%), higher blood eosinophil counts (median 0·27 × 109 cells per L vs 0·20 × 109 cells per L), more small airway dysfunction, and more exacerbations during 1 year of follow-up. Associations between PAL, age, and eosinophilic inflammation were validated in the U-BIOPRED cohort, whereas associations with sex, duration of asthma, and risk of exacerbations were not validated.INTERPRETATION: PAL is not only present in severe disease, but also in a considerable proportion of patients with milder disease. In patients with mild asthma, PAL is associated with eosinophilic inflammation and a higher risk of exacerbations. Our findings are important because they suggest that increasing treatment intensity should be considered in patients with milder asthma and PAL.FUNDING: Chiesi Farmaceutici and Dutch Ministry of Economic Affairs and Climate Policy (by means of the public-private partnership programme).

Published
2022

6. Treatment and Coronary Artery Aneurysm Formation in Kawasaki Disease: A Per-Day Risk Analysis

Author

Diana van Stijn, Justin M. Korbee, Stejara A. Netea, Vera C. de Winter, Koos A.H. Zwinderman, Irene M. Kuipers, Taco W. Kuijpers, Graduate School, General Paediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, 04 Woman - Child, AII - Inflammatory diseases, Epidemiology and Data Science, APH - Methodology, Paediatric Cardiology, APH - Quality of Care, and ARD - Amsterdam Reproduction and Development

Subjects
Pediatrics, Perinatology and Child Health, mental disorders, Coronary Aneurysm, nutritional and metabolic diseases, Humans, Immunoglobulins, Intravenous, Infant, cardiovascular diseases, Coronary Artery Disease, Mucocutaneous Lymph Node Syndrome, Coronary Vessels, Risk Assessment, Retrospective Studies
Abstract

Objective: To assess whether ‘treatment day’ is a significant predicting factor in Kawasaki disease and imposes a risk for coronary artery aneurysms (CAAs) in a per-day analysis. CAA formation can be reduced from 25% to 10% when treated with intravenous immunoglobulin (IVIG). Study design: Patient data from (n = 1016) a single center were collected for an observational cohort study. After exclusions, we retrospectively analyzed 776 patients in total. A multivariate analysis was performed with treatment day as a continuous variable (n = 691). Patients were categorized as no enlargement, small CAA, medium CAA, and giant CAA. Results: Late treatment per-day was a significant predicting factor for the development of larger CAAs. ORs for medium and giant CAAs per delayed day were 1.1 (95% CI 1.1-1.2) P < .05 and 1.2 (95% CI 1.1-1.2) P < .05, respectively. Conclusion: We showed that every day of delay in treatment of patients with Kawasaki disease inherently carries a risk of medium and giant aneurysm formation. There was no cut-off point for treatment day that could mark a safe zone.

Published
2021

8. Associations between gut microbiome, short chain fatty acids and blood pressure across ethnic groups: the HELIUS study

Author

B Verhaar, D Collard, A Prodan, J.H.M Levels, A.H Zwinderman, M.B Snijder, L Vogt, M.J.L Peters, M Muller, M Nieuwdorp, and B.J.H Van Den Born

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background Gut microbiome composition is shaped by a combination of host genetic make-up and dietary habits. In addition, large ethnic differences exist in microbiome composition. Several studies in humans and animals have shown that differences in gut microbiota and its metabolites, including short chain fatty acids (SCFA), are associated with blood pressure (BP). We hypothesized that gut microbiome composition and its metabolites may be differently associated with BP across ethnic groups. Purpose To investigate associations of gut microbiome composition and fecal SCFA levels with BP across different ethnic groups. Methods We assessed the association between gut microbiome composition and office BP among 4672 subjects (mean age 49.8±11.7 years, 52%F) of 6 different ethnic groups participating in the HELIUS study. Gut microbiome composition was determined using 16S rRNA sequencing. Associations between microbiome composition and blood pressure were assessed using machine learning prediction models. The resulting best predictors were correlated with BP using Spearman's rank correlations. Fecal SCFA levels were measured with high-performance liquid chromatography in an age- and body mass index (BMI)-matched subgroup of 200 participants with either extreme low or high systolic BP. Differences in abundances of best predictors and fecal SCFA levels between high and low BP groups were assessed with Mann-Whitney U tests. Results Gut microbiome composition explained 4.4% of systolic BP variance. Best predictors for systolic BP included Roseburia spp. (ρ −0.15, p Conclusions In this cross-sectional study, gut microbiome composition was moderately associated with BP. Associations were strongly divergent between ethnic groups, with strongest associations in Dutch participants. Intriguingly, while Dutch participants with high BP had lower abundances of several SCFA-producing microbes, they had higher fecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Academic Medical Center (AMC) of Amsterdam and the Public Health Service of Amsterdam (GGD Amsterdam) provided core financial support for HELIUS. The HELIUS study is also funded by research grants of the Dutch Heart Foundation (Hartstichting; grant no. 2010T084), the Netherlands Organization for Health Research and Development (ZonMw; grant no. 200500003), the European Integration Fund (EIF; grant no. 2013EIF013) and the European Union (Seventh Framework Programme, FP-7; grant no. 278901).

