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2. Stratified analyses refine association between TLR7 rare variants and severe COVID-19
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Rimoldi, Valeria, Paraboschi, Elvezia M., Bandera, Alessandra, Peyvandi, Flora, Grasselli, Giacomo, Blasi, Francesco, Malvestiti, Francesco, Pelusi, Serena, Bianco, Cristiana, Miano, Lorenzo, Lombardi, Angela, Invernizzi, Pietro, Gerussi, Alessio, Citerio, Giuseppe, Biondi, Andrea, Valsecchi, Maria Grazia, Cazzaniga, Marina Elena, Foti, Giuseppe, Beretta, Ilaria, D'Angiò, Mariella, Bettini, Laura Rachele, Farré, Xavier, Iraola-Guzmán, Susana, Kogevinas, Manolis, Castaño-Vinyals, Gemma, Garcia-Etxebarria, Koldo, Nafria, Beatriz, D'Amato, Mauro, Palom, Adriana, Begg, Colin, Clohisey, Sara, Hinds, Charles, Horby, Peter, Knight, Julian, Ling, Lowell, Maslove, David, McAuley, Danny, Millar, Johnny, Montgomery, Hugh, Nichol, Alistair, Openshaw, Peter J.M., Pereira, Alexandre C., Ponting, Chris P., Rowan, Kathy, Semple, Malcolm G., Shankar-Hari, Manu, Summers, Charlotte, Walsh, Timothy, Baillie, J. 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Proudfoot, Nicola, Slaughter, Melanie, Slevin, Kathryn, Thomas, Vicky, Walker, Danielle, Michael, Angiy, Collis, Matthew, Cosier, Tracey, Millen, Gemma, Richardson, Neil, Schumacher, Natasha, Weston, Heather, Rand, James, Baxter, Nicola, Henderson, Steven, Kennedy-Hay, Sophie, McParland, Christopher, Rooney, Laura, Sim, Malcolm, McCreath, Gordan, Akeroyd, Louise, Bano, Shereen, Bromley, Matt, Gurr, Lucy, Lawton, Tom, Morgan, James, Sellick, Kirsten, Warren, Deborah, Wilkinson, Brian, McGowan, Janet, Ledgard, Camilla, Stacey, Amelia, Pye, Kate, Bellwood, Ruth, Bentley, Michael, Bewley, Jeremy, Garland, Zoe, Grimmer, Lisa, Gumbrill, Bethany, Johnson, Rebekah, Sweet, Katie, Webster, Denise, Efford, Georgia, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Keshet-Price, Jocelyn, Randell, Georgina, Stammers, Katie, Bokhari, Maria, Linnett, Vanessa, Lucas, Rachael, McCormick, Wendy, Ritzema, Jenny, Sanderson, Amanda, Wild, Helen, Rostron, Anthony, Roy, Alistair, Woods, Lindsey, Cornell, Sarah, Wakinshaw, Fiona, Rogerson, Kimberley, Jarmain, Jordan, Parker, Robert, Reddy, Amie, Turner-Bone, Ian, Wilding, Laura, Harding, Peter, Abernathy, Caroline, Foster, Louise, Gratrix, Andrew, Martinson, Vicky, Parkinson, Priyai, Stones, Elizabeth, Carbral-Ortega, Llucia, Bercades, Georgia, Brealey, David, Hass, Ingrid, MacCallum, Niall, Martir, Gladys, Raith, Eamon, Reyes, Anna, Smyth, Deborah, Zitter, Letizia, Benyon, Sarah, Marriott, Suzie, Park, Linda, Keenan, Samantha, Gordon, Elizabeth, Quinn, Helen, Baines, Kizzy, Cagova, Lenka, Fofano, Adama, Garner, Lucie, Holcombe, Helen, Mepham, Sue, Mitchell, Alice Michael, Mwaura, Lucy, Praman, Krithivasan, Vuylsteke, Alain, Zamikula, Julie, Purewal, Bally, Rivers, Vanessa, Bell, Stephanie, Blakemore, Hayley, Borislavova, Borislava, Faulkner, Beverley, Gendall, Emma, Goff, Elizabeth, Hayes, Kati, Thomas, Matt, Worner, Ruth, Smith, Kerry, Stephens, Deanna, Mew, Louise, Mwaura, Esther, Stewart, Richard, Williams, Felicity, Wren, Lynn, Sutherland, Sara-Beth, Bevan, Emily, Martin, Jane, Trodd, Dawn, Watson, Geoff, Brown, Caroline Wrey, Collins, Amy, Khaliq, Waqas, Gude, Estefania Treus, Akinkugbe, Olugbenga, Bamford, Alasdair, Beech, Emily, Belfield, Holly, Bell, Michael, Davies, Charlene, Jones, Gareth A.L., McHugh, Tara, Meghari, Hamza, O'Neill, Lauran, Peters, Mark J., Ray, Samiran, Tomas, Ana Luisa, Burn, Iona, Hambrook, Geraldine, Manso, Katarina, Penn, Ruth, Shanmugasundaram, Pradeep, Tebbutt, Julie, Thornton, Danielle, Cole, Jade, Davies, Rhys, Duffin, Donna, Hill, Helen, Player, Ben, Thomas, Emma, Williams, Angharad, Griffin, Denise, Muchenje, Nycola, Mupudzi, Mcdonald, Partridge, Richard, Conyngham, Jo-Anna, Thomas, Rachel, Wright, Mary, Corral, Maria Alvarez, Jacob, Reni, Jones, Cathy, Denmade, Craig, Beavis, Sarah, Dale, Katie, Gascoyne, Rachel, Hawes, Joanne, Pritchard, Kelly, Stevenson, Lesley, Whileman, Amanda, Doble, Patricia, Hutter, Joanne, Pawley, Corinne, Shovelton, Charmaine, Vaida, Marius, Butcher, Deborah, O'Sullivan, Susie, Butterworth-Cowin, Nicola, Ahmad, Norfaizan, Barker, Joann, Bauchmuller, Kris, Bird, Sarah, Cawthron, Kay, Harrington, Kate, Jackson, Yvonne, Kibutu, Faith, Lenagh, Becky, Masuko, Shamiso, Mills, Gary H., Raithatha, Ajay, Wiles, Matthew, Willson, Jayne, Newell, Helen, Lye, Alison, Nwafor, Lorenza, Jarman, Claire, Rowland-Jones, Sarah, Foote, David, Cole, Joby, Thompson, Roger, Watson, James, Hesseldon, Lisa, Macharia, Irene, Chetam, Luke, Smith, Jacqui, Ford, Amber, Anderson, Samantha, Birchall, Kathryn, Housley, Kay, Walker, Sara, Milner, Leanne, Hanratty, Helena, Trower, Helen, Phillips, Patrick, Oxspring, Simon, Donne, Ben, Jardine, Catherine, Williams, Dewi, Hay, Alasdair, Flanagan, Rebecca, Hughes, Gareth, Latham, Scott, McKenna, Emma, Anderson, Jennifer, Hull, Robert, Rhead, Kat, Cruz, Carina, Pattison, Natalie, Charnock, Rob, McFarland, Denise, Cosgrove, Denise, Ahmed, Ashar, Morris, Anna, Jakkula, Srinivas, Ali, Asifa, Brady, Megan, Dale, Sam, Dance, Annalisa, Gledhill, Lisa, Greig, Jill, Hanson, Kathryn, Holdroyd, Kelly, Home, Marie, Kelly, Diane, Kitson, Ross, Matapure, Lear, Melia, Deborah, Mellor, Samantha, Nortcliffe, Tonicha, Pinnell, Jez, Robinson, Matthew, Shaw, Lisa, Shaw, Ryan, Thomis, Lesley, Wilson, Alison, Wood, Tracy, Bayo, Lee-Ann, Merwaha, Ekta, Ishaq, Tahira, Hanley, Sarah, Hibbert, Meg, Tetla, Dariusz, Woodford, Chrsitopher, Durga, Latha, Kennard-Holden, Gareth, Branney, Debbie, Frankham, Jordan, Pitts, Sally, White, Nigel, Laha, Shondipon, Verlander, Mark, Williams, Alexandra, Altabaibeh, Abdelhakim, Alvaro, Ana, Gilbert, Kayleigh, Ma, Louise, Mostoles, Loreta, Parmar, Chetan, Simpson, Kathryn, Jetha, Champa, Booker, Lauren, Pratley, Anezka, Adams, Colene, Agasou, Anita, Arden, Tracie, Bowes, Amy, Boyle, Pauline, Beekes, Mandy, Button, Heather, Capps, Nigel, Carnahan, Mandy, Carter, Anne, Childs, Danielle, Donaldson, Denise, Hard, Kelly, Hurford, Fran, Hussain, Yasmin, Javaid, Ayesha, Jones, James, Jose, Sanal, Leigh, Michael, Martin, Terry, Millward, Helen, Motherwell, Nichola, Rikunenko, Rachel, Stickley, Jo, Summers, Julie, Ting, Louise, Tivenan, Helen, Tonks, Louise, Wilcox, Rebecca, Holland, Maureen, Keenan, Natalie, Lyons, Marc, Wassall, Helen, Marsh, Chris, Mahenthran, Mervin, Carter, Emma, Kong, Thomas, Blackman, Helen, Creagh-Brown, Ben, Donlon, Sinead, Michalak-Glinska, Natalia, Mtuwa, Sheila, Pristopan, Veronika, Salberg, Armorel, Smith, Eleanor, Stone, Sarah, Piercy, Charles, Verula, Jerik, Burda, Dorota, Montaser, Rugia, Harden, Lesley, Mayangao, Irving, Marriott, Cheryl, Bradley, Paul, Harris, Celia, Anderson, Susan, Andrews, Eleanor, Birch, Janine, Collins, Emma, Hammerton, Kate, O'Leary, Ryan, Clark, Michele, Purvis, Sarah, Barber, Russell, Hewitt, Claire, Hilldrith, Annette, Jackson-Lawrence, Karen, Shepardson, Sarah, Wills, Maryanne, Butler, Susan, Tavares, Silvia, Cunningham, Amy, Hindale, Julia, Arif, Sarwat, Bean, Sarah, Burt, Karen, Spivey, Michael, Demetriou, Carrie, Eckbad, Charlotte, Hierons, Sarah, Howie, Lucy, Mitchard, Sarah, Ramos, Lidia, Serrano-Ruiz, Alfredo, White, Katie, Kelly, Fiona, Cristiano, Daniele, Dormand, Natalie, Farzad, Zohreh, Gummadi, Mahitha, Liyanage, Kamal, Patel, Brijesh, Salmi, Sara, Sloane, Geraldine, Thwaites, Vicky, Varghese, Mathew, Zborowski, Anelise C., Allan, John, Geary, Tim, Houston, Gordon, Meikle, Alistair, O'Brien, Peter, Forsey, Miranda, Kaliappan, Agilan, Nicholson, Anne, Riches, Joanne, Vertue, Mark, Allan, Elizabeth, Darlington, Kate, Davies, Ffyon, Easton, Jack, Kumar, Sumit, Lean, Richard, Menzies, Daniel, Pugh, Richard, Qiu, Xinyi, Davies, Llinos, Williams, Hannah, Scanlon, Jeremy, Davies, Gwyneth, Mackay, Callum, Lewis, Joannne, Rees, Stephanie, Oblak, Metod, Popescu, Monica, Thankachen, Mini, Higham, Andrew, Simpson, Kerry, Craig, Jayne, Baruah, Rosie, Morris, Sheila, Ferguson, Susie, Shepherd, Amy, Prockter Moore, Luke Stephen, Vizcaychipi, Marcela Paola, Gomes de Almeida Martins, Laura, Carungcong, Jaime, Mohamed Ali, Inthakab Ali, Beaumont, Karen, Blunt, Mark, Coton, Zoe, Curgenven, Hollie, Elsaadany, Mohamed, Fernandes, Kay, Ally, Sameena Mohamed, Rangarajan, Harini, Sarathy, Varun, Selvanayagam, Sivarupan, Vedage, Dave, White, Matthew, Gill, Mandy, Paul, Paul, Ratnam, Valli, Shelton, Sarah, Wynter, Inez, Carmody, Siobhain, Page, Valerie Joan, Beith, Claire Marie, Black, Karen, Clements, Suzanne, Morrison, Alan, Strachan, Dominic, Taylor, Margaret, Clarkson, Michelle, D'Sylva, Stuart, Norman, Kathryn, Auld, Fiona, Donnachie, Joanne, Edmond, Ian, Prentice, Lynn, Runciman, Nikole, Salutous, Dario, Symon, Lesley, Todd, Anne, Turner, Patricia, Short, Abigail, Sweeney, Laura, Murdoch, Euan, Senaratne, Dhaneesha, Hill, Michaela, Kannan, Thogulava, Laura, Wild, Crawley, Rikki, Crew, Abigail, Cunningham, Mishell, Daniels, Allison, Harrison, Laura, Hope, Susan, Inweregbu, Ken, Jones, Sian, Lancaster, Nicola, Matthews, Jamie, Nicholson, Alice, Wray, Gemma, Langton, Helen, Prout, Rachel, Watters, Malcolm, Novis, Catherine, Barron, Anthony, Collins, Ciara, Kaul, Sundeep, Passmore, Heather, Prendergast, Claire, Reed, Anna, Rogers, Paula, Shokkar, Rajvinder, Woodruff, Meriel, Middleton, Hayley, Polgar, Oliver, Nolan, Claire, Mahay, Kanta, Collier, Dawn, Hormis, Anil, Maynard, Victoria, Graham, Cheryl, Walker, Rachel, Knights, Ellen, Price, Alicia, Thomas, Alice, Thorpe, Chris, Behan, Teresa, Burnett, Caroline, Hatton, Jonathan, Heeney, Elaine, Mitra, Atideb, Newton, Maria, Pollard, Rachel, Stead, Rachael, Amin, Vishal, Anastasescu, Elena, Anumakonda, Vikram, Karthik, Komala, Kausar, Rizwana, Reid, Karen, Smith, Jacqueline, Imeson-Wood, Janet, Skinner, Denise, Gaylard, Jane, Mullan, Dee, Newman, Julie, Brown, Alison, Crickmore, Vikki, Debreceni, Gabor, Wilkins, Joy, Nicol, Liz, Reece-Anthony, Rosie, Birt, Mark, Ghosh, Alison, Williams, Emma, Allen, Louise, Beranova, Eva, Crisp, Nikki, Deery, Joanne, Hazelton, Tracy, Knight, Alicia, Price, Carly, Tilbey, Sorrell, Turki, Salah, Turney, Sharon, Cooper, Joshua, Finch, Cheryl, Liderth, Sarah, Quinn, Alison, Waddington, Natalia, Coventry, Tina, Fowler, Susan, MacMahon, Michael, McGregor, Amanda, Cowley, Anne, Highgate, Judith, Gregory, Jane, O'Connell, Susan, Smith, Tim, Barberis, Luigi, Gopal, Shameer, Harris, Nichola, Lake, Victoria, Metherell, Stella, Radford, Elizabeth, Daniel, Amelia, Finn, Joanne, Saha, Rajnish, White, Nikki, Donnison, Phil, Trim, Fiona, Eapen, Beena, Birch, Jenny, Bough, Laura, Goodsell, Josie, Tutton, Rebecca, Williams, Patricia, Williams, Sarah, Winter-Goodwin, Barbara, Nichol, Ailstair, Brickell, Kathy, Smyth, Michelle, Murphy, Lorna, Coetzee, Samantha, Gales, Alistair, Otahal, Igor, Raj, Meena, Sell, Craig, Hilltout, Paula, Evitts, Jayne, Tyler, Amanda, Waldron, Joanne, Beesley, Kate, Board, Sarah, Kubisz-Pudelko, Agnieszka, Lewis, Alison, Perry, Jess, Pippard, Lucy, Wood, Di, Buckley, Clare, Barry, Peter, Flint, Neil, Rekha, Patel, Hales, Dawn, Bunni, Lara, Jennings, Claire, Latif, Monica, Marshall, Rebecca, Subramanian, Gayathri, McGuigan, Peter J., Wasson, Christopher, Finn, Stephanie, Green, Jackie, Collins, Erin, King, Bernadette, Campbell, Andy, Smuts, Sara, Duffield, Joseph, Smith, Oliver, Mallon, Lewis, Claire, Watkins, Botfield, Liam, Butler, Joanna, Dexter, Catherine, Fletcher, Jo, Garg, Atul, Kuravi, Aditya, Ranga, Poonam, Virgilio, Emma, Belagodu, Zakaula, Fuller, Bridget, Gherman, Anca, Olufuwa, Olumide, Paramsothy, Remi, Stuart, Carmel, Oakley, Naomi, Kamundi, Charlotte, Tyl, David, Collins, Katy, Silva, Pedro, Taylor, June, King, Laura, Coates, Charlotte, Crowley, Maria, Wakefield, Phillipa, Beadle, Jane, Johnson, Laura, Sargeant, Janet, Anderson, Madeleine, Brady, Ailbhe, Chan, Rebekah, Little, Jeff, McIvor, Shane, Prady, Helena, Whittle, Helen, Mathew, Bijoy, Attwood, Ben, Parsons, Penny, Ward, Geraldine, Bremmer, Pamela, Joe, West, Tracy, Baird, Jim, Ruddy, Davies, Ellie, Sathe, Sonia, Dennis, Catherine, McGregor, Alastair, Parris, Victoria, Srikaran, Sinduya, Sukha, Anisha, Clarke, Noreen, Whiteside, Jonathan, Mascarenhas, Mairi, Donaldson, Avril, Matheson, Joanna, Barrett, Fiona, O'Hara, Marianne, Okeefe, Laura, Bradley, Clare, Eastgate-Jackson, Christine, Filipe, Helder, Martin, Daniel, Maharajh, Amitaa, Garcia, Sara Mingo, Pakou, Glykeria, De Neef, Mark, Dent, Kathy, Horsley, Elizabeth, Akhtar, Muhmmad Nauman, Pearson, Sandra, Potoczna, Dorota, Spencer, Sue, Clapham, Melanie, Harper, Rosemary, Poultney, Una, Rice, Polly, Mutch, Rachel, Armstrong, Lisa, Bates, Hayley, Dooks, Emma, Farquhar, Fiona, Hairsine, Brigid, McParland, Chantal, Packham, Sophie, Bi, Rehana, Scholefield, Barney, Ashton, Lydia, George, Linsha, Twiss, Sophie, Wright, David, Chablani, Manish, Kirkby, Amy, Netherton, Kimberley, Davies, Kim, O'Brien, Linda, Omar, Zohra, Perkins, Emma, Lewis, Tracy, Sutherland, Isobel, Burns, Karen, Ben Chandler, Dr, Elliott, Kerry, Mallinson, Janine, Turnbull, Alison, Gondo, Prisca, Hadebe, Bernard, Kayani, Abdul, Masunda, Bridgett, Anderson, Taya, Hawcutt, Dan, O'Malley, Laura, Rad, Laura, Rogers, Naomi, Saunderson, Paula, Allison, Kathryn Sian, Afolabi, Deborah, Whitbread, Jennifer, Jones, Dawn, Dore, Rachael, Halkes, Matthew, Mercer, Pauline, Thornton, Lorraine, Dawson, Joy, Garrioch, Sweyn, Tolson, Melanie, Aldridge, Jonathan, Kapoor, Ritoo, Loader, David, Castle, Karen, Humphreys, Sally, Tampsett, Ruth, Mackintosh, Katherine, Ayers, Amanda, Harrison, Wendy, North, Julie, Allibone, Suzanne, Genetu, Roman, Kasipandian, Vidya, Patel, Amit, Mac, Ainhi, Murphy, Anthony, Mahjoob, Parisa, Nazari, Roonak, Worsley, Lucy, Fagan, Andrew, Bemand, Thomas, Black, Ethel, Dela Rosa, Arnold, Howle, Ryan, Jhanji, Shaman, Baikady, Ravishankar Rao, Tatham, Kate Colette, Thomas, Benjamin, Bell, Dina, Boyle, Rosalind, Douglas, Katie, Glass, Lynn, Lee, Emma, Lennon, Liz, Rattray, Austin, Taylor, Abigail, Hughes, Rachel Anne, Thomas, Helen, Rees, Alun, Duskova, Michaela, Phipps, Janet, Brooks, Suzanne, Edwards, Michelle, Quaid, Sheena, Watson, Ekaterina, Brayne, Adam, Fisher, Emma, Hunt, Jane, Jackson, Peter, Kaye, Duncan, Love, Nicholas, Parkin, Juliet, Tuckey, Victoria, Van Koutrik, Lynne, Carter, Sasha, Andrew, Benedict, Findlay, Louise, Adams, Katie, Service, Jen, Williams, Alison, Cheyne, Claire, Saunderson, Anne, Moultrie, Sam, Odam, Miranda, Hall, Kathryn, Mapfunde, Isheunesu, Willis, Charlotte, Lyon, Alex, Sri-Chandana, Chunda, Scherewode, Joslan, Stephenson, Lorraine, Marsh, Sarah, Hardy, John, Houlden, Henry, Moncur, Eleanor, Tariq, Ambreen, Tucci, Arianna, Hobrok, Maria, Loosley, Ronda, McGuinness, Heather, Tench, Helen, Wolf-Roberts, Rebecca, Irvine, Val, Shelley, Benjamin, Gorman, Claire, Gupta, Abhinav, Timlick, Elizabeth, Brady, Rebecca, Milligan, Barry, Bellini, Arianna, Bryant, Jade, Mayer, Anton, Pickard, Amy, Roe, Nicholas, Sowter, Jason, Howlett, Alex, Fidler, Katy, Tagliavini, Emma, Donnelly, Kevin, Boos, Jannik, van der Made, Caspar I., Ramakrishnan, Gayatri, Coughlan, Eamon, Asselta, Rosanna, Löscher, Britt-Sabina, Valenti, Luca V.C., de Cid, Rafael, Bujanda, Luis, Julià, Antonio, Pairo-Castineira, Erola, May, Sandra, Zametica, Berina, Heggemann, Julia, Albillos, Agustín, Banales, Jesus M., Barretina, Jordi, Blay, Natalia, Bonfanti, Paolo, Buti, Maria, Fernandez, Javier, Marsal, Sara, Prati, Daniele, Ronzoni, Luisa, Sacchi, Nicoletta, Schultze, Joachim L., Riess, Olaf, Franke, Andre, Rawlik, Konrad, Ellinghaus, David, Hoischen, Alexander, Schmidt, Axel, and Ludwig, Kerstin U.
