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2. Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

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Florescu, S, Stanciu, D, Zaharia, M, Kosa, A, Codreanu, D, Kidwai, A, Masood, S, Kaye, C, Coutts, A, MacKay, L, Summers, C, Polgarova, P, Farahi, N, Fox, E, McWilliam, S, Hawcutt, D, Rad, L, O’Malley, L, Whitbread, J, Jones, D, Dore, R, Saunderson, P, Kelsall, O, Cowley, N, Wild, L, Thrush, J, Wood, H, Austin, K, Bélteczki, J, Magyar, I, Fazekas, Á, Kovács, S, Szőke, V, Donnelly, A, Kelly, M, Smyth, N, O’Kane, S, McClintock, D, Warnock, M, Campbell, R, McCallion, E, Azaiz, A, Charron, C, Godement, M, Geri, G, Vieillard-Baron, A, Johnson, P, McKenna, S, Hanley, J, Currie, A, Allen, B, McGoldrick, C, McMaster, M, Mani, A, Mathew, M, Kandeepan, R, Vignesh, C, TV, B, Ramakrishnan, N, James, A, Elvira, E, Jayakumar, D, Pratheema, R, Babu, S, Ebenezer, R, Krishnaoorthy, S, Ranganathan, L, Ganesan, M, Shree, M, Guilder, E, Butler, M, Cowdrey, K-A, Robertson, M, Ali, F, McMahon, E, Duffy, E, Chen, Y, Simmonds, C, McConnochie, R, O’Connor, C, El-Khawas, K, Richardson, A, Hill, D, Commons, R, Abdelkharim, H, Saxena, M, Muteithia, M, Dobell-Brown, K, Jha, R, Kalogirou, M, Ellis, C, Krishnamurthy, V, O’Connor, A, Thurairatnam, S, Mukherjee, D, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Maloney, G, Kittridge, L, Solesbury, A, Ramos, A, Collins, D, Brickell, K, Reid, L, Smyth, M, Breen, P, Spain, S, Curley, G, McEvoy, N, Geoghegan, P, Clarke, J, Silversides, J, McGuigan, P, Ward, K, O’Neill, A, Finn, S, Wright, C, Green, J, Collins, É, Knott, C, Smith, J, Boschert, C, Slieker, K, Ewalds, E, Sanders, A, Wittenberg, W, Geurts, H, Poojara, L, Sara, T, Nand, K, Reeve, B, Dechert, W, Phillips, B, Oritz-Ruiz de Gordoa, L, Affleck, J, Shaikh, A, Murray, A, Ramanan, M, Frakking, T, Pinnell, J, Robinson, M, Gledhill, L, Wood, T, Sanghavi, R, Bhonagiri, D, Ford, M, Parikh, HG, Avard, B, Nourse, M, McDonald, B, Edmunds, N, Hoiting, O, Peters, M, Rengers, E, Evers, M, Prinssen, A, Morgan, M, Cole, J, Hill, H, Davies, M, Williams, A, Thomas, E, Davies, R, Wise, M, Grimm, P, Soukup, J, Wetzold, R, Löbel, M, Starke, L, Lellouche, F, Lizotte, P, Declerq, P, Antoine, M, Stephanie, G, Jean-Pierre, E, François, B, Marion, B, Philippe, R, Pourcine, F, Monchi, M, Luis, D, Mercier, R, Sagnier, A, Verrier, N, Caplin, C, Richecoeu, J, Combaux, D, Siami, S, Aparicio, C, Vautier, S, Jeblaoui, A, Lemaire-Brunel, D, D'Aragon, F, Carbonneau, E, Leblond, J, Plantefeve, G, Leparco, C, Contou, D, Fartoukh, M, Courtin, L, Labbe, V, Voiriot, G, Salhi, S, Chassé, M, Carrier, F, Boumahni, D, Benettaib, F, Ghamraoui, A, Sement, A, Gachet, A, Hanisch, A, Haffiane, A, Boivin, A-H, Barreau, A, Guerineau, E, Poupblanc, S, Egreteau, P, Lefevre, M, Bocher, S, Le Loup, G, Le Guen, L, Carn, V, Bertel, M, Antcliffe, D, Templeton, M, Rojo, R, Coghlan, P, Smee, J, Barker, G, Finn, A, Kreb, G, Hoff, U, Hinrichs, C, Nee, J, Mackay, E, Cort, J, Whileman, A, Spencer, T, Spittle, N, Beavis, S, Padmakumar, A, Dale, K, Hawes, J, Moakes, E, Gascoyne, R, Pritchard, K, Stevenson, L, Cooke, J, Nemeth-Roszpopa, K, Gauli, B, Bastola, S, Muller, G, Nay, M-A, Kamel, T, Benzekri, D, Jacquier, S, Runge, I, Mathonnet, A, Barbier, F, Bretagnol, A, Carter, J, Van Der Heyden, K, Mehrtens, J, Morris, A, Morgan, S, Burke, T, Mercier, E, Chartier, D, Salmon, C, Dequin, P-F, Garot, D, Bellemare, D, Cloutier, È, Daher, R, Costerousse, O, Boulanger, M-C, Couillard-Chénard, É, Lauzier, F, Francoeur, C, Francois, B, Gay, A, Anne-Laure, F, Ramali, M, HC, O, Ghosh, A, Osagie, R, Arachchige, M, Hartley, M, Cheung, W, Wong, H, Seigne, P, Eustace, J, O'Callaghan, A-M, O'Brien, F, Bamford, P, Reid, A, Cawley, K, Faulkner, M, Pickering, C, Raj, A, Tsinaslanidis, G, Khade, R, Agha, G, Sekiwala, R, Smith, T, Brewer, C, Gregory, J, Limb, J, Cowton, A, O’Brien, J, Postlethwaite, K, Malakouti, S, Music, E, Ricketts, D, King, A, Clermont, G, Bart, R, Mayr, F, Schoenling, A, Andreae, M, Shetty, V, Brant, E, Malley, B, Donadee, C, Sackrowitz, R, Weissman, A, Yealy, D, Barton, D, Talia, N, Nikitas, N, Wells, C, Lankester, L, McMillan, H, Van den Oever, H, Kruisdijk-Gerritsen, A, Haidar, G, Bain, W, Barbash, I, Fitzpatrick, M, Franz, C, Kitsios, G, Moghbeli, K, Rosborough, B, Shah, F, Suber, T, Pulletz, M, Williams, P, Birch, J, Wiseman, S, Horton, S, Alegria, A, Turki, S, Elsefi, T, Crisp, N, Allen, L, Truman, N, Smith, M, Chukkambotla, S, Goddard, W, Duberley, S, Khan, M, Kazi, A, Simpson, J, Duke, G, Chan, P, Carter, B, Hunter, S, Voigt, I, Schueler, R, Blank, E, Hüning, V, Steffen, M, Goralski, P, Litton, E, Regli, A, Pellicano, S, Palermo, A, Eroglu, E, Bihari, S, Laver, RD, Jin, X, Brown, J, McIntyre, J, French, C, Bates, S, Towns, M, Yang, Y, McGain, F, McCullagh, I, Cairns, T, Hanson, H, Patel, B, Clement, I, Evetts, G, Touma, O, Holland, S, Hodge, C, Taylor, H, Alderman, M, Barnes, N, Da Rocha, J, Smith, C, Brooks, N, Weerasinghe, T, Sinclair, J-A, Abusamra, Y, Doherty, R, Cudlipp, J, Singh, R, Yu, H, Daebis, A, Ng, C, Kendrick, S, Saran, A, Makky, A, Greener, D, Rowe-Leete, L, Edwards, A, Bland, Y, Dolman, R, Foster, T, Laffey, J, McNicholas, B, Scully, M, Casey, S, Kernan, M, Brennan, A, Rangan, R, Tully, R, Corbett, S, McCarthy, A, Duffy, O, Burke, D, Linnett, V, Sanderson, A, Ritzema, J, Wild, H, Lucas, R, Marriott, Y, Andric, Z, Cviljevic, S, Br, R, Zapalac, M, Mirković, G, Khare, D, Pinder, M, Gopinath, A, Kannan, T, Dean, S, Vanmali, P, Depuydt, P, De Waele, J, De Bus, L, Fierens, J, Bracke, S, Vermassen, J, Vermeiren, D, Pugh, R, Lean, R, Qiu, X, Scanlan, J, Evans, A, Davies, G, Lewis, J, Plesnikova, Y, Khoud, A, Coetzee, S, Puxty, K, Cathcart, S, Rimmer, D, Bagot, C, Scott, K, Martin, L, Yusuff, H, Isgro, G, Brightling, C, Bourne, M, Craner, M, Boyles, R, Alexander, B, Roberts, T, Nelli, A, Rosenstein-Sisson, R, Speyer, R, Pech, Y, McCullough, J, Tallott, M, Vazquez-Grande, G, Marten, N, Liu, T, Siddiqui, A, Khanal, S, Amatya, S, Szakmany, T, Cherian, S, Williams, G, James, C, Waters, A, Prout, R, Stedman, R, Davies, L, Pegler, S, Kyeremeh, L, Moorhouse, L, Arbane, G, Marotti, M, Bociek, A, Campos, S, Van