Published
2020
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9. Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

Author

Mariska Bot, Yuri Milaneschi, Tahani Al-Shehri, Najaf Amin, Sanzhima Garmaeva, Gerrit L.J. Onderwater, Rene Pool, Carisha S. Thesing, Lisanne S. Vijfhuizen, Nicole Vogelzangs, Ilja C.W. Arts, Ayse Demirkan, Cornelia van Duijn, Marleen van Greevenbroek, Carla J.H. van der Kallen, Sebastian Köhler, Lannie Ligthart, Arn M.J.M. van den Maagdenberg, Dennis O. Mook-Kanamori, Renée de Mutsert, Henning Tiemeier, Miranda T. Schram, Coen D.A. Stehouwer, Gisela M. Terwindt, Ko Willems van Dijk, Jingyuan Fu, Alexandra Zhernakova, Marian Beekman, P. Eline Slagboom, Dorret I. Boomsma, Brenda W.J.H. Penninx, M. Beekman, H.E.D. Suchiman, J. Deelen, N. Amin, J.W. Beulens, J.A. van der Bom, N. Bomer, A. Demirkan, J.A. van Hilten, J.M.T.A. Meessen, R. Pool, M.H. Moed, J. Fu, G.L.J. Onderwater, F. Rutters, C. So-Osman, W.M. van der Flier, A.A.W.A. van der Heijden, A. van der Spek, F.W. Asselbergs, E. Boersma, P.M. Elders, J.M. Geleijnse, M.A. Ikram, M. Kloppenburg, I. Meulenbelt, S.P. Mooijaart, R.G.H.H. Nelissen, M.G. Netea, B.W.J.H. Penninx, C.D.A. Stehouwer, C.E. Teunissen, G.M. Terwindt, L.M. ’t Hart, A.M.J.M. van den Maagdenberg, P. van der Harst, I.C.C. van der Horst, C.J.H. van der Kallen, M.M.J. van Greevenbroek, W.E. van Spil, C. Wijmenga, A.H. Zwinderman, A. Zhernikova, J.W. Jukema, N. Sattar, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Epidemiology, Clinical Genetics, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Center for Liver, Digestive and Metabolic Diseases (CLDM), Neurosurgery, Amsterdam Neuroscience - Systems & Network Neuroscience, Amsterdam Neuroscience - Neurodegeneration, Dermatology, Obstetrics and Gynaecology, Graduate School, Cardiology, Public and occupational health, Gastroenterology and Hepatology, RS: FHML MaCSBio, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, Epidemiologie, RS: FSE MaCSBio, RS: FPN MaCSBio, Interne Geneeskunde, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: MA Endocrinologie (9), MUMC+: MA Maag Darm Lever (9), MUMC+: MA Hematologie (9), MUMC+: MA Medische Oncologie (9), MUMC+: MA Nefrologie (9), and MUMC+: MA Reumatologie (9)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Apolipoprotein B, Nutrition and Disease, Metabolite, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, Voeding en Ziekte, Metabolites, EPIDEMIOLOGY, Medicine, HETEROGENEITY, Depression (differential diagnoses), RISK, chemistry.chemical_classification, INSULIN-RESISTANCE, biology, Depression, CHOLESTEROL, Fatty Acids, ASSOCIATION, Apolipoprotein A1, lipids (amino acids, peptides, and proteins), medicine.medical_specialty, Pooled analysis, 03 medical and health sciences, MAGNETIC-RESONANCE METABOLOMICS, INFLAMMATION, SDG 3 - Good Health and Well-being, Internal medicine, Humans, Metabolomics, Triglycerides, METAANALYSIS, Biological Psychiatry, VLAG, Triglyceride, business.industry, Fatty acid, MAJOR DEPRESSION, 030104 developmental biology, Endocrinology, chemistry, biology.protein, business, Body mass index, 030217 neurology & neurosurgery, Biomarkers, Lipoprotein
Abstract

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

Published
2020
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10. IL-17-high asthma with features of a psoriasis immunophenotype