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- 2024
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3. Global, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021
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Bender, Rose Grace, Sirota, Sarah Brooke, Swetschinski, Lucien R, Dominguez, Regina-Mae Villanueva, Novotney, Amanda, Wool, Eve E, Ikuta, Kevin S, Vongpradith, Avina, Rogowski, Emma Lynn Best, Doxey, Matthew, Troeger, Christopher E, Albertson, Samuel B, Ma, Jianing, He, Jiawei, Maass, Kelsey Lynn, A.F.Simões, Eric, Abdoun, Meriem, Abdul Aziz, Jeza Muhamad, Abdulah, Deldar Morad, Abu Rumeileh, Samir, Abualruz, Hasan, Aburuz, Salahdein, Adepoju, Abiola Victor, Adha, Rishan, Adikusuma, Wirawan, Adra, Saryia, Afraz, Ali, Aghamiri, Shahin, Agodi, Antonella, Ahmadzade, Amir Mahmoud, Ahmed, Haroon, Ahmed, Ayman, Akinosoglou, Karolina, AL-Ahdal, Tareq Mohammed Ali, Al-amer, Rasmieh Mustafa, Albashtawy, Mohammed, AlBataineh, Mohammad T., Alemi, Hediyeh, Al-Gheethi, Adel Ali Saeed, Ali, Abid, Ali, Syed Shujait Shujait, Alqahtani, Jaber S, AlQudah, Mohammad, Al-Tawfiq, Jaffar A., Al-Worafi, Yaser Mohammed, Alzoubi, Karem H, Amani, Reza, Amegbor, Prince M, Ameyaw, Edward Kwabena, Amuasi, John H, Anil, Abhishek, Anyanwu, Philip Emeka, Arafat, Mosab, Areda, Damelash, Arefnezhad, Reza, Atalell, Kendalem Asmare, Ayele, Firayad, Azzam, Ahmed Y, Babamohamadi, Hassan, Babin, François-Xavier, Bahurupi, Yogesh, Baker, Stephen, Banik, Biswajit, Barchitta, Martina, Barqawi, Hiba Jawdat, Basharat, Zarrin, Baskaran, Pritish, Batra, Kavita, Batra, Ravi, Bayileyegn, Nebiyou Simegnew, Beloukas, Apostolos, Berkley, James A, Beyene, Kebede A, Bhargava, Ashish, Bhattacharjee, Priyadarshini, Bielicki, Julia A, Bilalaga, Mariah Malak, Bitra, Veera R, Brown, Colin Stewart, Burkart, Katrin, Bustanji, Yasser, Carr, Sinclair, Chahine, Yaacoub, Chattu, Vijay Kumar, Chichagi, Fatemeh, Chopra, Hitesh, Chukwu, Isaac Sunday, Chung, Eunice, Dadana, Sriharsha, Dai, Xiaochen, Dandona, Lalit, Dandona, Rakhi, Darban, Isaac, Dash, Nihar Ranjan, Dashti, Mohsen, Dashtkoohi, Mohadese, Dekker, Denise Myriam, Delgado-Enciso, Ivan, Devanbu, Vinoth Gnana Chellaiyan, Dhama, Kuldeep, Diao, Nancy, Do, Thao Huynh Phuong, Dokova, Klara Georgieva, Dolecek, Christiane, Dziedzic, Arkadiusz Marian, Eckmanns, Tim, Ed-Dra, Abdelaziz, Efendi, Ferry, Eftekharimehrabad, Aziz, Eyre, David William, Fahim, Ayesha, Feizkhah, Alireza, Felton, Timothy William, Ferreira, Nuno, Flor, Luisa S, Gaihre, Santosh, Gebregergis, Miglas W, Gebrehiwot, Mesfin, Geffers, Christine, Gerema, Urge, Ghaffari, Kazem, Goldust, Mohamad, Goleij, Pouya, Guan, Shi-Yang, Gudeta, Mesay Dechasa, Guo, Cui, Gupta, Veer Bala, Gupta, Ishita, Habibzadeh, Farrokh, Hadi, Najah R, Haeuser, Emily, Hailu, Wase Benti, Hajibeygi, Ramtin, Haj-Mirzaian, Arvin, Haller, Sebastian, Hamiduzzaman, Mohammad, Hanifi, Nasrin, Hansel, Jan, Hasnain, Md Saquib, Haubold, Johannes, Hoan, Nguyen Quoc, Huynh, Hong-Han, Iregbu, Kenneth Chukwuemeka, Islam, Md. Rabiul, Jafarzadeh, Abdollah, Jairoun, Ammar Abdulrahman, Jalili, Mahsa, Jomehzadeh, Nabi, Joshua, Charity Ehimwenma, Kabir, Md. Awal, Kamal, Zul, Kanmodi, Kehinde Kazeem, Kantar, Rami S., Karimi Behnagh, Arman, Kaur, Navjot, Kaur, Harkiran, Khamesipour, Faham, Khan, M Nuruzzaman, Khan suheb, Mahammed Ziauddin, Khanal, Vishnu, Khatab, Khaled, Khatib, Mahalaqua Nazli, Kim, Grace, Kim, Kwanghyun, Kitila, Aiggan Tamene Tamene, Komaki, Somayeh, Krishan, Kewal, Krumkamp, Ralf, Kuddus, Md Abdul, Kurniasari, Maria Dyah, Lahariya, Chandrakant, Latifinaibin, Kaveh, Le, Nhi Huu Hanh, Le, Thao Thi Thu, Le, Trang Diep Thanh, Lee, Seung Won, LEPAPE, Alain, Lerango, Temesgen L., Li, Ming-Chieh, Mahboobipour, Amir Ali, Malhotra, Kashish, Mallhi, Tauqeer Hussain, Manoharan, Anand, Martinez-Guerra, Bernardo Alfonso, Mathioudakis, Alexander G., Mattiello, Rita, May, Jürgen, McManigal, Barney, McPhail, Steven M, Mekene Meto, Tesfahun, Mendez-Lopez, Max Alberto Mendez, Meo, Sultan Ayoub, Merati, Mohsen, Mestrovic, Tomislav, Mhlanga, Laurette, Minh, Le Huu Nhat, Misganaw, Awoke, Mishra, Vinaytosh, Misra, Arup Kumar, Mohamed, Nouh Saad, Mohammadi, Esmaeil, Mohammed, Mesud, Mohammed, Mustapha, Mokdad, Ali H, Monasta, Lorenzo, Moore, Catrin E, Motappa, Rohith, Mougin, Vincent, Mousavi, Parsa, Mulita, Francesk, Mulu, Atsedemariam Andualem, Naghavi, Pirouz, Naik, Ganesh R, Nainu, Firzan, Nair, Tapas Sadasivan, Nargus, Shumaila, Negaresh, Mohammad, Nguyen, Hau Thi Hien, Nguyen, Dang H, Nguyen, Van Thanh, Nikolouzakis, Taxiarchis Konstantinos, Noman, Efaq Ali, Nri-Ezedi, Chisom Adaobi, Odetokun, Ismail A., Okwute, Patrick Godwin, Olana, Matifan Dereje, Olanipekun, Titilope O, Olasupo, Omotola O., Olivas-Martinez, Antonio, Ordak, Michal, Ortiz-Brizuela, Edgar, Ouyahia, Amel, Padubidri, Jagadish Rao, Pak, Anton, Pandey, Anamika, Pantazopoulos, Ioannis, Parija, Pragyan Paramita, Parikh, Romil R, Park, Seoyeon, Parthasarathi, Ashwaghosha, Pashaei, Ava, Peprah, Prince, Pham, Hoang Tran, Poddighe, Dimitri, Pollard, Andrew, Ponce-De-Leon, Alfredo, Prakash, Peralam Yegneswaran, Prates, Elton Junio Sady, Quan, Nguyen Khoi, Raee, Pourya, Rahim, Fakher, Rahman, Mosiur, Rahmati, Masoud, Ramasamy, Shakthi Kumaran, Ranjan, Shubham, Rao, Indu Ramachandra, Rashid, Ahmed Mustafa, Rattanavong, Sayaphet, Ravikumar, Nakul, Reddy, Murali Mohan Rama Krishna, Redwan, Elrashdy Moustafa Mohamed, Reiner, Robert C, Jr., Reyes, Luis Felipe, Roberts, Tamalee, Rodrigues, Mónica, Rosenthal, Victor Daniel, Roy, Priyanka, Runghien, Tilleye, Saeed, Umar, Saghazadeh, Amene, Saheb Sharif-Askari, Narjes, Saheb Sharif-Askari, Fatemeh, Sahoo, Soumya Swaroop, Sahu, Monalisha, Sakshaug, Joseph W, Salami, Afeez Abolarinwa, Saleh, Mohamed A., Salehi omran, Hossein, Sallam, Malik, Samadzadeh, Sara, Samodra, Yoseph Leonardo, Sanjeev, Rama Krishna, Sarasmita, Made Ary, Saravanan, Aswini, Sartorius, Benn, Saulam, Jennifer, Schumacher, Austin E, Seyedi, Seyed Arsalan, Shafie, Mahan, Shahid, Samiah, Sham, Sunder, Shamim, Muhammad Aaqib, Shamshirgaran, Mohammad Ali, Shastry, Rajesh P., Sherchan, Samendra P, Shiferaw, Desalegn, Shittu, Aminu, Siddig, Emmanuel Edwar, Sinto, Robert, Sood, Aayushi, Sorensen, Reed J D, Stergachis, Andy, Stoeva, Temenuga Zhekova, Swain, Chandan Kumar, Szarpak, Lukasz, Tamuzi, Jacques Lukenze, Temsah, Mohamad-Hani, Tessema, Melkamu B Tessema, Thangaraju, Pugazhenthan, Tran, Nghia Minh, Tran, Ngoc-Ha, Tumurkhuu, Munkhtuya, Ty, Sree Sudha, Udoakang, Aniefiok John, Ulhaq, Inam, Umar, Tungki Pratama, Umer, Abdurezak Adem, Vahabi, Seyed Mohammad, Vaithinathan, Asokan Govindaraj, Van den Eynde, Jef, Walson, Judd L, Waqas, Muhammad, Xing, Yuhan, Yadav, Mukesh Kumar, Yahya, Galal, Yon, Dong Keon, Zahedi Bialvaei, Abed, Zakham, Fathiah, Zeleke, Abyalew Mamuye, Zhai, Chunxia, Zhang, Zhaofeng, Zhang, Haijun, Zielińska, Magdalena, Zheng, Peng, Aravkin, Aleksandr Y, Vos, Theo, Hay, Simon I, Mosser, Jonathan F., Lim, Stephen S, Naghavi, Mohsen, Murray, Christopher J L, and Kyu, Hmwe Hmwe
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- 2024
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4. System-wide approaches to antimicrobial therapy and antimicrobial resistance in the UK: the AMR-X framework
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Abel, Kathryn, Agnew, Emily, Amos, James, Armstrong, Natalie, Armstrong-James, Darius, Ashfield, Thomas, Aston, Stephen, Baillie, J Kenneth, Baldwin, Steven, Barlow, Gavin, Bartle, Victoria, Bielicki, Julia, Brown, Colin, Carrol, Enitan, Clements, Michelle, Cooke, Graham, Dane, Aaron, Dark, Paul, Day, Jeremy, de-Soyza, Anthony, Dowsey, Andrew, Evans, Stephanie, Eyre, David, Felton, Timothy, Fowler, Tom, Foy, Robbie, Gannon, Karen, Gerada, Alessandro, Goodman, Anna, Harman, Tracy, Hayward, Gail, Holmes, Alison, Hopkins, Susan, Howard, Philip, Howard, Alexander, Hsia, Yingfen, Knight, Gwen, Lemoine, Nick, Koh, James, Macgowan, Alasdair, Marwick, Charis, Moore, Catrin, O’Brien, Seamus, Oppong, Raymond, Peacock, Sharon, Pett, Sarah, Pouwels, Koen, Queree, Chris, Rahman, Najib, Sculpher, Mark, Shallcross, Laura, Sharland, Michael, Singh, Jasvinder, Stoddart, Karen, Thomas-Jones, Emma, Townsend, Andrew, Ustianowski, Andrew, Van Staa, Tjeerd, Walker, Sarah, White, Peter, Wilson, Paul, Buchan, Iain, Woods, Beth, Bower, Peter, Llewelyn, Martin, and Hope, William
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- 2024
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5. Clinical trials of pneumonia management assess heterogeneous outcomes and measurement instruments
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Aliberti, Stefano, Barac, Aleksandra, Blasi, Francesco, Chastre, Jean, Clarke, Mike, Ciloniz, Catia, Dark, Paul, Dimopoulos, George, Fally, Markus, Felton, Timothy W., Gramegna, Andrea, Hansel, Jan, Haseeb, Faiuna, Kouta, Ahmed, Mathioudakis, Alexander G., Polverino, Eva, Roger, Claire, Robey, Rebecca C., Rovina, Nikoletta, Stolz, Daiana, Vestbo, Jørgen, Waterer, Grant, Welte, Tobias, Williams, Thomas, Williamson, Paula R., Wootton, Dan G., and van Wouter, Geffen
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- 2023
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6. Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling
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Alshaer, Mohammad H., Williams, Roy, Mousa, Mays J., Alexander, Kaitlin M., Maguigan, Kelly L., Manigaba, Kayihura, Maranchick, Nicole, Shoulders, Bethany R., Felton, Timothy W., Mathew, Sumith K., and Peloquin, Charles A.
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- 2023
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7. Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2): results of a randomised, double-blind, placebo-controlled, phase 3 trial
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Garibaldi, Brian T., Albertson, Timothy E., Sandrock, Christian, Lee, Janet S., Looney, Mark R., Tapson, Victor F., Wiysonge, Charles Shey, Velarde, Luis Humberto Anaya, Backenroth, Daniel, Bhushanan, Jisha, Brandenburg, Börries, Cárdenas, Vicky, Chen, Bohang, Chen, Fei, Chetty, Polan, Chu, Pei-Ling, Cooper, Kimberly, Custers, Jerome, Delanghe, Hilde, Duca, Anna, Henrick, Tracy, Juraszek, Jarek, Nalpas, Catherine, Peeters, Monika, Pinheiro, Jose, Roels, Sanne, Ryser, Martin F., Salas, Jose, Santoro Matias, Samantha, Scheys, Ilse, Shetty, Pallavi, Shukarev, Georgi, Stoddard, Jeffrey, Talloen, Willem, Tran, NamPhuong, Vaissiere, Nathalie, van Son-Palmen, Elisabeth, Xu, Jiajun, Goecker, Erin A., Greninger, Alexander L., Jerome, Keith R., Roychoudhury, Pavitra, Takuva, Simbarashe G., Accini Mendoza, Jose Luis, Achtyes, Eric, Ahsan, Habibul, Alhatemi, Azhar, Allen, Nancy, Arribas, Jose R., Bahrami, Ghazaleh, Bailon, Lucia, Bajwa, Ali, Baker, Jonathan, Baron, Mira, Benet, Susana, Berdaï, Driss, Berger, Patrick, Bertoch, Todd, Bethune, Claire, Bevilacqua, Sybille, Biagioni Santos, Maria Silvia, Binnian, Ian, Bisnauthsing, Karen, Boivin, Jean-Marc, Bollen, Hilde, Bonnet, Sandrine, Borobia, Alberto M., Botelho-Nevers, Elisabeth, Bright, Phil, Britten, Vianne, Brown, Claire, Buadi, Amanda, Buntinx, Erik, Burgess, Lesley, Bush, Larry, Capeding, Maria Rosario, Carr, Quito Osuna, Carrasco Mas, Amparo, Catala, Hélène, Cathie, Katrina, Caudill, T. Shawn, Cereto Castro, Fernando, Chau, Kénora, Chavoustie, Steven, Chowdhury, Marie, Chronos, Nicolas, Cicconi, Paola, Cifuentes, Liliana, Cobo, Sara Maria, Collins, Helen, Colton, Hayley, Cuaño, Carlos Rolando G., D'Onofrio, Valentino, Dargan, Paul, Darton, Thomas, Deane, Peter, Del Pozo, Jose Luis, Derdelinckx, Inge, Desai, Amisha, Dever, Michael, Díaz-Pollán, Beatriz, DiBuono, Mark, Doust, Matthew, Duncan, Christopher, Echave-Sustaeta, Jose Maria, Eder, Frank, Ellis, Kimberly, Elzi, Stanton, Emmett, Stevan, Engelbrecht, Johannes, Evans, Mim, Farah, Theo, Felton, Timothy, Ferreira, João Pedro, Floutier, Catherine, Flume, Patrick, Ford, Stacy, Fragoso, Veronica, Freedman, Andrew, Frentiu, Emilia, Galloway, Christopher, Galtier, Florence, Garcia Diaz, Julia, García García, Irene, Garcia, Alcaide, Gardener, Zoe, Gauteul, Pascale, Geller, Steven, Gibson, Andrew, Gillet, Claudia, Girerd, Nicolas, Girodet, Pierre-Olivier, Gler, Maria Tarcela, Glover, Richard, Go, Herschel Don D., Gokani, Karishma, Gonthier, Damien, Green, Christopher, Greenberg, Richard, Griffin, Carl, Grobbelaar, Coert, Guancia, Adonis, Hakkarainen, Gloria, Harris, James, Hassman, Michael, Heimer, Deirdre, Hellstrom-Louw, Elizabeth, Herades, Yoan, Holroyd, Christopher, Hussen, Nazreen, Isidro, Marie Grace Dawn, Jackson, Yvonne, Jain, Manish, João Filho, Esaú Custódio, Johnson, Daniel, Jones, Ben, Joseph, Natasha, Jumeras, Analyn, Junquera, Patricia, Kellett-Wright, Johanna, Kennedy, Patrick, Kilgore, Paul E., Kim, Kenneth, Kimmel, Murray, Konis, George, Kutner, Mark, Lacombe, Karine, Launay, Odile, Lazarus, Rajeka, Lederman, Samuel, Lefebvre, Gigi, Lennon Collins, Katrina, Leroux-Roels, Isabel, Lim, Kenneth Wilson O., Lins, Muriel, Liu, Edward, Llewelyn, Martin, Mahomed, Akbar, Maia, Bernardo Porto, Marín-Candon, Alícia, Martínez-Gómez, Xavier, Martinot, Jean Benoit, Mazzella, Andrea, McCaughan, Frank, McCormack, Louise, McGettigan, John, Mehra, Purvi, Mejeur, Rhonda, Miller, Vicki, Mills, Anthony, Molto Marhuenda, Jose, Moodley, Prebashan, Mora-Rillo, Marta, Mothe, Beatriz, Mullan, Daniel, Munro, Alasdair, Myers, Paul, Nell, Jeremy, Newman Lobato Souza, Tamara, O'Halloran, Jane A., Ochoa Mazarro, Maria Dolores, Oliver, Abigail, Onate Gutierrez, Jose Millan, Ortega, Jessica, Oshita, Masaru, Otero Romero, Susana, Overcash, Jeffrey Scott, Owens, Daniel, Packham, Alice, Pacurar, Mihaela, Paiva de Sousa, Leonardo, Palfreeman, Adrian, Pallares, Christian José, Patel, Rahul, Patel, Suchet, Pelkey, Leslie, Peluso, Denise, Penciu, Florentina, Pinto, S. Jerry, Pounds, Kevin, Pouzar, Joe, Pragalos, Antoinette, Presti, Rachel, Price, David, Qureshi, Ehsaan, Ramalho Madruga, José Valdez, Ramesh, Mayur, Rankin, Bruce, Razat, Béatrice, Riegel Santos, Breno, Riesenberg, Robert, Riffer, Ernie, Roche, Siobhan, Rose, Katie, Rosellini, Pietro, Rossignol, Patrick, Safirstein, Beth, Salazar, Hernan, Sanchez Vallejo, Gregorio, Santhosh, Smrithi, Seco-Meseguer, Enrique, Seep, Michael, Sherry, Emma, Short, Philip, Soentjens, Patrick, Solis, Joel, Soriano Viladomiu, Alejandro, Sorli, Caroline, Spangenthal, Selwyn, Spence, Niamh, Stephenson, Elaine, Strout, Cynthia, Surowitz, Ronald, Taladua, Kristy Michelle, Tellalian, David, Thalamas, Claire, Thiriphoo, Nang, Thomas, Judith, Thomas, Nicholas, Trout, Guillermo, Urroz, Mikel, Veekmans, Bernard, Veekmans, Laurent, Villalobos, Ralph Elvi M., Warren, Sarah, Webster, Brian, White, Alexander, Williams, Gail, Williams, Hayes, Wilson, Barbara, Winston, Alan, Wiselka, Martin, Zervos, Marcus, Hardt, Karin, Vandebosch, An, Sadoff, Jerald, Le Gars, Mathieu, Truyers, Carla, Lowson, David, Van Dromme, Ilse, Vingerhoets, Johan, Kamphuis, Tobias, Scheper, Gert, Ruiz-Guiñazú, Javier, Faust, Saul N, Spinner, Christoph D, Schuitemaker, Hanneke, Van Hoof, Johan, Douoguih, Macaya, and Struyf, Frank
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- 2022
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8. Composition and diversity analysis of the lung microbiome in patients with suspected ventilator-associated pneumonia
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Fenn, Dominic, Abdel-Aziz, Mahmoud I., van Oort, Pouline M. P., Brinkman, Paul, Ahmed, Waqar M., Felton, Timothy, Artigas, Antonio, Póvoa, Pedro, Martin-Loeches, Ignacio, Schultz, Marcus J., Dark, Paul, Fowler, Stephen J., and Bos, Lieuwe D. J.
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- 2022
- Full Text
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9. ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients
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Cunningham, Peter S., Kitchen, Gareth B., Jackson, Callum, Papachristos, Stavros, Springthorpe, Thomas, van Dellen, David, Gibbs, Julie, Felton, Timothy W., Wilson, Anthony J., Bannard-Smith, Jonathan, Rutter, Martin K., House, Thomas, Dark, Paul, Augustine, Titus, Akman, Ozgur E., Hazel, Andrew L., and Blaikley, John F.
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Mathematical models -- Usage ,Oscillation -- Measurement -- Health aspects ,Circadian rhythms -- Health aspects -- Measurement ,Data entry -- Methods ,Critically ill -- Physiological aspects ,Health care industry - Abstract
BACKGROUND. Assessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients. METHODS. We present ClinCirc. This method combines 2 existing mathematical methods (Lomb-Scargle periodogram and cosinor) sequentially and is designed to measure circadian oscillations from infrequently sampled clinical data. The accuracy of this method was compared against 9 other methods using simulated and frequently sampled biological data. ClinCirc was then evaluated in 13 intensive care unit (ICU) patients as well as in a separate cohort of 29 kidney-transplant recipients. Finally, the consequences of circadian alterations were investigated in a retrospective cohort of 726 kidney-transplant recipients. RESULTS. ClinCirc had comparable performance to existing methods for analyzing simulated data or clock transcript expression of healthy volunteers. It had improved accuracy compared with the cosinor method in evaluating circadian parameters in PER2:luc cell lines. In ICU patients, it was the only method investigated to suggest that loss of circadian oscillations in the peripheral oscillator was associated with inflammation, a feature widely reported in animal models. Additionally, ClinCirc was able to detect other circadian alterations, including a phase shift following kidney transplantation that was associated with the administration of glucocorticoids. This phase shift could explain why a significant complication of kidney transplantation (delayed graft dysfunction) oscillates according to the time of day kidney transplantation is performed. CONCLUSION. ClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients. FUNDING. UK Research and Innovation (UKRI), National Institute of Health Research (NIHR), Engineering and Physical Sciences Research Council (EPSRC), National Institute on Academic Anaesthesia (NIAA), Asthma+Lung UK, Kidneys for Life., Introduction Circadian biology has profound effects on both outcome and pathophysiology (1) in many disease models (2-5). The clinical relevance of these effects, however, remains opaque, since associations between clinical [...]
