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1. Elective Cancer Surgery in COVID-19-Free Surgical Pathways during the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study

Author: Writing Group (denotes joint first author) James, C Glasbey (UK), Dmitri Nepogodiev (UK), Joana FF Simoes (Portugal), Omar Omar (UK), Elizabeth Li (UK), Mary, L Venn (UK), Mohammad Abou Chaar (Jordan), Vita Capizzi (Italy), Daoud Chaudhry (UK), Anant Desai (UK), Jonathan, G Edwards (UK), Jonathan, P Evans (UK), Marco Fiore (Italy), Jose Flavio Videria (Portugal), Samuel, J Ford (UK), Ian Ganyli (USA), Ewen, A Griffiths (UK), Rohan, R Gujjuri (UK), Angelos, G Kolias (UK), Haytham MA Kaafarani (USA), Ana Minaya-Bravo (Spain), Siobhan, C McKay (UK), Helen, M Mohan (Ireland), Keith Roberts (UK), Carlos San Miguel-M&#233, ndez (Spain), Peter Pockney (Australia), Richard Shaw (UK), Neil, J Smart (UK), Grant, D Stewart (UK), Sudha Sundar (UK), Raghavan Vidya (UK), Aneel, A Bhangu (UK, Statistical analysis Glasbey JC, Overall guarantor)., Omar, O (Lead statistician), Bhangu, A CovidSurg Operations Committee Kwabena Siaw-Acheampong, Ruth, A Benson, Edward, Bywater, Daoud, Chaudhry, Brett, E Dawson, Jonathan, P Evans, James, C Glasbey, Rohan, R Gujjuri, Emily, Heritage, Conor, S Jones, Sivesh, K Kamarajah, Chetan, Khatri, Rachel, A Khaw, James, M Keatley, Andrew, Knight, Samuel, Lawday, Elizabeth, Li, Harvinder, S Mann, Ella, J Marson, Kenneth, A McLean, Siobhan, C Mckay, Emily, C Mills, Dmitri, Nepogodiev, Gianluca, Pellino, Maria, Picciochi, Elliott, H Taylor, Abhinav, Tiwari, Joana FF Simoes, Isobel, M Trout, Mary, L Venn, Richard JW Wilkin, International Cancer Leads (denotes specialty Principal Investigators) James C Glasbey (Chair), Aneel Bhangu., Colorectal: Neil, J Smart, Ana, Minaya-Bravo, Susan, Moug, Dale, Vimalchandran, Abigail, Vallance, Peter, Pockney, Oesophagogastric: Ewen, A Griffiths, Richard PT Evans, Philip, Townend, Hepatopancreatobilary: Keith Roberts, Siobhan, McKay, John, Isaac, Sohei, Satoi, Thoracic: John Edwards, Aman, S Coonar, Adrian, Marchbank, Edward, J Caruana, Georgia, R Layton, Akshay, Patel, Alessandro, Brunelli, Sarcoma: Samuel Ford, Anant, Desai, Alessandro, Gronchi, Marco, Fiore, Max, Almond, Fabio, Tirotta, Sinziana, Dumitra, Neurosurgery: Angelos Kolias, Stephen, J Price, Daniel, M Fountain, Michael, D Jenkinson, Peter, Hutchinson, Hani, J Marcus, Rory, J Piper, Laura, Lippa, Franco, Servadei, Ignatius, Esene, Christian, Freyschlag, Iuri, Neville, Gail, Rosseau, Karl, Schaller, Andreas, K Demetriades, Faith, Robertson, Alex, Alamri, Head and neck: Richard Shaw, Andrew, G Schache, Stuart, C Winter, Michael, Ho, Paul, Nankivell, Juan Rey Biel, Martin, Batstone, Ian, Ganly, Breast: Raghavan Vidya, Alex, Wilkins, Jagdeep, K Singh, Dinesh, Thekinkattil, Gynaecology: Sudha Sundar, Christina, Fotopoulou, Elaine, Leung, Tabassum, Khan, Luis, Chiva, Jalid, Sehouli, Anna, Fagotti, Paul, Cohen, Murat, Gutelkin, Rahel, Ghebre, Thomas, Konney, Rene, Pareja, Rob, Bristow, Sean, Dowdy, Shylasree TS Rajkumar, Joe, Ng, Keiiji, Fujiwara, Urology: Grant, D Stewart, Benjamin, Lamb, Krishna, Narahari, Alan, McNeill, Alexandra, Colquhoun, John, McGrath, Steve, Bromage, Ravi, Barod, Veeru, Kasivisvanathan, Dissemination Committee Joana FF Simoes (Chair), Tobias Klatte., Tom EF Abbott, Michel, Adamina, Adesoji, O Ademuyiwa, Arnav, Agarwal, Ehab, Alameer, Derek, Alderson, Felix, Alakaloko, Markus, Albertsmeiers, Osaid, Alser, Muhammad, Alshaar, Sattar, Alshryda, Alexis, P Arnaud, Knut Magne Augestad, Faris, Ayasra, Jos&#233, Azevedo, Brittany, K Bankhead-Kendall, Emma, Barlow, Ruth, Blanco-Colino, Amanpreet, Brar, Kerry, A Breen, Chris, Bretherton, Igor Lima Buarque, Joshua, Burke, Mohammad, Chaar, Sohini, Chakrabortee, Peter, Christensen, Daniel, Cox, Moises, Cukier, Miguel, F Cunha, Giana, H Davidson, Salomone Di Saverio, Thomas, M Drake, John, G Edwards, Muhammed, Elhadi, Sameh, Emile, Shebani, Farik, J Edward Fitzgerald, Samuel, Ford, Tatiana, Garmanova, Gaetano, Gallo, Dhruv, Ghosh, Gustavo Mendon&#231, a Ata&#237, de Gomes, Gustavo, Grecinos, Ewen, A Griffiths, Madalegna, Gr&#252, ndl, Constantine, Halkias, Ewen, M Harrison, Intisar, Hisham, Peter, J Hutchinson, Shelley, Hwang, Arda, Isik, Pascal, Jonker, Haytham MA Kaafarani, Angelos, Kolias, Schelto, Kruijff, Ismail, Lawani, Hans, Lederhuber, Sezai, Leventoglu, Andrey, Litvin, Andrew, Loehrer, Markus, W L&#246, ffler, Maria Aguilera Lorena, Maria Marta Madolo, Piotr, Major, Janet, Martin, Hassan, N Mashbari, Dennis, Mazingi, Symeon, Metallidis, Helen, M Mohan, Rachel, Moore, David, Moszkowicz, Joshua, S Ng-Kamstra, Mayaba, Maimbo, Milagros, Niquen, Faustin, Ntirenganya, Maricarmen, Olivos, Kacimi, Oussama, Oumaima, Outani, Marie Dione Parreno-Sacdalanm, Francesco, Pata, Carlos Jose Perez Rivera, Thomas, D Pinkney, Willemijn van der Plas, Ahmad, Qureshi, Dejan, Radenkovic, Antonio Ramos- De la Medina, Keith, Roberts, April, C Roslani, Martin, Ruteg&#229, Ir&#232, ne, Santos, Raza, Sayyed, Andrew, Schache, Andreas, A Schnitzbauer, Seyi-Olajide, Justina O., Neil, Sharma, Richard, Shaw, Sebastian, Shu, Kjetil, Soreide, Antonino, Spinelli, Grant, D Stewart, Malin, Sund, Sudha, Sundar, Stephen, Tabiri, Georgios, Tsoulfas, Gabrielle, H van Ramshorst, Raghavan, Vidya, Dale, Vimalachandran, Oliver, J Warren, Duane, Wedderburn, Naomi, Wright, EuroSurg, European Society of Coloproctology (ESCP), Global Initiative for Children&#8217, s Surgery (GICS), GlobalSurg, GlobalPaedSurg, ItSURG, PTSurg, SpainSurg, Italian Society of Colorectal Surgery (SICCR), Association of Surgeons in Training (ASiT), Irish Surgical Research Collaborative (ISRC), Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), Collaborators (denotes Site Principal Investigators) Argentina: Allemand C, Italian Society of Surgical Oncology (SICO)., Boccalatte, L, Figari, M, Lamm, M, Larra&#241, aga, J, Marchitelli, C, Noll, F, Odetto, D, Perrotta, M, Saadi, J, Zamora, L (Hospital Italiano De Buenos Aires), Alurralde, C, Caram, El, Eskinazi, D, Mendoza, Jp, Usandivaras M (Sanatorio, 9 De Julio Sa), Badra, R, Esteban, A, Garc&#237, a, Js, a, Pm, Gerchunoff, Ji, Lucchini, Sm, NIgra, Ma, Armenia: Hovhannisyan T, Vargas L (Sanatorio Allende)., Australia: Gould T, Stepanyan A (Nairi Medical Center)., Gourlay, R, Griffiths, B (Calvary Mater Newcastle), Gananadha S, McLaren M (Canberra Hospital), Cecire, J, Joshi, N, Salindera, S, Sutherland, A (Coffs Harbour Health Campus), Ahn, Jh, Charlton, G, Chen, S, Gauri, N, Hayhurst, R, Jang, S, Jia, F, Mulligan, C, Yang, W, Ye, G, Zhang, H (Concord Repatriation General Hospital), Ballal, M, Gibson, D, Hayne, D, Moss, J, Richards, T, Viswambaram, P, Vo UG (Fiona Stanley Hospital), Bennetts, J, Bright, T, Brooke-Smith, M, Fong, R, Gricks, B, Lam, Yh, Ong, Bs, Szpytma, M, Watson, D (Flinders Medical Centre), Bagraith, K, Caird, S, Chan, E, Dawson, C, Ho, D, Jeyarajan, E, Jordan, S, Lim, A, Nolan, Gj, Oar, A, Parker, D, Puhalla, H, Quennell, A, Rutherford, L, Townend, P, Von Papen, M, Wullschleger, M (Gold Coast University Hospital), Blatt, A, Cope, D, Egoroff, N, Fenton, M, Gani, J, Lott, N, Pockney, P, Shugg, N (John Hunter Hospital), Elliott M, Phung D (Lifehouse), Phan D, Townend D (Lismore Base Hospital), Bong C, Gundara J (Logan Hospital), Frankel, A (Princess Alexandra Hospital), Bowman S, Guerra GR (Queen Elizabeth Ii Jubilee Hospital), Bolt, J, Buddingh, K, Dudi-Venkata, Nn, Jog, S, Kroon, Hm, Sammour, T, Smith, R, Stranz, C (Royal Adelaide Hospital), Batstone, M, Lah, K, McGahan, W, Mitchell, D, Morton, A, Pearce, A, Roberts, M, Sheahan, G, Swinson, B (Royal Brisbane And Women&#8217, s Hospital), Alam, N, Banting, S, Chong, L, Choong, P, Clatworthy, S, Foley, D, Fox, A, Hii, Mw, Knowles, B, Mack, J, Read, M, Rowcroft, A, Ward, S, Austria: Lanner M (Kardinal Schwarzenberg Klinikum), Wright G (St Vincent&#8217, s Hospital)., K&#246, nigsrainer, I (Landeskrankenhaus Feldkirch), Bauer, M, Freyschlag, C, Kafka, M, Messner, F, 214, fner, D, Tsibulak, I (Medical University Of Innsbruck), Emmanuel, K, Grechenig, M, Gruber, R, Harald, M, hlberger, L, Presl, J, Azerbaijan: Namazov &#304, Wimmer A (Paracelsus Medical University Salzburg)., Barbados: Barker D, Samadov E (Leyla Medical Centerl)., Boyce, R, Corbin, S, Doyle, A, Eastmond, A, Gill, R, Haynes, A, Millar, S, O&#8217, Shea, M, Padmore, G, Paquette, N, Phillips, E, John S, St., Belgium: Flamey N, Walkes K (Queen Elizabeth Hospital)., Pattyn, P (Az Delta), Oosterlinck, W, Van den Eynde, J, Brazil: Gatti A, Van den Eynde R (Uz Leuven)., Nardi, C, Oliva, R (Hospital Geral De Pirajussara), De Cicco, R (Instituto De C&#226, ncer Dr Arnaldo Vieira De Carvalho), Cecconello, I, Gregorio, P, Pontual Lima, L, Ribeiro Junior, U, Takeda, F, Canada: Kidane B, Terra RM (Instituto Do C&#226, ncer De Estado De S&#227, o Paulo). Bulgaria: Sokolov M (University Hospital Alexandrovska)., Srinathan, S (Health Sciences Centre), Boutros, M, Caminsky, N, Ghitulescu, G, Jamjoum, G, Moon, J, Pelletier, J, Vanounou, T, Wong, S (Jewish General Hospital), Dumitra, S, Kouyoumdjian, A (Mcgill University Health Center), Johnston B, Russell C (Saint John Regional Hospital), Demyttenaere, S, Mary&#8217, s Hospital), Garfinkle R (St., Abou-Khalil, J, Nessim, C, Colombia: Almeciga A, Stevenson J (The Ottawa Hospital). Chile: Heredia F (Cl&#237, nica Universitaria De Concepci&#243, n)., Fletcher, A, Merchan A (Centro De Investigaciones Oncol&#243, gicas Cl&#237, nica San Diego, - Ciosad), Puentes LO (Hospital San Jos&#233, Croatia: Ba&#269, i&#263, G, Mendoza Quevedo J (Subred Sur Occidente De Kennedy (Hospital De Kennedy))., Karlovi&#263, D, Kr&#353, ul, D, Zeli&#263, M (University Hospital Center Rijeka), Luksic I, Mamic M (University Hospital Dubrava), Bakmaz, B, 262, oza, I, Dijan, E, Katusic, Z, Mihanovic, J, Cyprus: Frantzeskou K, Rakvin I (Zadar General Hospital)., Gouvas, N, Kokkinos, G, Papatheodorou, P, Pozotou, I, Stavrinidou, O, Czechia: Martinek L, Yiallourou A (Nicosia General Hospital)., Skrovina, M, Szubota, I (Hospital &amp, amp, Oncological Centre Novy Jicin), 381, ateck&#253, J (Slezsk&#225, Nemocnice V Opav&#283, P. o. ), Javurkova, V, Denmark: Avlund T, Klat J (University Hospital Ostrava)., Christensen, P, Harbjerg, Jl, Iversen, Lh, Kjaer, Dw, Kristensen, H&#248, Mekhael, M (Aarhus University Hospital), Ebbeh&#248, j, Al, Krarup, P, Schlesinger, N, Egypt: Abdelsamed A, Smith H (Bispebjerg Hospital)., Azzam, Ay, Salem, H, Seleim, A (Al Azhar University Hospitals), Abdelmajeed, A, Abdou, M, Abosamak, Ne, AL Sayed, M, Ashoush, F, Atta, R, Elazzazy, E, Elhoseiny, M, Elnemr, M, Elqasabi, Ms, Elsayed Hewalla ME, Elsherbini, I, Essam, E, Eweda, M, Ghallab, I, Hassan, E, Ibrahim, M, Metwalli, M, Mourad, M, Qatora, Ms, Ragab, M, Sabry, A, Saifeldin, H, Saleh Mesbah Mohamed Elkaffas, M, Samih, A, Samir Abdelaal, A, Shehata, S, Shenit, K (Alexandria Main University Hospital), Attia, D, Kamal, N, Osman, N (Alexandria Medical Research Institute), Abbas, Am, Abd Elazeem HAS, Abdelkarem, Mm, Alaa, S, Ali, Ak, Ayman, A, Azizeldine, Mg, Elkhayat, H, elghazaly S, M., Monib, Fa, Nageh, Ma, Saad, Mm, Salah, M, Shahine, M, Yousof, Ea, Youssef, A (Assiut University Hospital), Eldaly, A (El-Menshawy Hospital), ElFiky, M, Nabil, A (Kasr Alainy Faculty Of Medicine, Cairo, University), Amira, G, Sallam, I, Sherief, M, Sherif, A (Misr Cancer Center), Abdelrahman, A, Aboulkassem, H, Ghaly, G, Hamdy, R, Morsi, A, Sherif, G (National Cancer Institute), Abdeldayem, H, Abdelkader Salama, I, Balabel, M, Fayed, Y, Sherif AE (National Liver Institute, Finland: Kauppila J, Menoufia University). Ethiopia: Bekele D (Maddawalabu University Goba Referral Hospital)., Sarjanoja, E (L&#228, nsi-Pohja Central Hospital), Helminen, O, Huhta, H, France: Beyrne C, Kauppila JH (Oulu University Hospital)., Jouffret, L, Lugans, L, Marie-Macron, L (Centre Hospitalier Avignon), Chouillard E, De Simone B (Centre Hospitalier Intercommunal Poissy Saint Germain En Laye), Bettoni, J, Dakp&#233, S, Devauchelle, B, Lavagen, N, Testelin, S (Chu Amiens), Boucher, S, Breheret, R, Gueutier, A, Kahn, A, K&#252, n-Darbois, J (Chu Angers), Barrabe, A, Lakkis, Z, Louvrier, A, Manfredelli, S, Mathieu, P (Chu Besan&#231, on), Chebaro, A, Drubay, V, El amrani, M, Eveno, C, Lecolle, K, Legault, G, Martin, L, Piessen, G, Pruvot, Fr, Truant, S, Zerbib, P (Chu Lille), Ballouhey, Q, Barrat, B, Laloze, J, Salle, H, Taibi, A, Usseglio, J (Chu Limoges), Bergeat D, Merdrignac A (Chu Rennes - General Surgery), Le Roy, B, Perotto, Lo, Scalabre, A (Chu Saint Etienne), Aim&#233, A, Ezanno, A, Malgras, B (Hia Begin), Bouche P, Tzedakis S (H&#244, pital Cochin - Aphp), Cotte, E, Glehen, O, Lifante, J (Hopital Lyon Sud), D&#8217, Urso, A, Felli, E, Mutter, D, Pessaux, P, Seeliger, B (Hus, Pole H&#233, pato-Digestif, / Ihu- Strasbourg), Bardet, J, Berry, R, Boddaert, G, Bonnet, S, Brian, E, Denet, C, Fuks, D, Gossot, D, Grigoroiu, M, Laforest, A, Levy-Zauberman, Y, Louis-Sylvestre, C, Moumen, A, Pourcher, G, Seguin-givelet, A, Tribillon, E (Institut Mutualiste Montsouris), Duchalais, E, Espitalier, F, Ferron, C, Germany: Bork U, Malard O (Nantes University Hospital)., Distler, M, Fritzmann, J, Kirchberg, J, Praetorius, C, Riediger, C, Weitz, J, Welsch, T, Wimberger, P (Carl-Gustav-Carus University, Dresden), Tu, Beyer, K, Kamphues, C, Lauscher, J, Loch, Fn, Schineis, C (Charit&#233, University Medicine, Campus Benjamin Franklin), Albertsmeier, M, Angele, M, Kappenberger, A, Niess, H, Schiergens, T, Werner, J (Department of General, Visceral and Transplantation Surgery, Ludwig- Maximilians-Universitat Munich), Becker R, Jonescheit J (Heilig-Geist Hospital Bensheim), Pergolini I, Reim D (Klinikum Rechts Der Isar Tum School Of Medicine), Boeker, C, Hakami, I, Mall, J (Krh Nordstadt-Siloah Hospitals), Liokatis P, Smolka W (LMU Klinikum Campus Innenstadt), Nowak K, Reinhard T (Romed Klinikum Rosenheim), H&#246, lzle, F, Modabber, A, Winnand, P (University Hospital Aachen), Knitschke, M (University Hospital Giessen And Marburg), Kauffmann P, Wolfer S (University Hospital Goettingen / Universit&#228, tsmedizin Goettingen), Kleeff, J, Lorenz, K, Michalski, C, Ronellenfitsch, U, Schneider, R (University Hospital Halle (Saale)), Bertolani, E, nigsrainer, A, L&#246, ffler, Mw, Quante, M, Steidle, C, 220, berr&#252, ck, L, Yurttas, C (University Hospital Tuebingen), Betz, Cs, Bewarder, J, B&#246, ttcher, A, Burg, S, Busch, C, Gosau, M, Heuer, A, Izbicki, J, Klatte, To, Koenig, D, Moeckelmann, N, Nitschke, C, Priemel, M, Smeets, R, Speth, U, Thole, S, Uzunoglu, Fg, Vollkommer, T, Zeller, N (University Medical Center Hamburg- Eppendorf), Battista, Mj, Gillen, K, Hasenburg, A, Krajnak, S, Linz, V, Schwab, R (University Of Mainz, Greece: Angelou K, Department Of Gynaecology And Obstetrics)., Haidopoulos, D, Rodolakis, A (Alexandra General Hospital), Antonakis, P, Bramis, K, Chardalias, L, Contis, I, Dafnios, N, Dellaportas, D, Fragulidis, G, Gklavas, A, Konstadoulakis, M, Memos, N, Papaconstantinou, I, Polydorou, A, Theodosopoulos, T, Vezakis, A (Aretaieion Hospital), Antonopoulou, Mi, Manatakis, Dk, Tasis, N (Athens Naval And Veterans Hospital), Arkadopoulos, N, Danias, N, Economopoulou, P, Kokoropoulos, P, Larentzakis, A, Michalopoulos, N, Selmani, J, Sidiropoulos, T, Tsaousis, V, Vassiliu, P (Attikon University General Hospital), Bouchagier, K, Klimopoulos, S, Paspaliari, D, Stylianidis, G (Evaggelismos General Hospital), Baxevanidou, K, Bouliaris, K, Chatzikomnitsa, P, Efthimiou, M, Giaglaras, A, Kalfountzos, C, Koukoulis, G, Ntziovara, Am, Petropoulos, K, Soulikia, K, Tsiamalou, I, Zervas, K, Zourntou, S (General Hospital Of Larissa &#8220, Koutlimpaneio And Triantafylleio&#8221, Baloyiannis, I, Diamantis, A, Gkrinia, E, Hajiioannou, J, Korais, C, Koukoura, O, Perivoliotis, K, Saratziotis, A, Skoulakis, C, Symeonidis, D, Tepetes, K, Tzovaras, G, Zacharoulis, D (General University Hospital Of Larissa), Alexoudi, V, Antoniades, K, Astreidis, I, Christidis, P, Deligiannidis, D, Grivas, T, Ioannidis, O, Kalaitsidou, I, Loutzidou, L, Mantevas, A, Michailidou, D, Paraskevopoulos, K, Politis, S, Stavroglou, A, Tatsis, D, Tilaveridis, I, Vahtsevanos, K, Venetis, G (George Papanikolaou General Hospital Of Thessaloniki), Karaitianos I, Tsirlis T (Henry Dunant Hospital Center), Charalabopoulos, A, Liakakos, T, Mpaili, E, Schizas, D, Spartalis, E, Syllaios, A, Zografos, C (Laiko University Hospital), Anthoulakis, C, Christou, C, Papadopoulos, V, Tooulias, A, Tsolakidis, D, Tsoulfas, G, Zouzoulas, D (Papageorgiou General Hospital), Athanasakis, E, Chrysos, E, Tsiaousis, J, Xenaki, S, Hong Kong: Futaba K, Xynos E (University Hospital Of Heraklion Crete And Interclinic Hospital Of Crete)., Ho, Mf, Hon, Sf, Mak, Twc, Ng SSM (Prince Of Wales Hospital), Hungary: Banky B, Foo CC (Queen Mary Hospital)., Ireland: Aremu M, Suszt&#225, k N (Szent Borb&#225, la K&#243, rh&#225, z)., Canas-Martinez, A, Cullivan, O, Murphy, C, Owens, P, Pickett, L (Connolly Hospital Blanchardstown), Akmenkalne, L, Byrne, J, Corrigan, M, Cullinane, C, Daly, A, Fleming, C, Jordan, P, Killeen, S, Lynch, N, McCarthy, A, Mustafa, H, Brien, S, Leary, P, Syed, Was, Vernon, L (Cork University Hospital), Callanan, D, Huang, L, Ionescu, A, Sheahan, P (South Infirmary Victoria University Hospital), Balasubramanian, I, Boland, M, Conlon, K, Evoy, D, Fearon, N, Gallagher, T, Geraghty, J, Heneghan, H, Kennedy, N, Maguire, D, McCartan, D, McDermott, Ew, Prichard, Rs, Winter, D (St Vincent&#8217, s University Hospital), Alazawi, D, Barry, C, Boyle, T, Butt, W, Connolly, Em, Donlon, N, Donohue, C, Fahey, Ba, Farrell, R, Fitzgerald, C, Kinsella, J, Larkin, Jo, Lennon, P, Maguire, Pj, Mccormick, P, Mehigan, Bj, Mohan, H, Nugent, T, Sullivan, H, Ravi, N, Reynolds, Jv, Rogers, A, Shokuhi, P, Smith, J, Smith, La, James&#8217, s Hospital), Timon C (St., Bashir, Y, Bass, G, Connelly, T, Earley, H, Elliott, Ja, Gillis, A, Kavanagh, D, Neary, P, riordan, J, Reynolds, Is, Rice, D, Ridgway, P, Umair, M, Whelan, M (Tallaght Hospital), Carroll, P, Collins, C, Corless, K, Finnegan, L, Fowler, A, Hogan, A, Kerin, M, Lowery, A, McAnena, P, McKevitt, K, Nizami, K, Ryan, &#201, Samy, A (University Hospital Galway), Coffey, Jc, Cunningham, R, Devine, M, Nally, D, Peirce, C, Tormey, S (University Hospital Limerick), Hardy, N, Malley, S, Italy: Macina S (Asst Mantua), Ryan M (University Hospital Waterford/University College Cork)., Mariani, Nm, Opocher, E, Pisani Ceretti A (Asst Santi Paolo, E Carlo), Ferrari, F, Odicino, F, Sartori, E (Asst Spedali Civili, Ospedale Di Brescia), Cotsoglou C, Granieri S (Asst Vimercate), Bianco, F, Camillo&#8217, Colledan, M, Tornese, S, Zambelli MF (Asst-Papa Giovanni Xxiii- Bergamo), Bissolotti, G, Fusetti, S, Lemma, F (Azienda Ospedaliera Di Padova), Marino, M, Mirabella, A, Vaccarella, G (Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo), Agostini, C, Alemanno, G, Bartolini, I, Bergamini, C, Bruscino, A, Checcucci, C, De Vincenti, R, Di Bella, A, Fambrini, M, Fortuna, L, Maltinti, G, Muiesan, P, Petraglia, F, Prosperi, P, Ringressi, Mn, Risaliti, M, Sorbi, F, Taddei, A, Tucci, R (Azienda Ospedaliera Universitaria Careggi), Bassi, C, Campagnaro, T, Casetti, L, De Pastena, M, Esposito, A, Fontana, M, Guglielmi, A, Landoni, L, Malleo, G, Marchegiani, G, Nobile, S, Paiella, S, Pedrazzani, C, Rattizzato, S, Ruzzenente, A, Salvia, R, Turri, G, Tuveri, M (Azienda Ospedaliera Universitaria Integrata Di Verona), Bellora, P, Aloisio, G, Ferrari, M, Francone, E, Gentilli, S, Nikaj, H (Azienda Ospedaliero Universitaria Maggiore Della Carit&#224, Bianchini, M, Chiarugi, M, Coccolini, F, Di Franco, G, Furbetta, N, Gianardi, D, Guadagni, S, Morelli, L, Palmeri, M, Tartaglia, D (Azienda Ospedaliero Universitaria Pisana), Anania, G, Carcoforo, P, Chiozza, M, De Troia, A, Koleva Radica, M, Portinari, M, Sibilla, Mg, Urbani, A (Azienda Ospedaliero Universitaria Sant&#8217, anna), Fabbri, N, Feo, Cv, Gennari, S, Parini, S, Righini E (Azienda Unit&#224, Sanitaria Locale di Ferrara, - University of Ferrara), Ampollini, L, Bellanti, L, Bergonzani, M, Bertoli, G, Bocchialini, G, Angelo, G, Lanfranco, D, Musini, L, Poli, T, Santoro, Gp, Varazzani, A (Azienda Ospedaliero-Universitaria Di Parma), Aguzzoli, L, Borgonovo, G, Castro Ruiz, C, Coiro, S, Falco, G, Mandato, Vd, Mastrofilippo, V, Montella, Mt, Annessi, V, Zizzo M (Azienda Unit&#224, Sanitaria Locale, - Irccs Di Reggio Emilia), Grossi, U, Novello, S, Romano, M, Rossi, S, Zanus, G (Ca&#8217, Foncello Treviso-DISCOG-Universit Di Padova), Esposito, G, Frongia, F, Pisanu, A, Podda, M (Cagliari University Hospital), Belluco, C, Lauretta, A, Montori, G, Moras, L, Olivieri, M (Centro Di Riferimento Oncologico Di Aviano (Cro) Irccs), Bussu, F, Carta, Ag, Cossu, Ml, Cottu, P, Fancellu, A, Feo, Cf, Ginesu, Gc, Giuliani, G, Madonia, M, Perra, T, Piras, A, Porcu, A, Rizzo, D, Scanu, Am, Tedde, A, Tedde, M (Cliniche San Pietro, Sassari), A. o. u., Delrio, P, Rega D (Colorectal Surgical Oncology Unit, - Istituto Nazionale Tumori Fondazione, Pascale-I. r. c. c. s., ), Badalamenti, G, Campisi, G, Cordova, A, Franza, M, Maniaci, G, Rinaldi, G, Toia, F (Department Of Surgical, University Of Palermo), Oncological And Oral Sciences., Calabr&#242, M, Farnesi, F, Lunghi, Eg, Muratore, A, Pipitone Federico NS (Edoardo Agnelli), B&#224, mbina, F, Andrea, G, Familiari, P, Picotti, V (Fabrizio Spaziani), De Palma, G, Luglio, G, Pagano, G, Tropeano FP (Federico Ii University Hospital), Baldari, L, Beltramini, Ga, Boni, L, Cassinotti, E, Gianni&#8217, Pignataro, L, Torretta S (Fondazione Irccs Ca&#8217, Granda, - Ospedale Maggiore Policlinico), Abatini, C, Baia, M, Biasoni, D, Bogani, G, Cadenelli, P, Capizzi, V, Cioffi, Spb, Citterio, D, Comini, Lv, Cosimelli, M, Fiore, M, Folli, S, Gennaro, M, Giannini, L, Gronchi, A, Guaglio, M, Macchi, A, Martinelli, F, Mazzaferro, V, Mosca, A, Pasquali, S, Piazza, C, Raspagliesi, F, Rolli, L, Salvioni, R, Sarpietro, G, Sarre, C, Sorrentino, L (Fondazione Irccs Istituto Nazionale Dei Tumori, Milano), Agnes, A, Alfieri, S, Belia, F, Biondi, A, Cozza, V, Amore, A, Ugo, D, De Simone, V, Fagotti, A, Gasparini, G, Gordini, L, Litta, F, Lombardi, Cp, Lorenzon, L, Marra, Aa, Marzi, F, Moro, A, Parello, A, Perrone, E, Persiani, R, Ratto, C, Rosa, F, Saponaro, G, Scambia, G, Scrima, O, Sganga, G, Tudisco, R (Fondazione Policlinico Universitario Agostino Gemelli), Belli, A, Granata, V, Izzo, F, Palaia, R, Patrone R (Hpb Surgical Oncology Unit, - Istituto Nazionale Tumori Fondazione, Pascale- I. r. c. c. s., ), Carrano, Fm, Carvello, Mm, De Virgilio, A, Di Candido, F, Ferreli, F, Gaino, F, Mercante, G, Rossi, V, Spinelli, A, Spriano, G (Humanitas Clinical And Research Center Irccs, Rozzano (Mi) &amp, Humanitas, University, Department Of Biomedical Sciences, Pieve Emanuele (Mi)), Donati, Dm, Frisoni, T, Palmerini, E (Irccs Istituto Ortopedico Rizzoli), Aprile, A, Barra, F, Batistotti, P, Ferrero, S, Fregatti, P, Scabini, S, Sparavigna, M (Irccs Ospedale Policlinico San Martino), Asti, E, Bernardi, D, Bonavina, L, Lovece, A (University of Milan, IRCCS Policlinico San Donato), Adamoli, L, Ansarin, M, Cenciarelli, S, Chu, F, De Berardinis, R, Fumagalli Romario, U, Mastrilli, F, Pietrobon, G, Tagliabue M (Istituto Europeo Di Oncologia, - Irccs -Milano), Badellino, E, Ferrero, A, Massobrio, R (Mauriziano Hospital Torino, Italy), De Manzoni Garberini, A (Ospedale Civile Spirito Santo), Federico, P, Maida, P, Marra, E, Marte, G, Petrillo, A, Tammaro, T, Tufo, A (Ospedale Del Mare), Berselli, M, Borroni, G, Cocozza, E, Conti, L, Desio, M, Livraghi, L, Quintodei, V, Rizzi, A, Zullo A (Ospedale Di Circolo, E Fondazione Macchi (Varese)), Baldi, C, Corbellini, C, Sampietro GM (Ospedale Di Rho, - Asst Rhodense), Cellerino P (Ospedale Fatebenefratelli, E Oftalmico), Baldini, E, Capelli, P, Isolani, Sm, Ribolla, M (Ospedale Guglielmo Da Saliceto Piacenza), Bondurri, A, Colombo, F, Ferrario, L, Guerci, C, Maffioli, A (Ospedale Luigi Sacco Milano), Armao, T, Ballabio, M, Bisagni, P, Gagliano, A, Longhi, M, Madonini, M, Pizzini, P (Ospedale Maggiore Di Lodi), Baietti, Am, Biasini, M, Maremonti, P, Neri, F, Prucher, Gm, Ricci, S, Ruggiero, F, Zarabini AG (Ospedale Maggiore/Bellaria Carlo Alberto Pizzardi Ausl Bologna), Barmasse, R, Mochet, S, Usai, A (Ospedale Regionale Umberto Parini), Leonardo - Asl Napoli 3 Sud, Incollingo P (Ospedale S., Castellammare Di Stabia), Mancini, S, Marino Cosentino, L, Sagnotta, A (Ospedale San Filippo Neri), Fruscio, R, Grassi, T, Nespoli, Lc, Tamini, N (Ospedale San Gerardo), Anastasi, A, Bartalucci, B, Bellacci, A, Canonico, G, Capezzuoli, L, Di Martino, C, Ipponi, P, Linari, C, Montelatici, M, Nelli, T, Spagni, G, Tirloni, L, Vitali, A (Ospedale San Giovanni Di Dio), Abate, E, Casati, M, Casiraghi, T, Laface, L, Schiavo M (Ospedale Vittorio Emanuele Iii, - Carate Brianza), Arminio, A, Cotoia, A, Lizzi, V, Vovola, F (Ospedali Riuniti Azienda Ospedaliera Universitaria Foggia), Vergari, R (Ospedali Riuniti Di Ancona), Ugo, S, Depalma, N, 8220, Vito Fazzi&#8221, Spampinato MG (P. o., Bartolucci, P, Brachini, G, Bruzzaniti, P, Chiappini, A, Chiarella, V, Ciccarone, F, Cicerchia, Pm, Cirillo, B, De Toma, G, Di bartolomeo, A, Fiori, E, Fonsi, Gb, Franco, G, Frati, A, Giugliano, M, Iannone, I, La Torre, F, Lapolla, P, Leonardo, C, Marruzzo, G, Meneghini, S, Mingoli, A, Ribuffo, D, Salvati, M, Santoro, A, Sapienza, P, Scafa, Ak, Simonelli, L, Zambon M (Policlinico Umberto, I Sapienza University Of Rome), Capolupo, Gt, Carannante, F, Caricato, M, Mascian&#224, G, Mazzotta, E (Policlinico Universitario Campus Bio Medico Of Rome), Gattolin, A, Migliore, M, Rimonda, R, Sasia, D, Travaglio, E (Regina Montis Regalis Hospital, Mondov&#236, Cervellera, M, Gori, A, Sartarelli, L, orsola-Malpighi Hospital), Tonini V (S., Giacometti, M, Zonta, S (Ospedale San Biagio, Asl, VCO), Chessa, A, Fiorini, A, Norcini, C (San Giovanni Di Dio), Colletti, G, Confalonieri, M, Costanzi, A, Frattaruolo, C, Mari, G, Monteleone, M (San Leopoldo Mandic), Bandiera, A, Bocciolone, L, Bonavina, G, Candiani, M, De Nardi, P, Gagliardi, F, Medone, M, Mortini, P, Negri, G, Ottolina, J, Parise, P, Piloni, M, Sileri, P, Vignali, A (San Raffaele Scientific Institute, Milan), Belvedere, A, Bernante, P, Bertoglio, P, Boussedra, S, Brunocilla, E, Cipriani, R, Cisternino, G, De Crescenzo, E, De Iaco, P, Dondi, G, Frio, F, Jovine, E, Mineo Bianchi, F, Neri, J, Parlanti, D, Perrone, Am, Pezzuto, Ap, Pignatti, M, Pinto, V, Poggioli, G, Ravaioli, M, Rottoli, M, Schiavina, R, Serenari, M, Serra, M, Solli, P, Taffurelli, M, Tanzanu, M, Tesei, M, Violante, T, Zanotti, S (Sant&#8217, orsola Hospital, Alma Mater Studiorum University Of Bologna, Borghi, F, Cianflocca, D, Di Maria Grimaldi, S, Donati, D, Gelarda, E, Geretto, P, Giraudo, G, Giuffrida, Mc, Marano, A, Palagi, S, Pellegrino, L, Peluso, C, Testa V (Santa Croce, E Carle Hospital, Cuneo), Agresta, F, Prando, D, Zese M (Santa Maria Degli Angeli Hospital Ulss5, - Adria), Aquila, F, Gambacciani, C, Lippa, L, Pieri, F, Santonocito OS (Spedali Riuniti Di Livorno), Armatura, G, Bertelli, G, Frena, A, Marinello, P, Notte, F, Patauner, S, Moritz Hospital), Scotton G (St., Fulginiti, Sf, Gallo, G, Sammarco, G, Vescio, G (University &#8216, Magna Graecia&#8217, Of Catanzaro), Balercia, P, Catarzi, L, Consorti G (University Hospital Umberto, I Ancona), Di Marzo, F (Valtiberina), Japan: Daiko H, Fontana T (Vittorio Emanuele)., Ishikawa, M, Ishiyama, K, Iwata, S, Kanematsu, K, Kanemitsu, Y, Kato, T, Kawai, A, Kobayashi, E, Kobayashi Kato, M, Moritani, K, Nakatani, F, Oguma, J, Tanase, Y, Jordan: Al Abdallah M, Uno M (National Cancer Center Hospital)., Ayasra, F, Ayasra, Y, Qasem, A (Al-Basheer Hospital), Abu Za&#8217, nouneh FJ, Fahmawee, T, Hmedat, A, Ibrahim, A, Obeidat, K (King Abdullah University Hospital), Abdel Al, S, Abdel Jalil, R, Abou Chaar MK, Al-Masri, M, Al-Najjar, H, Alawneh, F, Alsaraireh, O, Elayyan, M, Ghanem, R, Libya: Alkadeeki G (Al-Jalaa Hospital), Lataifeh I (King Hussein Cancer Center)., Aldokali, N, Senossi, O, Subhi MT (Alkhadra Hospital), Burgan, D, Kamoka, E, Kilani, Ai, Salamah, A, Salem, M, Shuwayyah, A (National Cancer Institute, Sabratha, - Libya), Abdulwahed, E, Alshareea, E, Aribi, N, Aribi, S, Biala, M, Ghamgh, R, Morgom, M (Tripoli Central Hospital), Aldayri, Z, Ellojli, I, Lithuania: Bradulskis S, Kredan A (Tripoli University Hospital)., Dainius, E, Kubiliute, E, Kutkevi&#269, ius, J, Parseliunas, A, Subocius, A, Madagascar: Rasoaherinomenjanahary F, Venskutonis D (Lithuanian University Of Health Sciences Kaunas Clinical Hospital)., Razafindrahita, Jb, Malaysia: Ong EC (Bintulu), Samison LH (Joseph Ravoahangy Andrianavalona Hospital)., Hamdan, Kh, Ibrahim, Mr, Tan, Ja, Thanapal MR (Hospital Kuala Lumpur), Amin Sahid, N, Hayati, F, Jayasilan, J, Sriram, Rk, Subramaniam, S (Queen Elizabeth Hospital &amp, Universiti Malaysia Sabah, Kota, Kinabalu, Sabah, Malaysia), Che Jusoh, A, Hussain, Ah, Mohamed Sidek AS, Mohd Yunus MF, Soh, Jy, Wong, Mpk, Zakaria, Ad, Zakaria, Z (School Of Medical Sciences &amp, Hospital, Universiti Sains Malaysia), Fadzli, A, Fathi, Nq, Koh, Ps, Liew, Yt, Roslani, Ac, Tang, Cy, Teoh, Ly, Wong, Wj, Mexico: Alvarez MR, Yahaya AS (University Malaya Medical Centre)., Arrangoiz, R, Cordera, F, De la Rosa Abaroa MA, G&#243, mez-Pedraza, A, Hernandez, R, Maffuz-Aziz, A, Posada JA (Abc Medical Center), Becerra Garc&#237, a FC (Hospital San &#193, ngel Inn Chapultepec), Alfaro-Goldaracena, A, Buerba, Ga, Castillejos- Molina RA, Chan, C, Dominguez-Rosado, I, Medina-Franco, H, Mercado, M&#225, Oropeza- Aguilar, M, Pe&#241, a G&#243, mez Portugal, E, Posadas-Trujillo, Oe, Rodriguez-Covarrubias, F, Salgado-Nesme, N, Morocco: Arkha Y, Vilatoba M (Instituto Nacional De Ciencias M&#233, dicas Y Nutrici&#243, n &#8220, Salvador Zubir&#225, n&#8221, Bechri, H, El Ouahabi, A, Oudrhiri MY (Centre Hospitalier Universitaire Ibn Sina Rabat), Derkaoui hassani F, El abbadi N (Cheikh Zaid International University Hospital), Amrani, L, Belkhadir, Zh, Benkabbou, A, Chakib, O, El Ahmadi, B, El Bouazizi, Y, Essangri, H, Ghannam, A, Majbar, Am, Mohsine, R, Netherlands: Hompes R, Souadka A (Institut National D&#8217, oncologie)., Meima-van Praag, E, Pronk, Ajm, Sharabiany, S (Amsterdam Umc, University Of Amsterdam), Grotenhuis, B, Hartveld, L, Reijers, S, Van Houdt, W (Antoni Van Leeuwenhoek Ziekenhuis), Baaij, J, Bolster-van Eenennaam, M, De Graaff, M, Sloothaak, D, Van Duijvendijk, P (Gelre Ziekenhuis), Posma-Bouman, L (Slingeland Ziekenhuis), Derksen, T, Franken, J, Oosterling, S (Spaarne Gasthuis), De Bree, R (University Medical Center Utrecht), Konsten, J, Nigeria: Fidelis L, Van Heinsbergen M (Viecuri Medisch Centrum)., Sholadoye, Tt, Tolani, M (Ahmadu Bello University Teaching Hospital), Olaogun, J (Ekiti State University Teaching Hospital), Egbuchulem, Ik, Lawal, Ta, Ogundoyin, O, Olulana DI (University College Hospital), Abdur-Rahman, L, Adeyeye, A, Aremu, I, Bello, J, Olasehinde, O, Oman: Massoud J, Popoola A (University Of Ilorin Teaching Hospital)., Massoud, R, Pakistan: Jamal A, Sorour TM (Khoula Hospital)., Kerawala AA (Cancer Foundation Hospital), Memon, As, Nafees Ahmed, R, Pfau Civil Hospital), Rai L (Dr Ruth K. m., Ayub, B, Hassan, N, Martins, Rs, Ramesh, P, Sayyed, R (Patel Hospital), Butt, U, Kashif, M, Khan, Wh, Qureshi, A, Umar, M, Waris Farooka, M, Wasim, T (Services Hospital Lahore), Ayubi, A, Rashid, I, Peru: Falcon GM, Waqar SH (The Pakistan Institute Of Medical Sciences)., Philippines: Jocson R, Robles R (Instituto Regional De Enfermedades Neopl&#225, sicas Del Sur)., Teh, C (National Kidney &amp, Poland: Major P (Jagiellonian University Medical College), Transplant Institute)., Bobi&#324, ski, M, Kotarski, J, Rasoul-Peli&#324, ska, K (Medical University Of Lublin, Portugal: Azevedo C, Chair And Department Of Gynaecological Oncology And Gynaecology)., Machado, D, Mendes, F (Centro Hospitalar Cova Da Beira), De Sousa, X (Centro Hospitalar De Set&#250, bal), Fernandes, U, Ferreira, C, Guidi, G, Leal, C, Mar&#231, al, A, Marques, R, Martins, D, Melo, A, Tenreiro, N, Vaz Pereira, R, Vieira B (Centro Hospitalar De Tr&#225, s-Os-Montes, E Alto Douro, E. p. e., ), Almeida, Ji, Correia de S&#225, T, Costa, Mjma, Fernandes, V, Ferraz, I, Gil, Cg, Lima da Silva, C, Lopes, L, Machado, N, Marialva, J, Nunes Coelho, M, Pedro, J, Pereira, C, Reis, R, Ribeiro, A, Santos, R, Saraiva, P, Silva, R, Tavares, F, Teixeira M (Centro Hospitalar Do Tamega, E Sousa), Almeida, Ac, Amaral, Mj, Andrade, R, Athayde Nem&#233, sio, R, Breda, D, Camacho, C, Canhoto, C, Colino, M, Correia, S, Costa, M, De Barros, J, De Oliveira L&#243, pez AL, Duque, M, Garrido, S, Guerreiro, P, Guimar&#227, es, A, L&#225, zaro, A, Lopes, C, Martins, R, Nogueira, O, Oliveira, A, Oliveira, Jm, Rodrigues, M, Ruivo, A, Santos, E, Silva, M, Sim&#245, es, J, Valente da Costa A (Centro Hospitalar, E Universit&#225, rio De Coimbra), Almeida, A, Cavaleiro, S, Devezas, V, Faria, Cs, J&#225, come, F, Magalh&#227, es Maia, M, Nogueiro, J, Pereira, A, Pereira-Neves, A, Pina-Vaz, T, Santos-Sousa, H, Silveira, H, Vaz, S, Vieira P (Centro Hospitalar, E Universit&#225, rio De S&#227, o Jo&#227, Gomes da Costa A, Lobo Antunes I (Centro Hospitalar Lisboa Norte), Pinto J, Tojal A (Centro Hospitalar Tondela-Viseu), Cardoso, N, Cardoso, P, Domingues, Jc, Henriques, P, Manso, Mi, Martins dos Santos, G, Morais, H, Pereira, R, Revez, T, Ribeiro, R, Ribeiro, Vi, Soares, A, Sousa, S, Teixeira J (Centro Hospitalar Universit&#225, rio Do Algarve, - Unidade De Faro), Amorim, E, Baptista, Vh, Cunha, Mf, Dias, B, Fazenda, A, Melo Neves JP, Policarpo, F, Sampaio da N&#243, voa Gomes