Author

Jörgen Östling, Marleen van Geest, James P.R. Schofield, Zala Jevnikar, Susan Wilson, Jonathan Ward, Rene Lutter, Dominick E. Shaw, Per S. Bakke, Massimo Caruso, Sven-Erik Dahlen, Stephen J. Fowler, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Thomas Sandström, Kai Sun, Ioannis Pandis, Charles Auffray, Ana R. Sousa, Yike Guo, Ian M. Adcock, Peter Howarth, Kian Fan Chung, Jeanette Bigler, Peter J. Sterk, Paul J. Skipp, Ratko Djukanović, Outi Vaarala, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, K.F. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, Y. Guo, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, P. Howarth, A.J. James, R. Knowles, A.J. Knox, N. Krug, D. Lefaudeux, M.J. Loza, R. Lutter, A. Manta, S. Masefield, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, P. Montuschi, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, P. Powell, G. Praticò, M. Puig N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson, Antonios Aliprantis, David Allen, Kjell Alving, P. Badorrek, David Balgoma, S. Ballereau, Clair Barber, Manohara Kanangana Batuwitage, A. Bautmans, A. Bedding, A.F. Behndig, Jorge Beleta, A. Berglind, A. Berton, Grazyna Bochenek, Armin Braun, D. Campagna, Leon Carayannopoulos, C. Casaulta, Romanas Chaleckis, B. Dahlén, imothy Davison, Jorge De Alba, Inge De Lepeleire, Tamara Dekker, Ingrid Delin, P. Dennison, Annemiek Dijkhuis, Paul Dodson, Aleksandra Draper, K. Dyson, Jessica Edwards, L. El Hadjam, Rosalia Emma, Magnus Ericsson, C. Faulenbach, Breda Flood, G. Galffy, Hector Gallart, D. Garissi, J. Gent, M. Gerhardsson de Verdier, D. Gibeon, Cristina Gomez, Kerry Gove, Neil Gozzard, E. Guillmant-Farry, E. Henriksson, Lorraine Hewitt, U. Hoda, Richard Hu, Sile Hu, X. Hu, E. Jeyasingham, K. Johnson, N. Jullian, Juliette Kamphuis, Erika J. Kennington, Dyson Kerry, G. Kerry, M. Klüglich, Hugo Knobel, Johan Kolmert, J.R. Konradsen, Maxim Kots, Kosmas Kretsos, L. Krueger, Scott Kuo, Maciej Kupczyk, Bart Lambrecht, A.-S. Lantz, Christopher Larminie, L.X. Larsson, P. Latzin, N. Lazarinis, N. Lemonnier, Saeeda Lone-Latif, L.A. Lowe, Alexander Manta, Lisa Marouzet, Jane Martin, Caroline Mathon, L. McEvoy, Sally Meah, A. Menzies-Gow, Leanne Metcalf, Maria Mikus, Philip Monk, Shama Naz, K. Nething, Ben Nicholas, U. Nihlén, Peter Nilsson, R. Niven, B. Nordlund, S. Nsubuga, Antonio Pacino, Susanna Palkonen, J. Pellet, Giorgio Pennazza, Anne Petrén, Sandy Pink, C. Pison, Anthony Postle, Malayka Rahman-Amin, Lara Ravanetti, Emma Ray, Stacey Reinke, Leanne Reynolds, K. Riemann, Martine Robberechts, J.P. Rocha, C. Rossios, Kirsty Russell, Michael Rutgers, G. Santini, Marco Santoninco, M. Saqi, Corinna Schoelch, S. Scott, N. Sehgal, Marcus Sjödin, Barbara Smids, Caroline Smith, Jessica Smith, Katherine M. Smith, P. Söderman, A. Sogbessan, F. Spycher, Doroteya Staykova, S. Stephan, J. Stokholm, K. Strandberg, M. Sunther, M. Szentkereszty, L. Tamasi, K. Tariq, John-Olof Thörngren, Jonathan Thorsen, S. Valente, Marianne van de Pol, C.M. van Drunen, Jonathan Van Eyll, Jenny Versnel, Anton Vink, C. von Garnier, A. Vyas, Frans Wald, Samantha Walker, Kristiane Wetzel, Coen Wiegman, Siân Williams, Xian Yang, Elizabeth Yeyasingham, W. Yu Amgen, W. Zetterquist, Z. Zolkipli, A.H. Zwinderman, Publica, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Pulmonology, AII - Inflammatory diseases, Experimental Immunology, Ear, Nose and Throat, Epidemiology and Data Science, APH - Methodology, and Commission of the European Communities

Subjects
0301 basic medicine, Male, URINARY-EXCRETION, Allergy, Neutrophils, Inflammatory bowel disease, Cohort Studies, DOUBLE-BLIND, 0302 clinical medicine, Immunology and Allergy, POPULATION, Interleukin-13, Interleukin-17, psoriasis, BRODALUMAB, Up-Regulation, IL-17, Phenotype, 1107 Immunology, Biomarker (medicine), Female, Interleukin 17, medicine.symptom, Life Sciences & Biomedicine, ENDOTYPES, Signal Transduction, EXPRESSION, Adult, Settore BIO/14 - FARMACOLOGIA, Immunology, PHENOTYPES, Bronchi, 03 medical and health sciences, INFLAMMATION, Psoriasis, medicine, Humans, Interleukin 8, Asthma, U-BIOPRED Study Group, Science & Technology, business.industry, Gene Expression Profiling, biomarkers, Epithelial Cells, asthma, bronchial brushings, medicine.disease, bronchial biopsies, Neutrophilia, 030104 developmental biology, 030228 respiratory system, EXACERBATION, CELLS, Sputum, business, Transcriptome, Biomarkers
Abstract

Background The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Published
2019
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11. Antiplatelet and anticoagulant drugs do not affect visual outcome in neovascular age-related macular degeneration in the BRAMD trial

