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4. COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

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Abdukahil, SA, Abe, R, Abel, L, Absil, L, Acker, A, Adachi, S, Adam, E, Adriao, D, Ainscough, K, Hssain, AA, Tamlihat, YA, Akimoto, T, Al-Dabbous, T, Al-Fares, A, Al Qasim, E, Alalqam, R, Alex, B, Alexandre, K, Alfoudri, H, Alidjnou, KE, Aliudin, J, Allavena, C, Allou, N, Alves, J, Alves, R, Amaral, M, Ammerlaan, H, Ampaw, P, Andini, R, Andrejak, C, Angheben, A, Angoulvant, F, Ansart, S, Antonelli, M, De Brito, CAA, Arabi, Y, Aragao, I, Arcadipane, A, Arenz, L, Arlet, J-B, Arnold-Day, C, Arora, L, Artaud-Macari, E, Asensio, A, Assie, JB, Atique, A, Auchabie, J, Aumaitre, H, Azemar, L, Azoulay, C, Bach, B, Bachelet, D, Baillie, JK, Bak, E, Bakakos, A, Banisadr, F, Barbalho, R, Barclay, WS, Barnikel, M, Barrelet, A, Barrigoto, C, Basmaci, R, Rincon, DFB, Bedossa, A, Behilill, S, Beljantsev, A, Bellemare, D, Beltrame, A, Beluze, M, Benech, N, Benkerrou, D, Bennett, S, Bento, L, Berdal, J-E, Bergeaud, D, Bertolino, L, Bessis, S, Bevilcaqua, S, Bhavsar, K, Bin Humaid, F, Bissuel, F, Biston, P, Bitker, L, Blanco-Schweizer, P, Blot, M, Boccia, F, Bogaert, D, Bompart, F, Booth, G, Borges, D, Borie, R, Bos, J, Bosse, HM, Botelho-Nevers, E, Bouadma, L, Bouchaud, O, Bouchez, S, Bouhmani, D, Bouhour, D, Bouiller, K, Bouillet, L, Bouisse, C, Boureau, A-S, Bouscambert, M, Bouziotis, J, Boxma, B, Boyer-Besseyre, M, Boylan, M, Braga, C, Brandenburger, T, Brazzi, L, Breen, D, Breen, P, Brickell, K, Brozzi, N, Buchtele, N, Buesaquillo, C, Bugaeva, P, Buisson, M, Burhan, E, Bustos, IG, Butnaru, D, Carcel, S, Cabie, A, Cabral, S, Caceres, E, Callahan, M, Calligy, K, Calvache, JA, Camoes, J, Campana, V, Campbell, P, Canepa, C, Cantero, M, Caraux-Paz, P, Cardoso, F, Cardoso, S, Carelli, S, Carlier, N, Carney, G, Carpenter, C, Carret, M-C, Carrier, FM, Carson, G, Casanova, M-L, Cascao, M, Casimiro, J, Cassandra, B, Castaneda, S, Castanheira, N, Castor-Alexandre, G, Castrillon, H, Castro, I, Catarino, A, Catherine, F-X, Cavalin, R, Cavalli, GG, Cavayas, A, Ceccato, A, Cervantes-Gonzalez, M, Chair, A, Chakveatze, C, Chan, A, Chand, M, Chas, J, Chassin, C, Chen, A, Chen, Y-S, Cheng, MP, Cheret, A, Chiarabini, T, Chica, J, Chirouze, C, Chiumello, D, Cho, HJ, Cho, SM, Cholley, B, Cidade, JP, Herreros, JMC, Citarella, BW, Ciullo, A, Clarke, J, Clohisey, S, Codan, C, Cody, C, Coelho, A, Colin, G, Collins, M, Colombo, SM, Combs, P, Connelly, JP, Connor, M, Conrad, A, Contreras, S, Cooke, GS, Copland, M, Cordel, H, Corley, A, Cormican, S, Cornelis, S, Corpuz, AJ, Corvaisier, G, Couffignal, C, Couffin-Cadiergues, S, Courtois, R, D'Orleans, CC, Croonen, S, Crowl, G, Crump, J, Cruz, C, Csete, M, Cucino, A, Cullen, C, Cummings, M, Curley, G, Curlier, E, Custodio, P, D'Aragon, F, Filipe, ADS, Da Silveira, C, D'Ortenzio, E, Dabaliz, A-A, Dagens, AB, Dalton, H, Dalton, J, Daneman, N, Dankwa, EA, Dantas, J, De Castro, N, De Mendoza, D, Franca, RFDO, De Rosa, R, De Silva, T, De Vries, P, Dean, D, Debray, M-P, Dechert, W, Deconninck, L, Decours, R, Delacroix, I, Delavigne, K, Deligiannis, I, Dell'amore, A, Delobel, P, Demonchy, E, Denis, E, Deplanque, D, Depuydt, P, Desai, M, Descamps, D, Desvallee, M, Dewayanti, SR, Diallo, A, Diamantis, S, Dias, A, Diaz, JJD, Diaz, R, Didier, K, Diehl, J-L, Dieperink, W, Dimet, J, Dinot, V, Diouf, A, Dishon, Y, Djossou, F, Docherty, AB, Dong, A, Donnelly, CA, Donnelly, M, Donohue, C, Dorival, C, Douglas, JJ, Douma, R, Dournon, N, Downer, T, Downing, M, Drake, T, Dubee, V, Dubos, F, Ducancelle, A, Dudman, S, Dunning, J, Mangoni, ED, Duranti, S, Durham, L, Dussol, B, Duval, X, Dyrhol-Riise, AM, Eira, C, Vidal, JE, El Sanharawi, M, Elapavaluru, S, Elharrar, B, Elkheir, N, Ellerbroek, J, Ellis, R, Eloy, P, Elshazly, T, Enderle, I, Engelmann, I, Enouf, V, Epaulard, O, Esperatti, M, Esperou, H, Esposito-Farese, M, Estevao, J, Etienne, M, Ettalhaoui, N, Everding, AG, Evers, M, Fabre, I, Faheem, A, Fahy, A, Fairfield, CJ, Faria, P, Farshait, N, Fatoni, AZ, Faure, K, Fayed, M, Feely, N, Fernandes, J, Fernandes, M, Fernandes, S, Ferrao, J, Devouge, EF, Ferraz, M, Ferreira, B, Ferrer-Roca, R, Figueiredo-Mello, C, Flateau, C, Fletcher, T, Florio, LL, Foley, C, Fomin, V, Fonseca, CD, Fonseca, T, Fontela, P, Forsyth, S, Foti, G, Fourn, E, Fowler, R, Franch-Llasat, D, Fraser, C, Fraser, J, Freire, MV, Ribeiro, AF, Friedrich, C, Fry, S, Fuentes, N, Fukuda, M, Gomez-Junyent, J, Gaborieau, V, Gachet, B, Gaci, R, Gagliardi, M, Gagnard, J-C, Gagneux-Brunon, A, Gaiao, S, Gallagher, P, Curto, EG, Gamble, C, Garan, A, Garcia-Gallo, E, Garcia, R, Garot, D, Garrait, V, Gault, N, Gavin, A, Gaymard, A, Gebauer, J, Morlaes, LG, Germano, N, Ghosn, J, Giani, M, Giaquinto, C, Gibson, J, Gigante, T, Gilg, M, Giordano, G, Girvan, M, Gissot, V, Giwangkancana, G, Glikman, D, Glybochko, P, Gnall, E, Goco, G, Goehringer, F, Goepel, S, Goffard, J-C, Golob, J, Gorenne, I, Goujard, C, Goulenok, T, Grable, M, Grandin, EW, Granier, P, Grasselli, G, Green, CA, Greenhalf, W, Greffe, S, Grieco, DL, Griffee, M, Griffiths, F, Grigoras, I, Groenendijk, A, Lordemann, AG, Gruner, H, Gu, Y, Guedj, J, Guellec, D, Guerguerian, A-M, Guerreiro, D, Guery, R, Guillaumot, A, Guilleminault, L, Guimard, T, Haber, D, Hakak, S, Hall, M, Halpin, S, Hamer, A, Hamidfar, R, Hammond, T, Hardwick, H, Harley, K, Harrison, EM, Harrison, J, Hays, L, Heerman, J, Heggelund, L, Hendry, R, Hennessy, M, Henriquez-Trujillo, A, Hentzien, M, Hernandez-Montfort, J, Hidayah, A, Higgins, D, Higgins, E, Hinton, S, Hipolito-Reis, A, Hiraiwa, H, Hiscox, JA, Ho, AYW, Hoctin, A, Hoffmann, I, Hoiting, O, Holt, R, Holter, JC, Horby, P, Horcajada, JP, Hoshino, K, Hough, CL, Hsu, JM-Y, Hulot, J-S, Ijaz, S, Illes, H-G, Inacio, H, Dominguez, CI, Iosifidis, E, Irvine, L, Isgett, S, Isidoro, T, Isnard, M, Itai, J, Ivulich, D, Jaafoura, S, Jabot, J, Jackson, C, Jamieson, N, Jaureguiberry, S, Javidfar, J, Jean-Benoit, Z, Jego, F, Jenum, S, Sotomayor, RJ, Garcia, RNJ, Joseph, C, Joseph, M, Jouvet, P, Jung, H, Kafif, O, Kaguelidou, F, Kali, S, Kalomoiri, S, Kandamby, DH, Kandel, C, Kant, R, Kartsonaki, C, Kasugai, D, Katz, K, Johal, SK, Keating, S, Kelly, A, Kelly, S, Kennedy, L, Kennon, K, Kerroumi, Y, Kestelyn, E, Khalid, I, Khalil, A, Khan, C, Khan, I, Kho, ME, Khoo, S, Kida, Y, Kiiza, P, Kildal, AB, Kimmoun, A, Kindgen-Milles, D, Kitamura, N, Klenerman, P, Bekken, GK, Knight, S, Kobbe, R, Vasconcelos, MK, Korten, V, Kosgei, C, Krawczyk, K, Vecham, PK, Kumar, D, Kurtzman, E, Kutsogiannis, D, Kyriakoulis, K, L'her, E, Lachatre, M, Lacoste, M, Laffey, JG, Lagrange, M, Laine, F, Lambert, M, Lamontagne, F, Langelot-Richard, M, Lantang, EY, Lanza, M, Laouenan, C, Laribi, S, Lariviere, D, Launay, O, Lavie-Badie, Y, Law, A, Le Bihan, C, Le Bris, C, Le Coustumier, E, Le Falher, G, Le Gac, S, Le Hingrat, Q, Le Marechal, M, Le Mestre, S, Le Moing, V, Le Nagard, H, Le Turnier, P, Leon, R, Le, M, Santos, ML, Leal, E, Lee, J, Lee, SH, Lee, T, Leeming, G, Lefebvre, B, Lefebvre, L, Lefevre, B, Lellouche, F, Lemaignen, A, Lemee, V, Lemmink, G, Leone, M, Lepiller, Q, Lescure, F-X, Lesens, O, Lesouhaitier, M, Levy-Marchal, C, Levy, B, Levy, Y, Bassi, GL, Liang, J, Lim, WS, Lina, B, Lind, A, Lingas, G, Lion-Daolio, S, Liu, K, Loforte, A, Lolong, N, Lopes, D, Lopez-Colon, D, Loubet, P, Lucet, JC, Luna, CM, Lungu, O, Luong, L, Luton, D, Lyons, R, Mueller, F, Mueller, KE, Maasikas, O, Macdonald, S, Machado, M, Macheda, G, Sanchez, JM, Madhok, J, Mahieu, R, Mahy, S, Maier, LS, Maillet, M, Maitre, T, Malfertheiner, M, Malik, N, Maltez, F, Malvy, D, Mambert, M, Manda, V, Mandei, JM, Manning, E, Manuel, A, Malaque, CMSA, Marino, F, Mariz, CDA, Eid, CM, Marques, A, Marquis, C, Marsh, B, Marsh, L, Marshall, J, Martelli, CT, Martin-Blondel, G, Martin-Loeches, I, Martin-Quiros, A, Martin, D-A, Martin, E, Martinot, M, Rego, CM, Martins, A, Martins, J, Martucci, G, Marwali, EM, Jimenez, JFM, Maslove, D, Mason, S, Matan, M, Mathieu, D, Mattei, M, Matulevics, R, Maulin, L, Mc