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- 2023
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10. Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach
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Felton, Timothy
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615.1 ,Pharmacokinetics ,Pharmacodynamics ,Piperacillin-tazobactam - Abstract
Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic, frequently used for pulmonary infections. Lung antibiotic concentration reflects target site concentrations in patients with pneumonia. Critically ill patient’s exhibit marked pharmacokinetic (PK) variability. PTZ exposures resulting in maximal bacterial killing and prevention of emergence of drug resistance are not known. Administration of PTZ by extended infusions (EI) or using Bayesian dosage optimisation, instead of a fixed bolus regimen, may improve clinical outcomes. Experimental work was conducted in an in vitro hollow fibre infection model (HFIM) using two densities of Pseudomonas aeruginosa. Experimental data was described by a mathematical model allowing identification of PTZ exposures associated with bacterial killing and suppression of the emergence of resistance. The population PK of PTZ in the plasma and lung of 17 critically ill patients was estimated. Monte Carlo simulation was used to explore the proportion of patients that achieve the plasma and lung PTZ exposures associated with bacterial killing and resistance suppression and to determine the effect of administration schedule. Finally, the population PK of PTZ in the plasma of 146 critically ill patients was estimated and used to construct computer software that can individualise PTZ dosing. Precision of the dosing software was assessed in 8 additional individuals. At low bacterial density a trough piperacillin:MIC ratio of 3.4 for bolus and 10.4 for EI regimens were able to suppress the emergence of resistance. At higher bacterial density all regimens were associated with growth of a resistant sub-population. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated to pulmonary permeability. Simulations revealed that EI, compared with bolus dosing, of PTZ is associated with a higher likelihood of bacteria killing. Similar probability of developing resistance was predicted with PTZ administration by EI and by bolus administration. Performance of the dose optimisation software was satisfactory. Current PTZ regimens are insufficient to treat pneumonia in approximately 14% of critically ill patients. Delivery of PTZ by EI may be a more effective method of administration for some patients with nosocomial infections. Individualised PTZ regimens, delivering a target piperacillin concentration, identified in a HFIM, are achievable and should improved clinical outcomes. Patients with a high bacterial burden may required alternative therapeutic strategies to maximize bacterial killing and prevent antimicrobial resistance.
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- 2014
11. The effectiveness of frequent antibiotic use in reducing the risk of infection-related hospital admissions: results from two large population-based cohorts
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van Staa, Tjeerd Pieter, Palin, Victoria, Li, Yan, Welfare, William, Felton, Timothy W., Dark, Paul, and Ashcroft, Darren M.
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- 2020
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12. Understanding the nebulisation of antibiotics: the key role of lung microdialysis studies.
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Dhanani, Jayesh, Roberts, Jason A., Monsel, Antoine, Torres, Antoni, Kollef, Marin, Rouby, Jean-Jacques, Arvaniti, Kostoula, Assefi, Mona, Bassetti, Matteo, Blot, Stijn, Boisson, Matthieu, Bouglé, Adrien, Constantin, Jean-Michel, Dimopoulos, George, Dugernier, Jonathan, Dureau, Pauline, Felton, Timothy, Koutsoukou, Antonia, Kyriakoudi, Anna, and Laterre, Pierre-François
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Background: Nebulisation of antibiotics is a promising treatment for ventilator-associated pneumonia (VAP) caused by multidrug-resistant organisms. Ensuring effective antibiotic concentrations at the site of infection in the interstitial space fluid is crucial for clinical outcomes. Current assessment methods, such as epithelial lining fluid and tissue homogenates, have limitations in providing longitudinal pharmacokinetic data. Main body: Lung microdialysis, an invasive research technique predominantly used in animals, involves inserting probes into lung parenchyma to measure antibiotic concentrations in interstitial space fluid. Lung microdialysis offers unique advantages, such as continuous sampling, regional assessment of antibiotic lung concentrations and avoidance of bronchial contamination. However, it also has inherent limitations including the cost of probes and assay development, the need for probe calibration and limited applicability to certain antibiotics. As a research tool in VAP, lung microdialysis necessitates specialist techniques and resource-intensive experimental designs involving large animals undergoing prolonged mechanical ventilation. However, its potential impact on advancing our understanding of nebulised antibiotics for VAP is substantial. The technique may enable the investigation of various factors influencing antibiotic lung pharmacokinetics, including drug types, delivery devices, ventilator settings, interfaces and disease conditions. Combining in vivo pharmacokinetics with in vitro pharmacodynamic simulations can become feasible, providing insights to inform nebulised antibiotic dose optimisation regimens. Specifically, it may aid in understanding and optimising the nebulisation of polymyxins, effective against multidrug-resistant Gram-negative bacteria. Furthermore, lung microdialysis holds promise in exploring novel nebulisation therapies, including repurposed antibiotic formulations, bacteriophages and immunomodulators. The technique's potential to monitor dynamic biochemical changes in pneumonia, such as cytokines, metabolites and inflammation/infection markers, opens avenues for developing theranostic tools tailored to critically ill patients with VAP. Conclusion: In summary, lung microdialysis can be a potential transformative tool, offering real-time insights into nebulised antibiotic pharmacokinetics. Its potential to inform optimal dosing regimen development based on precise target site concentrations and contribute to development of theranostic tools positions it as key player in advancing treatment strategies for VAP caused by multidrug-resistant organisms. The establishment of international research networks, exemplified by LUMINA (lung microdialysis applied to nebulised antibiotics), signifies a proactive step towards addressing complexities and promoting multicentre experimental studies in the future. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Covariates in population pharmacokinetic studies of critically ill adults receiving β-lactam antimicrobials: a systematic review and narrative synthesis.
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Hansel, Jan, Mannan, Fahmida, Robey, Rebecca, Kumarendran, Mary, Bladon, Siân, Mathioudakis, Alexander G, Ogungbenro, Kayode, Dark, Paul, and Felton, Timothy W
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- 2024
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14. Association of piperacillin and vancomycin exposure on acute kidney injury during combination therapy.
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Venugopalan, Veena, Maranchick, Nicole, Hanai, Devorah, Hernandez, Yaima Jimenez, Joseph, Yuliya, Gore, Amanda, Desear, Kathryn, Peloquin, Charles, Neely, Michael, Felton, Timothy, Shoulders, Bethany, and Alshaer, Mohammad
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- 2024
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15. Impact of Beta-Lactam Target Attainment on Resistance Development in Patients with Gram-Negative Infections.
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Maranchick, Nicole F., Webber, Jessica, Alshaer, Mohammad H., Felton, Timothy W., and Peloquin, Charles A.
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GRAM-negative bacteria ,MULTIPLE regression analysis ,PSEUDOMONAS aeruginosa - Abstract
Background: The objective was to identify associations between beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets and Gram-negative bacteria resistance emergence in patients. Methods: Retrospective data were collected between 2016 to 2019 at the University of Florida Health-Shands Hospital in Gainesville, FL. Adult patients with two Gram-negative isolates receiving cefepime, meropenem, or piperacillin-tazobactam and who had plasma beta-lactam concentrations were included. Beta-lactam exposures and time free drug concentrations that exceeded minimum inhibitory concentrations (ƒT > MIC), four multiples of MIC (ƒT > 4× MIC), and free area under the time concentration curve to MIC (ƒAUC/MIC) were generated. Resistance emergence was defined as any increase in MIC or two-fold increase in MIC. Multiple regression analysis assessed the PK/PD parameter impact on resistance emergence. Results: Two hundred fifty-six patients with 628 isolates were included. The median age was 58 years, and 59% were males. Cefepime was the most common beta-lactam (65%) and Pseudomonas aeruginosa the most common isolate (43%). The mean daily ƒAUC/MIC ≥ 494 was associated with any increase in MIC (p = 0.002) and two-fold increase in MIC (p = 0.004). The daily ƒAUC/MIC ≥ 494 was associated with decreased time on antibiotics (p = 0.008). P. aeruginosa was associated with any increase in MIC (OR: 6.41, 95% CI [3.34–12.28]) or 2× increase in MIC (7.08, 95% CI [3.56–14.07]). Conclusions: ƒAUC/MIC ≥ 494 may be associated with decreased Gram-negative resistance emergence. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID
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Scott, Nicholas A, Pearmain, Laurence, Knight, Sean B, Brand, Oliver, Morgan, David J, Jagger, Christopher, Harbach, Sarah, Khan, Saba, Shuwa, Halima A, Franklin, Miriam, Kästele, Verena, Williams, Thomas, Prise, Ian, McClure, Flora A, Hackney, Pamela, Smith, Lara, Menon, Madhvi, Konkel, Joanne E, Lawless, Criag, Wilson, James, Mathioudakis, Aleaxander G, Stanel, Stefan C, Ustianowski, Andrew, Lindergard, Gabriella, Brij, Seema, Diar Bakerly, Nawar, Dark, Paul, Brightling, Christopher, Rivera-Ortega, Pilar, Lord, Graham M, Horsley, Alex, Piper Hanley, Karen, Felton, Timothy, Simpson, Angela, Grainger, John R, Hussell, Tracy, and Mann, Elizabeth R
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Pulmonary and Respiratory Medicine ,Chemokines, CXC/metabolism ,Receptors, Scavenger/metabolism ,Patient Acuity ,COVID-19 ,Convalescence ,Chemokine CXCL16 ,Lung Injury ,Receptors, Chemokine/metabolism ,Ligands ,Post-Acute COVID-19 Syndrome ,Monocytes/metabolism ,Influenza, Human ,Receptors, Virus/metabolism ,Humans ,Receptors, CXCR6 - Abstract
BackgroundCOVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).MethodsWe assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury.ResultsMonocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (pConclusionsOur data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.
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- 2023
17. Pharmacodynamics of Liposomal Amphotericin B and Flucytosine for Cryptococcal Meningoencephalitis: Safe and Effective Regimens for Immunocompromised Patients
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O'Connor, Lucy, Livermore, Joanne, Sharp, Andrew D., Goodwin, Joanne, Gregson, Lea, Howard, Susan J., Felton, Timothy W., Schwartz, Julie A., Neely, Michael N., Harrison, Thomas S., Perfect, John R., and Hope, William W.
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- 2013
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18. Rapid Generation of Pulmonary Organoids from Induced Pluripotent Stem Cells by Co-Culturing Endodermal and Mesodermal Progenitors for Pulmonary Disease Modelling.
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Mitchell, Adam, Yu, Chaowen, Zhao, Xiangjun, Pearmain, Laurence, Shah, Rajesh, Hanley, Karen Piper, Felton, Timothy, and Wang, Tao
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INDUCED pluripotent stem cells ,LUNG diseases ,ORGANOIDS ,EPIBLAST - Abstract
Differentiation of induced pluripotent stem cells to a range of target cell types is ubiquitous in monolayer culture. To further improve the phenotype of the cells produced, 3D organoid culture is becoming increasingly prevalent. Mature organoids typically require the involvement of cells from multiple germ layers. The aim of this study was to produce pulmonary organoids from defined endodermal and mesodermal progenitors. Endodermal and mesodermal progenitors were differentiated from iPSCs and then combined in 3D Matrigel hydrogels and differentiated for a further 14 days to produce pulmonary organoids. The organoids expressed a range of pulmonary cell markers such as SPA, SPB, SPC, AQP5 and T1α. Furthermore, the organoids expressed ACE2 capable of binding SARS-CoV-2 spike proteins, demonstrating the physiological relevance of the organoids produced. This study presented a rapid production of pulmonary organoids using a multi-germ-layer approach that could be used for studying respiratory-related human conditions. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Microbial Volatiles as Diagnostic Biomarkers of Bacterial Lung Infection in Mechanically Ventilated Patients.
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Ahmed, Waqar M, Fenn, Dominic, White, Iain R, Dixon, Breanna, Nijsen, Tamara M E, Knobel, Hugo H, Brinkman, Paul, Oort, Pouline M P Van, Schultz, Marcus J, Dark, Paul, Goodacre, Royston, Felton, Timothy, Bos, Lieuwe D J, Fowler, Stephen J, and Consortium, for the BreathDx
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TRYPTOPHAN metabolism ,LUNG disease diagnosis ,DIAGNOSIS of bacterial diseases ,MORTALITY risk factors ,BACTERIA classification ,ORGANIC compound analysis ,BIOMARKERS ,IN vitro studies ,HEAT ,BRONCHOALVEOLAR lavage ,INDOLE compounds ,CRITICALLY ill ,PATIENTS ,CULTURES (Biology) ,ARTIFICIAL respiration ,GAS chromatography ,STAPHYLOCOCCAL diseases ,MASS spectrometry ,STAPHYLOCOCCUS aureus ,RESEARCH funding ,RESPIRATION ,BACTERIAL diseases ,RECEIVER operating characteristic curves - Abstract
Background Early and accurate recognition of respiratory pathogens is crucial to prevent increased risk of mortality in critically ill patients. Microbial-derived volatile organic compounds (mVOCs) in exhaled breath could be used as noninvasive biomarkers of infection to support clinical diagnosis. Methods In this study, we investigated the diagnostic potential of in vitro – confirmed mVOCs in the exhaled breath of patients under mechanical ventilation from the BreathDx study. Samples were analyzed by thermal desorption–gas chromatography–mass spectrometry. Results Pathogens from bronchoalveolar lavage (BAL) cultures were identified in 45 of 89 patients and Staphylococcus aureus was the most commonly identified pathogen (n = 15). Of 19 mVOCs detected in the in vitro culture headspace of 4 common respiratory pathogens (S. aureus , Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli), 14 were found in exhaled breath samples. Higher concentrations of 2 mVOCs were found in the exhaled breath of patients infected with S. aureus compared to those without (3-methylbutanal: P <.01, area under the receiver operating characteristic curve [AUROC] = 0.81–0.87; and 3-methylbutanoic acid: P =.01, AUROC = 0.79–0.80). In addition, bacteria identified from BAL cultures that are known to metabolize tryptophan (E. coli , Klebsiella oxytoca , and Haemophilus influenzae) were grouped and found to produce higher concentrations of indole compared to breath samples with culture-negative (P =.034) and other pathogen-positive (P =.049) samples. Conclusions This study demonstrates the capability of using mVOCs to detect the presence of specific pathogen groups with potential to support clinical diagnosis. Although not all mVOCs were found in patient samples within this small pilot study, further targeted and qualitative investigation is warranted using multicenter clinical studies. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Efficacy and Safety of Posaconazole for Chronic Pulmonary Aspergillosis
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Felton, Timothy W., Baxter, Caroline, Moore, Caroline B., Roberts, Stephen A., Hope, William W., and Denning, David W.
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- 2010
21. Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction
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Satia, Imran, Tsamandouras, Nikolaos, Holt, Kimberley, Badri, Huda, Woodhead, Mark, Ogungbenro, Kayode, Felton, Timothy W., OʼByrne, Paul M., Fowler, Stephen J., and Smith, Jaclyn A.
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- 2017
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22. A 27-Year-Old Woman With Acute, Severe Asthma Who Developed Respiratory Failure
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Felton, Timothy W., Plested, Victoria, Walsham, Anna, Dark, Paul, O'Driscoll, Ronan, and Denning, David W.
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- 2010
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23. Alterations in T and B cell function persist in convalescent COVID-19 patients
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Ahmed, Rohan, Avery, Miriam, Birchall, Katharine, Charsley, Evelyn, Chenery, Alistair, Chew, Christine, Clark, Richard, Connolly, Emma, Connolly, Karen, Dawson, Simon, Durrans, Laura, Durrington, Hannah, Egan, Jasmine, Filbey, Kara, Fox, Claire, Francis, Helen, Franklin, Miriam, Glasgow, Susannah, Godfrey, Nicola, Gray, Kathryn J., Grundy, Seamus, Guerin, Jacinta, Hackney, Pamela, Hayes, Chantelle, Hardy, Emma, Harris, Jade, John, Anu, Jolly, Bethany, Kästele, Verena, Kerry, Gina, Lui, Sylvia, Lin, Lijing, Mathioudakis, Alex G., Mitchell, Joanne, Moizer, Clare, Moore, Katrina, Moss, Stuart, Baker, Syed Murtuza, Oliver, Rob, Padden, Grace, Parkinson, Christina, Phuycharoen, Michael, Saha, Ananya, Salcman, Barbora, Scott, Nicholas A., Sharma, Seema, Shaw, Jane, Shaw, Joanne, Shepley, Elizabeth, Smith, Lara, Stephan, Simon, Stephens, Ruth, Tavernier, Gael, Tudge, Rhys, Wareing, Louis, Warren, Roanna, Williams, Thomas, Willmore, Lisa, Younas, Mehwish, Shuwa, Halima A., Shaw, Tovah N., Knight, Sean B., Wemyss, Kelly, McClure, Flora A., Pearmain, Laurence, Prise, Ian, Jagger, Christopher, Morgan, David J., Khan, Saba, Brand, Oliver, Mann, Elizabeth R., Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Brightling, Christopher E., Brij, Seema, Felton, Timothy, Simpson, Angela, Grainger, John R., Hussell, Tracy, Konkel, Joanne E., and Menon, Madhvi
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- 2021
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24. Hypercapnia in COPD: Causes, Consequences, and Therapy.
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Csoma, Balázs, Vulpi, Maria Rosaria, Dragonieri, Silvano, Bentley, Andrew, Felton, Timothy, Lázár, Zsófia, and Bikov, Andras
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HYPERCAPNIA ,CHRONIC obstructive pulmonary disease ,MORTALITY risk factors ,NONINVASIVE ventilation - Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder that may lead to gas exchange abnormalities, including hypercapnia. Chronic hypercapnia is an independent risk factor of mortality in COPD, leading to epithelial dysfunction and impaired lung immunity. Moreover, chronic hypercapnia affects the cardiovascular physiology, increases the risk of cardiovascular morbidity and mortality, and promotes muscle wasting and musculoskeletal abnormalities. Noninvasive ventilation is a widely used technique to remove carbon dioxide, and several studies have investigated its role in COPD. In the present review, we aim to summarize the causes and effects of chronic hypercapnia in COPD. Furthermore, we discuss the use of domiciliary noninvasive ventilation as a treatment option for hypercapnia while highlighting the controversies within the evidence. Finally, we provide some insightful clinical recommendations and draw attention to possible future research areas. [ABSTRACT FROM AUTHOR]
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- 2022
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25. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report
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Horby, Peter, Juszczak, Edmund, Montgomery, Alan, Lim, Wei Shen, Emberson, Jonathan R., Mafham, Marion, Bell, Jennifer L., Linsell, Louise, Staplin, Natalie, Brightling, Christopher, Ustianowski, Andrew, Elmahi, Einas, Prudon, Benjamin, Green, Christopher, Felton, Timothy, Chadwick, David, Rege, Kanchan, Fegan, Christopher, Chappell, Lucy C., Faust, Saul N., Jaki, Thomas, Jeffery, Katie, Rowan, Kathryn, Braille, J. Kenneth, Haynes, Richard, and Landray, Martin J.
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General Medicine - Abstract
BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison.RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; PCONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).
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- 2020
26. Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis
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Mann, Elizabeth R., Menon, Madhvi, Knight, Sean Blandin, Konkel, Joanne E., Jagger, Christopher, Shaw, Tovah N., Krishnan, Siddharth, Rattray, Magnus, Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Lord, Graham, Simpson, Angela, Felton, Timothy, Ho, Ling Pei, Feldmann, Marc, Grainger, John R., Hussell, Tracy, Ahmed, Rohan, Shuwa, Halima Ali, Avery, Miriam, Birchall, Katharine, Brand, Oliver, Charsley, Evelyn, Chenery, Alistair, Chew, Christine, Clark, Richard, Connolly, Emma, Connolly, Karen, Dawson, Simon, Durrans, Laura, Durrington, Hannah, Egan, Jasmine, Fox, Claire, Francis, Helen, Franklin, Miriam, Glasgow, Susannah, Godfrey, Nicola, Gray, Kathryn J., Grundy, Seamus, Guerin, Jacinta, Hackney, Pamela, Iqbal, Mudassar, Hayes, Chantelle, Hardy, Emma, Harris, Jade, John, Anu, Jolly, Bethany, Kästele, Verena, Khan, Saba, Lindergard, Gabriella, Lui, Sylvia, Lowe, Lesley, Mathioudakis, Alex G., McClure, Flora A., Mitchell, Joanne, Moizer, Clare, Moore, Katrina, Morgan, David, Moss, Stuart, Baker, Syed Murtuza, Oliver, Rob, Padden, Grace, Parkinson, Christina, Pearmain, Laurence, Phuychareon, Mike, Saha, Ananya, Salcman, Barbora, Scott, Nicholas A., Sharma, Seema, Shaw, Jane, Shaw, Joanne, Shepley, Elizabeth, Smith, Lara, Stephan, Simon, Stephens, Ruth, Tavernier, Gael, Tudge, Rhys, Wareing, Louis, Warren, Roanna, Williams, Thomas, Willmore, Lisa, Younas, Mehwish, Horsley, Alex, Harrison, Tim, Porter, Joanna, Djukanovic, Ratko, Marciniak, Stefan, Brightling, Chris, McGarvey, Lorcan, and Davies, Jane
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business.industry ,T cell ,Inflammation ,Context (language use) ,Disease ,Clinical trial ,Pathogenesis ,Immune system ,medicine.anatomical_structure ,Intensive care ,Immunology ,medicine ,medicine.symptom ,business - Abstract
BackgroundThe pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation.MethodsThe Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset.FindingsLongitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering.InterpretationThis is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.FundingThe Kennedy Trust for Rheumatology Research, The Wellcome Trust, The Royal Society, The BBSRC, National Institute for Health Research (NIHR) Biomedical Research Centres (BRC).Research in contextEvidence before this studyAnalysis of the literature before the study via pubmed and bioRxiv searches using the terms COVID-19, SARS-CoV2, immune and inflammation (with the last search performed on 27th April 2020) showed evidence of an overactive immune response in a handful of studies in cross-sectional analyses all done at a single time point.Added value of this studyTo determine the role of the immune response in a disease process, it is necessary to correlate immune activity with clinical parameters dynamically. In this study patients presented to hospital at different stages of disease so we took samples at different time-points to provide an accurate picture of the relevant pathobiology. In order to avoid loss of large components of the immune system due to the processes of storage, longitudinal samples were interrogated in real time to reveal the full immune alterations in COVID-19.Implications of all the available evidenceRespiratory viruses continue to cause devastating global disease. The finding of altered myelopoiesis, with excess neutrophils and altered monocyte function, as dominant features in our study provides an incentive for clinical testing of therapeutics that specifically target this pathobiology. Given that inflammation is greatest prior to admission to intensive care, trials of specific immune-modulating therapies should be considered earlier in admission. Future studies of COVID-19 mechanisms should place more emphasis on longitudinal analyses since disease changes dramatically over time.