Author

Gabriëlle H.S. Buitendijk, Ann-Sofie M.E. Schauwvlieghe, Johannes R. Vingerling, Reinier O. Schlingemann, Caroline C.W. Klaver, R.O. Schlingemann, F.D. Verbraak, M. van Schooneveld, M. Wezel, H. Stam, C. Jansen-Kok, A. Althoff, D. Bakker, A. van der Zee, M. Stam, D.J. De Vries, J.R. Vingerling, N.C. Naus- Postema, K.L. De Roon Hertoge, C.C.W. Klaver, E. Kilic, Y. Noordzij, J. Noordzij, A. Vermij, A. Hooghart, G. Dijkman, I. Boesten, C. Kiewiet de Jonge, M. Kromhart- de Haas, C. Mollinger, J.W. Zwaan, L. Brink, A. Boolman, J.M.M. Hooymans, N. Kamminga, A. Huiskamp, G. Postma, M. Meinen, L. Uwantege, H.R. Luurtsema, J.F. Eisses, V.W. Ronardel de Lavalette, J.P. Van De Pol, C.B. Hoyng, A. de Vries, E. Huntink, A. Kalisingh, L. Hoeks, H. Hermans, A. Rotteveel, J. Weeda, C. Van Ast, M. van der Linden, H. Klaver, R. van Hierden, A. Coops, K. Corstanje, M. Jansen, N. van den Berg, A. Rulo, F. Gerbrandy, A. Tromp, O. Lopes Cardozol, E. Zola, B. Van Leeuwen, G. Dantuma, S. Koning, M. van Baekel, M. Selders, M. Zandee, M. Goudriaan, A. Langen, R.W.H. van de Mortel, A. Tetteroo, Y. de Groot, M.G.W. Dijkgraaf, R. De Haan, A.H. Zwinderman, A.M.E. Schauwvlieghe, S. Mehmedovic, J.J.W. van Dalen, I. Corten, E. Veenstra, Y. Strubel, T. Peto, P. Blows, P.J. Ringens, R. Geskus, R. van Leeuwen, ANS - Cellular & Molecular Mechanisms, Ophthalmology, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Epidemiology, Erasmus School of Law, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, Gastroenterology & Hepatology, Internal Medicine, Neurology, Econometrics, and Netherlands Institute for Neuroscience (NIN)

Subjects
Male, Vascular Endothelial Growth Factor A, Eye Hemorrhage, Visual acuity, genetic structures, Visual Acuity, Angiogenesis Inhibitors, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], law.invention, 0302 clinical medicine, Randomized controlled trial, law, 80 and over, Fluorescein Angiography, Non-U.S. Gov't, Tomography, Aged, 80 and over, Research Support, Non-U.S. Gov't, Multicenter Study, Bevacizumab, Randomized Controlled Trial, Intravitreal Injections, Platelet aggregation inhibitor, Female, medicine.symptom, Tomography, Optical Coherence, medicine.drug, medicine.medical_specialty, Visual impairment, Research Support, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Double-Blind Method, Internal medicine, Ranibizumab, medicine, Journal Article, Humans, Comparative Study, Aged, Retrospective Studies, business.industry, Anticoagulants, Odds ratio, Macular degeneration, medicine.disease, eye diseases, Ophthalmology, Optical Coherence, 030221 ophthalmology & optometry, Wet Macular Degeneration, sense organs, business, 030217 neurology & neurosurgery, Platelet Aggregation Inhibitors
Abstract

Purpose: To determine if use of antiplatelet or anticoagulant (AP/AC) medication influences visual acuity in patients with active neovascular age-related macular degeneration (N-AMD). Design: Retrospective analysis of data from a randomized controlled trial. Methods: SETTING: Multicenter. STUDY POPULATION: Total of 330 patients with active N-AMD from the BRAMD study, a comparative trial between bevacizumab and ranibizumab in the Netherlands. OBSERVATION PROCEDURES: Patients underwent an extensive ophthalmic examination. Visual acuity was categorized into functional vision (best-corrected visual acuity [BCVA] ≥ 0.5), visual impairment (BCVA < 0.5), and severe visual impairment (BCVA < 0.3). Fundus photographs were graded for presence of retinal or subretinal hemorrhages. Information on AP/AC medication was obtained through interview. Logistic regression analysis was used to determine associations between AP/AC medication and outcomes. Frequency of hemorrhages in users and non-users stratified for visual acuity categories was analyzed with ANCOVA. MAIN OUTCOME MEASURES: BCVA and presence of hemorrhages. Results: In total, 40.9% of the patients used AP/AC medication, of which 73.3% was aspirin. AP/AC use was not associated with visual impairment (adjusted odds ratio [OR] 0.79; 95% confidence interval [CI] 0.43-1.44) or severe visual impairment (adjusted OR 0.75; 95% CI 0.40-1.43). Patients on AP/AC presented with comparable frequencies of hemorrhages (27% vs 32%, P =.32, respectively). Similar results were found when analyses were restricted to aspirin users only. Conclusion: In our study, use of AP/AC medication was associated neither with visual decline nor with the occurrence of hemorrhages in patients with active N-AMD.