Miguel II, Veiga D (Centro Hospitalar Universitario Do Algarve, - Unidade De Portim&#227, Andrade, Ak, Bandovas, Jp, Borges, N, Branquinho, A, Chumbinho, B, Correia, J, Fidalgo, H, Figueiredo de Barros, I, Frade, S, Gomes, J, Maciel, J, Pina, S, Rodrigues, A, Silva, N, Silveira Nunes, I, Sousa, R (Centro Hospitalar Universit&#225, rio Lisboa Central), Ascens&#227, o, J, Azevedo, P, Costeira, B, Cunha, C, Garrido, R, Gomes, H, Louren&#231, o, I, Mendinhos, G, Miranda, P, Nobre Pinto, A, Peralta Ferreira, M, Ribeiro, J, Rio Rodrigues, L, Sousa Fernandes, M (Hospital Beatriz Angelo), Azevedo J (Hospital Da Horta, E. p. e. ), Galv&#227, o, D, Soares, Ac, Vieira, A, Vieira, B (Hospital De Santo Espirito Da Ilha Terceira), Patr&#237, cio, B, Santos, Pmdd, Vieira Paiva Lopes AC (Hospital De Torres Vedras, - Centro Hospitalar Do Oeste), Cunha, R, Faustino, A, Freitas, A, Martins, Ab, Mendes, Jr, Parreira, R, Rosa, J, Teves, M (Hospital Do Divino Esp&#237, rito Santo), Abreu da Silva, A, Claro, M, Costa Santos, D, Deus, Ac, Grilo JV (Hospital Do Litoral Alentejano), Borges, F, Corte Real, J, Henriques, S, Lima, Mj, Matos Costa, P (Hospital Garcia De Orta), Brito da Silva, F, Caiado, A, Fonseca, F (Instituto Portugu&#234, s De Oncologia De Lisboa Francisco Gentil), 194, ngelo, M, Baiao, Jm, Martins Jord&#227, Vieira Caro&#231, o, T (Ipo Coimbra), Messias, J, Millan, A, Salgado, I, Santos, P (Ipo Lisboa), Ba&#237, a, C, Canotilho, R, Correia, Am, Ferreira Pinto AP, Peyroteo, M, Puerto Rico: Escobar P, Videira JF (Ipo Porto)., R&#233, union: Kassir R, Maldonado Santiago M (Instituto Gineco Oncologico)., Romania: Bezede C, Sauvat F (Chu Reunion)., Chitul, A, Ciofic, E, Cristian, D, Grama, F (Coltea Clinical Hospital), Pirtea L, Secosan C (Emergency Clinical City Hospital), Bonci, E, Gata, V, Ion Chiricuta Institute Of Oncology), Titu S (Prof. Dr., Ginghina, O, Iordache, N, Russia: Garmanova T, Iosifescu RV (Saint John Emergency Hospital)., Kazachenko, E, Markaryan, D, Rodimov, S, Tsarkov, P, Tulina, I (Clinic Of Coloproctology And Minimally Invasive Surgery, Sechenov Medical State University), Litvina, Y, Provozina, A (Immanuel Kant Baltic Federal University, Regional Clinical Hospital), Agapov, M, Galliamov, E, Kakotkin, V, Kubyshkin, V, 1050, 1072, 1084, 1083, 1086, 1074, &#1040, (Moscow Research And Educational Center, Saudi Arabia: Alshahrani M, Lomonosov Moscow State University)., Alsharif, F, Eskander, M (Aseer Central Hospital), Al Raddadi, R, Majrashi, S, Mashat, A (East Jeddah General Hospital), Akeel, N, Alharthi, M, Aljiffry, M, Basendowah, M, Farsi, A, Ghunaim, M, Khoja, A, Maghrabi, A, Malibary, N, Nassif, M, Nawawi, A, Saleem, A, Samkari, A, Trabulsi, N (King Abdulaziz University Hospital), Al Awwad, S, Alghamdi, M, Alnumani, T, Nasser, M, Said bayazeed, A (King Fahad General Hospital), Alhefdhi, A, Almalik, O, Alomair, A, Alotaibi, N, Alresaini, F, Alsalamah, R, Alsobhi, S, Mahasin, Z, Othman, E, Velagapudi, S (King Faisal Specialist Hospital), Al Habes, H, Alamri, A, Alkarak, S, Alqannas, M, Alyami, M, Alzamanan, M, Cort&#233, s Guiral, D, Elawad, A (King Khalid Hospital), AlAamer, O, Alriyees, L, Alselaim, N (King Saud Bin Abdulaziz University For Health Sciences, King Abdullah International Medical Research Center, Ministry Of National Guard, Health, Affairs, General Surgery Department., ), Abdulkareem, A, Ajlan, A, Akkour, K, Al-Habib, A, Al-Khayal, K, Alatar, A, Alburakan, A, Alhalal, H, Alhassan, B, Alhassan, N, Alobeed, O, Alsaif, A, Alsaif, F, Alshammari, S, Alshaygy, I, Barry, M, Bin Nasser, A, Bin Traiki, T, Bokhari, A, Elwatidy, S, Helmi, H, Madkhali, A, Nouh, T, Rabah, Pd, Serbia: Paunovic I, Zubaidi A (King Saud University)., Slijepcevic, N (Centre For Endocrine Surgery, Clinical Centre Of Serbia), Aleksi&#263, L, Antic, A, Barisic, G, Ceranic, M, Galun, D, Gruba&#269, &#381, Jelenkovic, J, Kecmanovi&#263, Kmezi&#263, Knezevic, D, Krivokapic, Z, Latin&#269, Markovic, V, Mati&#263, Miladinov, M, Pavlov, M, Pejovic, I, Radenkovic, D, Tadic, B, Vasljevi&#263, J, Velickovic, D, Zivanovic, M (Clinic For Digestive Surgery, Perovic M, Srbinovic L (Clinic For Gynecology And Obstetrics Narodni Front), Andrijasevic, S, Bozanovic, T, Cerovic Popovic, R, Dokic, M, Janjic, T, Jeremic, K, Kadija, S, Ladjevic Likic, I, Mirkovic, L, Pantovic, S, Pilic, I, Radojevic, M, Stefanovic, A, Vidakovic, S, Vilendecic, Z (Clinic For Gynecology And Obstetrics, Clinical Center Of Serbia), Antic, S, Dun&#273, erovi&#263, Jelovac, D, Jezdic, Z, Konstantinovic, V, Kotlar, B, Kuzmanovic, C, Lazi&#263, Petrovic, M, Popovic, F, Pucar, A, Romic, M, Sumrak, S, Vujanac, V (Clinic For Maxillofacial Surgery, School Of Dental Medicine, University Of Belgrade), Bascarevic, V, Bogdanovi&#263, I, Gruji&#269, Ilic, R, Mili&#263, evi&#263, Milisavljevi&#263, F, Miljkovi&#263, Paunovic, A, 352, 263, epanovi&#263, V, Stanimirovic, A, Todorovic, M (Clinic For Neurosurgery, Jotic, A, Milovanovic, J, Trivic, A (Clinic For Otorhinolaryngology And Maxillofacial Surgery, Bumbasirevic, U, Dzamic, Z, Kajmakovi&#263, B, Prijovi&#263, N, Zivkovic, M (Clinic Of Urology, Buta, M, Cvetkovic, A, Djurisic, I, Gacic, S, Goran, M, Inic, Z, Jeftic, N, Jevric, M, Jokic, V, Markovic, I, Milanovi&#263, Nikolic, S, Pejnovic, L, Savkovi&#263, Spurnic, I, Stevic, D, Stojiljkovic, D, Vucic, N, Zegarac, M (Institute For Oncology And Radiology Of Serbia), Karamarkovic, A, Kenic, M, Kovacevic, B, Krdzic, I, Singapore: Chan CW, Milutinovi&#263, V (Zvezdara University Medical Center)., Slovakia: G&#225, lis B, Lieske B (National University Hospital)., South Africa: Almgla N, &#352, imko K (University Hospital Bratislava)., Bernon, M, Boutall, A, Cairncross, L, Herman, A, Hilton, T, Jonas, E, Kloppers, C, Malherbe, F, Mugla, W, Nel, D, Rayamajhi, S, Van Wyngaard, T, Spain: Casta&#241, o-Leon AM, Vogel J (Groote Schuur Hospital)., Delgado Fernandez, J, Eiriz Fernandez, C, Espino Segura-Illa, M, Esteban Sinovas, O, Garcia Perez, D, Gomez, P, Jimenez-Roldan, L, Lagares, A, Moreno- Gomez, L, Paredes, I, P&#233, rez N&#250, 241, ez, A, S&#225, nchez Aniceto, G, Santas, M (12 De Octubre University Hospital), Fern&#225, ndez Rodr&#237, guez, P, Paniagua Garc&#237, a Se&#241, orans, M, Sanchez- Santos, R, Vigorita, V (&#193, lvaro Cunqueiro Hospital), Acrich, E, Baena Sanfeliu, E, Barrios, O, Golda, T, Santanach, C, Serrano-Navidad, M, Sorribas Grifell, M, Vives RV (Bellvitge University Hospital), Escol&#224, D, Jim&#233, nez A (Comarcal Alt Pened&#233, Cayetano Paniagua L, G&#243, mez Fern&#225, ndez L (Consorci Sanitari De Terrassa), Artigues, E, Bernal-Sprekelsen, Jc, Catal&#225, Bauset JC (Consorcio Hospital General Universitario), Collera, P, Diaz Del Gobbo, R, Farre Font, R, Flores Clotet, R, mez D&#237, az CJ, Gu&#224, rdia, N, Guariglia, Ca, Osorio, A, Sanchez Jimenez, R, Sanchon, L, Soto Montesinos C (Fundaci&#243, Althaia, - Xarxa Assistencial Universit&#224, ria De Manresa), Albi Martin B, Garc&#237, a Villayz&#225, n JE (Fundaci&#243, n Jimenez Diaz University Hospital), Alonso-Lamberti, L, Assaf, M, Baeza Pintado, N, Carabias, A, a-Quijada, J, Huertas Fernandez MA, Jimenez Miram&#243, n, J, Jimenez, V, Jover, Jm, Landeo Ag&#252, ero SA, Leon, R, Mart&#237, n Salamanca MB, rez Sim&#243, n, V, Ponce, S, Rodriguez, Jl, Salazar, A, Valle Rubio, A (Getafe University Hospital), Aguado, H (Hell&#237, n Hospital), Aldecoa Ansorregui, I, Bravo Infante, R, De Lacy FB, Di Somma, A, D&#237, az-Feijoo, B, Ense&#241, at Nora, J, Fabregas, N, Ferr&#233, s, A, Gil Iba&#241, ez, B, Gonzalez Sanchez JJ, Gracia, I, Hoyos Castro JA, Lacy, Am, Langdon, C, Mombl&#225, n, D, Morales, X, Oleaga, L, Otero, A, Pedrosa, L, Poblete Carrizo, J, Reyes Figueroa LA, Roldan Ramos, P, Rumia-Arboix, J, Tercero-Uribe, Ai, Topczewski, Te, Torales, J, Torne, A, Torn&#233, R, Turrado-Rodriguez, V, Valero, R, Valverde, S (Hospital Clinic Barcelona), Anula, R, Cano-Valderrama, O, Del Campo Mart&#237, n, M, ez-Valladares, L, Dom&#237, nguez, I, Dziakova, J, a Alonso, M, a Romero, E, mez Latorre, L, Muguerza, Jm, Pizarro, Mj, Saez Carlin, P, nchez del Pueblo, C, nchez-Pernaute, A, Sanz Ortega, G, Sanz-Lopez, R, Torres, A (Hospital Cl&#237, nico De Madrid), Garc&#233, s-Albir, M, Lopez, F, n-Ar&#233, valo, J, Moro-Valdezate, D, Pla-Marti, V (Hospital Cl&#237, nico Universitario De Valencia), Beltr&#225, n de Heredia, J, De Andr&#233, s Asenjo, B, mez Sanz, T, Jezieniecki, C, Nu&#241, ez Del Barrio, H, Ortiz de Sol&#243, rzano Aurusa FJ, Romero de Diego, A, Ruiz Soriano, M, Trujillo D&#237, az, J, Vazquez fernandez, A (Hospital Cl&#237, nico Universitario De Valladolid), Lora-Cumplido P, Sosa MV (Hospital De Cabue&#241, es), Gonzalez-Gonzalez E, Minaya Bravo AM (Hospital Del Henares), Alonso de la Fuente, N, Cazador Labat, M, Cecchini, L, Espinosa, Ca, Jimenez Toscano, M, L&#243, pez Campillo, A, Mancebo, G, Martorell, P, Munarriz, M (Hospital Del Mar), Grau-Talens EJ, Martin-Perez B (Hospital Don Benito-Villanueva), Benavides Buleje JA, Carrasco Prats, M, ndez, Pv, ndez-L&#243, pez, A, a Escudero, D, a Porcel VJ, Garcia Soria, V, Gim&#233, nez Franc&#233, s, C, Gonz&#225, lez Valverde FM, Gurrea, E, pez-Morales, P, Marco Garrido, A, nez Alonso JA, Medina, E, Mu&#241, oz Camarena JM, Parra Ba&#241, os PA, a Ros, E, Ramirez Faraco, M, Ruiz-Mar&#237, Sanchez Rodriguez, C, Valero Soriano, M (Hospital General Reina Sof&#237, Estaire G&#243, mez, M, ndez Camu&#241, as, &#193, Garcia Santos EP, Jimenez Higuera, E, nez-Pinedo, C, oz-Atienza, V, Padilla-Valverde, D, Pic&#243, n Rodr&#237, guez, R, Redondo Calvo FJ, nchez-Garc&#237, a, S, Sanchez-Pelaez, D (Hospital General Universitario De Ciudad Real), Colombari, Rc, Del valle, E, ndez, M, Lozano Lominchar, P, n, L, Rey Valcarcel, C, Steiner, Ma, Tudela, M, Zorrilla Ort&#250, zar, J (Hospital General Universitario Gregorio Mara&#241, 243, Alcaide Matas, F, a P&#233, rez JM, Troncoso Pereira, P (Hospital Mateu Orfila), Mora-Guzm&#225, n, I (Hospital Santa B&#225, rbara), Abell&#225, Achalandabaso Boira, M, Jorba, R, Memba Ikuga, R, Olona, C, Sales Mallafr&#233, R (Hospital Universitari De Tarragona Joan Xxiii), Cavall&#233, Busquets, P, Gavalda Pellice MGP, Salinas Pe&#241, a, J (Hospital Universitari Sant Joan), Aragon Achig EJ, Barbier, L, Caja Vivancos, P, Gainza, A, a Gutierrez JJ, Mallabiabarrena Ormaechea, G, Mar&#237, n, H, Martin Playa, P, Melchor Corc&#243, stegui, I, Prieto Calvo, M, Rodriguez Fraga, A, Villalabeitia Ateca, I (Hospital Universitario Cruces), De Andres Olabarria, U, Dur&#225, n Ballesteros, M, ndez Pablos FJ, Ib&#225, ez-Aguirre, Fj, Sanz Larrainzar, A, Ugarte-Sierra, B (Hospital Universitario De Galdakao), De la Hoz Rodr&#237, guez, &#193, Di Martino, M, a Septiem, J, Martin-Perez, E, oz de Nova JL (Hospital Universitario De La Princesa), Calvo Espino P, Guillamot Ruano P (Hospital Universitario De M&#243, stoles), Colao Garc&#237, a, L, az P&#233, rez, D, Esteban Agust&#237, E, Galindo Jara, P, Gutierrez Samaniego, M, Hernandez Bartolome MA, Serrano Gonz&#225, lez, J (Hospital Universitario De Torrej&#243, n De Ardoz), Alonso Poza, A, Di&#233, guez, B, a-Conde, M, Hern&#225, ndez-Garc&#237, a, M, Losada, M (Hospital Universitario Del Sureste), Chiesa-Estomba, Cm, lez Garc&#237, a J&#193, Larruscain, E, Sistiaga-Su&#225, rez JA (Hospital Universitario Donostia), Alvarez, E, Chavarrias, N, Fr&#237, as, L, a Pineda, V, Geg&#250, ndez Sim&#243, n, A, Gort&#225, zar, S, Gracia, M, Guevara, J, ndez Gutierrez, A, Loayza, A, a Dolores DT, C, Melendez, M, Moreno-Palacios, E, Perez, Y, Prieto Nieto MI, Ramos- Mart&#237, n, P, Rubio-Perez, I, Saavedra, J, Sanchez-Mendez, Ji, Siegrist Ridruejo, J, Urbieta, A, Zapardiel, I (Hospital Universitario La Paz), Cantalejo diaz, M, De Miguel Ardevines MDC, Duque-Mall&#233, Gascon Ferrer, I, lez-Nicol&#225, s Tr&#233, bol MT, Gracia-Roche, C, Herrero Lopez, M, Jariod Ferrer UM, Lanzon, A, Martinez German, A, Matute, M, Redondo, C, nchez Fuentes, N, nchez-Rubio, M, Santero-Ramirez, Ms, Saud&#237, Sim&#243, n Sanz MV, Uson-Bouthelier, T (Hospital Universitario Miguel Servet), Blazquez Martin, A, Diez Alonso, M, a Rico, E, Garcia-Loarte Gomez, E, Garcia-Moreno Nisa, F, Gutierrez Calvo, A, Hernandez, P, Lasa, I, Mendoza-Moreno, F, Morales Palacios, N, Ovejero Merino, E, Vera Mansilla, C (Hospital Universitario Principe De Asturias), Acebes Garc&#237, a, F, Bail&#243, Bueno Ca&#241, ones AD, Choolani Bhojwani, E, Marcos-Santos, P, Miguel, T, Pacheco S&#225, nchez, D, rez-Saborido, B, Sanchez Gonzalez, J, Tejero-Pintor FJ (Hospital Universitario R&#237, o Hortega), Alconchel, F, Conesa, A, Gil Mart&#237, nez, J, Guti&#233, rrez Fern&#225, ndez AI, Lopez Abad, A, Nicol&#225, s-L&#243, pez, T, Ramirez Romero, P, Roca Calvo MJ, Rodrigues, K, Ruiz Manzanera JJ, Soriano AI (Hospital Universitario Virgen De La Arrixaca), Cano, A, Capitan-Morales, L, Cintas Catena, J, Gomez-Rosado, J, Oliva Mompean, F, rez S&#225, nchez MA, R&#237, o Lafuente FD, Torres Arcos, C, Valdes-Hernandez, J (Hospital Universitario Virgen Macarena), Cholewa, H, Domingo, S, Frasson, M, Lago, V, Marina Martin, T, nez Chicote, C, Sancho-Muriel J (Hospital Universitario, Y Polit&#233, cnico La Fe), Landaluce-olavarria A, Lecumberri D (Hospital Urduliz), Abad Gurumeta, A, Abad-Motos, A, nez-Hurtado, E, Ripoll&#233, s-Melchor, J, Ruiz Escobar, A (Infanta Leonor University Hospital), Cuadrado- Garc&#237, a, A, Garcia-Sancho Tellez, L, Heras Aznar, J, Mat&#233, P, Ortega V&#225, zquez, I, Picardo, Al, Rojo L&#243, pez JA, Sanchez Cabezudo Noguera, F, Serralta de Colsa, D (Infanta Sof&#237, a University Hospital), Anchuelo Latorre, J, Cagigas Fernandez, C, Cai&#241, a Ruiz, R, Gomez Ruiz, M, Hernanz, F, Jimeno Fraile, J, nez-P&#233, rez, P, Poch, C, Santarrufina Martinez, S, Valbuena Jabares, V (Marqu&#233, s De Valdecilla University Hospital), Moliner-S&#225, nchez, C, Pingarron-Martin, L, Rey-Biel, J, Ruiz Martin, I (Rey Juan Carlos University Hospital), Blas Laina JL, Cros, B, Escartin, J, Garcia Egea, J, Nogu&#233, Talal El-Abur, I, Y&#225, nez, C (Royo Villanova), Cagigal Ortega EP, Cervera, I, az Pe&#241, a, P, Elena, Gdcr, Enjuto, D, ndez Bernab&#233, s Garc&#237, a, R, Gonzalez, J, ndez, I, Herrera-Merino, N, Marqueta De Salas, M, Martinez Pascual, P, Perez Gonzalez, M, Ramos Bonilla, A, Rodr&#237, guez G&#243, mez, L (Severo Ochoa University Hospital), Besc&#243, Blanco-Colino, R, Brana, I, Caimari, B, De Pablo Garc&#237, a-Cuenca, A, Duran-Valles, F, Espin-Basany, E, Giralt L&#243, pez de Sagredo, J, Pamias, J, Pellino, G, Prat, N, Pujol Pina, R, Sri Lanka: Arulanantham A, Saez barba M (Vall D&#8217, hebron University Hospital)., Bandara, Gbk, Jayarajah, U, Ravindrakumar, S, Rodrigo VS (District General Hospital Chilaw), Srishankar S (Teaching Hospital Anuradhapura). Sudan: Ali karar AA (Al-Rajhi). Sweden: Elbe P, Lindqvist EK (Karolinska University Hospital), Taflin, H (Sahlgrenska University Hospital), 196, lg&#229, Heinius, G, Nordberg, M, Pieniowski, E (South General Hospital), Gkekas, I, fgren, N, Ruteg&#229, rd, M, Switzerland: Arigoni M, Sund M (Umea University Hospital)., Bernasconi, M, Christoforidis, D, Di Giuseppe, M, La Regina, D, Mongelli, F (Ente Ospedaliero Cantonale), Chevallay, M, Dwidar, O, Gialamas, E, Sauvain, M (Hopital De Pourtales), Klenke, F, Koll&#224, r, A, Kurze, C (Inselspital, Bern University Hospital, University Of Bern), Adamina, M, B&#228, chler, T, Crugnale, As, Giardini, M, Guglielmetti, L, Peros, G, Turkey: Aghayeva A, Solimene F (Kantonsspital Winterthur)., Hamzaoglu, I, Sahin, I (Acibadem Altunizade Hospital), Akaydin, E, Aliyeva, Z, Aytac, E, Baca, B, D&#252, lgero&#287, lu, O, Ozben, V, Ozmen, Bb, Uras, C (Acibadem Atakent Hospital), Arikan, Ae, Bilgin, Ia, Bozk&#305, rl&#305, Ceyhan, Go, Kara, H, Karahasano&#287, lu, T, Uras, C (Acibadem Maslak Hospital), Celik, H (Adana Baskent University), Meydanli MM (Ankara City Hospital), Akilli, H, Ayhan, A, Kuscu, E (Baskent University), Onan MA (Gazi University Medical Faculty Hospital), Akgor, U, Dincer, Ha, Erol, T, Gultekin, M, Orhan, N, Ozgul, N, Salman, Mc, Soyak, B (Hacettepe University Hospital), Alhamed, A, Erg&#252, n, S, OZcel&#305, k, Mf, Sanli, An, Uluda&#287, Velidedeoglu, M, Zengin AK (Istanbul Universty, - Cerrahpa&#351, a Medical Faculty), Bozkurt, Ma, Kara, Y, Kocata&#351, A (Kanuni Sultan Suleyman Training And Research Hospital), Cimenoglu, B, Demirhan, R, Lutfi Kirdar Training And Research Hospital), Saracoglu K (Kartal Dr., Azamat, I&#775, f, Balik, E, Bu&#287, ra, D, Giray, B, Kulle, Cb, Taskiran, C, Vatansever, D (Ko&#231, University Medical School), G&#246, zal, K, G&#252, ler, Sa, ken, H, Tatar, Oc, Utkan, Nz, Y&#305, ld&#305, r&#305, m, A, Y&#252, ksel, E (Kocaeli University Teaching Hospital), Akin, E, Altintoprak, F, Bayhan, Z, Cakmak, G, 199, apo&#287, lu, R, elebi, F, Demir, H, Dikicier, E, Firat, N, n&#252, ll&#252, Kamburo&#287, lu, Mb, Kocer, B, 231, 252, k, If, Mantoglu, B (Sakarya University Faculty Of Medicine), olak, E, Kucuk, Go, Uyanik MS (Samsun Training And Research Hospital), 304, lhan Varank Training And Research Hospital), G&#246, ksoy B (Sehit Prof. dr., Bozkurt, E, Citgez, B, Mihmanli, M, Tanal, M, Yetkin, G (Sisli Hamidiye Etfal Training And Research Hospital), Akalin, M, Arican, C, Avci, Ek, Aydin, C, Demirli At&#305, c&#305, Emiroglu, M, Kaya, T, Kebab&#231, 305, Kilinc, G, Kirmizi, Y, 287, c&#252, H, Salimo&#287, lu, S, Sert, I&#775, Tugmen, C, Tuncer, K, Uslu, G, Ye&#351, ilyurt, D (University Of Health Sciences Tepecik Training And Research Hospital), Karaman, E, Kolusar&#305, A (Van Yuzuncu Yil University, Medical, Faculty), Uganda: Benson O, Yildiz A (Yildirim Beyazit University Yenimahalle Training And Research Hospital)., United Kingdom: Agilinko J, Lule H (Kampala International University Teaching Hospital)., Ahmeidat, A, Barabasz, M, Bekheit, M, Cheung, Lk, Colloc, T, Cymes, W, Elhusseini, M, Gradinariu, G, Hannah, A, Kamera, Bs, Mignot, G, Shaikh, S, Sharma, P (Aberdeen Royal Infirmary), Abu-Nayla, I, Agrawal, A, Al-Mohammad, A, Ali, S, Ashcroft, J, Azizi, A, Baker, O, Balakrishnan, A, Byrne, M, Colquhoun, A, Cotter, A, Coughlin, P, Davies, Rj, Durrani, A, Elshaer, M, Fordington, S, Forouhi, P, Georgiades, F, Grimes, H, Habeeb, A, Hudson, V, Hutchinson, P, Irune, E, Jah, A, Khan, Dz, Kolias, A, Kyriacou, H, Lamb, B, Liau, S, Luke, L, Mahmoud, R, Mannion, R, Masterson, L, Mitrofan, Cg, Mohan, M, Morris, A, Murphy, S, Neill, R, Price, S, Pushpa-rajah, J, Raby-Smith, W, Ramzi, J, Rooney, S, Santarius, T, Singh, A, Stewart, Gd, Tan, Xs, Townson, A, Tweedle, E, Walker, C, Waseem, S, Yordanov, S (Addenbrooke&#8217, Jones, T, Kattakayam, A, Loh, C, Lunevicius, R, Pringle, S, Schache, A, Shaw, R, Sheel, A (Aintree University Hospital), Rossborough, C (Altnagelvin Area Hospital), Angelou, D, Choynowski, M, McAree, B, McCanny, A, Neely, D (Antrim Area Hospital- Northern Health And Social Care Trust), Tutoveanu, G (Barnsley Hospital Nhs Foundation Trust), Ahad, S, De La Cruz Monroy MFI, Mosley, F, Oktseloglou, V (Bradford Royal Infirmary), Alanbuki, A, Patel, M, Shabana, A (Brighton And Sussex Nhs Trust, Princess Royal Hospital), Perera, E, Raveendran, D, Ravi- Shankar, K, Thiruchelvam, J (Broomfield Hospital), Arrowsmith L, Campbell W (Causeway Hospital), Grove, T, Kontovounisios, C, Warren, O (Chelsea And Westminster Hospital), Rolland, P (Cheltenham General Hospital), Aggarwal, A, Brown, S, Jelley, C, Neal, N (Churchill Hospital), Clifford, R, Eardley, N, Krishnan, E, Manu, N, Martin, E, Roy Mahapatra, S, Serevina, Ol, Smith, C, Vimalachandran, D (Countess Of Chester Hospital), Bordenave, M, Houston, R, Putnam, G, Robson, A, Tustin, H (Cumberland Infirmary), Emslie, K, Labib, Pl, Marchbank, A, Miller, D, Minto, G, Natale, J, Nwinee, H, Panahi, P, Rogers, L (Derriford Hospital), Abubakar, A, Akhter Rahman MM, Kyk, Ko, Brien, H, Sasapu, K, Woodun, H (Diana Princess Of Wales Hospital Grimsby), Inglis R, Ng HJ (Dumfries And Galloway Royal Infirmary), De Gea Rico, A, Ghazali, N, Lambert, J, Markose, G, Math, S, Sarantitis, I, Shrestha, D, Sultana, A, Taggarsi, M, Timbrell, S, Vaz, Op, Vitone, L (East Lancashire Hospitals Nhs Trust), Day, A, Dent, H, Fahim, M, Waheed, S (East Surrey Hospital), Hunt A, Laskar N (East Sussex Healthcare (Conquest Hospital And Eastbourne District General Hospital)), Gupta, A, Steinke, J, Thrumurthy, S (Epsom &amp, St Helier University Hospitals Nhs Trust), Massie, E, McGivern, K, Rutherford, D, Wilson, M (Forth Valley Royal Hospital), Hardie J, Kazzaz S (Frimley Health Nhs Ft - Frimley Park), Handa, S, Kaushal, M, Kler, A, Patel, P, Redfern, J, Tezas, S (Furness General Hospital), Aawsaj, Y, Amonkar, S, Blackwell, L, Blake, D, Carter, J, Emerson, H, Fisher, A, Katory, M, Korompelis, P, McCormick, W, Mustafa, A, Pearce, L, Ratnavelu, N, Reehal, R (Gateshead Health Nhs Foundation Trust), Kretzmer, L, Lalou, L, Manku, B, Parwaiz, I, Stafford, J (George Eliot Hospital), Abdelkarim, M, Asqalan, A, Gala, T, Ibrahim, S, Maw, A, Mithany, R, Morgan, R, Sundaram Venkatesan, G (Glan Clwyd Hospital), Ang, K, Caruana, Ej, Chowdhry, Mf, Mohammad, A, Nakas, A, Rathinam, S (Glenfield Hospital), Boal, M, Brown, O, Dwerryhouse, S, Higgs, S, Vallance, A (Gloucestershire Royal Hospital), Boyd, E, Irvine, V, Kirk, A (Golden Jubilee National Hospital), Bakolas, G, Boulton, A, Chandock, A, Khan, T, Kumar, M (Good Hope Hospital), Agoston, P, Bill&#232, Challacombe, B, Fraser, S, Harrison-Phipps, K, King, J, Mehra, G, Mills, L, Najdy, M, Nath, R, Okiror, L, Pilling, J, Rizzo, V, Routledge, T, Sayasneh, A, Stroman, L, Wali, A (Guy&#8217, Fehervari, M, Fotopoulou, C, Habib, N, Hamrang-Yousefi, S, Jawad, Z, Jiao, L, Pai, M, Ploski, J, Rajagopal, P, Saso, S, Sodergren, M, Spalding, D (Hammersmith Hospital), Laws, S (Hampshire Hospitals Nhs Trust), Hardie C, McNaught C (Harrogate District Hospital), Alam, R, Budacan, A, Cahill, J, Kalkat, M, Karandikar, S, Kenyon, L, Naumann, D, Patel, A (Heartlands Hospital), Ayorinde, J, Chase, T, Cuming, T, Ghanbari, A, Humphreys, L, Tayeh, S (Homerton University Hospital), Aboelkassem Ibrahim, A, Bichoo, R, Cao, H, Chai, Akw, Choudhury, J, Evans, C, Fitzjohn, H, Ikram, H, Langstroth, M, Loubani, M, McMillan, A, Nazir, S, Qadri, Ssa, Robinson, A, Ross, E, Sehgal, T, Wilkins, A (Hull University Teaching Hospitals Nhs Trust), Dixon, J, Dunning, J, Freystaetter, K, Jha, M, Lester, S, Madhavan, A, Thulasiraman, Sv, Viswanath, Y (James Cook University Hospital), Curl-Roper, T, Delimpalta, C, Liao, Ccl, Velchuru, V, Westwood, E (James Paget Univeristy Nhs Foundation Trust Hospital), Belcher, E, Bond-Smith, G, Chidambaram, S, Di Chiara, F, Fasanmade, K, Fraser, L, Fu, H, Ganau, M, Gore, S, Graystone, J, Jeyaretna, D, Khatkar, H, Lami, M, Maher, M, Mastoridis, 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H., Beyrne, C., Jouffret, L., Lugans, L., Marie-Macron, L., Chouillard, E., De Simone, B., Bettoni, J., Dakpe, S., Devauchelle, B., Lavagen, N., Testelin, S., Boucher, S., Breheret, R., Gueutier, A., Kahn, A., Kun-Darbois, J., Barrabe, A., Lakkis, Z., Louvrier, A., Manfredelli, S., Mathieu, P., Chebaro, A., Drubay, V., El amrani, M., Eveno, C., Lecolle, K., Legault, G., Martin, L., Piessen, G., Pruvot, F. R., Truant, S., Zerbib, P., Ballouhey, Q., Barrat, B., Laloze, J., Salle, H., Taibi, A., Usseglio, J., Bergeat, D., Merdrignac, A., Le Roy, B., Perotto, L. O., Scalabre, A., Aime, A., Ezanno, A., Malgras, B., Bouche, P., Tzedakis, S., Cotte, E., Glehen, O., Kepenekian, V., Lifante, J., Passot, G., D'Urso, A., Felli, E., Mutter, D., Pessaux, P., Seeliger, B., Bardet, J., Berry, R., Boddaert, G., Bonnet, S., Brian, E., Denet, C., Fuks, D., Gossot, D., Grigoroiu, M., Laforest, A., Levy-Zauberman, Y., Louis-Sylvestre, C., Moumen, A., Pourcher, G., Seguin-Givelet, A., Tribillon, E., Duchalais, E., Espitalier, F., Ferron, C., Malard, O., Bork, U., Distler, M., Fritzmann, J., Kirchberg, J., Praetorius, C., Riediger, C., Weitz, J., Welsch, T., Wimberger, P., Beyer, K., Kamphues, C., Lauscher, J., Loch, F. N., Schineis, C., Albertsmeier, M., Angele, M., Kappenberger, A., Niess, H., Schiergens, T., Werner, J., Becker, R., Jonescheit, J., Pergolini, I., Reim, D., Boeker, C., Hakami, I., Mall, J., Liokatis, P., Smolka, W., Nowak, K., Reinhard, T., Holzle, F., Modabber, A., Winnand, P., Knitschke, M., Kauffmann, P., Wolfer, S., Kleeff, J., Lorenz, K., Michalski, C., Ronellenfitsch, U., Schneider, R., Bertolani, E., Konigsrainer, A., Loffler, M. W., Quante, M., Steidle, C., Uberruck, L., Yurttas, C., Betz, C. S., Bewarder, J., Bottcher, A., Burg, S., Busch, C., Gosau, M., Heuer, A., Izbicki, J., Klatte, T. O., Koenig, D., Moeckelmann, N., Nitschke, C., Priemel, M., Smeets, R., Speth, U., Thole, S., Uzunoglu, F. G., Vollkommer, T., Zeller, N., Battista, M. J., Gillen, K., Hasenburg, A., Krajnak, S., Linz, V., Schwab, R., Angelou, K., Haidopoulos, D., Rodolakis, A., Antonakis, P., Bramis, K., Chardalias, L., Contis, I., Dafnios, N., Dellaportas, D., Fragulidis, G., Gklavas, A., Konstadoulakis, M., Memos, N., Papaconstantinou, I., Polydorou, A., Theodosopoulos, T., Vezakis, A., Antonopoulou, M. I., Manatakis, D. K., Tasis, N., Arkadopoulos, N., Danias, N., Economopoulou, P., Kokoropoulos, P., Larentzakis, A., Michalopoulos, N., Selmani, J., Sidiropoulos, T., Tsaousis, V., Vassiliu, P., Bouchagier, K., Klimopoulos, S., Paspaliari, D., Stylianidis, G., Baxevanidou, K., Bouliaris, K., Chatzikomnitsa, P., Efthimiou, M., Giaglaras, A., Kalfountzos, C., Koukoulis, G., Ntziovara, A. M., Petropoulos, K., Soulikia, K., Tsiamalou, I., Zervas, K., Zourntou, S., Baloyiannis, I., Diamantis, A., Gkrinia, E., Hajiioannou, J., Korais, C., Koukoura, O., Perivoliotis, K., Saratziotis, A., Skoulakis, C., Symeonidis, D., Tepetes, K., Tzovaras, G., Zacharoulis, D., Alexoudi, V., Antoniades, K., Astreidis, I., Christidis, P., Deligiannidis, D., Grivas, T., Ioannidis, O., Kalaitsidou, I., Loutzidou, L., Mantevas, A., Michailidou, D., Paraskevopoulos, K., Politis, S., Stavroglou, A., Tatsis, D., Tilaveridis, I., Vahtsevanos, K., Venetis, G., Karaitianos, I., Tsirlis, T., Charalabopoulos, A., Liakakos, T., Mpaili, E., Schizas, D., Spartalis, E., Syllaios, A., Zografos, C., Anthoulakis, C., Christou, C., Papadopoulos, V., Tooulias, A., Tsolakidis, D., Tsoulfas, G., Zouzoulas, D., Athanasakis, E., Chrysos, E., Tsiaoussis, J., Xenaki, S., Xynos, E., Futaba, K., Ho, M. F., Hon, S. F., Mak, T. W. C., Ng, S. S. M., Foo, C. C., Banky, B., Susztak, N., Aremu, M., Canas-Martinez, A., Cullivan, O., Murphy, C., Owens, P., Pickett, L., Akmenkalne, L., Byrne, J., Corrigan, M., Cullinane, C., Daly, A., Fleming, C., Jordan, P., Killeen, S., Lynch, N., Mccarthy, A., Mustafa, H., O'Brien, S., O'Leary, P., Syed, W. A. S., Vernon, L., Callanan, D., Huang, L., Ionescu, A., Sheahan, P., Balasubramanian, I., Boland, M., Conlon, K., Evoy, D., Fearon, N., Gallagher, T., Geraghty, J., Heneghan, H., Kennedy, N., Maguire, D., Mccartan, D., Mcdermott, E. W., Prichard, R. S., Winter, D., Alazawi, D., Barry, C., Boyle, T., Butt, W., Connolly, E. M., Donlon, N., Donohue, C., Fahey, B. A., Farrell, R., Fitzgerald, C., Kinsella, J., Larkin, J. O., Lennon, P., Maguire, P. J., Mccormick, P., Mehigan, B. J., Nugent, T., O'Sullivan, H., Ravi, N., Reynolds, J. V., Rogers, A., Shokuhi, P., Smith, J., Smith, L. A., Timon, C., Bashir, Y., Bass, G., Connelly, T., Creavin, B., Earley, H., Elliott, J. A., Gillis, A., Kavanagh, D., Neary, P., O'Riordan, J., Reynolds, I. S., Rice, D., Ridgway, P., Umair, M., Whelan, M., Carroll, P., Collins, C., Corless, K., Finnegan, L., Fowler, A., Hogan, A., Kerin, M., Lowery, A., Mcanena, P., Mckevitt, K., Nizami, K., Ryan, E., Samy, A., Coffey, J. C., Cunningham, R., Devine, M., Nally, D., Peirce, C., Tormey, S., Hardy, N., O'Malley, S., Ryan, M., Macina, S., Mariani, N. M., Opocher, E., Pisani Ceretti, A., Ferrari, F., Odicino, F., Sartori, E., Cotsoglou, C., Granieri, S., Bianco, F., Camillo, A., Colledan, M., Tornese, S., Zambelli, M. F., Bissolotti, G., Fusetti, S., Lemma, F., Marino, M. V., Mirabella, A., Vaccarella, G., Agostini, C., Alemanno, G., Bartolini, I., Bergamini, C., Bruscino, A., Checcucci, C., De Vincenti, R., Di Bella, A., Fambrini, M., Fortuna, L., Maltinti, G., Muiesan, P., Petraglia, F., Prosperi, P., Ringressi, M. N., Risaliti, M., Sorbi, F., Taddei, A., Tucci, R., Bassi, C., Bortolasi, L., Campagnaro, T., Casetti, L., De Pastena, M., Esposito, A., Fontana, M., Guglielmi, A., Landoni, L., Malleo, G., Marchegiani, G., Nobile, S., Paiella, S., Pedrazzani, C., Rattizzato, S., Ruzzenente, A., Salvia, R., Turri, G., Tuveri, M., Bellora, P., D'Aloisio, G., Ferrari, M., Francone, E., Gentilli, S., Nikaj, H., Bianchini, M., Chiarugi, M., Coccolini, F., Di Franco, G., Furbetta, N., Gianardi, D., Guadagni, S., Morelli, L., Palmeri, M., Tartaglia, D., Anania, G., Carcoforo, P., Chiozza, M., De Troia, A., Koleva Radica, M., Portinari, M., Sibilla, M. G., Urbani, A., Fabbri, N., Feo, C. V., Gennari, S., Parini, S., Righini, E., Ampollini, L., Bellanti, L., Bergonzani, M., Bertoli, G., Bocchialini, G., D'Angelo, G., Lanfranco, D., Musini, L., Poli, T., Santoro, G. P., Varazzani, A., Aguzzoli, L., Borgonovo, G., Castro Ruiz, C., Coiro, S., Falco, G., Mandato, V. D., Mastrofilippo, V., Montella, M. T., Annessi, V., Zizzo, M., Grossi, U., Novello, S., Romano, M., Rossi, S., Zanus, G., Esposito, G., Frongia, F., Pisanu, A., Podda, M., Belluco, C., Lauretta, A., Montori, G., Moras, L., Olivieri, M., Bussu, F., Carta, A. G., Cossu, M. L., Cottu, P., Fancellu, A., Feo, C. F., Ginesu, G. C., Giuliani, G., Madonia, M., Perra, T., Piras, A., Porcu, A., Rizzo, D., Scanu, A. M., Tedde, A., Tedde, M., Delrio, P., Rega, D., Badalamenti, G., Campisi, G., Cordova, A., Franza, M., Maniaci, G., Rinaldi, G., Toia, F., Calabro, M., Farnesi, F., Lunghi, E. G., Muratore, A., Pipitone Federico, N. S., Bambina, F., D'Andrea, G., Familiari, P., Picotti, V., De Palma, G., Luglio, G., Pagano, G., Tropeano, F. P., Baldari, L., Beltramini, G. A., Boni, L., Cassinotti, E., Gianni, A., Pignataro, L., Torretta, S., Abatini, C., Baia, M., Biasoni, D., Bogani, G., Cadenelli, P., Cioffi, S. P. B., Citterio, D., Comini, L. V., Cosimelli, M., Folli, S., Gennaro, M., Giannini, L., Gronchi, A., Guaglio, M., Macchi, A., Martinelli, F., Mazzaferro, V., Mosca, A., Pasquali, S., Piazza, C., Raspagliesi, F., Rolli, L., Salvioni, R., Sarpietro, G., Sarre, C., Sorrentino, L., Agnes, A., Alfieri, S., Belia, F., Biondi, A., Cozza, V., D'Amore, A., D'Ugo, D., De Simone, V., Fagotti, A., Gasparini, G., Gordini, L., Litta, F., Lombardi, C. P., Lorenzon, L., Marra, A. A., Marzi, F., Moro, A., Parello, A., Perrone, E., Persiani, R., Ratto, C., Rosa, F., Saponaro, G., Scambia, G., Scrima, O., Sganga, G., Tudisco, R., Belli, A., Granata, V., Izzo, F., Palaia, R., Patrone, R., Carrano, F. M., Carvello, M. M., De Virgilio, A., Di Candido, F., Ferreli, F., Gaino, F., Mercante, G., Rossi, V., Spinelli, A., Spriano, G., Donati, D. M., Frisoni, T., Palmerini, E., Aprile, A., Barra, F., Batistotti, P., Ferrero, S., Fregatti, P., Scabini, S., Sparavigna, M., Asti, E., Bernardi, D., Bonavina, L., Lovece, A., Adamoli, L., Ansarin, M., Cenciarelli, S., Chu, F., De Berardinis, R., Fumagalli Romario, U., Mastrilli, F., Pietrobon, G., Tagliabue, M., Badellino, E., Ferrero, A., Massobrio, R., De Manzoni Garberini, A., Federico, P., Maida, P., Marra, E., Marte, G., Petrillo, A., Tammaro, T., Tufo, A., Berselli, M., Borroni, G., Cocozza, E., Conti, L., Desio, M., Livraghi, L., Quintodei, V., Rizzi, A., Zullo, A., Baldi, C., Corbellini, C., Sampietro, G. M., Cellerino, P., Baldini, E., Capelli, P., Isolani, S. M., Ribolla, M., Bondurri, A., Colombo, F., Ferrario, L., Guerci, C., Maffioli, A., Armao, T., Ballabio, M., Bisagni, P., Gagliano, A., Longhi, M., Madonini, M., Pizzini, P., Baietti, A. M., Biasini, M., Maremonti, P., Neri, F., Prucher, G. M., Ricci, S., Ruggiero, F., Zarabini, A. G., Barmasse, R., Mochet, S., Usai, A., Incollingo, P., Mancini, S., Marino Cosentino, L., Sagnotta, A., Fruscio, R., Grassi, T., Nespoli, L. C., Tamini, N., Anastasi, A., Bartalucci, B., Bellacci, A., Canonico, G., Capezzuoli, L., Di Martino, C., Ipponi, P., Linari, C., Montelatici, M., Nelli, T., Spagni, G., Tirloni, L., Vitali, A., Abate, E., Casati, M., Casiraghi, T., Laface, L., Schiavo, M., Arminio, A., Cotoia, A., Lizzi, V., Vovola, F., Vergari, R., D'Ugo, S., Depalma, N., Spampinato, M. G., Bartolucci, P., Brachini, G., Bruzzaniti, P., Chiappini, A., Chiarella, V., Ciccarone, F., Cicerchia, P. M., Cirillo, B., De Toma, G., Di bartolomeo, A., Fiori, E., Fonsi, G. B., Franco, G., Frati, A., Giugliano, M., Iannone, I., La Torre, F., Lapolla, P., Leonardo, C., Marruzzo, G., Meneghini, S., Mingoli, A., Ribuffo, D., Salvati, M., Santoro, A., Sapienza, P., Scafa, A. K., Simonelli, L., Zambon, M., Capolupo, G. T., Carannante, F., Caricato, M., Masciana, G., Mazzotta, E., Gattolin, A., Migliore, M., Rimonda, R., Sasia, D., Travaglio, E., Cervellera, M., Gori, A., Sartarelli, L., Tonini, V., Giacometti, M., Zonta, S., Chessa, A., Fiorini, A., Norcini, C., Colletti, G., Confalonieri, M., Costanzi, A., Frattaruolo, C., Mari, G., Monteleone, M., Bandiera, A., Bocciolone, L., Bonavina, G., Candiani, M., Candotti, G., De Nardi, P., Gagliardi, F., Medone, M., Mortini, P., Negri, G., Parise, P., Piloni, M., Sileri, P., Vignali, A., Belvedere, A., Bernante, P., Bertoglio, P., Boussedra, S., Brunocilla, E., Cipriani, R., Cisternino, G., De Crescenzo, E., De Iaco, P., Dondi, G., Frio, F., Jovine, E., Mineo