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- 2020
27. Aspergillus bronchitis without significant immunocompromise
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Chrdle, Ales, Mustakim, Sahlawati, Bright-Thomas, Rowland J., Baxter, Caroline G., Felton, Timothy, and Denning, David W.
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- 2012
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28. Peripheral neuropathy in patients on long-term triazole antifungal therapy
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Baxter, Caroline G., Marshall, Andrew, Roberts, Mark, Felton, Timothy W., and Denning, David W.
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- 2011
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29. Co-enrolment to UK Critical Care Studies – A 2019 update.
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Felton, Timothy, Pattison, Natalie, Fletcher, Simon, Finney, Simon, Walsh, Tim, and Dark, Paul
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- 2022
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30. The impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital
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Rautemaa-Richardson , Riina, Rautemaa, V, Al-Wathiqi, F, Moore, CB, Craig, L., Felton, Timothy, and Muldoon, Eavan
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Objectives: A concise invasive candidosis (IC) guideline (based on the ESCMID candidaemia guideline) utilising an informative biomarker (serumβ-1-3-D-glucan) was developed in 2013 by the antifungal stewardship (AFS) team and implemented with the help of an AFS Champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the IC guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds). Methods: All patients who were prescribed micafungin for suspected or proven IC during 4-month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data was analysed.Results: The number of patients treated for IC decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality to proven or probable IC decreased to 19% from 45% in 2003-2007. Antifungal consumption reduced by 49% from 2014 to 2016.Conclusions: The AFS program was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality from IC was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of IC.
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- 2018
31. TD/GC–MS analysis of volatile markers emitted from mono- and co-cultures of Enterobacter cloacae and Pseudomonas aeruginosa in artificial sputum
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Lawal, Oluwasola, Knobel, Hugo, Weda, Hans, Nijsen, Tamara M.E., Goodacre, Royston, Fowler, Stephen J., Ahmed, Waqar M., Artigas, Antonio, Bannard-Smith, J., Bos, Lieuwe D.J., Camprubi, Marta, Coelho, Luis, Dark, Paul, Davie, Alan, Diaz, Emili, Goma, Gemma, Felton, Timothy, Leopold, Jan Hendrik, van Oort, Pouline M.P., Povoa, Pedro, Portsmouth, Craig, Rattray, Nicholas J.W., Rijnders, Guus, Schultz, Marcus J., Steenwelle, Ruud, Sterk, Peter J., Valles, Jordi, Verhoeckx, Fred, Vink, Anton, White, Iain R., Winters, Tineke, Zakharkina, Tetyana, Inorganic Materials Science, Intensive Care Medicine, ACS - Heart failure & arrhythmias, AII - Infectious diseases, APH - Methodology, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Pulmonology, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation
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0301 basic medicine ,Microbiological culture ,Endocrinology, Diabetes and Metabolism ,030106 microbiology ,Clinical Biochemistry ,UT-Hybrid-D ,medicine.disease_cause ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,RS ,Microbiology ,03 medical and health sciences ,Manchester Institute of Biotechnology ,Enterobacter cloacae ,medicine ,Volatile organic compounds ,Axenic ,biology ,Bacteria ,Pseudomonas aeruginosa ,Chemistry ,biology.organism_classification ,Antimicrobial ,ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology ,3. Good health ,030104 developmental biology ,Sputum ,Gas chromatography–mass spectrometry ,medicine.symptom ,Infection - Abstract
Introduction: Infections such as ventilator-associated pneumonia (VAP) can be caused by one or more pathogens. Current methods for identifying these pathogenic microbes often require invasive sampling, and can be time consuming, due to the requirement for prolonged cultural enrichment along with selective and differential plating steps. This results in delays in diagnosis which in such critically ill patients can have potentially life-threatening consequences. Therefore, a non-invasive and timely diagnostic method is required. Detection of microbial volatile organic compounds (VOCs) in exhaled breath is proposed as an alternative method for identifying these pathogens and may distinguish between mono- and poly-microbial infections. Objectives: To investigate volatile metabolites that discriminate between bacterial mono- and co-cultures. Methods: VAP-associated pathogens Enterobacter cloacae and Pseudomonas aeruginosa were cultured individually and together in artificial sputum medium for 24 h and their headspace was analysed for potential discriminatory VOCs by thermal desorption gas chromatography–mass spectrometry. Results: Of the 70 VOCs putatively identified, 23 were found to significantly increase during bacterial culture (i.e. likely to be released during metabolism) and 13 decreased (i.e. likely consumed during metabolism). The other VOCs showed no transformation (similar concentrations observed as in the medium). Bacteria-specific VOCs including 2-methyl-1-propanol, 2-phenylethanol, and 3-methyl-1-butanol were observed in the headspace of axenic cultures of E. cloacae, and methyl 2-ethylhexanoate in the headspace of P. aeruginosa cultures which is novel to this investigation. Previously reported VOCs 1-undecene and pyrrole were also detected. The metabolites 2-methylbutyl acetate and methyl 2-methylbutyrate, which are reported to exhibit antimicrobial activity, were elevated in co-culture only. Conclusion: The observed VOCs were able to differentiate axenic and co-cultures. Validation of these markers in exhaled breath specimens could prove useful for timely pathogen identification and infection type diagnosis.
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- 2018
32. Detection and quantification of exhaled volatile organic compounds in mechanically ventilated patients – comparison of two sampling methods.
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van Oort, Pouline M. P., White, Iain R., Ahmed, Waqar, Johnson, Craig, Bannard-Smith, Jonathan, Felton, Timothy, Bos, Lieuwe D., Goodacre, Royston, Dark, Paul, and Fowler, Stephen J.
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THERMAL desorption ,VOLATILE organic compounds ,SAMPLING methods ,INTENSIVE care patients ,AIR sampling - Abstract
Exhaled breath analysis is a promising new diagnostic tool, but currently no standardised method for sampling is available in mechanically ventilated patients. We compared two breath sampling methods, first using an artificial ventilator circuit, then in "real life" in mechanically ventilated patients on the intensive care unit. In the laboratory circuit, a 24-component synthetic-breath volatile organic compound (VOC) mixture was injected into the system as air was sampled: (A) through a port on the exhalation limb of the circuit and (B) through a closed endo-bronchial suction catheter. Sorbent tubes were used to collect samples for analysis by thermal desorption-gas chromatography-mass spectrometry. Realistic mechanical ventilation rates and breath pressure–volume loops were established and method detection limits (MDLs) were calculated for all VOCs. Higher yields of VOCs were retrieved using the closed suction catheter; however, for several VOCs MDLs were compromised due to the background signal associated with plastic and rubber components in the catheters. Different brands of suction catheter were compared. Exhaled VOC data from 40 patient samples collected at two sites were then used to calculate the proportion of data analysed above the MDL. The relative performance of the two methods differed depending on the VOC under study and both methods showed sensitivity towards different exhaled VOCs. Furthermore, method performance differed depending on recruitment site, as the centres were equipped with different brands of respiratory equipment, an important consideration for the design of multicentre studies investigating exhaled VOCs in mechanically ventilated patients. [ABSTRACT FROM AUTHOR]
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- 2021
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33. Untargeted Molecular Analysis of Exhaled Breath as a Diagnostic Test for Ventilator-Associated Lower Respiratory Tract Infections (BreathDx).
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van Oort, Pouline M. P., Nijsen, Tamara M., White, Iain R., Knobel, Hugo H., Felton, Timothy, Rattray, Nicholas, Lawal, Oluwasola, Bulut, Murtaza, Ahmed, Waqar, Artigas, Antonio, Povoa, Pedro R., Martin-Loeches, Ignacio, Weda, Hans, Goodacre, Royston, Schultz, Marcus J., Dark, Paul M., Fowler, Stephen J., Bos, Lieuwe D., van Oort, Pouline Mp, and BreathDx Consortium
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VENTILATOR-associated pneumonia ,RESPIRATORY infections ,BREATH tests ,DIAGNOSIS methods ,RESEARCH ,MECHANICAL ventilators ,RESEARCH methodology ,EVALUATION research ,COMPARATIVE studies ,RESEARCH funding ,ROUTINE diagnostic tests ,RESPIRATION - Abstract
Patients suspected of ventilator-associated lower respiratory tract infections (VA-LRTIs) commonly receive broad-spectrum antimicrobial therapy unnecessarily. We tested whether exhaled breath analysis can discriminate between patients suspected of VA-LRTI with confirmed infection, from patients with negative cultures. Breath from 108 patients suspected of VA-LRTI was analysed by gas chromatography-mass spectrometry. The breath test had a sensitivity of 98% at a specificity of 49%, confirmed with a second analytical method. The breath test had a negative predictive value of 96% and excluded pneumonia in half of the patients with negative cultures. Trial registration number: UKCRN ID number 19086, registered May 2015. [ABSTRACT FROM AUTHOR]
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- 2022
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34. Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents
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Zeitlinger, Markus, Koch, Birgit C. P., Bruggemann, Roger, De Cock, Pieter, Felton, Timothy, Hites, Maya, Le, Jennifer, Luque, Sonia, MacGowan, Alasdair P., Marriott, Deborah J. E., Muller, Anouk E., Nadrah, Kristina, Paterson, David L., Standing, Joseph F., Telles, João P., Wölfl-Duchek, Michael, Thy, Michael, and Roberts, Jason A.
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ANTIVIRAL agents ,SARS-CoV-2 ,ANTI-infective agents ,MIDDLE East respiratory syndrome ,DRUG interactions ,PHARMACODYNAMICS - Abstract
There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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35. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19.
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Mann, Elizabeth R., Menon, Madhvi, Knight, Sean Blandin, Konkel, Joanne E., Jagger, Christopher, Shaw, Tovah N., Krishnan, Siddharth, Rattray, Magnus, Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Lord, Graham M., Simpson, Angela, Felton, Timothy, Ho, Ling-Pei, Feldmann, Marc, Grainger, John R., and Hussell, Tracy
- Abstract
Myeloid upheaval in severe COVID-19: Severe COVID-19 disease is associated with immune hyperactivation accompanied by "cytokine storm." Mann et al. used longitudinal analysis of fresh blood samples from hospitalized COVID-19 patients to search for biomarkers that signal impending progression to severe disease. Several phenotypic and functional abnormalities of CD14
+ blood monocytes emerged as early-stage biomarkers predictive of increased severity of disease. Monocytes from patients with severe COVID-19 activated in vitro with lipopolysaccharide displayed increased proliferation and decreased expression of the prostaglandin-synthesizing cyclooxygenase-2 (COX-2) enzyme. Premature release of immature myeloid cells from the bone marrow contributes to innate immune dysfunction, causing more extensive lung damage and poorer clinical outcomes. These findings suggest that early treatment of COVID-19 targeting emergency myelopoiesis may help reduce the risk of subsequent clinical deterioration. COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells of hospitalized patients during the peak of the COVID-19 pandemic in the United Kingdom. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1, and IP-10 and modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, and enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of patients with COVID-19 and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission, suggesting that immunomodulating therapies would be most beneficial at early time points. [ABSTRACT FROM AUTHOR]- Published
- 2020
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36. Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin.
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Rouby, J. J., Sole-Lleonart, C., Rello, J., the European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia, Monsel, Antoine, Constantin, Jean-Michel, Bouglé, Adrien, Blot, Stijn, Poulakou, Garyphalia, Pontikis, Konstantinos, Kyriakoudi, Anna, Koutsoukou, Antonia, Dimopoulos, George, Routsi, Christina, Arvaniti, Kostoula, Pereira, Jose Manuel, Felton, Timothy, Dhanani, Jayesh, Roberts, Jason, and Bassetti, Matteo
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VENTILATOR-associated pneumonia ,BRONCHOALVEOLAR lavage ,MEDICAL personnel ,POSITIVE end-expiratory pressure ,GRAM-negative bacteria ,ANTI-infective agents - Abstract
Why and when to administer nebulized aminoglycosides and colistin in VAP The main reason for nebulizing aminoglycosides and colistin in VAP is to bypass the alveolar-capillary barrier which offers a severe obstacle to lung penetration following intravenous administration. In comparison to intravenous route, nebulized aminoglycosides and colistin can achieve significantly higher lung tissue concentrations necessary for the effective treatment of VAP due to MDR GNB [[1]]. In 2018, the French Society of Anaesthesia and Intensive Care Medicine (FSAICM) and the French Intensive Care Society (FICS) published guidelines regarding hospital-acquired pneumonia (HAP) in the intensive care unit [[11]], and recommended nebulized colistin and/or aminoglycosides alone in HAP due to MDR GNB susceptible to colistin and/or aminoglycosides, when no other antibiotics can be used. [Extracted from the article]
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- 2020
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37. Isavuconazole and voriconazole for the treatment of chronic pulmonary aspergillosis: A retrospective comparison of rates of adverse events.
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Bongomin, Felix, Maguire, Niamh, Moore, Caroline B., Felton, Timothy, and Rautemaa‐Richardson, Riina
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PULMONARY aspergillosis ,VORICONAZOLE ,ANTIFUNGAL agents ,TRIAZOLES ,DRUG side effects - Abstract
Summary: Background: Long‐term oral triazole antifungal therapy is the cornerstone of management for patients with chronic pulmonary aspergillosis (CPA). Itraconazole is the first‐line choice of treatment. Voriconazole, posaconazole or isavuconazole can be used as alternative treatments in case of resistance or intolerance. All of these can cause significant adverse drug reactions. Objectives: To evaluate how CPA patients tolerate voriconazole and isavuconazole after prior triazole therapy. Methods: We performed a retrospective observational study at the UK National Aspergillosis Centre. Medical records for all consecutive CPA patients started on isavuconazole and voriconazole during an observation period of 12 and 6 months respectively were analysed. Results: During this study period, 20 patients were started on isavuconazole and 21 patients on voriconazole. Adverse events were seen in 18 of 21 (86%) the patients in the voriconazole group and 12 of 20 (60%) in the isavuconazole group (P = 0.02). For those who developed adverse events to these agents, the rates of discontinuation of therapy were comparable (ie 10/18 [56%], voriconazole vs 8/12 [67%], isavuconazole; P = 0.54). Five (25%) patients in the isavuconazole group who were intolerant to other triazoles tolerated the standard dose of isavuconazole. Conclusions: Compared with isavuconazole, adverse events were significantly higher in CPA patients commenced on voriconazole. Isavuconazole may be an option for those patients who are intolerant to other triazoles. [ABSTRACT FROM AUTHOR]
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- 2019
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38. COVID-19 Clinical Trials: Unraveling a Methodological Gordian Knot.
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Mathioudakis, Alexander G, Fally, Markus, Hashad, Rola, Knight, Sean, Felton, Timothy, and Vestbo, Jørgen
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CORONAVIRUS disease treatment ,VIRAL pneumonia ,GLUCOCORTICOIDS ,RESEARCH ,CLINICAL trials ,DEXAMETHASONE ,RESEARCH methodology ,COVID-19 ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,EPIDEMICS ,HYDROXYCHLOROQUINE ,ANTIMALARIALS ,INTRAVENOUS injections ,DISEASE management - Published
- 2020
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39. BreathDx - molecular analysis of exhaled breath as a diagnostic test for ventilator-associated pneumonia: protocol for a European multicentre observational study.
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van Oort, Pouline M. P., Nijsen, Tamara, Weda, Hans, Knobel, Hugo, Dark, Paul, Felton, Timothy, Rattray, Nicholas J. W., Lawal, Oluwasola, Ahmed, Waqar, Portsmouth, Craig, Sterk, Peter J., Schultz, Marcus J., Zakharkina, Tetyana, Artigas, Antonio, Povoa, Pedro, Martin-Loeches, Ignacio, Fowler, Stephen J., Bos, Lieuwe D. J., and BreathDx Consortium
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VENTILATOR-associated pneumonia ,PNEUMONIA diagnosis ,VOLATILE organic compounds ,MICROBIAL metabolism ,MICROBIAL physiology ,THERMAL desorption ,ORGANIC compound analysis ,ACADEMIC medical centers ,BIOCHEMISTRY ,BODY fluids ,BREATH tests ,COMPARATIVE studies ,EXPERIMENTAL design ,GAS chromatography ,INTENSIVE care units ,LONGITUDINAL method ,MASS spectrometry ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,LOGISTIC regression analysis ,EVALUATION research ,DIAGNOSIS - Abstract
Background: The diagnosis of ventilator-associated pneumonia (VAP) remains time-consuming and costly, the clinical tools lack specificity and a bedside test to exclude infection in suspected patients is unavailable. Breath contains hundreds to thousands of volatile organic compounds (VOCs) that result from host and microbial metabolism as well as the environment. The present study aims to use breath VOC analysis to develop a model that can discriminate between patients who have positive cultures and who have negative cultures with a high sensitivity.Methods/design: The Molecular Analysis of Exhaled Breath as Diagnostic Test for Ventilator-Associated Pneumonia (BreathDx) study is a multicentre observational study. Breath and bronchial lavage samples will be collected from 100 and 53 intubated and ventilated patients suspected of VAP. Breath will be analysed using Thermal Desorption - Gas Chromatography - Mass Spectrometry (TD-GC-MS). The primary endpoint is the accuracy of cross-validated prediction for positive respiratory cultures in patients that are suspected of VAP, with a sensitivity of at least 99% (high negative predictive value).Discussion: To our knowledge, BreathDx is the first study powered to investigate whether molecular analysis of breath can be used to classify suspected VAP patients with and without positive microbiological cultures with 99% sensitivity.Trial Registration: UKCRN ID number 19086, registered May 2015; as well as registration at www.trialregister.nl under the acronym 'BreathDx' with trial ID number NTR 6114 (retrospectively registered on 28 October 2016). [ABSTRACT FROM AUTHOR]- Published
- 2017
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40. Posaconazole: The Case for Therapeutic Drug Monitoring.
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Howard, Susan J, Felton, Timothy W, Gomez-Lopez, Alicia, and Hope, William W
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- 2012
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41. ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial.
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Wilkinson, Tom, Dixon, Rupert, Page, Clive, Carroll, Miles, Griffiths, Gareth, Ho, Ling-Pei, De Soyza, Anthony, Felton, Timothy, Lewis, Keir E, Phekoo, Karen, Chalmers, James D, Gordon, Anthony, McGarvey, Lorcan, Doherty, Jillian, Read, Robert C, Shankar-Hari, Manu, Martinez-Alier, Nuria, O'Kelly, Michael, Duncan, Graeme, and Walles, Roelize
- Abstract
Objectives: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage.Trial Design: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols.Participants: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland.Intervention and Comparator: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents.Main Outcomes: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses).Randomisation: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents.Blinding (masking): The trial is open label and no blinding is currently planned in the study.Numbers To Be Randomised (sample Size): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study.Trial Status: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year.Trial Registration: EudraCT 2020-001736-95 , registered 28th April 2020.Full Protocol: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. [ABSTRACT FROM AUTHOR]- Published
- 2020
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42. Correction to: Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin.
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Rouby, J. J., Sole-Lleonart, C., Rello, J., the European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia, Monsel, Antoine, Constantin, Jean-Michel, Bouglé, Adrien, Blot, Stijn, Poulakou, Garyphalia, Pontikis, Konstantinos, Kyriakoudi, Anna, Koutsoukou, Antonia, Dimopoulos, George, Routsi, Christina, Arvaniti, Kostoula, Pereira, Jose Manuel, Felton, Timothy, Dhanani, Jayesh, Roberts, Jason, and Bassetti, Matteo
- Subjects
VENTILATOR-associated pneumonia ,GRAM-negative bacteria ,KLEBSIELLA pneumoniae - Abstract
The original version of this article unfortunately contained a mistake. There was a typographical error in Figure 1: "Nebulization time ≤ 30 min" (first light blue square) should be replaced by "Nebulization time ≤ 90 min". The authors apologize for the mistake. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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43. Investigating the interaction between Candida albicans and Klebsiella species within in vitro dual-species biofilm in ventilator-associated pneumonia model
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Alhindi, Zain, Richardson, Malcolm, Felton, Timothy, and Richardson, Riina
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616.2 ,dual-species biofilm ,K. pneumoniae ,C. albicans ,VAP - Abstract
Ventilator-associated pneumonia (VAP) is defined as a hospital-acquired pneumonia commonly occurring in intensive care units in a patient after 48h of mechanical ventilation via an endotracheal tube (ETT) or tracheostomy tube. It is one of the most common infectious complications in critically ill patients. The prevalence of VAP varies between 9-65% and mortality rates are high (15- 76%). It has been reported that microbial biofilms cover the ETT after 7-10 days depending on the in vitro method of assessment used. A number of microorganisms play a dominant role in VAP, many of which can form biofilms on ETT surfaces, including Klebsiella pneumoniae. The presence of Candida spp. in respiratory secretions of patients with VAP has been associated with longer mechanical ventilation, prolonged stay and worse outcomes. Furthermore, colonisation of ETT by Candida species, principally, Candida albicans, has been associated with the development of VAP caused by a number of bacteria. The present research was designed to further analyse the relationship between Klebsiella species and C. albicans within dual species biofilm in in vitro VAP model. Klebsiella spp. was chosen as its emergency of resistance is increasing in ventilated patients. Antimicrobial effects of meropenem (MEM) and fluconazole (FLC) were examined against single and dual-species biofilms. Four clinically paired Klebsiella spp. and C. albicans were used. Single and dual-species biofilms were grown in 24-well plates for up to 72h. Biofilms were exposed to MEM and/or FLC at different concentrations (0.4, 4.0 and 400 mg/L, reflecting sub, peri and supra-MIC concentrations) for 24h. Then, biofilms were analysed for cell viability using culture (CFU/mL). A qPCR molecular method based on propidium monoazide (PMA) was used in qPCR to aid live/dead discrimination. The metabolic activities of the biofilms were measured by using the 2,3-bis (2-methoxy-4-nitro-5-sulphophenyl)-5- [(phenylamino) carbonyl]-2H-tetrazolium hydroxide colorimetric assay (XTT). Electron microscopy (EM) and confocal laser scanning microscopy (CLSM) were used to visualise any changes in biofilms structure following treatment. In vitro biofilms revealed that all isolates in single and co-culture conditions showed a gradual increase in the number of cells and metabolic activity over time, reaching peak values between 72 h and 96 h. Supra-MIC concentrations of both MEM and FLC were effective in reducing biofilm viability and metabolic activity of both isolates. In contrast, sub-MIC and peri-MIC concentrations of FLC and MEM increased the metabolic activities and viability of the biofilms. Our results suggest that treating dual-species biofilms associated with VAP with sub-MIC or peri-MIC concentrations of MEM and FLC may allow bacteria and fungi to form barriers against the antimicrobial agents in form of mature biofilms.