Evoy, N, McCarthy, A, McCloskey, C, McConnochie, R, McDermott, S, McDonald, S, McElwee, S, McEvoy, N, McGeer, A, McGuinness, N, McLean, KA, McNicholas, B, Meaney, E, Mear-Passard, C, Mechlin, M, Mele, F, Menon, K, Mentre, F, Mentzer, AJ, Mercier, N, Merckx, A, Mergler, B, Merson, L, Mesquita, A, Meybeck, A, Meynert, AM, Meyssonnier, V, Meziane, A, Mezidi, M, Michelanglei, C, Mihnovits, V, Maldonado, HM, Mone, M, Moin, A, Molina, D, Molinos, E, Monteiro, A, Montes, C, Montrucchio, G, Moore, S, Moore, SC, Morales-Cely, L, Moro, L, Tutillo, DRM, Motos, A, Mouquet, H, Perrot, CM, Moyet, J, Mullaert, J, Munblit, D, Murphy, D, Murris, M, Myrodia, DM, N'guyen, Y, Neant, N, Neb, H, Nekliudov, NA, Neto, R, Neumann, E, Neves, B, Ng, PY, Ng, WY, Choileain, ON, Nichol, A, Nonas, S, Noret, M, Norman, L, Notari, A, Noursadeghi, M, Nowicka, K, Nseir, S, Nunez, JI, Nyamankolly, E, O'Donnell, M, O'Hearn, K, O'Neil, C, Occhipinti, G, Ogston, T, Ogura, T, Oh, T-H, Ohshimo, S, Oinam, BCS, Oliveira, AP, Oliveira, J, Olliaro, P, Ong, DSY, Oosthuyzen, W, Openshaw, PJM, Orozco-Chamorro, CM, Orquera, A, Osatnik, J, Ouamara, N, Ouissa, R, Owyang, C, Oziol, E, Povoas, D, Pagadoy, M, Pages, J, Palacios, M, Palmarini, M, Panarello, G, Panda, PK, Panigada, M, Pansu, N, Papadopoulos, A, Parra, B, Pasquier, J, Patauner, F, Patrao, L, Paul, C, Paul, M, Paulos, J, Paxton, WA, Payen, J-F, Pearse, I, Peek, GJ, Peelman, F, Peiffer-Smadja, N, Peigne, V, Pejkovska, M, Peltan, ID, Pereira, R, Perez, D, Perpoint, T, Pesenti, A, Petrousova, L, Petrov-Sanchez, V, Peytavin, G, Pharand, S, Piagnerelli, M, Picard, W, Picone, O, Piel-Julian, M, Pierobon, C, Pimentel, C, Piroth, L, Pius, R, Piva, S, Plantier, L, Plotkin, D, Poissy, J, Pokorska-Spiewak, M, Poli, S, Pollakis, G, Popielska, J, Postma, DF, Povoa, P, Powis, J, Prapa, S, Prebensen, C, Preiser, J-C, Prestre, V, Price, N, Prinssen, A, Pritchard, MG, Proenca, L, Puechal, O, Purcell, G, Quesada, L, Quist-Paulsen, E, Quraishi, M, Ratsep, I, Rossler, B, Rabaud, C, Rafiq, M, Ragazzo, G, Rainieri, F, Ramakrishnan, N, Ramanathan, K, Rammaert, B, Rapp, C, Rasmin, M, Rau, C, Rebaudet, S, Redl, S, Reeve, B, Reid, L, Reis, R, Remppis, J, Remy, M, Renk, H, Resende, L, Resseguier, A-S, Revest, M, Rewa, O, Reyes, LF, Richardson, D, Richier, L, Riera, J, Rios, AL, Rishu, A, Rispal, P, Risso, K, Nunez, MAR, Rizer, N, Roberto, A, Roberts, S, Robertson, DL, Robineau, O, Roche-Campo, F, Rodari, P, Rodeia, S, Abreu, JR, Roilides, E, Rojek, A, Romaru, J, Roncon-Albuquerque, R, Roriz, M, Rosa-Calatrava, M, Rose, M, Rosenberger, D, Rossanese, A, Rossignol, B, Rossignol, P, Roy, C, Roze, B, Russell, CD, Ryckaert, S, Holten, AR, Choez, XS, Saba, I, Sadat, M, Saidani, N, Salazar, L, Sales, G, Sallaberry, S, Salvator, H, Sanchez-Miralles, A, Sanchez, O, Sancho-Shimizu, V, Sandhu, G, Sandulescu, O, Santos, M, Sarfo-Mensah, S, Sarton, B, Saviciute, E, Savvidou, P, Scarsbrook, J, Schermer, T, Scherpereel, A, Schneider, M, Schroll, S, Schwameis, M, Scott-Brown, J, Scott, JT, Sedillot, N, Seitz, T, Semaille, C, Semple, MG, Senneville, E, Sequeira, F, Sequeira, T, Shadowitz, E, Shamsah, M, Sharma, P, Shaw, CA, Shaw, V, Shiban, N, Shime, N, Shimizu, H, Shimizu, K, Shrapnel, S, Shum, HP, Mohammed, NS, Sigfrid, L, Silva, C, Silva, MJ, Sin, WC, Skogen, V, Smith, S, Smood, B, Smyth, M, Snacken, M, So, D, Solis, M, Solomon, J, Solomon, T, Somers, E, Sommet, A, Song, MJ, Song, R, Song, T, Sonntagbauer, M, Soum, E, Uva, MS, Sousa, M, Souza-Dantas, V, Sperry, A, Sriskandan, S, Staudinger, T, Stecher, S-S, Stienstra, Y, Stiksrud, B, Streinu-Cercel, A, Strudwick, S, Stuart, A, Stuart, D, Sultana, A, Summers, C, Surovcova, M, Svistunov, AA, Syrigos, K, Sztajnbok, J, Szuldrzynski, K, Teoule, F, Tabrizi, S, Tagherset, L, Talarek, E, Taleb, S, Talsma, J, Van Tan, L, Tanaka, H, Tanaka, T, Taniguchi, H, Tardivon, C, Tattevin, P, Taufik, MA, Tedder, RS, Teixeira, J, Tellier, M-C, Terpstra, P, Terrier, O, Terzi, N, Tessier-Grenier, H, Thibault, V, Thiberville, S-D, Thill, B, Thompson, AAR, Thompson, S, Thomson, D, Thomson, EC, Thuy, DB, Thwaites, RS, Timashev, PS, Timsit, J-F, Vijayaraghavan, BKT, Toki, M, Tonby, K, Santos-Olmo, RMT, Torres, A, Torres, M, Trioux, T, Trieu, HT, Tromeur, C, Trontzas, I, Troost, J, Trouillon, T, Tual, C, Tubiana, S, Tuite, H, Turtle, LCW, Twardowski, P, Uchiyama, M, Ullrich, R, Uribe, A, Usman, A, Val-Flores, L, Van de Velde, S, Van den Berge, M, Van der Feltz, M, Van der Vekens, N, Van der Voort, P, Van der Werf, S, Van Dyk, M, Van Gulik, L, Van Hattem, J, Van Lelyveld, S, Van Netten, C, Vanel, N, Vanoverschelde, H, Vauchy, C, Veislinger, A, Velazco, J, Ventura, S, Verbon, A, Vieira, C, Villanueva, JA, Villar, J, Villeneuve, P-M, Villoldo, A, Chau, NVV, Visseaux, B, Visser, H, Vuorinen, A, Vuotto, F, Wang, C-H, Wei, J, Weil, K, Wesselius, S, Wham, M, Whelan, B, White, N, Wiedemann, A, Wille, K, Wils, E-J, Xynogalas, I, Suen, JY, Yacoub, S, Yamazaki, M, Yazdanpanah, Y, Yelnik, C, Yerkovich, S, Yokoyama, T, Yonis, H, Young, P, Yuliarto, S, Zabbe, M, Zacharowski, K, Zahran, M, Zambon, M, Zanella, A, Zawadka, K, Zayyad, H, Zoufaly, A, Zucman, D, Abdukahil, SA, Abe, R, Abel, L, Absil, L, Acker, A, Adachi, S, Adam, E, Adriao, D, Ainscough, K, Hssain, AA, Tamlihat, YA, Akimoto, T, Al-Dabbous, T, Al-Fares, A, Al Qasim, E, Alalqam, R, Alex, B, Alexandre, K, Alfoudri, H, Alidjnou, KE, Aliudin, J, Allavena, C, Allou, N, Alves, J, Alves, R, Amaral, M, Ammerlaan, H, Ampaw, P, Andini, R, Andrejak, C, Angheben, A, Angoulvant, F, Ansart, S, Antonelli, M, De Brito, CAA, Arabi, Y, Aragao, I, Arcadipane, A, Arenz, L, Arlet, J-B, Arnold-Day, C, Arora, L, Artaud-Macari, E, Asensio, A, Assie, JB, Atique, A, Auchabie, J, Aumaitre, H, Azemar, L, Azoulay, C, Bach, B, Bachelet, D, Baillie, JK, Bak, E, Bakakos, A, Banisadr, F, Barbalho, R, Barclay, WS, Barnikel, M, Barrelet, A, Barrigoto, C, Basmaci, R, Rincon, DFB, Bedossa, A, Behilill, S, Beljantsev, A, Bellemare, D, Beltrame, A, Beluze, M, Benech, N, Benkerrou, D, Bennett, S, Bento, L, Berdal, J-E, Bergeaud, D, Bertolino, L, Bessis, S, Bevilcaqua, S, Bhavsar, K, Bin Humaid, F, Bissuel, F, Biston, P, Bitker, L, Blanco-Schweizer, P, Blot, M, Boccia, F, Bogaert, D, Bompart, F, Booth, G, Borges, D, Borie, R, Bos, J, Bosse, HM, Botelho-Nevers, E, Bouadma, L, Bouchaud, O, Bouchez, S, Bouhmani, D, Bouhour, D, Bouiller, K, Bouillet, L, Bouisse, C, Boureau, A-S, Bouscambert, M, Bouziotis, J, Boxma, B, Boyer-Besseyre, M, Boylan, M, Braga, C, Brandenburger, T, Brazzi, L, Breen, D, Breen, P, Brickell, K, Brozzi, N, Buchtele, N, Buesaquillo, C, Bugaeva, P, Buisson, M, Burhan, E, Bustos, IG, Butnaru, D, Carcel, S, Cabie, A, Cabral, S, Caceres, E, Callahan, M, Calligy, K, Calvache, JA, Camoes, J, Campana, V, Campbell, P, Canepa, C, Cantero, M, Caraux-Paz, P, Cardoso, F, Cardoso, S, Carelli, S, Carlier, N, Carney, G, Carpenter, C, Carret, M-C, Carrier, FM, Carson, G, Casanova, M-L, Cascao, M, Casimiro, J, Cassandra, B, Castaneda, S, Castanheira, N, Castor-Alexandre, G, Castrillon, H, Castro, I, Catarino, A, Catherine, F-X, Cavalin, R, Cavalli, GG, Cavayas, A, Ceccato, A, Cervantes-Gonzalez, M, Chair, A, Chakveatze, C, Chan, A, Chand, M, Chas, J, Chassin, C, Chen, A, Chen, Y-S, Cheng, MP, Cheret, A, Chiarabini, T, Chica, J, Chirouze, C, Chiumello, D, Cho, HJ, Cho, SM, Cholley, B, Cidade, JP, Herreros, JMC, Citarella, BW, Ciullo, A, Clarke, J, Clohisey, S, Codan, C, Cody, C, Coelho, A, Colin, G, Collins, M, Colombo, SM, Combs, P, Connelly, JP, Connor, M, Conrad, A, Contreras, S, Cooke, GS, Copland, M, Cordel, H, Corley, A, Cormican, S, Cornelis, S, Corpuz, AJ, Corvaisier, G, Couffignal, C, Couffin-Cadiergues, S, Courtois, R, D'Orleans, CC, Croonen, S, Crowl, G, Crump, J, Cruz, C, Csete, M, Cucino, A, Cullen, C, Cummings, M, Curley, G, Curlier, E, Custodio, P, D'Aragon, F, Filipe, ADS, Da Silveira, C, D'Ortenzio, E, Dabaliz, A-A, Dagens, AB, Dalton, H, Dalton, J, Daneman, N, Dankwa, EA, Dantas, J, De Castro, N, De Mendoza, D, Franca, RFDO, De Rosa, R, De Silva, T, De Vries, P, Dean, D, Debray, M-P, Dechert, W, Deconninck, L, Decours, R, Delacroix, I, Delavigne, K, Deligiannis, I, Dell'amore, A, Delobel, P, Demonchy, E, Denis, E, Deplanque, D, Depuydt, P, Desai, M, Descamps, D, Desvallee, M, Dewayanti, SR, Diallo, A, Diamantis, S, Dias, A, Diaz, JJD, Diaz, R, Didier, K, Diehl, J-L, Dieperink, W, Dimet, J, Dinot, V, Diouf, A, Dishon, Y, Djossou, F, Docherty, AB, Dong, A, Donnelly, CA, Donnelly, M, Donohue, C, Dorival, C, Douglas, JJ, Douma, R, Dournon, N, Downer, T, Downing, M, Drake, T, Dubee, V, Dubos, F, Ducancelle, A, Dudman, S, Dunning, J, Mangoni, ED, Duranti, S, Durham, L, Dussol, B, Duval, X, Dyrhol-Riise, AM, Eira, C, Vidal, JE, El