Nieuwkoop, K, Ottens, T, Visser, Y, Van den Berg, L, Van der Kraan-Donker, A, Brett, S, Arias, S, Hall, R, Paneru, H, Koirala, S, Paudel, P, Wilson, M, Vaara, S, Pettilä, L, Heinonen, J, Pettilä, V, Jain, S, Gupta, A, Holbrook, C, Antoine, P, Meziani, F, Allam, H, Cattelan, J, Clere-Jehl, R, Helms, J, Kummerlen, C, Merdji, H, Monnier, A, Rahmani, H, Studer, A, Schneider, F, Castelain, V, Morel, G, L’Hotellier, S, Ochin, E, Vanjak, C, Rouge, P, Bendjemar, L, Albert, M, Serri, K, Cavayas, A, Duplaix, M, Williams, V, Catorze, NJTADS, Pereira, TNAL, Ferreira, RMC, Bastos, JMPS, Batista, TMO, Badie, J, Berdaguer, F, Malfroy, S, Mezher, C, Bourgoin, C, Moneger, G, Bouvier, E, Muñoz-Bermúdez, R, Marin-Corral, J, Degracia, A, Gómez, F, López, M, Aceto, R, Aghemo, A, Badalamenti, S, Brunetta, E, Cecconi, M, Ciccarelli, M, Constantini, E, Greco, M, Folci, M, Selmi, C, Voza, A, Henning, J, Bonner, S, Hugill, K, Cirstea, E, Wilkinson, D, Jones, J, Altomy, M, Karlikowski, M, Sutherland, H, Wilhelmsen, E, Woods, J, North, J, Pletz, M, Hagel, S, Ankert, J, Kolanos, S, Bloos, F, Simons, K, Van Zuylen, T, Bouman, A, Kumar, N, Panwar, R, Poulter, A-L, Sunkara, K, Szigligeti, G, Leszkoven, J, Rochwerg, B, Karachi, T, Oczkowski, S, Centofanti, J, Millen, T, Sundaran, D, Hollos, L, Turns, M, Walsh, J, Al Qasim, E, Alswaidan, L, Hegazy, M, Arishi, H, Al Amri, A, AlQahtani, S, Naidu, B, Tlayjeh, H, Hussain, S, Al Enezi, F, Abdukahil, SA, Hopkins, P, Noble, H, O’Reilly, K, Mehta, R, Wong, O, Makanju, E, Rao, D, Sikondari, N, Saha, S, Corcoran, E, Pappa, E, Cockrell, M, Donegan, C, Balaie, M, Nickoleit-Bitzenberger, D, Schaaf, B, Meermeier, W, Prebeg, K, Azzaui, H, Hower, M, Brieger, K-G, Elender, C, Sabelhaus, T, Riepe, A, Akamp, C, Kremling, J, Klein, D, Landsiedel-Mechenbier, E, Laha, S, Verlander, M, Jha, A, Megarbane, B, Voicu, S, Deye, N, Malissin, I, Sutterlin, L, Mrad, A, Lehalleur, A, Naim, G, Nguyen, P, Ekhérian, J-M, Boué, Y, Sidéris, G, Vodovar, D, Guérin, E, Grant, C, Brain, M, Mineall, S, Paramasivam, E, Wilby, E, Ogg, B, Howcroft, C, Aspinwall, A, Charlton, S, Gould, R, Mistry, D, Awan, S, Bedford, C, Carr-Wilkinson, J, Hall, A, Gardiner-Hill, C, Maloney, C, Brunskill, N, Watchorn, O, Hardy, C, Qureshi, H, Flint, N, Nicholson, S, Southin, S, Ghattaoraya, A, Harding, D, O’Halloran, S, Collins, A, Smith, E, Trues, E, Borgatta, B, Turner-Bone, I, Reddy, A, Wilding, L, Wilson, C, Surti, Z, Aneman, A, Miller, J, White, H, Estensen, K, Morrison, L, Sutton, J, Cooper, M, Warnapura, L, Agno, R, Sathianathan, P, Shaw, D, Ijaz, N, Spong, A, Sabaretnam, S, Burns, D, Lang, E, Tate, M, Fischer, R, Biradar, V, Soar, N, Golden, D, Davey, M, Seaman, R, Osborne, A, Bannard-Smith, J, Clark, R, Birchall, K, Henry, J, Pomeroy, F, Quayle, R, Wylie, K, Sukuraman, A, John, M, Sibin, S, Leditschke, A, Finnis, M, Jongebloed, K, Khwaja, K, Campisi, J, Van Vonderen, M, Pietersma, M, Vrolijk, L, Kampschreur, L, Van Gulik, L, Makowski, A, Misztal, B, Haider, S, Liao, A, Squires, R, Oborska, A, Kayani, A, Kalchko-Veyssal, S, Prabakaran, R, Hadebe, B, KalchkoVeyssal, S, Williams, T, Song, R, Morpeth, S, Lai, V, Habraken, H, Stewart, R, Mwaura, E, Mew, L, Wren, L, Willams, F, Sutherland, S-B, Rebello, R, Shehabi, Y, Al-Bassam, W, Hulley, A, Kadam, U, Sathianathan, K, Innes, R, Doble, P, Graham, L, Shovelton, C, Dean, T, Salahuddin, N, Aryal, D, Koirala, K, Rai, N, Luitel, S, Seppelt, I, Whitehead, C, Lowrey, J, Gresham, R, Masters, K, Hamlyn, V, Hawkins, N, Roynon-Reed, A, Cutler, S, Lewis, S, Lazaro, J, Newman, T, Aravindan, L, Asghar, A, Bartholomew, J, Bayne, M, Beddows, S, Birch, C, Brend, M, Byrne, R, Campbell, D, Campbell, H, Chambers, E, Clinton, A, Collins, J, Crawshaw, S, Dawson, LA, Donaldson, K, Drake, C, Dyas, S, Ellis, Y, Gilmour, K, Goodwin, J, Halden, S, Hall, AS, Hanson, J, Harper, H, Harrison, S, Hayes, A, Hodgson, H, Hurford, S-A, Jackson, S, Levett, C, Lock, S, Lockett, T, Logan, M, Lomme, K, Luo, J, Marsh, E, Mguni, N, Monaghan, H, Murphy, S, Muzengi, N, Naz, M, O'Kell, E, Oliver, A, O'Reilly, J, Pearson, K, Porter, D, Potter, A, Rook, C, Rounds, C, Sheffield, J, Shirley, K, Siewersk, C, Skinner, T, Speight, H, Sutu, M, Unsworth, A, Van’t Hoff, W, Walker, S, Williams, H, Williamson, D, Williamson, JD, Duan, E, Tsang, J, Patterson, L, Austin, P, Chapman, S, Cabrelli, L, Fletcher, S, Nortje, J, Fottrell-Gould, D, Randell, G, Stammers, K, Healey, G, Pinto, M, Borrill, Z, Duncan, T, Ustianowski, A, Uriel, A, Eltayeb, A, Alfonso, J, Hey, S, Shaw, J, Fox, C, Lindergard, G, Charles, B, Blackledge, B, Connolly, K, Harris, J, Cuesta, J, Xavier, K, Purohit, D, Elhassan, M, Haldeos, A, Vincent, R, Abdelrazik, M, Jenkins, S, Ganesan, A, Kumar, R, Carter, D, Bakthavatsalam, D, Frater, A, Saleem, M, Everitt, R, Hacking, D, Zaman, M, Elmahi, E, Jones, A, Hall, K, Phillips, M, Terrill, L, Mills, G, Raithatha, A, Bauchmuller, K, Ryalls, K, Harrington, K, Bowler, H, Sall, J, Bourne, R, Gross, J, Massey, N, Adebambo, O, Long, M, Tony, K, Juffermans, N, Koopmans, M, Dujardin, R, Alderink, B, Rowland, M, Hutton, P, Bashyal, A, Davidson, N, Hird, C, Chhablani, M, Phalod, G, Kirkby, A, Archer, S, Netherton, K, Reschreiter, H, Camsooksai, J, Patch, S, Humphrey, C, Flynn, G, Harrington, C, Kruger, P, Walsham, J, Meyer, J, Harward, M, Jones, C, Sathe, S, Roche, L, Davies, E, Skinner, D, Gaylard, J, Newman, J, Pogson, D, Rose, S, Daly, Z, Brimfield, L, Nown, A, Parekh, D, Bergin, C, Bates, M, McGhee, C, Lynch, D, Bhandal, K, Tsakiridou, K, Bamford, A, Cooper, L, Whitehouse, T, Veenith, T, Forster, E, O'Connell, M, Sim, M, Hay, S, Henderson, S, Nygren, M, Valentine, E, Katary, A, Bell, G, Wilcox, L, Mataliotakis, M, Smith, P, Ali, M, Isguzar, A, Phull, M-K, Zaidi, A, Pogreban, T, Rosaroso, L, Harvey, D, Lowe, B, Meredith, M, Ryan, L, Schouten, J, Pickkers, P, Roovers, N, Klop-Riehl, M, Van der Eng, H, Sloots-Cuppen, S, Preijers, L, Van Oosten, N, Moine, P, Heming, N, Maxime, V, Bossard, I, Nicholier, T, Clair, B, Orlikowski, D, Bounab, R, Abdeladim, L, Baker, S, Duroux, M, Ratcliffe, M, Sy, E, Mailman, J, Lee, S, Gupta, C, Kassir, S, López, R, Rodríguez-Gómez, J, Cárcel, S, Carmona, R, De