Bianchi, F., Neri, J., Parlanti, D., Perrone, A. M., Pezzuto, A. P., Pignatti, M., Pinto, V., Poggioli, G., Ravaioli, M., Rottoli, M., Schiavina, R., Serenari, M., Serra, M., Solli, P., Taffurelli, M., Tanzanu, M., Tesei, M., Violante, T., Zanotti, S., Borghi, F., Cianflocca, D., Di Maria Grimaldi, S., Gelarda, E., Geretto, P., Giraudo, G., Giuffrida, M. C., Marano, A., Palagi, S., Pellegrino, L., Peluso, C., Testa, V., Agresta, F., Prando, D., Zese, M., Aquila, F., Gambacciani, C., Lippa, L., Pieri, F., Santonocito, O. S., Armatura, G., Bertelli, G., Frena, A., Marinello, P., Notte, F., Patauner, S., Scotton, G., Fulginiti, S. F., Gallo, G., Sammarco, G., Vescio, G., Balercia, P., Catarzi, L., Consorti, G., Di Marzo, F., Fontana, T., Daiko, H., Ishikawa, M., Ishiyama, K., Iwata, S., Kanematsu, K., Kanemitsu, Y., Kato, T., Kawai, A., Kobayashi, E., Kobayashi Kato, M., Moritani, K., Nakatani, F., Oguma, J., Tanase, Y., Uno, M., Al Abdallah, M., Ayasra, F., Ayasra, Y., Qasem, A., Abu Za'nouneh, F. J., Fahmawee, T., Hmedat, A., Ibrahim, A., Obeidat, K., Abdel Al, S., Abdel Jalil, R., Abou Chaar, M. K., Al-Masri, M., Al-Najjar, H., Alawneh, F., Alsaraireh, O., Elayyan, M., Ghanem, R., Lataifeh, I., Alkadeeki, G. Z., Al Maadany, F. S., Aldokali, N., Senossi, O., Subhi, M. T., Burgan, D., Kamoka, E., Kilani, A. I., Salamah, A., Salem, M., Shuwayyah, A., Abdulwahed, E., Alshareea, E., Aribi, N., Aribi, S., Biala, M., Ghamgh, R., Morgom, M., Aldayri, Z., Ellojli, I., Kredan, A., Bradulskis, S., Dainius, E., Kubiliute, E., Kutkevicius, J., Parseliunas, A., Subocius, A., Venskutonis, D., Rasoaherinomenjanahary, F., Razafindrahita, J. B., Samison, L. H., Ong, E. C., Hamdan, K. H., Ibrahim, M. R., Tan, J. A., Thanapal, M. R., Amin Sahid, N., Hayati, F., Jayasilan, J., Sriram, R. K., Subramaniam, S., Che Jusoh, A., Hussain, A. H., Mohamed Sidek, A. S., Mohd Yunus, M. F., Soh, J. Y., Wong, M. P. K., Zakaria, A. D., Zakaria, Z., Fadzli, A., Fathi, N. Q., Koh, P. S., Liew, Y. T., Roslani, A. C., Tang, C. Y., Teoh, L. Y., Wong, W. J., Yahaya, A. S., Alvarez, M. R., Arrangoiz, R., Cordera, F., De La Rosa Abaroa, M. A., Gomez-Pedraza, A., Hernandez, R., Maffuz-Aziz, A., Posada, J. A., Becerra Garcia, F. C., Alfaro-Goldaracena, A., Buerba, G. A., Castillejos-Molina, R. A., Chan, C., Dominguez-Rosado, I., Medina-Franco, H., Mercado, M. A., Oropeza-Aguilar, M., Pena Gomez Portugal, E., Posadas-Trujillo, O. E., Rodriguez-Covarrubias, F., Salgado-Nesme, N., Vilatoba, M., Arkha, Y., Bechri, H., El Ouahabi, A., Oudrhiri, M. Y., Derkaoui hassani, F., El Abbadi, N., Amrani, L., Belkhadir, Z. H., Benkabbou, A., Chakib, O., El Ahmadi, B., El Bouazizi, Y., Essangri, H., Ghannam, A., Majbar, A. M., Mohsine, R., Souadka, A., Hompes, R., Meima-Van Praag, E. M., Pronk, A. J. M., Sharabiany, S., Grotenhuis, B., Hartveld, L., Reijers, S., Van Houdt, W., Baaij, J., Bolster-Van Eenennaam, M., De Graaff, M., Sloothaak, D., Van Duijvendijk, P., Posma-Bouman, L., Derksen, T., Franken, J., Oosterling, S., De Bree, R., Konsten, J., Van Heinsbergen, M., Fidelis, L., Sholadoye, T. T., Tolani, M. A., Olaogun, J., Egbuchulem, I. K., Lawal, T. A., Ogundoyin, O., Olulana, D. I., Abdur-Rahman, L., Adeyeye, A., Aremu, I., Bello, J., Olasehinde, O., Popoola, A., Massoud, J., Massoud, R., Sorour, T. M., Jamal, A., Kerawala, A. A., Memon, A. S., Nafees Ahmed, R., Rai, L., Ayub, B., Hassan, N., Martins, R. S., Ramesh, P., Sayyed, R., Butt, U., Kashif, M., Khan, W. H., Qureshi, A., Umar, M., Waris Farooka, M., Wasim, T., Ayubi, A., Rashid, I., Waqar, S. H., Falcon, G. M., Robles, R., Jocson, R., Teh, C., Major, P., Bobinski, M., Kotarski, J., Rasoul-Pelinska, K., Azevedo, C., Machado, D., Mendes, F., De Sousa, X., Fernandes, U., Ferreira, C., Guidi, G., Leal, C., Marcal, A., Marques, R., Martins, D., Melo, A., Tenreiro, N., Vaz Pereira, R., Vieira, B., Almeida, J. I., Correia de Sa, T., Costa, M. J. M. A., Fernandes, V., Ferraz, I., Gil, C. G., Lima Da Silva, C., Lopes, L., Machado, N., Marialva, J., Nunes Coelho, M., Pedro, J., Pereira, C., Reis, R., Ribeiro, A., Santos, R., Saraiva, P., Silva, R., Tavares, F., Teixeira, M., Almeida, A. C., Amaral, M. J., Andrade, R., Athayde Nemesio, R., Breda, D., Camacho, C., Canhoto, C., Colino, M., Correia, S., De Barros, J., De Oliveira Lopez, A. L., Duque, M., Garrido, S., Guerreiro, P., Guimaraes, A., Lazaro, A., Lopes, C., Nogueira, O., Oliveira, A., Oliveira, J. M., Rodrigues, M., Ruivo, A., Santos, E., Silva, M., Simoes, J., Valente Da Costa, A., Almeida, A., Cavaleiro, S., Devezas, V., Faria, C. S., Jacome, F., Magalhaes Maia, M., Nogueiro, J., Pereira, A., Pereira-Neves, A., Pina-Vaz, T., Santos-Sousa, H., Silveira, H., Vaz, S., Vieira, P., Gomes Da Costa, A., Lobo Antunes, I., Pinto, J., Tojal, A., Cardoso, N., Cardoso, P., Domingues, J. C., Henriques, P., Manso, M. I., Martins Dos Santos, G., Morais, H., Pereira, R., Revez, T., Ribeiro, R., Ribeiro, V. I., Sousa, S., Teixeira, J., Amorim, E., Baptista, V. H., Cunha, M. F., Dias, B., Fazenda, A., Melo Neves, J. P., Policarpo, F., Sampaio Da Novoa Gomes Miguel, I. I., Veiga, D., Andrade, A. K., Bandovas, J. P., Borges, N., Branquinho, A., Chumbinho, B., Correia, J., Fidalgo, H., Figueiredo De Barros, I., Frade, S., Gomes, J., Maciel, J., Pina, S., Rodrigues, A., Silva, N., Silveira Nunes, I., Sousa, R., Ascensao, J., Azevedo, P., Costeira, B., Cunha, C., Garrido, R., Gomes, H., Lourenco, I., Mendinhos, G., Miranda, P., Nobre Pinto, A., Peralta Ferreira, M., Ribeiro, J., Rio Rodrigues, L., Sousa Fernandes, M., Azevedo, J., Galvao, D., Soares, A. C., Vieira, A., Patricio, B., Santos, P. M. D. D., Vieira Paiva Lopes, A. C., Cunha, R., Faustino, A., Freitas, A., Martins, A. B., Mendes, J. R., Parreira, R., Rosa, J., Teves, M., Abreu Da Silva, A., Claro, M., Costa Santos, D., Deus, A. C., Grilo, J. V., Borges, F., Corte Real, J., Henriques, S., Lima, M. J., Matos Costa, P., Brito da Silva, F., Caiado, A., Fonseca, F., Angelo, M., Baiao, J. M., Martins Jordao, D., Vieira Caroco, T., Messias, J., Millan, A., Salgado, I., Baia, C., Canotilho, R., Correia, A. M., Ferreira Pinto, A. P., Peyroteo, M., Videira, J. F., Escobar, P., Maldonado Santiago, M., Kassir, R., Sauvat, F., Bezede, C., Chitul, A., Ciofic, E., Cristian, D., Grama, F., Pirtea, L., Secosan, C., Bonci, E., Gata, V., Titu, S., Ginghina, O., Iordache, N., Iosifescu, R. V., Garmanova, T., Kazachenko, E., Markaryan, D., Rodimov, S., Tsarkov, P., Tulina, I., Litvina, Y., Provozina, A., Agapov, M., Galliamov, E., Kakotkin, V., Kubyshkin, V., Alshahrani, M., Alsharif, F., Eskander, M., Al Raddadi, R., Majrashi, S., Mashat, A., Akeel, N., Alharthi, M., Aljiffry, M., Basendowah, M., Farsi, A., Ghunaim, M., Khoja, A., Maghrabi, A., Malibary, N., Nassif, M., Nawawi, A., Saleem, A., Samkari, A., Trabulsi, N., Al Awwad, S., Alghamdi, M., Alnumani, T., Nasser, M., Said bayazeed, A., Alhefdhi, A., Almalik, O., Alomair, A., Alotaibi, N., Alresaini, F., Alsalamah, R., Alsobhi, S., Mahasin, Z., Othman, E., Velagapudi, S., Ghedan, S., Alharthi, R., Awad, S., Sharara, M., Abdelrahman, S., Althobaiti, W., Al Habes, H., Alamri, A., Alkarak, S., Alqannas, M., Alyami, M., Alzamanan, M., Cortes Guiral, D., Elawad, A., Alaamer, O., Alriyees, L., Alselaim, N., Abdulkareem, A., Ajlan, A., Akkour, K., Al-Habib, A., Al-Khayal, K., Alatar, A., Alburakan, A., Alhalal, H., Alhassan, B., Alhassan, N., Alobeed, O., Alsaif, A., Alsaif, F., Alshammari, S., Alshaygy, I., Barry, M., Bin Nasser, A., Bin Traiki, T., Bokhari, A., Elwatidy, S., Helmi, H., Madkhali, A., Nouh, T., Rabah, P. D., Zubaidi, A., Paunovic, I., Slijepcevic, N., Aleksic, L., Antic, A., Barisic, G., Ceranic, M., Galun, D., Grubac, Z., Jelenkovic, J., Kecmanovic, D., Kmezic, S., Knezevic, D., Krivokapic, Z., Latincic, S., Markovic, V., Matic, S., Miladinov, M., Pavlov, M., Pejovic, I., Radenkovic, D., Tadic, B., Vasljevic, J., Velickovic, D., Zivanovic, M., Perovic, M., Srbinovic, L., Andrijasevic, S., Bozanovic, T., Cerovic Popovic, R., Dokic, M., Janjic, T., Jeremic, K., Kadija, S., Ladjevic Likic, I., Mirkovic, L., Pantovic, S., Pilic, I., Radojevic, M., Stefanovic, A., Vidakovic, S., Vilendecic, Z., Antic, S., Dunderovic, D., Jelovac, D., Jezdic, Z., Konstantinovic, V., Kotlar, B., Kuzmanovic, C., Lazic, M., Petrovic, M., Popovic, F., Pucar, A., Romic, M., Sumrak, S., Vujanac, V., Bascarevic, V., Bogdanovic, I., Grujicic, D., Ilic, R., Milicevic, M., Milisavljevic, F., Miljkovic, A., Paunovic, A., Scepanovic, V., Stanimirovic, A., Todorovic, M., Jotic, A., Milovanovic, J., Trivic, A., Bumbasirevic, U., Dzamic, Z., Kajmakovic, B., Prijovic, N., Zivkovic, M., Buta, M., Cvetkovic, A., Djurisic, I., Gacic, S., Goran, M., Inic, Z., Jeftic, N., Jevric, M., Jokic, V., Markovic, I., Milanovic, M., Nikolic, S., Pejnovic, L., Savkovic, N., Spurnic, I., Stevic, D., Stojiljkovic, D., Vucic, N., Zegarac, M., Karamarkovic, A., Kenic, M., Kovacevic, B., Krdzic, I., Milutinovic, V., Lieske, B., Galis, B., Simko, K., Almgla, N., Bernon, M., Boutall, A., Cairncross, L., Herman, A., Hilton, T., Jonas, E., Kloppers, C., Malherbe, F., Mugla, W., Nel, D., Rayamajhi, S., Van Wyngaard, T., Vogel, J., Castano-Leon, A. M., Delgado Fernandez, J., Eiriz Fernandez, C., Espino Segura-Illa, M., Esteban Sinovas, O., Garcia Perez, D., Gomez, P., Jimenez-Roldan, L., Lagares, A., Moreno-Gomez, L., Paredes, I., Perez Nunez, A., Sanchez Aniceto, G., Santas, M., Fernandez Rodriguez, P., Paniagua Garcia Senorans, M., Sanchez-Santos, R., Vigorita, V., Acrich, E., Baena Sanfeliu, E., Barrios, O., Golda, T., Santanach, C., Serrano-Navidad, M., Sorribas Grifell, M., Vives, R. V., Escola, D., Jimenez, A., Cayetano Paniagua, L., Gomez Fernandez, L., Artigues, E., Bernal-Sprekelsen, J. C., Catala Bauset, J. C., Collera, P., Diaz Del Gobbo, R., Farre Font, R., Flores Clotet, R., Gomez Diaz, C. J., Guardia, N., Guariglia, C. A., Osorio, A., Sanchez Jimenez, R., Sanchon, L., Soto Montesinos, C., Albi Martin, B., Garcia Villayzan, J. E., Alonso-Lamberti, L., Assaf, M., Baeza Pintado, N., Carabias, A., Garcia-Quijada, J., Huertas Fernandez, M. A., Jimenez Miramon, J., Jimenez, V., Jover, J. M., Landeo Aguero, S. A., Leon, R., Martin Salamanca, M. B., Perez Simon, V., Ponce, S., Rodriguez, J. L., Salazar, A., Valle Rubio, A., Aguado, H., Aldecoa Ansorregui, I., Bravo Infante, R., De Lacy, F. B., Di Somma, A., Diaz-Feijoo, B., Ensenat Nora, J., Fabregas, N., Ferres, A., Gil Ibanez, B., Gonzalez Sanchez, J. J., Gracia, I., Hoyos Castro, J. A., Lacy, A. M., Langdon, C., Momblan, D., Morales, X., Oleaga, L., Otero, A., Pedrosa, L., Poblete Carrizo, J., Reyes Figueroa, L. A., Roldan Ramos, P., Rumia-Arboix, J., Tercero-Uribe, A. I., Topczewski, T. E., Torales, J., Torne, A., Torne, R., Turrado-Rodriguez, V., Valero, R., Valverde, S., Anula, R., Cano-Valderrama, O., Del Campo Martin, M., Diez-Valladares, L., Dominguez, I., Dziakova, J., Garcia Alonso, M., Garcia Romero, E., Gomez Latorre, L., Muguerza, J. M., Pizarro, M. J., Saez Carlin, P., Sanchez Del Pueblo, C., Sanchez-Pernaute, A., Sanz Ortega, G., Sanz-Lopez, R., Torres, A., Garces-Albir, M., Lopez, F., Martin-Arevalo, J., Moro-Valdezate, D., Pla-Marti, V., Beltran De Heredia, J., De Andres Asenjo, B., Gomez Sanz, T., Jezieniecki, C., Nunez Del Barrio, H., Ortiz De Solorzano Aurusa, F. J., Romero De Diego, A., Ruiz Soriano, M., Trujillo Diaz, J., Vazquez Fernandez, A., Lora-Cumplido, P., Sosa, M. V., Gonzalez-Gonzalez, E., Minaya Bravo, A. M., Alonso de la Fuente, N., Cazador Labat, M., Cecchini, L., Espinosa, C. A., Jimenez Toscano, M., Lopez Campillo, A., Mancebo, G., Martorell, P., Munarriz, M., Grau-Talens, E. J., Martin-Perez, B., Benavides Buleje, J. A., Carrasco Prats, M., Fernandez, P. V., Fernandez-Lopez, A., Garcia Escudero, D., Garcia Porcel, V. J., Garcia Soria, V., Gimenez Frances, C., Gonzalez Valverde, F. M., Gurrea, E., Lopez-Morales, P., Marco Garrido, A., Martinez Alonso, J. A., Medina, E., Munoz Camarena, J. M., Parra Banos, P. A., Pena Ros, E., Ramirez Faraco, M., Ruiz-Marin, M., Sanchez Rodriguez, C., Valero Soriano, M., Estaire Gomez, M., Fernandez Camunas, A., Garcia Santos, E. P., Jimenez Higuera, E., Martinez-Pinedo, C., Munoz-Atienza, V., Padilla-Valverde, D., Picon Rodriguez, R., Redondo Calvo, F. J., Sanchez-Garcia, S., Sanchez-Pelaez, D., Colombari, R. C., Del valle, E., Fernandez, M., Lozano Lominchar, P., Rey Valcarcel, C., Steiner, M. A., Tudela, M., Zorrilla Ortuzar, J., Alcaide Matas, F., Garcia Perez, J. M., Troncoso Pereira, P., Mora-Guzman, I., Abellan, M., Achalandabaso Boira, M., Jorba, R., Memba Ikuga, R., Olona, C., Sales Mallafre, R., Cavalle Busquets, P., Gavalda Pellice, M. G. P., Salinas Pena, J., Aragon Achig, E. J., Barbier, L., Caja Vivancos, P., Gainza, A., Garcia Gutierrez, J. J., Mallabiabarrena Ormaechea, G., Marin, H., Martin Playa, P., Melchor Corcostegui, I., Prieto Calvo, M., Rodriguez Fraga, A., Villalabeitia Ateca, I., De Andres Olabarria, U., Duran Ballesteros, M., Fernandez Pablos, F. J., Ibanez-Aguirre, F. J., Sanz Larrainzar, A., Ugarte-Sierra, B., De La Hoz Rodriguez, A., Di Martino, M., Garcia Septiem, J., Martin-Perez, E., Munoz De Nova, J. L., Calvo Espino, P., Guillamot Ruano, P., Colao Garcia, L., Diaz Perez, D., Esteban Agusti, E., Galindo Jara, P., Gutierrez Samaniego, M., Hernandez Bartolome, M. A., Serrano Gonzalez, J., Alonso Poza, A., Dieguez, B., Garcia-Conde, M., Hernandez-Garcia, M., Losada, M., Chiesa-Estomba, C. M., Gonzalez Garcia, J. A., Larruscain, E., Sistiaga-Suarez, J. A., Alvarez, E., Chavarrias, N., Frias, L., Garcia Pineda, V., Gegundez Simon, A., Gortazar, S., Gracia, M., Guevara, J., Hernandez Gutierrez, A., Loayza, A., Maria Dolores, D. T., Marti, C., Melendez, M., Moreno-Palacios, E., Perez, Y., Prieto Nieto, M. I., Ramos-Martin, P., Rubio-Perez, I., Saavedra, J., Sanchez-Mendez, J. I., Siegrist Ridruejo, J., Urbieta, A., Zapardiel, I., Cantalejo diaz, M., De Miguel Ardevines, M. D. C., Duque-Mallen, V., Gascon Ferrer, I., Gonzalez-Nicolas Trebol, M. T., Gracia-Roche, C., Herrero Lopez, M., Jariod Ferrer, U. M., Lanzon, A., Martinez German, A., Matute, M., Redondo, C., Sanchez Fuentes, N., Sanchez-Rubio, M., Santero-Ramirez, M. S., Saudi, S., Simon Sanz, M. V., Uson-Bouthelier, T., Blazquez Martin, A., Diez Alonso, M., Garcia Rico, E., Garcia-Loarte Gomez, E., Garcia-Moreno Nisa, F., Gutierrez Calvo, A., Hernandez, P., Lasa, I., Mendoza-Moreno, F., Morales Palacios, N., Ovejero Merino, E., Vera Mansilla, C., Acebes Garcia, F., Bailon, M., Bueno Canones, A. D., Choolani Bhojwani, E., Marcos-Santos, P., Miguel, T., Pacheco Sanchez, D., Perez-Saborido, B., Sanchez Gonzalez, J., Tejero-Pintor, F. J., Alconchel, F., Conesa, A., Gil Martinez, J., Gutierrez Fernandez, A. I., Lopez Abad, A., Nicolas-Lopez, T., Ramirez Romero, P., Roca Calvo, M. J., Rodrigues, K., Ruiz Manzanera, J. J., Soriano, A. I., Cano, A., Capitan-Morales, L., Cintas Catena, J., Gomez-Rosado, J., Oliva Mompean, F., Perez Sanchez, M. A., Rio Lafuente, F. D., Torres Arcos, C., Valdes-Hernandez, J., Cholewa, H., Domingo, S., Frasson, M., Lago, V., Marina Martin, T., Martinez Chicote, C., Sancho-Muriel, J., Landaluce-Olavarria, A., Lecumberri, D., Abad Gurumeta, A., Abad-Motos, A., Martinez-Hurtado, E., Ripolles-Melchor, J., Ruiz Escobar, A., Cuadrado-Garcia, A., Garcia-Sancho Tellez, L., Heras Aznar, J., Mate, P., Ortega Vazquez, I., Picardo, A. L., Rojo Lopez, J. A., Sanchez Cabezudo Noguera, F., Serralta De Colsa, D., Anchuelo Latorre, J., Cagigas Fernandez, C., Caina Ruiz, R., Gomez Ruiz, M., Hernanz, F., Jimeno Fraile, J., Martinez-Perez, P., Poch, C., Santarrufina Martinez, S., Valbuena Jabares, V., Moliner-Sanchez, C., Pingarron-Martin, L., Rey-Biel, J., Ruiz Martin, I., Blas Laina, J. L., Cros, B., Escartin, J., Garcia Egea, J., Nogues, A., Talal El-Abur, I., Yanez, C., Cagigal Ortega, E. P., Cervera, I., Diaz Pena, P., Elena, G. D. C. R., Enjuto, D., Fernandez Bernabe, P., Garces Garcia, R., Gonzalez, J., Hernandez, I., Herrera-Merino, N., Marqueta De Salas, M., Martinez Pascual, P., Perez Gonzalez, M., Ramos Bonilla, A., Rodriguez Gomez, L., Bescos, C., Blanco-Colino, R., Brana, I., Caimari, B., De Pablo Garcia-Cuenca, A., Duran-Valles, F., Espin-Basany, E., Giralt Lopez De Sagredo, J., Pamias, J., Pellino, G., Prat, N., Pujol Pina, R., Saez Barba, M., Arulanantham, A., Bandara, G. B. K., Jayarajah, U., Ravindrakumar, S., Rodrigo, V. S., Srishankar, S., Ali Karar, A. A., Elbe, P., Lindqvist, E. K., Taflin, H., Alga, A., Heinius, G., Nordberg, M., Pieniowski, E., Gkekas, I., Lofgren, N., Rutegard, M., Sund, M., Arigoni, M., Bernasconi, M., Christoforidis, D., Di Giuseppe, M., La Regina, D., Mongelli, F., Chevallay, M., Dwidar, O., Gialamas, E., Sauvain, M., Klenke, F., Kollar, A., Kurze, C., Adamina, M., Bachler, T., Crugnale, A. S., Giardini, M., Guglielmetti, L., Peros, G., Solimene, F., Aghayeva, A., Hamzaoglu, I., Sahin, I., Akaydin, E., Aliyeva, Z., Aytac, E., Baca, B., Dulgeroglu, O., Ozben, V., Ozmen, B. B., Uras, C., Arikan, A. E., Bilgin, I. A., Bozkirli, B., Ceyhan, G. O., Kara, H., Karahasanoglu, T., Celik, H., Meydanli, M. M., Akilli, H., Ayhan, A., Kuscu, E., Onan, M. A., Akgor, U., Dincer, H. A., Erol, T., Gultekin, M., Orhan, N., Ozgul, N., Salman, M. C., Soyak, B., Alhamed, A., Ergun, S., Ozcelik, M. F., Sanli, A. N., Uludag, S. S., Velidedeoglu, M., Zengin, A. K., Bozkurt, M. A., Kara, Y., Kocatas, A., Cimenoglu, B., Demirhan, R., Saracoglu, K., Azamat, I. F., Balik, E., Bugra, D., Giray, B., Kulle, C. B., Taskiran, C., Vatansever, D., Gozal, K., Guler, S. A., Koken, H., Tatar, O. C., Utkan, N. Z., Yildirim, A., Yuksel, E., Akin, E., Altintoprak, F., Bayhan, Z., Cakmak, G., Capoglu, R., Celebi, F., Demir, H., Dikicier, E., Firat, N., Gonullu, E., Kamburoglu, M. B., Kocer, B., Kucuk, I. F., Mantoglu, B., Colak, E., Kucuk, G. O., Uyanik, M. S., Goksoy, B., Bozkurt, E., Citgez, B., Mihmanli, M., Tanal, M., Yetkin, G., Akalin, M., Arican, C., Avci, E. K., Aydin, C., Demirli Atici, S., Emiroglu, M., Kaya, T., Kebabci, E., Kilinc, G., Kirmizi, Y., Ogucu, H., Salimoglu, S., Sert, I., Tugmen, C., Tuncer, K., Uslu, G., Yesilyurt, D., Karaman, E., Kolusari, A., Yildiz, A., Benson, O., Lule, H., Agilinko, J., Ahmeidat, A., Barabasz, M., Bekheit, M., Cheung, L. K., Colloc, T., Cymes, W., Elhusseini, M., Gradinariu, G., Hannah, A., Kamera, B. S., Mignot, G., Shaikh, S., Sharma, P., Abu-Nayla, I., Agrawal, A., Al-Mohammad, A., Ali, S., Ashcroft, J., Azizi, A., Baker, O., Balakrishnan, A., Byrne, M., Colquhoun, A., Cotter, A., Coughlin, P., Davies, R. J., Durrani, A., Elshaer, M., Fordington, S., Forouhi, P., Georgiades, F., Grimes, H., Habeeb, A., Hudson, V., Hutchinson, P., Irune, E., Jah, A., Khan, D. Z., Kyriacou, H., Lamb, B., Liau, S., Luke, L., Mahmoud, R., Mannion, R., Masterson, L., Mitrofan, C. G., Mohan, M., Morris, A., Murphy, S., O'Neill, R., Price, S., Pushpa-Rajah, J., Raby-Smith, W., Ramzi, J., Rooney, S., Santarius, T., Singh, A., Tan, X. S., Townson, A., Tweedle, E., Walker, C., Waseem, S., Yordanov, S., Jones, T., Kattakayam, A., Loh, C., Lunevicius, R., Pringle, S., Schache, A., Sheel, A., Rossborough, C., Angelou, D., Choynowski, M., Mcaree, B., Mccanny, A., Neely, D., Tutoveanu, G., Ahad, S., De La Cruz Monroy, M. F. I., Mosley, F., Oktseloglou, V., Alanbuki, A., Patel, M., Shabana, A., Perera, E., Raveendran, D., Ravi-Shankar, K., Thiruchelvam, J., Arrowsmith, L., Campbell, W., Grove, T., Kontovounisios, C., Warren, O., Rolland, P., Aggarwal, A., Brown, S., Jelley, C., Neal, N., Clifford, R., Eardley, N., Krishnan, E., Manu, N., Martin, E., Roy Mahapatra, S., Serevina, O. L., Smith, C., Vimalachandran, D., Bordenave, M., Houston, R., Putnam, G., Robson, A., Tustin, H., Emslie, K., Labib, P. L., Marchbank, A., Miller, D., Minto, G., Natale, J., Nwinee, H., Panahi, P., Rogers, L., Abubakar, A., Akhter Rahman, M. M., Ko, K. Y. K., O'Brien, H., Sasapu, K., Woodun, H., Inglis, R., Ng, H. J., De Gea Rico, A., Ghazali, N., Lambert, J., Markose, G., Math, S., Sarantitis, I., Shrestha, D., Sultana, A., Taggarsi, M., Timbrell, S., Vaz, O. P., Vitone, L., Day, A., Dent, H., Fahim, M., Waheed, S., Hunt, A., Laskar, N., Gupta, A., Steinke, J., Thrumurthy, S., Massie, E., Mcgivern, K., Rutherford, D., Wilson, M., Hardie, J., Kazzaz, S., Handa, S., Kaushal, M., Kler, A., Patel, P., Redfern, J., Tezas, S., Aawsaj, Y., Amonkar, S., Blackwell, L., Blake, D., Carter, J., Emerson, H., Fisher, A., Katory, M., Korompelis, P., Mccormick, W., Mustafa, A., Pearce, L., Ratnavelu, N., Reehal, R., Kretzmer, L., Lalou, L., Manku, B., Parwaiz, I., Stafford, J., Abdelkarim, M., Asqalan, A., Gala, T., Ibrahim, S., Maw, A., Mithany, R., Morgan, R., Sundaram Venkatesan, G., Ang, K., Caruana, E. J., Chowdhry, M. F., Mohammad, A., Nakas, A., Rathinam, S., Boal, M., Brown, O., Dwerryhouse, S., Higgs, S., Vallance, A., Boyd, E., Irvine, V., Kirk, A., Bakolas, G., Boulton, A., Chandock, A., Khan, T., Kumar, M., Agoston, P., Bille, A., Challacombe, B., Fraser, S., Harrison-Phipps, K., King, J., Mehra, G., Mills, L., Najdy, M., Nath, R., Okiror, L., Pilling, J., Rizzo, V., Routledge, T., Sayasneh, A., Stroman, L., Wali, A., Fehervari, M., Fotopoulou, C., Habib, N., Hamrang-Yousefi, S., Jawad, Z., Jiao, L., Pai, M., Ploski, J., Rajagopal, P., Saso, S., Sodergren, M., Spalding, D., Laws, S., Hardie, C., Mcnaught, C., Alam, R., Budacan, A., Cahill, J., Kalkat, M., Karandikar, S., Kenyon, L., Naumann, D., Patel, A., Ayorinde, J., Chase, T., Cuming, T., Ghanbari, A., Humphreys, L., Tayeh, S., Aboelkassem Ibrahim, A., Bichoo, R., Cao, H., Chai, A. K. W., Choudhury, J., Evans, C., Fitzjohn, H., Ikram, H., Langstroth, M., Loubani, M., Mcmillan, A., Nazir, S., Qadri, S. S. A., Robinson, A., Ross, E., Sehgal, T., Wilkins, A., Dixon, J., Dunning, J., Freystaetter, K., Jha, M., Lester, S., Madhavan, A., Thulasiraman, S. V., Viswanath, Y., Curl-Roper, T., Delimpalta, C., Liao, C. C. L., Velchuru, V., Westwood, E., Belcher, E., Bond-Smith, G., Chidambaram, S., Di Chiara, F., Fasanmade, K., Fraser, L., Fu, H., Ganau, M., Gore, S., Graystone, J., Jeyaretna, D., Khatkar, H., Lami, M., Maher, M., Mastoridis, S., Mihai, R., Piper, R., Prabhu, S., Risk, O. B. F., Selbong, U., Shah, K., Smillie, R., Soleymani majd, H., Sravanam, S., Stavroulias, D., Tebala, G. D., Vatish, M., Verberne, C., Wallwork, K., Winter, S., Bhatti, M. I., Boyd-Carson, H., Elsey, E., Gemmill, E., Herrod, P., Jibreel, M., Lenzi, E., Saafan, T., Sapre, D., Sian, T., Watson, N., Athanasiou, A., Bourke, G., Bradshaw, L., Brunelli, A., Burke, J., Coe, P., Costigan, F., Elkadi, H., Johnstone, J., Kanatas, A., Kantola, V., Kaufmann, A., Laios, A., Lam, S., Macinnes, E., Munot, S., Nahm, C., Otify, M., Pompili, C., Smith, I., Theophilou, G., Toogood, G., Wade, R., Ward, D., West, C., Annamalai, S., Ashmore, C., Boddy, A., Hossain, T., Kourdouli, A., Gvaramadze, A., Jibril, A., Prusty, L., Thekkinkattil, D., Harky, A., Shackcloth, M., Askari, A., Cirocchi, N., Kudchadkar, S., Patel, K., Sagar, J., Shaw, S., Talwar, R., Abdalla, M., Edmondson, R., Ismail, O., Jones, D., Newton, K., Stylianides, N., Aderombi, A., Andaleeb, U., Bajomo, O., Beatson, K., Garrett, W., Mehmood, M., Ng, V., Al-Habsi, R., Divya, G. 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D, Geddes, A, Mccaul, J, Mcmahon, J, H Khan, A, Khan, F, Mansuri, A, Mukherjee, S, Sarigul, M, Singh, S, L Tan, K, Woodham, A, Adiamah, A, Brewer, H, Chowdhury, A, Evans, J, Humes, D, Jackman, J, Koh, A, Lewis-Lloyd, C, Oyende, O, Reilly, J, Worku, D, Cool, P, Cribb, G, Shepherd, K, Bisset, C, Moug, S, Elson, N, Faulkner, G, Saleh, P, Underwood, C, Brixton, G, Findlay, L, Klatte, T, Majkowska, A, Manson, J, Potter, R, Bhalla, A, Chia, Z, Daliya, P, Goyal, A, Grimley, E, Hamad, A, Kumar, A, L Malcolm, F, Theophilidou, E, Bowden, J, Campain, N, Daniels, I, Fowler, G, John, J, Massey, L, Mcdermott, F, Mcgrath, J, Mclennan, A, Ng, M, Pascoe, J, Rajaretnam, N, Bulathsinhala, S, Davidson, B, Fusai, G, Hidalgo Salinas, C, Machairas, N, Pissanou, T, M Pollok, J, A Raptis, D, Soggiu, F, Tzerbinis, H, E Xyda, S, Beamish, A, Davies, E, Foulkes, R, Magowan, D, Nassa, H, Ooi, R, Price, C, Smith, L, Solari, F, Tang, A, Williams, G, Al-Tamimi, Y, Bacon, A, Beasley, N, Chew, D, Crank, M, Ilenkovan, N, Macdonald, M, Narice, B, Rominiyi, O, Thompson, A, Varley, I, Drake, T, Harrison, E, Linder, G, Mayes, J, Mcgregor, R, Skipworth, R, Zamvar, V, Hawkin, P, Raymond, T, Ryska, O, Baron, R, Dunne, D, Gahunia, S, Halloran, C, Howes, N, Mckinney, R, Mcnicol, F, Russ, J, Szatmary, P, R Tan, J, Thomas, A, Whelan, P, Anzak, A, Banerjee, A, Fuwa, O, Hughes, F, D Jayasinghe, J, Knowles, C, Kocher, H, Leal Silva, I, S Ledesma, F, Minicozzi, A, Navaratne, L, Rahman, R, Ramamoorthy, R, Sohrabi, C, Thaha, M, Thakur, B, Venn, M, Yip, V, Baumber, R, Parry, J, Evans, S, Jeys, L, Morris, G, Parry, M, Ahmadi, N, Aresu, G, M Barrett-Brown, Z, S Coonar, A, Durio Yates, H, Gearon, D, Hogan, J, King, M, Peryt, A, S Pradeep, I, Adishesh, M, Atherton, R, Baxter, K, Brocklehurst, M, Chaudhury, M, Krishnamohan, N, Mcaleer, J, Owens, G, Parkin, E, Patkar, P, Phang, I, Aladeojebi, A, Ali, M, Barmayehvar, B, Gaunt, A, Gowda, M, Halliday, E, Kitchen, M, Mansour, F, Thomas, M, Zakai, D, Abbassi-Ghadi, N, Assalaarachchi, H, Currie, A, Flavin, M, Frampton, A, Hague, M, Hammer, C, Hopper, J, Horsnell, J, Humphries, S, Kamocka, A, K Madhuri, T, Preston, S, Singh, P, Stebbing, J, Tailor, A, Walker, D, Aljanadi, F, Jones, M, Mhandu, P, O'Donnell, C, Turkington, R, Al-Ishaq, Z, Bhasin, S, S Bodla, A, Burahee, A, Crichton, A, Fossett, R, Pigadas, N, Pickford, S, Rahman, E, Snee, D, Vidya, R, Yassin, N, Fountain, D, T Hasan, M, Karabatsou, K, Laurente, R, Pathmanaban, O, Al-Mukhtar, A, Edwards, J, Giblin, A, Kelty, C, Lee, M, Lye, G, Newman, T, Sharkey, A, Steele, C, Sureshkumar Shah, N, Whitehall, E, Athwal, R, Baker, A, Jones, L, Konstantinou, C, Ramcharan, S, Vatish, J, Wilkin, R, Ethunandan, M, K Sekhon, G, Shields, H, Singh, R, Wensley, F, Lawday, S, Lyons, A, Abbott, T, Anwar, S, Ghufoor, K, Chung, E, Hagger, R, Hainsworth, A, Karim, A, Owen, H, Ramwell, A, Williams, K, Baker, C, Davies, A, Gossage, J, Kelly, M, Knight, W, Hall, J, Harris, G, James, G, Kang, C, J Lin, D, D Rajgor, A, Royle, T, Scurrah, R, Steel, B, J Watson, L, Choi, D, Hutchison, R, Jain, A, Luoma, V, Marcus, H, May, R, Menon, A, Pramodana, B, Webber, L, A Aneke, I, Asaad, P, Brown, B, Collis, J, Duff, S, Khan, A, Moura, F, Wadham, B, Warburton, H, Elmoslemany, T, Jenkinson, M, Millward, C, Zakaria, R, Mccluney, S, Parmar, C, Shah, S, Allison, J, S Babar, M, Collard, B, Goodrum, S, Lau, K, Scott, R, Thomas, E, Whitmore, H, Balasubramaniam, D, Jayasankar, B, Kapoor, S, Ramachandran, A, Elhamshary, A, Imam, Smb, Kapriniotis, K, Kasivisvanathan, V, Lindsay, J, Rakhshani-Moghadam, S, Beech, N, Chand, M, Green, L, Kalavrezos, N, Kiconco, H, Mcewen, R, Schilling, C, Sinha, D, Pereca, J, Chopra, S, Egbeare, D, Thomas, R, Combellack, T, Jones, Sef, Kornaszewska, M, Mohammed, M, Sharma, A, Tahhan, G, Valtzoglou, V, Williams, J, Eskander, P, Gash, K, Gourbault, L, Hanna, M, Maccabe, T, Newton, C, Olivier, J, Rozwadowski, S, Teh, E, West, D, Al-Omishy, H, Baig, M, Bates, H, Di Taranto, G, Dickson, K, Dunne, N, Gill, C, Howe, D, Jeevan, D, Khajuria, A, Martin-Ucar AMcEvoy, K, Naredla, P, Robertson, S, Sait, M, R Sarma, D, Shanbhag, S, Shortland, T, Simmonds, S, Skillman, J, Tewari, N, Walton, G, A Akhtar, M, Brunt, A, Mcintyre, J, Milne, K, M Rashid, M, Sgro, A, E Stewart, K, Turnbull, A, Aguilar Gonzalez, M, Talukder, S, Boyle, C, Fernando, D, Gallagher, K, Laird, A, Tham, D, Bath, M, Patki, P, Tanabalan, C, Arif, T, Magee, C, Nambirajan, T, Powell, S, Vinayagam, R, Flindall, I, Hanson, A, Mahendran, V, Green, S, Lim, M, Macdonald, L, Miu, V, Onos, L, Sheridan, K, Young, R, Alam, F, Griffiths, O, Houlden, C, Jones, R, S Kolli, V, K Lala, A, Leeson, S, Peevor, R, Seymour, Z, Chen, L, Henderson, E, Loehrer, A, Brown, K, Fleming, D, Heron, C, Hill, C, Kay, H, Leede, E, Mcelhinney, K, Olson, K, C Osterberg, E, Riley, C, Srikanth, P, Thornhill, M, Blazer, D, Dilalla, G, S Hwang, E, Lee, W, Lidsky, M, Plichta, J, Rosenberger, L, Scheri, R, Turnage, K, Visgauss, J, Zani, S, Farma, J, Clark, J, Kwon, D, Etchill, E, E Gabre-Kidan AJenny, H, Kent, A, Ladd, M, Long, C, Malapati, H, Margalit, A, Rapaport, S, Rose, J, Stevens, K, Tsai, L, Vervoort, D, Yesantharao, P, Dehal, A, Klaristenfeld, D, Huynh, K, Brown, L, Ganly, I, Mullinax, J, Gusani, N, Hazelton, J, Maines, J, S Oh, J, Ssentongo, A, Ssentongo, P, Azam, M, Choudhry, A, Marx, W, Fleming, J, Fuson, A, Gigliotti, J, Ovaitt, A, Ying, Y, K Abel, M, Andaya, V, Bigay, K, A Boeck, M, Chern, H, Corvera, C, El-Sayed, I, Glencer, A, Ha, P, Hamilton, Bc, Heaton, C, Hirose, K, M Jablons, D, Kirkwood, K, Z Kornblith, L, R Kratz, J, Lee, R, N Miller, P, Nakakura, E, Nunez-Garcia, B, O'Donnell, R, Ozgediz, D, Park, P, Robinson, B, Sarin, A, Sheu, B, Varma, M, Wai, K, Wustrack, R, J Xu, M, Beswick, D, Goddard, J, Manor, J, Song, J, Fullmer, T, Gaskill, C, Gross, N, Kiong, K, L Roland, C, N Zafar, S, Abdallah, M, Abouassi, A, Almasri, M, Kulkarni, G, Marwan, H, Mehdi, M, Aoun, S, S Ban, V, H Batjer, H, Caruso, J, Abbott, D, Acher, A, Aiken, T, Barrett, J, Foley, E, Schwartz, P, Hawkins, A, Maiga, A, Laufer, J, Scasso, S, Surgery, Graduate School, Glasbey, J, Nepogodiev, D, Simoes, J, Omar, O, Li, E, Abou Chaar, M, Chaudhry, D, Videria, J, Gujjuri, R, Kaafarani, H, Minaya-Bravo, A, Mckay, S, Roberts, K, Miguel-Mendez, C, Smart, N, Stewart, G, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), COVIDSurg Collaborative, Kolias, Angelos [0000-0003-3992-0587], Stewart, Grant [0000-0003-3188-9140], Apollo - University of Cambridge Repository, Glasbey JC, Nepogodiev D, Simoes JFF, Omar O, Li E, Venn ML, Pgdme, Abou Chaar MK, Capizzi V, Chaudhry D, Desai A, Edwards JG, Evans JP, Fiore M, Videria JF, Ford SJ, Ganly I, Griffiths EA, Gujjuri RR, Kolias AG, Kaafarani HMA, Minaya-Bravo A, McKay SC, Mohan HM, Roberts KJ, San Miguel-Méndez C, Pockney P, Shaw R, Smart NJ, Stewart GD, Sundar Mrcog S, Vidya R, Bhangu AA, COVIDSurg Collaborative, Palmerini Emanuela, Frisoni Tommaso, Donati Davide, A Belvedere, P Bernante, P Bertoglio, S Boussedra, E Brunocilla, R Cipriani, G Cisternino, E De Crescenzo, P De Iaco, G Dondi, F Frio, E Jovine, F Mineo Bianchi, J Neri, D Parlanti, A M Perrone, A P Pezzuto, M Pignatti, V Pinto, G Poggioli, M Ravaioli, M Rottoli, R Schiavina, M Serenari, M Serra, P Solli, M Taffurelli, M Tanzanu, M Tesei, T Violante, S Zanotti, V Tonini, M Cervellera, A Gori, L Sartarelli, Glasbey, James C, Simoes, Joana F F, Venn, Mary L, Pgdme, null, Abou Chaar, Mohammad K, Edwards, Jonathan G, Evans, Jonathan P, Videria, Jose Flavio, Ford, Samuel J, Griffiths, Ewen A, Gujjuri, Rohan R, Kolias, Angelos G, Kaafarani, Haytham M A, McKay, Siobhan C, Mohan, Helen M, Roberts, Keith J, Smart, Neil J, Stewart, Grant D, Sundar Mrcog, Sudha, and Bhangu, Aneel A, Toia, F
Subjects: Male, Cancer Research, Outcome Assessment, International Cooperation, Settore MED/18 - CHIRURGIA GENERALE, Settore MED/19 - Chirurgia Plastica, 030230 surgery, Aged, Aged, 80 and over, COVID-19, Cohort Studies, Critical Care, Elective Surgical Procedures, Epidemics, Female, Humans, Logistic Models, Middle Aged, Neoplasms, Outcome Assessment, Health Care, Postoperative Complications, SARS-CoV-2, 0302 clinical medicine, Operating theater, cohort studies, Health care, middle aged, 80 and over, Medicine, Lung, Cancer, COVID-19/epidemiology, OUTCOMES, Manchester Cancer Research Centre, Pulmonary Complication, ORIGINAL REPORTS, aged, Oncology, 030220 oncology & carcinogenesis, Pneumonia & Influenza, Patient Safety, Elective Surgical Procedure, Life Sciences & Biomedicine, 6.4 Surgery, Cohort study, Human, medicine.medical_specialty, elective surgical procedures/methods, Logistic Model, Health Care, Clinical Sciences, Oncology and Carcinogenesis, Epidemic, [SDV.CAN]Life Sciences [q-bio]/Cancer, cancer surgery, SARS-CoV-2 pandemic, epidemics, COVIDSurg Collaborative, NO, outcome assessment, health care/methods, 03 medical and health sciences, male, Settore MED/28 - Malattie Odontostomatologiche, Clinical Research, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Elective surgery, Elective Cancer Surgery in SARS-CoV-2, Elective Cancer Surgery in COVID-19, covid 19, sars-cov-2, Science & Technology, business.industry, Prevention, ResearchInstitutes_Networks_Beacons/mcrc, Evaluation of treatments and therapeutic interventions, 1103 Clinical Sciences, Pneumonia, Odds ratio, medicine.disease, Good Health and Well Being, neoplasms/surgery, critical care/methods, Emergency medicine, postoperative complications/prevention & control, Neoplasm, Postoperative Complication, Cohort Studie, business, aged, 80 and over, SARS-CoV-2/physiology, logistic models
Abstract: PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks. Copyright © 2020 American Society of Clinical Oncology. All rights reserved. Bowel and Cancer Research; Sarcoma UK; Yorkshire Cancer Research; European Society of Coloproctology; National Institute for Health Research: 16.136.79; Bowel Disease Research Foundation; Urology Foundation Supported by a National Institute for Health Research (NIHR) Global Health Research Unit grant (NIHR 16.136.79) using UK aid from the UK government to support global health research, Association of Coloproctology of Great Britain and Ireland, Bowel & Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, The Urology Foundation, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research. The funders had no role in the study design; data collection, analysis, and interpretation; or writing of this report. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or UK Department of Health and Social Care.
Published: 2021

2. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Vistoria J., Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J., Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Kuijpers, Taco W., Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L., Davila, Sonia, European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Vistoria J., Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J., Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Kuijpers, Taco W., Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L., and Davila, Sonia
Abstract: Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
Published: 2019

3. Comorbidities in the UK Primary Sjögren’s Syndrome Registry

Author: Jessica Tarn, Dennis Lendrem, Michael Barnes, John Casement, Wan-Fai Ng, Newcastle University [Newcastle], Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Queen Mary University of London (QMUL), Newcastle Upon Tyne Hospitals NHS Foundation Trust, This work was supported by Foundation of Research in Rheumatology (FOREUM): (grant number: 022). This work received infrastructure support from the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the NIHR Clinical Research Facility, based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and from the Arthritis Research UK and Versus Arthritis Newcastle upon Tyne Experimental Arthritis Treatment Centre. The UKPSSR received grant support from the UK Medical Research Council (grant number G0800629 to W-FN, SJB, BG) and British Sjögren’s Syndrome Association. This work was supported, in part, by the National Institute for Health Research: NIHR202635 - Artificial Intelligence Multimorbidity Development Award and the Innovative Medicines Initiative 2 Joint Undertaking (JU) (NECESSITY grant agreement No 806975) receiving support from the European Union’s Horizon 2020 research and innovation program and EFPIA., European Project: 806975,NECESSITY, European Project: (grant No 116060),IMPRiND, Piatrova, Alena, NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID, and EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking. - IMPRiND - (grant No 116060) - INCOMING
Subjects: [SDV]Life Sciences [q-bio], Immunology, stratified medicine, Pain, crossectional analysis, United Kingdom, [SDV] Life Sciences [q-bio], comorbidity, Sjogren's syndrome, Humans, Immunology and Allergy, Registries, polypharmacy, Fatigue
Abstract: IntroductionPrimary Sjögren’s Syndrome (PSS) is a chronic disease characterised by symptoms of oral and ocular dryness, pain, fatigue, anxiety and depression. PSS patients can be subclassified by the pattern of severity of these five key symptoms using the Newcastle Sjögren’s Stratification Tool (NSST). Although PSS is often associated with one or more comorbidities, the relationship between comorbidities, polypharmacy, and PSS symptom burden is unclear. Using data from the UK Primary Sjögren’s Syndrome Registry (UKPSSR) we describe the landscape of polypharmacy and comorbidities in PSS.MethodsThe UKPSSR is research biobank of clinically well-defined PSS patients where clinical, demographic, comorbidities and concomitant medications data are recorded. Patients were subclassified into the four NSST subgroups: Low Symptom Burden (LSB), High Symptom Burden (HSB), Dryness Dominated Fatigue (DDF) and Pain Dominated Fatigue (PDF). Group analyses of comorbid conditions and polypharmacy scores were performed. Comorbidity and Polypharmacy Scores (CPS) were modelled as a function of age, sex, symptom duration, body mass index (BMI), current immunosuppressant and hydroxychloroquine prescriptions and NSST subgroup.ResultsThere were marked differences in the number and the nature of comorbidities associated with the NSST subgroups. LSB and DDF patients were characterized by fewer comorbidities and medications. In contrast, HSB and PDF patients were associated with more comorbidities and were more likely to be prescribed multiple medications. Group analysis shows that HSB patients are more closely associated with peripheral vascular disease and infection whereas the PDF patients were associated with cardiovascular disease and gastrointestinal comorbidities. Comorbidity and polypharmacy scores increase with age and BMI regardless of symptom subgroup and symptom duration. In addition, the longer the reported symptom duration the higher the associated comorbidities and polypharmacy scores.ConclusionComorbid conditions are more prevalent in some subgroups of the PSS cohort but increase with age and BMI across the entire cohort. It is unclear from these data whether specific comorbid conditions are a consequence of PSS or represent shared aetiology or pathogenetic susceptibility. Regardless, these findings may have implications for disease management and clinical trial design.
Published: 2022

4. Review article: The need for more efficient and patient‐oriented drug development pathways in NASH—setting the scene for platform trials

Author: Di Prospero, Nicholas A., Anstee, Quentin M., Mesenbrinck, Peter, Kjær, Mette S, Rivera-Esteban, Jesús, Sena, Elena, Genesca, Joan, Pericas, Juan M, Manzano-Nunez, Ramiro, Institut Català de la Salut, [Pericàs JM, Rivera-Esteban J, Sena E, Manzano R, Genescà J] Unitat Hepàtica, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Di Prospero NA] Janssen Research and Development, Raritan, New Jersey, USA. [Anstee QM] Liver Unit, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. [Mesenbrinck P] Analytics Department, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. [Kjaer MS] Novo Nordisk A/S, Bagsværd, Denmark, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Medicaments - Desenvolupament, enfermedades del sistema digestivo::enfermedades hepáticas::hígado graso::esteatosis hepática no alcohólica [ENFERMEDADES], Esteatosi hepàtica - Tractament, Hepatology, técnicas de investigación::desarrollo de medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Gastroenterology, Digestive System Diseases::Liver Diseases::Fatty Liver::Non-alcoholic Fatty Liver Disease [DISEASES], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Pharmacology (medical), Other subheadings::Other subheadings::/drug therapy [Other subheadings], Investigative Techniques::Drug Development [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
Abstract: Drug development; Non-alcoholic steatohepatitis; Study designs Desenvolupament de fàrmacs; Esteatohepatitis no alcohòlica; Dissenys d'estudi Desarrollo de fármacos; Esteatohepatitis no alcohólica; Diseños de estudio Background and Aims Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Methods Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Results Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. Conclusions PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, ‘proof-of-platform’ at a smaller scale needs to be provided. JMP reports having received consulting fees from Boehringer-Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. NAdP works for Janssen. QMA is Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. He reports research Grant Funding: Allergan/Tobira, AstraZeneca, Boehringer-Ingelheim, Glaxo SmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd. Consultancy: 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer-Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics. Speaker: Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape. Royalties: Elsevier Ltd. PM works for Novartis. MSK is an employee of and a shareholder in Novo Nordisk A/S. JG has received consulting fees from Boehringer-Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. JRE has received speaking fees from Gilead. FT lab’ work has been supported by the German Research Foundation (DFG, CRC/TR 362) and research grants from Gilead, Allergan, Bristol-Myers Squibb and Inventiva. VR consults for and Intercept, Novo Nordisk, Galmed, Poxel, NGM, Madrigal, Enyo, Sagimet, 89 Bio, Prosciento, Terns, and Theratechnologies, and received grants from Intercept and Gilead.
Published: 2023

5. Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons

Author: Juan M. Pericàs, Frank Tacke, Quentin M. Anstee, Nicholas A. Di Prospero, Mette Skalshøj Kjær, Peter Mesenbrink, Franz Koenig, Joan Genescà, Vlad Ratziu, Institut Català de la Salut, [Pericàs JM, Genescà J] Unitat Hepàtica, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centros de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. [Tacke F] Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany. [Anstee QM] Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NIHR Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK. [Di Prospero NA] Janssen Research and Development, Raritan, New Jersey, USA. [Kjær MS] Novo Nordisk, Bagsværd, Denmark. [Mesenbrink P] Analytics Department, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. [Koenig F] Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria. [Ratziu V] Department of Hepatology, Pitié-Salpêtrière Hospital, France, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Medicaments - Desenvolupament, enfermedades del sistema digestivo::enfermedades hepáticas::hígado graso::esteatosis hepática no alcohólica [ENFERMEDADES], Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], Hepatology, técnicas de investigación::desarrollo de medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Digestive System Diseases::Liver Diseases::Fatty Liver::Non-alcoholic Fatty Liver Disease [DISEASES], Esteatosi hepàtica - Complicacions, Other subheadings::Other subheadings::/complications [Other subheadings], Investigative Techniques::Drug Development [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
Abstract: Non-alcoholic steatohepatitis; Drug development; Non-invasive biomarkers Esteatohepatitis no alcohólica; Desarrollo de fármacos; Biomarcadores no invasivos Esteatohepatitis no alcohòlica; Desenvolupament de medicaments; Biomarcadors no invasius Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH. EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Children’s Tumor Foundation, Global Alliance for TB Drug Development Non-profit Organisation, Springworks Therapeutics Inc.
Published: 2023

6. Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

Author: Ashish Dugar, Eugenio Mercuri, Xiaodong Wang, Volker Straub, Baoguang Han, Daniela Leone, Navid Khan, Dan Wang, Erica Koenig, Laurent Servais, Andreea Mihaela Seferian, Michela Guglieri, Mariacristina Scoto, Francesco Muntoni, University of Oxford, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Liège (CHU-Liège), Université de Liège, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Sarepta Therapeutics, University of Oxford [Oxford], I-Motion Institut [CHU Trousseau], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università cattolica del Sacro Cuore [Roma] (Unicatt), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], and Gestionnaire, Hal Sorbonne Université
Subjects: Duchenne muscular dystrophy, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Population, Oligonucleotides, Walk Test, golodirsen, Biochemistry, Dystrophin, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Internal medicine, Multicenter trial, Drug Discovery, Genetics, medicine, Clinical endpoint, Humans, education, Molecular Biology, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Exons, medicine.disease, Original Papers, Exon skipping, 3. Good health, Clinical trial, Muscular Dystrophy, Duchenne, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ambulatory, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, business, 030217 neurology & neurosurgery, exon skipping
Abstract: The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P
Published: 2022

7. Developing an Evidence and Theory Based Multimodal Integrative Intervention for the Management of Renal Cachexia: A Theory of Change

Author: Carolyn Blair, Adrian Slee, Andrew Davenport, Denis Fouque, William Johnston, Kamyar Kalantar-Zadeh, Peter Maxwell, Clare McKeaveney, Robert Mullan, Helen Noble, Sam Porter, David Seres, Joanne Shields, Ian Swaine, Miles Witham, Joanne Reid, CarMeN, laboratoire, Queen's University [Belfast] (QUB), University College of London [London] (UCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), University of California [Irvine] (UC Irvine), University of California (UC), Antrim Area Hospital - Northern Health and Social Care Trust [Antrim, Northern Ireland] (AAH-NHSCT), Bournemouth University [Poole] (BU), Columbia University Irving Medical Center (CUIMC), Belfast City Hospital, University of Greenwich, Newcastle University [Newcastle], and Newcastle Upon Tyne Hospitals NHS Foundation Trust
Subjects: theory of change, [SDV.BA] Life Sciences [q-bio]/Animal biology, Leadership and Management, [SDV.BA]Life Sciences [q-bio]/Animal biology, Health Policy, kidney disease, Health Informatics, have no competing interest, cachexia, Article, complex intervention, Health Information Management, renal disease, end-stage kidney disease, multimodal intervention, personal and public involvement
Abstract: In this study, we aimed to develop a theoretical framework for a multimodal, integrative, exercise, anti-inflammatory and dietary counselling (MMIEAD) intervention for patients with renal cachexia with reference to how this addresses the underlying causal pathways for renal cachexia, the outcomes anticipated, and how these will be evaluated. We used a Theory of Change (ToC) approach to guide six steps. Step 1 included inputs from a workshop to obtain key stakeholder views on the potential development of a multimodal intervention for renal cachexia. Step 2 included the findings of a mixed-methods study with Health Care Practitioners (HCPs) caring for individuals with End Stage Kidney Disease (ESKD) and cachexia. Step 3 included the results from our systematic literature review on multimodal interventions for cachexia management. In step 4, we used the body of our research team’s cachexia research and wider relevant research to gather evidence on the specific components of the multimodal intervention with reference to how this addresses the underlying causal pathways for renal cachexia. In steps 5 and 6 we developed and refined the ToC map in consultation with the core research team and key stakeholders which illustrates how the intervention components of MMIEAD interact to achieve the intended long-term outcomes and anticipated impact. The results of this study provide a theoretical framework for the forthcoming MMIEAD intervention for those with renal cachexia and in subsequent phases will be used to determine whether this intervention is effective. To the best of our knowledge no other multimodal intervention trials for cachexia management have reported a ToC. Therefore, this research may provide a useful framework and contribute to the ongoing development of interventions for cachexia management.
Published: 2022
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8. Use of sponge-assisted endoluminal vacuum therapy for the treatment of colorectal anastomotic leaks: expert panel consensus

Author: Willem A Bemelman, Alberto Arezzo, Tomasz Banasiewicz, Richard Brady, Eloy Espín-Basany, Omar Faiz, Rosa M Jimenez-Rodriguez, Institut Català de la Salut, [Bemelman WA] Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. [Arezzo A] Department of Surgical Sciences, University of Torino, Turin, Italy. [Banasiewicz T] Poznan University of Medical Sciences, Department of General, Endocrinological Surgery and Gastroenterological Oncology, Poznań, Poland. [Brady R] Newcastle Centre for Bowel Disease Research Group, Department of Colorectal Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK. [Espín-Basany E] Unitat de Cirurgia de Còlon i Recte, Servei de Cirurgia General i Digestiva, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Faiz O] St Mark’s Hospital, London, UK. [Jimenez-Rodriguez RM] Unidad de Coloproctología, Department of Surgery, Hospital Universitario Virgen del Rocío, Sevilla, Spain, Vall d'Hebron Barcelona Hospital Campus, Surgery, CCA - Cancer Treatment and Quality of Life, and Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Consensus, Còlon - Càncer - Cirurgia - Complicacions, Vacuum, Presa de decisions, Anastomotic Leak, Otros calificadores::Otros calificadores::/cirugía [Otros calificadores], General Medicine, Recte - Càncer - Cirurgia - Complicacions, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Psychological Phenomena::Mental Processes::Thinking::Decision Making::Consensus [PSYCHIATRY AND PSYCHOLOGY], Other subheadings::Other subheadings::/surgery [Other subheadings], Pathological Conditions, Signs and Symptoms::Pathologic Processes::Postoperative Complications::Anastomotic Leak [DISEASES], Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], afecciones patológicas, signos y síntomas::procesos patológicos::complicaciones posoperatorias::fuga anastomótica [ENFERMEDADES], Humans, fenómenos psicológicos::procesos mentales::pensamiento::toma de decisión::consenso [PSIQUIATRÍA Y PSICOLOGÍA], Colorectal Neoplasms, Negative-Pressure Wound Therapy
Abstract: Background Anastomotic leaks represent one of the most significant complications of colorectal surgery and are the primary cause of postoperative mortality and morbidity. Sponge-assisted endoluminal vacuum therapy (EVT) has emerged as a minimally invasive technique for the management of anastomotic leaks; however, there are questions regarding patient selection due to the heterogeneous nature of anastomotic leaks and the application of sponge-assisted EVT by surgeons. Method Seven colorectal surgical experts participated in a modified nominal group technique to establish consensus regarding key questions that arose from existing gaps in scientific evidence and the variability in clinical practice. After a bibliographic search to identify the available evidence and sequential meetings with participants, a series of recommendations and statements were formulated and agreed upon. Results Thirty-seven recommendations and statements on the optimal use of sponge-assisted EVT were elaborated on and unanimously agreed upon by the group of experts. The statements and recommendations answer 10 key questions about the indications, benefits, and definition of the success rate of sponge-assisted EVT for the management of anastomotic leaks. Conclusion Although further research is needed to resolve clinical and technical issues associated with sponge-assisted EVT, the recommendations and statements produced from this project summarize critical aspects to consider when using sponge-assisted EVT and to assist those involved in the management of patients with colorectal anastomotic leaks.
Published: 2022

9. Novel DNM1L variants impair mitochondrial dynamics through divergent mechanisms

Author: Kelsey A Nolden, John M Egner, Jack J Collier, Oliver M Russell, Charlotte L Alston, Megan C Harwig, Michael E Widlansky, Souphatta Sasorith, Inês A Barbosa, Andrew GL Douglas, Julia Baptista, Mark Walker, Deirdre E Donnelly, Andrew A Morris, Hui Jeen Tan, Manju A Kurian, Kathleen Gorman, Santosh Mordekar, Charu Deshpande, Rajib Samanta, Robert McFarland, R Blake Hill, Robert W Taylor, Monika Oláhová, Medical College of Wisconsin [Milwaukee] (MCW), Newcastle University [Newcastle], McGill University = Université McGill [Montréal, Canada], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), King‘s College London, University Hospital Southampton NHS Foundation Trust, University of Southampton, Plymouth University, Belfast City Hospital, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Central Manchester University Hospitals [Manchester, U.K.], University College of London [London] (UCL), Children's Health Ireland [Crumlin, Dublin, Ireland] (CHI), University College Dublin [Dublin] (UCD), Sheffield Children's NHS Foundation Trust, Guy's and St Thomas' NHS Foundation Trust [London, UK], University Hospitals Leicester, and MORNET, Dominique
Subjects: [SDV] Life Sciences [q-bio], Ecology, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract: Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like geneDNM1L, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathologicalDNM1Lvariants impair mitochondrial network maintenance by divergent mechanisms.
Published: 2022

10. Revisiting the JOQUER trial: stratification of primary Sjögren’s syndrome and the clinical and interferon response to hydroxychloroquine

Author: Dennis Lendrem, Iris L A Bodewes, Nadia Howard-Tripp, Jessica Tarn, Marjan A. Versnel, Alexis Collins, Raphaèle Seror, Jacques-Eric Gottenberg, Xavier Mariette, James Wason, Wan-Fai Ng, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Erasmus University Medical Center [Rotterdam] (Erasmus MC), CHU Strasbourg, Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunopathologie et chimie thérapeutique (ICT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bicêtre, seror, raphaele, and Immunology
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Placebo, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Interferon, Internal medicine, medicine, Immunology and Allergy, Clinical Trials, 030212 general & internal medicine, Depression (differential diagnoses), 030203 arthritis & rheumatology, business.industry, Repeated measures design, Hydroxychloroquine, [SDV] Life Sciences [q-bio], Sjögren’s syndrome, Anxiety, Sjögren's syndrome, Sjogren s, medicine.symptom, business, medicine.drug
Abstract: To re-analyse the clinical outcomes and interferon (IFN) activity data from the JOQUER trial, a phase III trial investigating hydroxychloroquine (HCQ) in patients with primary Sjögren’s syndrome (pSS), after stratifying patients into putative pathobiological subgroups utilizing the Newcastle Sjögren’s Stratification Tool (NSST) based on patient-reported symptoms of dryness, pain, fatigue, anxiety and depression. 107 patients were assigned to one of four subgroups using NSST at baseline—the high symptom burden (HSB), pain dominant with fatigue (PDF), dryness dominant with fatigue (DDF) and low symptom burden (LSB). Endpoints were re-analysed after stratification, testing for treatment differences within subgroups and adjusting for baseline differences using a repeated measures covariate model. The HSB subgroup (n = 32) showed a relative improvement in ESSPRI of 1.49 points (95% CI 0.54–2.43; p = 0.002) within 12 weeks in patients taking HCQ compared to placebo, with no further changes after 24 weeks. For the LSB subgroup (n = 14), the ESSPRI worsened in the placebo but not the HCQ arm after 12 weeks (mean difference 1.44, 95% CI 0.05–2.83, p = 0.042). Neither the HSB nor the LSB patients showed significant changes in IFN activity at 24 weeks. There were no significant differences in ESSPRI in the PDF (n = 39) and DDF (n = 22) patients taking HCQ. However, significant reductions in overall IFN score at 24 weeks were seen in both PDF (difference at 24 weeks; 6.41, 95% CI, 2.48–10.34, p = 0.002) and DDF (difference at 24 weeks; 7.23, 95% CI, 1.85–12.6, p = 0.009) without improvement in ESSPRI. Although the JOQUER trial reported no overall benefit from HCQ in pSS patients, stratification suggests that both HSB and LSB subgroups may respond to HCQ. However, these patients may benefit through mechanisms other than the reduction of IFN activities.
Published: 2021

11. Variability of Primary Sjögren's Syndrome Is Driven by Interferon α and Interferon α Blood Levels Are Associated With the Class II HLA–DQ Locus

Author: Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Hélène, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana‐Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, Gottenberg, Jacques Eric, Dernis, Emmanuelle, Devauchelle‐Pensec, Valerie, Dieude, Philippe, Dubost, Jean‐Jacques, Fauchais, Anne‐Laure, Goeb, Vincent, Hachulla, Eric, Hatron, Pierre Yves, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Salliot, Carinne, Rist, Stephanie, Saraux, Alain, Vittecoq, Olivier, Nocturne, Gaétane, Ravaud, Philippe, Seror, Raphaèle, Abel, Laurent, Alcover, Andres, Aschard, Hugues, Astrom, Kalla, Bousso, Philippe, Bruhns, Pierre, Cumano, Ana, Demangel, Caroline, Deriano, Ludovic, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gelpi, Odile, GompertsBoneca, Ivo, Hasan, Milena, Hercberg, Serge, Lantz, Olivier, Leclerc, Claude, Mouquet, Hugo, Pellegrini, Sandra, Pol, Stanislas, Rausell, Antonio, Rogge, Lars, Sakuntabhai, Anavaj, Schwartz, Olivier, Shorte, Spencer, Soumelis, Vassili, Tangy, Frédéric, Tartour, Eric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie‐Noëlle, Albert, Matthew L., Biomédecine computationelle des systèmes / Computational systems biomedicine, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie Translationnelle - Translational Immunology lab, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Lausanne University Hospital, University of Bergen (UiB), Oklahoma Medical Research Foundation (OMRF), University of Oklahoma Health Sciences Center (OUHSC), Université de Strasbourg (UNISTRA), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biogen Inc. [Cambridge, MA, USA], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant 806975). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Unionand the European Federation of Pharmaceutical Industries and Associations. This work was also supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal Skin Disease grant R01-AR-065953). The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome(ASSESS) national multicenter prospective cohort was formed in 2006 with aFrench Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Dr. Gottenberg’s work was supported by Bristol Myers Squibbfor transcriptomic analysis of the ASSESS and Norwegian cohorts and by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögrenet des syndromes secs). Drs. Trutschel’s and Schwikowski’s work was supported by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs)., Milieu Intérieur Consortium, ASSESS study investigators, and NECESSITY Consortium: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo GompertsBoneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci., European Project: 806975,NECESSITY, Clauss, Isabelle, and NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID
Subjects: Proteomics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sjogren's Syndrome, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, HLA-DQ Antigens, Immunology, Humans, Interferon-alpha, Immunology and Allergy, Prospective Studies
Abstract: Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA–DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., Arthritis & Rheumatology, 74 (12), ISSN:2326-5191, ISSN:2326-5205
Published: 2022

12. Noncoding RNAs in age-related cardiovascular diseases

Author: Amela Jusic, Pınar Buket Thomas, Stephanie Bezzina Wettinger, Soner Dogan, Rosienne Farrugia, Carlo Gaetano, Bilge Güvenç Tuna, Florence Pinet, Emma L. Robinson, Simon Tual-Chalot, Konstantinos Stellos, Yvan Devaux, Luxembourg Institute of Health (LIH), Université de Maltèpe - Maltepe Üniversitesi - Maltepe University [Turquie], University of Malta [Malta], Yeditepe University, Istituti Clinici Scientifici Maugeri [Pavia] (IRCCS Pavia - ICS Maugeri), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Colorado Anschutz [Aurora], Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, AJ is funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Actions grant agreement 893435. CG is funded by 'Progetto IMMUNHUB Regione Lombardia' and 'Progetto di rete Ageing IRCCS: progetto IRMA, progetto SIRI'. FP has received a grant by the French Government, managed by the National Research Agency (ANR) under the program 'Investissements d’avenir' with the reference ANR-16-RHUS-0003. ELR is funded by an American Heart Association postdoctoral fellowship (AHA Award Number: 829504). YD is funded by the EU Horizon 2020 project COVIRNA (Grant Agreement # 101016072), the National Research Fund (grants # C14/BM/8225223, C17/BM/11613033 and COVID-19/2020-1/14719577/miRCOVID), the Ministry of Higher Education and Research, and the Heart Foundation-Daniel Wagner of Luxembourg. KS is supported by grants from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (MODVASC, grant agreement No 759248) and the German Research Foundation DFG (SFB834 B12, project number 75732319). STC is supported by a grant from the British Society for Research on Ageing., and ANR-16-RHUS-0003,STOP-AS,STOP-AS(2016)
Subjects: Aging, RNA, Untranslated, Noncoding RNAs, [SDV]Life Sciences [q-bio], Heart, Cardiovascular disease, Biochemistry, Cardiovascular System, MicroRNAs, Ageing, Inflammageing, Neurology, Cardiovascular Diseases, Humans, RNA, Long Noncoding, Molecular Biology, Biotechnology
Abstract: International audience; Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the adult population worldwide and represent a severe economic burden and public health concern. The majority of human genes do not code for proteins. However, noncoding transcripts play important roles in ageing that significantly increases the risk for CVDs. Noncoding RNAs (ncRNAs) are critical regulators of multiple biological processes related to ageing such as oxidative stress, mitochondrial dysfunction and chronic inflammation. NcRNAs are also involved in pathophysiological developments within the cardiovascular system including arrhythmias, cardiac hypertrophy, fibrosis, myocardial infarction and heart failure. In this review article, we cover the roles of ncRNAs in cardiovascular ageing and disease as well as their potential therapeutic applications in CVDs.
Published: 2022

13. Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease

Author: Kyle Thompson, Lucas Bianchi, Francesca Rastelli, Florence Piron-Prunier, Sophie Ayciriex, Claude Besmond, Laurence Hubert, Magalie Barth, Inês A. Barbosa, Charu Deshpande, Manali Chitre, Sarju G. Mehta, Eric J.M. Wever, Pascale Marcorelles, Sandra Donkervoort, Dimah Saade, Carsten G. Bönnemann, Katherine R. Chao, Chunyu Cai, Susan T. Iannaccone, Andrew F. Dean, Robert McFarland, Frédéric M. Vaz, Agnès Delahodde, Robert W. Taylor, Agnès Rötig, Newcastle University [Newcastle], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), King‘s College London, Guy's and St Thomas NHS Foundation Trust [London], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), University of Amsterdam [Amsterdam] (UvA), Amsterdam Public Health Research Institute [The Netherlands], Amsterdam UMC - Amsterdam University Medical Center, Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Texas Southwestern Medical Center [Dallas], Newcastle Upon Tyne Hospitals NHS Foundation Trust, This study was financially supported by the Agence Nationale de la Recherche through the Investissements d'Avenir program ANR-10-IAHU-01 (A.R., L.B., C.B., and L.H.), the E-Rare project GENOMIT (01GM1207, A.R. and L.B.), the French National Agency for Research (ANR-16-CE16-0025-04, A.D. and F.P.-P.), and the 'Association Francaise contre les Myopathies' (AFM -MITOSCREEN, project no. 17122, A.D. and F.P.-P.). We acknowledge the use of bioresources of the Necker Imagine DNA biobank (BB-033-00065). R.M. and R.W.T. are supported by the Wellcome Trust Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) International Center for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the UK NIHR Biomedical Research Center for Aging and Age-Related Disease Award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the Lily Foundation, and the UK NHS Specialist Commissioners, which funds the 'Rare Mitochondrial Disorders of Adults and Children' Diagnostic Service in Newcastle upon Tyne. R.W.T. also receives financial support from the Pathology Society. K.T. and I.A.B. were supported by the Lily Foundation. C.G.B. is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Bussy, Agnès, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, APH - Personalized Medicine, and APH - Methodology
Subjects: [CHIM.ANAL] Chemical Sciences/Analytical chemistry, WES/WGS, OXPHOS defect, mitochondria, mitochondrial disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [CHIM] Chemical Sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Medicine, [CHIM]Chemical Sciences, mitochondrial phospholipid, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, cardiolipin, Genetics (clinical)
Abstract: International audience; Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.
Published: 2022

14. Diagnostic Advances in Childhood Tuberculosis-Improving Specimen Collection and Yield of Microbiological Diagnosis for Intrathoracic Tuberculosis

Author: Eric Wobudeya, Maryline Bonnet, Elisabetta Ghimenton Walters, Pamela Nabeta, Rinn Song, Wilfred Murithi, Walter Mchembere, Bunnet Dim, Jean-Voisin Taguebue, Joanna Orne-Gliemann, Mark P. Nicol, Olivier Marcy, Makerere University [Kampala, Ouganda] (MAK), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Stellenbosch University, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Foundation for Innovative New Diagnostics (FIND), University of Oxford, Kenya Medical Research Institute (KEMRI), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Fondation Chantal Biya (FCB), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD), The University of Western Australia (UWA), University of Cape Town, Admin, Oskar, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Global Health in the Global South (GHiGS), Institut de Recherche pour le Développement (IRD)- Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Microbiology (medical), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, General Immunology and Microbiology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Microbiological tests, Sample collection methods, Infectious Diseases, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Diagnosis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Tuberculosis, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Molecular Biology, Children
Abstract: International audience; There is no microbiological gold standard for childhood tuberculosis (TB) diagnosis. The paucibacillary nature of the disease, challenges in sample collection in young children, and the limitations of currently available microbiological tests restrict microbiological confirmation of intrathoracic TB to the minority of children. Recent WHO guidelines recommend the use of novel rapid molecular assays as initial diagnostic tests for TB and endorse alternative sample collection methods for children. However, the uptake of these tools in high-endemic settings remains low. In this review, we appraise historic and new microbiological tests and sample collection techniques that can be used for the diagnosis of intrathoracic TB in children. We explore challenges and possible ways to improve diagnostic yield despite limitations, and identify research gaps to address in order to improve the microbiological diagnosis of intrathoracic TB in children.
Published: 2022

15. European Stroke Organisation (ESO)-European Society for Minimally Invasive Neurological Therapy (ESMINT) expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischemic stroke and anterior circulation large vessel occlusion

Author: Guillaume Turc, Georgios Tsivgoulis, Heinrich J Audebert, Hieronymus Boogaarts, Pervinder Bhogal, Gian Marco De Marchis, Ana Catarina Fonseca, Pooja Khatri, Mikaël Mazighi, Natalia Pérez de la Ossa, Peter D Schellinger, Daniel Strbian, Danilo Toni, Philip White, William Whiteley, Andrea Zini, Wim van Zwam, Jens Fiehler, Beeldvorming, MUMC+: DA BV Medisch Specialisten Radiologie (9), RS: Carim - B05 Cerebral small vessel disease, RS: Carim - B06 Imaging, GHU Paris Psychiatrie et Neurosciences, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University General Hospital ' Attikon ' [Athens, Greece], The University of Tennessee Health Science Center [Memphis] (UTHSC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Radboud University Medical Center [Nijmegen], Royal Free Hospital [London, UK], University of Basel (Unibas), Universidade de Lisboa = University of Lisbon (ULISBOA), University of Cincinnati (UC), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospital Germans Trias i Pujol [Barcelona, Spain], Ruhr-Universität Bochum [Bochum], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Newcastle Upon Tyne Hospitals NHS Foundation Trust, University of Edinburgh, Maggiore-Bellaria Hospital [Bologna], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), and Martinez Rico, Clara
Subjects: thrombolysis, Mechanical Thrombolysis, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], RECANALIZATION, GUIDELINES, Brain Ischemia, EARLY MANAGEMENT, All institutes and research themes of the Radboud University Medical Center, Fibrinolytic Agents, Thrombolytic Therapy/methods, ALTEPLASE, Humans, Thrombolytic Therapy, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PLASMINOGEN-ACTIVATOR, Ischemic Stroke, HEALTH-CARE PROFESSIONALS, OUTCOMES, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Fibrinolytic Agents/therapeutic use, Mechanical Thrombolysis/methods, Brain Ischemia/drug therapy, General Medicine, stroke, ARTERY-OCCLUSION, Treatment Outcome, Thrombectomy/methods, thrombectomy, ENDOVASCULAR TREATMENT, standards, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Surgery, TRIAL, Neurology (clinical), Stroke/drug therapy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Six randomized controlled clinical trials have assessed whether mechanical thrombectomy (MT) alone is non-inferior to intravenous thrombolysis (IVT) plus MT within 4.5 hours of symptom onset in patients with anterior circulation large vessel occlusion (LVO) ischemic stroke and no contraindication to IVT. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted with the European Society of Minimally Invasive Neurological Therapy (ESMINT) according to ESO standard operating procedure based on the GRADE system. We identified two relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert opinion was provided if insufficient evidence was available to provide recommendations based on the GRADE approach.For stroke patients with anterior circulation LVO directly admitted to a MT-capable center (‘mothership’) within 4.5 hours of symptom onset and eligible for both treatments, we recommend IVT plus MT over MT alone (moderate evidence, strong recommendation). MT should not prevent the initiation of IVT, nor should IVT delay MT. In stroke patients with anterior circulation LVO admitted to a center without MT facilities and eligible for IVT ≤4.5 hours and MT, we recommend IVT followed by rapid transfer to a MT capable-center (‘drip-and-ship’) in preference to omitting IVT (low evidence, strong recommendation). Expert consensus statements on ischemic stroke on awakening from sleep are also provided. Patients with anterior circulation LVO stroke should receive IVT in addition to MT if they have no contraindications to either treatment.
Published: 2022

16. The identification, assessment and management of difficult-to-treat depression: An international consensus statement

Author: Allan H. Young, Gin S Malhi, RH McAllister-Williams, Eduard Vieta, Philip Gorwood, Afzal Javed, Peter Falkai, Andrew Papadopoulos, A. J. Rush, Celso Arango, Jair C. Soares, Malcolm Hopwood, Pierre Blier, Koen Demyttenaere, Siegfried Kasper, Martinez Rico, Clara, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Instituto de Investigación Sanitaria Gregorio Marañón [Madrid, Spain] ( IiSGM), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), University of Ottawa [Ottawa], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Ludwig Maximilian University [Munich] (LMU), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Melbourne, University of Warwick [Coventry], Medizinische Universität Wien = Medical University of Vienna, The University of Sydney, Royal North Shore Hospital (RNSH), The University of Texas Health Science Center at Houston (UTHealth), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), King‘s College London, South London and Maudsley NHS Foundation Trust, Somerset Partnership NHS Foundation Trust, Duke University [Durham], Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Duke-NUS Medical School [Singapore], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: VAGUS NERVE-STIMULATION, TRANSCRANIAL MAGNETIC STIMULATION, medicine.medical_specialty, Consensus, 2016 CLINICAL GUIDELINES, SEROTONIN REUPTAKE INHIBITORS, medicine.medical_treatment, Clinical Neurology, GENERALIZED ANXIETY DISORDER, Difficult-to-treat depression, Depressive Disorder, Treatment-Resistant, DOUBLE-BLIND, 03 medical and health sciences, POSTTRAUMATIC-STRESS-DISORDER, 0302 clinical medicine, Pharmacotherapy, Diagnosis, medicine, Humans, Symptom control, COGNITIVE-BEHAVIORAL THERAPY, Intensive care medicine, Neurostimulation, Psychiatry, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Science & Technology, Conceptualization, Depression, Clinical management, business.industry, Treatment options, MAJOR DEPRESSION, medicine.disease, 3. Good health, 030227 psychiatry, Psychotherapy, Psychiatry and Mental health, Clinical Psychology, Management implications, Quality of Life, TREATMENT-RESISTANT DEPRESSION, Neurosciences & Neurology, Treatment-resistant depression, business, Life Sciences & Biomedicine, Psychosocial, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: BACKGROUND: Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials - often termed "treatment resistant depression". A broader, perhaps more empathic concept of "difficult-to-treat depression" (DTD) was considered. METHODS: A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic. RESULTS: The group proposed that DTD be defined as "depression that continues to cause significant burden despite usual treatment efforts". All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive. LIMITATIONS: The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials. CONCLUSIONS: DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients. ispartof: Journal of Affective Disorders vol:267 pages:264-282 ispartof: location:Netherlands status: published
Published: 2020

17. The global NAFLD policy review and preparedness index: Are countries ready to address this silent public health challenge?