Sanharawi, M, Elapavaluru, S, Elharrar, B, Elkheir, N, Ellerbroek, J, Ellis, R, Eloy, P, Elshazly, T, Enderle, I, Engelmann, I, Enouf, V, Epaulard, O, Esperatti, M, Esperou, H, Esposito-Farese, M, Estevao, J, Etienne, M, Ettalhaoui, N, Everding, AG, Evers, M, Fabre, I, Faheem, A, Fahy, A, Fairfield, CJ, Faria, P, Farshait, N, Fatoni, AZ, Faure, K, Fayed, M, Feely, N, Fernandes, J, Fernandes, M, Fernandes, S, Ferrao, J, Devouge, EF, Ferraz, M, Ferreira, B, Ferrer-Roca, R, Figueiredo-Mello, C, Flateau, C, Fletcher, T, Florio, LL, Foley, C, Fomin, V, Fonseca, CD, Fonseca, T, Fontela, P, Forsyth, S, Foti, G, Fourn, E, Fowler, R, Franch-Llasat, D, Fraser, C, Fraser, J, Freire, MV, Ribeiro, AF, Friedrich, C, Fry, S, Fuentes, N, Fukuda, M, Gomez-Junyent, J, Gaborieau, V, Gachet, B, Gaci, R, Gagliardi, M, Gagnard, J-C, Gagneux-Brunon, A, Gaiao, S, Gallagher, P, Curto, EG, Gamble, C, Garan, A, Garcia-Gallo, E, Garcia, R, Garot, D, Garrait, V, Gault, N, Gavin, A, Gaymard, A, Gebauer, J, Morlaes, LG, Germano, N, Ghosn, J, Giani, M, Giaquinto, C, Gibson, J, Gigante, T, Gilg, M, Giordano, G, Girvan, M, Gissot, V, Giwangkancana, G, Glikman, D, Glybochko, P, Gnall, E, Goco, G, Goehringer, F, Goepel, S, Goffard, J-C, Golob, J, Gorenne, I, Goujard, C, Goulenok, T, Grable, M, Grandin, EW, Granier, P, Grasselli, G, Green, CA, Greenhalf, W, Greffe, S, Grieco, DL, Griffee, M, Griffiths, F, Grigoras, I, Groenendijk, A, Lordemann, AG, Gruner, H, Gu, Y, Guedj, J, Guellec, D, Guerguerian, A-M, Guerreiro, D, Guery, R, Guillaumot, A, Guilleminault, L, Guimard, T, Haber, D, Hakak, S, Hall, M, Halpin, S, Hamer, A, Hamidfar, R, Hammond, T, Hardwick, H, Harley, K, Harrison, EM, Harrison, J, Hays, L, Heerman, J, Heggelund, L, Hendry, R, Hennessy, M, Henriquez-Trujillo, A, Hentzien, M, Hernandez-Montfort, J, Hidayah, A, Higgins, D, Higgins, E, Hinton, S, Hipolito-Reis, A, Hiraiwa, H, Hiscox, JA, Ho, AYW, Hoctin, A, Hoffmann, I, Hoiting, O, Holt, R, Holter, JC, Horby, P, Horcajada, JP, Hoshino, K, Hough, CL, Hsu, JM-Y, Hulot, J-S, Ijaz, S, Illes, H-G, Inacio, H, Dominguez, CI, Iosifidis, E, Irvine, L, Isgett, S, Isidoro, T, Isnard, M, Itai, J, Ivulich, D, Jaafoura, S, Jabot, J, Jackson, C, Jamieson, N, Jaureguiberry, S, Javidfar, J, Jean-Benoit, Z, Jego, F, Jenum, S, Sotomayor, RJ, Garcia, RNJ, Joseph, C, Joseph, M, Jouvet, P, Jung, H, Kafif, O, Kaguelidou, F, Kali, S, Kalomoiri, S, Kandamby, DH, Kandel, C, Kant, R, Kartsonaki, C, Kasugai, D, Katz, K, Johal, SK, Keating, S, Kelly, A, Kelly, S, Kennedy, L, Kennon, K, Kerroumi, Y, Kestelyn, E, Khalid, I, Khalil, A, Khan, C, Khan, I, Kho, ME, Khoo, S, Kida, Y, Kiiza, P, Kildal, AB, Kimmoun, A, Kindgen-Milles, D, Kitamura, N, Klenerman, P, Bekken, GK, Knight, S, Kobbe, R, Vasconcelos, MK, Korten, V, Kosgei, C, Krawczyk, K, Vecham, PK, Kumar, D, Kurtzman, E, Kutsogiannis, D, Kyriakoulis, K, L'her, E, Lachatre, M, Lacoste, M, Laffey, JG, Lagrange, M, Laine, F, Lambert, M, Lamontagne, F, Langelot-Richard, M, Lantang, EY, Lanza, M, Laouenan, C, Laribi, S, Lariviere, D, Launay, O, Lavie-Badie, Y, Law, A, Le Bihan, C, Le Bris, C, Le Coustumier, E, Le Falher, G, Le Gac, S, Le Hingrat, Q, Le Marechal, M, Le Mestre, S, Le Moing, V, Le Nagard, H, Le Turnier, P, Leon, R, Le, M, Santos, ML, Leal, E, Lee, J, Lee, SH, Lee, T, Leeming, G, Lefebvre, B, Lefebvre, L, Lefevre, B, Lellouche, F, Lemaignen, A, Lemee, V, Lemmink, G, Leone, M, Lepiller, Q, Lescure, F-X, Lesens, O, Lesouhaitier, M, Levy-Marchal, C, Levy, B, Levy, Y, Bassi, GL, Liang, J, Lim, WS, Lina, B, Lind, A, Lingas, G, Lion-Daolio, S, Liu, K, Loforte, A, Lolong, N, Lopes, D, Lopez-Colon, D, Loubet, P, Lucet, JC, Luna, CM, Lungu, O, Luong, L, Luton, D, Lyons, R, Mueller, F, Mueller, KE, Maasikas, O, Macdonald, S, Machado, M, Macheda, G, Sanchez, JM, Madhok, J, Mahieu, R, Mahy, S, Maier, LS, Maillet, M, Maitre, T, Malfertheiner, M, Malik, N, Maltez, F, Malvy, D, Mambert, M, Manda, V, Mandei, JM, Manning, E, Manuel, A, Malaque, CMSA, Marino, F, Mariz, CDA, Eid, CM, Marques, A, Marquis, C, Marsh, B, Marsh, L, Marshall, J, Martelli, CT, Martin-Blondel, G, Martin-Loeches, I, Martin-Quiros, A, Martin, D-A, Martin, E, Martinot, M, Rego, CM, Martins, A, Martins, J, Martucci, G, Marwali, EM, Jimenez, JFM, Maslove, D, Mason, S, Matan, M, Mathieu, D, Mattei, M, Matulevics, R, Maulin, L, Mc Evoy, N, McCarthy, A, McCloskey, C, McConnochie, R, McDermott, S, McDonald, S, McElwee, S, McEvoy, N, McGeer, A, McGuinness, N, McLean, KA, McNicholas, B, Meaney, E, Mear-Passard, C, Mechlin, M, Mele, F, Menon, K, Mentre, F, Mentzer, AJ, Mercier, N, Merckx, A, Mergler, B, Merson, L, Mesquita, A, Meybeck, A, Meynert, AM, Meyssonnier, V, Meziane, A, Mezidi, M, Michelanglei, C, Mihnovits, V, Maldonado, HM, Mone, M, Moin, A, Molina, D, Molinos, E, Monteiro, A, Montes, C, Montrucchio, G, Moore, S, Moore, SC, Morales-Cely, L, Moro, L, Tutillo, DRM, Motos, A, Mouquet, H, Perrot, CM, Moyet, J, Mullaert, J, Munblit, D, Murphy, D, Murris, M, Myrodia, DM, N'guyen, Y, Neant, N, Neb, H, Nekliudov, NA, Neto, R, Neumann, E, Neves, B, Ng, PY, Ng, WY, Choileain, ON, Nichol, A, Nonas, S, Noret, M, Norman, L, Notari, A, Noursadeghi, M, Nowicka, K, Nseir, S, Nunez, JI, Nyamankolly, E, O'Donnell, M, O'Hearn, K, O'Neil, C, Occhipinti, G, Ogston, T, Ogura, T, Oh, T-H, Ohshimo, S, Oinam, BCS, Oliveira, AP, Oliveira, J, Olliaro, P, Ong, DSY, Oosthuyzen, W, Openshaw, PJM, Orozco-Chamorro, CM, Orquera, A, Osatnik, J, Ouamara, N, Ouissa, R, Owyang, C, Oziol, E, Povoas, D, Pagadoy, M, Pages, J, Palacios, M, Palmarini, M, Panarello, G, Panda, PK, Panigada, M, Pansu, N, Papadopoulos, A, Parra, B, Pasquier, J, Patauner, F, Patrao, L, Paul, C, Paul, M, Paulos, J, Paxton, WA, Payen, J-F, Pearse, I, Peek, GJ, Peelman, F, Peiffer-Smadja, N, Peigne, V, Pejkovska, M, Peltan, ID, Pereira, R, Perez, D, Perpoint, T, Pesenti, A, Petrousova, L, Petrov-Sanchez, V, Peytavin, G, Pharand, S, Piagnerelli, M, Picard, W, Picone, O, Piel-Julian, M, Pierobon, C, Pimentel, C, Piroth, L, Pius, R, Piva, S, Plantier, L, Plotkin, D, Poissy, J, Pokorska-Spiewak, M, Poli, S, Pollakis, G, Popielska, J, Postma, DF, Povoa, P, Powis, J, Prapa, S, Prebensen, C, Preiser, J-C, Prestre, V, Price, N, Prinssen, A, Pritchard, MG, Proenca, L, Puechal, O, Purcell, G, Quesada, L, Quist-Paulsen, E, Quraishi, M, Ratsep, I, Rossler, B, Rabaud, C, Rafiq, M, Ragazzo, G, Rainieri, F, Ramakrishnan, N, Ramanathan, K, Rammaert, B, Rapp, C, Rasmin, M, Rau, C, Rebaudet, S, Redl, S, Reeve, B, Reid, L, Reis, R, Remppis, J, Remy, M, Renk, H, Resende, L, Resseguier, A-S, Revest, M, Rewa, O, Reyes, LF, Richardson, D, Richier, L, Riera, J, Rios, AL, Rishu, A, Rispal, P, Risso, K, Nunez, MAR, Rizer, N, Roberto, A, Roberts, S, Robertson, DL, Robineau, O, Roche-Campo, F, Rodari, P, Rodeia, S, Abreu, JR, Roilides, E, Rojek, A, Romaru, J, Roncon-Albuquerque, R, Roriz, M, Rosa-Calatrava, M, Rose, M, Rosenberger, D, Rossanese, A, Rossignol, B, Rossignol, P, Roy, C, Roze, B, Russell, CD, Ryckaert, S, Holten, AR, Choez, XS, Saba, I, Sadat, M, Saidani, N, Salazar, L, Sales, G, Sallaberry, S, Salvator, H, Sanchez-Miralles, A, Sanchez, O, Sancho-Shimizu, V, Sandhu, G, Sandulescu, O, Santos, M, Sarfo-Mensah, S, Sarton, B, Saviciute, E, Savvidou, P, Scarsbrook, J, Schermer, T, Scherpereel, A, Schneider, M, Schroll, S, Schwameis, M, Scott-Brown, J, Scott, JT, Sedillot, N, Seitz, T, Semaille, C, Semple, MG, Senneville, E, Sequeira, F, Sequeira, T, Shadowitz, E, Shamsah, M, Sharma, P, Shaw, CA, Shaw, V, Shiban, N, Shime, N, Shimizu, H, Shimizu, K, Shrapnel, S, Shum, HP, Mohammed, NS, Sigfrid, L, Silva, C, Silva, MJ, Sin, WC, Skogen, V, Smith, S, Smood, B, Smyth, M, Snacken, M, So, D, Solis, M, Solomon, J, Solomon, T, Somers, E, Sommet, A, Song, MJ, Song, R, Song, T, Sonntagbauer, M, Soum, E, Uva, MS, Sousa, M, Souza-Dantas, V, Sperry, A, Sriskandan, S, Staudinger, T, Stecher, S-S, Stienstra, Y, Stiksrud, B, Streinu-Cercel, A, Strudwick, S, Stuart, A, Stuart, D, Sultana, A, Summers, C, Surovcova, M, Svistunov, AA, Syrigos, K, Sztajnbok, J, Szuldrzynski, K, Teoule, F, Tabrizi, S, Tagherset, L, Talarek, E, Taleb, S, Talsma, J, Van Tan, L, Tanaka, H, Tanaka, T, Taniguchi, H, Tardivon, C, Tattevin, P, Taufik, MA, Tedder, RS, Teixeira, J, Tellier, M-C, Terpstra, P, Terrier, O, Terzi, N, Tessier-Grenier, H, Thibault, V, Thiberville, S-D, Thill, B, Thompson, AAR, Thompson, S, Thomson, D, Thomson, EC, Thuy, DB, Thwaites, RS, Timashev, PS, Timsit, J-F, Vijayaraghavan, BKT, Toki, M, Tonby, K, Santos-Olmo, RMT, Torres, A, Torres, M, Trioux, T, Trieu, HT, Tromeur, C, Trontzas, I, Troost, J, Trouillon, T, Tual, C, Tubiana, S, Tuite, H, Turtle, LCW, Twardowski, P, Uchiyama, M, Ullrich, R, Uribe, A, Usman, A, Val-Flores, L, Van de Velde, S, Van den Berge, M, Van der Feltz, M, Van der Vekens, N, Van der Voort, P, Van der Werf, S, Van Dyk, M, Van Gulik, L, Van Hattem, J, Van Lelyveld, S, Van Netten, C, Vanel, N, Vanoverschelde, H, Vauchy, C, Veislinger, A, Velazco, J, Ventura, S, Verbon, A, Vieira, C, Villanueva, JA, Villar, J, Villeneuve, P-M, Villoldo, A, Chau, NVV, Visseaux, B, Visser, H, Vuorinen, A, Vuotto, F, Wang, C-H, Wei, J, Weil, K, Wesselius, S, Wham, M, Whelan, B, White, N, Wiedemann, A, Wille, K, Wils, E-J, Xynogalas, I, Suen, JY, Yacoub, S, Yamazaki, M, Yazdanpanah, Y, Yelnik, C, Yerkovich, S, Yokoyama, T, Yonis, H, Young, P, Yuliarto, S, Zabbe, M, Zacharowski, K, Zahran, M, Zambon, M, Zanella, A, Zawadka, K, Zayyad, H, Zoufaly, A, and Zucman, D