la Fuente, C, Rodriguez, M, Jan Hassing, R, Greven, F, Huijbens, D, Roebers, L, Verheij, H, Miles, H, Attokaran, A, Buehner, U, Williams, E, Chapman, M, O’Connor, S, Glasby, K, Rivett, J, Brown, N, Kutsogiannis, D, Thompson, P, Rooney, K, Rodden, N, Thomson, N, McGlynn, D, Abel, L, Gemmell, L, Sundaram, R, Hornsby, J, Walden, A, Keating, L, Frise, M, Rai, S, Bartley, S, Schuster-Bruce, M, Pitts, S, Miln, R, Purandare, L, Vamplew, L, Dempster, D, Gummadi, M, Dormand, N, Wang, S, Spivey, M, Bean, S, Burt, K, Moore, L, Hammonds, F, Richards, C, Campbell, L, Smyth, K, Day, C, Zitter, L, Benyon, S, Singh, J, Lynch, C, Mikusek, J, Deacon, B, Turner, K, Baker, E, Hickey, J, Champanerkar, S, Aitken, L, LewisProsser, L, Ahmad, N, Wiles, M, Willson, J, Grecu, I, Martin, J, Wrey Brown, C, Arias, A-M, Bevan, E, Westlake, S, Craven, T, Hope, D, Singleton, J, Clark, S, McCulloch, C, Biddie, S, Welters, I, Hamilton, D, Williams, K, Waugh, V, Mulla, S, Waite, A, Roman, J, Martinez, M, Johnston, B, Puthucheary, Z, Martin, T, Santos, F, Uddin, R, Fernandez, M, Seidu, F, Somerville, A, Pakats, M-L, Begum, S, Shahid, T, Presneill, J, Barge, D, Byrne, K, Janin, P, Yarad, E, Bass, F, Hammond, N, Vuylsteke, A, Chan, C, Victor, S, Waterson, S, McNamara, R, Boardman, M, Gattas, D, Buhr, H, Coles, J, Matsa, R, Gellamucho, M, Creagh-Brown, B, Marriot, C, Salberg, A, Zouita, L, Stone, S, Michalak, N, Donlon, S, Mtuwa, S, Mayangao, I, Verula, J, Burda, D, Harris, C, Jones, E, Bradley, P, Tarr, E, Harden, L, Piercy, C, Nolan, J, Kerslake, I, Cook, T, Simpson, T, Dalton, J, Demetriou, C, Mitchard, S, Ramos, L, White, K, Johnson, T, Headdon, W, Spencer, S, White, A, Howie, L, Reay, M, Watts, A, Traverse, E, Jennings, S, Anumakonda, V, Tuckwell, C, Harrow, K, Matthews, J, McGarry, K, Moore, V, Smith, L, Summerfield, A, Dark, P, Harvey, A, Doonan, R, McMorrow, L, Knowles, K, Pendlebury, J, Perez, J, Marsden, T, Taylor, M, Michael, A, Collis, M, Claxton, A, Habeichi, W, Horner, D, Slaughter, M, Thomas, V, Proudfoot, N, Keatley, C, Donnison, P, Casey, R, Irving, B, Matimba-Mupaya, W, Reed, C, Anthony, A, Trim, F, Cambalova, L, Robertson, D, Wilson, A, Hulme, J, Kannan, S, Kinney, F, Senya, H, Ratnam, V, Gill, M, Kirk, J, Shelton, S, Schweikert, S, Wibrow, B, Anstey, M, Rauniyar, R, Khoso, N, Asif, N, Taqdees, H, Frey, C, Scano, R, McKee, M, Murphy, P, Thomas, M, Worner, R, Faulkner, B, Gendall, E, Hayes, K, Blakemore, H, Borislavova, B, Deshpande, K, Van Haren, F, Konecny, P, Inskip, D, Tung, R, Hayes, L, Murphy, L, Neill, A, Reidy, B, O’Dwyer, M, Ryan, D, Ainscough, K, Hamilton-Davies, C, Mfuko, C, Abbass, H, Mandadapu, V, Leaver, S, Patel, K, Farnell-Ward, S, Saluzzio, R, Rawlins, S, Sicat, C, De Keulenaer, B, Ferrier, J, Fysh, E, Davda, A, Mevavala, B, Cook, D, Clarke, F, Banach, D, Fernández de Pinedo Artaraz, Z, Cabreros, L, Latham, V, Kruisselbrink, R, Brochard, L, Burns, K, Sandhu, G, Khalid, I, White, I, Croft, M, Holland, N, Pereira, R, Nair, P, Buscher, H, Reynolds, C, Newman, S, Santamaria, J, Barbazza, L, Homes, J, Smith, R, Zaki, A, Johnson, D, Garrard, H, Juhaz, V, Brown, L, Pemberton, A, Roy, A, Rostron, A, Woods, L, Cornell, S, Fowler, R, Adhikari, N, Kamra, M, Marinoff, N, Garrett, P, Murray, L, Brailsford, J, Fennessy, G, Mulder, J, Morgan, R, Pillai, S, Harford, R, Ivatt, H, Evans, D, Richards, S, Roberts, E, Bowen, J, Ainsworth, J, Kuitunen, A, Karlsson, S, Vahtera, A, Kiiski, H, Ristimäki, S, Albrett, J, Jackson, C, Kirkham, S, Tamme, K, Reinhard, V, Ellervee, A, Põldots, L, Rennit, P, Svitškar, N, Browne, T, Grimwade, K, Goodson, J, Keet, O, Callender, O, Udy, A, McCracken, P, Young, M, Board, J, Martin, E, Kasipandian, V, Patel, A, Allibone, S, Mary-Genetu, R, English, S, Watpool, I, Porteous, R, Miezitis, S, McIntyre, L, Brady, K, Vale, C, Shekar, K, Lavana, J, Parmar, D, Peake, S, Kurenda, C, Hormis, A, Walker, R, Collier, D, Kimpton, S, Oakley, S, Bhagani, S, De Neef, M, Garcia, S, Maharajh, A, Nandani, A, Dobson, J, Fernando, G, Eastgate, C, Gomez, K, Abdi, Z, Tatham, K, Jhanji, S, Black, E, Dela Rosa, A, Howle, R, Baikady, R, Drummond, A, Dearden, J, Philbin, J, Munt, S, Gopal, S, Pooni, J-S, Ganguly, S, Smallwood, A, Metherell, S, Naeem, A, Fagan, L, Ryan, E, Mariappa, V, Foulds, A, Revill, A, Bhattarai, B, De Jonge, E, Wigbers, J, Del Prado, M, Cremer, O, Mulier, J, Peters, A, Romberg, B, Schutgens, R, Troeman, D, Van Opdorp, M, Besten, H, Brakké, K, Barber, R, Hilldrith, A, Kluge, S, Nierhaus, A, Jarczak, D, Roedl, K, Kochanek, M, Rueß-Paterno, G, Mc-Kenzie, J, Eichenauer, D, Shimabukuro-Vornhagen, A, Wilcox, E, Del Sorbo, L, Abdelhady, H, Romagnuolo, T, Simpson, S, Maiden, M, Horton, M, Trickey, J, Krajinovic, V, Kutleša, M, Kotarski, V, Brohi, F, Jagannathan, V, Clark, M, Purvis, S, Wetherill, B, Brajković, A, Babel, J, Sever, H, Dragija, L, Kušan, I, Dushianthan, A, Cusack, R, De Courcy-Golder, K, Salmon, K, Burnish, R, Smith, S, Ruiz, W, Duke, Z, Johns, M, Male, M, Gladas, K, Virdee, S, Swabe, J, Tomlinson, H, Rohde, G, Grünewaldt, A, Bojunga, J, Petros, S, Kunz, K, Schütze, B, Weismann, D, Frey, A, Drayss, M, Goebeler, ME, Flor, T, Fragner, G, Wahl, N, Totzke, J, Sayehli, C, Hakak, S, Altaf, W, O'Sullivan, M, Murphy, A, Walsh, L, Rega La Valle, A, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Wyatt, R, Morgan, K, Varghese, S, Willis, J, Stratton, E, Kyle, L, Putensen, D, Drury, K, Skorko, A, Bremmer, P, Ward, G, Bassford, C, Sligl, W, Baig, N, Rewa, O, Bagshaw, S, Basile, K, Stavor, D, Burbee, D, McNamara, A, Wunderley, R, Bensen, N, Adams, P, Vita, T, Buhay, M, Scholl, D, Gilliam, M, Winters, J, Doherty, K, Berryman, E, Ghaffari, M, Marroquin, O, Quinn, K, Garrard, W, Kalchthaler, K, Beard, G, Skrtich, A, Bagavathy, K, Drapola, D, Bryan-Morris, K, Arnold, J, Reynolds, B, Hussain, M, Dunsavage, J, Saiyed, S, Hernandez, E, Goldman, J, Brown, C, Comp, S, Raczek, J, Morris, J, Vargas