- Published
- 2020
44. Dexamethasone in Hospitalized Patients with Covid-19.
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Horby, Peter, Lim, Wei Shen, Emberson, Jonathan R., Mafham, Marion, Bell, Jennifer L., Linsell, Louise, Staplin, Natalie, Brightling, Christopher, Ustianowski, Andrew, Elmahi, Einas, Prudon, Benjamin, Green, Christopher, Felton, Timothy, Chadwick, David, Rege, Kanchan, Fegan, Christopher, Chappell, Lucy C., Faust, Saul N., Jaki, Thomas, and Jeffery, Katie
- Subjects
- *
COVID-19 , *HOSPITAL patients , *DEXAMETHASONE , *ARTIFICIAL respiration , *MEDICAL research - Abstract
BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Gluco-corticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.996) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical 7 ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.096; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS In patients hospitalized with Covid-19, the use of dexamethasone resulted in ower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National In stitute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673 .) [ABSTRACT FROM AUTHOR]
- Published
- 2021
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45. Breath Analysis for Diagnosis of Ventilator-Associated Pneumonia
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Van Oort, Pouline Maria Petra, DARK, PAUL PM, FELTON, TIMOTHY TW, Dark, Paul, Fowler, Stephen, and Felton, Timothy
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Critical care ,Mechanical ventilation ,Respiratory infection ,Intensive Care ,Breath analysis ,Ventilator-associated pneumonia ,Breathomics - Abstract
Introduction: Mechanical ventilation on the Intensive Care Unit (ICU) is a life-saving intervention but can be associated with the development of ventilator-associated pneumonia (VAP). Diagnosing VAP remains challenging and many patients receive antimicrobial treatment unnecessarily, contributing to the well-known global problem of antimicrobial resistance. Breath analysis offers a novel diagnostic perspective in critically ill mechanically ventilated patients. Two breath sampling methods have already been developed and shall be investigated in patients suspected of VAP on ICU. Thus proof will be sought that these volatile compounds can distinguish between the presence and absence of VAP.Methods: A ventilator circuit was constructed to model the patient setting on ICU. Two methods of breath sampling were investigated: 1) a semi-invasive method using a suction catheter inserted via the endotracheal tube; and 2) a non-invasive method that sampled in the external ventilator connection circuit. A quality control (QC) mix was inserted in the ventilator circuit. Samples were collected on steel adsorbent tubes, which were analysed using Thermal Desorption – Gas Chromatography – Mass Spectrometry (TD – GC – MS). On three ICUs in Greater Manchester a proof-of-concept study was set up to test both breath sampling techniques in critically ill patients suspected of VAP.Results: Both breath sampling methods resulted in good chromatograms reflecting signals deriving from the compounds of the QC mix. The compounds with relatively large molecular weight were not sampled as well using the non-invasive compared to the semi-invasive method. The semi-invasive method resulted in contaminating signals on the chromatograms. The clinical study suffers from a low recruitment rate, which appears to be due to a reduction in the prevalence of VAP on the participating ICUs. Discussion: A realistic model of human mechanical ventilation was established. A QC mix mimicking compounds present in exhaled breath was successfully inserted in the system and sampled using non-invasive and semi-invasive breath sampling methods. Standard curve linearity and detection limits of the system were determined. The clinical study is currently recruiting and data is being collected.
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- 2016
46. Beta-lactam target attainment and associated outcomes in patients with bloodstream infections.
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Alshaer, Mohammad H., Maranchick, Nicole, Alexander, Kaitlin M., Manigaba, Kayihura, Shoulders, Bethany R., Felton, Timothy W., Mathew, Sumith K., and Peloquin, Charles A.
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MULTIPLE regression analysis , *TREATMENT effectiveness , *CEFEPIME , *PIPERACILLIN , *MEROPENEM - Abstract
• f T >4 × MIC was a significant predictor of negative blood culture on day 7 • Patients who achieved 100% f T >4 × MIC had a shorter time to negative blood culture • No association was identified between exposure and symptom improvement and mortality To evaluate the association between early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters and therapy outcomes in bloodstream infection (BSI). Adult patients who received cefepime, meropenem, or piperacillin/tazobactam for BSI and had concentrations measured were included. Beta-lactam exposure was generated and the time that free concentration remained above the minimum inhibitory concentration (f T >MIC) and four multiples of MIC (f T >4 × MIC) were calculated for times 0-24 h and 0-7 days of therapy. Multiple regression analysis was performed to evaluate the impact of PK/PD on microbiological and clinical outcomes. A total of 204 patients and 213 BSI episodes were included. The mean age was 58 years and weight 83 kg. Age, Sequential Organ Failure Assessment (SOFA) score, haemodialysis, Pitt bacteraemia score, and hours of empiric antibiotic therapy were significantly associated with certain outcomes and retained in the final model. In multiple regression analysis, f T >4 × MIC at 0-24 h and 0-7 days was a significant predictor of negative blood culture on day 7 (P =0.0161 and 0.0068, respectively). In the time-to-event analysis, patients who achieved 100% f T >4 × MIC at 0-24 h and 0-7 days had a shorter time to negative blood culture compared with those who did not (log-rank P =0.0004 and 0.0014, respectively). No significant associations were identified between PK/PD parameters and other outcomes, including improvement in symptoms at day 7 and 30-day mortality. Early and cumulative achievement of f T >4 × MIC was a significant predictor of microbiological outcome in patients with BSI. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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47. Mapping the human genetic architecture of COVID-19
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Niemi, MEK, Karjalainen, J, Liao, RG, Neale, BM, Daly, M, Ganna, A, Pathak, GA, Andrews, SJ, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, EC, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, MA, Wendt, FR, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H-N, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, MJ, Smith, GD, Willer, CJ, Buxbaum, JD, Mehtonen, J, Finucane, H, Cordioli, M, Martin, AR, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, MK, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, VG, van Heel, D, Deelen, P, Richards, JB, Nakanishi, T, Biesecker, L, Kerchberger, VE, Kenneth, J, Mari, F, Bernasconi, A, Ceri, S, Canakoglu, A, Wolford, B, Faucon, A, Dutta, AK, Schurmann, C, Harry, E, Birney, E, Nguyen, H, Nasir, J, Kaunisto, M, Solomonson, M, Dueker, N, Vadgama, N, Limou, S, Rahmouni, S, Mbarek, H, Darwish, D, Uddin, MM, Albertos, R, Perez-Tur, J, Li, R, Folkersen, L, Moltke, I, Koelling, N, Teumer, A, Kousathanas, A, Utrilla, A, Verdugo, RA, Zarate, R, Medina-Gomez, C, Gomez-Cabrero, D, Carnero-Montoro, E, Cadilla, CL, Moreno-Estrada, A, Garmendia, A, Moya, L, Sedaghati-Khayat, B, Boua, PR, Fave, M-J, Francioli, L, Lemacon, A, Migeotte, I, Patel, S, Varnai, R, Szentpeteri, JL, Sipeky, C, Colombo, F, von Hohenstaufen, K, Lio, P, Vallerga, C, Wang, Q, Tanigawa, Y, Im, H, Han, C, Song, H, Lim, J, Lee, Y, Kim, S, Im, S, Atanasovska, B, Ahmad, HF, Boer, C, Jansen, P, Franke, L, Kaja, E, Pasko, D, Kennis-Szilagyi, I, Kornilov, SA, Prijatelj, V, Prokic, I, Sivanadhan, I, Perumal, S, Esmaeeli, S, Pearson, NM, Auton, A, Shelton, JF, Shastri, AJ, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, O'Connell, J, Ye, C, Weldon, CH, Perera, M, O'Leary, K, Tuck, M, O'Brien, T, Meltzer, D, O'Donnell, P, Nutescu, E, Yang, G, Alarcon, C, Herrmann, S, Mazurek, S, Banagan, J, Hamidi, Z, 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Lambermont, B, Morrison, DR, Mooser, V, Forgetta, V, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Brassard, N, Durand, M, Schurr, E, Lepage, P, Ragoussis, J, Auld, D, Chasse, M, Kaufmann, DE, Lathrop, GM, Adra, D, Davis, LK, Cox, NJ, Below, JE, Sealock, JM, Faucon, AB, Shuey, MM, Polikowsky, HG, Petty, LE, Shaw, DM, Chen, H-H, Zhu, W, Ludwig, KU, Schroeder, J, Maj, C, Rolker, S, Noethen, MM, Fazaal, J, Keitel, V, Jensen, B-EO, Feldt, T, Kurth, I, Marx, N, Dreher, M, Pink, I, Cornberg, M, Illig, T, Lehmann, C, Schommers, P, Augustin, M, Rybniker, J, Knopp, L, Eggermann, T, Volland, S, Altmueller, J, Berger, MM, Brenner, T, Hinney, A, Witzke, O, Bals, R, Herr, C, Ludwig, N, Walter, J, Fuchsberger, C, Pattaro, C, De Grandi, A, Pramstaller, P, Emmert, D, Melotti, R, Foco, L, Mascalzoni, D, Gogele, M, Domingues, F, Hicks, A, Gignoux, CR, Wicks, SJ, Crooks, K, Barnes, KC, Daya, M, Shortt, J, Rafaels, N, Chavan, S, Goldstein, DB, Kiryluk, K, Sengupta, S, Chung, W, Reilly, MP, Khan, A, Wang, C, Povysil, G, Bhardwaj, N, Gharavi, AG, Ionita-Laza, I, Shang, N, O'Byrne, SM, Nandakumar, R, Menon, A, So, YS, Hod, E, Pendrick, D, Park, S-K, Kim, H-L, Kang, CK, Lee, H-J, Song, K-H, Yoon, KJ, Paik, N-J, Seok, W, Yoon, H, Joo, E-J, Chang, Y, Ryu, S, Park, WB, Park, JS, Park, KU, Ham, SY, Jung, J, Kim, ES, Kim, HB, Ellinghaus, D, Degenhardt, F, Caceres, M, Juzenas, S, Lenz, TL, Albillos, A, Julia, A, Heidecker, B, Garcia, F, Kurth, F, Tran, F, Hanses, F, Zoller, H, Holter, JC, Fernandez, J, Sander, LE, Rosenstiel, P, Koehler, P, de Cid, R, Asselta, R, Schreiber, S, Hehr, U, Prati, D, Baselli, G, Valenti, L, Bujanda, L, Banales, JM, Duga, S, D'Amato, M, Romero-Gomez, M, Buti, M, Invernizzi, P, Franke, A, Hov, JR, Karlsen, TH, Folseraas, T, Maya-Miles, D, Teles, A, Azuure, C, Wacker, EM, Uellendahl-Werth, F, Elabd, H, Arora, J, Lerga-Jaso, J, Wienbrandt, L, Ruehlemann, MC, Wendorff, M, Vadla, MS, Lenning, OB, Oezer, O, Myhre, R, Raychaudhuri, S, Tanck, A, Gassner, C, Hemmrich-Stanisak, G, Kaessens, J, Basso, MEF, Schulzky, M, Wittig, M, Braun, N, Wesse, T, Albrecht, W, Yi, X, Ortiz, AB, Garrido Chercoles, A, Ruiz, A, Mantovani, A, Holten, AR, Mayer, A, Cherubini, A, Protti, A, Aghemo, A, Gerussi, A, Ramirez, A, Braun, A, Barreira, A, Lleo, A, Kildal, AB, Glueck, A, Carreras Nolla, A, Latiano, A, Dyrhol-Riise, AM, Muscatello, A, Voza, A, Rando-Segura, A, Solier, A, Karina, B, Cortes, B, Mateos, B, Nafria-Jimenez, B, Schaefer, B, Bellinghausen, C, Ferrando, C, Quereda, C, Skurk, C, Thibeault, C, Spinner, CD, Lange, C, Hu, C, Cappadona, C, Bianco, C, Sancho, C, Hoff, DAL, Galimberti, D, Jimenez, D, Pestana, D, Toapanta, D, Azzolini, E, Scarpini, E, Helbig, ET, Urrechaga, E, Paraboschi, EM, Pontali, E, Reverter, E, Navas, E, Arana, E, Garcia Sanchez, F, Ceriotti, F, Malvestiti, F, Mesonero, F, Pezzoli, G, Lamorte, G, Neb, H, My, I, Hernandez, I, de Rojas, I, Galvan-Femenia, I, Heyckendorf, J, Badia, JR, Schneider, J, Goikoetxea, J, Kraft, J, Mueller, KE, Gaede, KI, Garcia-Etxebarria, K, Tonby, K, Heggelund, L, Izquierdo-Sanchez, L, Sumoy, L, Lippert, LJ, Terranova, L, Garbarino, L, Tellez, L, Roade, L, Ostadreza, M, Intxausti, M, Kogevinas, M, Gutierrez-Stampa, MA, Vehreschild, MJGT, Marquie, M, Castoldi, M, Cecconi, M, Boada, M, Seilmaier, MJ, Mazzocco, M, Rodriguez-Gandia, M, Imaz Ayo, N, Blay, N, Martinez, N, Cornely, OA, Palmieri, O, Tentorio, P, Rodrigues, PM, Espana, PP, Hoffmann, P, Bacher, P, Suwalski, P, de Pablo, R, Nieto, R, Badalamenti, S, Ciesek, S, Bombace, S, Wilfling, S, Brunak, S, Heilmann-Heimbach, S, Ripke, S, Bahmer, T, Landmesser, U, Protzer, U, Rimoldi, V, Skogen, V, Andrade, V, Moreno, V, Poller, W, Farre, X, Wang, X, Khodamoradi, Y, Karadeniz, Z, de Salazar, A, Palom, A, Garcia-Fernandez, A-E, Blanco-Grau, A, Zanella, A, Bandera, A, Nebel, A, Biondi, A, Caba Llero-Garralda, A, Gori, A, Lind, A, Fracanzani, AL, Peschuck, A, Pesenti, A, De la Horra, C, Milani, C, Paccapelo, C, Angelini, C, Cea, C, Muniz-Diaz, E, Sandoval, E, Calderon, EJ, Solligard, E, Aziz, F, Martinelli-Boneschi, F, Peyvandi, F, Blasi, F, Medrano, FJ, Rodriguez-Frias, F, Mueller, F, Grasselli, G, Costantino, G, Cardamone, G, Foti, G, Matullo, G, Kurihara, H, Afset, JE, Damas, JK, Ampuero, J, Martin, J, Erdmann, J, Bergan, J, Goerg, S, Ferrusquia-Acosta, J, Hernandez Quero, J, Delgado, J, Guerrero, JM, Risnes, K, Bettini, LR, Moreira, L, Gustad, LT, Santoro, L, Scudeller, L, Riveiro-Barciela, M, Schaefer, M, Carrabba, M, Valsecchi, MG, Hernandez-Tejero, M, Acosta-Herrera, M, D'Angio, M, Baldini, M, Cazzaniga, M, Ciccarelli, M, Bocciolone, M, Miozzo, M, Chueca, N, Montano, N, Faverio, P, Preatoni, P, Bonfanti, P, Omodei, P, Castro, P, Ferrer, R, Gualtierotti, R, Gallego-Duran, R, Morilla, R, Haider, S, Marsal, S, Aneli, S, Pelusi, S, 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Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Tanaka, Hiromu, Morita, Atsuho, Lee, Ho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Mikami, Yohei, Tomono, Kazunori, Kato, Kazuto, Matsuda, Fumihiko, Takahashi, Meiko, Hizawa, Nobuyuki, Takeda, Yoshito, Hirata, Haruhiko, Shiroyama, Takayuki, Miyawaki, Satoru, Suzuki, Ken, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Takahashi, Kunihiko, Anzai, Tatsuhiko, Hasegawa, Takanori, Ito, Satoshi, Koike, Ryuji, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro, Nakajima, Jun, Nannya, Yasuhito, Omae, Yosuke, Takahashi, Kazuhisa, Harada, Norihiro, Hiki, Makoto, Takagi, Haruhi, Nakamura, Ai, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Ishiguro, Takashi, Takayanagi, Noboru, Isono, Taisuke, Takaku, Yotaro, Takano, Kenji, Anan, Ryusuke, Nakajima, Yukiko, Nakano, Yasushi, Nishio, Kazumi, Ueda, Soichiro, Hayashi, Reina, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Mitamura, Keiko, Saito, Fumitake, Ueda, Tetsuya, Azuma, Masanori, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Yoshiyama, Takashi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Watanabe, Kazuyoshi, Manabe, Tadashi, Ito, Fumimaro, Fukui, Takahiro, Funatsu, Yohei, Koh, Hidefumi, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Saito, Fukuki, Yoshiya, Kazuhisa, Yoshihara, Tomoyuki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Nishi, Koichi, Nishitsuji, Masaru, Tani, Maiko, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Ogura, Takashi, Kitamura, Hideya, Murohashi, Kota, Nakachi, Ichiro, Baba, Rie, Arai, Daisuke, Fuke, Satoshi, Saito, Hiroshi, Kuwahara, Naota, Fujiwara, Akiko, Okada, Takenori, Baba, Tomoya, Noda, Junya, Mashimo, Shuko, Yagi, Kazuma, Shiomi, Tetsuya, Hashiguchi, Mizuha, Odani, Toshio, Mochimaru, Takao, Oyamada, Yoshitaka, Mori, Nobuaki, Izumi, Namiki, Nagata, Kaoru, Taki, Reiko, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Gon, Yasuhiro, Fujitani, Shigeki, Tsuchida, Tomoya, Yoshida, Toru, Kagaya, Takashi, Kita, Toshiyuki, Sakagami, Satoru, Kimizuka, Yoshifumi, Kawana, Akihiko, Nakamura, Yoshihiko, Ishikura, Hiroyasu, Takata, Tohru, Kikuchi, Takahide, Taniyama, Daisuke, Nakamura, Morio, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Ito, Akihiro, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Hashimoto, Naozumi, Wakahara, Keiko, Ando, Akira, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Sageshima, Hisako, Nakada, Taka-Aki, Abe, Ryuzo, Shimada, Tadanaga, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Yamasaki, Masaki, Hashimoto, Satoru, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Takada, Minoru, Kanda, Hidenori, Komase, Yuko, Sano, Fumiaki, Asano, Koichiro, Oguma, Tsuyoshi, Harada, Masahiro, Takahashi, Takeshi, Shibusawa, Takayuki, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Izumo, Takehiro, Inomata, Minoru, Awano, Nobuyasu, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Kitagawa, Yuichiro, Yoshida, Shozo, Ogura, Shinji, Nishiyama, Kei, Yoshida, Kousuke, Beppu, Satoru, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Inoue, Yoshiaki, Yamagata, Kunihiro, Chiba, Shigeru, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Shibata, Yoko, Tanino, Yoshinori, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Imamura, Tomonori, Umeda, Akira, Shimada, Hisato, Endo, Mayu, Hayashi, Shinichi, Takahashi, Mai, Nakano, Shigefumi, Yatomi, Masakiyo, Maeno, Toshitaka, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Boezen, Marike, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith. M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P. S., Obeidat, Ma’En, Hernández Cordero, Ana I., Sin, Don D., Bossé, Yohan, Joubert, Philippe, Hao, Ke, Nickle, David, Timens, Wim, van den Berge, Maarten, Feng, Yen-Chen Anne, Mercader, Josep, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Green, Robert C., Perez, Emma F., Zöllner, Sebastian, Wang, Jiongming, Beck, Andrew, Sloofman, Laura G., Ascolillo, Steven, Sebra, Robert P., Collins, Brett L., Levy, Te, Sealfon, Stuart C., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Chaudhary, Kumardeep, Belbin, Gillian M., Preuss, Michael, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., Salib, Irene, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Zyndorf, Marissa, Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Abul-Husn, Noura S., Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Loos, Ruth J. F., Nadkarni, Girish N., Do, Ron, O’Reilly, Paul, Huckins, Laura