Abstract

BACKGROUND: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. METHODS: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. RESULTS: 'Typical' symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. INTERPRETATION: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Published
2021

7. The tackiness of photocomposite prepregs. Adhesion and Bounding

Author

Gautier, Karine, Barthoumi, S, Gachet, B, Allonas, Xavier, Laboratoire de Physique et Mécanique Textiles (LPMT), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Laboratoire de Photochimie et d'Ingénierie Macromoléculaires (LPIM), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SPI.MECA]Engineering Sciences [physics]/Mechanics [physics.med-ph]
Published
2019

9. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Author

Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, Encephalopathy, Myoclonic Jerk, SYNGAP1, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, fluids and secretions, Medizinische Fakultät, Intellectual disability, mental disorders, Genetics, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Exome, Genetics (clinical), reproductive and urinary physiology, ddc:618, business.industry, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

Published
2016
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11. COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

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Abdukahil, Sheryl, Hssain, Ali, Tamlihat, Younes, Alidjnou, Kazali, de Brito, Carlos, Assie, Jean, Rincon, Diego, Humaid, Felwa, Bosse, Hans, Calvache, Jose, Carrier, François, Cavalli, Giulio, Cheng, Matthew, Cho, Hwa, Cho, Sung, Cidade, Jose, Herreros, Jose, Citarella, Barbara, Colombo, Sebastiano, Corpuz, Arianne, D’orleans, Charles, de Oliveira França, Rafael, Dewayanti, Santi, Diaz, Juan, Douglas, James, Mangoni, Emanuele, Dyrhol-Riise, Anne, Vidal, José, Sanharawi, Mohammed, Everding, Anna, Fatoni, Arie, Devouge, Eglantine, Florio, Letizia, Fonseca, Claudio, Freire, Marcela, Ribeiro, Ana, Curto, Elena, Morlaes, Louis, Grandin, Edward, Grieco, Domenico, Lordemann, Anja, Ho, Antonia, Holter, Jan, Horcajada, Juan, Dominguez, Carmen, Sotomayor, Ruth, García, Ruth, Kandamby, Darshana, Johal, Simreen, Kildal, Anders, Bekken, Gry, Vasconcelos, Malte, Vecham, Pavan, Lantang, Eka, Santos, Marta, Lee, Su, Bassi, Gianluigi, Lim, Wei, Lucet, Jean, Müller, Karl, Sanchez, Juan, Maier, Lars, Sant, Ceila, Eid, Charbel, Martelli, Celina, Rego, Caroline, Marwali, Eva, Jimenez, Juan, Maldonado, Hugo, Tutillo, Diego, Perrot, Clara, Myrodia, Dimitra, Ng, Pauline, Ng, Wing, Choileain, Orna, Oinam, Budha, Oliveira, Ana, Orozco-Chamorro, Claudia, Panda, Prasan, Reyes, Luis, Rios, Ana, Nuñez, Maria, Abreu, Julia, Holten, Aleksander, Choez, Xavier, Shum, Hoi, Mohammed, Nassima, Silva, Maria, Sin, Wai, Song, Myung, Uva, Maria, Svistunov, Magdalena, Thuy, Duong, Vijayaraghavan, Bharath, Santos-Olmo, Rosario, Trieu, Huynh, Villanueva, Joy, Abdukahil, Sheryl Ann, Abe, Ryuzo, Abel, Laurent, Absil, Lara, Acker, Andrew, Adachi, Shingo, Adam, Elisabeth, Adrião, Diana, Ainscough, Kate, Hssain, Ali Ait, Tamlihat, Younes Ait, Akimoto, Takako, Al-Dabbous, Tala, Al-Fares, Abdulrahman, Al Qasim, Eman, Alalqam, Razi, Alex, Beatrice, Alexandre, Kévin, Alfoudri, Huda, Alidjnou, Kazali Enagnon, Aliudin, Jeffrey, Allavena, Clotilde, Allou, Nathalie, Alves, João, Alves, Rita, Amaral, Maria, Ammerlaan, Heidi, Ampaw, Phoebe, Andini, Roberto, Andrejak, Claire, Angheben, Andrea, Angoulvant, François, Ansart, Séverine, Antonelli, Massimo, de Brito, Carlos Alexandre Antunes, Arabi, Yaseen, Aragao, Irene, Arcadipane, Antonio, Arenz, Lukas, Arlet, Jean-Benoît, Arnold-Day, Christel, Arora, Lovkesh, Artaud-Macari, Elise, Asensio, Angel, Assie, Jean Baptiste, Atique, Anika, Auchabie, Johann, Aumaitre, Hugues, Azemar, Laurène, Azoulay, Cécile, Bach, Benjamin, Bachelet, Delphine, Baillie, J. Kenneth, Bak, Erica, Bakakos, Agamemnon, Banisadr, Firouzé, Barbalho, Renata, Barclay, Wendy, Barnikel, Michaela, Barrelet, Audrey, Barrigoto, Cleide, Basmaci, Romain, Rincon, Diego Fernando Bautista, Bedossa, Alexandra, Behilill, Sylvie, Beljantsev, Aleksandr, Bellemare, David, Beltrame, Anna, Beluze, Marine, Benech, Nicolas, Benkerrou, Dehbia, Bennett, Suzanne, Bento, Luís, Berdal, Jan-Erik, Bergeaud, Delphine, Bertolino, Lorenzo, Bessis, Simon, Bevilcaqua, Sybille, Bhavsar, Krishna, Humaid, Felwa Bin, Bissuel, François, Biston, Patrick, Bitker, Laurent, Blanco-Schweizer, Pablo, Blot, Mathieu, Boccia, Filomena, Bogaert, Debby, Bompart, François, Booth, Gareth, Borges, Diogo, Borie, Raphaël, Bos, Jeannet, Bosse, Hans Martin, Botelho-Nevers, Elisabeth, Bouadma, Lila, Bouchaud, Olivier, Bouchez, Sabelline, Bouhmani, Dounia, Bouhour, Damien, Bouiller, Kévin, Bouillet, Laurence, Bouisse, Camille, Boureau, Anne-Sophie, Bouscambert, Maude, Bouziotis, Jason, Boxma, Bianca, Boyer-Besseyre, 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Sarton, Benjamine, Saviciute, Egle, Savvidou, Parthena, Scarsbrook, Joshua, Schermer, Tjard, Scherpereel, Arnaud, Schneider, Marion, Schroll, Stephan, Schwameis, Michael, Scott-Brown, James, Scott, Janet, Sedillot, Nicholas, Seitz, Tamara, Semaille, Caroline, Semple, Malcolm, Senneville, Eric, Sequeira, Filipa, Sequeira, Tânia, Shadowitz, Ellen, Shamsah, Mohammad, Sharma, Pratima, Shaw, Catherine, Shaw, Victoria, Shiban, Nisreen, Shime, Nobuaki, Shimizu, Hiroaki, Shimizu, Keiki, Shrapnel, Sally, Shum, Hoi Ping, Mohammed, Nassima Si, Sigfrid, Louise, Silva, Catarina, Silva, Maria Joao, Sin, Wai Ching, Skogen, Vegard, Smith, Sue, Smood, Benjamin, Smyth, Michelle, Snacken, Morgane, So, Dominic, Solis, Monserrat, Solomon, Joshua, Solomon, Tom, Somers, Emily, Sommet, Agnès, Song, Myung Jin, Song, Rima, Song, Tae, Sonntagbauer, Michael, Soum, Edouard, Uva, Maria Sousa, Sousa, Marta, Souza-Dantas, Vicente, Sperry, Alexandra, Sriskandan, Shiranee, Staudinger, Thomas, Stecher, Stephanie-Susanne, Stienstra, Ymkje, Stiksrud, Birgitte, Streinu-Cercel, Adrian, Streinu-Cercel, Anca, Strudwick, Samantha, Stuart, Ami, Stuart, David, Sultana, Asfia, Summers, Charlotte, Svistunov, Magdalena Surovcová Andrey A., Syrigos, Konstantinos, Sztajnbok, Jaques, Szuldrzynski, Konstanty, Téoulé, François, Tabrizi, Shirin, Tagherset, Lysa, Talarek, Ewa, Taleb, Sara, Talsma, Jelmer, Le Van, Tan, Tanaka, Hiroyuki, Tanaka, Taku, Taniguchi, Hayato, Tardivon, Coralie, Tattevin, Pierre, Taufik, M. Azhari, Tedder, Richard, Teixeira, João, Tellier, Marie-Capucine, Terpstra, Pleun, Terrier, Olivier, Terzi, Nicolas, Tessier-Grenier, Hubert, Thibault, V., Thiberville, Simon-Djamel, Thill, Benoît, Thompson, A., Thompson, Shaun, Thomson, David, Thomson, Emma, Thuy, Duong Bich, Thwaites, Ryan, Timashev, Peter, Timsit, Jean-François, Vijayaraghavan, Bharath Kumar Tirupakuzhi, Toki, Maria, Tonby, Kristian, Santos-Olmo, Rosario Maria Torres, Torres, Antoni, Torres, Margarida, Trioux, Théo, Trieu, Huynh Trung, Tromeur, Cécile, Trontzas, Ioannis, Troost, Jonathan, Trouillon, Tiffany, Tual, Christelle, Tubiana, Sarah, Tuite, Helen, Turtle, Lance, Twardowski, Pawel, Uchiyama, Makoto, Ullrich, Roman, Uribe, Alberto, Usman, Asad, Val-Flores, Luís, van de Velde, Stijn, van den Berge, Marcel, van Der Feltz, Machteld, van Der Vekens, Nicky, van Der Voort, Peter, van Der Werf, Sylvie, van Dyk, Marlice, van Gulik, Laura, van Hattem, Jarne, van Lelyveld, Steven, van Netten, Carolien, Vanel, Noémie, Vanoverschelde, Henk, Vauchy, Charline, Veislinger, Aurélie, Velazco, Jorge, Ventura, Sara, Verbon, Annelies, Vieira, César, Villanueva, Joy Ann, Villar, Judit, Villeneuve, Pierre-Marc, Villoldo, Andrea, van Vinh Chau, Nguyen, Visseaux, Benoit, Visser, Hannah, Vuorinen, Aapeli, Vuotto, Fanny, Wang, Chih-Hsien, Wei, Jia, Weil, Katharina, Wesselius, Sanne, Wham, Murray, Whelan, Bryan, White, Nicole, Wiedemann, Aurélie, Wille, Keith, Wils, Evert-Jan, Xynogalas, Ioannis, Suen, Jacky, Yacoub, Sophie, Yamazaki, Masaki, Yazdanpanah, Yazdan, Yelnik, Cécile, Yerkovich, Stephanie, Yokoyama, Toshiki, Yonis, Hodane, Young, Paul, Yuliarto, Saptadi, Zabbe, Marion, Zacharowski, Kai, Zahran, Maram, Zambon, Maria, Zanella, Alberto, Zawadka, Konrad, Zayyad, Hiba, Zoufaly, Alexander, Zucman, David, Abdukahil, S. A., Abe, R., Abel, L., Absil, L., Acker, A., Adachi, S., Adam, E., Adriao, D., Ainscough, K., Hssain, A. A., Tamlihat, Y. A., Akimoto, T., Al-Dabbous, T., Al-Fares, A., Al Qasim, E., Alalqam, R., Alex, B., Alexandre, K., Alfoudri, H., Alidjnou, K. E., Aliudin, J., Allavena, C., Allou, N., Alves, J., Alves, R., Amaral, M., Ammerlaan, H., Ampaw, P., Andini, R., Andrejak, C., Angheben, A., Angoulvant, F., Ansart, S., Antonelli, M., De Brito, C. A. A., Arabi, Y., Aragao, I., Arcadipane, A., Arenz, L., Arlet, J. -B., Arnold-Day, C., Arora, L., Artaud-Macari, E., Asensio, A., Assie, J. B., Atique, A., Auchabie, J., Aumaitre, H., Azemar, L., Azoulay, C., Bach, B., Bachelet, D., Baillie, J. K., Bak, E., Bakakos, A., Banisadr, F., Barbalho, R., Barclay, W. S., Barnikel, M., Barrelet, A., Barrigoto, C., Basmaci, R., Rincon, D. F. B., Bedossa, A., Behilill, S., Beljantsev, A., Bellemare, D., Beltrame, A., Beluze, M., Benech, N., Benkerrou, D., Bennett, S., Bento, L. I., Berdal, J. -E., Bergeaud, D., Bertolino, L., Bessis, S., Bevilcaqua, S., Bhavsar, K., Humaid, F. B., Bissuel, F., Biston, P., Bitker, L., Blanco-Schweizer, P., Blot, M., Boccia, F., Bogaert, D., Bompart, F., Booth, G., Borges, D., Borie, R., Bos, J., Bosse, H. M., Botelho-Nevers, E., Bouadma, L., Bouchaud, O., Bouchez, S., Bouhmani, D., Bouhour, D., Bouiller, K., Bouillet, L., Bouisse, C., Boureau, A. -S., Bouscambert, M., Bouziotis, J., Boxma, B., Boyer-Besseyre, M., Boylan, M., Braga, C., Brandenburger, T., Brazzi, L., Breen, D., Breen, P., Brickell, K., Brozzi, N., Buchtele, N., Buesaquillo, C., Bugaeva, P., Buisson, M., Burhan, E., Bustos, I. G., Butnaru, D., Carcel, S., Cabie, A., Cabral, S., Caceres, E., Callahan, M., Calligy, K., Calvache, J. A., Camoes, J., Campana, V., Campbell, P., Canepa, C., Cantero, M., Caraux-Paz, P., Cardoso, F., Cardoso, S., Carelli, S., Carlier, N., Carney, G., Carpenter, C., Carret, M. -C., Carrier, F. M., Carson, G., Casanova, M. -L., Cascao, M., Casimiro, J., Cassandra, B., Castaneda, S., Castanheira, N., Castor-Alexandre, G., Castrillon, H., Castro, I., Catarino, A., Catherine, F. -X., Cavalin, R., Cavalli, G. G., Cavayas, A., Ceccato, A., Cervantes-Gonzalez, M., Chair, A., Chakveatze, C., Chan, A., Chand, M., Chas, J., Chassin, C., Chen, A., Chen, Y. -S., Cheng, M. P., Cheret, A., Chiarabini, T., Chica, J., Chirouze, C., Chiumello, D., Cho, H. J., Cho, S. M., Cholley, B., Cidade, J. P., Herreros, J. M. C., Citarella, B. W., Ciullo, A., Clarke, J., Clohisey, S., Codan, C., Cody, C., Coelho, A., Colin, G., Collins, M., Colombo, S. M., Combs, P., Connelly, J. P., Connor, M., Conrad, A., Contreras, S., Cooke, G. S., Copland, M., Cordel, H., Corley, A., Cormican, S., Cornelis, S., Corpuz, A. J., Corvaisier, G., Couffignal, C., Couffin-Cadiergues, S., Courtois, R., D'Orleans, C. C., Croonen, S., Crowl, G., Crump, J., Cruz, C., Csete, M., Cucino, A., Cullen, C., Cummings, M., Curley, G., Curlier, E., Custodio, P., D'Aragon, F., Da Silva Filipe, A., Da Silveira, C., D'Ortenzio, E., Dabaliz, A. -A., Dagens, A. B., Dalton, H., Dalton, J., Daneman, N., Dankwa, E. A., Dantas, J., De Castro, N., De Mendoza, D., De Oliveira Franca, R. F., De Rosa, R., De Silva, T., De