Published
2018

12. A Study Into Predictors for the Speed of Response to Electroconvulsive Therapy

Author

E.M. Koomen, D. H. Linszen, S. Vothknecht, King H. Kho, A.H. Zwinderman, N.M.P. Cornelissen, B.A. Blansjaar, Other departments, Epidemiology and Data Science, and Adult Psychiatry

Subjects
Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Neuroscience (miscellaneous), behavioral disciplines and activities, Energy index, Statistics, Nonparametric, Electroconvulsive therapy, Predictive Value of Tests, Rating scale, Chart review, mental disorders, medicine, Humans, Electroconvulsive Therapy, Psychiatry, Rapid response, Application methods, Depressive Disorder, Major, Regression analysis, Middle Aged, Psychiatry and Mental health, Treatment Outcome, Predictive value of tests, Physical therapy, Regression Analysis, Female, Psychology
Abstract

The efficacy of electroconvulsive therapy (ECT) has been firmly established in the treatment of depression. However, prediction of the speed of response to ECT is an issue that needs to be further explored. This study aims to examine the presence of predictors for the speed of response. In a retrospective chart review using 57 patients suffering from major depression who received ECT, the relation of several patient and ECT variables with the speed of response was explored. Response was defined as a drop of at least 35% in Hamilton rating scale of depression (HRSD) score from baseline after 3 or 4 ECT sessions. Patients received ECT with an aged-based stimulus dosage in a clinical setting. Multiple regression analysis showed that high baseline HRSD score and high seizure energy index (SEI) were significantly and independently associated with a rapid response. In a regression model, baseline HRSD score and SEI can be used to predict the speed of response to ECT. Rapid responders to ECT achieved remission significantly more often than slow responders did. SEI can be modified by the clinician. This offers the possibility to optimize ECT treatment.

Published
2004
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13. Statistics Applied to Clinical Trials

Author

Ton J. Cleophas, A.H. Zwinderman, Ton J. Cleophas, and A.H. Zwinderman

Subjects
Drugs--Testing--Statistical methods, Clinical trials--Statistical methods
Abstract

In 1948 the first randomized controlled trial was published by the English Medical Research Council in the British Medical Journal. Until then, observations had been uncontrolled. Initially, trials frequently did not confirm the hypotheses to be tested. This phenomenon was attributed to low sensitivity due to small samples, as well as inappropriate hypotheses based on biased prior trials. Additional flaws were recognized and, subsequently, were better accounted for: carryover effects due to insufficient washout from previous treatments, time effects due to external factors and the natural history of the condition under study, bias due to asymmetry between treatment groups, lack of sensitivity due to a negative correlation between treatment responses, and so on. Such flaws, mainly of a technical nature, have been largely corrected and led to trials after 1970 being of significantly higher quality. The past decade has focused, in addition to technical aspects, on the need for circumspection in the planning and conducting of clinical trials. As a consequence, prior to approval, clinical trial protocols are now routinely scrutinized by different circumstantial organs, including ethics committees, institutional and federal review boards, national and international scientific organizations, and monitoring committees charged with conducting interim analyses. This book not only explains classical statistical analyses of clinical trials, but also addresses relatively novel issues, including equivalence testing, interim analyses, sequential analyses, and meta-analyses, and provides a framework of the best statistical methods currently available for such purposes. This book is not only useful for investigators involved in the field of clinical trials, but also for all physicians who wish to better understand the data of trials as currently published.

Published
2013

14. Comparison of quantitative ultrasound parameters with dual energy X-ray absorptiometry in pre- and postmenopausal women

Author

Dave H. Schweitzer, A.G.H. Smals, E.F.L. Dubois, C.W.D. van de Meerendonk, J.P.W. van den Bergh, and A.H. Zwinderman

Subjects
Adult, musculoskeletal diseases, medicine.medical_specialty, Bone disease, Osteoporosis, Absorptiometry, Photon, Endocrinology, Predictive Value of Tests, Linear regression, Internal Medicine, Humans, Medicine, Osteoporosis, Postmenopausal, Dual-energy X-ray absorptiometry, Aged, Ultrasonography, Femoral neck, Bone mineral, medicine.diagnostic_test, business.industry, Ultrasound, Middle Aged, musculoskeletal system, medicine.disease, Quantitative ultrasound, medicine.anatomical_structure, Premenopause, Linear Models, Physical therapy, Female, business
Abstract

Quantitative ultrasound (QUS) has been claimed as an alternative technique for risk assessment of hip fractures associated with osteoporosis. However, reports concerning modest correlations between QUS parameters and dual energy X-ray absorptiometry (DXA) in women raise questions about the reliability of QUS technology to predict bone mineral density (BMD). Partially, the lack of stronger correlations may be due to heterogeneity in bone architecture deterioration which may be more pronounced in older than in younger women. Therefore, it was thought important to study QUS/DXA interrelationships in subgroups of pre- and postmenopausal women.We studied 217 pre- and postmenopausal women between the ages of 25 and 75 years, who were referred for a BMD measurement because of osteoporosis in at least one family member either in the first or in the second degree. All women had a calcaneal QUS and a DXA measurement at the lumbar spine, total hip and femoral neck.The linear regression coefficients between the QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) and DXA at the various sites in the group as a whole were 0.53 to 0.54 (P0.0001). Significantly lower regression coefficients between BUA and DXA at the total hip and the femoral neck were found in premenopausal women (r=0.31 and 0.38, P0.0001) compared to postmenopausal women (r=0.56 and 0.53, P0.0001). For SOS there was no significant difference between the regression coefficients in the pre- and postmenopausal group. The overall prevalence of osteoporosis as assessed by DXA in the total group was 25% (6% in the pre- and 36% in the postmenopausal group). BUA failed to detect osteoporosis in all five premenopausal women but also in 20 out of 50 postmenopausal women with osteoporosis according to DXA measurements. SOS measurements were even worse in this respect.Linear regression coefficients between calcaneal QUS parameters and DXA are only modest considering a group of 25--75-year-old Dutch women. In the subgroup of premenopausal women correlations between BUA and BMD at the hip and femoral neck are worse compared to those in postmenopausal women. The predictive value of QUS parameters for BMD is limited, therefore it is not appropriate to use QUS as a surrogate for DXA.