M., Ferreira, Manuel A. R., Abecasis, Goncalo R., Leader, Joseph B., Cantor, Michael N., Justice, Anne E., Carey, Dave J., Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Horowitz, Julie E., Baras, Ari, Gass, Matthew C., Yadav, Ashish, Mirshahi, Tooraj, Jan Hottenga, Jouke, Bartels, Meike, de Geus, Eco J. C., Nivard, Michel G., Verma, Anurag, Ritchie, Marylyn D., Rader, Daniel, Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Zara, Federico, Salpietro, Vincenzo, Scala, Marcello, Iacomino, Michele, Scudieri, Paolo, Bocciardi, Renata, Minetti, Carlo, Riva, Antonella, Vari, Maria Stella, Rahier, Jean-Françoi, Giorgio, Elisa, Carli, Diana, Louis, Edouad, Bulik, Cynthia M., Landén, Mikael, Brusco, Alfredo, Ferrero, Giovanni Battista, Madia, Francesca, Fundín, Bengt, Ismail, Said I., Saad, Chadi, Al-Sarraj, Yaser, Badji, Radja Messai, Al-Muftah, Wadha, Al Thani, Asma, Afifi, Nahla, Klovins, Jani, Rovite, Vita, Rescenko, Raimond, Peculis, Raiti, Ustinova, Monta, Zeberg, Hugo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Johnson, Ruth, Geschwind, Daniel H., Freimer, Nelson, Butte, Manish J., Ding, Yi, Chiu, Alec, Chang, Timothy S., Boutros, Paul, Moutsianas, Louka, Caulfield, Mark J., Scott, Richard H., Walker, Susan, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Fowler, Tom, Rendon, Augusto, Chan, Georgia, Arumugam, Prabhu, Karczewski, Konrad J., Wilson, Daniel J., Spencer, Chris A., Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikola, Turley, Patrick, Gupta, Rahul, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Churchhouse, Claire, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Daly, Mark J., Bryant, Sam, Satterstrom, F. Kyle, Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicola, Armstrong, Jacob, Rudkin, Justine K., Callier, Shawneequa, Cusick, Caroline, Soranzo, Nicole, Zhao, Jing Hua, Danesh, John, Di Angelantonio, Emanuele, Butterworth, Adam S., Sun, Yan V., Huffman, Jennifer E., Cho, Kelly, O’Donnell, Christopher J., Tsao, Phil, Gaziano, J. Michael, Peloso, Gina, Ho, Yuk-Lam, Mian, Michael, Scaggiante, Federica, Chang, Xiao, Glessner, Joseph R., Hakonarson, Hakon, Mcguigan, Peter J., Prockter Moore, Luke Stephen, Vizcaychipi, Marcela Paola, Hall, Kathryn, Campbell, Andy, Nichol, Ailstair, Ward, Geraldine, Page, Valerie Joan, Semple, Malcolm G., Adeniji, Kayode, Agranoff, Daniel, Agwuh, Ken, Ail, Dhiraj, Aldera, Erin L., Alegria, Ana, Angus, Brian, Ashish, Abdul, Atkinson, Dougal, Bari, Shahedal, Barlow, Gavin, Barnass, Stella, Barrett, Nichola, Bassford, Christopher, Basude, Sneha, Baxter, David, Beadsworth, Michael, Bernatoniene, Jolanta, Berridge, John, Best, Nicola, Bothma, Pieter, Chadwick, David, Brittain-Long, Robin, Bulteel, Naomi, Burden, Tom, Burtenshaw, Andrew, Caruth, Vikki, Chambler, Duncan, Chee, Nigel, Child, Jenny, Chukkambotla, Srikanth, Clark, Tom, Collini, Paul, Cosgrove, Catherine, Cupitt, Jason, Cutino-Moguel, Maria-Teresa, Dark, Paul, Dawson, Chri, Dervisevic, Samir, Donnison, Phil, Douthwaite, Sam, Drummond, Andrew, Durand, Ingrid, Dushianthan, Ahilanadan, Dyer, Tristan, Evans, Cariad, Eziefula, Chi, Fegan, Christopher, Finn, Adam, Fullerton, Duncan, Garg, Sanjeev, Garg, Atul, Gkrania-Klotsas, Effrossyni, Godden, Jo, Goldsmith, Arthur, Graham, Clive, Hardy, Elaine, Hartshorn, Stuart, Harvey, Daniel, Havalda, Peter, Hawcutt, Daniel B., Hobrok, Maria, Hodgson, Luke, Hormis, Anil, Jacobs, Michael, Jain, Susan, Jennings, Paul, Kaliappan, Agilan, Kasipandian, Vidya, Kegg, Stephen, Kelsey, Michael, Kendall, Jason, Kerrison, Caroline, Kerslake, Ian, Koch, Oliver, Koduri, Gouri, Koshy, George, Laha, Shondipon, Laird, Steven, Larkin, Susan, Leiner, Tama, Lillie, Patrick, Limb, Jame, Linnett, Vanessa, Little, Jeff, Lyttle, Mark, Macmahon, Michael, Macnaughton, Emily, Mankregod, Ravish, Masson, Huw, Matovu, Elijah, Mccullough, Katherine, Mcewen, Ruth, Meda, Manjula, Mills, Gary H., Minton, Jane, Ward, Karl, Mirfenderesky, Mariyam, Mohandas, Kavya, Mok, Quen, Moon, Jame, Moore, Elinoor, Morgan, Patrick, Morris, Craig, Mortimore, Katherine, Moses, Samuel, Mpenge, Mbiye, Mulla, Rohinton, Murphy, Michael, Nagel, Megan, Nagarajan, Thapa, Nelson, Mark, O’Shea, Matthew K., Otahal, Igor, Ostermann, Marlie, Pais, Mark, Panchatsharam, Selva, Papakonstantinou, Danai, Paraiso, Hassan, Patel, Brij, Pattison, Natalie, Pepperell, Justin, Peters, Mark, Phull, Mandeep, Pintus, Stefania, Pooni, Jagtur Singh, Post, Frank, Price, David, Prout, Rachel, Rae, Nikola, Reschreiter, Henrik, Reynolds, Tim, Richardson, Neil, Roberts, Mark, Roberts, Devender, Rose, Alistair, Rousseau, Guy, Ryan, Brendan, Saluja, Taranprit, Shah, Aarti, Shanmuga, Prad, Sharma, Anil, Shawcross, Anna, Sizer, Jeremy, Shankar-Hari, Manu, Smith, Richard, Snelson, Catherine, Spittle, Nick, Staines, Nikki, Stambach, Tom, Stewart, Richard, Subudhi, Pradeep, Szakmany, Tama, Tatham, Kate, Thomas, Jo, Thompson, Chri, Thompson, Robert, Tridente, Ascanio, Tupper-Carey, Darell, Twagira, Mary, Ustianowski, Andrew, Vallotton, Nick, Vincent-Smith, Lisa, Visuvanathan, Shico, Vuylsteke, Alan, Waddy, Sam, Wake, Rachel, Walden, Andrew, Welters, Ingeborg, Whitehouse, Tony, Whittaker, Paul, Whittington, Ashley, Papineni, Padmasayee, Wijesinghe, Meme, Williams, Martin, Wilson, Lawrence, Cole, Sarah, Winchester, Stephen, Wiselka, Martin, Wolverson, Adam, Wooton, Daniel G., Workman, Andrew, Yates, Bryan, Young, Peter, Beale, Rupert, Bretherick, Andrew D., Clohisey, Sara, Fourman, Max Head, Furniss, Jame, Gountouna, Elvina, Grimes, Graeme, Haley, Chri, Harrison, David, Hayward, Caroline, Keating, Sean, Klaric, Lucija, Klenerman, Paul, Law, Andy, Meynert, Alison M., Millar, Jonathan, Pairo-Castineira, Erola, Parkinson, Nichola, Ponting, Chris P., Porteous, David J., Rawlik, Konrad, Richmond, Anne, Rowan, Kathy, Russell, Clark D., Shen, Xia, Shih, Barbara, Tenesa, Albert, Vitart, Veronique, Wang, Bo, Wilson, James F., Wu, Yang, Yang, Jian, Yang, Zhijian, Zechner, Marie, Zhai, Ranran, Zheng, Chenqing, Norman, Lisa, Pius, Riinu, Drake, Thomas M., Fairfield, Cameron J., Knight, Stephen R., Mclean, Kenneth A., Murphy, Derek, Shaw, Catherine A., Dalton, Jo, Girvan, Michelle, Saviciute, Egle, Roberts, Stephanie, Harrison, Janet, Marsh, Laura, Connor, Marie, Halpin, Sophie, Jackson, Clare, Gamble, Carrol, Leeming, Gary, Law, Andrew, Wham, Murray, Hendry, Ro, Scott-Brown, Jame, Begg, Colin, Hinds, Charle, Wai Ho, Antonia Ying, Horby, Peter W., Knight, Julian, Ling, Lowell, Maslove, David, Mcauley, Danny, Montgomery, Hugh, Nichol, Alistair, Openshaw, Peter J. M., Summers, Charlotte, Walsh, Timothy, Armstrong, Lisa, Bates, Hayley, Dooks, Emma, Farquhar, Fiona, Hairsine, Brigid, Mcparland, C., Packham, Sophie, Alldis, Zoe, Astin-Chamberlain, Raine, Bibi, Fatima, Biddle, Jack, Blow, Sarah, Bolton, Matthew, Borra, Catherine, Bowles, Ruth, Burton, Maudrian, Choudhury, Yasmin, Collier, David, Cox, Amber, Easthope, Amy, Ebano, Patrizia, Fotiadis, Stavro, Gurasashvili, Jana, Halls, Rosslyn, Hartridge, Pippa, Kallon, Delordson, Kassam, Jamila, Lancoma-Malcolm, Ivone, Matharu, Maninderpal, May, Peter, Mitchelmore, Oliver, Newman, Tabitha, Patel, Mital, Pheby, Jane, Pinzuti, Irene, Prime, Zoe, Prysyazhna, Oleksandra, Shiel, Julian, Taylor, Melanie, Tierney, Carey, Wood, Suzanne, Zak, Anne, Zongo, Olivier, Forsey, Miranda, Nicholson, Anne, Riches, Joanne, Vertue, Mark, Wasson, Christopher, Finn, Stephanie, Green, Jackie, Collins, Erin, King, Bernadette, Grauslyte, Lina, Hussain, Musarat, Pogreban, Tatiana, Rosaroso, Lace, Salciute, Erika, Franke, George, Wong, Joanna, George, Aparna, Akeroyd, Louise, Bano, Shereen, Bromley, Matt, Gurr, Lucy, Lawton, Tom, Morgan, Jame, Sellick, Kirsten, Warren, Deborah, Wilkinson, Brian, Mcgowan, Janet, Ledgard, Camilla, Stacey, Amelia, Pye, Kate, Bellwood, Ruth, Bentley, Michael, Loosley, Ronda, Mcguinness, Heather, Tench, Helen, Wolf-Roberts, Rebecca, Gibson, Sian, Lyle, Amanda, Mcneela, Fiona, Radhakrishnan, Jayachandran, Hughes, Alistair, Ali, Asifa, Brady, Megan, Dale, Sam, Dance, Annalisa, Gledhill, Lisa, Greig, Jill, Hanson, Kathryn, Holdroyd, Kelly, Home, Marie, Kelly, Diane, Kitson, Ro, Matapure, Lear, Melia, Deborah, Mellor, Samantha, Nortcliffe, Tonicha, Pinnell, Jez, Robinson, Matthew, Shaw, Lisa, Shaw, Ryan, Thomis, Lesley, Wilson, Alison, Wood, Tracy, Bayo, Lee-Ann, Merwaha, Ekta, Ishaq, Tahira, Hanley, Sarah, Antcliffe, David, Banach, Dorota, Brett, Stephen, Coghlan, Phoebe, Fernandez, Ziortza, Gordon, Anthony, Rojo, Roceld, Arias, Sonia Sousa, Templeton, Maie, Jha, Rajeev, Krishnamurthy, Vinodh, Lim, Lai, Bi, Rehana, Scholefield, Barney, Ashton, Lydia, Williams, Alison, Cheyne, Claire, Saunderson, Anne, Allan, Angela, Anderson, Felicity, Kaye, Callum, Liew, Jade, Medhora, Jasmine, Scott, Teresa, Trumper, Erin, Botello, Adriana, Polgarova, Petra, Stroud, Katerina, Meaney, Eoghan, Jones, Megan, Ng, Anthony, Agrawal, Shruti, Pathan, Nazima, White, Deborah, Daubney, Esther, Elston, Kay, Parker, Robert, Reddy, Amie, Turner-Bone, Ian, Wilding, Laura, Harding, Peter, Jacob, Reni, Jones, Cathy, Denmade, Craig, Croft, Maria, White, Ian, Lim, Li, Griffin, Denise, Muchenje, Nycola, Mupudzi, Mcdonald, Partridge, Richard, Conyngham, Jo-Anna, Thomas, Rachel, Wright, Mary, Corral, Maria Alvarez, Bastion, Victoria, Clarke, Daphene, David, Beena, Kent, Harriet, Lorusso, Rachel, Lubimbi, Gamu, Murdoch, Sophie, Penacerrada, Melchizedek, Thomas, Alastair, Valentine, Jennifer, Vochin, Ana, Wulandari, Retno, Djeugam, Brice, Dawson, Joy, Garrioch, Sweyn, Tolson, Melanie, Aldridge, Jonathan, de Almeida Martins, Laura Gome, Carungcong, Jaime, Beavis, Sarah, Dale, Katie, Gascoyne, Rachel, Hawes, Joanne, Pritchard, Kelly, Stevenson, Lesley, Whileman, Amanda, Cowley, Anne, Highgate, Judith, Crawley, Rikki, Crew, Abigail, Cunningham, Mishell, Daniels, Allison, Harrison, Laura, Hope, Susan, Inweregbu, Ken, Jones, Sian, Lancaster, Nicola, Matthews, Jamie, Nicholson, Alice, Wray, Gemma, Benham, Leonie, Bradshaw, Zena, Brown, Joanna, Caswell, Melanie, Melling, Sarah, Preston, Stephen, Slawson, Nicola, Stoddard, Emma, Warden, Scott, Combes, Edward, Joefield, Teishel, Monnery, Sonja, Beech, Valerie, Trotman, Sallyanne, Hopkins, Bridget, Scriven, Jame, Thrasyvoulou, Laura, Willis, Heather, Anderson, Susan, Birch, Janine, Collins, Emma, Hammerton, Kate, O’Leary, Ryan, Abernathy, Caroline, Foster, Louise, Gratrix, Andrew, Martinson, Vicky, Parkinson, Priyai, Stones, Elizabeth, Carbral-Ortega, Llucia, Kapoor, Ritoo, Loader, David, Castle, Karen, Brandwood, Craig, Smith, Lara, Clark, Richard, Birchall, Katie, Kolakaluri, Laurel, Baines, Deborah, Sukumaran, Anila, Mapfunde, Isheunesu, Meredith, Megan, Morris, Lucy, Ryan, Lucy, Clark, Amy, Sampson, Julia, Peters, Cecilia, Dent, Martin, Langley, Margaret, Ashraf, Saima, Wei, Shuying, Andrew, Angela, Chablani, Manish, Kirkby, Amy, Netherton, Kimberley, Bates, Michelle, Dasgin, Jo, Gill, Jaspret, Nilsson, Annette, Apetri, Elena, Basikolo, Cathrine, Blackledge, Bethan, Catlow, Laura, Charles, Bethan, Doonan, Reece, Harris, Jade, Harvey, Alice, Horner, Daniel, Knowles, Karen, Lee, Stephanie, Lomas, Diane, Lyons, Chloe, Marsden, Tracy, Mclaughlan, Danielle, Mcmorrow, Liam, Pendlebury, Jessica, Perez, Jane, Poulaka, Maria, Proudfoot, Nicola, Slaughter, Melanie, Slevin, Kathryn, Thomas, Vicky, Walker, Danielle, Michael, Angiy, Collis, Matthew, Clark, Martyn, Coulding, Martina, Jude, Edward, Mccormick, Jacqueline, Mercer, Oliver, Potla, Darsh, Rehman, Hafiz, Savill, Heather, Turner, Victoria, Davey, Miriam, Golden, David, Seaman, Rebecca, Hunt, Jodie, Dearden, Joy, Dobson, Emma, Mulcahy, Michelle, Munt, Sheila, O’Connor, Grainne, Philbin, Jennifer, Rishton, Chloe, Tully, Redmond, Winnard, Sarah, Cagova, Lenka, Fofano, Adama, Garner, Lucie, Holcombe, Helen, Mepham, Sue, Mitchell, Alice Michael, Mwaura, Lucy, Praman, K., Vuylsteke, Alain, Zamikula, Julie, Bercades, Georgia, Brealey, David, Hass, Ingrid, Maccallum, Niall, Martir, Glady, Raith, Eamon, Reyes, Anna, Smyth, Deborah, Taylor, Abigail, Hughes, Rachel Anne, Thomas, Helen, Rees, Alun, Duskova, Michaela, Phipps, Janet, Brooks, Suzanne, Edwards, Michelle, Alexander, Peter, Allen, Schvearn, Bradley-Potts, Joanne, Brantwood, Craig, Egan, Jasmine, Felton, Timothy, Padden, Grace, Ward, Luke, Moss, Stuart, Glasgow, Susannah, Beesley, Kate, Board, Sarah, Kubisz-Pudelko, Agnieszka, Lewis, Alison, Perry, Je, Pippard, Lucy, Wood, Di, Buckley, Clare, Brown, Alison, Gregory, Jane, O’Connell, Susan, Smith, Tim, Belagodu, Zakaula, Fuller, Bridget, Gherman, Anca, Olufuwa, Olumide, Paramsothy, Remi, Stuart, Carmel, Oakley, Naomi, Kamundi, Charlotte, Tyl, David, Collins, Katy, Silva, Pedro, Taylor, June, King, Laura, Coates, Charlotte, Crowley, Maria, Wakefield, Phillipa, Beadle, Jane, Johnson, Laura, Sargeant, Janet, Anderson, Madeleine, Jardine, Catherine, Williams, Dewi, Parris, Victoria, Quaid, Sheena, Watson, Ekaterina, Melville, Julie, Naisbitt, Jay, Joseph, Rosane, Lazo, Maria, Walton, Olivia, Neal, Alan, Hill, Michaela, Kannan, Thogulava, Wild, Laura, Allan, Elizabeth, Darlington, Kate, Davies, Ffyon, Easton, Jack, Kumar, Sumit, Lean, Richard, Menzies, Daniel, Pugh, Richard, Qiu, Xinyi, Davies, Llino, Williams, Hannah, Scanlon, Jeremy, Davies, Gwyneth, Mackay, Callum, Lewis, Joannne, Rees, Stephanie, Coetzee, Samantha, Gales, Alistair, Raj, Meena, Sell, Craig, Langton, Helen, Watters, Malcolm, Novis, Catherine, Arbane, Gill, Bociek, Aneta, Campos, Sara, Grau, Neu, Jones, Tim Owen, Lim, Rosario, Marotti, Martina, Whitton, Christopher, Barron, Anthony, Collins, Ciara, Kaul, Sundeep, Passmore, Heather, Prendergast, Claire, Reed, Anna, Rogers, Paula, Shokkar, Rajvinder, Woodruff, Meriel, Middleton, Hayley, Polgar, Oliver, Nolan, Claire, Thwaites, Vicky, Mahay, Kanta, Sri-Chandana, Chunda, Scherewode, Joslan, Stephenson, Lorraine, Marsh, Sarah, Bancroft, Hollie, Bellamy, Mary, Carmody, Margaret, Daglish, Jacqueline, Moore, Faye, Rhodes, Joanne, Sangombe, Mirriam, Kadiri, Salma, Ayers, Amanda, Harrison, Wendy, North, Julie, Cavazza, Anna, Cockrell, Maeve, Corcoran, Eleanor, Depante, Maria, Finney, Clare, Jerome, Ellen, Mcphail, Mark, Nayak, Monalisa, Noble, Harriet, O’Reilly, Kevin, Pappa, Evita, Saha, Rohit, Saha, Sian, Smith, John, Knighton, Abigail, Gill, Mandy, Paul, Paul, Ratnam, Valli, Shelton, Sarah, Wynter, Inez, Baptista, David, Crowe, Rebecca, Fernandes, Rita, Herdman-Grant, Rosaleen, Joseph, Anna, Loveridge, Adam, Mckenley, India, Morino, Eriko, Naranjo, Andre, Simms, Richard, Sollesta, Kathryn, Swain, Andrew, Venkatesh, Harish, Khera, Jacyntha, Fox, Jonathan, Barber, Russell, Hewitt, Claire, Hilldrith, Annette, Jackson-Lawrence, Karen, Shepardson, Sarah, Wills, Maryanne, Butler, Susan, Tavares, Silvia, Cunningham, Amy, Hindale, Julia, Arif, Sarwat, George, Linsha, Twiss, Sophie, Wright, David, Holland, Maureen, Keenan, Natalie, Lyons, Marc, Wassall, Helen, Marsh, Chri, Mahenthran, Mervin, Carter, Emma, Kong, Thoma, Adanini, Oluronke, Bhatia, Nikhil, Msiska, Maine, Mew, Louise, Mwaura, Esther, Williams, Felicity, Wren, Lynn, Sutherland, Sara-Beth, Battle, Ceri, Brinkworth, Elaine, Harford, Rachel, Murphy, Carl, Newey, Luke, Rees, Tabitha, Williams, Marie, Arnold, Sophie, Hardy, John, Houlden, Henry, Moncur, Eleanor, Tariq, Ambreen, Tucci, Arianna, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Keshet-Price, Jocelyn, Randell, Georgina, Stammers, Katie, Abdelrazik, Marwa, Bakthavatsalam, Dhanalakshmi, Elhassan, Munzir, Ganesan, Arunkumar, Haldeos, Anne, Moreno-Cuesta, Jeronimo, Purohit, Dharam, Vincent, Rachel, Xavier, Kugan, Rohit, Kumar, Alasdair, Frater, Saleem, Malik, David, Carter, Jenkins, Samuel, Lamond, Zoe, Wall, Alanna, Reynolds, Jessica, Campbell, Helen, Thompsom, Maria, Dodds, Steve, Duffy, Stacey, Butcher, Deborah, O’Sullivan, Susie, Butterworth-Cowin, Nicola, Deacon, Bethan, Hibbert, Meg, Pothecary, Carla, Tetla, Dariusz, Woodford, Christopher, Durga, Latha, Kennard-Holden, Gareth, de Gordoa, Laura Ortiz-Ruiz, Peasgood, Emily, Phillips, Claire, Skinner, Denise, Gaylard, Jane, Mullan, Dee, Newman, Julie, Davies, Ellie, Roche, Lisa, Sathe, Sonia, Brimfield, Lutece, Daly, Zoe, Pogson, David, Rose, Steve, Collins, Amy, Khaliq, Waqa, Gude, Estefania Treu, Allen, Louise, Beranova, Eva, Crisp, Nikki, Deery, Joanne, Hazelton, Tracy, Knight, Alicia, Price, Carly, Tilbey, Sorrell, Turki, Salah, Turney, Sharon, Giles, Julian, Booth, Simon, Bell, Gillian, English, Katy, Katary, Amro, Wilcox, Louise, Campbell, Rachael, Clarke, Noreen, Whiteside, Jonathan, Mascarenhas, Mairi, Donaldson, Avril, Matheson, Joanna, Barrett, Fiona, O’Hara, Marianne, O’Keefe, Laura, Bradley, Clare, Collier, Dawn, Walker, Rachel, Maynard, Victoria, Patel, Tahera, Smith, Matthew, Kazi, Aayesha, Hartley, Janice, Dykes, Joseph, Hijazi, Muhammad, Keith, Sarah, Khan, Meherunnisa, Ryan-Smith, Janet, Springle, Philippa, Thomas, Jacqueline, Truman, Nick, Saad, Samuel, Coleman, Dabheoc, Fine, Christopher, Matt, Roseanna, Gay, Bethan, Dalziel, Jack, Ali, Syamlan, Goodchild, Drew, Harling, Rhiannan, Bhatterjee, Ravi, Goddard, Wendy, Davison, Chloe, Duberly, Stephen, Hargreaves, Jeanette, Bolton, Rachel, Verlander, Mark, Williams, Alexandra, Blackman, Helen, Creagh-Brown, Ben, Donlon, Sinead, Michalak-Glinska, Natalia, Mtuwa, Sheila, Pristopan, Veronika, Salberg, Armorel, Smith, Eleanor, Stone, Sarah, Piercy, Charle, Verula, Jerik, Burda, Dorota, Montaser, Rugia, Harden, Lesley, Mayangao, Irving, Marriott, Cheryl, Bradley, Paul, Harris, Celia, Cooper, Joshua, Finch, Cheryl, Liderth, Sarah, Quinn, Alison, Waddington, Natalia, Fidler, Katy, Tagliavini, Emma, Donnelly, Kevin, Abel, Lynn, Brett, Michael, Digby, Brian, Gemmell, Lisa, Hornsby, Jame, Macgoey, Patrick, O’Neil, Pauline, Price, Richard, Rodden, Natalie, Rooney, Kevin, Sundaram, Radha, Thomson, Nicola, Flanagan, Rebecca, Hughes, Gareth, Latham, Scott, Mckenna, Emma, Anderson, Jennifer, Hull, Robert, Rhead, Kat, Branney, Debbie, Frankham, Jordan, Pitts, Sally, White, Nigel, Cristiano, Daniele, Dormand, Natalie, Farzad, Zohreh, Gummadi, Mahitha, Liyanage, Kamal, Patel, Brijesh