Jr., J, Weiss, D, Hensley, J, Kochert, E, Wnuk, C, Nemeth, C, Mowery, B, Hutchinson, C, Winters, L, McAdams, D, Walker, G, Minnier, T, Wisniewski, M, Mayak, K, McCreary, E, Bariola, R, Viehman, A, Daley, J, Lopus, A, Schmidhofer, M, Ambrosino, R, Keen, S, Toffalo, S, Stambaugh, M, Trimmer, K, Perri, R, Casali, S, Medva, R, Massar, B, Beyerl, A, Burkey, J, Keeler, S, Lowery, M, Oncea, L, Daugherty, J, Sevilla, C, Woelke, A, Dice, J, Weber, L, Roth, J, Ferringer, C, Beer, D, Fesz, J, Carpio, L, Colin, G, Zinzoni, V, Maquigneau, N, Henri-Lagarrigue, M, Pouplet, C, Reill, L, Distler, M, Maselli, A, Martynoga, R, Trask, K, Butler, A, Attwood, B, Parsons, P, Campbell, B, Smith, A, Page, V, Zhao, X, Oza, D, Abrahamson, G, Sheath, B, Young, P, Young, C, Lesona, E, Navarra, L, Cruz, R, Delaney, K, Aguilar-Dano, A, Gojanovic, M, Rhodes, J, Anderson, T, Morris, S, Nayyar, V, Bowen, D, Kong, J, Joy, J, Fuchs, R, Lambert, B, Tai, C, Thomas, A, Keen, A, Tierney, C, Omer, N, Bacon, G, Tridente, A, Shuker, K, Anders, J, Greer, S, Scott, P, Millington, A, Buchanan, P, Binnie, A, Powell, E, McMillan, A, Luk, T, Aref, N, Denmade, C, Sadera, G, Jacob, R, Hughes, D, Sterba, M, Geng, W, Digby, S, Southern, D, Reddy, H, Hulse, S, Campbell, A, Garton, M, Watkins, C, Smuts, S, Quinn, A, Simpson, B, McMillan, C, Finch, C, Hill, C, Cooper, J, Budd, J, Small, C, O’Leary, R, Collins, E, Holland, A, Alexander, P, Felton, T, Ferguson, S, Sellers, K, Ward, L, Yates, D, Birkinshaw, I, Kell, K, Scott, Z, Pearson, H, Hashmi, M, Hassan, N, Panjwani, A, Umrani, Z, Shaikh, M, Ain, Q, Kanwal, D, Van Bree, S, Bouw-Ruiter, M, Osinga, M, Van Zanten, A, McEldrew, R, Rashan, S, Singh, V, Azergui, N, Bari, S, Beltran, M, Brugman, C, Groeneveld, E, Jafarzadeh, M, Keijzer-Timmers, N, Kester, E, Koelink, M, Kwakkenbos-Craanen, M, Okundaye, C, Parker, L, Peters, S, Post, S, Rietveld, I, Scheepstra-Beukers, I, Schreuder, G, Smit, A, Brillinger, N, Markgraf, R, Eichinger, F, Doran, P, Anjum, A, Best-Lane, J, Barton, F, Miller, L, Richards-Belle, A, Saull, M, Sprinckmoller, S, Wiley, D, Darnell, R, Au, C, Lindstrum, K, Cheng, A, Forbes, A, Heritier, S, Trapani, T, Cuthbertson, B, Manoharan, V, Dondrop, A, Tolppa, T, Ehrmann, S, Hullegie, S, Povoa, P, Beasley, R, Daneman, N, McGloughlin, S, Paterson, D, Venkatesh, B, De Jong, M, Uyeki, T, Baillie, K, Netea, M, Orr, K, Patanwala, A, Tong, S, Cooper, N, Galea, J, Leavis, H, Ogungbenro, K, Patawala, A, Rademaker, E, Youngstein, T, Carrier, M, Fergusson, D, Hunt, B, Kumar, A, Laffan, M, Lother, S, Middeldorp, S, Stanworth, S, De Man, A, Masse, M-H, Abraham, J, Arnold, D, Begin, P, Charlewood, R, Chasse, M, Coyne, M, Daly, J, Gosbell, I, Harvala-Simmonds, H, MacLennan, S, McDyer, J, Menon, D, Pridee, N, Roberts, D, Thomas, H, Tinmouth, A, Triulzi, D, Walsh, T, Wood, E, Calfee, C, O’Kane, C, Shyamsundar, M, Sinha, P, Thompson, T, Young, I, Burrell, A, Ferguson, N, Hodgson, C, Orford, N, Phua, J, Baron, R, Epelman, S, Frankfurter, C, Gommans, F, Kim, E, Leaf, D, Vaduganathan, M, Van Kimmenade, R, Sanil, A, Van Beurden, M, Effelaar, E, Schotsman, J, Boyd, C, Harland, C, Shearer, A, Wren, J, Attanayaka, U, Darshana, S, Ishani, P, Udayanga, I, Higgins, AM, Berry, LR, Lorenzi, E, Murthy, S, McQuilten, Z, Mouncey, PR, Al-Beidh, F, Annane, D, Arabi, YM, Beane, A, Van Bentum-Puijk, W, Bhimani, Z, Bonten, MJM, Bradbury, CA, Brunkhorst, FM, Buzgau, A, Buxton, M, Charles, WN, Cove, M, Detry, MA, Estcourt, LJ, Fagbodun, EO, Fitzgerald, M, Girard, TD, Goligher, EC, Goossens, H, Haniffa, R, Hills, T, Horvat, CM, Huang, DT, Ichihara, N, Lamontagne, F, Marshall, JC, McAuley, DF, McGlothlin, A, McGuinness, SP, McVerry, BJ, Neal, MD, Nichol, AD, Parke, RL, Parker, JC, Parry-Billings, K, Peters, SEC, Reyes, LF, Rowan, KM, Saito, H, Santos, MS, Saunders, CT, Serpa-Neto, A, Seymour, CW, Shankar-Hari, M, Stronach, LM, Turgeon, AF, Turner, AM, Van de Veerdonk, FL, Zarychanski, R, Green, C, Lewis, RJ, Angus, DC, McArthur, CJ, Berry, S, Derde, LPG, Gordon, AC, Webb, SA, Lawler, PR, Comm REMAP-CAP Investigators, Apollo - University of Cambridge Repository, Intensive Care Medicine, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pittsburgh Foundation, PF, Amgen, Health Research Board, HRB: CTN 2014-012, Horizon 2020 Framework Programme, H2020: 101003589, Translational Breast Cancer Research Consortium, TBCRC, Canadian Institutes of Health Research, IRSC: 158584, Heart and Stroke Foundation of Canada, HSF, National Institute for Health and Care Research, NIHR, European Commission, EC, National Health and Medical Research Council, NHMRC: 1101719, APP194811, CS-2016-16-011, GNT2008447, RP-2015-06-18, Office of Health and Medical Research, OHMR, Health Research Council of New Zealand, HRC: 16/631, Eisai, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Université Pierre et Marie Curie, UPMC, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, Funding/Support : The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1 (#602525), the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union’s Horizon 2020 research and innovation programme (#101003589), the Australian National Health and Medical Research Council (#APP1101719), the Australian Medical Research Future Fund (#APP2002132), the Health Research Council of New Zealand (#16/631), the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584) and the Canadian Institute of Health Research COVID-19 Rapid Research Funding (#447335), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Wellcome Trust Innovations Project (215522), the Minderoo Foundation, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the Translational Breast Cancer Research Consortium, the NSW Office of Health and Medical Research, Amgen, Eisai, and the Pittsburgh Foundation. Dr Higgins is funded by an NHMRC Emerging Leadership Fellowship (GNT2008447). Dr McQuilten is funded by an NHMRC Emerging Leadership Fellowship (APP194811). Dr Gordon is funded by an NIHR Research Professorship (RP-2015-06-18) and Dr Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011). Dr Turgeon is the Chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. Dr Lawler is supported by a career award from the Heart and Stroke Foundation of Canada., and European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014)