Published
2001

15. Statistics Applied to Clinical Trials : Self-Assessment Book

Author

Ton J. Cleophas, A.H. Zwinderman, A.F. Cleophas, Ton J. Cleophas, A.H. Zwinderman, and A.F. Cleophas

Subjects
Pharmacology, Internal medicine, Cardiology, Biometry
Abstract

The authors have taught statistics and given statistics workshops in France and the Netherlands for almost 4 years by now. Their material, mainly on power point, consists of 12 lectures that have been continuously changed and improved by interaction with various audiences. For the purpose of the current book simple English text has been added to the formulas and figures, and the power points sheets have been rewritten in the format given by Kluwer Academic Publishers. Cartoons have been removed, since this is not so relevant for the transmission of thought through a written text, and at the end of each lecture (chapter) a representative number of questions and exercises for self-assessment have been added. At the end of the book detailed answers to the questions and exercises per lecture are given. The book has been produced with the same size and frontpage as the textbook'Statistics Applied To Clinical Trials'by the same authors and edited by same publishers ( 2nd Edition, DordrechtiBostonlLondon, 2002), and can be applied together with the current self-assessment book or separately. The current self-assessment book is different from the texbook, because it focuses on the most important aspects rather than trying to be complete. So, it does not deal with all of the subjects assessed in the texbook. Instead, it repeats on and on the principle things that are needed for every analysis, and it gives many examples that are further explained by arrows in the figures.

Published
2012

16. Statistics Applied to Clinical Trials

Author

Ton J. Cleophas, A.H. Zwinderman, Ton J. Cleophas, and A.H. Zwinderman

Subjects
Biometry
Abstract

In 1948 the first randomized controlled trial was published by the English Medical Research Council in the British Medical Journal. Until then, observations had been uncontrolled. Initially, trials frequently did not confirm hypotheses to be tested. This phenomenon was attributed to low sensitivity due to small samples, as well as inappropriate hypotheses based on biased prior trials. Additional flaws were recognized and subsequently were better accounted for: carryover effects due to insufficient washout from previous treatments, time effects due to external factors and the natural history of the condition under study, bias due to asymmetry between treatment groups, lack of sensitivity due to a negative correlation between treatment responses, etc. Such flaws, mainly of a technical nature, have been largely corrected and led to trials after 1970 being of significantly better quality than before. The past decade has focused, in addition to technical aspects, on the need for circumspection in planning and conducting of clinical trials. As a consequence, prior to approval, clinical trial protocols are now routinely scrutinized by different circumstantial bodies, including ethics committees, institutional and federal review boards, national and international scientific organizations, and monitoring committees charged with conducting interim analyses. This book not only explains classical statistical analyses of clinical trials, but addresses relatively novel issues, including equivalence testing, interim analyses, sequential analyses, and meta-analyses, and provides a framework of the best statistical methods currently available for such purposes. The book is not only useful for investigators involved in the field of clinical trials, but also for all physicians who wish to better understand the data of trials as currently published.

Published
2011

17. An international multicenter phase III study of chemoradiotherapy versus chemoradiotherapy plus hyperthermia for locally advanced cervical cancer

Author

Terje Nordberg, Rainer Fietkau, Johannes Crezee, Astrid Keijser, R. D. Issels, A.H. Zwinderman, Lars H. Lindner, Peter Wust, Anneke M. Westermann, Lukas J.A. Stalpers, Olav Mella, Baukje Flameling, Oliver J. Ott, and Josefine Rauch

Subjects
0301 basic medicine, Oncology, Cervical cancer, Hyperthermia, Cancer Research, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Standard treatment, Brachytherapy, Locally advanced, 02 engineering and technology, 021001 nanoscience & nanotechnology, medicine.disease, Radiation therapy, 03 medical and health sciences, 030104 developmental biology, Internal medicine, Medicine, 0210 nano-technology, business, Chemoradiotherapy
Abstract

e17023Background: Standard treatment of locally advanced cervical carcinoma consists of concurrent radiotherapy (including brachytherapy) and chemotherapy (weekly cisplatin 40 mg/m2), or chemoradio...