Author: Jeffrey V. Lazarus, Henry E. Mark, Marcela Villota-Rivas, Adam Palayew, Patrizia Carrieri, Massimo Colombo, Mattias Ekstedt, Gamal Esmat, Jacob George, Giulio Marchesini, Katja Novak, Ponsiano Ocama, Vlad Ratziu, Homie Razavi, Manuel Romero-Gómez, Marcelo Silva, C. Wendy Spearman, Frank Tacke, Emmanuel A. Tsochatzis, Yusuf Yilmaz, Zobair M. Younossi, Vincent W.-S. Wong, Shira Zelber-Sagi, Helena Cortez-Pinto, Quentin M. Anstee, Samir Rouabhia, Hasmik Ghazinyan, Natacha Jreige Iskandar, Michael Trauner, Gulnara Aghayeva, Flloyd Carter, Kannan Sridharan, Mamun Al Mahtab, Sven Francque, Nicolas Kodjoh, Ruben Muñoz Camacho, Motswedi Anderson, Claudia Pinto Marques Souza de Oliveira, Lyudmila Mateva, Abdel Karim Serme, Antonieta A. Soares Martins, Mark G. Swain, Narcisse Patrice Komas, Ming-Hua Zheng, Patricio Lopez Jaramillo, Omar Alfaro Murillo, Ivana Mikolasevic, Emmelia Vounou, Radan Brůha, Charles Mbendi Nlombi, Maja Thiele, Marlene Perez, Juan José Suárez M, Imam Waked, Riina Salupere, Hailemichael Desalegn, Hannele Yki-Järvinen, Tengiz Tsertsvadze, Lali Sharvadze, Maia Butsashvili, Yaw Asante Awuku, Georgios Papatheodoridis, Bela Hunyady, Einar Stefan Bjornsson, Ajay Duseja, Cosmas Rinaldi A. Lesmana, Reza Malekzadeh, Suzanne Norris, Kazuhiko Koike, Alexander V. Nersesov, Missiani Ochwoto, Mohammad Jamal, Tobokalova Saparbu, Ieva Tolmane, Raymond Sayegh, Dhastagir Sultan Sheriff, Jonas Valantinas, Joseph Weber, Isaac Thom Shawa, Soek-Siam Tan, Sophia E. Martínez Vázquez, Oidov Baatarkhuu, Undram Lkhagvaa, Tsolmon Jadamba, Tahiri Mohammed, K.C Sudhamshu, Kirsten Coppell, Charles Onyekwere, Dafina Nikolova, Mette Vesterhus, Khalid Al-Naamani, Saeed Hamid, Juan Paredes Méndez, María Cecilia Cabrera Cabrejos, Robert Flisiak, Esther A. Torres, Shahrad Taheri, Ki-Chul Sung, Turcanu Adela, Liana Gheorghe, Faisal M. Sanai, Tamara Milovanovic, George Boon Bee Goh, Marek Rac, Anuradha Dassanayake, Shahinaz Bedri Osama, M. Elsanousi, Jean-François Dufour, Jia-Horng Kao, Dilshod Saidi, Sombat Treeprasertsuk, Ger Koek, Asma Labidi, Igor Skrypnyk, Maryam Salem AlKhatry, Shakhlo Sadirova, Shokhista Bakieva, Edford Sinkala, Repositório da Universidade de Lisboa, Lazarus, Jeffrey V., Mark, Henry E., Villota-Rivas, Marcela, Palayew, Adam, Carrieri, Patrizia, Colombo, Massimo, Ekstedt, Mattias, Esmat, Gamal, George, Jacob, Marchesini, Giulio, Novak, Katja, Ocama, Ponsiano, Ratziu, Vlad, Razavi, Homie, Romero-Gómez, Manuel, Silva, Marcelo, Spearman, C. Wendy, Tacke, Frank, Tsochatzis, Emmanuel A., Yilmaz, Yusuf, Younossi, Zobair M., Wong, Vincent W.-S., Zelber-Sagi, Shira, Cortez-Pinto, Helena, Anstee, Quentin M., NAFLD policy review collaborators, University of Barcelona, EASL International Liver Foundation [Geneva, Switzerland] (ILF), University of Washington [Seattle], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), IRCCS San Raffaele Hospital, Linköping University (LIU), Cairo University, The University of Sydney, University of Bologna/Università di Bologna, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Makerere University [Kampala, Ouganda] (MAK), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Center for Disease Analysis Foundation [Lafayette, CO, États-Unis], Biomedicine Institute of Sevilla [Seville, Spain], Hospital Universitario Austral, University of Cape Town, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute for Liver & Digestive Health [London, UK], Marmara University [Kadıköy - İstanbul], Inova Medicine [Falls Church, Virginia, USA] (IM), The Chinese University of Hong Kong [Hong Kong], University of Haifa [Haifa], Tel Aviv Sourasky Medical Center [Te Aviv], Universidade de Lisboa = University of Lisbon (ULISBOA), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, EASL International Liver Foundation, Bristol-Myers Squibb, Genfit, MSD, Gilead Sciences, Allergan Foundation, Pfizer, Resoundant, Wong, Vincent Wai-Sun, and Malbec, Odile
Subjects: policy preparedness, Adult, [SDV]Life Sciences [q-bio], non-alcoholic steatohepatitis (NASH), multiple correspondence analysis, Global Health, digestive system, Policy preparednesss, Non-alcoholic fatty liver disease (NAFLD), liver health, Non-alcoholic Fatty Liver Disease, Humans, Obesity, Non-alcoholic steatohepatitis (NASH), BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, global public health, Hepatology, Liver health, nutritional and metabolic diseases, health policy, digestive system diseases, Health policy, Multiple correspondence analysis, [SDV] Life Sciences [q-bio], Policy, Policy preparedness, Public Health, Global public health
Abstract: [Background & Aims]: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, yet largely underappreciated liver condition which is closely associated with obesity and metabolic disease. Despite affecting an estimated 1 in 4 adults globally, NAFLD is largely absent on national and global health agendas., [Methods]: We collected data from 102 countries, accounting for 86% of the world population, on NAFLD policies, guidelines, civil society engagement, clinical management, and epidemiologic data. A preparedness index was developed by coding questions into 6 domains (policies, guidelines, civil awareness, epidemiology and data, NAFLD detection, and NAFLD care management) and categorising the responses as high, medium, and low; a multiple correspondence analysis was then applied., [Results]: The highest scoring countries were India (42.7) and the United Kingdom (40.0), with 32 countries (31%) scoring zero out of 100. For 5 of the domains a minority of countries were categorised as high-level while the majority were categorised as low-level. No country had a national or sub-national strategy for NAFLD and, [Conclusions]: Although NAFLD is a pressing public health problem, no country was found to be well prepared to address it. There is a pressing need for strategies to address NAFLD at national and global levels., The data collection and analysis were funded by the EASL International Liver Foundation with support from, Intercept, Bristol-Myers-Squibb Company, Genfit, and MSD. Data collection for the original European data was funded by the EASL International Liver Foundation supported by Gilead Sciences Europe Ltd., Allergan Pharmaceutical International Ltd., Bristol-Myers-Squibb Company, Pfizer Inc., and Resoundant Inc.
Published: 2021

18. Comparison of clinical prediction rules for ruling out cirrhosis in nonalcoholic fatty liver disease (NAFLD)

Author: Danielle, Brandman, Marie, Boyle, Stuart, McPherson, Mark L, Van Natta, Arun J, Sanyal, Kris, Kowdley, Brent, Neuschwander-Tetri, Naga, Chalasani, Manal F, Abdelmalek, Norah A, Terrault, Art, McCullough, Ricki, Bettencourt, Cyrielle, Caussy, David E, Kleiner, Cynthia, Behling, James, Tonascia, Quentin M, Anstee, Rohit, Loomba, University of California [San Francisco] (UC San Francisco), University of California (UC), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Virginia Commonwealth University (VCU), Swedish Medical Center [Seattle, WA, USA] (SMC), Saint Louis University (SLU), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Duke University [Durham], University of Southern California (USC), Cleveland Clinic, University of California [San Diego] (UC San Diego), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), National Institutes of Health [Bethesda] (NIH), National Cancer Institute [Bethesda] (NCI-NIH), Sharp Memorial Hospital [San Diego, CA, USA] (SMH), and CarMeN, laboratoire
Subjects: nonalcoholic fatty liver disease, Adult, Liver Cirrhosis, Hepatology, cirrhosis, [SDV]Life Sciences [q-bio], Biopsy, Gastroenterology, Fibrosis, Article, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, noninvasive assessment, Liver, Non-alcoholic Fatty Liver Disease, Clinical Decision Rules, Elasticity Imaging Techniques, Humans, Pharmacology (medical), Female
Abstract: International audience; BACKGROUND AND AIMS: Patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy-proven cirrhosis in NAFLD. METHODS: Adult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB-4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort. RESULTS: 147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95-0.97). FIB-4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84-0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92-0.96), and FIB-4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87-0.89). CONCLUSIONS: This cross-sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and \textless65, unlikely to have cirrhosis so higher-risk patients maintain access to specialty care.
Published: 2021

19. International retrospective natural history study of LMNA-related congenital muscular dystrophy Short Title: LMNA-CMD natural history

Author: Ben Yaou, Rabah, Yun, Pomi, D’Amico, Adele, Francesco, Muntoni, Bönnemann, Carsten, Yaou, Rabah, Dabaj, Ivana, Norato, Gina, Donkervoort, Sandra, Xiong, Hui, Nascimento, Andrés, Maggi, Lorenzo, Sarkozy, Anna, Monges, Soledad, Bertoli, Marta, Komaki, Hirofumi, Mayer, Michèle, Mercuri, Eugenio, Zanoteli, Edmar, Castiglioni, Claudia, Marini-Bettolo, Chiara, D'Amico, Adele, Deconinck, Nicolas, Desguerre, Isabelle, Erazo-Torricelli, Ricardo, Gurgel-Giannetti, Juliana, Ishiyama, Akihiko, Kleinsteuber, Karin, Lagrue, Emmanuelle, Laugel, Vincent, Mercier, Sandra, Messina, Sonia, Politano, Luisa, Ryan, Monique, Sabouraud, Pascal, Schara, Ulrike, Siciliano, Gabriele, Vercelli, Liliana, Voit, Thomas, Yoon, Grace, Alvarez, Rachel, Muntoni, Francesco, Pierson, Tyler, GóMez-Andrés, David, Foley, A Reghan, Quijano-Roy, Susana, Bonne, Gisèle, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Hôpital Raymond Poincaré [AP-HP], Peking University [Beijing], Institut de Recerca Pediàtrica Hospital Sant Joan de Déu [Barcelona, Spain], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Department of Neurology, Great Ormond Street Hospital for Children [London] (GOSH), Hospital Nacional de Pediatría J.P. Garrahan, Newcastle Upon Tyne Hospitals NHS Foundation Trust, National Center of Neurology and Psychiatry, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Filière Neuromusculaire (FILNEMUS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de chirurgie pédiatrique [CHU Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Reims (CHU Reims), and Centre de Recherche en Myologie
Subjects: muscular dystrophy, Laminopathies, striated muscle, early onset, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], LMNA
Abstract: International audience; Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (Median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never aquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (Median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (Median: 7 years, range 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopedic, cardiac, and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.
Published: 2021

20. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Bertrand Isidor, Ruth Armstrong, Thabo M. Yates, Susan M. White, Ruth Richardson, Solveig Heide, Katherine B. Burke, Tjitske Kleefstra, Marie Vincent, Meena Balasubramanian, Maria Irene Valenzuela Palafoll, Sébastien Küry, Rolph Pfundt, Ruth Newbury-Ecob, Sahar Mansour, Wendy K. Chung, Caroline Nava, Sofia Douzgou, Erika Leenders, Annachiara De Sandre-Giovannoli, Saba Sharif, Andrew E. Fry, Helen Stewart, Nicola K. Ragge, Alexander J. M. Dingemans, Pradeep C. Vasudevan, Alison Foster, Sahar Elouej, Shadi Albaba, François-Guillaume Debray, Boris Keren, Serwet Demirdas, Francis H. Sansbury, Thomas Scheffner, Arie van Haeringen, Alice S. Brooks, Meyke Schouten, Helen Cox, Kate Wilson, Sheffield Children's NHS Foundation Trust, University of Sheffield [Sheffield], Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Birmingham Children’s Hospital, Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], Addenbrooke's Hospital, Cambridge University NHS Trust, University Hospital of Wales, Oxford Brookes University, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), St. George’s Hospital University, Oxford University Hospitals NHS Foundation Trust, Partenaires INRAE, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Leiden University Medical Center (LUMC), Reutlingen University, Centre Hospitalier Universitaire de Liège (CHU-Liège), Murdoch Children's Research Institute (MCRI), University of Melbourne, Vall d'Hebron University Hospital [Barcelona], University Hospitals Bristol, Clinical Genetics, Institut Català de la Salut, [Balasubramanian M] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK. [Dingemans AJM] Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. [Albaba S] Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Richardson R] Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK. [Yates TM] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Cox H] West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK. [Palafoll MIV] Servei de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Medicina Genètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University Hospital of Wales (UHW), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Universiteit Leiden
Subjects: Male, Pediatrics, Genetic testing, Developmental Disabilities, Craniofacial Abnormalities, Intellectual disability, Missense mutation, Child, Genetics (clinical), trastornos mentales::trastornos del desarrollo neurológico::discapacidades del desarrollo [PSIQUIATRÍA Y PSICOLOGÍA], 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 030305 genetics & heredity, Cognition, Syndrome, Autism spectrum disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, 3. Good health, Fenotip, Sin3 Histone Deacetylase and Corepressor Complex, Phenotype, Autism spectrum disorder, Child, Preschool, Cohort, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Trastorns del desenvolupament - Aspectes genètics, Infants, medicine.medical_specialty, Adolescent, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Article, 03 medical and health sciences, Mental Disorders::Neurodevelopmental Disorders::Developmental Disabilities [PSYCHIATRY AND PSYCHOLOGY], Intellectual Disability, Genetics, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Attention deficit hyperactivity disorder, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], Autism, business, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS]
Abstract: Trastornos del espectro autista; Prueba genética Trastorns de l'espectre autista; Prova genètica Autism spectrum disorders; Genetic testing Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12. Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation
Published: 2021

21. Differences between current clinical guidelines for screening, diagnosis and management of non-alcoholic fatty liver disease and real-world practice: a targeted literature review

Author: Cyrielle Caussy, Branko Popovic, Elisabetta Bugianesi, Jörn M. Schattenberg, Quentin M. Anstee, CarMeN, laboratoire, University Medical Center of the Johannes Gutenberg-University Mainz, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Università degli studi di Torino = University of Turin (UNITO), and Sanofi-Aventis Deutschland GmbH [Francfort, Allemagne]
Subjects: nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, medicine.medical_specialty, literature review, [SDV]Life Sciences [q-bio], Liver fibrosis, digestive system, Gastroenterology, Diagnosis, Differential, Liver disease, real-world practice, Liver steatosis, Non-alcoholic Fatty Liver Disease, Internal medicine, Nonalcoholic fatty liver disease, medicine, Humans, Mass Screening, nonalcoholic steatohepatitis, liver fibrosis, Hepatology, business.industry, nutritional and metabolic diseases, food and beverages, medicine.disease, Obesity, digestive system diseases, [SDV] Life Sciences [q-bio], clinical guidelines, Practice Guidelines as Topic, business
Abstract: International audience; INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and is associated with obesity and metabolic comorbidities. Liver steatosis can progress to nonalcoholic steatohepatitis (NASH) exhibiting a relevant risk of fibrosis and ultimately liver failure. To date, no approved treatment for NASH to reduce its clinical and humanistic burden has been developed. AREAS COVERED: We undertook a literature review to identify English language, national and international clinical guidelines for NAFLD regarding diagnosis, assessment and management, and determined their points of agreement and difference. Additionally, we investigated published literature relating to real-world management of NAFLD and NASH. EXPERT OPINION: National (China, England/Wales, Italy, the USA) and international society (Asia-Pacific, Europe, World Gastroenterology Organization) guidelines were identified and analyzed. All guidelines addressed identifying and diagnosing subjects with likely NAFLD, as well as assessment and management of individuals with risk factors for advanced disease, including fibrosis. Real-world practice reveals widespread suboptimal awareness and implementation of guidelines. In the absence of proven therapeutics, such gaps risk failure to recognize patients in need of specialist care and monitoring, highlighting the need for clear, easy-to-apply care pathways to aid in reducing the clinical and humanistic burden of NAFLD and NASH.
Published: 2021

22. Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases

Author: Zurek, Birte, Ellwanger, Kornelia, Vissers, Lisenka E. L. M., Schüle, Rebecca, Synofzik, Matthis, Töpf, Ana, de Voer, Richarda M., Laurie, Steven, Matalonga, Leslie, Gilissen, Christian, Ossowski, Stephan, ’t Hoen, Peter A. C., Vitobello, Antonio, Schulze-Hentrich, Julia M., Riess, Olaf, Brunner, Han G., Brookes, Anthony J., Rath, Ana, Bonne, Gisèle, Gumus, Gulcin, Verloes, Alain, Hoogerbrugge, Nicoline, Evangelista, Teresinha, Harmuth, Tina, Swertz, Morris, Spalding, Dylan, Hoischen, Alexander, Beltran, Sergi, Graessner, Holm, Haack, Tobias B., Demidov, German, Sturm, Marc, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, Brunner, Han, Scheffer, Hans, Steyaert, Wouter, Sablauskas, Karolis, Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Bros-Facer, Virginie, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, Van de Vondel, Liedewei, Beijer, Danique, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Marcé-Grau, Anna, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA Klinische Genetica (5), Zurek, Birte [0000-0002-8200-7542], Ellwanger, Kornelia [0000-0003-4845-5795], Vissers, Lisenka ELM [0000-0001-6470-5497], Synofzik, Matthis [0000-0002-2280-7273], de Voer, Richarda M [0000-0002-8222-0343], Laurie, Steven [0000-0003-3913-5829], Gilissen, Christian [0000-0003-1693-9699], 't Hoen, Peter AC [0000-0003-4450-3112], Vitobello, Antonio [0000-0003-3717-8374], Brookes, Anthony J [0000-0001-8686-0017], Rath, Ana [0000-0003-4308-6337], Bonne, Gisèle [0000-0002-2516-3258], Verloes, Alain [0000-0003-4819-0264], Hoogerbrugge, Nicoline [0000-0003-2393-8141], Harmuth, Tina [0000-0002-4833-8057], Spalding, Dylan [0000-0002-4285-2493], Beltran, Sergi [0000-0002-2810-3445], Graessner, Holm [0000-0001-9803-7183], Apollo - University of Cambridge Repository, Zurek, B., Ellwanger, K., Vissers, L. E. L. M., Schule, R., Synofzik, M., Topf, A., de Voer, R. M., Laurie, S., Matalonga, L., Gilissen, C., Ossowski, S., 't Hoen, P. A. C., Vitobello, A., Schulze-Hentrich, J. M., Riess, O., Brunner, H. G., Brookes, A. J., Rath, A., Bonne, G., Gumus, G., Verloes, A., Hoogerbrugge, N., Evangelista, T., Harmuth, T., Swertz, M., Spalding, D., Hoischen, A., Beltran, S., Graessner, H., Nigro, V., Banfi, S., Torella, A., Piluso, G., Dürr, Alexandra, Lohmann, Katja, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschuetz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, University of Tübingen, Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Leicester, Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), EURORDIS-Rare Diseases Europe (Bureau de Paris), EURORDIS - Plateforme Maladies Rares [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center Groningen [Groningen] (UMCG), European Molecular Biology Laboratory [Hinxton], Universitat de Barcelona (UB), SOLVE-RD Consortium, Projekt DEAL, Unión Europea. Comisión Europea. H2020, European Reference Network for Rare Neurological Diseases (ERN-RND), Haack, T. B., Demidov, G., Sturm, M., Kessler, C., Wayand, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Heutink, P., Brunner, H., Scheffer, H., Steyaert, W., Sablauskas, K., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., te Paske, I., Janssen, E., de Boer, E., Steehouwer, M., Yaldiz, B., Kleefstra, T., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Clayton-Smith, J., Banka, S., Alexander, E., Jackson, A., Faivre, L., Thauvin, C., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Garcia, C., Fernandez-Callejo, M., Hernandez, C., Pico, D., Paramonov, I., Lochmuller, H., Bros-Facer, V., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Nelson, I., Yaou, R. B., Metay, C., Eymard, B., Cohen, E., Atalaia, A., Stojkovic, T., Macek, M., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Havlovicova, M., Kremlik, V., Parkinson, H., Keane, T., Senf, A., Robinson, P., Danis, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Vandrovcova, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., Van de Vondel, L., Beijer, D., de Jonghe, P., Musacchia, F., Ferlini, A., Selvatici, R., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Velde, J. K., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Drunat, S., Rooryck, C., Trimouille, A., Castello, R., Morleo, M., Pinelli, M., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Balicza, P., Molnar, M. J., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., Macaya, A., Marce-Grau, A., Osorio, A. N., de Benito, D. N., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Cruz, P. M. R., Hackman, P., Johari, M., Savarese, M., Udd, B., Horvath, R., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., Rump, A., Gestionnaire, HAL Sorbonne Université 5, Centre de Recherche en Myologie, Medicum, University of Helsinki, and Department of Medical and Clinical Genetics
Subjects: Computer science, Consensus Development Conferences as Topic, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Diseases, Pan european, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Intersectoral Collaboration, Genetics (clinical), Exome sequencing, 0303 health sciences, 030305 genetics & heredity, Medical genetics, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, diagnosis [Rare Diseases], Europe, GENOME, Chemistry, New disease, Patient representatives, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], methods [Genetic Testing], MEDLINE, Socio-culturale, 03 medical and health sciences, Viewpoint, Rare Diseases, Exome Sequencing, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, genetics [Genetic Diseases, Inborn], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Information Dissemination, Genetic Diseases, Inborn, Correction, Data science, diagnosis [Genetic Diseases, Inborn], Data sharing, methods [Exome Sequencing], 3111 Biomedicine, Human medicine, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Rare disease
Abstract: For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. This research is supported (not financially) by four ERNs: (1) The ERN for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA)-Project ID No 869189; (2) The ERN on Rare Neurological Diseases (ERN-RND)-Project ID No 739510; (3) The ERN for Neuromuscular Diseases (ERN Euro-NMD)-Project ID No 870177; (4) The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS)-Project ID No 739547. The ERNs are co-funded by the European Union within the framework of the Third Health Programme. Open Access funding enabled and organized by Projekt DEAL. Sí
Published: 2021

23. The Enduring Experience in Dry Eye Diagnosis: A Non-Interventional Study Comparing the Experiences of Patients Living With and Without Sjögren’s Syndrome

Author: Genevieve Garrigos, Christophe Baudouin, Maurizio Rolando, Marc Labetoulle, Jean-Sebastien Garrigue, Gysbert van Setten, Elisabeth M. Messmer, Francisco C Figueiredo, Gestionnaire, Hal Sorbonne Université, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle University [Newcastle], Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Institut Hospitalo-Universitaire FOReSIGHT, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Ludwig Maximilian University [Munich] (LMU), Karolinska Institutet [Stockholm], Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and Institut Hospitalo-Universitaire FOReSIGHT (IHU FOReSIGHT)
Subjects: Patient experience, Quality of life, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Disease, 01 natural sciences, Patient advocacy, Non-Sjögren’s syndrome, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Dry eye disease, 0101 mathematics, Survey, Original Research, business.industry, 010102 general mathematics, 3. Good health, Country differences, Contact lens, [SDV] Life Sciences [q-bio], Ophthalmology, Sjögren’s syndrome, Non interventional, 030221 ophthalmology & optometry, Observational study, Sjogren s, business
Abstract: Introduction Previous studies have examined the patient experience regarding the diagnosis and management of dry eye disease (DED). The current study explored the ways in which the DED diagnostic pathway differs for those living with and without Sjögren’s syndrome (SS), to identify aspects that influence the patient experience and associated quality of life (QoL). Methods An observational/descriptive, non-interventional, retrospective, self-reported online survey was conducted among adults living in France, Spain and Italy who were diagnosed with DED (with/without SS), were using topical DED treatments (≥ 6 months), and were not contact lens users. Recruitment was via an online database for non-SS participants and through local patient advocacy groups for SS respondents. Results The analysis included 827 respondents; 416 (50.3%) had SS and 82% were female. The mean age was 55 (SD 11; range 16–99) years. The mean age at diagnosis was 46 (SD 12; range 13–78) years and 50 (SD 10; range 21–73) years for SS and non-SS groups, respectively (p
Published: 2021

24. The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease

Author: Hardy, Timothy, Wonders, Kristy, Younes, Ramy, Aithal, Guruprasad P, Aller, Rocio, Allison, Michael, Bedossa, Pierre, Betsou, Fay, Boursier, Jerome, Brosnan, M Julia, Burt, Alastair, Cobbold, Jeremy, Cortez-Pinto, Helena, Day, Chris P, Dufour, Jean-Francois, Ekstedt, Mattias, Francque, Sven, Harrison, Stephen, Miele, Luca, Nasr, Patrik, Papatheodoridis, George, Petta, Salvatore, Tiniakos, Dina, Torstenson, Richard, Valenti, Luca, Holleboom, Adriaan G, Yki-Jarvinen, Hannele, Geier, Andreas, Romero-Gomez, Manuel, Ratziu, Vlad, Bugianesi, Elisabetta, Schattenberg, Jörn M, Anstee, Quentin M, LITMUS Consortium, Newcastle University [Newcastle], Università degli studi di Torino (UNITO), University of Nottingham, UK (UON), Universidad de Valladolid [Valladolid] (UVa), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Integrated BioBank of Luxembourg (IBBL), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Pfizer, Oxford University Hospitals NHS Trust, University of Oxford [Oxford], Universidade de Lisboa (ULISBOA), University of Bern, Linköping University (LIU), University of Antwerp (UA), Università cattolica del Sacro Cuore [Roma] (Unicatt), National and Kapodistrian University of Athens (NKUA), Università degli studi di Palermo - University of Palermo, University of Milan, University of Helsinki, University of Würzburg, Hospital Universitario Virgen del Rocío [Sevilla], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University Medical Center [Mainz], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Vascular Medicine, ACS - Diabetes & metabolism, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, LITMUS Consortium, Innovative Medicines Initiative, European Commission, Department of Medicine, HUS Internal Medicine and Rehabilitation, Helsinki University Hospital Area, Hardy T., Wonders K., Younes R., Aithal G.P., Aller R., Allison M., Bedossa P., Betsou F., Boursier J., Brosnan M.J., Burt A., Cobbold J., Cortez-Pinto H., Day C.P., Dufour J.-F., Ekstedt M., Francque S., Harrison S., Miele L., Nasr P., Papatheodoridis G., Petta S., Tiniakos D., Torstenson R., Valenti L., Holleboom A.G., Yki-Jarvinen H., Geier A., Romero-Gomez M., Ratziu V., Bugianesi E., Schattenberg J.M., Anstee Q.M., Harrison, Seamus Conor [0000-0003-1480-1143], and Apollo - University of Cambridge Repository
Subjects: Liver Cirrhosis, PROGNOSIS, Cirrhosis, SCORING SYSTEM, [SDV]Life Sciences [q-bio], PROGRESSION, Disease, Biomarker, Cirrhosis, NAFLD, NASH, STEATOHEPATITIS, DEFINITIONS, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Pharmacology (medical), 030212 general & internal medicine, Longitudinal Studies, Registries, ComputingMilieux_MISCELLANEOUS, media_common, Pharmacology. Therapy, Fatty liver, Liver Neoplasms, NASH, General Medicine, 3. Good health, Liver, 317 Pharmacy, Cohort, 0305 other medical science, Cohort study, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, Geriatrik, QUESTIONNAIRE, NAFLD, Biomarker, 610 Medicine & health, 03 medical and health sciences, medicine, STEATOSIS, media_common.cataloged_instance, Humans, ALGORITHM, European union, Intensive care medicine, 030505 public health, business.industry, CONSUMPTION, STAGING SYSTEM, medicine.disease, Diabetes Mellitus, Type 2, Geriatrics, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, Human medicine, Steatohepatitis, business
Abstract: © 2020 The Author(s)., Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS ‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace., The European NAFLD Registry is supported by the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the European Union Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377, which receives support from the Horizon 2020 Framework Program of European Union and EFPIA. It has also received support from the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413, the FLIP consortium funded by the Framework Program 7 of the European Union under grant agreement 241762, and an EASL Registry Grant from the European Association for the Study of the Liver.
Published: 2020

25. Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

Author: Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara–Schmidt, Ulrike, Hentschel, Andreas, Chinnery, Patrick F., Kölbel, Heike, Roos, Andreas, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Paramonov, Ida, Peters, Sophia, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Van Der Velde, Joeri K., Vitobello, Antonio, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G., Houlden, Henry, Lau, Jarred, Lochmüller, Hanns, Macken, William L., Musacchia, Francesco, Nascimento, Andres, Natera-De Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D. S., Polavarapu, Kiran, Cruz, Pedro M. Rodriguez, Sarkozy, Anna, Selvatici, Rita, Thompson, Rachel, Torella, Annalaura, Udd, Bjarne, Van De Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Schon, Katherine [0000-0001-8054-8954], Horvath, Rita [0000-0002-9841-170X], Apollo - University of Cambridge Repository, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), University of Cambridge [UK] (CAM), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Aberdeen, Ruhr-Universität Bochum [Bochum], University Children's Hospital of Essen [Essen, Germany], Enzo Cohen, Isabel Cuesta, Daniel Danis, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Christian Gilissen, Mridul Johari, Steven Laurie, Shuang Li, Isabelle Nelson, Ida Paramonov, Sophia Peters, Sivakumar Prasanth, Peter Robinson, Karolis Sablauskas, Marco Savarese, Wouter Steyaert, Joeri K van der Velde, Antonio Vitobello, Jonathan Baets, Danique Beijer, Gisèle Bonne, Judith Cossins, Teresinha Evangelista, Alessandra Ferlini, Peter Hackman, Michael G Hanna, Henry Houlden, Jarred Lau, Hanns Lochmüller, William L Macken, Francesco Musacchia, Andres Nascimento, Daniel Natera-de Benito, Vincenzo Nigro, Giulio Piluso, Veronica Pini, Robert D S Pitceathly, Kiran Polavarapu, Pedro M Rodriguez Cruz, Anna Sarkozy, Rita Selvatici, Rachel Thompson, Annalaura Torella, Bjarne Udd, Liedewei Van de Vondel, Jana Vandrovcova, Irina Zaharieva, Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara-Schmidt, Ulrike, Hentschel, Andrea, Chinnery, Patrick F, Kölbel, Heike, Roos, Andrea, Horvath, Rita, Nigro, Vincenzo, Torella, Annalaura, and Piluso, Giulio
Subjects: 0301 basic medicine, Male, Proteome, 45/41, Developmental Disabilities, Medizin, 45/22, Biology, Bioinformatics, Nervous System Malformations, Brief Communication, 82/80, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Cerebellum, 38/23, Genetics research, Genetics, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Exome, Genetic Testing, Gene, Cerebellar hypoplasia, Genetics (clinical), Exome sequencing, Proteomic Profile, Proteomic Profiling, 82/58, 631/208/514/2254, brief-communication, 692/308/2056, Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Spinal muscular atrophy, medicine.disease, 3. Good health, 030104 developmental biology, Congenital muscular dystrophy, Next-generation sequencing, 030217 neurology & neurosurgery, Transcription Factors
Abstract: TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Several authors of this study are members of the European Reference Network for Neuromuscular disease, Project ID No 739543. This study was supported by the AFM (grant 21644 to AR), the framework of the NME-GPS project by the European Regional Development Fund (AR/US/AS), the support by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung (AH and AS), the European Research Council (RH), the Wellcome Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH) and the Evelyn Trust (RH). This research was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1 and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care
Published: 2020

26. EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2

Author: Massimo Galli, Dieter Wiek, Pedro Machado, Annamaria Iagnocco, Iain B. McInnes, Tanja Stamm, Hans W J Bijlsma, Gerd R Burmester, Bernard Combe, Hendrik Schulze-Koops, Peter J. M. Openshaw, Laure Gossec, Josef S Smolen, Ulf Mueller-Ladner, Féline P B Kroon, Loreto Carmona, Xavier Mariette, John D. Isaacs, Robert Landewé, Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Zuyderland MC, University College of London [London] (UCL), Leiden University Medical Center (LUMC), Utrecht Brain Center [UMC], University Medical Center [Utrecht], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Instituto de Salud Musculoesqueletica (InMusc), Hôpital Lapeyronie [Montpellier] (CHU), Università degli Studi di Milano = University of Milan (UNIMI), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Torino = University of Turin (UNITO), Newcastle Upon Tyne Hospitals NHS Foundation Trust, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Glasgow, Kerckhoff-Klinik, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Medizinische Universität Wien = Medical University of Vienna, Deutsche Rheuma-Liga Bundesverband e.V, Ludwig Maximilian University [Munich] (LMU), Salvy-Córdoba, Nathalie, and Universiteit Leiden
Subjects: antirheumatic agents, MESH: Coronavirus Infections, Quality indicators, Disease, MESH: Rheumatic Diseases, 0302 clinical medicine, Epidemiology, MESH: Musculoskeletal Diseases, Medicine, Immunology and Allergy, MESH: COVID-19, 030212 general & internal medicine, skin and connective tissue diseases, Potential impact, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Health services research, epidemiology, health services research, patient care team, quality indicators, health care, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Betacoronavirus, MESH: Immunosuppressive Agents, medicine.medical_specialty, MESH: Pandemics, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, MESH: Societies, Medical, Context (language use), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rheumatology, MESH: Rheumatology, MESH: SARS-CoV-2, MESH: Clinical Laboratory Techniques, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Health care, MESH: COVID-19 Testing, Living document, MESH: Pneumonia, Viral, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Family medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, business, MESH: Glucocorticoids
Abstract: International audience; The provisional EULAR recommendations address several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus, and the disease caused by SARS-CoV-2, COVID-19 and are meant for patients with rheumatic and musculoskeletal diseases (RMD) and their caregivers. A task force of 20 members was convened by EULAR that met several times by videoconferencing in April 2020. The task force finally agreed on five overarching principles and 13 recommendations covering four generic themes: (1) General measures and prevention of SARS-CoV-2 infection. (2) The management of RMD when local measures of social distancing are in effect. (3) The management of COVID-19 in the context of RMD. (4) The prevention of infections other than SARS-CoV-2. EULAR considers this set of recommendations as a ‘living document’ and a starting point, which will be updated as soon as promising new developments with potential impact on the care of patients with RMD become available.
Published: 2020

27. Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Author: Colin G. Miles, Heather J. Cordell, Simon A. Ramsbottom, Meral Gunay-Aygun, Shirlee Shril, Elisa Molinari, John A. Sayer, Helena L. Spiewak, Laura A. Devlin, Peter E. Thelwall, Sophie Saunier, Flora Silbermann, Friedhelm Hildebrandt, Katrina M Wood, Gavin J. Clowry, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Harvard Medical School [Boston] (HMS), National Human Genome Research Institute (NHGRI), Johns Hopkins University School of Medicine [Baltimore], and Saunier, Sophie
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Severity of Illness Index, Retina, Joubert syndrome, Mice, 03 medical and health sciences, Cystic kidney disease, Antigens, Neoplasm, Chloride Channels, Cerebellum, medicine, Animals, Abnormalities, Multiple, Genetic Predisposition to Disease, genetics, Eye Abnormalities, Barttin, Genetics, Cystic kidney, modifier, Genes, Modifier, Multidisciplinary, Genetic heterogeneity, Biological Sciences, Kidney Diseases, Cystic, medicine.disease, Phenotype, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Cytoskeletal Proteins, Disease Models, Animal, Ciliopathy, 030104 developmental biology, ciliopathy, Mutation, Kidney Diseases, Rare disease, Kidney disease
Abstract: Significance Our current understanding of genetic disease is often inadequate, largely due to genetic background effects that modify disease presentation. This is particularly challenging for rare diseases that lack sufficient numbers of patients for genome-wide association studies. We show in a series of experiments using a murine model of Joubert syndrome, a multisystem ciliopathy, that a single locus is a modifier of cystic kidney disease. We go on to show that the human homolog plays a similar role in disease using a cohort of patients. These findings make a significant contribution to the underplayed (and often ignored) role of genetic background in murine models and how this can be exploited to understand further rare inherited disease., Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.
Published: 2020

28. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society

Author: Lyon, Alexander R., Dent, Susan, Stanway, Susanna, Earl, Helena, Brezden‐Masley, Christine, Cohen‐Solal, Alain, Tocchetti, Carlo G., Moslehi, Javid, Groarke, John D., Bergler‐Klein, Jutta, Khoo, Vincent, Tan, Li Ling, Anker, Markus S., Haehling, Stephan, Maack, Christoph, Pudil, Radek, Barac, Ana, Thavendirnathan, Paaladinesh, Ky, Bonnie, Neilan, Tomas G., Belenkov, Yury, Rosen, Stuart D., Iakobishvili, Zaza, Sverdlov, Aaron L., Hajjar, Ludhmila A., Macedo, Ariane V. S., Manisty, Charlotte, Ciardiello, Fortunato, Farmakis, Dimitrios, De Boer, Rudolf A., Skouri, Hadi, Suter, Thomas M., Cardinale, Daniela, Witteles, Ronald M., Fradley, Michael G., Herrmann, Joerg, Cornell, Robert F., Wechelaker, Ashutosh, Mauro, Michael J., Milojkovic, Dragana, Lavallade, Hugues, Ruschitzka, Frank, Coats, Andrew J. S., Seferovic, Petar M., Chioncel, Ovidiu, Thum, Thomas, Bauersachs, Johann, Andres, M. Sol, Wright, David J., López‐Fernández, Teresa, Plummer, Chris, Lenihan, Daniel, Imperial College London, Duke University [Durham], The Royal Marsden, University of Cambridge [UK] (CAM), Mount Sinai Hospital [Toronto, Canada] (MSH), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II = Università degli studi di Napoli Federico II, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Medizinische Universität Wien = Medical University of Vienna, Monash University [Melbourne], Shanghai Center for Plant Stress Biology [CAS] (PSC), Chinese Academy of Sciences [Beijing] (CAS), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Georg-August-University = Georg-August-Universität Göttingen, Hannover Medical School [Hannover] (MHH), Charles University [Prague] (CU), Georgetown University [Washington] (GU), University Health Network, University of Toronto, University of Pennsylvania, Massachusetts General Hospital [Boston], Sechenov First Moscow State Medical University, University College of London [London] (UCL), Tel Aviv University (TAU), University of Newcastle [Australia] (UoN), Universidade de São Paulo = University of São Paulo (USP), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, University of Cyprus [Nicosia] (UCY), University Medical Center Groningen [Groningen] (UMCG), American University of Beirut Faculty of Medicine and Medical Center (AUB), University of Bern, IRCCS Ospedale San Raffaele [Milan, Italy], Stanford University, Mayo Clinic [Rochester], Memorial Sloan Kettering Cancer Center (MSKCC), Hammersmith Hospital NHS Imperial College Healthcare, King's College Hospital (KCH), University hospital of Zurich [Zurich], University of Warwick [Coventry], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), University of Belgrade [Belgrade], Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C.C. Iliescu' [Bucharest, Romania], University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Royal Brompton Hospital, Liverpool Heart and Chest Hospital NHS Trust [UK] (LH&CH), La Paz University Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), leboeuf, Christophe, Lyon, Alexander R, Dent, Susan, Stanway, Susanna, Earl, Helena, Brezden-Masley, Christine, Cohen-Solal, Alain, Tocchetti, Carlo G, Moslehi, Javid, Groarke, John D, Bergler-Klein, Jutta, Khoo, Vincent, Tan, Li Ling, Anker, Markus S, von Haehling, Stephan, Maack, Christoph, Pudil, Radek, Barac, Ana, Thavendirnathan, Paaladinesh, Ky, Bonnie, Neilan, Tomas G, Belenkov, Yury, Rosen, Stuart D, Iakobishvili, Zaza, Sverdlov, Aaron L, Hajjar, Ludhmila A, Macedo, Ariane V S, Manisty, Charlotte, Ciardiello, Fortunato, Farmakis, Dimitrio, De Boer, Rudolf A, Skouri, Hadi, Suter, Thomas M, Cardinale, Daniela, Witteles, Ronald M, Fradley, Michael G, Herrmann, Joerg, Cornell, Robert F, Wechelaker, Ashutosh, Mauro, Michael J, Milojkovic, Dragana, de Lavallade, Hugue, Ruschitzka, Frank, Coats, Andrew J S, Seferovic, Petar M, Chioncel, Ovidiu, Thum, Thoma, Bauersachs, Johann, Andres, M Sol, Wright, David J, López-Fernández, Teresa, Plummer, Chri, Lenihan, Daniel, Lyon, Alexander R., Brezden‐masley, Christine, Cohen‐solal, Alain, Tocchetti, Carlo G., Groarke, John D., Bergler‐klein, Jutta, Anker, Markus S., Haehling, Stephan, Neilan, Tomas G., Rosen, Stuart D., Sverdlov, Aaron L., Hajjar, Ludhmila A., Macedo, Ariane V. S., De Boer, Rudolf A., Suter, Thomas M., Witteles, Ronald M., Fradley, Michael G., Cornell, Robert F., Mauro, Michael J., Lavallade, Hugue, Coats, Andrew J. S., Seferovic, Petar M., Andres, M. Sol, Wright, David J., and López‐fernández, Teresa
Subjects: Male, Heart failure, Androgen Antagonists, Antineoplastic Agents, Middle Aged, Risk Assessment, Cardiotoxicity, Risk prediction, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardio-oncology, risk factor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Neoplasms, Humans, Female, Aged
Abstract: This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for CML targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. This article is protected by copyright. All rights reserved.
Published: 2020

29. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Mavaddat, N., Antoniou, A.C., Mooij, T.M., Hooning, M.J., Heemskerk-Gerritsen, B.A., Nogues, C., Laborde, L., Breysse, E., Stoppa-Lyonnet, D., Gauthier-Villars, M., Buecher, B., Caron, O., Fourme-Mouret, E., Fricker, J.P., Lasset, C., Bonadona, V., Berthet, P., Faivre, L., Luporsi, E., Mari, V., Gladieff, L., Gesta, P., Sobol, H., Eisinger, F., Longy, M., Dugast, C., Colas, C., Coupier, I., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Nguyen, T.D., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J.M., Maugard, C., Bignon, Y.J., Demange, L., Penet, C., Dreyfus, H., Cohen-Haguenauer, O., Venat-Bouvet, L., Leroux, D., Zattara-Cannoni, H., Fert-Ferrer, S., Bera, O., Ellis, S., Barrowdale, D., Frost, D., Evans, D.G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., Hogervorst, F.B.L., Collee, J.M., Asperen, C.J. van, Mensenkamp, A.R., Ausems, M.G.E.M., Meijers-Heijboer, H.E.J., Engelen, K. van, Blok, M.J., Oosterwijk, J.C., Verloop, J., Broek, E. van den, Mourits, M.J.E., Koppert, L.B., Hopper, J.L., John, E.M., Chung, W.K., Andrulis, I.L., Daly, M.B., Buys, S.S., Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C.F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A.M., Roos-Blom, M.J., Leeuwen, F.E. van, Arver, B., Olsson, H., Schmutzler, R.K., Engel, C., Kast, K., Phillips, K.A., Terry, M.B., Milne, R.L., Goldgar, D.E., Rookus, M.A., Andrieu, N., Easton, D.F., GENEPSO, EMBRACE, HEBON, kConFab Investigators, IBCCS, kConFab, BCFR, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Erasmus MC Cancer Institute, Rotterdam, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Curie [Paris], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Catherine-de-Sienne [Nantes] (CCS), Manchester University NHS Foundation Trust (MFT), Guy's & St Thomas' NHS Foundation Trust, Chapel Allerton Hospital, University of Leeds, Royal Marsden NHS Foundation Trust, Royal Devon & Exeter Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Wessex clinical genetics service, Vrije Universiteit Amsterdam [Amsterdam] (VU), University Medical Center Groningen [Groningen] (UMCG), Department of Medical Genetics, University Medical Center [Utrecht], Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, Department of Epidemiology, Cancer Prevention Institute of California, Columbia University [New York], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Division of Population Science, Fox Chase Cancer Center, Department of Internal Medicine, Huntsman Cancer Institute, Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Medizinische Universität Wien = Medical University of Vienna, National Institute of Oncology, Masaryk Memorial Cancer Institute (MMCI), Masaryk University [Brno] (MUNI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, The Netherlands Cancer Institute [Amsterdam, The Netherlands], Radiumhemmet, Karolinska University Hospital [Stockholm], Department of Oncology, Lund University Hospital, Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Cancer Epidemiology Centre, Cancer Council Victoria, International Agency for Cancer Research (IACR), Netherlands Cancer Institute, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Andrieu, Nadine, Human genetics, Epidemiology and Data Science, Mavaddat, Nasim [0000-0003-0307-055X], Eeles, Ros [0000-0002-3698-6241], Engel, Christoph [0000-0002-7247-282X], Apollo - University of Cambridge Repository, Pomeranian Medical University-International Hereditary Cancer Centre, Masaryk Memorial Cancer Institute (RECAMO), Columbia Mailman School of Public Health-Columbia University [New York], Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Antoniou, Antonis [0000-0001-9223-3116], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Medical Oncology, Surgery, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), United States Department of Health and Human Services, Ministerio de Economía y Competitividad (España), Unión Europea. Comisión Europea. European Research Council (ERC), Norwegian EEA Financial Mechanism, Hungarian Scientific Research Fund (Hungría), Ministry of Education, Youth and Sports (República Checa), MH CZ -DRO (MMCI), National Health and Medical Research Council (Australia), Australian National Breast Cancer Foundation, Cancer Australia, ERA-NET TRANSAN JTC 2012 Cancer, Transcan grant, Biotechnology and Biological Sciences Research Council (Reino Unido), Pink Ribbons Project, Netherlands Organisation of Scientific Research, Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Deutsche Krebshilfe, National Institute for Health Research (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Ministry of Economic Development, Innovation and Export Trade-grant, Canadian Institutes of Health Research, Cancer Research UK, NIH National Cancer Institute (NCI), United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Ministerio de Economia y Competividad (MINECO), European Research Council (ERC), Hungarian Research Grants, MEYS -NPS I, National Health and Medical Research Council of Australia, BBMRI grant, Pink Ribbon grants, Netherlands Organisation of Scientific Research grant, KWF Kankerbestrijding, Instituto de Salud Carlos III - ISCIII, National Institute for Health Research (NIHR), European Union Seventh Framework Program (2007-2013), Canadian Institutes of Health Research (CIHR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), United States of Department of Health & Human Services, European Research Council, APH - Quality of Care, APH - Methodology, Graduate School, ARD - Amsterdam Reproduction and Development, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: endocrine system diseases, SURGERY, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 0302 clinical medicine, BRCA2 Mutation, Breast cancer, Surgical oncology, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Salpingo-oophorectomy/methods, 0303 health sciences, Natural menopause, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics, BRCA1 Protein, Breast Neoplasms/epidemiology, Incidence (epidemiology), Incidence, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, OVARIAN, BRCA2 Protein/genetics, 3. Good health, Menopause, Risk-reducing salpingo-oophorectomy, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SURVIVAL, Female, Research Article, Cohort study, Adult, medicine.medical_specialty, Salpingo-oophorectomy, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:RC254-282, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, METAANALYSIS, 030304 developmental biology, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, CONSORTIUM, risk-reducing salpingo-oophorectomy, International Agencies, medicine.disease, BRCA1, BRCA2, KCONFAB, REDUCTION, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, LINK, Mutation, BRCA1 Protein/genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Risk Reduction Behavior
Abstract: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. The BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. CNIO was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). CNIO was also partially supported by FISPI16/00440. INHERIT was supported by the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant #CRN-87521-and the Ministry of Economic Development, Innovation and Export Trade-grant #PSR-SIIRI-701. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l' Innovation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. Jacques Simard is a Chairholder of the Canada Research Chair in Oncogenetics. EMBRACE is supported by the Cancer Research UK grants C1287/A23382 and C1287/A16563. D. Gareth Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by the Cancer Research UK grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Antonis C. Antoniou is funded by Cancer Research UK grants C12292/A20861 and C12292/A11174. MT is funded by the European Union Seventh Framework Program (2007-2013)/European Research Council (310018). The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837, Rita K. Schmutzler). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and the Ligue Nationale Contre le Cancer and is being supported by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008). HCSC was supported by CIBERONC 161200301 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. The IHCC was supported by Grant PBZ_ KBN_122/P05/2004 and ERA-NET TRANSAN JTC 2012 Cancer 12-054 (ERA-NET-TRANSCAN/07/2014). This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195); the Australian National Breast Cancer Foundation (IF 17); the National Health and Medical Research Council (454508, 288704, 145684); the National Institute of Health U.S.A. (1RO1CA159868); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation fellow. MODSQUAD-Czech Republic, Brno, was supported by MH CZ -DRO (MMCI, 00209805) and by MEYS -NPS I -LO1413 to LF and MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, NKFI OTKA K-112228, and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced Grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Sí
Published: 2020

30. Modern-day environmental factors in the pathogenesis of osteoarthritis

Author: Ian J. Wallace, Francis Berenbaum, Daniel E. Lieberman, David T. Felson, Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Harvard University [Cambridge], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Newcastle Upon Tyne Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), and University of Manchester [Manchester]
Subjects: 0301 basic medicine, Osteoarthritis, Disease, Risk Assessment, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Risk Factors, Environmental health, Prevalence, medicine, Humans, Obesity, Metabolic Syndrome, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 030203 arthritis & rheumatology, business.industry, Disease progression, Mismatch theory, medicine.disease, Diet, 3. Good health, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Disease Progression, Sedentary Behavior, Metabolic syndrome, Risk assessment, business
Abstract: International audience; The prevalence of osteoarthritis (OA) is rising for reasons that are not fully understood. In this Opinion article, we review the possibility that OA is an evolutionary mismatch disease, which is a disease more common today than in the past because genes inherited from previous generations are inadequately or imperfectly adapted to modern environmental conditions. We focus on four major environmental factors in OA pathogenesis that have become ubiquitous within the past half-century: obesity, metabolic syndrome, dietary changes and physical inactivity. Because a cure for OA does not yet exist, prevention strategies that target these modifiable environmental factors are needed to curb further increases in OA prevalence.
Published: 2018

31. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Author: Katrina M Wood, Stephania Bitetti, Mohammed Zarhrate, Rafiqul Hussain, Vicky Brocklebank, Meghan Acres, Vincent Bondet, Ruyue Sun, Tracy A Briggs, Rui Chen, John H. Livingston, Richard E. Randall, Robert Wynn, Claire L. Harris, Darragh Duffy, Cécile Fourrage, Florian Gothe, Christopher J A Duncan, Sophie Hambleton, Stephen M. Hughes, Karin R. Engelhardt, Julija Pavaine, Leo A. H. Zeef, Jonathan Coxhead, Dan F. Young, Yanick J. Crow, Aneta Mikulasova, Victoria G. Shuttleworth, Bronte M. Corner, Gillian I. Rice, Edmund Cheesman, Barbara A. Innes, Ronnie Wright, David J. Kavanagh, Angela Grainger, Simon C. Lovell, Andrew J. Skelton, Benjamin J. Thompson, Newcastle University [Newcastle], University of Manchester [Manchester], Ludwig-Maximilians-Universität München (LMU), University of St Andrews [Scotland], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Leeds, Central Manchester University Hospitals NHS Foundation Trust, Royal Manchester Children's Hospital, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Newcastle Upon Tyne Hospitals NHS Foundation Trust, Université Paris Descartes - Paris 5 (UPD5), University of Edinburgh, British Infection Association (to C.J.A.D.), Wellcome Trust [211153/Z/18/Z (to C.J.A.D.), 207556/Z/17/Z (S.H.), and 101788/Z/13/Z (to D.F.Y. and R.E.R.)], Sir Jules Thorn Trust [12/JTA (to S.H.)], UK National Institute of Health Research [TRF-2016-09-002 (to T.A.B.)], NIHR Manchester Biomedical Resource Centre (to T.A.B.), Medical Research Foundation (to T.A.B.), Medical Research Council [MRC, MR/N013840/1 (to B.J.T.)], MRC/Kidney Research UK [MR/R000913/1 (to Vicky Brocklebank)], Deutsche Forschungsgemeinschaft [GO 2955/1-1 (to F.G.)], Agence Nationale de la Recherche [ANR-10-IAHU-01 (to Y.J.C.) and CE17001002 (to Y.J.C. and D.D.)], European Research Council [GA 309449 (Y.J.C.), 786142-E-T1IFNs], Newcastle University (to C.J.A.D.), and ImmunoQure for provision of antibodies (Y.J.C. and D.D.). C.L.H. and R.S. were funded by start-up funding from Newcastle University. D.K. has received funding from the Medical Research Council, Wellcome Trust, Kidney Research UK, Macular Society, NCKRF, AMD Society, and Complement UK, honoraria for consultancy work from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Novartis, and Idorsia, and is a director of and scientific advisor to Gyroscope Therapeutics., We are grateful to the patients and our thoughts are with their family, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Génétiques Imagine [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-10-IAHU-0001/10-IAHU-0001,Imagine,Imagine(2010)
Subjects: 0301 basic medicine, biology, Immunology, General Medicine, stat, Loss of heterozygosity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Germline mutation, Interferon, Transcription (biology), 030220 oncology & carcinogenesis, biology.protein, medicine, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Missense mutation, STAT2, Transcription factor, medicine.drug
Abstract: International audience; Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
Published: 2019

32. Real-world data in retinal diseases treated with anti-vascular endothelial growth factor (anti-VEGF) therapy – a systematic approach to identify and characterize data sources

Author: Paul Mitchell, Obaro Evuarherhe, Gemma Carter, Jean-François Korobelnik, James S Talks, Taiji Sakamoto, Robert Finger, Tien Yin Wong, Vincent Daien, Bora Eldem, Joao Carrasco, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The University of Sydney, Hacettepe University = Hacettepe Üniversitesi, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Westmead Institute for Medical Research, University of Bonn, Kagoshima University Graduate School of Medical and Dental Sciences, Duke-National University of Singapore Graduate Medical School, Department of Pharmacology [Oxford], University of Oxford [Oxford], Internationaler Hauptsitz von Consumer Health, University of Oxford, and Salvy-Córdoba, Nathalie
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, Choroidal neovascularization, Visual Acuity, MEDLINE, Information Storage and Retrieval, Angiogenesis Inhibitors, Scientific literature, Disease, Retinal vein occlusion, 03 medical and health sciences, 0302 clinical medicine, lcsh:Ophthalmology, Diabetic macular edema, medicine, Humans, Medical physics, 030212 general & internal medicine, Anti vegf, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Age-related macular degeneration, Anti-VEGF, Usability, General Medicine, Real-world data, Retinal diseases, 3. Good health, Ophthalmology, Systematic review, lcsh:RE1-994, Intravitreal Injections, 030221 ophthalmology & optometry, Observational study, business, Real world data, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: Background Real-world data (RWD) has been a valuable addition to the scientific literature regarding treatment pathways, clinical outcomes and characteristics of patients with retinal diseases in recent years. Registries, observational studies and patient databases are often used for real-world research. However, there is limited information for each data source on the design, consistency, data captured, limitations and usability for assessing research questions. Using a systematic approach, we identified RWD sources for patients with retinal diseases and assessed them for completeness of data relating to different outcomes. Methods A systematic literature review was carried out to identify RWD sources for patients with retinal disease. Potentially relevant articles published between 2006 and 2016 were screened following electronic searches in Embase and MEDLINE. Congress and supplementary searches were undertaken to identify RWD sources that may not be referenced in full publications. For each data source, availability and quantity of data on baseline status, clinical outcomes, treatment and management, safety, and patient-reported and economic burden were assessed using a bespoke completeness assessment tool based on International Consortium for Health Outcomes Measurement guidelines for macular degeneration. Completeness of data for each area of interest in each data source was assessed and rated using a ‘good–moderate–poor’ rating system based on availability and quantity of available data. Each data source was then given an overall score based on its score for each of the 7 areas of interest. Results A total of 128 RWD sources from 32 countries were identified. Of the identified sources, 64 sources from 16 countries of interest were analyzed. Most of these sources provided information on baseline status and clinical outcomes and treatment, but few collected data on economic and patient-reported burden. Of the RWD sources analyzed, 10 scored highly in the overall completeness assessment, collecting data on most or all of the areas of interest; these sources are considered to be robust data sources for performing ophthalmology real-world studies. Conclusions The study provides a comprehensive list of RWD sources for patients with retinal disease, many of which will be useful for conducting real-world studies in the field of ophthalmology.
Published: 2019

33. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J, Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, Gormley, Stuart, Hamilton, Shea, Herberg, Jethro, Hourmat, Bernardo, Hoggart, Clive, Kaforou, Myrsini, Sancho-Shimizu, Vanessa, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Bokhandi, S, Power, Sue, Barham, Heather, Pathan, N, Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S, Patel, S, McCorkell, Jenni, Davies, P, Cratev, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R, Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C, White, Sonia, Fortune, PM, Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, Martinon-Torres, Nazareth, Martinon Sanchez, Jose Maria, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, Rivero Calle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J, Palacios, Alba, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, AM Tutu, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Paulus, Stephane, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Agbeko, Rachel, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngane, Sey, Gibbi, Saidykhan, Momodou, Cole, Fatoumatta, Thomas, Gilleh, Antonio, Martin, Walcher, Wolfgang, Geishofer, Gotho, Klobassa, Daniela, Martin, Mueller, Pfurtscheller, Klaus, Reiter, Karl, Roedl, Siegfried, Zobel, Gerfried, Zoehrer, Bettina, Toepke, Baerbel, Fucik, Peter, Gabriel, Markwart, Penzien, Johann M, Diab, Gedeon, Miething, Robert, Deeg, KH, Hammer, Jurg, Varnholt, Verena, Schmidt, Andreas, Bindl, Lutz, Sillaber, Ursula, Huemer, Christian, Meier, Primrose, Simic-Schleicher, G, Markart, Markus, Pfau, Eberhard, Broede, Hans, Ausserer, Bernd, Kalhoff, Hermann, Arpe, Volker, Schweitzer-Krantz, Susanne, Kasper, Johannes-Martin, Loranth, Kathrin, Bittrich, Hans J, Simma, Burkhard, Klinge, Jens, Fedlmaier, Michael, Weigand, Nicola, Herting, Egbert, Grube, Regina, Fusch, Christoph, Gruber, Alois, Schimmel, Ulf, Knaufer-Schiefer, Suzanne, Laessig, Wolfgang, Hennenberger, Axel, von der Wense, Axel, Tillmann, Roland, Schwarick, Juergen, Sitzmann, Friedrich C, Streif, Werner, Mueller, Herbert, Kurnik, Peter, Groneck, Peter, Weiss, Ute, Groeblacher-Roth, Helene, Bensch, Juergen, Moser, Reinhard, Schwarz, Rudolf, Lenz, Kurt, Hofmann, Thomas, Goepel, Wolfgang, Schulz, Dietrich, Berger, Thomas, Hauser, Erwin, Foerster, Kai Martin, Peters, Jochen, Nicolai, T Homas, Kumlien, Bjoern, Beckmann, Regina, Seitz, Christiane, Hueseman, D, Schuermann, Roland, Ta, Van Hop, Weikmann, Eckart, Evert, W, Hautz, Juergen, Seidenberg, Juergen, Wocko, Lucia, Luigs, Petra, Reiter, Hans-Ludwig, Quietzach, J, Koenig, Michael, Herrmann, Johanna, Mitter, Horst, Seidler, Ekkehard, Maak, Bernhard, Sperl, Wolfgang, Zwiauer, Karl, Meissl, Manfred, Koch, Reinhard, Cremer, Manfred, Breuer, HA, Goerke, W, Nossal, Robert, Pernice, Walter, Brangenberg, Ralf, Salzer, Hans R, Koch, Hartmut, Schaller, Gerhard, Paky, Franz, Strasser, Friedrich, Eitelberger, Franz, Sontheimer, D, Lischka, Andreas, Kronberger, Martina, Dilch, Alfred, Scheibenpflug, Christian, Bruckner, Robert, Mahler, Klaus, Runge, Klaus, Kunze, Wolfgang, Schermann, Peter, Consortium, EUCLIDS, European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, University of Zurich, Borghini, Lisa, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Png, Eileen [0000-0001-5586-6395], Wright, Victoria J [0000-0001-7826-1516], Schlapbach, Luregn J [0000-0003-2281-2598], Salas, Antonio [0000-0002-2336-702X], Martinon-Torres, Federico [0000-0002-9023-581X], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, AII - Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Neurology, ANS - Neuroinfection & -inflammation, Medical Microbiology and Infection Prevention, Pediatrics, Public Health, Posfay Barbe, Klara, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), APH - Aging & Later Life, Amsterdam Reproduction & Development (AR&D), and Pediatric surgery
Subjects: 0301 basic medicine, Candidate gene, Hypopharyngeal Neoplasms / microbiology, Meningococcal Infections / microbiology, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], MathematicsofComputing_GENERAL, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], lcsh:Medicine, Neisseria meningitidis, Regulatory Sequences, Nucleic Acid, Cohort Studies, 0302 clinical medicine, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, Hypopharyngeal Neoplasms / pathology, BINDING, Tumor Cells, Cultured, lcsh:Science, Genetics, Multidisciplinary, ddc:618, Cultured, TheoryofComputation_GENERAL, High-Throughput Nucleotide Sequencing, Genomics, Phenotype, 3. Good health, ddc, Tumor Cells, Multidisciplinary Sciences, GENOME, Science & Technology - Other Topics, Neisseria meningitidis / isolation & purification, Single-nucleotide polymorphism, 610 Medicine & health, KAPPA-B, Biology, Hypopharyngeal Neoplasms / genetics, Polymorphism, Single Nucleotide, Article, Meningococcal Infections / epidemiology, 03 medical and health sciences, SEQUENCE VARIATION, Genetic predisposition, Journal Article, Humans, Meningitis, Meningococcal Infections / genetics, Genetic Predisposition to Disease, Nucleic Acid, Polymorphism, General, Gene, Genotyping, Neisseria meningitidis / genetics, Genetic Association Studies, Genetic association, Genetic association study, 1000 Multidisciplinary, Science & Technology, Hypopharyngeal Neoplasms, genetic variants, meningococcal disease, lcsh:R, Single Nucleotide, EUCLIDS consortium, Gene regulation, Meningococcal Infections, 030104 developmental biology, 10036 Medical Clinic, Case-Control Studies, lcsh:Q, Software_PROGRAMMINGLANGUAGES, Regulatory Sequences, 030217 neurology & neurosurgery
Abstract: EUCLIDS consortium., Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes., This work has been partially funded by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement No. 279185. The UK meningococcal cohort was established with support from Meningitis Research Foundation through grants to Imperial College London. The Research from Newcastle partners was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The ESIGEM Research group activities were supported by grants from Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud: proyecto GePEM PI16/01478) (A.S.); Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2016), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007–2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010–2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I + D + I and ‘fondos FEDER’ (F.M.T.). The Swiss Pediatric Sepsis study was funded by grants from the Swiss National Science Foundation (342730_153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. The Western Europe Meningococcal Study was supported by grants no 8842, 10112 and 12710 of the Oesterreichische Nationalbank (Austria), grants A3-16.K-8/2008-11 and A3-16.K-8/2006–9 of the Department for Science and Research of the Styrian federal government (Austria) and the non for profit association ‘In Vita’, Graz (Austria).
Published: 2019

34. Décodage de l'hématopoïèse fétale hépatique humaine

Author: Ben Millar, Laura Jardine, Rachel Rowell, Gary Reynolds, Sarah A. Teichmann, Anindita Roy, Orit Rozenblatt-Rosen, Emily Stephenson, Elisa Laurenti, Michal Slyper, Issac Goh, Aviv Regev, Frankie Greig, Lira Mamanova, Orr Ashenberg, Monika S. Kowalczyk, Barbara A. Innes, Jong-Eun Park, David McDonald, Berthold Göttgens, Corina Moldovan, Kile Green, Matthew D. Young, Danielle Dionne, Peter D. Carey, Irene Roberts, Mirjana Efremova, Zhichao Miao, Rachel A. Botting, Alain Chédotal, Simone Webb, Bo Li, Elizabeth Poyner, Steven Lisgo, Marcin Tabaka, Peter Vegh, Andrew Fuller, Yorick Gitton, Roser Vento-Tormo, Susan Lindsay, David Dixon, Sam Behjati, Meghan Acres, Alexandra-Chloé Villani, Michael J. T. Stubbington, Jaume Bacardit, Emily Calderbank, Dorin-Mirel Popescu, Daniel Maunder, Krzysztof Polanski, James Fletcher, Michael W. Mather, Kerstin B. Meyer, Timothy L. Tickle, Andrew Filby, Muzlifah Haniffa, Calderbank, Emily [0000-0002-9559-6593], Gottgens, Berthold [0000-0001-6302-5705], Laurenti, Elisa [0000-0002-9917-9092], Teichmann, Sarah [0000-0002-6294-6366], Apollo - University of Cambridge Repository, Institute of Cellular Medicine [Newcastle], Newcastle University [Newcastle], The Wellcome Trust Sanger Institute [Cambridge], Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institute of Genetic Medicine [Newcastle], School of Computing Science [Newcastle], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], Structure des macromolécules biologiques et mécanismes de reconnaissance (SMBMR), Centre National de la Recherche Scientifique (CNRS), NIHR Liver Biomedical Research Unit, University of Birmingham [Birmingham], Institute of Genetic Medicine, Analyse de données, Modélisation et Apprentissage automatique [Grenoble] (AMA ), Laboratoire d'Informatique de Grenoble (LIG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), and Ludwig Institute for Cancer Research Ltd.
Subjects: 0301 basic medicine, skin, kidney, Liver cytology, Lymphoid Tissue, [SDV]Life Sciences [q-bio], Population, Biology, Article, immunology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Fetus, medicine, Humans, Yolk sac, Progenitor cell, education, yolk-sac, education.field_of_study, Multidisciplinary, Blood Cells, Gene Expression Profiling, Stem Cells, haematopoiesis, Flow Cytometry, 3. Good health, Cell biology, single cell RNA-sequencing, Hematopoiesis, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, human development, Cellular Microenvironment, Liver, 030220 oncology & carcinogenesis, embryonic structures, Erythropoiesis, Female, Stem cell, Single-Cell Analysis
Abstract: International audience; Definitive haematopoiesis in the fetal liver supports self-renewal anddifferentiation of haematopoietic stem cells and multipotent progenitors(HSC/MPPs) but remains poorly defined in humans. Here, using single-celltranscriptome profiling of approximately 140,000 liver and 74,000 skin, kidneyand yolk sac cells, we identify the repertoire of human blood and immune cellsduring development. We infer differentiation trajectories from HSC/MPPs andevaluate the influence of the tissue microenvironment on blood and immune celldevelopment. We reveal physiological erythropoiesis in fetal skin and thepresence of mast cells, natural killer and innate lymphoid cell precursors in theyolk sac. We demonstrate a shift in the haemopoietic composition of fetal liverduring gestation away from being predominantly erythroid, accompanied by aparallel change in differentiation potential of HSC/MPPs, which we functionallyvalidate. Our integrated map of fetal liver haematopoiesis provides a blueprintfor the study of paediatric blood and immune disorders, and a reference forharnessing the therapeutic potential of HSC/MPPs.
Published: 2019

35. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies

Author: Ramos-Casals, M., Brito-Zeron, P., Bombardieri, S., Bootsma, H., De Vita, S., Dorner, T., Fisher, B. A., Gottenberg, J. -E., Hernandez-Molina, G., Kocher, A., Kostov, B., Kruize, A. A., Mandl, T., W. -F., Ng, Retamozo, S., Seror, R., Shoenfeld, Y., Siso-Almirall, A., Tzioufas, A. G., Vitali, C., Bowman, S., EULAR-Sjögren Syndrome Task Force Group: Sebastian A, Mariette X., Saraux, A, Vissink, A, Rasmussen, A, Hofauer, B, Armagan, B, Feijoo-Massó, C, Shiboski, Ch, Baldini, C, Vollenweider, C, Sene, D, Hammenfors, D, Isenberg, D, Danda, D, Bartoloni, E, Hospital Clinic i Provincial de Barcelona (SCReN), CELLEX-IDIBAPS Department of Autoimmune Diseases, Barcelona, H. CIMA-Sanitas, Barcelona, University of Pisa - Università di Pisa, University of Groningen [Groningen], Ospedale 'Santa Maria della Misericordia' = University Hospital 'Santa Maria della Misericordia', Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Birmingham [Birmingham], Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], University Hospital Basel [Basel], Bern University Hospital [Berne] (Inselspital), Transverse group for research in primary care [Barcelona], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat Politècnica de Catalunya [Barcelona] (UPC), University Medical Center [Utrecht], Skane University Hospital [Malmo], Lund University [Lund], Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Universidad de Córdoba = University of Córdoba [Córdoba], Universidad Nacional de Córdoba [Argentina], Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Saint Petersburg University (SPBU), CAP Les Corts (CAPSBE), National and Kapodistrian University of Athens (NKUA), Santo Stefano Riabilitazione, University Hospitals Birmingham [Birmingham, Royaume-Uni], Centre National de la Recherche Scientifique (CNRS)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Rheumatology Unit, Cordoba (Institute University of Biomedical Sciences University of Cordoba (IUCBC), Universitat Politècnica de Catalunya. Departament d'Estadística i Investigació Operativa, and Salvy-Córdoba, Nathalie
Subjects: MESH: Antirheumatic Agents, Autoimmune diseases, MESH: Hydroxychloroquine, Matemàtiques i estadística::Matemàtica aplicada a les ciències [Àrees temàtiques de la UPC], Azathioprine, Administration, Ophthalmic, MESH: Cyclosporine, 0302 clinical medicine, Adrenal Cortex Hormones, MESH: Muscarinic Agonists, Epidemiology, Immunology and Allergy, 030212 general & internal medicine, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, treatment, Anti-Inflammatory Agents, Non-Steroidal, 92 Biology and other natural sciences::92B Mathematical biology in general [Classificació AMS], [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Anti-Inflammatory Agents, Non-Steroidal, MESH: Administration, Ophthalmic, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Sjogren's Syndrome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antirheumatic Agents, Cyclosporine, Rituximab, MESH: Immunosuppressive Agents, MESH: Lubricant Eye Drops, sjøgren's syndrome, MESH: Saliva, Artificial, autoimmune diseases, Immunosuppressive Agents, medicine.drug, Hydroxychloroquine, medicine.medical_specialty, Biomatemàtica, Immunology, Muscarinic Agonists, General Biochemistry, Genetics and Molecular Biology, Lubricant Eye Drops, MESH: Adrenal Cortex Hormones, 03 medical and health sciences, Therapeutic approach, Rheumatology, medicine, Humans, Intensive care medicine, Glucocorticoids, Sjøgren's syndrome, Biomathematics, 030203 arthritis & rheumatology, MESH: Humans, business.industry, Abatacept, Saliva, Artificial, Evidence-based medicine, medicine.disease, Belimumab, Treatment, stomatognathic diseases, MESH: Sjogren's Syndrome, MESH: Glucocorticoids, business, Rheumatism
Abstract: International audience; The therapeutic management of Sjögren syndrome (SjS) has not changed substantially in recent decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed at developing the first EULAR evidence and consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, physicians undergoing specialist training, medical students, the pharmaceutical industry and drug regulatory organisations following the 2014 EULAR standardised operating procedures. The Task Force (TF) included specialists in rheumatology, internal medicine, oral health, ophthalmology, gynaecology, dermatology and epidemiology, statisticians, general practitioners, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. The TF endorsed the presentation of general principles for the management of patients with SjS as three overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence, starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic disease. The recommendations address the use of topical oral (saliva substitutes) and ocular (artificial tear drops, topical non-steroidal anti-inflammatory drugs, topical corticosteroids, topical CyA, serum tear drops) therapies, oral muscarinic agonists (pilocarpine, cevimeline), hydroxychloroquine, oral glucocorticoids, synthetic immunosuppressive agents (cyclophosphamide, azathioprine, methotrexate, leflunomide and mycophenolate), and biological therapies (rituximab, abatacept and belimumab). For each recommendation, levels of evidence (mostly modest) and TF agreement (mostly very high) are provided. The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the management of primary 2002 SjS patients and on discussions between a large and broadly international TF. The recommendations synthesise current thinking on SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations.
Published: 2019

36. Monitoring multiple cortical regions during walking in young and older adults: dual-task response and comparison challenges

Author: Lynn Rochester, Lisa Alcock, Samuel Stuart, Rodrigo Vitório, Annette Pantall, Oregon Health and Science University, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Universidade Estadual Paulista (Unesp)
Subjects: Male, medicine.medical_specialty, B100, fNIRS, Walking, 050105 experimental psychology, Premotor cortex, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Cognition, Physiology (medical), Cortical activity, medicine, Humans, 0501 psychology and cognitive sciences, Prefrontal cortex, Aged, Retrospective Studies, Aged, 80 and over, Cerebral Cortex, Spectroscopy, Near-Infrared, Supplementary motor area, business.industry, General Neuroscience, 05 social sciences, Age Factors, Middle Aged, SMA, Gait, C600, Neuropsychology and Physiological Psychology, medicine.anatomical_structure, Older adults, Functional near-infrared spectroscopy, Female, Primary motor cortex, business, Psychomotor Performance, 030217 neurology & neurosurgery
Abstract: Made available in DSpace on 2019-10-06T15:25:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01 Biotechnology Research Center, Tabriz University of Medical Sciences Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) National Institute on Disability and Rehabilitation Research Performance of several tasks simultaneously (dual-tasks) is common in everyday walking. Studies indicate that dual-task walking performance declines with age together with cognitive function, but neural mechanisms underpinning deficits remain unclear. Recent developments in mobile imaging techniques, such as functional near infrared spectroscopy (fNIRS), allow real-time monitoring of cortical activity during walking. This study aimed to: 1) examine activity in motor and cognitive cortical regions when walking with a dual-task in young and older adults; and 2) determine the effect of cognition on dual-task cortical activity changes. Seventeen young (20.3 ± 1.2 years) and eighteen older adults (72.6 ± 8.0 years) performed dual-task conditions, lasting 5 min, with alternating 30-second experimental blocks. The primary outcome was cortical activity, assessed by measuring changes in oxygenated haemoglobin (HbO2) concentrations. Cortical regions of interest (ROI) included motor regions (premotor cortex (PMC), supplementary motor area (SMA), primary motor cortex (M1)), and cognitive regions (prefrontal cortex (PFC)). Cognitive domains were assessed using standard tests and accelerometers were used to extract gait features. Cortical activity increased with a dual-task in PMC, SMA and M1 but not in PFC regions across groups, with response most evident with initial task exposure. Older adults did not increase SMA activity with a dual-task to the same level as young adults. Dual-task cortical response was consistently associated with greater executive function across groups. In conclusion, both young and older adults responded in a similar manner to dual-task conditions. Dual-task walking activated multiple motor regions in both groups, but no significant change occurred for cognitive region activation. Cortical activation with a dual-task related to executive function. Department of Neurology Oregon Health and Science University Institute of Neuroscience Newcastle University Newcastle upon Tyne Hospitals NHS Foundation Trust Instituto de Biociências Universidade Estadual Paulista (UNESP), Campus Rio Claro Institute of Ageing Clinical Ageing Research Unit Campus for Ageing and Vitality Newcastle University Instituto de Biociências Universidade Estadual Paulista (UNESP), Campus Rio Claro
Published: 2019

37. Association between night-time surgery and occurrence of intraoperative adverse events and postoperative pulmonary complications