Subjects
Adult, Male, corticosteroid, [SDV]Life Sciences [q-bio], Critical Illness, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], antiplatelet, Lopinavir, Adaptive platform trial randomized controlled trial intensive care, pneumonia COVID-19 antiplatelet immunoglobulin antiviral corticosteroid immune modulation anticoagulation, All institutes and research themes of the Radboud University Medical Center, Adrenal Cortex Hormones, Humans, anticoagulation, intensive care, pneumonia, COVID-19 Serotherapy, Original Investigation, Medicine(all), immune modulation, Ritonavir, SARS-CoV-2, COVID-19, Anticoagulants, Bayes Theorem, General Medicine, Middle Aged, antiviral, Receptors, Interleukin-6, Adaptive platform trial, randomized controlled trial, Female, Human medicine, immunoglobulin, Follow-Up Studies, Hydroxychloroquine
Abstract

ImportanceThe longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.ObjectiveTo determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, Setting, and ParticipantsPrespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.InterventionsPatients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main Outcomes and MeasuresThe main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.ResultsAmong 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.Conclusions and RelevanceAmong critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Published
2023
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5. The dangers of misrepresenting wildlife trade: Response to Natusch et al. (2021)

Author

Edwards, D.P., D'Cruze, N., Altherr, S., Hughes, A., Janssen, J., Nijman, V., Pasachnik, S.A., Scheffers, B.R., Shepherd, C.R., Sy, E., Auliya, Mark, Edwards, D.P., D'Cruze, N., Altherr, S., Hughes, A., Janssen, J., Nijman, V., Pasachnik, S.A., Scheffers, B.R., Shepherd, C.R., Sy, E., and Auliya, Mark

Abstract

no abstract

Published
2021

11. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD

Author

Caussy, C, Hsu, C, Lo, MT, Liu, A, Bettencourt, R, Ajmera, VH, Bassirian, S, Hooker, J, Sy, E, Richards, L, Schork, N, Schnabl, B, Brenner, DA, Sirlin, CB, Chen, CH, and Loomba, R

Subjects
Genetics of NAFLD in Twins Consortium
Abstract

© 2018 by the American Association for the Study of Liver Diseases. Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG:0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG:0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).

Published
2018
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13. Little engines that could: computing in small energetic countries

Author

Dedrick, Jason L., Goodman, Sy E., and Kraemer, Kenneth L.