Vries, P., Dean, D., Debray, M. -P., Dechert, W., Deconninck, L., Decours, R., Delacroix, I., Delavigne, K., Deligiannis, I., Dell'Amore, A., Delobel, P., Demonchy, E., Denis, E., Deplanque, D., Depuydt, P., Desai, M., Descamps, D., Desvallee, M., Dewayanti, S. R., Diallo, A., Diamantis, S., Dias, A., Diaz, J. J. D., Diaz, R., Didier, K., Diehl, J. -L., Dieperink, W., Dimet, J., Dinot, V., Diouf, A., Dishon, Y., Djossou, F., Docherty, A. B., Dong, A., Donnelly, C. A., Donnelly, M., Donohue, C., Dorival, C., Douglas, J. J., Douma, R., Dournon, N., Downer, T., Downing, M., Drake, T., Dubee, V., Dubos, F., Ducancelle, A., Dudman, S., Dunning, J., Durante-Mangoni, E., Duranti, S., Durham, L., Dussol, B., Duval, X., Dyrhol-Riise, A. M., Eira, C., Vidal, J. E., Sanharawi, M. E., Elapavaluru, S., Elharrar, B., Elkheir, N., Ellerbroek, J., Ellis, R., Eloy, P., Elshazly, T., Enderle, I., Engelmann, I., Enouf, V., Epaulard, O., Esperatti, M., Esperou, H., Esposito-Farese, M., Estevao, J., Etienne, M., Ettalhaoui, N., Everding, A. G., Evers, M., Fabre, I., Faheem, A., Fahy, A., Fairfield, C. J., Faria, P., Farshait, N., Fatoni, A. Z., Faure, K., Fayed, M., Feely, N., Fernandes, J., Fernandes, M., Fernandes, S., Ferrao, J., Devouge, E. F., Ferraz, M., Ferreira, B., Ferrer-Roca, R., Figueiredo-Mello, C., Flateau, C., Fletcher, T., Florio, L. L., Foley, C., Fomin, V., Fonseca, C. D., Fonseca, T., Fontela, P., Forsyth, S., Foti, G., Fourn, E., Fowler, R., Franch-Llasat, D., Fraser, C., Fraser, J., Freire, M. V., Ribeiro, A. F., Friedrich, C., Fry, S., Fuentes, N., Fukuda, M., Gomez-Junyent, J., Gaborieau, V., Gachet, B., Gaci, R., Gagliardi, M., Gagnard, J. -C., Gagneux-Brunon, A., Gaiao, S., Gallagher, P., Curto, E. G., Gamble, C., Garan, A., Garcia-Gallo, E., Garcia, R., Garot, D., Garrait, V., Gault, N., Gavin, A., Gaymard, A., Gebauer, J., Morlaes, L. G., Germano, N., Ghosn, J., Giani, M., Giaquinto, C., Gibson, J., Gigante, T., Gilg, M., Giordano, G., Girvan, M., Gissot, V., Giwangkancana, G., Glikman, D., Glybochko, P., Gnall, E., Goco, G., Goehringer, F., Goepel, S., Goffard, J. -C., Golob, J., Gorenne, I., Goujard, C., Goulenok, T., Grable, M., Grandin, E. W., Granier, P., Grasselli, G., Green, C. A., Greenhalf, W., Greffe, S., Grieco, D. L., Griffee, M., Griffiths, F., Grigoras, I., Groenendijk, A., Lordemann, A. G., Gruner, H., Gu, Y., Guedj, J., Guellec, D., Guerguerian, A. -M., Guerreiro, D., Guery, R., Guillaumot, A., Guilleminault, L., Guimard, T., Haber, D., Hakak, S., Hall, M., Halpin, S., Hamer, A., Hamidfar, R., Hammond, T., Hardwick, H., Harley, K., Harrison, E. M., Harrison, J., Hays, L., Heerman, J., Heggelund, L., Hendry, R., Hennessy, M., Henriquez-Trujillo, A., Hentzien, M., Hernandez-Montfort, J., Hidayah, A., Higgins, D., Higgins, E., Hinton, S., Hipolito-Reis, A., Hiraiwa, H., Hiscox, J. A., Ho, A. Y. W., Hoctin, A., Hoffmann, I., Hoiting, O., Holt, R., Holter, J. C., Horby, P., Horcajada, J. P., Hoshino, K., Hough, C. L., Hsu, J. M. -Y., Hulot, J. -S., Ijaz, S., Illes, H. -G., Inacio, H., Dominguez, C. I., Iosifidis, E., Irvine, L., Isgett, S., Isidoro, T., Isnard, M., Itai, J., Ivulich, D., Jaafoura, S., Jabot, J., Jackson, C., Jamieson, N., Jaureguiberry, S., Javidfar, J., Jean-Benoit, Z., Jego, F., Jenum, S., Sotomayor, R. J., Garcia, R. N. J., Joseph, C., Joseph, M., Jouvet, P., Jung, H., Kafif, O., Kaguelidou, F., Kali, S., Kalomoiri, S., Kandamby, D. H., Kandel, C., Kant, R., Kartsonaki, C., Kasugai, D., Katz, K., Johal, S. K., Keating, S., Kelly, A., Kelly, S., Kennedy, L., Kennon, K., Kerroumi, Y., Kestelyn, E., Khalid, I., Khalil, A., Khan, C., Khan, I., Kho, M. E., Khoo, S., Kida, Y., Kiiza, P., Kildal, A. B., Kimmoun, A., Kindgen-Milles, D., Kitamura, N., Klenerman, P., Bekken, G. K., Knight, S., Kobbe, R., Vasconcelos, M. K., Korten, V., Kosgei, C., Krawczyk, K., Vecham, P. K., Kumar, D., Kurtzman, E., Kutsogiannis, D., Kyriakoulis, K., L'Her, E., Lachatre, M., Lacoste, M., Laffey, J. G., Lagrange, M., Laine, F., Lambert, M., Lamontagne, F., Langelot-Richard, M., Lantang, E. Y., Lanza, M., Laouenan, C., Laribi, S., Lariviere, D., Launay, O., Lavie-Badie, Y., Law, A., Le Bihan, C., Le Bris, C., Le Coustumier, E., Le Falher, G., Le Gac, S., Le Hingrat, Q., Le Marechal, M., Le Mestre, S., Le Moing, V., Le Nagard, H., Le Turnier, P., Leon, R., Le, M., Santos, M. L., Leal, E., Lee, J., Lee, S. H., Lee, T., Leeming, G., Lefebvre, B., Lefebvre, L., Lefevre, B., Lellouche, F., Lemaignen, A., Lemee, V., Lemmink, G., Leone, M., Lepiller, Q., Lescure, F. -X., Lesens, O., Lesouhaitier, M., Levy-Marchal, C., Levy, B., Levy, Y., Bassi, G. L., Liang, J., Lim, W. S., Lina, B., Lind, A., Lingas, G., Lion-Daolio, S., Liu, K., Loforte, A., Lolong, N., Lopes, D., Lopez-Colon, D., Loubet, P., Lucet, J. C., Luna, C. M., Lungu, O., Luong, L., Luton, D., Lyons, R., Muller, F., Muller, K. E., Maasikas, O., Macdonald, S., Machado, M., Macheda, G., Sanchez, J. M., Madhok, J., Mahieu, R., Mahy, S., Maier, L. S., Maillet, M., Maitre, T., Malfertheiner, M., Malik, N., Maltez, F., Malvy, D., Mambert, M., Manda, V., Mandei, J. M., Manning, E., Manuel, A., Sant, C. M., Malaque, A., Marino, F., De Araujo Mariz, C., Eid, C. M., Marques, A., Marquis, C., Marsh, B., Marsh, L., Marshall, J., Martelli, C. T., Martin-Blondel, G., Martin-Loeches, I., Martin-Quiros, A., Martin, D. -A., Martin, E., Martinot, M., Rego, C. M., Martins, A., Martins, J., Martucci, G., Marwali, E. M., Jimenez, J. F. M., Maslove, D., Mason, S., Matan, M., Mathieu, D., Mattei, M., Matulevics, R., Maulin, L., Mc Evoy, N., Mccarthy, A., Mccloskey, C., Mcconnochie, R., Mcdermott, S., Mcdonald, S., Mcelwee, S., Mcevoy, N., Mcgeer, A., Mcguinness, N., Mclean, K. A., Mcnicholas, B., Meaney, E., Mear-Passard, C., Mechlin, M., Mele, F., Menon, K., Mentre, F., Mentzer, A. J., Mercier, N., Merckx, A., Mergler, B., Merson, L., Mesquita, A., Meybeck, A., Meynert, A. M., Meyssonnier, V., Meziane, A., Mezidi, M., Michelanglei, C., Mihnovits, V., Maldonado, H. M., Mone, M., Moin, A., Molina, D., Molinos, E., Monteiro, A., Montes, C., Montrucchio, G., Moore, S., Moore, S. C., Morales-Cely, L., Moro, L., Tutillo, D. R. M., Motos, A., Mouquet, H., Perrot, C. M., Moyet, J., Mullaert, J., Munblit, D., Murphy, D., Murris, M., Myrodia, D. M., N'Guyen, Y., Neant, N., Neb, H., Nekliudov, N. A., Neto, R., Neumann, E., Neves, B., Ng, P. Y., Ng, W. Y., Choileain, O. N., Nichol, A., Nonas, S., Noret, M., Norman, L., Notari, A., Noursadeghi, M., Nowicka, K., Nseir, S., Nunez, J. I., Nyamankolly, E., O'Donnell, M., O'Hearn, K., O'Neil, C., Occhipinti, G., Ogston, T., Ogura, T., Oh, T. -H., Ohshimo, S., Oinam, B. C. S., Oliveira, A. P., Oliveira, J., Olliaro, P., Ong, D. S. Y., Oosthuyzen, W., Openshaw, P. J. M., Orozco-Chamorro, C. M., Orquera, A., Osatnik, J., Ouamara, N., Ouissa, R., Owyang, C., Oziol, E., Povoas, D., Pagadoy, M., Pages, J., Palacios, M., Palmarini, M., Panarello, G., Panda, P. K., Panigada, M., Pansu, N., Papadopoulos, A., Parra, B., Pasquier, J., Patauner, F., Patrao, L., Paul, C., Paul, M., Paulos, J., Paxton, W. A., Payen, J. -F., Pearse, I., Peek, G. J., Peelman, F., Peiffer-Smadja, N., Peigne, V., Pejkovska, M., Peltan, I. D., Pereira, R., Perez, D., Perpoint, T., Pesenti, A., Petrousova, L., Petrov-Sanchez, V., Peytavin, G., Pharand, S., Piagnerelli, M., Picard, W., Picone, O., Piel-Julian, M., Pierobon, C., Pimentel, C., Piroth, L., Pius, R., Piva, S., Plantier, L., Plotkin, D., Poissy, J., Pokorska-Spiewak, M., Poli, S., Pollakis, G., Popielska, J., Postma, D. F., Povoa, P., Powis, J., Prapa, S., Prebensen, C., Preiser, J. -C., Prestre, V., Price, N., Prinssen, A., Pritchard, M. 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S., Saba, I., Sadat, M., Saidani, N., Salazar, L., Sales, G., Sallaberry, S., Salvator, H., Sanchez-Miralles, A., Sanchez, O., Sancho-Shimizu, V., Sandhu, G., Sandulescu, O., Santos, M., Sarfo-Mensah, S., Sarton, B., Saviciute, E., Savvidou, P., Scarsbrook, J., Schermer, T., Scherpereel, A., Schneider, M., Schroll, S., Schwameis, M., Scott-Brown, J., Scott, J. T., Sedillot, N., Seitz, T., Semaille, C., Semple, M. G., Senneville, E., Sequeira, F., Sequeira, T., Shadowitz, E., Shamsah, M., Sharma, P., Shaw, C. A., Shaw, V., Shiban, N., Shime, N., Shimizu, H., Shimizu, K., Shrapnel, S., Shum, H. P., Mohammed, N. S., Sigfrid, L., Silva, C., Silva, M. J., Sin, W. C., Skogen, V., Smith, S., Smood, B., Smyth, M., Snacken, M., So, D., Solis, M., Solomon, J., Solomon, T., Somers, E., Sommet, A., Song, M. J., Song, R., Song, T., Sonntagbauer, M., Soum, E., Uva, M. S., Sousa, M., Souza-Dantas, V., Sperry, A., Sriskandan, S., Staudinger, T., Stecher, S. -S., Stienstra, Y., Stiksrud, B., Streinu-Cercel, A., Strudwick, S., Stuart, A., Stuart, D., Sultana, A., Summers, C., Svistunov, M. S. A. A., Syrigos, K., Sztajnbok, J., Szuldrzynski, K., Teoule, F., Tabrizi, S., Tagherset, L., Talarek, E., Taleb, S., Talsma, J., Le Van, T., Tanaka, H., Tanaka, T., Taniguchi, H., Tardivon, C., Tattevin, P., Taufik, M. A., Tedder, R. S., Teixeira, J., Tellier, M. -C., Terpstra, P., Terrier, O., Terzi, N., Tessier-Grenier, H., Thibault, V., Thiberville, S. -D., Thill, B., Thompson, A. A. R., Thompson, S., Thomson, D., Thomson, E. C., Thuy, D. B., Thwaites, R. S., Timashev, P. S., Timsit, J. -F., Vijayaraghavan, B. K. T., Toki, M., Tonby, K., Santos-Olmo, R. M. T., Torres, A., Torres, M., Trioux, T., Trieu, H. T., Tromeur, C., Trontzas, I., Troost, J., Trouillon, T., Tual, C., Tubiana, S., Tuite, H., Turtle, L. C. W., Twardowski, P., Uchiyama, M., Ullrich, R., Uribe, A., Usman, A., Val-Flores, L., Van De Velde, S., Van Den Berge, M., Van Der Feltz, M., Van Der Vekens, N., Van Der Voort, P., Van Der Werf, S., Van Dyk, M., Van Gulik, L., Van Hattem, J., Van Lelyveld, S., Van Netten, C., Vanel, N., Vanoverschelde, H., Vauchy, C., Veislinger, A., Velazco, J., Ventura, S., Verbon, A., Vieira, C., Villanueva, J. A., Villar, J., Villeneuve, P. -M., Villoldo, A., Van Vinh Chau, N., Visseaux, B., Visser, H., Vuorinen, A., Vuotto, F., Wang, C. -H., Wei, J., Weil, K., Wesselius, S., Wham, M., Whelan, B., White, N., Wiedemann, A., Wille, K., Wils, E. -J., Xynogalas, I., Suen, J. Y., Yacoub, S., Yamazaki, M., Yazdanpanah, Y., Yelnik, C., Yerkovich, S., Yokoyama, T., Yonis, H., Young, P., Yuliarto, S., Zabbe, M., Zacharowski, K., Zahran, M., Zambon, M., Zanella, A., Zawadka, K., Zayyad, H., Zoufaly, A., Zucman, D., Apollo - University of Cambridge Repository, Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Department of Mathematics and Statistics, Wichita State University, Service d'Anésthésie Réanimation [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by the Department for International Development and Wellcome Trust [215091/Z/18/Z], the Bill and Melinda Gates Foundation [OPP1209135]. Country-specific support was provided by the Canadian Institutes of Health Research Coronavirus Rapid Research Funding Opportunity [OV2170359], the Health Research Board Ireland [CTN Award 2014-012], National Institute for Health Research (NIHR) [award CO-CIN-01], the Medical Research Council (MRC) [grant MC_PC_19059], the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], NIHR HPRU in Respiratory Infections at Imperial College London with PHE [award 200927], Liverpool Experimental Cancer Medicine Centre [grant reference C18616/A25153], NIHR Biomedical Research Centre at Imperial College London [IS-BRC-1215-20013], EU Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) [FP7 project 602525], National Institutes of Health (NIH) [UL1TR002240], and NIHR Clinical Research Network infrastructure support. We acknowledge the generous support of all ISARIC Partners who have contributed data and expertise to this analysis, with or without dedicated funding. The views expressed are those of the authors and not necessarily those of the funders or institutions listed above., European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), Infectious diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Medical Research Council (MRC), National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, UK Research and Innovation, and BOZEC, Erwan