V., Salmi, Sara, Sloane, Geraldine, Varghese, Mathew, Zborowski, Anelise C., Bean, Sarah, Burt, Karen, Spivey, Michael, Eastgate-Jackson, Christine, Filipe, Helder, Martin, Daniel, Maharajh, Amitaa, Garcia, Sara Mingo, De Neef, Mark, Lynch, Ceri, Howe, Gwenllian Sera, Singh, Jayaprakash, Turner, Keri, Ellis, Hannah, Stroud, Natalie, Cherian, Shiney, Cutler, Sean, Heron, Anne Emma, Roynon-Reed, Anna, Williams, Gemma, Richards, Owen, Cheema, Yusuf, Ahmad, Norfaizan, Barker, Joann, Bauchmuller, Kri, Bird, Sarah, Cawthron, Kay, Harrington, Kate, Jackson, Yvonne, Kibutu, Faith, Lenagh, Becky, Masuko, Shamiso, Raithatha, Ajay, Wiles, Matthew, Willson, Jayne, Newell, Helen, Lye, Alison, Nwafor, Lorenza, Jarman, Claire, Rowland-Jones, Sarah, Foote, David, Cole, Joby, Thompson, Roger, Watson, Jame, Hesseldon, Lisa, Macharia, Irene, Chetam, Luke, Smith, Jacqui, Ford, Amber, Anderson, Samantha, Birchall, Kathryn, Housley, Kay, Walker, Sara, Milner, Leanne, Hanratty, Helena, Trower, Helen, Phillips, Patrick, Oxspring, Simon, Donne, Ben, Bevan, Emily, Martin, Jane, Trodd, Dawn, Watson, Geoff, Brown, Caroline Wrey, Bunni, Lara, Jennings, Claire, Latif, Monica, Marshall, Rebecca, Subramanian, Gayathri, Bandla, Nageswar, Gellamucho, Minnie, Davies, Michelle, Thompson, Christopher, Trim, Fiona, Eapen, Beena, Ahmed, Cecilia, Baines, Balvinder, Clamp, Sarah, Colley, Julie, Haq, Risna, Hayes, Anne, Hulme, Jonathan, Hussain, Samia, Joseph, Sibet, Kumar, Rita, Maqsood, Zahira, Purewal, Manjit, Chandler, Ben, Elliott, Kerry, Mallinson, Janine, Turnbull, Alison, Dent, Kathy, Horsley, Elizabeth, Akhtar, Muhmmad Nauman, Pearson, Sandra, Potoczna, Dorota, Spencer, Sue, Blakemore, Hayley, Borislavova, Borislava, Faulkner, Beverley, Gendall, Emma, Goff, Elizabeth, Hayes, Kati, Thomas, Matt, Worner, Ruth, Smith, Kerry, Stephens, Deanna, Delgado, Carlos Castro, Dawson, Deborah, Ding, Lijun, Durrant, Georgia, Ezeobu, Obiageri, Farnell-Ward, Sarah, Harrison, Abiola, Kanu, Rebecca, Leaver, Susannah, Maccacari, Elena, Manna, Soumendu, Saluzzio, Romina Peperman, Queiroz, Joana, Samakomva, Tinashe, Sicat, Christine, Texeira, Joana, Da Gloria, Edna Fernande, Lisboa, Ana, Rawlins, John, Mathew, Jisha, Kinch, Ashley, Hurt, William Jame, Shah, Nirav, Clark, Victoria, Thanasi, Maria, Yun, Nikki, Patel, Kamal, Crickmore, Vikki, Debreceni, Gabor, Wilkins, Joy, Nicol, Liz, Burn, Iona, Hambrook, Geraldine, Manso, Katarina, Penn, Ruth, Shanmugasundaram, Pradeep, Tebbutt, Julie, Thornton, Danielle, Rostron, Anthony, Roy, Alistair, Woods, Lindsey, Cornell, Sarah, Wakinshaw, Fiona, Rogerson, Kimberley, Jarmain, Jordan, Anderson, Peter, Archer, Katie, Austin, Karen, Davis, Caroline, Durie, Alison, Kelsall, Olivia, Thrush, Jessica, Vigurs, Charlie, Wood, Hannah-Louise, Tranter, Helen, Harrison, Alison, Cowley, Nichola, Mcalindon, Michael, Digby, Stephen, Low, Emma, Morgan, Aled, Cother, Naiara, Rankin, Tobia, Clayton, Sarah, Mccurdy, Alex, Allibone, Suzanne, Mary-Genetu, Roman, Patel, Amit, Mac, Ainhi, Murphy, Anthony, Mahjoob, Parisa, Nazari, Roonak, Worsley, Lucy, Fagan, Andrew, Mohamed Ali, Inthakab Ali, Beaumont, Karen, Blunt, Mark, Coton, Zoe, Curgenven, Hollie, Elsaadany, Mohamed, Fernandes, Kay, Ally, Sameena Mohamed, Rangarajan, Harini, Sarathy, Varun, Selvanayagam, Sivarupan, Vedage, Dave, White, Matthew, Fernandez-Roman, Jaime, Hamilton, David O., Johnson, Emily, Johnston, Brian, Martinez, Maria Lopez, Mulla, Suleman, Shaw, David, Waite, Alicia A. C., Waugh, Victoria, Welters, Ingeborg D., Williams, Karen, Bemand, Thoma, Black, Ethel, Rosa, Arnold Dela, Howle, Ryan, Jhanji, Shaman, Baikady, Ravishankar Rao, Tatham, Kate Colette, Thomas, Benjamin, Halkes, Matthew, Mercer, Pauline, Thornton, Lorraine, West, Joe, Baird, Tracy, Ruddy, Jim, Reece-Anthony, Rosie, Birt, Mark, Cowton, Amanda, Kay, Andrea, Kent, Melanie, Potts, Kathryn, Wilkinson, Ami, Naylor, Suzanne, Brown, Ellen, Clark, Michele, Purvis, Sarah, Cole, Jade, Davies, Rhy, Duffin, Donna, Hill, Helen, Player, Ben, Thomas, Emma, Williams, Angharad, Beith, Claire Marie, Black, Karen, Clements, Suzanne, Morrison, Alan, Strachan, Dominic, Taylor, Margaret, Clarkson, Michelle, D’Sylva, Stuart, Norman, Kathryn, Coventry, Tina, Fowler, Susan, Mcgregor, Amanda, Brady, Ailbhe, Chan, Rebekah, Mcivor, Shane, Prady, Helena, Whittle, Helen, Mathew, Bijoy, Clapham, Melanie, Harper, Rosemary, Poultney, Una, Rice, Polly, Mutch, Rachel, Baird, Yolanda, Butler, Aaron, Chadbourn, Indra, Folkes, Linda, Fox, Heather, Gardner, Amy, Gomez, Raquel, Hobden, Gillian, King, Kirsten, Margarson, Michael, Martindale, Tim, Meadows, Emma, Raynard, Dana, Thirlwall, Yvette, Helm, David, Margalef, Jordi, Greer, Sandra, Shuker, Karen, Smuts, Sara, Duffield, Joseph, Smith, Oliver, Mallon, Lewi, Claire, Watkin, Birkinshaw, Isobel, Carter, Joseph, Howard, Kate, Ingham, Joanne, Joy, Rosie, Pearson, Harriet, Roche, Samantha, Scott, Zoe, Knights, Ellen, Price, Alicia, Thomas, Alice, Thorpe, Chri, Abraheem, Azmerelda, Bamford, Peter, Cawley, Kathryn, Dunmore, Charlie, Faulkner, Maria, Girach, Rumanah, Jeffrey, Helen, Jones, Rhianna, London, Emily, Nagra, Imrun, Nasir, Farah, Sainsbury, Hannah, Smedley, Clare, Khade, Reena, Sundar, Ashok, Tsinaslanidis, George, Behan, Teresa, Burnett, Caroline, Hatton, Jonathan, Heeney, Elaine, Mitra, Atideb, Newton, Maria, Pollard, Rachel, Stead, Rachael, Birch, Jenny, Bough, Laura, Goodsell, Josie, Tutton, Rebecca, Williams, Patricia, Williams, Sarah, Winter-Goodwin, Barbara, Auld, Fiona, Donnachie, Joanne, Edmond, Ian, Prentice, Lynn, Runciman, Nikole, Salutous, Dario, Symon, Lesley, Todd, Anne, Turner, Patricia, Short, Abigail, Sweeney, Laura, Murdoch, Euan, Senaratne, Dhaneesha, Burns, Karen, Higham, Andrew, Anderson, Taya, Hawcutt, Dan, O’Malley, Laura, Rad, Laura, Rogers, Naomi, Saunderson, Paula, Allison, Kathryn Sian, Afolabi, Deborah, Whitbread, Jennifer, Jones, Dawn, Dore, Rachael, Lankester, Liana, Nikitas, Nikita, Wells, Colin, Stowe, Bethan, Spencer, Kayleigh, Cathcart, Susanne, Duffy, Katharine, Puxty, Alex, Puxty, Kathryn, Turner, Lynne, Ireland, Jane, Semple, Gary, Barry, Peter, Hilltout, Paula, Evitts, Jayne, Tyler, Amanda, Waldron, Joanne, Irvine, Val, Shelley, Benjamin, Akinkugbe, Olugbenga, Bamford, Alasdair, Beech, Emily, Belfield, Holly, Bell, Michael, Davies, Charlene, Jones, Gareth A. L., Mchugh, Tara, Meghari, Hamza, O’Neill, Lauran, Peters, Mark J., Ray, Samiran, Tomas, Ana Luisa, Gorman, Claire, Gupta, Abhinav, Timlick, Elizabeth, Brady, Rebecca, Bonner, Stephen, Hugill, Keith, Jones, Jessica, Liggett, Steven, Bashyal, Archana, Davidson, Neil, Hutton, Paula, Mckechnie, Stuart, Wilson, Jean, Flint, Neil, Rekha, Patel, Hales, Dawn, Cruz, Carina, Gopal, Shameer, Harris, Nichola, Lake, Victoria, Metherell, Stella, Radford, Elizabeth, Clement, Ian, Patel, Bijal, Gulati, A., Hays, Carole, Webster, K., Hudson, Anne, Webster, Andrea, Stephenson, Elaine, Mccormack, Louise, Slater, Victoria, Nixon, Rachel, Hanson, Helen, Fearby, Maggie, Kelly, Sinead, Bridgett, Victoria, Robinson, Philip, Almaden-Boyle, Christine, Austin, Pauline, Cabrelli, Louise, Cole, Stephen, Casey, Matt, Chapman, Susan, Whyte, Clare, Brayne, Adam, Fisher, Emma, Hunt, Jane, Jackson, Peter, Kaye, Duncan, Love, Nichola, Parkin, Juliet, Tuckey, Victoria, van Koutrik, Lynne, Carter, Sasha, Andrew, Benedict, Findlay, Louise, Adams, Katie, Bruce, Michelle, Connolly, Karen, Duncan, Tracy, T. -Michael, Helen, Lindergard, Gabriella, Hey, Samuel, Fox, Claire, Alfonso, Jordan, Durrans, Laura Jayne, Guerin, Jacinta, Hruska, Martin, Eltayeb, Ayaa, Lamb, Thoma, Hodgkiss, Tracey, Cooper, Lisa, Rothwell, Joanne, Dennis, Catherine, Mcgregor, Alastair, Srikaran, Sinduya, Sukha, Anisha, Davies, Kim, O’Brien, Linda, Omar, Zohra, Perkins, Emma, Lewis, Tracy, Sutherland, Isobel, Brooke, Hollie, Buckley, Sarah, Suarez, Jose Cebrian, Charlesworth, Ruth, Hansson, Karen, Norris, John, Poole, Alice, Rose, Alastair, Sandhu, Rajdeep, Sloan, Brendan, Smithson, Elizabeth, Thirumaran, Muthu, Wagstaff, Veronica, Metcalfe, Alexandra, Camsooksai, Julie, Humphrey, Charlotte, Jenkins, Sarah, Wadams, Beverley, Death, Yasmin, Adams, Colene, Agasou, Anita, Arden, Tracie, Bowes, Amy, Boyle, Pauline, Beekes, Mandy, Button, Heather, Capps, Nigel, Carnahan, Mandy, Carter, Anne, Childs, Danielle, Donaldson, Denise, Hard, Kelly, Hurford, Fran, Hussain, Yasmin, Javaid, Ayesha, Jones, Jame, Jose, Sanal, Leigh, Michael, Martin, Terry, Millward, Helen, Motherwell, Nichola, Rikunenko, Rachel, Stickley, Jo, Summers, Julie, Ting, Louise, Tivenan, Helen, Tonks, Louise, Wilcox, Rebecca, Bokhari, Maria, Lucas, Rachael, Mccormick, Wendy, Ritzema, Jenny, Sanderson, Amanda, Wild, Helen, Baxter, Nicola, Henderson, Steven, Kennedy-Hay, Sophie, Mcparland, Christopher, Rooney, Laura, Sim, Malcolm, Mccreath, Gordan, Brunton, Mark, Caterson, Je, Coles, Holly, Frise, Matthew, Rai, Sabi Gurung, Keating, Liza, Tilney, Emma, Bartley, Shauna, Bhuie, Parminder, Downes, Charlotte, Holding, Kathleen, Riches, Katie, Hilton, Mary, Hayman, Mel, Subramanian, Deepak, Daniel, Priya, Zitter, Letizia, Benyon, Sarah, Marriott, Suzie, Park, Linda, Keenan, Samantha, Gordon, Elizabeth, Quinn, Helen, Baines, Kizzy, Andrew, Gillian, Barclay, Lucy, Callaghan, Marie, Clark, Sarah, Hope, Dave, Marshall, Lucy, Mcculloch, Corrienne, Briton, Kate, Singleton, Jo, Birch, Sophie, Simpson, Kerry, Craig, Jayne, Demetriou, Carrie, Eckbad, Charlotte, Hierons, Sarah, Howie, Lucy, Mitchard, Sarah, Ramos, Lidia, Serrano-Ruiz, Alfredo, White, Katie, Kelly, Fiona, Amin, Vishal, Anastasescu, Elena, Anumakonda, Vikram, Karthik, Komala, Kausar, Rizwana, Reid, Karen, Smith, Jacqueline, Imeson-Wood, Janet, Bellini, Arianna, Bryant, Jade, Mayer, Anton, Pickard, Amy, Roe, Nichola, Sowter, Jason, Howlett, Alex, Criste, Kristine, Cusack, Rebecca, Golder, Kim, Golding, Hannah, Jones, Oliver, Leggett, Samantha, Male, Michelle, Marani, Martyna, Prager, Kirsty, Williams, Toran, Roberts, Belinda, Salmon, Karen, Gondo, Prisca, Hadebe, B., Kayani, Abdul, Masunda, Bridgett, Ahmed, Ashar, Morris, Anna, Jakkula, Sriniva, Long, Kate, Whiteley, Simon, Wilby, Elizabeth, Ogg, Bethan, Moultrie, Sam, Odam, M., Bewley, Jeremy, Garland, Zoe, Grimmer, Lisa, Gumbrill, Bethany, Johnson, Rebekah, Sweet, Katie, Webster, Denise, Efford, Georgia, Bennett, Sara, Goodwin, Emma, Jackson, Matthew, Kent, Alissa, Tibke, Clare, Woodyatt, Wiesia, Zaki, Ahmed, Daniel, Amelia, Finn, Joanne, Saha, Rajnish, Bremmer, Pamela, Allan, J., Geary, T., Houston, Gordon, Meikle, A., O’Brien, P., Bell, Dina, Boyle, Rosalind, Douglas, Katie, Glass, Lynn, Lee, Emma, Lennon, Liz, Rattray, Austin, Charnock, Rob, Mcfarland, Denise, Cosgrove, Denise, Attwood, Ben, Parsons, Penny, Carmody, Siobhain, Oblak, Metod, Popescu, Monica, Thankachen, Mini, Baruah, Rosie, Morris, Sheila, Ferguson, Susie, Shepherd, Amy, Altabaibeh, Abdelhakim, Alvaro, Ana, Gilbert, Kayleigh, Ma, Louise, Mostoles, Loreta, Parmar, Chetan, Simpson, Kathryn, Jetha, Champa, Booker, Lauren, Pratley, Anezka, Cosier, Tracey, Millen, Gemma, Schumacher, Natasha, Weston, Heather, Rand, Jame, Alex, Beatrice, Bach, Benjamin, Barclay, Wendy S., Bogaert, Debby, Chand, Meera, Cooke, Graham S., Docherty, Annemarie B., Dunning, Jake, da Silva Filipe, Ana, Fletcher, Tom, Green, Christoper A., Harrison, Ewen M., Hiscox, Julian A., Ijaz, Samreen, Khoo, Saye, Lim, Wei Shen, Mentzer, Alexander J., Merson, Laura, Noursadeghi, Mahdad, Moore, Shona C., Palmarini, Massimo, Paxton, William A., Pollakis, Georgio, Price, Nichola, Rambaut, Andrew, Robertson, David L., Sancho-Shimizu, Vanessa, Scott, Janet T., de Silva, Thushan, Sigfrid, Louise, Solomon, Tom, Sriskandan, Shiranee, Stuart, David, Tedder, Richard S., Thomson, Emma C., Roger Thompson, A. A., Thwaites, Ryan S., Turtle, Lance C. W., Gupta, Rishi K., Palmieri, Carlo, Swann, Olivia V., Zambon, Maria, Dumas, Marc-Emmanuel, Griffin, Julian L., Takats, Zoltan, Chechi, Kanta, Andrikopoulos, Petro, Osagie, Anthonia, Olanipekun, Michael, Liggi, Sonia, Lewis, Matthew R., Correia, Gonçalo dos Santo, Sands, Caroline J., Takis, Panteleimon, Maslen, Lynn, Greenhalf, William, Shaw, Victoria, Mcdonald, Sarah E., Keating, Seán, Ahmed, Katie A., Armstrong, Jane A., Ashworth, Milton, Asiimwe, Innocent G., Bakshi, Siddharth, Barlow, Samantha L., Booth, Laura, Brennan, Benjamin, Bullock, Katie, Catterall, Benjamin W. A., Clark, Jordan J., Clarke, Emily A., Cooper, Louise, Cox, Helen, Davis, Christopher, Dincarslan, Oslem, Dunn, Chri, Dyer, Philip, Elliott, Angela, Evans, Anthony, Finch, Lorna, Fisher, Lewis W. S., Foster, Terry, Garcia-Dorival, Isabel, Gunning, Philip, Hartley, Catherine, Jensen, Rebecca L., Jones, Christopher B., Jones, Trevor R., Khandaker, Shadia, King, Katharine, Kiy, Robyn T., Koukorava, Chrysa, Lake, Annette, Lant, Suzannah, Latawiec, Diane, Lavelle-Langham, Lara, Lefteri, Daniella, Lett, Lauren, Livoti, Lucia A., Mancini, Maria, Mcdonald, Sarah, Mcevoy, Laurence, Mclauchlan, John, Metelmann, Soeren, Miah, Nahida S., Middleton, Joanna, Mitchell, Joyce, Murphy, Ellen G., Penrice-Randal, Rebekah, Pilgrim, Jack, Prince, Tessa, Reynolds, Will, Ridley, P. Matthew, Sales, Debby, Shaw, Victoria E., Shears, Rebecca K., Small, Benjamin, Subramaniam, Krishanthi S., Szemiel, Agnieska, Taggart, Aislynn, Tanianis-Hughes, Jolanta, Thomas, Jordan, Trochu, Erwan, van Tonder, Libby, Wilcock, Eve, Zhang, J. Eunice, Flaherty, Lisa, Maziere, Nicole, Cass, Emily, Carracedo, Alejandra Doce, Carlucci, Nicola, Holmes, Anthony, Massey, Hannah, Murphy, Lee, Wrobel, Nicola, Mccafferty, Sarah, Morrice, Kirstie, Maclean, Alan, Armstrong, Ruth, Boz, Ceilia, Brown, Adam, Coutts, Audrey, Cullum, Louise, Day, Nicky, Donnelly, Lorna, Duncan, Esther, Fawkes, Angie, Finernan, Paul, Gilchrist, Tammy, Golightly, Ailsa, Hafezi, Katarzyna, Law, Dawn, Law, Rachel, Law, Sarah, Macgillivray, Louise, Mal, Hanning, Mcmaster, Ellie, Meikle, Jen, Oosthuyzen, Wilna, Paterson, Trevor, Stenhouse, Andrew, Swets, Maaike, Szoor-McElhinney, Helen, Taneski, Filip, Wackett, Tony, Ward, Mairi, Weaver, Jane, Coyle, Judy, Gallagher, Bernadette, Lidstone-Scott, Rebecca, Hamilton, Debbie, Schon, Katherine, Furlong, Anita, Biggs, Heather, Griffiths, Fiona, Andrews, Eleanor, Brickell, Kathy, Smyth, Michelle, Murphy, Lorna, Carson, Gail, Hardwick, Hayley, Donohue, Chloe, Pérez-Tur, Jordi [0000-0002-9111-1712], Martín, Javier [0000-0002-2202-0622], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], A list of authors and their affiliations appears in the Supplementary Information, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-21-COVR-0039,GenMIS-C,Recherche 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Bocciolone, M., Miozzo, M., Chueca, N., Montano, N., Faverio, P., Preatoni, P., Bonfanti, P., Omodei, P., Castro, P., Ferrer, R., Gualtierotti, R., Gallego-Durán, R., Morilla, R., Haider, S., Marsal, S., Aneli, S., Pelusi, S., Bosari, S., Aliberti, S., Dudman, S., Zheng, T., Pumarola, T., Cejudo, T.G., Monzani, V., Friaza, V., Peter, W., Dopazo, X., May, S., Grimsrud, M.M., Gudbjartsson, D.F., Stefansson, K., Sulem, P., Sveinbjornsson, G., Melsted, P., Norddahl, G., Swerford Moore, K.H., Thorsteinsdottir, U., Holm, H., Alarcón-Riquelme, M.E., Bernardo, D., Martínez-Bueno, M., Rello, S.R., Magi, R., Milani, L., Metspalu, A., Laisk, T., Läll, K., Lepamets, M., Esko, T., Reimann, E., Naaber, P., Laane, E., Pesukova, J., Peterson, P., Kisand, K., Tabri, J., Allos, R., Hensen, K., Starkopf, J., Ringmets, I., Tamm, A., Kallaste, A., Alavere, H., Metsalu, K., Puusepp, M., Kristiansson, K., Koskelainen, S., Perola, M., Donner, K., Kivinen, K., Palotie, A., Bochud, P.Y., Boillat, N., Nussle, S.G., Albrich, W., Pagani, J.L., Zu Bentrup, F.M., Viollet, R.M., Kampouri, E.E., Meuwly, J.Y., D'Acremont, V., Younes, S.E., Albrich, W.C., O'Mahony, L., Kleger, G.R., Kahlert, C.R., Negro, T.R., Carreras, A., Galván-Femenía, I., Farré, X., Cortés, B., Mercader, J.M., Guindo-Martinez, M., Torrents, D., Garcia-Aymerich, J., Castaño-Vinyals, G., Dobaño, C., Gori, M., Mondelli, M.U., Castelli, F., Vaghi, M., Rusconi, S., Montagnani, F., Bargagli, E., Franchi, F., Mazzei, M.A., Cantarini, L., Tacconi, D., Feri, M., Scala, R., Spargi, G., Nencioni, C., Bandini, M., Caldarelli, G.P., Spagnesi, M., Canaccini, A., Ognibene, A., D'Arminio Monforte, A., Girardis, M., Antinori, A., Francisci, D., Schiaroli, E., Scotton, P.G., Panese, S., Scaggiante, R., Monica, M.D., Capasso, M., Fiorentino, G., Castori, M., Aucella, F., Di Biagio, A., Masucci, L., Valente, S., Mandalà, M., Zucchi, P., Giannattasio, F., Coviello, D.A., Mussini, C., Bosio, G., Tavecchia, L., Crotti, L., Rizzi, M., La Rovere, 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Reid, K., Imeson-Wood, J., Bellini, A., Bryant, J., Pickard, A., Roe, N., Sowter, J., Howlett, A., Criste, K., Cusack, R., Golder, K., Golding, H., Jones, O., Leggett, S., Male, M., Marani, M., Prager, K., Williams, T., Roberts, B., Salmon, K., Gondo, P., Kayani, A., Masunda, B., Ahmed, A., Morris, A., Jakkula, S., Long, K., Whiteley, S., Wilby, E., Ogg, B., Moultrie, S., Bewley, J., Garland, Z., Grimmer, L., Gumbrill, B., Sweet, K., Webster, D., Efford, G., Bennett, S., Goodwin, E., Jackson, M., Kent, A., Tibke, C., Woodyatt, W., Zaki, A., Daniel, A., Finn, J., Bremmer, P., Houston, G., O'Brien, P., Bell, D., Boyle, R., Douglas, K., Glass, L., Lee, E., Lennon, L., Rattray, A., Charnock, R., McFarland, D., Cosgrove, D., Attwood, B., Parsons, P., Carmody, S., Oblak, M., Popescu, M., Thankachen, M., Baruah, R., Morris, S., Ferguson, S., Shepherd, A., Altabaibeh, A., Alvaro, A., Gilbert, K., Ma, L., Mostoles, L., Parmar, C., Jetha, C., Booker, L., Pratley, A., Cosier, T., Millen, G., Schumacher, N., Weston, H., Rand, J., Alex, B., Bach, B., Barclay, W.S., Bogaert, D., Chand, M., Cooke, G.S., Docherty, A.B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C.A., Harrison, E.M., Hiscox, J.A., Ijaz, S., Khoo, S., Lim, W.S., Mentzer, A.J., Merson, L., Noursadeghi, M., Moore, S.C., Palmarini, M., Paxton, W.A., Pollakis, G., Price, N., Rambaut, A., Robertson, D.L., Sancho-Shimizu, V., Scott, J.T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R.S., Thomson, E.C., Roger