Subjects
Information technology, Microcomputer industry, Computer industry, Information technology -- International aspects, Computer industry -- International aspects
Abstract

How do very small countries, here defined as having fewer than 10 million people, find places for themselves in the information technologies (IT) arena? Does success require accommodation in the […]

Published
1995

14. Hémangioblastome de l’angle ponto-cérébelleux : rapport de cas

Author

Sy, E C N, Faye, M, Thioub, M, Mbaye, M, Wague, D, Diop, S, and Thiam, A.B

Subjects
cerebellopontine angle, hemangioblastoma angle ponto-cérébelleux, Hémangioblastome
Abstract

L’hémangioblastome de l’angle ponto-cérébelleux (APC) est rare. Le diagnostic différentiel peut se poser avec le schwannome vestibulaire, car ces deux entités peuvent avoir des caractéristiques identiques à l’imagerie par résonance magnétique (IRM). L’exérèse des hémangioblastomes solides peut être difficile à cause de leur hypervascularisation et leur difficulté à la dissection circonférentielle. L’embolisation et la radiochirurgie préopératoire permettent de limiter le saignement per opératoire. Nous rapportons un cas d’hémangioblastome de l’angle ponto-cérébelleux, opéré 6 ans après une radiochirurgie par voie rétro- sigmoïdienne qui était considéré au départ comme un schwannome vestibulaire atypique.Mots clés : angle ponto-cérébelleux, Hémangioblastome.English AbstractHemangioblastoma of the cerebellopontine angle is very rare. The differential diagnosis is vestibular schwannoma, because these two entities can have identical characteristics to magnetic resonance imaging. Hemangioblastoma solids dissection can be very tough because it is highly vascularised and their difficulty in circumferential dissection. Embolization and radiosurgery preoperative is used to reduce operative bleeding. Here it’s a case report of a hemangioblastoma of the cerebellopontine angle surgery, six years after radiosurgery through retrosigmoidienne which was seen initially as an atypical vestibular Schwannoma.Key words: cerebellopontine angle, hemangioblastoma

Published
2018

15. Association Between Obesity and Discordance in Fibrosis Stage Determination by Magnetic Resonance vs Transient Elastography in Patient, with Nonalcoholic Liver Disease

Author

CAUSSY, Cyrielle, Chen, Jie, Alquiraish, M. H., Cepin, S., Nguyen, P., Hernandez, C., Yin, M., Bettencourt, R., Cachay, E. R., Jayakumar, S., Fortney, L., Hooker, J., Sy, E., Valasek, M. A., Rizo, E., Richards, L., Brenner, D. A., Sirlin, C. B., Ehman, R. L., Loomba, R., Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Berkeley Wireless Research Center [Berkeley] (BWRC), University of California [Berkeley], University of California-University of California, Department of Oceanography and Fisheries, University of Reading (UOR), Department of Medicine, University of California [San Diego] (UC San Diego), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), UC San Diego NAFLD Research Center, and UC San Diego School of Medicine

Subjects
Liver Cirrhosis, Adult, Male, Magnetic Resonance Elastography, Adolescent, Nonalcoholic Fatty Liver Disease, Magnetic, Biopsy, [SDV]Life Sciences [q-bio], Chronic Liver Disease and Cirrhosis, Clinical Sciences, mr elastography, sampling variability, fatty, Oral and gastrointestinal, Body Mass Index, Young Adult, Non-alcoholic Fatty Liver Disease, Clinical Research, Resonance Elastography, 80 and over, steatosis, xl probe, Humans, biopsy, Transient Elastography, Obesity, hepatic-fibrosis, Aged, Gastroenterology & Hepatology, Liver Disease, cirrhosis, Middle Aged, Magnetic Resonance Imaging, Cross-Sectional Studies, stiffness measurement, Elasticity Imaging Techniques, Liver Fibrosis, Female, Digestive Diseases, performance
Abstract

International audience; BACKGROUND & AIMS: Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques used to detect liver fibrosis in nonalcoholic fatty liver disease. MRE detects fibrosis more accurately than TE, but MRE is more expensive, and the concordance between MRE and TE have not been optimally assessed in obese patients. It is important to determine under which conditions TE and MRE produce the same readings, so that some patients can simply undergo TE evaluation to detect fibrosis. We aimed to assess the association between body mass index (BMI) and discordancy between MRE and TE findings, using liver biopsy as the reference, and validated our findings in a separate cohort. METHODS: We performed a cross-sectional study of 119 adults with nonalcoholic fatty liver disease who underwent MRE, TE with M and XL probe, and liver biopsy analysis from October 2011 through January 2017 (training cohort). MRE and TE results were considered to be concordant if they found patients to have the same stage fibrosis as liver biopsy analysis. We validated our findings in 75 adults with nonalcoholic fatty liver disease who underwent contemporaneous MRE, TE, and liver biopsy at a separate institution from March 2010 through May 2013. The primary outcome was rate of discordance between MRE and TE in determining stage of fibrosis (stage 2-4 vs 0-1). Secondary outcomes were the rate of discordance between MRE and TE in determining dichotomized stage of fibrosis (1-4 vs 0, 3-4 vs 0-2, and 4 vs 0-3). RESULTS: In the training cohort, there was 43.7% discordance in findings from MRE versus TE. BMI associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.69; 95% confidence interval, 1.15-2.51; P = .008) after multivariable adjustment by age and sex. The findings were confirmed in the validation cohort: there was 45.3% discordance in findings from MRE versus TE. BMI again associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.52; 95% confidence interval, 1.04-2.21; P = .029) after multivariable adjustment by age and sex. CONCLUSIONS: We identified and validated BMI as a factor significantly associated with discordance of findings from MRE versus TE in assessment of fibrosis stage. The degree of discordancy increases with BMI.

Published
2018
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16. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD

Author

CAUSSY, Cyrielle, Hsu, C., Lo, M. T., Liu, A., Bettencourt, R., Ajmera, V. H., Bassirian, S., Hooker, J., Sy, E., Richards, L., Schork, N., Schnabl, B., Brenner, D. A., Sirlin, C. B., Chen, C. H., Loomba, R., Genetics, Nafld Twins Consortium, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oceanography and Fisheries, University of Reading (UOR), Department of Medicine, University of California [San Diego] (UC San Diego), University of California-University of California, Dept Anim Ind, Livestock Ind Sect, Council of agriculture, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), UC San Diego NAFLD Research Center, and UC San Diego School of Medicine

Subjects
Liver Cirrhosis, Adult, Male, [SDV]Life Sciences [q-bio], Chronic Liver Disease and Cirrhosis, Clinical Sciences, Immunology, steatohepatitis, prospective twin, Medical Biochemistry and Metabolomics, Proof of Concept Study, Genetics of NAFLD in Twins Consortium, Oral and gastrointestinal, Non-alcoholic Fatty Liver Disease, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Aged, human blood metabolites, risk, Phenylpropionates, Gastroenterology & Hepatology, Liver Disease, cirrhosis, association, nonalcoholic, dysbiosis, Middle Aged, Metformin, Gastrointestinal Microbiome, Cross-Sectional Studies, fatty liver-disease, identification, Female, Digestive Diseases, metaanalysis
Abstract

International audience; Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P \textless 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was R-G:0.57,95%CI:0.27-0.80, P \textless 0.001 and with fibrosis was R-G:0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).

Published
2018

18. Magnetic resonance elastography vs. transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease

Author

Park, C.C., primary, Nguyen, P., additional, Hernandez, C., additional, Bettencourt, R., additional, Ramirez, K.S., additional, Fortney, L.E., additional, Hooker, J., additional, Sy, E., additional, Alquiraish, M.H., additional, Valasek, M.A., additional, Rizo, E., additional, Richards, L., additional, Brenner, D., additional, Sirlin, C.B., additional, and Loomba, R., additional

Published
2017
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42. Obesity is highly associated with a non-home discharge following total ankle arthroplasty.