Published
2016
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18. More than thirty-five years of coarctation repair

Author

Hans A. Huysmans, A.H. Zwinderman, Arie-Pieter Kappetein, J. Rohmer, and Ad J.J.C. Bogers

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Medicine, Surgery, Cardiology and Cardiovascular Medicine, business
Published
1994
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19. In-vivo three-dimensional carpal bone kinematics during flexion-extension and radio-ulnar deviation of the wrist: Dynamic motion versus step-wise static wrist positions

Author

Simon D. Strackee, R. Jonges, Bart Carelsen, Geert J. Streekstra, A.H. Zwinderman, Leendert Blankevoort, M. Foumani, Plastic, Reconstructive and Hand Surgery, Amsterdam Cardiovascular Sciences, Other Research, Biomedical Engineering and Physics, Amsterdam Movement Sciences, Orthopedic Surgery and Sports Medicine, Amsterdam Public Health, Epidemiology and Data Science, and Radiology and Nuclear Medicine

Subjects
musculoskeletal diseases, Male, Models, Anatomic, Wrist Joint, Computer science, Biomedical Engineering, Biophysics, Ulna, Kinematics, Wrist, Rotation, Models, Biological, Sensitivity and Specificity, Young Adult, Imaging, Three-Dimensional, Screw axis, medicine, Humans, Orthopedics and Sports Medicine, Range of Motion, Articular, Carpal Bones, Dynamic motion, Orthodontics, Carpal Joints, Rehabilitation, Reproducibility of Results, Anatomy, musculoskeletal system, body regions, Carpal bones, Radius, medicine.anatomical_structure, Ligament, Ulnar deviation, Female
Abstract

An in-vivo approach to the measurement of three-dimensional motion patterns of carpal bones in the wrist may have future diagnostic applications, particularly for ligament injuries of the wrist. Static methods to measure carpal kinematics in-vivo only provide an approximation of the true kinematics of the carpal bones. This Study is aimed at finding the difference between dynamically and statically acquired carpal kinematics. For eight healthy subjects, static and a dynamic measurements of the carpal kinematics were performed for a flexion-extension and a radio-ulnar deviation movement. Dynamic scans were acquired by using a four-dimensional X-ray imaging system during an imposed cyclic motion. To assess static kinematics of the wrists, three-dimensional rotational X-ray scans were acquired during step-wise flexion-extension and radio-ulnar deviation. The helical axis rotations and the rotation components. i.e. flexion-extension, radio-ulnar deviation and pro-supination were the primary parameters. Linear mixed model statistical analysis was used to determine the significance of the difference between the dynamically and statically acquired rotations of the carpal bones. Small and in most cases negligible differences were observed between the dynamic motion and the step-wise static motion of the carpal bones. The conclusion is that in the case of individuals without any pathology of the wrist, carpal kinematics can be studied either dynamically or statically. Further research is required to investigate the dynamic in-vivo carpal kinematics in patients with dynamic wrist problems. (C) 2009 Elsevier Ltd. All rights reserved

Published
2009

20. The neural crest as a possible pathogenetic factor in coarctation of the aorta and bicuspid aortic valve

Author

J. Rohmer, Hans A. Huysmans, A.P. Kappetein, Robert E. Poelmann, A.C. Gittenberger-de Groot, and A.H. Zwinderman

Subjects
Pulmonary and Respiratory Medicine, Aortic arch, Aortic valve, medicine.medical_specialty, business.industry, Coarctation of the aorta, Neural crest, medicine.disease, Surgery, Bicuspid aortic valve, medicine.anatomical_structure, Maldevelopment, Internal medicine, medicine.artery, cardiovascular system, medicine, Cardiology, In patient, cardiovascular diseases, Cardiology and Cardiovascular Medicine, Congenital cardiac malformations, business
Abstract

Patients (n = 109) operated on for coarctation of the aorta were analyzed for occurrence of associated cardiac and noncardiac anomalies. Attention was also paid to the prevalence of cardiac anomalies in the relatives of these patients. Of the patients with coarctation of the aorta, 57 (52%) had a bicuspid aortic valve. Forty-three (39%) of the 109 patients had one or more noncardiac anomalies. In 29 (27%) patients the noncardiac anomaly involved the head/neck structures. Noncardiac anomalies were much more prevalent in patients with coarctation and bicuspid aortic valve, especially anomalies involving the head/neck structures: 44% compared to 8% of patients with a normal aortic valve. Congenital cardiac malformations were present in relatives in the first or second degree of 18% of the patients. Bicuspid aortic valve was more prevalent in patients with an affected relative (75%) than in patients with unaffected relatives (47%). Recent studies showed that the neural crest plays an important role in the development of cardiac and a variety of noncardiac structures. The cardiac structures derived from the neural crest involve the outflow tract of the heart and the aortic arch system. Maldevelopment of neural crest cells could therefore be responsible for the combined occurrence of outflow tract (e.g., bicuspid aortic valve), aortic arch (e.g., coarctation), and noncardiac anomalies. This study supports the concept that some anomalies of the aortic arch system, including aortic coarctation, are cardiovascular manifestations of a spectrum of anomalies involving the head and neck region that may be due to a genetic-environmental disorder of the neural crest.