Subjects
Male, Abdominal pain, Pediatrics, 030204 cardiovascular system & hematology, Logistic regression, 0302 clinical medicine, Diagnosis, wc_505, Medicine, ISARIC Clinical Characterisation Group, Prospective Studies, 030212 general & internal medicine, Child, wa_105, COVID-19, Case definition, SARS-CoV-2, Symptoms, Aged, Female, Hospitalization, Hospitals, Humans, Middle Aged, General Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Infectious Diseases, Cohort, Vomiting, qw_160, medicine.symptom, Life Sciences & Biomedicine, Diagnosi, Human, Microbiology (medical), medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Nausea, Symptom, Age and sex, Microbiology, 1117 Public Health and Health Services, 03 medical and health sciences, Hospital, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Science & Technology, business.industry, 1103 Clinical Sciences, Prospective Studie, Observational study, wf_100, business
Abstract

Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Published
2021
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12. Systematic review on oral antibacterial relay therapy for acute staphylococcal prosthetic joint infections treated with debridement, antibiotics and implant retention (DAIR).

Author

Gachet B, Dechartres A, Senneville E, and Robineau O

Abstract

Background: The management of acute prosthetic joint infections (PJIs) often involves a debridement, antibiotics and implant retention (DAIR) strategy., Objective: Our objective was to conduct a systematic review and a network meta-analysis (NMA) to assess the comparative effectiveness of available oral antimicrobial regimens for the treatment of acute staphylococcal PJIs treated with DAIR., Methods: We conducted a systematic review searching articles from databases creation until 31 December 2023. We included articles on acute staphylococcal PJIs managed with DAIR with an oral antibiotic regimen relaying the initial management. The primary outcome was the remission rate., Results: Out of the 2421 studies screened, six studies completed the systematic review criteria: one randomized controlled trial and five observational studies. There was heterogeneity in patients' populations, duration and posology of treatments, definition of outcome and length of follow-up. Studies revealed 10 antibiotic regimens and most data focusing on five combinations recommended by the IDSA's guidelines: rifampicin associated to fluoroquinolone, clindamycin, cycline, linezolid or trimethoprim-sulfamethoxazole. Treatment comparisons were often secondary, without adjustment for confounding factors, resulting in a high risk of bias. Owing to inconsistencies a complete analysis, including an NMA was not possible., Conclusion: The available data highlight five companions to rifampicin, however, there is insufficient evidence to compare them. The literature does not provide a basis for rationalizing alternatives when rifampicin cannot be used., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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13. IncC plasmid genome rearrangements influence the vertical and horizontal transmission tradeoff in Escherichia coli .

Author

Allain M, Morel-Journel T, Condamine B, Gibeaux B, Gachet B, Gschwind R, Denamur E, and Landraud L

Subjects
Gene Transfer, Horizontal genetics, Genome, Bacterial genetics, Anti-Bacterial Agents pharmacology, Escherichia coli Infections microbiology, Escherichia coli Infections transmission, Plasmids genetics, Escherichia coli genetics, Drug Resistance, Multiple, Bacterial genetics, Conjugation, Genetic
Abstract

It has been shown that an evolutionary tradeoff between vertical (host growth rate) and horizontal (plasmid conjugation) transmissions contributes to global plasmid fitness. As conjugative IncC plasmids are important for the spread of multidrug resistance (MDR), in a broad range of bacterial hosts, we investigated vertical and horizontal transmissions of two multidrug-resistant IncC plasmids according to their backbones and MDR-region rearrangements, upon plasmid entry into a new host. We observed plasmid genome deletions after conjugation in three diverse natural Escherichia coli clinical strains, varying from null to high number depending on the plasmid, all occurring in the MDR region. The plasmid burden on bacterial fitness depended more on the strain background than on the structure of the MDR region, with deletions appearing to have no impact. Besides, we observed an increase in plasmid transfer rate, from ancestral host to new clinical recipient strains, when the IncC plasmid was rearranged. Finally, using a second set of conjugation experiments, we investigated the evolutionary tradeoff of the IncC plasmid during the critical period of plasmid establishment in E. coli K-12, by correlating the transfer rates of deleted or non-deleted IncC plasmids and their costs on the recipient strain. Plasmid deletions strongly improved conjugation efficiency with no negative growth effect. Our findings indicate that the flexibility of the MDR-region of the IncC plasmids can promote their dissemination, and provide diverse opportunities to capture new resistance genes. In a broader view, they suggest that the vertical-horizontal transmission tradeoff can be manipulated by the plasmid to improve its fitness., Competing Interests: The authors declare no conflict of interest.

Published
2024
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14. Prevalence, causes, and clinical associations of anemia in patients with systemic sclerosis: A cohort study.

Author

Gachet B, Jouvray M, Koether V, Collet A, Morell-Dubois S, Sanges S, Sobanski V, Hachulla E, and Launay D

Abstract

Background: Anemia is considered a risk factor of severity in systemic sclerosis. Yet, limited data are available on the frequency and causes of anemia in systemic sclerosis. The objectives of our study were to determine the frequency and causes of anemia in systemic sclerosis, to analyze the clinical and biological characteristics of patients with anemia, and to assess the association between anemia and systemic sclerosis prognosis., Methods: We conducted a prospective single-center study from January 2017 to May 2022. Patients underwent a hemoglobin assay and a standardized etiological workup to determine the causes of anemia at the initial visit. Clinical and biological parameters were compared between patients with anemia and those with normal hemoglobin levels. We followed up patients until May 2023 and compared their survival., Results: A total of 502 systemic sclerosis patients, including 107 diffuse cutaneous systemic sclerosis, were included. At enrollment, 100 patients had anemia. The primary cause of anemia was iron deficiency (40%). Among the 32 patients with iron deficiency-associated anemia who underwent gastrointestinal exploration, 56% had digestive bleeding, with upper gastrointestinal tract involvement being the main cause (90%). Patients with anemia at enrollment had higher systemic sclerosis severity scores and more gastrointestinal symptoms compared to patients without anemia (p < 0.05). They exhibited higher systolic pulmonary artery pressure, lower anemia-corrected diffusing capacity for carbon monoxide, and lower forced vital capacity (p < 0.05). During follow-up, 65 patients (14.8%) died. After adjusting for age, systemic sclerosis subtypes, forced vital capacity, and pulmonary arterial hypertension, anemia at inclusion was associated with a higher mortality rate (hazard ratio: 1.94 (95% confidence interval: 1.39-2.48), p = 0.02)., Conclusion: Our study shows a high frequency of anemia among patients with systemic sclerosis. Most anemias are due to iron deficiency, and gastrointestinal exploration can identify bleeding in the majority of the cases. In addition, our study confirms that systemic sclerosis patients with anemia have a more severe disease and a higher mortality rate., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Published
2024
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15. Immune checkpoint inhibitors-associated cranial nerves involvement: a systematic literature review on 136 patients.