Author

Sy E, Albright RH, Sorensen T, Sorensen MD, Klein EE, Weil L Jr, and Fleischer AE

Abstract

Studies have shown that non-home discharge following orthopedic procedures is associated with a higher risk of 30-day complications and significantly increases medical costs. The purpose of this study was to identify risk factors for being discharged to a non-home destination following total ankle arthroplasty (TAA). We included patients undergoing TAA from the American College of Surgeons National Surgical Quality Improvement Program database (NSQIP) between 2014 and 2019. TAA was identified using CPT codes 27702, 27703 and 27704. Logistic regression models were used to assess the association between discharge location (home versus non-home) and a series of exposure variables (e.g., patient demographics, patient health characteristics, and operative factors). A total of 1,704 patients were included, experiencing a 3.6% short term complication rate (61/1,704). 8.5% of the population were discharged to a non-home destination. In the final adjusted model, patients who were older [OR 1.11; 95%CI 1.08, 1.13], female [OR 2.94; 95%CI 2.04, 4.34], obese [OR 1.93; 95%CI 1.29, 2.89], had surgery in an inpatient setting [OR 5.73; 95%CI 1.78, 18.46], and ASA class IV [OR 10.65; 95%CI 1.03, 110.61] were at greater risk for a non-home discharge. People living with obesity experienced a nearly 2x greater likelihood of being discharged to a non-home destination after TAA despite their preoperative functional (e.g., ASA class) and metabolic status (i.e., diabetes). Opportunities to mitigate this risk will be needed to lessen the financial burden of TAA surgery as a growing number of obese patients become eligible for TAA in the US., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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43. Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

Author

Turgeon AF, Fergusson DA, Clayton L, Patton MP, Neveu X, Walsh TS, Docherty A, Malbouisson LM, Pili-Floury S, English SW, Zarychanski R, Moore L, Bonaventure PL, Laroche V, Verret M, Scales DC, Adhikari NKJ, Greenbaum J, Kramer A, Rey VG, Ball I, Khwaja K, Wise M, Harvey D, Lamontagne F, Chabanne R, Algird A, Krueper S, Pottecher J, Zeiler F, Rhodes J, Rigamonti A, Burns KEA, Marshall J, Griesdale DE, Sisconetto LS, Kutsogiannis DJ, Roger C, Green R, Boyd JG, Wright J, Charbonney E, Nair P, Astles T, Sy E, Hébert PC, Chassé M, Gomez A, Ramsay T, Taljaard M, Fox-Robichaud A, Tinmouth A, St-Onge M, Costerousse O, and Lauzier F

Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, Critical Illness, Depression etiology, Glasgow Outcome Scale, Hemoglobins analysis, Quality of Life, Anemia blood, Anemia etiology, Anemia therapy, Brain Injuries, Traumatic blood, Brain Injuries, Traumatic complications, Brain Injuries, Traumatic diagnosis, Brain Injuries, Traumatic therapy, Erythrocyte Transfusion adverse effects, Erythrocyte Transfusion methods
Abstract

Background: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear., Methods: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months., Results: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively., Conclusions: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.)., (Copyright © 2024 Massachusetts Medical Society.)

Published
2024
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44. Impact of Rounding Checklists on the Outcomes of Patients Admitted to ICUs: A Systematic Review and Meta-Analysis.

Author

MacKinnon KM, Seshadri S, Mailman JF, and Sy E

Subjects
Humans, Length of Stay, Teaching Rounds methods, Checklist, Intensive Care Units, Hospital Mortality
Abstract

Objectives: To evaluate the effectiveness of ICU rounding checklists on outcomes., Data Sources: Five electronic databases (MEDLINE, Embase, CINAHL, Cochrane Library, and Google Scholar) were searched from inception to May 10, 2024., Study Selection: Cohort studies, case-control studies, and randomized controlled trials comparing the use of rounding checklists to no checklists were included. Other article types were excluded., Data Extraction: The primary outcome was in-hospital mortality. Secondary outcomes included ICU and 30-day mortality; hospital and ICU length of stay (LOS); duration of mechanical ventilation; and frequency of catheter-associated urinary tract infections, central line-associated bloodstream infections (CLABSI), and ventilator-associated pneumonia. Additional outcomes included healthcare provider perceptions of checklists., Data Synthesis: Pooled estimates were obtained using an inverse-variance random-effects meta-analysis model. Certainty of evidence was evaluated using Grading of Recommendations Assessment, Development, and Evaluation. There were 30 included studies (including > 32,000 patients) in the review. Using an ICU rounding checklist was associated with reduced in-hospital mortality (risk ratio [RR] 0.80; 95% CI, 0.70-0.92; 12 observational studies; 17,269 patients; I2 = 48%; very low certainty of evidence). The use of an ICU rounding checklist was also associated with reduced ICU mortality (8 observational studies, p = 0.006), 30-day mortality (2 observational studies, p < 0.001), hospital LOS (11 observational studies, p = 0.02), catheter-associated urinary tract infections (CAUTI) (6 observational studies, p = 0.01), and CLABSI (6 observational studies, p = 0.02). Otherwise, there were no significant differences with using ICU rounding checklists on other patient-related outcomes. Healthcare providers' perceptions of checklists were generally positive., Conclusions: The use of an ICU rounding checklist may improve in-hospital mortality, as well as other important patient-related outcomes. However, well-designed randomized studies are necessary to increase the certainty of evidence and determine which elements should be included in an ICU rounding checklist., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Published
2024
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45. Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

Author

Cook D, Deane A, Lauzier F, Zytaruk N, Guyatt G, Saunders L, Hardie M, Heels-Ansdell D, Alhazzani W, Marshall J, Muscedere J, Myburgh J, English S, Arabi YM, Ostermann M, Knowles S, Hammond N, Byrne KM, Chapman M, Venkatesh B, Young P, Rajbhandari D, Poole A, Al-Fares A, Reis G, Johnson D, Iqbal M, Hall R, Meade M, Hand L, Duan E, Clarke F, Dionne JC, Tsang JLY, Rochwerg B, Karachi T, Lamontagne F, D'Aragon F, St Arnaud C, Reeve B, Geagea A, Niven D, Vazquez-Grande G, Zarychanski R, Ovakim D, Wood G, Burns KEA, Goffi A, Wilcox ME, Henderson W, Forrest D, Fowler R, Adhikari NKJ, Ball I, Mele T, Binnie A, Trop S, Mehta S, Morgan I, Loubani O, Vanstone M, Fiest K, Charbonney E, Cavayas YA, Archambault P, Rewa OG, Lau V, Kristof AS, Khwaja K, Williamson D, Kanji S, Sy E, Dennis B, Reynolds S, Marquis F, Lellouche F, Rahman A, Hosek P, Barletta JF, Cirrone R, Tutschka M, Xie F, Billot L, Thabane L, and Finfer S

Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, Double-Blind Method, Intensive Care Units, Pneumonia, Ventilator-Associated etiology, Stress, Physiological, Critical Illness therapy, Gastrointestinal Hemorrhage etiology, Gastrointestinal Hemorrhage prevention & control, Pantoprazole therapeutic use, Pantoprazole adverse effects, Pantoprazole administration & dosage, Peptic Ulcer prevention & control, Proton Pump Inhibitors therapeutic use, Proton Pump Inhibitors adverse effects, Proton Pump Inhibitors administration & dosage, Respiration, Artificial adverse effects
Abstract

Background: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear., Methods: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding., Results: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups., Conclusions: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.)., (Copyright © 2024 Massachusetts Medical Society.)

Published
2024
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46. Evaluating service needs for veno-venous extracorporeal membrane oxygenation in patients with severe acute respiratory distress syndrome in Saskatchewan.