Published
1991
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21. Effects of maintenance electroconvulsive therapy on cognitive functions

Author

H. Middelkoop, S. Vothknecht, King H. Kho, B.A. Blansjaar, van M.J.M. Schaick, A.H. Zwinderman, Other departments, and Epidemiology and Data Science

Subjects
Male, medicine.medical_specialty, Time Factors, medicine.drug_class, medicine.medical_treatment, Neuroscience (miscellaneous), behavioral disciplines and activities, Electroconvulsive therapy, Pharmacotherapy, mental disorders, Neuropsychologia, medicine, Humans, Prospective Studies, Electroconvulsive Therapy, Aged, Depressive Disorder, medicine.diagnostic_test, Cognitive disorder, Neuropsychology, Cognition, Mood stabilizer, Neuropsychological test, Middle Aged, medicine.disease, Antidepressive Agents, Psychiatry and Mental health, Treatment Outcome, Physical therapy, Female, Psychology, Cognition Disorders, Clinical psychology
Abstract

Background This study examined cognitive side effects of maintenance electroconvulsive (ECT) in comparison with maintenance pharmacotherapy after index ECT. Method Clinical outcome data and neuropsychological measurements were compared in 11 maintenance ECT patients and 13 control patients treated with maintenance pharmacotherapy after index ECT. Data were gathered in a prospective naturalistic study during follow-up. Results There were no significant differences in patient characteristics and effects of index ECT between groups. In control patients treated with maintenance pharmacotherapy, cognitive function as well as depression ratings remained stable. During maintenance ECT neuropsychological test performance and depression ratings improved slightly but not significantly. Conclusions Neuropsychological functioning during the maintenance phase of treatment did not differ between the two treatment groups. Cognitive function remained stable during maintenance ECT.

Published
2003

22. Statistics Applied to Clinical Trials

Author

Ton J. Cleophas, A.H. Zwinderman, Toine F. Cleophas, Eugene P. Cleophas, Ton J. Cleophas, A.H. Zwinderman, Toine F. Cleophas, and Eugene P. Cleophas

Subjects
Probabilities, Medicine—Research, Biology—Research, Biometry, Statistics
Abstract

In clinical medicine appropriate statistics has become indispensable to evaluate treatment effects. Randomized controlled trials are currently the only trials that truly provide evidence-based medicine. Evidence based medicine has become crucial to optimal treatment of patients. We can define randomized controlled trials by using Christopher J. Bulpitt's definition “a carefully and ethically designed experiment which includes the provision of adequate and appropriate controls by a process of randomization, so that precisely framed questions can be answered”. The answers given by randomized controlled trials constitute at present the way how patients should be clinically managed. In the setup of such randomized trial one of the most important issues is the statistical basis. The randomized trial will never work when the statistical grounds and analyses have not been clearly defined beforehand. All endpoints should be clearly defined in order to perform appropriate power calculations. Based on these power calculations the exact number of available patients can be calculated in order to have a sufficient quantity of individuals to have the predefined questions answered. Therefore, every clinical physician should be capable to understand the statistical basis of well performed clinical trials. It is therefore a great pleasure that Drs. T. J. Cleophas, A. H. Zwinderman, and T. F. Cleophas have published a book on statistical analysis of clinical trials. The book entitled “Statistics Applied to Clinical Trials” is clearly written and makes complex issues in statistical analysis transparant.

Published
2008

24. Statistics Applied to Clinical Trials

Author

Ton J. Cleophas, A.H. Zwinderman, T.F. Cleophas, Toine F. Cleophas, Eugene P. Cleophas, Ton J. Cleophas, A.H. Zwinderman, T.F. Cleophas, Toine F. Cleophas, and Eugene P. Cleophas

Subjects
Clinical trials--Statistical methods, Drugs--Testing--Statistical methods
Abstract

Includes indexes.

Published
2006

25. 65 Kinomic profiling identifies PKC/Akt and beta-catenin/TCF mediated signal transduction as important targets of celecoxib in colon cancer

Author

J.B. Tuynman, Maikel P. Peppelenbosch, A.H. Zwinderman, E.M.J. Boon, and D.J. Richel

Subjects
Cancer Research, Beta-catenin, biology, Chemistry, Colorectal cancer, medicine.disease, Oncology, Celecoxib, medicine, Cancer research, biology.protein, Signal transduction, Protein kinase B, Protein kinase C, medicine.drug
Published
2004
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27. Idiopathic impaired spermatogenesis: genetic epidemiology is unlikely to provide a short-cut to better understanding.

Author

Judith Gianotten, M.Paola Lombardi, A.H. Zwinderman, Richard J. Lilford, and Fulco van der Veen

Subjects
SPERMATOGENESIS, GENETICS, EMBRYOLOGY, BIRTH control
Abstract

The aetiology of impaired spermatogenesis is unknown in the majority of subfertile men. From several studies of concordance for involuntary childlessness among men, we can conclude that there is a substantial familial component in male subfertility and that shared loci segregating through families can be assumed. We now know that deletions on the Y chromosome, which do not penetrate fully, account for some of these cases. There are good reasons to suspect that other cases result from mutations in genes located elsewhere in the genome. In this article, we discuss different approaches to unravelling the molecular basis of impaired spermatogenesis originating from genetic abnormalities in chromosomes other than the Y chromosome. Genetic mapping studies are in general a good approach to detect disease-causing genes that are segregating through a population; they can provide a shortcut to unravelling the biochemistry of a disease. In this paper, we explain our reasons for arguing that linkage and association studies are no promising means to identify the genes causing impaired spermatogenesis. We conclude that direct screening of candidate genes for mutations will be necessary to detect genes involved in impaired spermatogenesis. However, this approach requires studies of the biochemical pathways of normal and abnormal spermatogenesis. Since we have a poor understanding of these pathways, more research is needed into the biochemistry of spermatogenesis. [ABSTRACT FROM AUTHOR]

Published
2004
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