Thompson, A.A., Thwaites, R.S., Turtle, LCW, Gupta, R.K., Palmieri, C., Swann, O.V., Zambon, M., Dumas, M.E., Griffin, J.L., Takats, Z., Chechi, K., Andrikopoulos, P., Osagie, A., Olanipekun, M., Liggi, S., Lewis, M.R., Correia, GDS, Sands, C.J., Takis, P., Maslen, L., Greenhalf, W., Shaw, V., McDonald, S.E., Ahmed, K.A., Armstrong, J.A., Ashworth, M., Asiimwe, I.G., Bakshi, S., Barlow, S.L., Booth, L., Brennan, B., Bullock, K., Catterall, BWA, Clark, J.J., Clarke, E.A., Cox, H., Dincarslan, O., Dunn, C., Dyer, P., Elliott, A., Evans, A., Finch, L., Fisher, LWS, Foster, T., Garcia-Dorival, I., Gunning, P., Hartley, C., Jensen, R.L., Jones, C.B., Jones, T.R., Khandaker, S., Kiy, R.T., Koukorava, C., Lake, A., Lant, S., Latawiec, D., Lavelle-Langham, L., Lefteri, D., Lett, L., Livoti, L.A., Mancini, M., McDonald, S., McEvoy, L., McLauchlan, J., Metelmann, S., Miah, N.S., Middleton, J., Mitchell, J., Murphy, E.G., Penrice-Randal, R., Pilgrim, J., Prince, T., Reynolds, W., Ridley, P.M., Sales, D., Shaw, V.E., Shears, R.K., Small, B., Subramaniam, K.S., Szemiel, A., Taggart, A., Tanianis-Hughes, J., Trochu, E., van Tonder, L., Wilcock, E., Zhang, J.E., Flaherty, L., Maziere, N., Cass, E., Carracedo, A.D., Carlucci, N., Holmes, A., Massey, H., Murphy, L., Wrobel, N., McCafferty, S., Morrice, K., MacLean, A., Armstrong, R., Boz, C., Coutts, A., Cullum, L., Day, N., Donnelly, L., Duncan, E., Fawkes, A., Finernan, P., Gilchrist, T., Golightly, A., Hafezi, K., Law, D., Law, R., Law, S., Macgillivray, L., Maclean, A., Mal, H., Mcmaster, E., Meikle, J., Oosthuyzen, W., Paterson, T., Stenhouse, A., Swets, M., Szoor-McElhinney, H., Taneski, F., Wackett, T., Ward, M., Weaver, J., Coyle, J., Gallagher, B., Lidstone-Scott, R., Hamilton, D., Schon, K., Furlong, A., Biggs, H., Griffiths, F., Andrews, E., Brickell, K., Smyth, M., Carson, G., Hardwick, H., Donohue, C., Neale, Benjamin M. [0000-0003-1513-6077], Apollo - University of Cambridge Repository, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Infectious diseases, Center of Experimental and Molecular Medicine, APH - Aging & Later Life, APH - Global Health, APH - Quality of Care, Amsterdam institute for Infection and Immunity, APH - Health Behaviors & Chronic Diseases, Global Health, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Anesthesiology, ACS - Diabetes & metabolism, APH - Digital Health, APH - Personalized Medicine, ACS - Microcirculation, Niemi, M. E. K., Liao, R. G., Neale, B. M., Pathak, G. A., Andrews, S. J., Schulte, E. C., Karim, M. A., Wendt, F. R., Kim, H. -N., Uddin, M. J., Smith, G. D., Willer, C. J., Buxbaum, J. D., Martin, A. R., Balaconis, M. K., Sankaran, V. G., Brent Richards, J., Eric Kerchberger, V., Kenneth Baillie, J., Dutta, A. K., Uddin, M. M., Perez-Tur, J., Verdugo, R. A., Zarate, R., Medina-Gomez, C., Gomez-Cabrero, D., Cadilla, C. L., Boua, P. R., Fave, M. -J., Lemacon, A., Szentpeteri, J. L., Ahmad, H. F., Kornilov, S. A., Prokic, I., Pearson, N. M., Shelton, J. F., Shastri, A. J., Weldon, C. H., Brouwer, M. C., Vlaar, A. P. J., Joost Wiersinga, W., Algera, A. G., Bogaard, H. J., Bonta, P. I., Grobusch, M. P., Hermans, S. M., Hovius, J. W., de Jong, M. D., Nossent, E. J., Prins, J. M., Schultz, M. J., Stijnis, C. S., Minnaar, R. P., van Uffelen, K. W. J., Wolterman, R. A., Ball, C. A., Mccurdy, S., Hong, E. L., Baltzell, A. H., Goffard, J. -C., Peree, H., Leonard, P., Giot, J. -B., Sauvage, A. -S., Wery, M., Morrison, D. R., Chasse, M., Kaufmann, D. E., Mark Lathrop, G., Davis, L. K., Cox, N. J., Below, J. E., Sealock, J. M., Faucon, A. B., Shuey, M. M., Polikowsky, H. G., Petty, L. E., Shaw, D. M., Chen, H. -H., Ludwig, K. U., Schroder, J., Nothen, M. M., Jensen, B. -E. O., Altmuller, J., Berger, M. M., Gogele, M., Gignoux, C. R., Wicks, S. J., Barnes, K. C., Goldstein, D. B., Reilly, M. P., Gharavi, A. G., O'Byrne, S. M., So, Y. S., Park, S. -K., Kim, H. -L., Kang, C. K., Lee, H. -J., Song, K. -H., Yoon, K. J., Paik, N. -J., Joo, E. -J., Park, W. B., Park, J. S., Park, K. U., Ham, S. Y., Kim, E. S., Kim, H. B., Caceres, M., Lenz, T. L., Julia, A., Holter, J. C., Fernandez, J., Sander, L. E., Banales, J. M., Romero-Gomez, M., Hov, J. R., Karlsen, T. H., Wacker, E. M., Elabd, H., Ruhlemann, M. C., Vadla, M. S., Lenning, O. B., Ozer, O., Kassens, J., Figuera Basso, M. E., Ortiz, A. B., Chercoles, A. G., Holten, A. R., Kildal, A. B., Gluck, A., Nolla, A. C., Dyrhol-Riise, A. M., Spinner, C. D., Hoff, D. A. L., Jimenez, D., Pestana, D., Helbig, E. T., Paraboschi, E. M., Sanchez, F. G., Hernandez, I., Galvan-Femenia, I., Badia, J. R., Muller, K. E., Gaede, K. I., Lippert, L. J., Tellez, L., Gutierrez-Stampa, M. A., Vehreschild, M. J. G. T., Marquie, M., Seilmaier, M. J., Rodriguez-Gandia, M., Ayo, N. I., Martinez, N., Cornely, O. A., Rodrigues, P. M., Espana, P. P., Garcia-Fernandez, A. -E., Fracanzani, A. L., Muniz-Diaz, E., Calderon, E. J., Solligard, E., Medrano, F. J., Muller, F., Afset, J. E., Damas, J. K., Ferrusquia-Acosta, J., Quero, J. H., Guerrero, J. M., Bettini, L. R., Gustad, L. T., Valsecchi, M. G., D'Angio, M., Gallego-Duran, R., Cejudo, T. G., Grimsrud, M. M., Gudbjartsson, D. F., Moore, K. H. S., Alarcon-Riquelme, M. E., Martinez-Bueno, M., Rello, S. R., Lall, K., Bochud, P. -Y., Nussle, S. G., Meyer zu Bentrup, F., Merlet Viollet, R., Guery, B., Hugli, O., Gonseth Nussle, S., Estoppey Younes, S., Rochat Negro, T., Mercader, J. M., Castano-Vinyals, G., Dobano, C., Mondelli, M. U., Mazzei, M. A., Caldarelli, G. P., Monforte, A. D., Scotton, P. G., Monica, M. D., Mandala, M., Coviello, D. A., La Rovere, M. T., Segala, F. V., Mencarelli, M. A., Pinto, A. M., Carriero, M. L., Ann Belli, M., Antoni, M. D., Miraglia, F. G., Parisi, S. G., Squeo, G. M., Botta, G., Hunt, K. A., Trembath, R. C., Martin, H. C., Griffiths, C. J., Curtis, C. J., Huang, Q. Q., Lee, S. H., Macarthur, D., Maclaughlin, B., Smith, A. V., Boughton, A. P., Li, K. W., Lefaive, J., Jannes, C. E., Krieger, J. E., Pereira, A. C., Lima, I. R., Tada, M. T., Mccarthy, M., Lee, J. E., Lee, H. S., Jang, H. Y., Kim, Y. -S., Kwon, K. T., Kim, S. -W., Kim, J. Y., Jang, Y. R., Kim, H., Lee, J. Y., Choe, K. -W., Kang, Y. M., Jee, S. H., Jung, K. J., Schroth, G. P., Desouza, F., Cirulli, E. T., Schiabor Barrett, K. M., Washington, N. L., Lu, J. T., Ramirez, J. M., Grzymski, J. J., Minano, J. I. E., Aguirre, L. A., Lopez-Collazo, E., Lozano-Rodriguez, R., Avendano-Ortiz, J., Arcos, V. T., Montalban-Hernandez, K. M., Quiroga, J. V., Martin-Quiros, A., Nakada, T. -A., Vonk, J. M., Ori, A. P. S., Hernandez Cordero, A. I., Sin, D. D., Bosse, Y., Feng, Y. -C. A., Weiss, S. T., Karlson, E. W., Smoller, J. W., Murphy, S. N., Meigs, J. B., Woolley, A. E., Green, R. C., Perez, E. F., Zollner, S., Sloofman, L. G., Sebra, R. P., Collins, B. L., Sealfon, S. C., Jordan, D. M., Thompson, R. C., Belbin, G. M., Underwood, S. J., Hiester, L. L., Charney, A. W., Beckmann, N. D., Schadt, E. E., Abul-Husn, N. S., Cho, J. H., Kenny, E. E., Loos, R. J. F., Nadkarni, G. N., Huckins, L. M., Ferreira, M. A. R., Abecasis, G. R., Leader, J. B., Cantor, M. N., Justice, A. E., Carey, D. J., Josyula, N. S., Kosmicki, J. A., Horowitz, J. E., Gass, M. C., Hottenga, J. J., de Geus, E. J. C., Nivard, M. G., Ritchie, M. D., Verma, S. S., Vari, M. S., Rahier, J. -F., Bulik, C. M., Landen, M., Ferrero, G. B., Fundin, B., Ismail, S. I., Badji, R. M., Hultstrom, M., Geschwind, D. H., Butte, M. J., Chang, T. S., Caulfield, M. J., Scott, R. H., Odhams, C. A., Karczewski, K. J., Wilson, D. J., Spencer, C. A., Crook, D. W., Wyllie, D. H., O'Connell, A. M., Atkinson, E. G., Walters, R. K., Palmer, D. S., Goldstein, J. I., Kyle Satterstrom, F., Earle, S. G., Lin, S. -K., Rudkin, J. K., Zhao, J. H., Butterworth, A. S., Sun, Y. V., Huffman, J. E., O'Donnell, C. J., Michael Gaziano, J., Ho, Y. -L., Glessner, J. R., Mcguigan, P. J., Moore, L. S. P., Vizcaychipi, M. P., Page, V. J., Aldera, E. L., Cutino-Moguel, M. -T., Durand, I., Hawcutt, D. B., Macmahon, M., Macnaughton, E., Mccullough, K., Mcewen, R., O'Shea, M. K., Pooni, J. S., Wooton, D. G., Bretherick, A. D., Fourman, M. H., Meynert, A. M., Ponting, C. P., Porteous, D. J., Russell, C. D., Wilson, J. F., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Shaw, C. A., Ho, A. Y. W., Horby, P. W., Mcauley, D., Openshaw, P. J. M., Semple, M. G., Mcgowan, J., Mcguinness, H., Mcneela, F., Bayo, L. -A., Arias, S. S., Conyngham, J. -A., Corral, M. A., de Almeida Martins, L. G., Mclaughlan, D., Mcmorrow, L., Mccormick, J., Mitchell, A. M., Maccallum, N., Hughes, R. A., Jones, T. O., Mcphail, M., Mckenley, I., Sutherland, S. -B., de Gordoa, L. O. -R., Gude, E. T., Macgoey, P., Mckenna, E., Patel, B. V., Zborowski, A. C., Garcia, S. M., Howe, G. S., Heron, A. E., Mills, G. H., Brown, C. W., Akhtar, M. N., Delgado, C. C., Saluzzio, R. P., Da Gloria, E. F., Hurt, W. J., Wood, H. -L., Mcalindon, M., Mccurdy, A., Ali, I. A. M., Ally, S. M., Hamilton, D. O., Lopez Martinez, M., Waite, A. A. C., Welters, I. D., Rosa, A. D., Baikady, R. R., Tatham, K. C., Beith, C. M., Mcgregor, A., Mcivor, S., Allison, K. S., Jones, G. A. L., Mchugh, T., Peters, M. J., Tomas, A. L., Mckechnie, S., Mccormack, L., Michael, H. T., Durrans, L. J., Suarez, J. C., Death, Y., Mccormick, W., Mccreath, G., Rai, S. G., Mcculloch, C., Mcfarland, D., Barclay, W. S., Cooke, G. S., Docherty, A. B., Green, C. A., Harrison, E. M., Hiscox, J. A., Lim, W. S., Mentzer, A. J., Paxton, W. A., Robertson, D. L., Scott, J. T., Tedder, R. S., Thomson, E. C., Thwaites, R. S., Gupta, R. K., Swann, O. V., Dumas, M. -E., Griffin, J. L., Lewis, M. R., dos Santos Correia, G., Sands, C. J., Mcdonald, S. E., Ahmed, K. A., Armstrong, J. A., Asiimwe, I. G., Barlow, S. L., Catterall, B. W. A., Clark, J. J., Clarke, E. A., Fisher, L. W. S., Jensen, R. L., Jones, C. B., Jones, T. R., Kiy, R. T., Livoti, L. A., Mcdonald, S., Mcevoy, L., Mclauchlan, J., Miah, N. S., Moore, S. C., Murphy, E. G., Matthew Ridley, P., Shaw, V. E., Shears, R. K., Subramaniam, K. S., Eunice Zhang, J., Carracedo, A. D., Mccafferty, S., Turtle, L. C. W., Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, HUS Helsinki and Uusimaa Hospital District, University of Helsinki, Research Programs Unit, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, and University of Zurich
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Male ,45/43 ,Autoimmunity ,Autoimmunity/genetics ,Body Mass Index ,COVID-19/genetics ,COVID-19/virology ,Critical Illness ,Female ,Genetic Loci/genetics ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Geographic Mapping ,Hospitalization ,Host-Pathogen Interactions/genetics ,Humans ,Inflammation/complications ,Information Dissemination ,Multifactorial Inheritance ,Racial Groups/genetics ,SARS-CoV-2/pathogenicity ,Smoking ,environmental risk factors ,Q1 ,631/208 ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Genetics, Genome-wide association studies, SARS-CoV-2, Viral infection ,GWAS ,Aetiology ,Lung ,QC ,0303 health sciences ,HERITABILITY ,3. Good health ,covid-19 ,Science & Technology - Other Topics ,Identification (biology) ,Infection ,Human ,631/208/205/2138 ,Settore BIO/11 - Biologia Molecolare ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Clinical Research ,Biodefense ,Genetics ,GENOME-WIDE ASSOCIATION ,Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP] ,METAANALYSIS ,1000 Multidisciplinary ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Science & Technology ,Prevention ,Racial Groups ,Pneumonia ,genetic architecture ,Human genetics ,Genetic Loci ,genetic factors ,570 Life sciences ,biology ,030217 neurology & neurosurgery ,Medizin ,Infektionsmedicin ,Genome-wide association studies ,Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Pandemic ,2.1 Biological and endogenous factors ,pandemi ,Multidisciplinary ,article ,Public Health, Global Health, Social Medicine and Epidemiology ,Racial Group ,10124 Institute of Molecular Life Sciences ,Host-Pathogen Interaction ,Multidisciplinary Sciences ,Infectious Diseases ,Host-Pathogen Interactions ,Critical Illne ,COVID-19, GWAS, genetic factors, environmental risk factors, therapy ,Infectious Medicine ,Coronavirus disease 2019 (COVID-19) ,SUSCEPTIBILITY LOCI ,General Science & Technology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Computational biology ,Biology ,Vaccine Related ,692/699/255/2514 ,Environmental risk ,Mendelian randomization ,COVID-19 Host Genetics Initiative ,QH426 ,631/326/596/4130 ,030304 developmental biology ,Inflammation ,therapy ,SARS-CoV-2 ,Human Genome ,COVID-19 ,Genetic architecture ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,Emerging Infectious Diseases ,Good Health and Well Being ,Viral infection ,3111 Biomedicine - Abstract
Niemi, Mari E. K. et al. 39 páginas, figuras y tablas. Contiene material suplementario., The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
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- 2021
48. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions.
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Roberts, Jason A, Abdul-Aziz, Mohd H, Lipman, Jeffrey, Mouton, Johan W, Vinks, Alexander A, Felton, Timothy W, Hope, William W, Farkas, Andras, Neely, Michael N, Schentag, Jerome J, Drusano, George, Frey, Otto R, Theuretzbacher, Ursula, and Kuti, Joseph L
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- *
CRITICALLY ill , *ANTIBIOTICS , *PHARMACOKINETICS , *PATHOGENIC microorganisms , *MICROBIOLOGICAL techniques , *DRUG efficacy , *SERUM albumin , *MEDICAL care - Abstract
Summary: Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness. [ABSTRACT FROM AUTHOR]
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- 2014
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- View/download PDF
49. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19
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Laurence Pearmain, Andrew Ustianowski, Ling Pei Ho, Syed Murtuza Baker, Thomas Williams, Joanna Porter, Hannah Durrington, Saba Khan, Nawar Diar Bakerly, Angela Simpson, Sean Knight, Alistair Chenery, Magnus Rattray, Alex Horsley, Ratko Djukanovic, Nicholas Scott, Paul Dark, Siddharth Krishnan, Alexander G Mathioudakis, Tovah Shaw, Chris Brightling, Madhvi Menon, Tracy Hussell, Oliver Brand, Mann, Elizabeth R [0000-0002-0803-0357], Jagger, Christopher [0000-0002-8310-9516], Shaw, Tovah N [0000-0002-8107-2836], Krishnan, Siddharth [0000-0002-9270-7083], Rattray, Magnus [0000-0001-8196-5565], Bakerly, Nawar Diar [0000-0003-2102-1997], Felton, Timothy [0000-0001-6868-6633], Grainger, John R [0000-0002-4052-5923], Hussell, Tracy [0000-0001-7186-6141], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,Myeloid ,Coronavirus Infections/blood ,Severity of Illness Index ,Monocytes ,0302 clinical medicine ,Medicine ,Longitudinal Studies ,Prospective Studies ,Research Articles ,Pneumonia, Viral/blood ,United Kingdom/epidemiology ,General Medicine ,Middle Aged ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Inflammation Mediators/blood ,Disease Progression ,Female ,Host Microbial Interactions/immunology ,Inflammation Mediators ,Coronavirus Infections ,Adult ,T cell ,CD14 ,Pneumonia, Viral ,Immunology ,macromolecular substances ,03 medical and health sciences ,Betacoronavirus ,Immune system ,Immunity ,Humans ,Pandemics ,Aged ,Innate immune system ,Betacoronavirus/immunology ,Host Microbial Interactions ,business.industry ,SARS-CoV-2 ,Monocyte ,R-Articles ,Cyclooxygenase 2/immunology ,COVID-19 ,Monocytes/immunology ,biochemical phenomena, metabolism, and nutrition ,United Kingdom ,Immunity, Innate ,Coronavirus ,030104 developmental biology ,Ki-67 Antigen ,Cyclooxygenase 2 ,Bone marrow ,Ki-67 Antigen/immunology ,business ,Biomarkers ,Biomarkers/blood - Abstract
Longitudinal analysis of the immune response in COVID-19 patients identifies a myeloid signature associated with severe disease., COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.
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- 2020
50. Clinical trials of pneumonia management assess heterogeneous outcomes and measurement instruments.
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Mathioudakis AG, Fally M, Hansel J, Robey RC, Haseeb F, Williams T, Kouta A, Welte T, Wootton DG, Clarke M, Waterer G, Dark P, Williamson PR, Vestbo J, and Felton TW
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- Adult, Humans, Treatment Outcome, Clinical Trials as Topic, Pneumonia diagnosis, Pneumonia therapy
- Abstract
Objectives: To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes., Study Design and Setting: Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome., Results: We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs., Conclusion: This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society., Competing Interests: Declaration of competing interest The authors declare no conflict of interest related to this work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
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