Author

Saha B, Drapak S, Mailman JF, Kassir S, and Sy E

Subjects
Humans, Saskatchewan, Retrospective Studies, Extracorporeal Membrane Oxygenation, COVID-19 therapy, Respiratory Distress Syndrome therapy
Abstract

To determine the number of patients with acute respiratory distress syndrome (ARDS) who would be eligible to receive veno-venous extracorporeal membrane oxygenation (VV-ECMO). We conducted a retrospective observational study of ARDS patients admitted to Regina General Hospital Intensive Care Unit (ICU). VV-ECMO eligibility was assessed using selection criteria from the Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Syndrome trial (EOLIA), the Extracorporeal Life Support Organization (ELSO), New South Wales (NSW), Critical Care Services Ontario (CCSO) and a Regina-restrictive criteria. Of 415 patients admitted between October 16, 2018, and January 21, 2021, 103 (25%) had mild, 175 (42%) had moderate, and 64 (15%) had severe ARDS. Of the cohort, 144 (35%) had bacterial pneumonia, 86 (21%) had viral pneumonia (including COVID-19), and 72 (17%) had aspiration pneumonia. Using the EOLIA, ELSO, NSW, CCSO and Regina-restrictive criteria, 7/415 (1.7%), 6/415 (1.5%), 19/415 (4.6%), 26/415 (6.3%) and 12/415 (2.9%) were eligible for VV-ECMO, respectively. Of all ECMO-eligible patients, only one (2.4%) actually received VV-ECMO, 20/42 (48%) received prone positioning and 21/42 (50%) received neuromuscular blockade. There is potential for service expansion of VV-ECMO in Regina; however, there is still a need to improve the delivery of evidence-based ARDS therapies., (© 2023. Springer Nature Limited.)

Published
2023
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47. Medial Double Arthrodesis Through Single Approach.

Author

Sy E and Sorensen MD

Subjects
Adult, Humans, Arthrodesis, Foot, Tendons, Arthritis, Posterior Tibial Tendon Dysfunction
Abstract

Triple arthrodesis is a time-tested procedure toward primary salvage in the context of posterior tibial tendon dysfunction, symptomatic rigid and severe hindfoot malalignment, end-stage degenerative and posttraumatic arthritis, and sequelae of paralytic diseases. Today, the indication for hindfoot arthrodesis is applied to correct painful deformities and arthritic joints, such as advanced cases of adult-acquired flatfoot secondary to ligament collapse and insufficiency of the posterior tibial tendon. Although the triple arthrodesis is an effective and reliable outcome procedure, the popularity of a medial double arthrodesis has increased., (Published by Elsevier Inc.)

Published
2023
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48. Treatments and Outcomes of Critically Ill Patients with Candida spp. Colonization of the Lower Respiratory Tract in Regina, Saskatchewan.

Author

Lanigan A, Mailman JF, Kassir S, Schmidt K, Lee SB, and Sy E

Abstract

Background: Among critically ill patients receiving mechanical ventilation, Candida spp. are commonly detected in the lower respiratory tract (LRT). This is generally considered to represent colonization., Objective: To evaluate the use of antifungal treatments and the clinical outcomes of patients with Candida colonization of the LRT., Methods: This retrospective analysis involved consecutive patients admitted to the intensive care unit between April 2016 and May 2021with positive results on Candida spp. testing of LRT samples. Data related to antifungal treatment and clinical outcomes were analyzed descriptively, and multivariable logistic regression was performed., Results: Of 200 patients initially identified, 160 (80%) died in hospital. Antifungal therapy was given to 103 (51.5%) of the patients, with treatment being more likely among those with shock and those who received parenteral nutrition. Mortality was high among patients with positive Candida results on LRT culture, regardless of treatment. Multivariable logistic regression, with adjustment for age, sex, comorbidities, and sequential organ failure assessment (SOFA) score, showed that antifungal treatment was associated with lower odds of death (odds ratio 0.39, 95% confidence interval 0.17-0.87) compared with no treatment (p = 0.021)., Conclusions: This study showed higher mortality rates than have been reported previously. Further investigation into the role of antifungal therapy among critically ill patients with Candida spp. colonization is required., Competing Interests: Competing interests: None declared., (2023 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

Published
2023
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49. Determining the sustainability of legal wildlife trade.

Author

Hughes A, Auliya M, Altherr S, Scheffers B, Janssen J, Nijman V, Shepherd CR, D'Cruze N, Sy E, and Edwards DP

Subjects
Animals, Commerce, Animals, Wild, Endangered Species, Conservation of Natural Resources, Wildlife Trade, Ecosystem
Abstract

Exploitation of wildlife represents one of the greatest threats to species survival according to the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services. Whilst detrimental impacts of illegal trade are well recognised, legal trade is often equated to being sustainable despite the lack of evidence or data in the majority of cases. We review the sustainability of wildlife trade, the adequacy of tools, safeguards, and frameworks to understand and regulate trade, and identify gaps in data that undermine our ability to truly understand the sustainability of trade. We provide 183 examples showing unsustainable trade in a broad range of taxonomic groups. In most cases, neither illegal nor legal trade are supported by rigorous evidence of sustainability, with the lack of data on export levels and population monitoring data precluding true assessments of species or population-level impacts. We propose a more precautionary approach to wildlife trade and monitoring that requires those who profit from trade to provide proof of sustainability. We then identify four core areas that must be strengthened to achieve this goal: (1) rigorous data collection and analyses of populations; (2) linking trade quotas to IUCN and international accords; (3) improved databases and compliance of trade; and (4) enhanced understanding of trade bans, market forces, and species substitutions. Enacting these core areas in regulatory frameworks, including CITES, is essential to the continued survival of many threatened species. There are no winners from unsustainable collection and trade: without sustainable management not only will species or populations become extinct, but communities dependent upon these species will lose livelihoods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. However, the authors are members of the following IUCN/SSC specialist groups: Asian Songbird Trade (VN, CSR), pigeon and dove (CSR), hornbill (CSR), primates (VN), bears (VN, CSR), pangolin (CRS), small carnivores (CRS), otter (CRS), tortoise and freshwater turtles (CRS, MA, SA), skinks (JJ), monitor lizards (MA, JJ, ES), molluscs (VN). Their views may or may not represent those of some members of the IUCN/SSC. Some of the authors are previous (VN) or current members (JJ) of national CITES Scientific Authorities. This manuscript represents the views of the authors and does not necessarily reflect that of the respective CITES Scientific Authorities., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2023
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50. Identification and Quantification of a Problematic Host Cell Protein to Support Therapeutic Protein Development.

Author

E SY, Hu Y, Molden R, Qiu H, and Li N

Subjects
Animals, Cricetinae, Chromatography, Liquid methods, Lipase, Cricetulus, CHO Cells, Tandem Mass Spectrometry methods, Antibodies, Monoclonal chemistry
Abstract

Monitoring of residual host cell proteins (HCPs) in therapeutic protein is essential to ensure product quality, safety and efficacy. Despite the development of advanced mass spectrometry techniques and optimized workflows, identifying and quantifying all problematic HCPs present at low levels remain challenging. Here, we developed a practical, effective strategy for the identification and quantification of low abundance HCPs, which facilitates the improvement of downstream purification process to eliminate potentially problematic HCPs. A case study of using this strategy to investigate a problematic HCP is presented. Initially, a commonly used native digestion approach coupled with UPLC-MS/MS was applied for HCP profiling, wherein several lipases and proteases were identified in a monoclonal antibody named mAb1 in early stages of purification process development. A highly active lipase, liver carboxylesterase (CES), was found to be responsible for polysorbate 80 degradation. To facilitate process improvement, after the identification of CES, we developed a highly sensitive LC-MS/MS-MRM assay with a lower limit of quantification of 0.05 ppm for routine monitoring of the CES in mAb1 produced through the different processes. This workflow was applied in low-level lipase identification and absolute quantification, which facilitated the investigation of polysorbate degradation and downstream purification improvement to further remove the problematic HCP. The current MRM method increased the sensitivity of HCP quantification by over 10-fold that in previously published studies, thus meeting the needs for quantification of problematic HCPs at sub-ppm to ppb levels during drug development. This workflow could be readily adapted to the detection and quantification of other problematic HCPs present at extremely low levels in therapeutic protein drug candidates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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