Author

Pichon S, Aigrain P, Lacombe C, Lemarchant B, Ledoult E, Koether V, Leurs A, Zebian G, Launay D, Gachet B, and Levy C

Subjects
Humans, Cranial Nerves drug effects, Cranial Nerve Diseases chemically induced, Immune Checkpoint Inhibitors adverse effects
Abstract

Objective: Describe the demographic data and clinical phenotype of cranial palsy induced by immune checkpoint inhibitors (CNP-ICI)., Methods: A systematic literature review of the literature was performed in Pubmed, Web of Science, and Embase, including 68 articles and 136 patients (PROSPERO no. CRD42024517262)., Results: Out of the 1205 articles screened, 68 articles were included after fulfilling the inclusion criteria, for a total of 136 patients. All articles were case reports and case series. In the cohort studied, 52% of patients were treated with anti PD-1/PDL-1 therapies, 14% with anti CTLA-4 therapies, and 34% with a combination of anti CTLA-4 and anti PD-1/PDL-1 therapies. The facial nerve was the most affected cranial nerve, involved in 38% of cases, followed by the optic nerve (35%), the cochleovestibular nerve (12%), and the abducens nerve (10%). The median time from the initial immune checkpoint inhibitor (ICI) injection to the onset CNP-ICI was 10 weeks (IQR 4-20). Magnetic resonance imaging demonstrated contrast enhancement or abnormal signal of the affected nerve in 43% of cases. Cerebrospinal fluid analysis indicated lymphocytic pleocytosis in 59% of cases. At the onset of immune-related adverse events, 89% of patients discontinued immunotherapy, and 92% received treatment for CNP-ICI. Treatment regimens included corticosteroids in 86% of cases, intravenous immunoglobulin in 21%, and plasma exchange in 5.1%. Among the whole population, 33% achieved recovery, 52% showed clinical improvement, 16% remained stable, and 3% experienced worsening of their condition. Rechallenge with immunotherapy was significantly associated with the emergence of new immune-related Adverse Events (irAEs)., Conclusion: ICI therapy may lead to cranial nerve involvement, particularly affecting the facial nerve, typically presenting around 10 weeks after treatment initiation. While corticosteroid therapy often resulted in patient improvement, rechallenging with ICIs were associated with new irAEs., (© 2024. The Author(s).)

Published
2024
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16. Dalbavancin as suppressive therapy for implant-related infections: a case series with therapeutic drug monitoring and review of the literature.

Author

Lafon-Desmurs B, Gachet B, Hennart B, Valentin B, Roosen G, Degrendel M, Loiez C, Beltrand E, D'Elia P, Migaud H, Robineau O, and Senneville E

Subjects
Humans, Retrospective Studies, Male, Aged, Female, Middle Aged, Aged, 80 and over, Teicoplanin analogs & derivatives, Teicoplanin therapeutic use, Teicoplanin administration & dosage, Drug Monitoring, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents administration & dosage, Prosthesis-Related Infections drug therapy
Abstract

Implant-related infections may need suppressive antibiotic therapy (SAT). We describe a SAT strategy using dalbavancin with therapeutic drug monitoring (TDM). This is a retrospective bicentric study of patients with implant-related infection who received dalbavancin SAT between January 2021 and September 2023. Fifteen patients were included. Median number of injections was 4 (IQR: 2-7). Median time between two reinjections was 57 days (IQR 28-82). Dalbavancin plasma concentrations were above 4 mg/L for 97.9% of dosages (93/95) and above 8 mg/L for 85% (81/95). These results support the use of dalbavancin SAT for implant-related infections., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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17. Outcomes in orthopedic device infections due to Streptococcus agalactiae: a retrospective cohort study.

Author

Diarra A, Gachet B, Beltrand E, Dartus J, Loiez C, Fiaux E, Patoz P, Robineau O, and Senneville E

Subjects
Humans, Retrospective Studies, Male, Female, Aged, Middle Aged, Risk Factors, Aged, 80 and over, Treatment Failure, Comorbidity, Treatment Outcome, Streptococcus agalactiae, Streptococcal Infections microbiology, Streptococcal Infections drug therapy, Streptococcal Infections epidemiology, Prosthesis-Related Infections microbiology, Prosthesis-Related Infections drug therapy, Anti-Bacterial Agents therapeutic use
Abstract

Background: Group B streptococci (Streptococcus agalactiae) (GBS) is a rare cause of prosthetic joint infection (PJI) occurring in patients with comorbidities and seems to be associated with a poor outcome. Depiction of GBS PJI is scarce in the literature., Methods: A retrospective survey in 2 referral centers for bone joint infections was done Patients with a history of PJI associated with GBS between 2014 and 2019 were included. A descriptive analysis of treatment failure was done. Risk factors of treatment failure were assessed., Results: We included 61 patients. Among them, 41 had monomicrobial (67%) infections. The median duration of follow-up was 2 years (interquartile range 2.35) Hypertension, obesity, and diabetes mellitus were the most reported comorbidities (49%, 50%, and 36% respectively). Death was observed in 6 individuals (10%) during the initial management. The rate of success was 63% (26/41). Removal of the material was not associated with remission (p = 0.5). We did not find a specific antibiotic regimen associated with a better outcome., Conclusion: The results show that S. agalactiae PJIs are associated with high rates of comorbidities and a high treatment failure rate with no optimal treatment so far., (© 2024. The Author(s).)

Published
2024
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18. Dissemination of IncI plasmid encoding bla CTX-M-1 is not hampered by its fitness cost in the pig's gut.

Author

Allain M, Mahérault AC, Gachet B, Martinez C, Condamine B, Magnan M, Kempf I, Denamur E, and Landraud L

Subjects
Animals, Swine, Anti-Bacterial Agents, Plasmids genetics, beta-Lactamases genetics, beta-Lactamases metabolism, Escherichia coli, Escherichia coli Infections microbiology
Abstract

Multiresistance plasmids belonging to the IncI incompatibility group have become one of the most pervasive plasmid types in extended-spectrum beta-lactamase-producing Escherichia coli of animal origin. The extent of the burden imposed on the bacterial cell by these plasmids seems to modulate the emergence of "epidemic" plasmids. However, in vivo data in the natural environment of the strains are scarce. Here, we investigated the cost of a bla CTX-M-1 -IncI1 epidemic plasmid in a commensal E. coli animal strain, UB12-RC, before and after oral inoculation of 15 6- to 8-week- old specific-pathogen-free pigs. Growth rate in rich medium was determined on (i) UB12-RC and derivatives, with or without plasmid, in vivo and/or in vitro evolved, and (ii) strains that acquired the plasmid in the gut during the experiment. Although bla CTX-M-1 -IncI1 plasmid imposed no measurable burden on the recipient strain after conjugation and during the longitudinal carriage in the pig's gut, we observed a significant difference in the bacterial growth rate between IncI1 plasmid-carrying and plasmid-free isolates collected during in vivo carriage. Only a few mutations on the chromosome of the UB12-RC derivatives were detected by whole-genome sequencing. RNA-Seq analysis of a selected set of these strains showed that transcriptional responses to the bla CTX-M-1 -IncI1 acquisition were limited, affecting metabolism, stress response, and motility functions. Our data suggest that the effect of IncI plasmid on host cells is limited, fitness cost being insufficient to act as a barrier to IncI plasmid spread among natural population of E. coli in the gut niche., Competing Interests: The authors declare no conflict of interest.

Published
2023
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19. Deep mutational scanning reveals the molecular determinants of RNA polymerase-mediated adaptation and tradeoffs.

Author

Choudhury A, Gachet B, Dixit Z, Faure R, Gill RT, and Tenaillon O

Subjects
Mutation, Phenotype, DNA-Directed RNA Polymerases genetics, DNA-Directed RNA Polymerases metabolism, Transcription, Genetic
Abstract

RNA polymerase (RNAP) is emblematic of complex biological systems that control multiple traits involving trade-offs such as growth versus maintenance. Laboratory evolution has revealed that mutations in RNAP subunits, including RpoB, are frequently selected. However, we lack a systems view of how mutations alter the RNAP molecular functions to promote adaptation. We, therefore, measured the fitness of thousands of mutations within a region of rpoB under multiple conditions and genetic backgrounds, to find that adaptive mutations cluster in two modules. Mutations in one module favor growth over maintenance through a partial loss of an interaction associated with faster elongation. Mutations in the other favor maintenance over growth through a destabilized RNAP-DNA complex. The two molecular handles capture the versatile RNAP-mediated adaptations. Combining both interaction losses simultaneously improved maintenance and growth, challenging the idea that growth-maintenance tradeoff resorts only from limited resources, and revealing how compensatory evolution operates within RNAP., (© 2023. Springer Nature Limited.)

Published
2023
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20. The bacterial genetic determinants of Escherichia coli capacity to cause bloodstream infections in humans.

Author

Burgaya J, Marin J, Royer G, Condamine B, Gachet B, Clermont O, Jaureguy F, Burdet C, Lefort A, de Lastours V, Denamur E, Galardini M, and Blanquart F

Subjects
Humans, Escherichia coli, Genes, Bacterial, Virulence genetics, Phylogeny, Escherichia coli Infections genetics, Escherichia coli Infections microbiology, Sepsis genetics
Abstract

Escherichia coli is both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostic, prevention and treatment is still lacking. We used a collection of 912 BSI and 370 commensal E. coli isolates collected in France over a 17-year period (2000-2017). We compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity continuously increased through 1980, 2000, to 2010. Together our findings imply that E. coli exhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Burgaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2023
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21. Systemic sclerosis associated interstitial lung disease: a survey of current practices in France.

Author

Nicolas A, Leroy S, Mouthon L, Uzunhan Y, Cottin V, Mekinian A, Queyrel V, Hachulla E, Gachet B, Launay D, and Martis N

Abstract

Background: Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc)., Objective: We performed an overview of the diagnostic approaches, follow-up and treatment strategies used in France for the management of SSc-associated ILD (SSc-ILD)., Design Structured Nationwide Online Surveymethods: A structured nationwide online survey was submitted to participants via the French Medical Societies for Internal Medicine and Pneumology, and research groups on SSc-ILD from May 2018 to June 2020. The 79 multiple-choice and 9 open-ended questions covered the screening of ILD at baseline, monitoring of patients with established SSc-ILD and its management. Fourteen optional vignettes exploring different clinical phenotypes of SSc-ILD were submitted to evaluate therapeutic decisions., Results: All of the 93 participants screened SSc patients for ILD at baseline with 83 (89%) participants relying on a systematic chest computed tomography (CT) scan. Pulmonary function tests (PFT) were prescribed by 87 (94%) participants at baseline and during follow-up. Treatment was started based on abnormal PFT (95%), chest CT scan characteristics (89%), worsening dyspnoea (72%) and drop in SpO 2 during 6-min walk tests (66%). First-line therapy was cyclophosphamide (CYC) (89%), mycophenolate mofetil (MMF) (83%) and prednisone (73%). Rituximab as second-line immunosuppressive therapy (41%) was preferred to antifibrotic agents (18%), and a median daily prednisone dose of 10 mg (interquartile range, 10-15) was prescribed by 73% participants. Extensive SSc-ILD with worsening PFT (95%), regardless of diffusing capacity for carbon monoxide values and skin extension, were more likely to be treated, and CYC was favoured over MMF ( p  < 0.01). Extensive SSc-ILD with disease duration of less than 5 years was also a criterium for treatment initiation., Conclusion: This overview of practices in diagnosis, follow-up and treatment of SSc-ILD in France describes real-life management of patients. It highlights heterogeneity in this management and gaps in current strategies that should be addressed to improve and harmonize clinical practices in SSc-ILD., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Published
2023
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22. Do Anti-Biofilm Antibiotics Have a Place in the Treatment of Diabetic Foot Osteomyelitis?

Author

Senneville E, Gachet B, Blondiaux N, and Robineau O

Abstract

The choice of antibiotic regimens for use in patients presenting with diabetic foot osteomyelitis and their duration differs according to the situation. Antibiotics play a more important role in the medical option where no infected bone has been resected, while their role is reduced but not negligible in the case of surgical options. Some studies have reported the presence of biofilm structures in bone samples taken from patients with diabetic foot osteomyelitis, which raises the question of the place of anti-biofilm antibiotic regimens in this setting. During the last two decades, clinical studies have suggested a potential benefit for anti-biofilm antibiotics, mainly rifampicin against staphylococci and fluoroquinolones against gram-negative bacilli. However, no data from randomized controlled studies have been reported so far. The present work provides a summary of the available data on the question of the place of anti-biofilm antibiotics for the treatment of diabetic foot osteomyelitis, but also the potential limitations of such treatments.

Published
2023
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23. A Microbiota-Dependent Response to Anticancer Treatment in an In Vitro Human Microbiota Model: A Pilot Study With Hydroxycarbamide and Daunorubicin.

Author

Hobson CA, Vigué L, Magnan M, Chassaing B, Naimi S, Gachet B, Claraz P, Storme T, Bonacorsi S, Tenaillon O, and Birgy A

Subjects
Daunorubicin pharmacology, Feces microbiology, Humans, Pilot Projects, RNA, Ribosomal, 16S genetics, Gastrointestinal Microbiome, Microbiota
Abstract

Background: Anticancer drug efficacy is linked to the gut microbiota's composition, and there is a dire need to better understand these interactions for personalized medicine. In vitro microbiota models are promising tools for studies requiring controlled and repeatable conditions. We evaluated the impact of two anticancer drugs on human feces in the MiniBioReactor Array (MBRA) in vitro microbiota system., Methods: The MBRA is a single-stage continuous-flow culture model, hosted in an anaerobic chamber. We evaluated the effect of a 5-day treatment with hydroxycarbamide or daunorubicine on the fecal bacterial communities of two healthy donors. 16S microbiome profiling allowed analysis of microbial richness, diversity, and taxonomic changes., Results: In this host-free setting, anticancer drugs diversely affect gut microbiota composition. Daunorubicin was associated with significant changes in alpha- and beta-diversity as well as in the ratio of Firmicutes/Bacteroidetes in a donor-dependent manner. The impact of hydroxycarbamide on microbiota composition was not significant., Conclusion: We demonstrated, for the first time, the impact of anticancer drugs on human microbiota composition, in a donor- and molecule-dependent manner in an in vitro human microbiota model. We confirm the importance of personalized studies to better predict drug-associated-dysbiosis in vivo , linked to the host's response to treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hobson, Vigué, Magnan, Chassaing, Naimi, Gachet, Claraz, Storme, Bonacorsi, Tenaillon and Birgy.)

Published
2022
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24. Rifabutin versus rifampicin bactericidal and antibiofilm activities against clinical strains of Staphylococcus spp. isolated from bone and joint infections.

Author

Thill P, Robineau O, Roosen G, Patoz P, Gachet B, Lafon-Desmurs B, Tetart M, Nadji S, Senneville E, and Blondiaux N

Subjects
Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Biofilms, Humans, Microbial Sensitivity Tests, Rifabutin pharmacology, Rifabutin therapeutic use, Rifampin pharmacology, Rifampin therapeutic use, Staphylococcal Infections drug therapy, Staphylococcus
Abstract

Background: Staphylococci account for approximately 60% of periprosthetic joint infections (PJIs). Rifampicin (RMP) combination therapy is generally considered to be the treatment of choice for staphylococcal PJIs but carries an important risk of adverse events and drug-drug interactions. Rifabutin (RFB) shares many of the properties of rifampicin but causes fewer adverse events., Objectives: To compare the minimal inhibitory concentration (MIC), the minimum bactericidal concentrations (MBC), and the minimum biofilm eradication concentrations (MBEC) of rifabutin and rifampicin for staphylococcal clinical strains isolated from PJIs., Methods: 132 clinical strains of rifampicin-susceptible staphylococci [51 Staphylococcus aureus (SA), 48 Staphylococcus epidermidis (SE) and 33 other coagulase-negative staphylococci (CoNS)] were studied. The MBC and the MBEC were determined using the MBEC® Assay for rifabutin and rifampicin and were compared., Results: When compared with the rifampicin MIC median value, the rifabutin MIC median value was significantly higher for SA (P < 0.05), but there was no statistically significant difference for SE (P = 0.25) and CoNS (P = 0.29). The rifabutin MBC median value was significantly higher than that of rifampicin for SA (P = 0.003) and was lower for SE (P = 0.003) and CoNS (P = 0.03). Rifabutin MBEC median value was statistically lower than that of rifampicin for all strains tested., Conclusions: Using the determination of MBEC values, our study suggests that rifabutin is more effective than rifampicin against clinical strains of Staphylococcus spp. obtained from PJIs. Using MBECs instead of MICs seems to be of interest when considering biofilms. In vivo higher efficacy of rifabutin when compared with rifampicin needs to be confirmed., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2022
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25. Severe SARS-CoV-2 patients develop a higher specific T-cell response.

Author

Demaret J, Lefèvre G, Vuotto F, Trauet J, Duhamel A, Labreuche J, Varlet P, Dendooven A, Stabler S, Gachet B, Bauer J, Prevost B, Bocket L, Alidjinou EK, Lambert M, Yelnik C, Meresse B, Dubuquoy L, Launay D, Dubucquoi S, Montaigne D, Woitrain E, Maggiotto F, Bou Saleh M, Top I, Elsermans V, Jeanpierre E, Dupont A, Susen S, Brousseau T, Poissy J, Faure K, and Labalette M

Abstract

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot)., Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T-CoV-Spot assay, we assessed T-cell and antibody responses in mild, moderate and severe SARS-CoV-2 patients and in control samples collected before the outbreak., Results: Specific T cells were assessed in 60 consecutive patients (mild, n  = 26; moderate, n  = 10; and severe patients, n  = 24) during their follow-up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in n  = 60 (100%), n  = 56 (93.3%), n  = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T-CoV-Spot assay showed a specificity of 96.7% (95% CI, 88.5-99.6%) and a specificity of 90.3% (75.2-98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti-S1 and anti-RBD serum antibodies., Conclusion: IFNγ T-CoV-Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long-lived memory T-cell response after vaccination. Our study demonstrates that SARS-CoV-2 patients developing a severe disease achieve a higher adaptive immune response., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Published
2020
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26. Highly reactive photothermal initiating system based on sulfonium salts for the photoinduced thermal frontal cationic polymerization of epoxides: a way to create carbon-fiber reinforced polymers.

Author

Gachet B, Lecompère M, Croutxé-Barghorn C, Burr D, L'Hostis G, and Allonas X

Abstract

A new combination of sulfonium salts has been investigated to cure opaque and thick carbon composite materials through photoinduced thermal frontal polymerization reaction. The photopolymerization occurs at the surface of the cycloaliphatic epoxide through the excitation of a triarylsulfonium salt and releases enough heat to decompose an alkyl-based sulfonium salt acting as a latent thermal initiator. Thus, a thermal front propagates into the medium leading to the polymerization of the whole sample. Thermal properties and optimal parameters are investigated to obtain frontal polymerization in the depth of the material. Front velocities were as high as 12.9 cm min -1 and were found to increase with an increasing concentration of thermal sulfonium salt. The effect of an addition of carbon filler is investigated with a concentration of up to 50 wt%, which allows the formation of a composite material with a high content of carbon without the need for thermal post curing., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Published
2020
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27. Airway Mucus Restricts Neisseria meningitidis Away from Nasopharyngeal Epithelial Cells and Protects the Mucosa from Inflammation.

Author

Audry M, Robbe-Masselot C, Barnier JP, Gachet B, Saubaméa B, Schmitt A, Schönherr-Hellec S, Léonard R, Nassif X, and Coureuil M

Subjects
Cell Line, Humans, Models, Theoretical, Mucositis immunology, Mucositis microbiology, Epithelial Cells immunology, Epithelial Cells microbiology, Immunologic Factors metabolism, Mucus metabolism, Nasopharynx immunology, Nasopharynx microbiology, Neisseria meningitidis immunology
Abstract

Neisseria meningitidis is an inhabitant of the nasopharynx, from which it is transmitted from person to person or disseminates in blood and becomes a harmful pathogen. In this work, we addressed colonization of the nasopharyngeal niche by focusing on the interplay between meningococci and the airway mucus that lines the mucosa of the host. Using Calu-3 cells grown in air interface culture (cells grown with the apical domain facing air), we studied meningococcal colonization of the mucus and the host response. Our results suggested that N. meningitidis behaved like commensal bacteria in mucus, without interacting with human cells or actively transmigrating through the cell layer. As a result, type IV pili do not play a role in this model, and meningococci did not trigger a strong innate immune response from the Calu-3 cells. Finally, we have shown that this model is suitable for studying interaction of N. meningitidis with other bacteria living in the nasopharynx and that Streptococcus mitis , but not Moraxella catarrhalis , can promote meningococcal growth in this model. IMPORTANCE N. meningitidis is transmitted from person to person by aerosol droplets produced by breathing, talking, or coughing or by direct contact with a contaminated fluid. The natural reservoir of N. meningitidis is the human nasopharynx mucosa, located at the back of the nose and above the oropharynx. The means by which meningococci cross the nasopharyngeal wall is still under debate, due to the lack of a convenient and relevant model mimicking the nasopharyngeal niche. Here, we took advantage of Calu-3 cells grown in air interface culture to study how meningococci colonize the nasopharyngeal niche. We report that the airway mucus is both a niche for meningococcal growth and a protective barrier against N. meningitidis infection. As such, N. meningitidis behaves like commensal bacteria and is unlikely to induce infection without an external trigger., (Copyright © 2019 Audry et al.)

Published
2019
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28. Advantage of the F2:A1:B- IncF Pandemic Plasmid over IncC Plasmids in In Vitro Acquisition and Evolution of bla CTX-M Gene-Bearing Plasmids in Escherichia coli.

Author

Mahérault AC, Kemble H, Magnan M, Gachet B, Roche D, Le Nagard H, Tenaillon O, Denamur E, Branger C, and Landraud L

Subjects
Anti-Bacterial Agents pharmacology, Cefotaxime pharmacology, Escherichia coli drug effects, Microbial Sensitivity Tests, Mutation genetics, beta-Lactamases genetics, Escherichia coli enzymology, Escherichia coli genetics, Plasmids genetics, beta-Lactamases metabolism
Abstract

Despite a fitness cost imposed on bacterial hosts, large conjugative plasmids play a key role in the diffusion of resistance determinants, such as CTX-M extended-spectrum β-lactamases. Among the large conjugative plasmids, IncF plasmids are the most predominant group, and an F2:A1:B- IncF-type plasmid encoding a CTX-M-15 variant was recently described as being strongly associated with the emerging worldwide Escherichia coli sequence type 131 (ST131)-O25b:H4 H 30Rx/C2 sublineage. In this context, we investigated the fitness cost of narrow-range F-type plasmids, including the F2:A1:B- IncF-type CTX-M-15 plasmid, and of broad-range C-type plasmids in the K-12-like J53-2 E. coli strain. Although all plasmids imposed a significant fitness cost to the bacterial host immediately after conjugation, we show, using an experimental-evolution approach, that a negative impact on the fitness of the host strain was maintained throughout 1,120 generations with the IncC-IncR plasmid, regardless of the presence or absence of cefotaxime, in contrast to the F2:A1:B- IncF plasmid, whose cost was alleviated. Many chromosomal and plasmid rearrangements were detected after conjugation in transconjugants carrying the IncC plasmids but not in transconjugants carrying the F2:A1:B- IncF plasmid, except for insertion sequence (IS) mobilization from the fliM gene leading to the restoration of motility of the recipient strains. Only a few mutations occurred on the chromosome of each transconjugant throughout the experimental-evolution assay. Our findings indicate that the F2:A1:B- IncF CTX-M-15 plasmid is well adapted to the E. coli strain studied, contrary to the IncC-IncR CTX-M-15 plasmid, and that such plasmid-host adaptation could participate in the evolutionary success of the CTX-M-15-producing pandemic E. coli ST131-O25b:H4 lineage., (Copyright © 2019 Mahérault et al.)

Published
2019
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29. Acute toxoplasmosis in an immunocompetent traveller to Senegal.

Author

Gachet B, Elbaz A, Boucher A, Robineau O, Fréalle E, Ajana F, Delannoy PY, Thellier D, Boussekey N, Meybeck A, and Senneville E

Subjects
Antibodies, Protozoan blood, France, Humans, Immunoglobulin G blood, Immunoglobulin M blood, Male, Middle Aged, Senegal, Toxoplasma immunology, Toxoplasmosis pathology, Immunocompetence, Toxoplasmosis diagnosis, Toxoplasmosis immunology, Travel
Published
2018
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30. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

Author

Mignot C, von Stülpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, Rastetter A, Gachet B, Marie Y, Korenke GC, Borggraefe I, Hoffmann-Zacharska D, Szczepanik E, Rudzka-Dybała M, Yiş U, Çağlayan H, Isapof A, Marey I, Panagiotakaki E, Korff C, Rossier E, Riess A, Beck-Woedl S, Rauch A, Zweier C, Hoyer J, Reis A, Mironov M, Bobylova M, Mukhin K, Hernandez-Hernandez L, Maher B, Sisodiya S, Kuhn M, Glaeser D, Weckhuysen S, Myers CT, Mefford HC, Hörtnagel K, Biskup S, Lemke JR, Héron D, Kluger G, and Depienne C

Abstract

Objective: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations., Methods: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed., Results: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15., Conclusions: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Published
2016
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