Author: Cortegiani A, Gregoretti C, Neto A, Hemmes S, Ball L, Canet J, Hiesmayr M, Hollmann M, Mills G, Melo M, Putensen C, Schmid W, Severgnini P, Wrigge H, de Abreu M, Schultz M, Pelosi P, Kroell W, Metzler H, Struber G, Wegscheider T, Gombotz H, Urbanek B, Kahn D, Momeni M, Pospiech A, Lois F, Forget P, Grosu I, Poelaert J, van Mossevelde V, van Malderen M, Dylst D, van Melkebeek J, Beran M, de Hert S, De Baerdemaeker L, Heyse B, Van Limmen J, Wyffels P, Jacobs T, Roels N, De Bruyne A, van de Velde S, Leva B, Damster S, Plichon B, Juros-Zovko M, Djonovic-Omanovic D, Pernar S, Zunic J, Miskovic P, Zilic A, Kvolik S, Ivic D, Azenic-Venzera D, Skiljic S, Vinkovic H, Oputric I, Juricic K, Frkovic V, Kopic J, Mirkovic I, Karanovic N, Carev M, Dropulic N, Saric J, Erceg G, Dvorscak M, Mazul-Sunko B, Pavicic A, Goranovic T, Maldini B, Radocaj T, Gavranovic Z, Mladic-Batinica I, Sehovic M, Stourac P, Harazim H, Smekalova O, Kosinova M, Kolacek T, Hudacek K, Drab M, Brujevic J, Vitkova K, Jirmanova K, Volfova I, Dzurnakova P, Liskova K, Dudas R, Filipsky R, el Kafrawy S, Abdelwahab H, Metwally T, Abdel-Razek A, El-Shaarawy A, Hasan W, Ahmed A, Yassin H, Magdy M, Abdelhady M, Mahran M, Herodes E, Kivik P, Oganjan J, Aun A, Sormus A, Sarapuu K, Mall M, Karjagin J, Futier E, Petit A, Gerard A, Marret E, Solier M, Jaber S, Prades A, Krassler J, Merzky S, Uhlig C, Kiss T, Bundy A, Bluth T, Gueldner A, Spieth P, Scharffenberg M, Thiem D, Koch T, Treschan T, Schaefer M, Bastin B, Geib J, Weiss M, Kienbaum P, Pannen B, Gottschalk A, Konrad M, Westerheide D, Schwerdtfeger B, Simon P, Reske A, Nestler C, Valsamidis D, Stroumpoulis K, Antholopoulos G, Andreou A, Karapanos D, Theodorak K, Gkiokas G, Tasoulis M, Sidiropoulou T, Zafeiropoulou F, Florou P, Pandazi A, Tsaousi G, Nouris C, Pourzitaki C, Bystritski D, Pizov R, Eden A, Pesce C, Campanile A, Marrella A, Grasso S, De Michele M, Bona F, Giacoletto G, Sardo E, Sottosanti L, Solca M, Volta C, Spadaro S, Verri M, Ragazzi R, Zoppellari R, Cinnella G, Raimondo P, La Bella D, Mirabella L, D'antini D, Molin A, Brunetti I, Gratarola A, Pellerano G, Sileo R, Pezzatto S, Montagnani L, Pasin L, Landoni G, Zangrillo A, Beretta L, Di Parma A, Tarzia V, Dossi R, Sassone M, Sances D, Tredici S, Spano G, Castellani G, Delunas L, Peradze S, Venturino M, Arpino I, Sher S, Tommasino C, Rapido F, Morelli P, Vargas M, Servillo G, Raineri S, Montalto F, Russotto V, Giarratano A, Baciarello M, Generali M, Cerati G, Leykin Y, Bressan F, Bartolini V, Zamidei L, Brazzi L, Liperi C, Sales G, Pistidda L, Brugnoni E, Musella G, Bacuzzi A, Muhardri D, Gecaj-Gashi A, Sada F, Bytyqi A, Karbonskiene A, Aukstakalniene R, Teberaite Z, Salciute E, Tikuisis R, Miliauskas P, Jurate S, Kontrimaviciute E, Tomkute G, Xuereb J, Bezzina M, Borg F, Wiersma I, Binnekade J, Bos L, Boer C, Duvekot A, in 't Veld B, Werger A, Dennesen P, Severijns C, De Jong J, Hering J, van Beek R, Ivars S, Jammer I, Breidablik A, Hodt K, Fjellanger F, Avalos M, Mellin-Olsen J, Andersson E, Shafi-Kabiri A, Molina R, Wutai S, Morais E, Tareco G, Ferreira D, Amaral J, Castro M, Cadilha S, Appleton S, Parente S, Correia M, Martins D, Monteirosa A, Ricardo A, Rodrigues S, Horhota L, Grintescu I, Mirea L, Corneci D, Negoita S, Dutu M, Garotescu I, Filipescu D, Prodan A, Droc G, Fota R, Popescu M, Tomescu D, Petcu A, Tudoroiu M, Moise A, Guran C, Gherghina I, Costea D, Cindea I, Copotoiu S, Copotoiu R, Barsan V, Tolcser Z, Riciu M, Moldovan S, Veres M, Gritsan A, Kapkan T, Gritsan G, Korolkov O, Kulikov A, Lubnin A, Ovezov A, Prokoshev P, Lugovoy A, Anipchenko N, Babayants A, Komissarova I, Zalina K, Likhvantsev V, Fedorov S, Lazukic A, Pejakovic J, Mihajlovic D, Kusnierikova Z, Zelinkova M, Bruncakova K, Polakovicova L, Sobona V, Novak-Supe B, Pekle-Golez A, Jovanov M, Strazisar B, Markovic-Bozic J, Novak-Jankovic V, Voje M, Grynyuk A, Kostadinov I, Spindler-Vesel A, Moral V, Unzueta M, Puigbo C, Fava J, Moret E, Nunez M, Sendra M, Brunelli A, Rodenas F, Monedero P, Martinez F, Temino M, Simon A, Larriba A, Lisi A, Perez G, Martinez R, Granell M, Vivo J, Ruiz C, Ibanez J, Pastor E, Soro M, Ferrando C, Defez M, Alvares-Santullano C, Perez R, Rico J, Jawad M, Saeed Y, Gillberg L, Bengisun Z, Kazbek B, Coskunfirat N, Boztug N, Sanli S, Yilmaz M, Hadimioglu N, Senturk N, Camci E, Kucukgoncu S, Sungur Z, Sivrikoz N, Ozgen S, Toraman F, Selvi O, Senturk O, Yildiz M, Kuvaki B, Gunenc F, Kucukguclu S, Ozbilgin S, Maral J, Canli S, Arun O, Saltali A, Aydogan E, Akgun F, Sanlikarip C, Karaman F, Mazur A, Vorotyntsev S, Rousseau G, Barrett C, Stancombe L, Shelley B, Scholes H, Limb J, Rafi A, Wayman L, Deane J, Rogerson D, Williams J, Yates S, Rogers E, Pulletz M, Moreton S, Jones S, Venkatesh S, Burton M, Brown L, Goodall C, Rucklidge M, Fuller D, Nadolski M, Kusre S, Lundberg M, Everett L, Nutt H, Zuleika M, Carvalho P, Clements D, Creagh-Brown B, Watt P, Raymode P, Pearse R, Mohr O, Raj A, Creary T, Chishti A, Bell A, Higham C, Cain A, Gibb S, Mowat S, Franklin D, West C, Minto G, Boyd N, Calton E, Walker R, Mackenzie F, Ellison B, Roberts H, Chikungwa M, Jackson C, Donovan A, Foot J, Homan E, Montgomery J, Portch D, Mercer P, Palmer J, Paddle J, Fouracres A, Datson A, Andrew A, Welch L, Rose A, Varma S, Simeson K, Rambhatla M, Susarla J, Marri S, Kodaganallur K, Das A, Algarsamy S, Colley J, Davies S, Szewczyk M, Smith T, Fernandez-Bustamante A, Luzier E, Almagro A, Fernando L, Sulemanji D, Sprung J, Weingarten T, Kor D, Scavonetto F, Tze Y, LAS VEGAS Investigators, PROVE Network, European Soc Anaesthesiology, Cortegiani, A, Gregoretti, C, Neto, A, Hemmes, S, Ball, L, Canet, J, Hiesmayr, M, Hollmann, M, Mills, G, Melo, M, Putensen, C, Schmid, W, Severgnini, P, Wrigge, H, Gama de Abreu, M, Schultz, M, Pelosi, P, Kroell, W, Metzler, H, Struber, G, Wegscheider, T, Gombotz, H, Urbanek, B, Kahn, D, Momeni, M, Pospiech, A, Lois, F, Forget, P, Grosu, I, Poelaert, J, Mossevelde, V, van Malderen, M, Dylst, D, Melkebeek, J, Beran, M, Hert, S, Baerdemaeker, L, Heyse, B, Limmen, J, Wyffels, P, Jacobs, T, Roels, N, Bruyne, A, Velde, S, Marina, J, Dejana, D, Pernar, S, Zunic, J, Miskovic, P, Zilic, A, Kvolik, S, Ivic, D, Darija, A, Skiljic, S, Vinkovic, H, Oputric, I, Juricic, K, Frkovic, V, Kopic, J, Mirkovic, I, Saric, J, Erceg, G, Dvorscak, M, Branka, M, Pavicic, A, Goranovic, T, Maldini, B, Radocaj, T, Gavranovic, Z, Inga, M, Sehovic, M, Stourac, P, Harazim, H, Smekalova, O, Kosinova, M, Kolacek, T, Hudacek, K, Drab, M, Brujevic, J, Vitkova, K, Jirmanova, K, Volfova, I, Dzurnakova, P, Liskova, K, Dudas, R, Filipsky, R, Kafrawy, S, Abdelwahab, H, Metwally, T, Ahmed, A, Ahmed Mostafa, E, Hasan, W, Yassin, H, Magdy, M, Abdelhady, M, Mahran, M, Herodes, E, Kivik, P, Oganjan, J, Aun, A, Sormus, A, Sarapuu, K, Mall, M, Karjagin, J, Futier, E, Petit, A, Gerard, A, Marret, E, Solier, M, Jaber, S, Prades, A, Krassler, J, Merzky, S, Abreu, M, Uhlig, C, Kiss, T, Bundy, A, Bluth, T, Gueldner, A, Spieth, P, Scharffenberg, M, Thiem, D, Koch, T, Treschan, T, Schaefer, M, Bastin, B, Geib, J, Weiss, M, Kienbaum, P, Pannen, B, Gottschalk, A, Konrad, M, Westerheide, D, Schwerdtfeger, B, Simon, P, Reske, A, Nestler, C, Valsamidis, D, Stroumpoulis, K, Antholopoulos, G, Andreou, A, Karapanos, D, Theodorak, K, Gkiokas, G, Tasoulis, M, Sidiropoulou, T, Zafeiropoulou, F, Florou, P, Pandazi, A, Tsaousi, G, Nouris, C, Pourzitaki, C, Bystritski, D, Pizov, R, Eden, A, Pesce, C, Campanile, A, Marrella, A, Grasso, S, Michele, M, Bona, F, Giacoletto, G, Sardo, E, Sottosanti, L, Solca, M, Volta, C, Spadaro, S, Verri, M, Ragazzi, R, Zoppellari, R, Cinnella, G, Raimondo, P, Bella, D, Mirabella, L, D'Antini, D, Molin, A, Brunetti, I, Gratarola, A, Pellerano, G, Sileo, R, Pezzatto, S, Montagnani, L, Pasin, L, Landoni, G, Zangrillo, A, Beretta, L, Parma, A, Tarzia, V, Dossi, R, Sassone, M, Sances, D, Tredici, S, Spano, G, Castellani, G, Delunas, L, Peradze, S, Venturino, M, Arpino, I, Sher, S, Tommasino, C, Rapido, F, Morelli, P, Vargas, M, Servillo, G, Raineri, S, Montalto, F, Russotto, V, Giarratano, A, Baciarello, M, Generali, M, Cerati, G, Leykin, Y, Bressan, F, Bartolini, V, Zamidei, L, Brazzi, L, Liperi, C, Sales, G, Pistidda, L, Brugnoni, E, Musella, G, Bacuzzi, A, Muhardri, D, Agreta, G, Sada, F, Bytyqi, A, Karbonskiene, A, Aukstakalniene, R, Teberaite, Z, Salciute, E, Tikuisis, R, Miliauskas, P, Jurate, S, Kontrimaviciute, E, Tomkute, G, Xuereb, J, Bezzina, M, Borg, F, Wiersma, I, Binnekade, J, Bos, L, Boer, C, Duvekot, A, Veld, B, Werger, A, Dennesen, P, Severijns, C, Jong, J, Hering, J, Beek, R, Ivars, S, Jammer, I, Breidablik, A, Hodt, K, Fjellanger, F, Avalos, M, Jannicke, M, Andersson, E, Amir, S, Molina, R, Wutai, S, Morais, E, Tareco, G, Ferreira, D, Amaral, J, Castro, M, Cadilha, S, Appleton, S, Parente, S, Correia, M, Martins, D, Monteirosa, A, Ricardo, A, Rodrigues, S, Horhota, L, Grintescu, I, Mirea, L, Corneci, D, Negoita, S, Dutu, M, Popescu Garotescu, I, Filipescu, 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Kazbek, B, Coskunfirat, N, Boztug, N, Sanli, S, Yilmaz, M, Hadimioglu, N, Senturk, N, Camci, E, Kucukgoncu, S, Sungur, Z, Sivrikoz, N, Ozgen, S, Toraman, F, Selvi, O, Senturk, O, Yildiz, M, Kuvaki, B, Gunenc, F, Kucukguclu, S, Ozbilgin, S, Maral, J, Canli, S, Arun, O, Saltali, A, Aydogan, E, Akgun, F, Sanlikarip, C, Karaman, F, Mazur, A, Vorotyntsev, S, Rousseau, G, Barrett, C, Stancombe, L, Shelley, B, Scholes, H, Limb, J, Rafi, A, Wayman, L, Deane, J, Rogerson, D, Williams, J, Yates, S, Rogers, E, Pulletz, M, Moreton, S, Jones, S, Venkatesh, S, Burton, M, Brown, L, Goodall, C, Rucklidge, M, Fuller, D, Nadolski, M, Kusre, S, Lundberg, M, Everett, L, Nutt, H, Zuleika, M, Carvalho, P, Clements, D, Ben, C, Watt, P, Raymode, P, Pearse, R, Mohr, O, Raj, A, Creary, T, Chishti, A, Bell, A, Higham, C, Cain, A, Gibb, S, Mowat, S, Franklin, D, West, C, Minto, G, Boyd, N, Calton, E, Walker, R, Mackenzie, F, Ellison, B, Roberts, H, Chikungwa, M, Jackson, C, Donovan, A, Foot, J, Homan, E, Montgomery, J, Portch, D, Mercer, P, Palmer, J, Paddle, J, Fouracres, A, Datson, A, Andrew, A, Welch, L, Rose, A, Varma, S, Simeson, K, Rambhatla, M, Susarla, J, Marri, S, Kodaganallur, K, Das, A, Algarsamy, S, Colley, J, Davies, S, Szewczyk, M, Smith, T, Ana, F, Luzier, E, Almagro, A, Fernando, L, Sulemanji, D, Sprung, J, Weingarten, T, Kor, D, Scavonetto, F, Tze, Y, Acibadem University Dspace, Anesthesiology, Graduate School, Intensive Care Medicine, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, ACS - Heart failure & arrhythmias, Università degli studi di Palermo - University of Palermo, University of Amsterdam [Amsterdam] (UvA), Hospital Israelita Albert Einstein [São Paulo, Brazil], IRCCS Ospedale Policlinico San Martino [Genoa, Italy], Massachusetts General Hospital [Boston], University Hospital Bonn, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU 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S., Hemmes, S. N. T., Ball, L., Canet, J., Hiesmayr, M., Hollmann, M. W., Mills, G. H., Melo, M. F. V., Putensen, C., Schmid, W., Severgnini, P., Wrigge, H., Gama de Abreu, M., Schultz, M. J., Pelosi, P., Kroell, W., Metzler, H., Struber, G., Wegscheider, T., Gombotz, H., Urbanek, B., Kahn, D., Momeni, M., Pospiech, A., Lois, F., Forget, P., Grosu, I., Poelaert, J., Mossevelde, V., van Malderen, M. C., Dylst, D., Melkebeek, J. V., Beran, M., Hert, S. D., Baerdemaeker, L. D., Heyse, B., Limmen, J. V., Wyffels, P., Jacobs, T., Roels, N., Bruyne, A. D., Velde, S. V. D., Marina, J. Z., Dejana, D. O., Pernar, S., Zunic, J., Miskovic, P., Zilic, A., Kvolik, S., Ivic, D., Darija, A. V., Skiljic, S., Vinkovic, H., Oputric, I., Juricic, K., Frkovic, V., Kopic, J., Mirkovic, I., Saric, J. P., Erceg, G., Dvorscak, M. B., Branka, M. S., Pavicic, A. M., Goranovic, T., Maldini, B., Radocaj, T., Gavranovic, Z., Inga, M. B., Sehovic, M., Stourac, P., Harazim, H., Smekalova, O., Kosinova, M., Kolacek, T., Hudacek, K., Drab, M., Brujevic, J., Vitkova, K., Jirmanova, K., Volfova, I., Dzurnakova, P., Liskova, K., Dudas, R., Filipsky, R., Kafrawy, S. E., Abdelwahab, H. H., Metwally, T., Ahmed, A. R., Ahmed Mostafa, E. S., Hasan, W. F., Ahmed, A. G., Yassin, H., Magdy, M., Abdelhady, M., Mahran, M., Herodes, E., Kivik, P., Oganjan, J., Aun, A., Sormus, A., Sarapuu, K., Mall, M., Karjagin, J., Futier, E., Petit, A., Gerard, A., Marret, E., Solier, M., Jaber, S., Prades, A., Krassler, J., Merzky, S., Abreu, M. G. D., Uhlig, C., Kiss, T., Bundy, A., Bluth, T., Gueldner, A., Spieth, P., Scharffenberg, M., Thiem, D. T., Koch, T., Treschan, T., Schaefer, M., Bastin, B., Geib, J., Weiss, M., Kienbaum, P., Pannen, B., Gottschalk, A., Konrad, M., Westerheide, D., Schwerdtfeger, B., Simon, P., Reske, A., Nestler, C., Valsamidis, D., Stroumpoulis, K., Antholopoulos, G., Andreou, A., Karapanos, D., Theodorak, K., Gkiokas, G., Tasoulis, M. K., Sidiropoulou, T., Zafeiropoulou, F., Florou, P., Pandazi, A., Tsaousi, G., Nouris, C., Pourzitaki, C., Bystritski, D., Pizov, R., Eden, A., Pesce, C. V., Campanile, A., Marrella, A., Grasso, S., Michele, M. D., Bona, F., Giacoletto, G., Sardo, E., Sottosanti, L. G. V., Solca, M., Volta, C. A., Spadaro, S., Verri, M., Ragazzi, R., Zoppellari, R., Cinnella, G., Raimondo, P., Bella, D. L., Mirabella, L., D'Antini, D., Molin, A., Brunetti, I., Gratarola, A., Pellerano, G., Sileo, R., Pezzatto, S., Montagnani, L., Pasin, L., Landoni, G., Zangrillo, A., Beretta, L., Parma, A. L. D., Tarzia, V., Dossi, R., Sassone, M. E., Sances, D., Tredici, S., Spano, G., Castellani, G., Delunas, L., Peradze, S., Venturino, M., Arpino, I., Sher, S., Tommasino, C., Rapido, F., Morelli, P., Vargas, M., Servillo, G., Raineri, S. M., Montalto, F., Russotto, V., Giarratano, A., Baciarello, M., Generali, M., Cerati, G., Leykin, Y., Bressan, F., Bartolini, V., Zamidei, L., Brazzi, L., Liperi, C., Sales, G., Pistidda, L., Brugnoni, E., Musella, G., Bacuzzi, A., Muhardri, D., Agreta, G. G., Sada, F., Bytyqi, A., Karbonskiene, A., Aukstakalniene, R., Teberaite, Z., Salciute, E., Tikuisis, R., Miliauskas, P., Jurate, S., Kontrimaviciute, E., Tomkute, G., Xuereb, J., Bezzina, M., Borg, F. J., Hemmes, S., Schultz, M., Hollmann, M., Wiersma, I., Binnekade, J., Bos, L., Boer, C., Duvekot, A., Veld, B. I. '., Werger, A., Dennesen, P., Severijns, C., Jong, J. D., Hering, J., Beek, R. V., Ivars, S., Jammer, I. B., Breidablik, A., Hodt, K. S., Fjellanger, F., Avalos, M. V., Jannicke, M. O., Andersson, E., Amir, S. K., Molina, R., Wutai, S., Morais, E., Tareco, G., Ferreira, D., Amaral, J., Castro, M. D. L. G., Cadilha, S., Appleton, S., Parente, S., Correia, M., Martins, D., Monteirosa, A., Ricardo, A., Rodrigues, S., Horhota, L., Grintescu, I. M., Mirea, L., Grintescu, I. C., Corneci, D., Negoita, S., Dutu, M., Popescu Garotescu, I., Filipescu, D., Prodan, A. B., Droc, G., Fota, R., Popescu, M., Tomescu, D., Petcu, A. M., Tudoroiu, M. I., Moise, A., Guran, C. T., Gherghina, I., Costea, D., Cindea, I., Copotoiu, S. M., Copotoiu, R., Barsan, V., Tolcser, Z., Riciu, M., Moldovan, S. G., Veres, M., Gritsan, A., Kapkan, T., Gritsan, G., Korolkov, O., Kulikov, A., Lubnin, A., Ovezov, A., Prokoshev, P., Lugovoy, A., Anipchenko, N., Babayants, A., Komissarova, I., Zalina, K., Likhvantsev, V., Fedorov, S., Lazukic, A., Pejakovic, J., Mihajlovic, D., Kusnierikova, Z., Zelinkova, M., Bruncakova, K., Polakovicova, L., Sobona, V., Barbka, N. S., Ana, P. G., Jovanov, M., Strazisar, B., Jasmina, M. B., Vesna, N. J., Voje, M., Grynyuk, A., Kostadinov, I., Alenka, S. V., Moral, V., Unzueta, M. C., Puigbo, C., Fava, J., Moret, E., Nunez, M. R., Sendra, M., Brunelli, A., Rodenas, F., Monedero, P., Martinez, F. H., Temino, M. J. Y., Simon, A. M., Larriba, A. D. A., Lisi, A., Perez, G., Martinez, R., Granell, M., Vivo, J. T., Ruiz, C. S., Andres Ibanez, J. A. D., Pastor, E., Soro, M., Ferrando, C., Defez, M., Cesar Aldecoa, A. S., Perez, R., Rico, J., Jawad, M., Saeed, Y., Gillberg, L., Bengisun, Z. K., Kazbek, B. K., Coskunfirat, N., Boztug, N., Sanli, S., Yilmaz, M., Hadimioglu, N., Senturk, N. M., Camci, E., Kucukgoncu, S., Sungur, Z., Sivrikoz, N., Ozgen, S. U., Toraman, F., Selvi, O., Senturk, O., Yildiz, M., Kuvaki, B., Gunenc, F., Kucukguclu, S., Ozbilgin, S., Maral, J., Canli, S., Arun, O., Saltali, A., Aydogan, E., Akgun, F. N., Sanlikarip, C., Karaman, F. M., Mazur, A., Vorotyntsev, S., Rousseau, G., Barrett, C., Stancombe, L., Shelley, B., Scholes, H., Limb, J., Rafi, A., Wayman, L., Deane, J., Rogerson, D., Williams, J., Yates, S., Rogers, E., Pulletz, M., Moreton, S., Jones, S., Venkatesh, S., Burton, M., Brown, L., Goodall, C., Rucklidge, M., Fuller, D., Nadolski, M., Kusre, S., Lundberg, M., Everett, L., Nutt, H., Zuleika, M., Carvalho, P., Clements, D., Ben, C. B., Watt, P., Raymode, P., Pearse, R., Mohr, O., Raj, A., Creary, T., Chishti, A., Bell, A., Higham, C., Cain, A., Gibb, S., Mowat, S., Franklin, D., West, C., Minto, G., Boyd, N., Mills, G., Calton, E., Walker, R., Mackenzie, F., Ellison, B., Roberts, H., Chikungwa, M., Jackson, C., Donovan, A., Foot, J., Homan, E., Montgomery, J., Portch, D., Mercer, P., Palmer, J., Paddle, J., Fouracres, A., Datson, A., Andrew, A., Welch, L., Rose, A., Varma, S., Simeson, K., Rambhatla, M., Susarla, J., Marri, S., Kodaganallur, K., Das, A., Algarsamy, S., Colley, J., Davies, S., Szewczyk, M., Smith, T., Ana, F. B., Luzier, E., Almagro, A., Melo, M. V., Fernando, L., Sulemanji, D., Sprung, J., Weingarten, T., Kor, D., Scavonetto, F., Tze, Y., Cortegiani A., Gregoretti C., Neto A.S., Hemmes S.N.T., Ball L., Canet J., Hiesmayr M., Hollmann M.W., Mills G.H., Melo M.F.V., Putensen C., Schmid W., Severgnini P., Wrigge H., Gama de Abreu M., Schultz M.J., Pelosi P., Kroell W., Metzler H., Struber G., Wegscheider T., Gombotz H., Urbanek B., Kahn D., Momeni M., Pospiech A., Lois F., Forget P., Grosu I., Poelaert J., Mossevelde V., van Malderen M.C., Dylst D., Melkebeek J.V., Beran M., Hert S.D., Baerdemaeker L.D., Heyse B., Limmen J.V., Wyffels P., Jacobs T., Roels N., Bruyne A.D., Velde S.V.D., Marina J.Z., Dejana D.O., Pernar S., Zunic J., Miskovic P., Zilic A., Kvolik S., Ivic D., Darija A.V., Skiljic S., Vinkovic H., Oputric I., Juricic K., Frkovic V., Kopic J., Mirkovic I., Saric J.P., Erceg G., Dvorscak M.B., Branka M.S., Pavicic A.M., Goranovic T., Maldini B., Radocaj T., Gavranovic Z., Inga M.B., Sehovic M., Stourac P., Harazim H., Smekalova O., Kosinova M., Kolacek T., Hudacek K., Drab M., Brujevic J., Vitkova K., Jirmanova K., Volfova I., Dzurnakova P., Liskova K., Dudas R., Filipsky R., Kafrawy S.E., Abdelwahab H.H., Metwally T., Ahmed A.R., Ahmed Mostafa E.S., Hasan W.F., Ahmed A.G., Yassin H., Magdy M., Abdelhady M., Mahran M., Herodes E., Kivik P., Oganjan J., Aun A., Sormus A., Sarapuu K., Mall M., Karjagin J., Futier E., Petit A., Gerard A., Marret E., Solier M., Jaber S., Prades A., Krassler J., Merzky S., Abreu M.G.D., Uhlig C., Kiss T., Bundy A., Bluth T., Gueldner A., Spieth P., Scharffenberg M., Thiem D.T., Koch T., Treschan T., Schaefer M., Bastin B., Geib J., Weiss M., Kienbaum P., Pannen B., Gottschalk A., Konrad M., Westerheide D., Schwerdtfeger B., Simon P., Reske A., Nestler C., Valsamidis D., Stroumpoulis K., Antholopoulos G., Andreou A., Karapanos D., Theodorak K., Gkiokas G., Tasoulis M.K., Sidiropoulou T., Zafeiropoulou F., Florou P., Pandazi A., Tsaousi G., Nouris C., Pourzitaki C., Bystritski D., Pizov R., Eden A., Pesce C.V., Campanile A., Marrella A., Grasso S., Michele M.D., Bona F., Giacoletto G., Sardo E., Sottosanti L.G.V., Solca M., Volta C.A., Spadaro S., Verri M., Ragazzi R., Zoppellari R., Cinnella G., Raimondo P., Bella D.L., Mirabella L., D'antini D., Molin A., Brunetti I., Gratarola A., Pellerano G., Sileo R., Pezzatto S., Montagnani L., Pasin L., Landoni G., Zangrillo A., Beretta L., Parma A.L.D., Tarzia V., Dossi R., Sassone M.E., Sances D., Tredici S., Spano G., Castellani G., Delunas L., Peradze S., Venturino M., Arpino I., Sher S., Tommasino C., Rapido F., Morelli P., Vargas M., Servillo G., Raineri S.M., Montalto F., Russotto V., Giarratano A., Baciarello M., Generali M., Cerati G., Leykin Y., Bressan F., Bartolini V., Zamidei L., Brazzi L., Liperi C., Sales G., Pistidda L., Brugnoni E., Musella G., Bacuzzi A., Muhardri D., Agreta G.G., Sada F., Bytyqi A., Karbonskiene A., Aukstakalniene R., Teberaite Z., Salciute E., Tikuisis R., Miliauskas P., Jurate S., Kontrimaviciute E., Tomkute G., Xuereb J., Bezzina M., Borg F.J., Hemmes S., Schultz M., Hollmann M., Wiersma I., Binnekade J., Bos L., Boer C., Duvekot A., Veld B.I.'., Werger A., Dennesen P., Severijns C., Jong J.D., Hering J., Beek R.V., Ivars S., Jammer I.B., Breidablik A., Hodt K.S., Fjellanger F., Avalos M.V., Jannicke M.O., Andersson E., Amir S.K., Molina R., Wutai S., Morais E., Tareco G., Ferreira D., Amaral J., Castro M.D.L.G., Cadilha S., Appleton S., Parente S., Correia M., Martins D., Monteirosa A., Ricardo A., Rodrigues S., Horhota L., Grintescu I.M., Mirea L., Grintescu I.C., Corneci D., Negoita S., Dutu M., Popescu Garotescu I., Filipescu D., Prodan A.B., Droc G., Fota R., Popescu M., Tomescu D., Petcu A.M., Tudoroiu M.I., Moise A., Guran C.T., Gherghina I., Costea D., Cindea I., Copotoiu S.M., Copotoiu R., Barsan V., Tolcser Z., Riciu M., Moldovan S.G., Veres M., Gritsan A., Kapkan T., Gritsan G., Korolkov O., Kulikov A., Lubnin A., Ovezov A., Prokoshev P., Lugovoy A., Anipchenko N., Babayants A., Komissarova I., Zalina K., Likhvantsev V., Fedorov S., Lazukic A., Pejakovic J., Mihajlovic D., Kusnierikova Z., Zelinkova M., Bruncakova K., Polakovicova L., Sobona V., Barbka N.S., Ana P.G., Jovanov M., Strazisar B., Jasmina M.B., Vesna N.J., Voje M., Grynyuk A., Kostadinov I., Alenka S.V., Moral V., Unzueta M.C., Puigbo C., Fava J., Moret E., Nunez M.R., Sendra M., Brunelli A., Rodenas F., Monedero P., Martinez F.H., Temino M.J.Y., Simon A.M., Larriba A.D.A., Lisi A., Perez G., Martinez R., Granell M., Vivo J.T., Ruiz C.S., Andres Ibanez J.A.D., Pastor E., Soro M., Ferrando C., Defez M., Cesar Aldecoa A.S., Perez R., Rico J., Jawad M., Saeed Y., Gillberg L., Bengisun Z.K., Kazbek B.K., Coskunfirat N., Boztug N., Sanli S., Yilmaz M., Hadimioglu N., Senturk N.M., Camci E., Kucukgoncu S., Sungur Z., Sivrikoz N., Ozgen S.U., Toraman F., Selvi O., Senturk O., Yildiz M., Kuvaki B., Gunenc F., Kucukguclu S., Ozbilgin S., Maral J., Canli S., Arun O., Saltali A., Aydogan E., Akgun F.N., Sanlikarip C., Karaman F.M., Mazur A., Vorotyntsev S., Rousseau G., Barrett C., Stancombe L., Shelley B., Scholes H., Limb J., Rafi A., Wayman L., Deane J., Rogerson D., Williams J., Yates S., Rogers E., Pulletz M., Moreton S., Jones S., Venkatesh S., Burton M., Brown L., Goodall C., Rucklidge M., Fuller D., Nadolski M., Kusre S., Lundberg M., Everett L., Nutt H., Zuleika M., Carvalho P., Clements D., Ben C.B., Watt P., Raymode P., Pearse R., Mohr O., Raj A., Creary T., Chishti A., Bell A., Higham C., Cain A., Gibb S., Mowat S., Franklin D., West C., Minto G., Boyd N., Mills G., Calton E., Walker R., Mackenzie F., Ellison B., Roberts H., Chikungwa M., Jackson C., Donovan A., Foot J., Homan E., Montgomery J., Portch D., Mercer P., Palmer J., Paddle J., Fouracres A., Datson A., Andrew A., Welch L., Rose A., Varma S., Simeson K., Rambhatla M., Susarla J., Marri S., Kodaganallur K., Das A., Algarsamy S., Colley J., Davies S., Szewczyk M., Smith T., Ana F.B., Luzier E., Almagro A., Melo M.V., Fernando L., Sulemanji D., Sprung J., Weingarten T., Kor D., Scavonetto F., Tze Y., Hemmes, Snt, Hollmann, Mw, Mills, Gh, Melo, Mfv, Schultz, Mj, on behalf of the LAS VEGAS Investigators the PROVE Network and the Clinical Trial Network of the European Society of, Anaesthesiology, Maltepe Üniversitesi, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service d'anesthésiologie, and Selçuk Üniversitesi
Subjects: Lung Diseases, Postoperative Complications/epidemiology, Male, Internationality, Intraoperative Complication, medicine.medical_treatment, Settore MED/41 - Anestesiologia, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Lung Disease, Cohort Studies, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Anesteziologija i reanimatologija, 0302 clinical medicine, 030202 anesthesiology, Risk Factors, patient safety, Medicine, General anaesthesia, postoperative complication, Prospective Studies, intraoperative complications, Statistics & numerical data, Prospective cohort study, Incidence (epidemiology), Incidence, general anaesthesia, intraoperative complications, patient safety, postoperative complications, pulmonary, Middle Aged, Operative, 3. Good health, Surgical Procedures, Operative, Female, general anaesthesia, postoperative complications, pulmonary, Cohort study, Human, Adult, medicine.medical_specialty, Lung Diseases/epidemiology, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, NO, 03 medical and health sciences, Intraoperative Complications/epidemiology, After-Hours Care, Humans, MED/41 - ANESTESIOLOGIA, Adverse effect, Aged, Mechanical ventilation, Surgical Procedures, business.industry, Risk Factor, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Anesthesiology and Reanimatology, intraoperative complication, Surgery, After-Hours Care/statistics & numerical data, Anesthesiology and Pain Medicine, Clinical trial, MESH: After-hours Care / statistics & numerical data, Lung diseases / epidemiology, Surgical procedures, operative, Prospective Studie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort Studie, business
Abstract: WOS: 000458513600019, PubMed: 30770054, Background: The aim of this post hoc analysis of a large cohort study was to evaluate the association between night-time surgery and the occurrence of intraoperative adverse events (AEs) and postoperative pulmonary complications (PPCs). Methods: LAS VEGAS (Local Assessment of Ventilatory Management During General Anesthesia for Surgery) was a prospective international 1-week study that enrolled adult patients undergoing surgical procedures with general anaesthesia and mechanical ventilation in 146 hospitals across 29 countries. Surgeries were defined as occurring during 'daytime' when induction of anaesthesia was between 8: 00 AM and 7: 59 PM, and as 'night-time' when induction was between 8: 00 PM and 7: 59 AM. Results: Of 9861 included patients, 555 (5.6%) underwent surgery during night-time. The proportion of patients who developed intraoperative AEs was higher during night-time surgery in unmatched (43.6% vs 34.1%; P, NIHeNHLBI [1R34HL123438]; European Society of Anaesthesiology, The LAS VEGAS study was co-funded and endorsed by the European Society of Anaesthesiology, which had no role in the study design nor data analysis and interpretation. MFVM was supported by NIHeNHLBI (1R34HL123438).
Published: 2019

38. The use of real-world evidence for evaluating anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration

Author: Bora Eldem, Taiji Sakamoto, Jean-François Korobelnik, Robert Finger, Tien Yin Wong, Paul Mitchell, Daien, Cardillo Ja, James S Talks, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Bonn, Hacettepe University = Hacettepe Üniversitesi, Kagoshima University Graduate School of Medical and Dental Sciences, University of São Paulo (USP), The Westmead Institute for Medical Research, Duke-National University of Singapore Graduate Medical School, CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, Visual Acuity, Effectiveness, Angiogenesis Inhibitors, Clinical practice, Real world evidence, law.invention, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), MESH: Intravitreal Injections, Quality of Life, Ranibizumab/administration & dosage, Wet Macular Degeneration/drug therapy, Randomized controlled trial, law, Ranibizumab, Medicine, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Intensive care medicine, Noninterventional, business.industry, Gold standard, Real-life, Macular degeneration, Medical research, medicine.disease, 3. Good health, Clinical Practice, Clinical trial, Ophthalmology, Real-world, Retinal disease, Intravitreal Injections, 030221 ophthalmology & optometry, Wet Macular Degeneration, business, 030217 neurology & neurosurgery, Neovascular age-related macular degeneration
Abstract: International audience; Randomized controlled trials are the gold standard in medical research, providing evidence of the efficacy of a treatment in well-defined patient populations. By contrast, real-world studies explore the effectiveness of treatments in routine clinical practice, often with diverse patient populations. Although both randomized controlled trials and real-world studies contribute to the understanding of the benefits and risks of therapies, they generate different types of data and serve complementary purposes. Real-world studies evaluating the management of neovascular age-related macular degeneration have shown that visual outcomes achieved with anti-vascular endothelial growth factor in clinical practice often differ from those derived from clinical trials, highlighting the importance of assessing such outcomes in real-world studies. Benefits include finding variations in treatment provision, leading to: service improvements; the understanding of the need for continued and higher than previously provided treatment frequency; and new treatment regimens such as treat-and-extend. There is potential for the scope of real-world studies to be expanded to include other patient outcomes, such as quality of life, thus providing decision-makers with additional information to complement the data collected in randomized controlled trials. Physicians, patients, and regulators stand to gain much from further development and the conduct of real-world studies. We provide an overview of the importance of real-world evidence in the management of neovascular age-related macular degeneration with anti-vascular endothelial growth factor therapy, describe sources of real-world evidence, and assess the relative strengths and limitations of randomized controlled trials and real-world studies.
Published: 2017

39. Autosomal recessive primary microcephaly due to ASPM mutations: An update

Author: Martine Doco-Fenzy, Monique Elmaleh-Bergès, Berten Ceulemans, Sandrine Passemard, David Geneviève, Anita Rauch, Daniel Amram, Anais Ernault, Bernd Wollnick, Christine Francannet, Alain Verloes, Abdelaziz Sefiani, Pascaline Letard, Julie Désir, Marc Abramowicz, Brigitte Benzacken, Clothilde Rivier-Ringenbach, Toni Kasole Lubala, Yusuf Tunca, Vincent El Ghouzzi, Mathilde Nizon, Laurence Faivre, Marion Gérard, Koenraad Devriendt, Nathalie Pouvreau, Sophie Guilmin Crepon, Massimiliano Rossi, Hélène Maurey, C. Geoffrey Woods, Julia Metreau, Séverine Drunat, Michèle Mathieu-Dramard, Yves Sznajer, Cyril Gitiaux, Tiffany Busa, Geneviève Pierquin, Corinne Alberti, Sabine Sigaudy, Elise Schaefer, Stéphanie Arpin, Sébastien Lebon, Marta Bertoli, Pierre Gressens, Sophie Julia, Siham Chafai Elalaoui, Sarah Duerinckx, Sanaa Nasserereddine, Yoann Vial, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Mohamed V, Rabat, Maroc, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lubumbashi (UNILU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Ibn Rochd [Casablanca], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Liège (CHU-Liège), L'Hôpital Nord-Ouest [Villefranche sur Saône], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Université Catholique de Louvain = Catholic University of Louvain (UCL), Gülhane School of Medicine, Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Georg-August-University = Georg-August-Universität Göttingen, University of Cambridge [UK] (CAM), University hospital of Zurich [Zurich], Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Paris 13 (UP13), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), CHU Clermont-Ferrand, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Toulouse [Toulouse], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Lubumbashi, Georg-August-University [Göttingen], Richard, Nicolas, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, UFR Santé, Médecine et Biologie Humaine ( UFR SMBH ), Université Paris 13 ( UP13 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Hôpital Bretonneau-CHRU Tours, Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hospices Civils de Lyon ( HCL ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique 1426 ( CIC 1426 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Passemard, Sandrine [0000-0002-0242-4566], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Microcephaly, MESH: Geography, Intellectual disability, ASPM, brain development, brain imaging, MESH: Cognition, [SDV.GEN] Life Sciences [q-bio]/Genetics, Spindle pole body, MESH: Magnetic Resonance Imaging, Cohort Studies, Neurodevelopmental disorder, Cognition, MESH: Nerve Tissue Proteins, MESH: Cohort Studies, Genetics (clinical), MESH: Genetic Association Studies, Genetics, 0303 health sciences, Geography, primary microcephaly, 030305 genetics & heredity, Brain development, MESH: Infant, Magnetic Resonance Imaging, 3. Good health, intellectual disability, Child, Preschool, Autosomal Recessive Primary Microcephaly, Brain size, Female, MESH: Mutation, Brain imaging, Nerve Tissue Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Microcephaly, Primary microcephaly, 03 medical and health sciences, medicine, Humans, Family, Gene, MESH: Family, Genetic Association Studies, 030304 developmental biology, Centrosome, MCPH, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genetic heterogeneity, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, 030104 developmental biology, centrosome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Human medicine, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female
Abstract: Autosomal recessive microcephaly or MicroCephaly Primary Hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The Abnormal SPindle-like Microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities. This article is protected by copyright. All rights reserved. ispartof: Human Mutation vol:39 issue:3 pages:319-332 ispartof: location:United States status: published
Published: 2017

40. The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

Author: Ng, Yi Shiau, Alston, Charlotte L., Diodato, Daria, Morris, Andrew A., Ulrick, Nicole, Kmoch, Stanislav, Houstek, Josef, Martinelli, Diego, Haghighi, Alireza, Atiq, Mehnaz, Gamero, Montserrat Anton, Garcia-Martinez, Elena, Kratochvilova, Hana, Santra, Saikat, Brown, Ruth M., Brown, Garry K., Ragge, Nicola, Monavari, Ahmad, Pysden, Karen, Ravn, Kirstine, Casey, Jillian P., Khan, Arif, Chakrapani, Anupam, Vassallo, Grace, Simons, Cas, McKeever, Karl, O'Sullivan, Siobhan, Childs, Anne-Marie, Ostergaard, Elsebet, Vanderver, Adeline, Goldstein, Amy, Vogt, Julie, Taylor, Robert W., McFarland, Robert, [Ng, Yi Shiau] Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England, [Alston, Charlotte L.] Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England, [Taylor, Robert W.] Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England, [McFarland, Robert] Newcastle Univ, Inst Neurosci, Wellcome Trust Ctr Mitochondrial Res, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England, [Diodato, Daria] Children Res Hosp Bambino Gesu, Neuromuscular & Neurodegenerat Dis Unit, Rome, Italy, [Morris, Andrew A.] Cent Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Dept Med Genet, Manchester, Lancs, England, [Ulrick, Nicole] George Washington Univ, Sch Med, Childrens Natl Hlth Syst, Dept Neurol, Washington, DC USA, [Vanderver, Adeline] George Washington Univ, Sch Med, Childrens Natl Hlth Syst, Dept Neurol, Washington, DC USA, [Kmoch, Stanislav] Charles Univ Prague, Inst Inherited Metab Disorders, Fac Med 1, Prague, Czech Republic, [Houstek, Josef] Acad Sci Czech Republic, Inst Physiol, Prague, Czech Republic, [Martinelli, Diego] Children Res Hosp Bambino Gesu, Div Metab, Rome, Italy, [Haghighi, Alireza] Harvard Med Sch, Dept Genet, Boston, MA USA, [Haghighi, Alireza] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA, [Haghighi, Alireza] Brigham & Womens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA, [Atiq, Mehnaz] Aga Khan Univ, Dept Pediat, Karachi, Pakistan, [Gamero, Montserrat Anton] Hosp Univ Reina Sofia, Pediat Nephrol Unit, Cordoba, Spain, [Garcia-Martinez, Elena] Hosp Univ Reina Sofia, Pediat Nephrol Unit, Cordoba, Spain, [Kratochvilova, Hana] Charles Univ Prague, Fac Med 1, Dept Pediat & Adolescent Med, Prague, Czech Republic, [Kratochvilova, Hana] Gen Univ Hosp Prague, Prague, Czech Republic, [Santra, Saikat] Birmingham Childrens Hosp NHS Fdn Trust, Dept Clin Inherited Metab Disorders, Birmingham, W Midlands, England, [Brown, Ruth M.] Oxford Univ Hosp NHS Fdn Trust, Churchill Hosp, Oxford Med Genet Labs, Oxford, England, [Brown, Garry K.] Oxford Univ Hosp NHS Fdn Trust, Churchill Hosp, Oxford Med Genet Labs, Oxford, England, [Ragge, Nicola] Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Serv, Clin Genet Unit, Birmingham, W Midlands, England, [Monavari, Ahmad] Temple St Childrens Univ Hosp, Natl Ctr Inherited Metab Disorders, Dublin, Ireland, [Pysden, Karen] Leeds Gen Infirm, Dept Paediat Med, Leeds, W Yorkshire, England, [Childs, Anne-Marie] Leeds Gen Infirm, Dept Paediat Med, Leeds, W Yorkshire, England, [Ravn, Kirstine] Rigshosp, Copenhagen Univ Hosp, Dept Clin Genet, Copenhagen, Denmark, [Ostergaard, Elsebet] Rigshosp, Copenhagen Univ Hosp, Dept Clin Genet, Copenhagen, Denmark, [Casey, Jillian P.] Temple St Childrens Univ Hosp, Dept Clin Genet, Dublin, Ireland, [Khan, Arif] Leicester Royal Infirm, Leicester Childrens Hosp, Leicester, Leics, England, [Chakrapani, Anupam] Great Ormond St Hosp NHS Fdn Trust, Dept Metab Med, London, England, [Vassallo, Grace] Cent Manchester Univ Hosp NHS Fdn Trust, Dept Paediat Neurol, Manchester, Lancs, England, [Simons, Cas] Univ Queensland, Inst Mol Biosci, St Lucia, Qld, Australia, [McKeever, Karl] Royal Belfast Hosp Sick Children, Dept Paediat Med, Belfast, Antrim, North Ireland, [O'Sullivan, Siobhan] Royal Belfast Hosp Sick Children, Dept Paediat Med, Belfast, Antrim, North Ireland, [Goldstein, Amy] Childrens Hosp Pittsburgh, Div Child Neurol, Pittsburgh, PA USA, [Vogt, Julie] Univ Birmingham, Sch Clin & Expt Med, Ctr Rare Dis & Personalised Med, Dept Med & Mol Genet, Birmingham, W Midlands, England, [Ragge, Nicola] Oxford Brookes Univ, Fac Hlth & Life Sci, Oxford, England, Wellcome Trust, Medical Research Council, UK NHS Specialised Services and Newcastle upon Tyne Hospitals NHS Foundation Trust, National Institute for Health Research (NIHR), Charles University, BIOCEV -Biotechnology and Biomedicine Centre of the Academy of Sciences, European Regional Development Fund, Grant Agency of the Czech Republic, Ministry of Education of the Czech Republic, Ministry of Education, Ministry of Health of the Czech Republic, MRC, National Institute for Health Research, and NIHR Newcastle Biomedical Research Centre
Subjects: Translation, Complex deficiencies, Rmnd1 mutation, Defect, Renal-failure, Encephaloneuromyopathy
Abstract: Background Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects. Methods We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype–phenotype correlates and performed survival analysis to identify prognostic factors. Results We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement. Conclusions The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.
Published: 2016

41. Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study

Author: Miguel Ferrer, Ann W. Morgan, Beatriz Joven, John D. Isaacs, Theologia Sarafidou, Enrique Raya, Rafael Cáliz, Javier Narváez, Ariana Montes, Ana Márquez, C. Magro, Javier Martín, F. Navarro-Sarabia, Moreira Vf, María del Carmen Ordóñez, Lara Valor, Alejandro Balsa, Antonio Fernández-Nebro, Juan José Alegre-Sancho, Arturo Rodríguez de la Serna, Anne Barton, Rosa Garcia-Portales, Manuel J. Moreno-Ramos, Antonio Gonzalez, Anthony G. Wilson, Francisco J. Blanco, Patricia Carreira, Yiannis Vasilopoulos, Juan J. Gomez-Reino, Darren Plant, Berta Magallares, Juan D. Cañete, Eva Perez-Pampin, Dora Pascual-Salcedo, Universitat de Barcelona, Instituto de Salud Carlos III, European Commission, [Montes,A, Perez-Pampin,E] Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. [Navarro-Sarabia, F, Moreira,V] Rheumatology Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain. [Rodríguez de la Serna,A, Magallares,B] Rheumatology Unit, Hospital Santa Creu e San Pau, Barcelona, Spain. [Vasilopoulos,Y, Sarafidou,T] Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece. [Fernández-Nebro,A, Ordóñez,MC] Servicio de Reumatología, HRU Carlos Haya, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Narváez,J] Department of Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain. [Cañete,Jd] Rheumatology Unit, Hospital Clinic, Barcelona, Spain. [Marquez,A] Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. [Pascual-Salcedo,D] Department of Immunology, Instituto de Investigación Hospital Universitario La Paz, Hospital La Paz, Madrid, Spain. [Joven,B, Carreira,P] Department of Rheumatology, Hospital 12 de Octubre, Madrid, Spain. [Moreno-Ramos,MJ] Department of Rheumatology, Hospital Virgen de la Arrixaca, Murcia, Spain. [Caliz,R, Ferrer,NA] Rheumatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Garcia-Portales,R] Department of Rheumatology, Hospital Virgen de la Victoria, Málaga, Spain. [Blanco,FJ] Rheumatology Department, Instituto de Investigacion Biomedica-Complejo Hospitalario Universitario A Coruna, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. [Magro,C, Raya,E] Department of Rheumatology, Hospital Clínico San Cecilio, Granada, Spain. [Valor,L] Rheumatology Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [Alegre-Sancho,JJ] Department of Rheumatology, Hospital Doctor Peset, Valencia, Spain. [Balsa,A] Department of Rheumatology, Instituto de Investigación Hospital Universitario La Paz, Hospital Universitario La Paz, Madrid, Spain.[Martin,J] Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. [Plant,D] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. [Isaacs,J] Musculoskeletal Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, Newcastle, UK. [Morgan,AW] Leeds Institute of Rheumatic and Musculoskeletal Medicine, St. James's University Hospital, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK. [Barton,A] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Arthritis Research UK-Centre for Genetics and Genomics, The University of Manchester, Manchester, UK. [Wilson,AG] University College Dublin, Dublin, Ireland. [Gómez-Reino,JJ] Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. [Gonzalez,A] Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Laboratorio Investigacion 10, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain., Funding was provided by grants PI11/01048, PI12/01909 and by RETICS Program, RD08/0075/0019 and RD12/0009/0008 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union, UAM. Departamento de Medicina, and Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)
Subjects: Male, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings], Immunoglobulin G, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Arthritis, Rheumatoid, Immunology and Allergy, Single nucleotide, skin and connective tissue diseases, biology, IgG1 allotype, Drugs, Enfermedades reumáticas, Middle Aged, Allotype, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Monokines::Tumor Necrosis Factor-alpha [Medical Subject Headings], Articulaciones, Treatment Outcome, Estudi de casos, Rheumatoid arthritis, Diseases::Musculoskeletal Diseases::Rheumatic Diseases [Medical Subject Headings], Arthritis rheumatoid, Antirheumatic Agents, Teràpia genètica, Tumor necrosis factor alpha, Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Antibody, Medicaments, medicine.drug, Research Article, Adult, musculoskeletal diseases, medicine.medical_specialty, Genotype, Medicina, Anatomy::Musculoskeletal System::Skeleton::Joints [Medical Subject Headings], Immunology, Molecular Sequence Data, Artritis reumatoide, Polymorphism, Single Nucleotide, Gene therapy, Rheumatology, Internal medicine, Diseases::Musculoskeletal Diseases::Joint Diseases::Arthritis::Arthritis, Rheumatoid [Medical Subject Headings], medicine, Adalimumab, Humans, Polymorphism, Immunoglobulin Allotypes, Base Sequence, business.industry, Tumor Necrosis Factor-alpha, medicine.disease, Infliximab, Factor de necrosis tumoral alfa, Treatment, biology.protein, Case studies, business, Genotipo
Abstract: Montes, Ariana et al., [Introduction] We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA)., [Methods] The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria., [Results] An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication., [Conclusions] Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA., Funding was provided by grants PI11/01048, PI12/01909 and by RETICS Program, RD08/0075/0019 and RD12/0009/0008 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union.
Published: 2015

42. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author: Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Andrew, Lee, Daniel, Barrowdale, Sue, Healey, Sinilnikova, Olga M., Caligo, Maria A., Niklas, Loman, Katja, Harbst, Annika, Lindblom, Brita, Arver, Richard, Rosenquist, Per, Karlsson, Kate, Nathanson, Susan, Domchek, Tim, Rebbeck, Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Zlowocka Perlowska, E., Elzbieta Złowowcka Perłowska, Ana, Osorio, Mercedes, Duran, Raquel, Andres, Javier, Benitez, Ute, Hamann, Hogervorst, Frans B., Van, A., Van Os, Theo A., Senno, Verhoef, Meijers Heijboer, Hanne E. J., Juul, Wijnen, Gomez Garcia, Encarna B., Ligtenberg, Marjolijn J., Mieke, Kriege, Margriet Collee, J., Margreet Gem Ausems, Oosterwijk, Jan C., Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Rogers, Mark T., Alan, Donaldson, Huw, Dorkins, Godwin, Andrew K., Betsy, Bove, Dominique Stoppa Lyonnet, Claude, Houdayer, Bruno, Buecher, De Pauw, A., Antoine Pauw, D. E., Sylvie, Mazoyer, Alain, Calender, Melanie, Leone, Brigitte Bressac De Paillerets, Olivier, Caron, Hagay, Sobol, Marc, Frenay, Fabienne, Prieur, Sandra, Ferrer, Isabelle, Mortemousque, Saundra, Buys, Mary, Daly, Alexander, Miron, Terry, Mb, Terry, Mu, Mary, Terry, Hopper, John L., John, Em, Esther, John M., Melissa, Southey, David, Goldgar, Singer, Christian F., Anneliese Fink Retter, Muy Kheng Tea, Geschwantler Kaulich, D., Daphne, Kaulich, Hansen, Thomas V. O., Nielsen, Finn C., Barkardottir, Rosa B., Mia, Gaudet, Tomas, Kirchhoff, Joseph, V., Joseph, Vijai, Ana Dutra Clarke, Kenneth, Offit, Marion, Piedmonte, Judy, Kirk, David, Cohn, Jean, Hurteau, John, Byron, James, Fiorica, Toland, Amanda E., Marco, Montagna, Cristina, Oliani, Evgeny, Imyanitov, Claudine, Isaacs, Laima, Tihomirova, Ignacio, Blanco, Conxi, Lazaro, Alex, Teule, Del Valle, J., Gayther, Simon A., Kunle, Odunsi, Jenny, Gross, Karlan, Beth Y., Edith, Olah, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Jansen Van Rensburg, E., Elizabeth Van Rensburg, Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorothea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Muranen, Taru A., Bernard, Lesperance, Spurdle, Amanda B., Neuhausen, Susan L., Ding, Yuan C., Xianshu, Wang, Zachary, Fredericksen, Pankratz, Vernon S., Lindor, Noralane M., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Loud, Jennifer T., Andrulis, Irene L., Hilmi, Ozcelik, Anna, Mulligan, Gord, Glendon, Mads, Thomassen, Anne Marie Gerdes, Jensen, Uffe B., Anne Bine Skytte, Kruse, Torben A., Georgia Chenevix Trench, Couch, Fergus J., Jacques, Simard, Easton, Douglas F., Swedish Breast, Cancer Study S. B., Facility, Research H., Study, E., Collaborators, Study G., Investigators, K., Swe Brca Cimba, Embrace, Hebon, Study Gemo Collaborators, Kconfab, Investigators, BMC, Ed., Collaborative Oncological Gene-environment Study - COGS - - EC:FP7:HEALTH2009-05-01 - 2014-01-31 - 223175 - VALID, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Genetics and Population Health Division, Queensland Institute of Medical Research, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Oncology, Lund University Hospital, Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Sahlgrenska University Hospital [Gothenburg], Abramson Cancer Center, University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Postgraduate School of Molecular Medicine, Warsaw Medical University, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Institute of Biology and Molecular Genetics, Universidad de Valladolid [Valladolid] (UVa), Medical Oncology Division, Hospital Clínico de Zaragoza, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Family Cancer Clinic, Netherlands Cancer Institute, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), VU Medical Center, Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, Department of Human Genetics, Radboud University [Nijmegen], Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Department of Genetics, VU University Medical Center [Amsterdam], Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Oncogenetics Team, The Institute of Cancer Research-Royal Marsden NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Addenbrookes Hospital, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Royal Devon & Exeter Hospital, Medical Genetics Unit, University College of London [London] (UCL), Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Department of Medical Genetics, Queen's University [Belfast] (QUB), Oxford Regional Genetics Service, Churchill Hospital Oxford Centre for Haematology, All Wales Medical Genetics Services, Singleton Hospital, Clinical Genetics Department, St Michael's Hospital, North West Thames Regional Genetics Service, Kennedy-Galton Centre, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Clinical Molecular Genetics Laboratory, Fox Chase Cancer Center, Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, Institut Gustave Roussy (IGR), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Consultation de génétique, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Laboratoire de Génétique Chromosomique, CH Chambéry, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Internal Medicine, Huntsman Cancer Institute, Division of Population Science, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Department of Epidemiology, Columbia University [New York], Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Cancer Prevention Institute of California, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Dept of OB/GYN and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Pathology, University of Iceland [Reykjavik]-Landspitali - University Hospital, Epidemiology Research Program, American Cancer Society, Department of Environmental Medicine, New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Australia New Zealand (ANZGOG), Westmead Hospital [Sydney], Ohio State University [Columbus] (OSU), Evanston CCOP - NorthShore University Health System, University of Chicago, Southern Pines Women's Health Center, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Sarasota Memorial Healthcare, Tufts Medical Center, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, U.O.C. di Oncologia, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Latvian Biomedical Research and Study Centre [Rīga], Genetic Counselling Unit, IDIBELL-Catalan Institute of Oncology, Molecular Diagnostic Unit, Department of Preventive Medicine, University of Southern California (USC)-Keck School of Medicine [Los Angeles], University of Southern California (USC), Department of Gynecologic Oncology, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Department of Molecular Genetics, National Institute of Oncology, Cancer Research Initiatives Foundation, Sime Darby Medical Centre-Malaysia and University Malaya Cancer Research Institute-University Malaya Medical Centre, Jonsson Comprehensive Cancer Center at UCLA, Jonsson Comprehensive Cancer Center, UCSF Cancer Risk Program, University of California (UC), Departments of Medicine, Epidemiology, and Biostatistics, UCSF, Cancer Genetics Laboratory, University of Pretoria [South Africa], Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ludwig-Maximilians-Universität München (LMU), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universitätsklinikum Ulm - University Hospital of Ulm, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Heidelberg University Hospital [Heidelberg], University Hospital Carl Gustav Carus, Universität Regensburg (UR), University Hospital Frankfurt a.M., Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Hemato-oncology service, Hôpital du Sacré-Coeur de Montréal, Department of Population Sciences, Beckman Research Institute of City of Hope, Department of Laboratory Medicine and Pathology, Mayo Clinic, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), Cancer Bioimmunotherapy Unit, IRCCS-Centro di Riferimento Oncologico, Università degli Studi di Firenze = University of Florence (UniFI), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Laboratory Medicine, St Michael's Hospital-Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Ontario Cancer Genetics Network, Cancer Care Ontario, Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Skejby Hospital, Department of Laboratory Medicine and Pathology and Health Sciences Research, This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175), from the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program and by the Canadian Breast Cancer Research Alliance-grant #019511. This research was also supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. ACA is a CR-UK Senior Cancer Research Fellow, DFE is CR-UK Principal Research Fellow, GCT is a NHMRC Senior Principal Research Fellow, J.S. is Chairholder of the Canada Research Chair in Oncogenetics, on behalf of CIMBA, SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators and kConFab Investigators, European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), Pediatric Surgery, Neurology, Medical Oncology, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Roswell Park Cancer Institute [Buffalo] (RPCI), Universität Leipzig, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Pomeranian Medical University-International Hereditary Cancer Centre, Radboud university [Nijmegen], University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Georgetown University, University of California, Westfälische Wilhelms-Universität Münster (WWU), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human genetics, and CCA - Oncogenesis
Subjects: Oncology, Medicin och hälsovetenskap, Estrogen receptor, Genome-wide association study, HORMONE-RELATED PROTEIN, Chromosomes, Human, Pair 9 - genetics, Medical and Health Sciences, 0302 clinical medicine, 610 Medical sciences Medicine, CDKN2A, Risk Factors, Genotype, INVESTIGATORS, Chromosomes, Human, Pair 12 - genetics, skin and connective tissue diseases, MAMMOGRAPHIC DENSITY, Medicine(all), 0303 health sciences, BRCA1 Protein, Middle Aged, BRCA2 Protein, 3. Good health, DNA-Binding Proteins, Hereditary Breast and Ovarian Cancer Syndrome - genetics, 030220 oncology & carcinogenesis, Hereditary Breast and Ovarian Cancer Syndrome, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 9, Research Article, Adult, Breast cancer, BRCA1, BRCA2, medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, ddc:610, GENOME-WIDE ASSOCIATION, ddc:611, Genetic Association Studies, 030304 developmental biology, Aged, Gynecology, Chromosomes, Human, Pair 12, CONSORTIUM, BRCA1 Protein - genetics, ALLELES, medicine.disease, BRCA2 Protein - genetics, Cancer and Oncology, GENETIC MODIFIERS, Ovarian cancer, Transcription Factors
Abstract: INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers., published_or_final_version
Published: 2012

43. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author: Antoniou, A. C., Kartsonaki, C., Sinilnikova, O. M., Soucy, P., Mcguffog, L., Healey, S., Lee, A., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Barile, M., Pensotti, V., Pasini, B., Dolcetti, R., Giannini, Giuseppe, Laura Putignano, A., Varesco, L., Radice, P., Mai, P. L., Greene, M. H., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A. M., Kruse, T. A., Jensen, U. B., Cruger, D. G., Caligo, M. A., Laitman, Y., Milgrom, R., Kaufman, B., Paluch Shimon, S., Friedman, E., Loman, N., Harbst, K., Lindblom, A., Arver, B., Ehrencrona, H., Melin, B., Nathanson, K. L., Domchek, S. M., Rebbeck, T., Jakubowska, A., Lubinski, J., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Gorski, B., Osorio, A., Cajal, T. R., Fostira, F., Andres, R., Benitez, J., Hamann, U., Hogervorst, F. B., Rookus, M. A., Hooning, M. J., Nelen, M. R., Van Der Luijt, R. B., Van Os, T. A. M., Van Asperen, C. J., Devilee, P., Meijers Heijboer, H. E. J., Garcia, E. B. G., Peock, S., Cook, M., Frost, D., Platte, R., Leyland, J., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Eccles, D., Ong, K. R., Cook, J., Douglas, F., Paterson, J., John Kennedy, M., Miedzybrodzka, Z., Godwin, A., Stoppa Lyonnet, D., Buecher, B., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Lasset, C., Leroux, D., Faivre, L., Bronner, M., Prieur, F., Nogues, C., Rouleau, E., Pujol, P., Coupier, I., Frenay, M., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Tea, M. K., Pfeiler, G., Catharina Dressler, A., Hansen, T. V. O., Jonson, L., Ejlertsen, B., Barkardottir, R. B., Kirchhoff, T., Offit, K., Piedmonte, M., Rodriguez, G., Small, L., Boggess, J., Blank, S., Basil, J., Azodi, M., Toland, A. E., Montagna, M., Tognazzo, S., Agata, S., Imyanitov, E., Janavicius, R., Lazaro, C., Blanco, I., Pharoah, P. D. P., Sucheston, L., Karlan, B. Y., Walsh, C. S., Olah, E., Bozsik, A., Teo, S. H., Seldon, J. L., Beattie, M. S., Van Rensburg, E. J., Sluiter, M. D., Diez, O., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ruehl, I., Varon Mateeva, R., Kast, K., Deissler, H., Niederacher, D., Arnold, N., Gadzicki, D., Schonbuchner, I., Caldes, T., De La Hoya, M., Nevanlinna, H., Aittomaki, K., Dumont, M., Chiquette, J., Tischkowitz, M., Chen, X. Q., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Fredericksen, Z., Wang, X., Pankratz, V. S., Couch, F., Simard, J., Easton, D. F., Chenevix Trench, G., Karlsson, P., Nordling, M., Bergman, A., Einbeigi, Z., Stenmark Askmalm, M., Liedgren, S., Borg, A., Olsson, H., Kristoffersson, U., Jernstrom, H., Henriksson, K., Von Wachenfeldt, A., Liljegren, A., Barbany Bustinza, G., Rantala, J., Gronberg, H., Stattin, E. L., Emanuelsson, M., Brandell, R. R., Dahl, N., Hogervorst, F. B. L., Verhoef, S., Verheus, M., Veer, L. V., Van Leeuwen, F. E., Collee, M., Van Den Ouweland, A. M. W., Jager, A., Tilanus Linthorst, M. M. A., Seynaeve, C., Wijnen, J. T., Vreeswijk, M. P., Tollenaar, R. A., Ligtenberg, M. J., Hoogerbrugge, N., Ausems, M. G., Aalfs, C. M., Van Os, T. A., Gille, J. J. P., Waisfisz, Q., Gomez Garcia, E. B., Van Roozendaal, C. E., Blok, M. J., Caanen, B., Oosterwijk, J. C., Van Der Hout, A. H., Mourits, M. J., Vasen, H. F., Gregory, H., Morrison, P., Jeffers, L., Cole, T., Mckeown, C., Hoffman, J., Donaldson, A., Downing, S., Taylor, A., Murray, A., Rogers, M. T., Mccann, E., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Brewer, C., Kivuva, E., Searle, A., Goodman, S., Hill, K., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Whaite, A., Dorkins, H., Barwell, J., Chu, C., Miller, J., Ellis, I., Houghton, C., Taylor, J., Side, L., Male, A., Berlin, C., Eason, J., Collier, R., Claber, O., Jobson, I., Walker, L., Mcleod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Bancroft, E., D'Mello, L., Page, E., Ardern Jones, A., Kohut, K., Wiggins, J., Castro, E., Mitra, A., Robertson, L., Quarrell, O., Bardsley, C., Hodgson, S., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Lucassen, A., Crawford, G., Mcbride, D., Smalley, S., University of Groningen, Clinical Genetics, Medical Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Queensland Institute of Medical Research, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Consortium for Genomics Technology (Cogentech), Department of Genetics, Biology and Biochemistry, University of Turin, Cancer Bioimmunotherapy Unit, IRCCS-Centro di Riferimento Oncologico, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' [Rome], Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Ontario Cancer Genetics Network, Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital ( MSH ), Department of Clinical Genetics, Odense University Hospital, Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Department of Oncology, Lund University Hospital, Karolinska University Hospital [Stockholm], Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Radiation Sciences and Oncology, Umeå University, Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine-Abramson Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University-International Hereditary Cancer Centre, Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, International Hereditary Cancer Center, Pomeranian Medical University, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Department of Medical Oncology, Hospital Sant Pau, Medical Oncology Division, Hospital Clínico de Zaragoza, Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum ( DKFZ ), Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Wessex Clinical Genetics Service, Princess Anne Hospital, West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Addenbrookes Hospital, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Service de Génétique Oncologique, INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), génétique, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Service d'onco-hématologie et génétique, CHU Grenoble, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Santé Publique, Hôpital René HUGUENIN (Saint-Cloud)-INSTITUT CURIE, Laboratoire d'Oncogénétique, CRLCC René Huguenin, Institut de recherche en cancérologie de Montpellier ( IRCM - U896 Inserm - UM1 ), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, Consultation d'oncogénétique, CRLCC Antoine Lacassagne, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] ( HMS ), Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Division of Special Gynecology, Medical University of Vienna-Department of OB/GYN, Department of Clinical Biochemistry, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Rigshospitalet [Copenhagen], Department of Pathology, Landspitali-University Hospital, Department of Environmental Medicine, New York University School of Medicine-NYU Cancer Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, State Research Institute Innovative Medicine Center, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Genetic Counselling Unit, Department of Molecular Genetics, National Institute of Oncology, Cancer Research Initiatives Foundation, Sime Darby Medical Centre-Malaysia and University Malaya Cancer Research Institute-University Malaya Medical Centre, Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, Technical University of Munich ( TUM ), Ludwig-Maximillians University, Charite berlin, University Hospital Carl Gustav Carus, University Hospital Ulm, University Hospital Düsseldorf-Heinrich-Heine-Universität Düsseldorf [Düsseldorf], University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel ( CAU ), Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] ( MHH ), University of Würzburg, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Genetics, Portuguese Oncology Institute, Department of Medical Genetics, Mayo Clinic, Department of Laboratory Medicine and Pathology, Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Clinical Genetics [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Tel Aviv University (TAU), Uppsala University, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Abramson Cancer Center-Perelman School of Medicine, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Pomeranian Medical University [Szczecin] (PUM), Hospital de la Santa Creu i Sant Pau, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universiteit Leiden-Universiteit Leiden, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Newcastle Upon Tyne Hospitals NHS Foundation Trust, University of Kansas Medical Center [Kansas City, KS, USA], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut Curie [Paris]-Hôpital René HUGUENIN (Saint-Cloud), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Harvard Medical School [Boston] (HMS), Medizinische Universität Wien = Medical University of Vienna, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Department of Clinical Biochemistry [Rigshospitalet], Copenhagen University Hospital, New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Roswell Park Cancer Institute [Buffalo] (RPCI), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Hannover Medical School [Hannover] (MHH), Julius-Maximilians-Universität Würzburg (JMU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital René HUGUENIN (Saint-Cloud)-Institut Curie [Paris], CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Universität Leipzig [Leipzig], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), University of Florence (UNIFI), Mount Sinai Hospital (MSH), Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Hôpital René HUGUENIN (Saint-Cloud), Technical University of Munich (TUM), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Human genetics, CCA - Oncogenesis, Human Genetics, Klinische Genetica, and RS: GROW - School for Oncology and Reproduction
Subjects: MESH : BRCA2 Protein, MESH : Aged, Estrogen receptor, Genome-wide association study, MESH : Breast Neoplasms, VARIANTS, MESH : Chromosomes, Human, Pair 1, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Chromosomes, Human, Pair 6, MESH: BRCA2 Protein, 0302 clinical medicine, MESH: Risk Factors, Risk Factors, Genotype, CONFER SUSCEPTIBILITY, Chromosomes, Human, MESH : Female, skin and connective tissue diseases, Genetics (clinical), POPULATION, MESH: Heterozygote, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, BRCA1 Protein, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH : Adult, Middle Aged, MESH : Risk Factors, 3. Good health, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, MESH : Mutation, Adult, MESH : Heterozygote, Heterozygote, MESH: Mutation, MESH: Chromosomes, Human, Pair 6, MESH: Chromosomes, Human, Pair 1, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Breast Neoplasms, Biology, MESH: Chromosomes, Human, Polymorphism, Single Nucleotide, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, LOCUS, SNP, Humans, MESH : Middle Aged, MESH : BRCA1 Protein, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Alleles, MESH: BRCA1 Protein, 030304 developmental biology, Aged, BRCA2 Protein, MESH: Humans, 2Q35, MESH: Alleles, MESH : Humans, MESH: Adult, medicine.disease, MESH : Chromosomes, Human, ESTROGEN-RECEPTOR, Mutation, Cancer research, MESH : Genetic Predisposition to Disease, GENETIC MODIFIERS, MESH : Alleles, MESH: Female, MESH: Breast Neoplasms
Abstract: Item does not contain fulltext Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
Published: 2011

44. Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

Author: Maxwell, C.A., Benitez, J., Gomez-Baldo, L., Osorio, A., Bonifaci, N., Fernandez-Ramires, R., Costes, S.V., Guino, E., Chen, H., Evans, G.J.R., Mohan, P., Catala, I., Petit, A., Aguilar, H., Villanueva, A., Aytes, A., Serra-Musach, J., Rennert, G., Lejbkowicz, F., Peterlongo, P., Manoukian, S., Peissel, B., Ripamonti, C.B., Bonanni, B., Viel, A., Allavena, A., Bernard, L., Radice, P., Friedman, E., Kaufman, B., Laitman, Y., Dubrovsky, M., Milgrom, R., Jakubowska, A., Cybulski, C., Gorski, B., Jaworska, K., Durda, K., Sukiennicki, G., Lubinski, J., Shugart, Y.Y., Domchek, S.M., Letrero, R., Weber, B.L., Hogervorst, F.B.L., Rookus, M.A., Collee, J.M., Devilee, P., Ligtenberg, M.J., Luijt, R.B. van der, Aalfs, C.M., Waisfisz, Q., Wijnen, J., Roozendaal, C.E.P. van, Easton, D.F., Peock, S., Cook, M., Oliver, C., Frost, D., Harrington, P., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Eccles, D., Douglas, F., Brewer, C., Nevanlinna, H., Heikkinen, T., Couch, F.J., Lindor, N.M., Wang, X.S., Godwin, A.K., Caligo, M.A., Lombardi, G., Loman, N., Karlsson, P., Ehrencrona, H., Wachenfeldt, A. von, Barkardottir, R.B., Hamann, U., Rashid, M.U., Lasa, A., Caldes, T., Andres, R., Schmitt, M., Assmann, V., Stevens, K., Offit, K., Curado, J., Tilgner, H., Guigo, R., Aiza, G., Brunet, J., Castellsague, J., Martrat, G., Urruticoechea, A., Blanco, I., Tihomirova, L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Schmutzler, R.K., Wappenschmidt, B., Meindl, A., Arnold, N., Deissler, H., Varon-Mateeva, R., Sutter, C., Niederacher, D., Imyamitov, E., Sinilnikova, O.M., Stoppa-Lyonne, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., Spurdle, A.B., Beesley, J., Chen, X.Q., Healey, S., Barcellos-Hoff, M.H., Vidal, M., Gruber, S.B., Lazaro, C., Capella, G., McGuffog, L., Nathanson, K.L., Antoniou, A.C., Chenevix-Trench, G., Fleisch, M.C., Moreno, V., Pujana, M.A., HEBON, EMBRACE, SWE-BRCA, BCFR, GEMO Study Collaborators, kConFab, Human genetics, CCA - Innovative therapy, Universitat de Barcelona, Faculteit der Geneeskunde, Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Biomarkers and Susceptibility Unit, Life Science Division [LBNL Berkeley], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Child and Family Research Institute, Department of Pathology, University Hospital of Bellvitge, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, Department of Genetics, Biology and Biochemistry, University of Turin, Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Department of Genetics and Pathology, Pomeranian Medical University-International Hereditary Cancer Centre, Unit of Statistical Genetics, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health, Abramson Cancer Center, University of Pennsylvania [Philadelphia], Family Cancer Clinic, Netherlands Cancer Institute, Department of Epidemiology, Department of Clinical Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Department of Human Genetics, Radboud university [Nijmegen], Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), VU University Medical Center [Amsterdam], Center for Human and Clinical Genetics, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Department of Oncology, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Wessex Clinical Genetics Service, Princess Anne Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Royal Devon & Exeter Hospital, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Medical Genetics, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Lawrence], Section of Genetic Oncology, Pisa University Hospital-University of Pisa - Università di Pisa, Lund University Hospital, Sahlgrenska University Hospital [Gothenburg], Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Karolinska University Hospital [Stockholm], Landspitali-University Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Deutsches Krebsforschungszentrum, Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Medical Oncology Division, Hospital Clínico de Zaragoza, Department of Internal Medicine III, University of Rostock, Center for Experimental Medicine, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE)-Institute of Tumor Biology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Bioinformatics and Genomics Group, Centre for Genomic Regulation (CRG), Genetic Counseling and Hereditary Cancer Programme, Latvian Biomedical Research and Study Centre [Rīga], Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Division of Population Science, Fox Chase Cancer Center, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Universitätsklinikum Ulm - University Hospital of Ulm, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Heidelberg University Hospital [Heidelberg], University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], N. N. Petrov Institute of Oncology, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Génétique moléculaire, signalisation et cancer (GMSC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Pathologie moléculaire des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, Hôtel-Dieu-CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Queensland Institute of Medical Research, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute [Boston]-Department of Cancer Biology, Department of Genetics [Boston], Department of Internal Medicine, Epidemiology, Human Genetics, Department of Obstetrics and Gynaecologie, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], This work was funded by the Spanish Ministries of Health, and Science ane Innovation (CB07/02/2005, FIS 08/1120, 08/1359, 08/1635, and 09/02483, RTICCC RD06/0020/1060 and RD06/0020/0028, Transversal Action Against Cancer, the Spanish Biomedical Research Centre Networks for Epidemiology and Public Health, and Rare Diseases, and the 'Ramón y Cajal' Young Investigator Program), the Spanish National Society of Medical Oncology (2010), the Spanish Association Against Cancer (AECC 2010), the AGAUR Catalan Government Agency (2009SGR1489 and 2009SGR293, and the Beatriu Pinós Postdoctoral Program), the Ramón Areces Foundation (XV), the 'Roses Contra el Càncer' Foundation, the Michael Cuccione Foundation for Childhood Cancer Research, Cancer Research-UK (C490/A10119, C1287/A8874, C1287/A10118, C5047/A8385, and C8197/A10123), the National Institute for Health Research (UK), the Association for International Cancer Research (AICR-07-0454), the Ligue National Contre le Cancer (France), the Association 'Le cancer du sein, parlons-en!', the Dutch Cancer Society (NKI 1998-1854, 2004-3088, and 2007-3756), the Fondazione Italiana per la Ricerca sul Cancro ('Hereditary Tumors'), the Associazione Italiana per la Ricerca sul Cancro (4017), the Italian Ministero della Salute (RFPS-2006-3-340203 and 'Progetto Tumori Femminili'), the Italian Ministero dell'Universita' e Ricerca (RBLAO3-BETH), the Fondazione IRCCS Istituto Nazionale Tumori (INT '5×1000'), the Fondazione Cassa di Risparmio di Pisa (Istituto Toscano Tumori), the National Breast Cancer Foundation (Australia), the Australian National Health and Medical Research Council (145684, 288704, and 454508), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, the Cancer Foundation of Western Australia, the German Cancer Aid (107054), the Center for Molecular Medicine Cologne (TV93), the National Cancer Institute (USA, CA128978 and CA122340), National Institutes of Health (RFA-CA-06-503, BCFR U01 CA69398, CA69417, CA69446, CA69467, CA69631, and CA69638), the Research Triangle Institute Informatics Support Center (RFP N02PC45022-46), the Specialized Program of Research Excellence (SPORE P50 CA83638 and CA113916), the Department of Defense Breast Cancer Research Program (05/0612), the Eileen Stein Jacoby Fund, the Breast Cancer Research Foundation, the Marianne and Robert MacDonald Foundation, the Komen Foundation, the Helsinki University Central Hospital Research Fund, the Academy of Finland (110663), the Finnish Cancer Society, the Sigrid Juselius Foundation, and the EU FP7 (223175, HEALTH-F2-2009-223175)., HEBON, EMBRACE, SWE-BRCA, BCFR, GEMO Study Collaborators, kConFab, Human Genetics, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Università degli studi di Torino = University of Turin (UNITO), Tel Aviv University (TAU), International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), University of Pennsylvania, Universiteit Leiden-Universiteit Leiden, Radboud University [Nijmegen], University of Kansas Medical Center [Kansas City, KS, USA], Uppsala University, Université de Lille-UNICANCER-Université de Lille-UNICANCER, Autard, Delphine, Neurology, and Pathology
Subjects: Mama -- Càncer -- Aspectes genètics, MESH: Extracellular Matrix Proteins, endocrine system diseases, Cellular differentiation, Genes, BRCA2, Genes, BRCA1, Microtubules, MESH: Genotype, 0302 clinical medicine, Breast cancer, Aurora Kinases, MESH: Genetic Variation, Biology (General), skin and connective tissue diseases, 0303 health sciences, Extracellular Matrix Proteins, Tumor, MESH: Microtubules, Cancer Risk Factors, 3. Good health, Hyaluronan Receptors, Oncology, Receptors, Estrogen, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, MESH: Receptors, Estrogen, Medicine, General Agricultural and Biological Sciences, Genotype, QH301-705.5, MESH: Antigens, CD44, General Biochemistry, Genetics and Molecular Biology, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Genetics, Cancer Genetics, Humans, Progenitor cell, Biology, MESH: BRCA1 Protein, MESH: Humans, CD44, Genetic Variation, Epithelial Cells, Oncogenes, medicine.disease, BRCA1, BRCA2, Genes, Carcinogenesis, MESH: Genes, BRCA1, MESH: Female, MESH: Genes, BRCA2, Population Genetics, HeLa Cells, Epithelial cells, medicine.disease_cause, MESH: BRCA2 Protein, Cell polarity, Basic Cancer Research, Receptors, Breast, MESH: Breast, MESH: Heterozygote, Aurora Kinase A, Cèl·lules epitelials, biology, BRCA1 Protein, General Neuroscience, MESH: Genetic Predisposition to Disease, Cell Polarity, Biological Sciences, BRCA2 Protein, Mama -- Càncer -- Aspectes moleculars, Protein-Serine-Threonine Kinases, Female, Stem cell, MESH: Cell Polarity, Research Article, Oncogens, Heterozygote, MESH: Cell Line, Tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Protein Serine-Threonine Kinases, Cell Line, Càncer de mama, Cell Line, Tumor, Regulació genètica, medicine, Genetic Predisposition to Disease, Antigens, 030304 developmental biology, General Immunology and Microbiology, Human Genetics, Estrogen, MESH: HeLa Cells, Genetics of Disease, biology.protein, Cancer research, Gene Function, MESH: Breast Neoplasms
Abstract: Genetic analysis identifies the HMMR gene as a modifier of the breast cancer risk associated with BRCA1 gene mutation, while cell biological analysis of the protein product suggests a function in regulating development of the mammary gland., Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio (wHR) = 1.09 (95% CI 1.02–1.16), ptrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94–1.16), ptrend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM., Author Summary Mutations in two genes that were initially identified as predisposing carriers to early-onset breast cancer, BRCA1 and BRCA2, cause similar perturbations in cellular responses to DNA damage but predispose carriers to distinct tumor types. Thus, the two genes may trigger different carcinogenic processes. We have used genetic analyses of affected families to uncover additional genetic variation that is linked to the risk of developing cancer for carriers of BRCA1 mutations. This variation falls within a centrosomal gene, named HMMR. The protein product of HMMR, which is called RHAMM, works in concert with BRCA1 to regulate the structure of normal breast cells as they grow and become polarized. This polarization process depends upon a balance between the activities of BRCA1 and the Aurora kinase A, with the kinase opposing BRCA1 function and promoting growth. Our findings provide new insights into the mechanism through which BRCA1 may promote commitment of initially bipotent mammary cells towards the luminal lineage, and how loss of this function may predispose cells to become breast tumors of a basal-like type.
Published: 2011

45. Common Inhibition of Both β-Glucosidases and β-Mannosidases by Isofagomine Lactam Reflects Different Conformational Itineraries for Pyranoside Hydrolysis

Author: Carl Morland, James M. Macdonald, Florence Vincent, Carlos M. G. A. Fontes, Robert V. Stick, Tracey M. Gloster, Gideon J. Davies, José A. M. Prates, Fernando M. V. Dias, Harry J. Gilbert, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of St Andrews [Scotland], Imperial College London, Institute for Cell and Molecular Biosciences, The Medical School, University of Newcastle (UoN), Newcastle Upon Tyne Hospitals NHS Foundation Trust, Universidade de Lisboa (ULISBOA), NZYTech Genes & Enzymes, University of Newcastle [Australia] (UoN), University of York [York, UK], Universidade de Lisboa = University of Lisbon (ULISBOA), and University of Newcastle [Callaghan, Australia] (UoN)
Subjects: Mannosidase, Anomer, Lactams, Stereochemistry, Molecular Conformation, Context (language use), 010402 general chemistry, 01 natural sciences, Biochemistry, Enzyme catalysis, chemistry.chemical_compound, Piperidines, Hydrolase, Cellulases, Glycoside hydrolase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Mannosidases, Enzyme Inhibitors, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Pyrans, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 010405 organic chemistry, Hydrolysis, Organic Chemistry, beta-Mannosidase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 0104 chemical sciences, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Kinetics, chemistry, Lactam, Molecular Medicine, Imino Pyranoses
Abstract: The ninety sequence-based families of glycoside hydrolases (GHs) and the correspondingly large diversity of protein topologies are a rich framework for studying variations in the catalytic mechanism of enzymatic glycoside hydrolysis. Such hydrolysis features oxocarbenium-ion-like transition states in which the anomeric centre becomes sp hybridised and partial positive charge accumulates, primarily across the endocyclic O5 C1 bond. For pyranosides, such a species demands planarity of C5, O5, C1 and C2 at or near the transition state; a situation accommodated only by the H3 and H4 (half-chair) conformations (or their closely related envelope forms) and B and B2,5 boats. Initial assumptions that all glycosidases harness H3 conformations are incorrect; indeed, the utilisation of different transition states for the hydrolysis of glycosides is an emerging theme in glycobiology (Scheme 1) and one that suggests a route for specific enzyme inhibition. Isofagomine lactam (1) displays an “in-plane” carbonyl at C2 and is, not surprisingly, a reasonable b-glucosidase inhibitor, with family GH1 b-glucosidases from Thermotoga maritima (TmGH1) and sweet almond inhibited with Ki values of 130 nm (this work, Figure 1) and 29 mm, respectively. Compound 1 has previously been shown to be an equally potent b-mannosidase inhibitor, with the snail b-mannosidase inhibited with a Ki of 9 mm ; this is superficially extremely counter-intuitive. Here, such Ki values for mannosidases are rationalised through structural analysis of 1 in complex with both an exo b-mannanase/b-mannosidase and a b-glucosidase. This work strongly supports previous proposals that b-mannosidases utilise a novel conformational itinerary, featuring a B2,5 transition state. The ground-state axial O2 of mannose is thus pseudo-equatorial at the transition state in a way that should be harnessed in future generations of mannosidase inhibitors. Recently we described the conformational agenda of a retaining GH26 b-mannanase. Trapping of the S5 conformation for the “Michaelis” complex of unhydrolysed substrate, together with the S2 conformation for the covalent intermediate, suggested a novel conformational itinerary for these enzymes through a B2,5 transition state consistent with earlier proposals, notably by Sinnott and Horton. Glycoside hydrolases thus appear to be harnessing the full conformational itinerary in a way that is both enzyme and substrate dependent (this was recently reviewed in the context of inhibition by Vasella and colleagues). Conformational considerations suggest that retaining mannosidase transition-state mimics should thus feature the pseudo-equatorial O2 of the B2,5 conformation of mannose. Isofagomine lactam 1, synthesised by both Stick and Bols, contains an in-plane carbonyl at C2. In elegant work, Bols reports a Ki of 9 mm for the snail b-mannosidase; [4] this inspired us to study the three-dimensional structures of 1 bound to both TmGH1 and a Cellvibrio mixtus exo b-mannanase (CmMan5, which is totally specific for manno-configured substrates). “Dual” inhibition of b-glucosidases and b-mannosidases has also been reported for the hydropyridazone compounds, which show similarity to isofagomine lactam, as discussed below. The three-dimensional structures of TmGH1 and CmMan5 in complex with 1 were determined by X-ray [a] Dr. F. Vincent, T. M. Gloster, Prof. G. J. Davies Structural Biology Laboratory, Department of Chemistry The University of York, Heslington, York, YO10 5YW (UK). Fax: (+44)1904-328266 E-mail : davies@ysbl.york.ac.uk
Published: 2004

46. Insights into the Molecular Determinants of Substrate Specificity in Glycoside Hydrolase Family 5 Revealed by the Crystal Structure and Kinetics of Cellvibrio mixtus Mannosidase 5A

Author: Louise E. Tailford, Florence Vincent, Luís M. A. Ferreira, Maria S.J. Centeno, José A. M. Prates, Fernando M. V. Dias, Gavin Pell, Gideon J. Davies, Harry J. Gilbert, Carlos M. G. A. Fontes, Instituto Superior Técnico, Universidade Técnica de Lisboa, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Newcastle University [Newcastle], Centro de Investigaçao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária-Technical University of Lisbon, Faculdade de Medicina Veterinária, University of York [York, UK], University of Newcastle [Australia] (UoN), Newcastle Upon Tyne Hospitals NHS Foundation Trust, Universidade de Lisboa = University of Lisbon (ULISBOA), NZYTech Genes & Enzymes, University of Newcastle [Callaghan, Australia] (UoN), UK Research & Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC) BBS/B/05974 B20376, and Universidade de Lisboa (ULISBOA)
Subjects: Mannosidase, Stereochemistry, Cellvibrio, Mannose, Biochemistry, Catalysis, Substrate Specificity, 03 medical and health sciences, chemistry.chemical_compound, Hydrolase, Glycoside hydrolase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Glycoside hydrolase family 5, Hydrolysis, 030302 biochemistry & molecular biology, beta-Mannosidase, Glycosidic bond, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, biology.organism_classification, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Kinetics, Aglycone, chemistry, Multigene Family, Crystallization
Abstract: The enzymatic hydrolysis of the glycosidic bond is central to numerous biological processes. Glycoside hydrolases, which catalyze these reactions, are grouped into families based on primary sequence similarities. One of the largest glycoside hydrolase families is glycoside hydrolase family 5 (GH5), which contains primarily endo-acting enzymes that hydrolyze beta-mannans and beta-glucans. Here we report the cloning, characterization, and three-dimensional structure of the Cellvibrio mixtus GH5 beta-mannosidase (CmMan5A). This enzyme releases mannose from the nonreducing end of mannooligosaccharides and polysaccharides, an activity not previously observed in this enzyme family. CmMan5A contains a single glycone (-1) and two aglycone (+1 and +2) sugar-binding subsites. The -1 subsite displays absolute specificity for mannose, whereas the +1 subsite does not accommodate galactosyl side chains but will bind weakly to glucose. The +2 subsite is able to bind to decorated mannose residues. CmMan5A displays similar activity against crystalline and amorphous mannans, a property rarely attributed to glycoside hydrolases. The 1.5 A crystal structure reveals that CmMan5A adopts a (beta/alpha)(8) barrel fold, and superimposition with GH5 endo-mannanases shows that dramatic differences in the length of three loops modify the active center accessibility and thus modulate the specificity from endo to exo. The most striking and significant difference is the extended loop between strand beta8 and helix alpha8 comprising residues 378-412. This insertion forms a "double" steric barrier, formed by two short beta-strands that function to "block" the substrate binding cleft at the edge of the -1 subsite forming the "exo" active center topology of CmMan5A.
Published: 2004

47. Exploring the link between MORF4L1 and risk of breast cancer

Author: Martrat, G., Maxwell, C.A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X.Q., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J., Bodmer, D., Ausems, M.G.E.M., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E.J., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Oskar, T., Couch, F.J., Wang, X.S., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., Pujana, M.A., EMBRACE, kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Human Genetics, BMC, Ed., Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Department of Cellular and Structural Biology, The University of Texas Health Science Center at Houston (UTHealth)-Sam and Ann Barshop Institute for Longevity and Aging Studies, Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Biomarkers and Susceptibility Unit, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Biomedical Research Centre Network for Rare Diseases (CIBERER), Genetic Counseling and Hereditary Cancer Programme, Section of Cancer Genetics, Institute of cancer research, Department of Human Genetics, Julius-Maximilians-Universität Würzburg (JMU), Strangeways Research Laboratory, University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Genetic Medicine, St Mary's Hospital-NHS Foundation Trust-Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Ferguson-Smith Centre for Clinical Genetics, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Queen Mary University of London (QMUL)-St George's Hospital, Department of Clinical Genetics, Royal Devon & Exeter Hospital, Northern Ireland Regional Genetics Centre, Belfast City Hospital, South East of Scotland Regional Genetics Service, Western General Hospital, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine-Fondazione IRCCS Istituto Nazionale Tumori (INT), Department of Preventive and Predictive Medicine, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Fondazione IRCCS INT, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), Fiorgen Foundation for Pharmacogenomics, Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, IEO, Division of Genetics and Population Health, Queensland Institute of Medical Research, Department of Epidemiology, The Netherlands Cancer Institute, Family Cancer Clinic, Department of Surgical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), DNA Diagnostics, Radboud University Medical Center [Nijmegen], Department of Medical Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University Hospital Maastricht, VU Medical Center, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (MEGA), University of Melbourne-Melbourne School of Population Health, Division of Population Science, Fox Chase Cancer Center, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University, Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, The Institute of Oncology, Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Sackler Faculty of Medicine, Tel Aviv University (TAU), Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Department of Medicine, Medical Genetics, Abramson Cancer Center-Perelman School of Medicine, Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland [Reykjavik], Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Health Sciences Research, Statistical Assessment Service, Department of Physiology, Universität zu Lübeck = University of Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, Medical Oncology Branch, Hospital Clínico San Carlos, Human Cancer Genetics Programme, CIBER de Enfermedades Raras (CIBERER)-Spanish National Cancer Research Centre, Division of Hematopoiesis and Gene Therapy, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas [Madrid] (CIEMAT), Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Instituto de Genética Humana, Pontificia Universidad Javeriana (PUJ), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion, Vilnius University [Vilnius]-Hospital Santariskiu Clinics, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, The CIMBA data management is supported by Cancer Research - UK., kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Autonomous University of Barcelona, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Oncology-University of Cambridge [UK] (CAM), University of Turin, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Tel Aviv University [Tel Aviv], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universität zu Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Universiteit Leiden-Universiteit Leiden, Skåne University Hospital-Lund University [Lund], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Faculteit der Geneeskunde, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Human genetics, CCA - Oncogenesis, Biomedical Research Centre Network for Epidemiology and Public Health ( CIBERESP ), The University of Texas Health Science Center at San Antonio-Sam and Ann Barshop Institute for Longevity and Aging Studies, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Biomedical Research Centre Network for Rare Diseases ( CIBERER ), University of Würzburg, University of Cambridge [UK] ( CAM ) -Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ) -Department of Oncology, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Queen Mary University of London ( QMUL ) -St George's Hospital, IFOM, Istituto FIRC di Oncologia Molecolare ( IFOM ), Università degli Studi di Roma 'La Sapienza' [Rome], University of Florence, Erasmus MC-Daniel den Hoed Cancer Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Harvard Medical School [Boston] ( HMS ), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology ( MEGA ), University of Pennsylvania School of Medicine, University of Pennsylvania School of Medicine-Abramson Cancer Center, Centro de Investigaciones Energéticas, Deutsches Krebsforschungszentrum ( DKFZ ), Pontificia Universidad Javeriana, University of Pisa [Pisa], University of Kansas Medical Center, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Jean Perrin, CRLCC Oscar Lambret, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Hôpital Bretonneau-CHRU Tours, and Universitat de Barcelona
Subjects: DNA Repair, Genes, BRCA2, RAD51, Genes, BRCA1, Germ-Cell, Helicase Brip1, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Breast cancer, Fanconi anemia, Risk Factors, Replication Protein A, Teknik och teknologier, Homologous Recombination, skin and connective tissue diseases, C-Elegans, Genetics, Medicine(all), ddc:616, 0303 health sciences, Mutation, Fanconi Anemia Complementation Group D2 Protein, Nuclear Proteins, Anèmia aplàstica, 3. Good health, 030220 oncology & carcinogenesis, Chromodomain Protein, Engineering and Technology, Female, RNA Interference, Fanconi Anemia Complementation Group N Protein, Aplastic anemia, Research Article, BRCA2 Mutation Carrier, DNA repair, PALB2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, Càncer de mama, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, Two-Hybrid System Techniques, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Caenorhabditis elegans, Gene, 030304 developmental biology, Phenocopy, Caenorhabditis-Elegan, Tumor Suppressor Proteins, medicine.disease, BRCA1, BRCA2, Pancreatic-Cancer, Fanconi Anemia, Genes, Cancer and Oncology, Fanconi-Anemia, Cancer research, Rad51 Recombinase, Susceptibility Gene, DNA Damage, Transcription Factors
Abstract: Introduction Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

48. Make lithium great again – Precisely!

Author: Frank Bellivier, Bruno Etain, Allan H. Young, Jan Scott, David A. Cousins, Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), King‘s College London, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, and Etain, Bruno
Subjects: Sleep latency, recurrent suicide attempt, childhood maltreatment, non-coding RNA, Meta-regression, Comorbidity, Clinical markers, GWAS, genetics, Dual diagnosis, validation, Multi-omics, response, Energy, MESH: Risk, burnout, substance use disorder, Vaccination, Laterality, Catatonia, Genomics, Quality, Diagnostic delay, machine learning, Mood stabilisers, Suicidal behavior, depression, treatment-resistant depression, Epigenetics, levels of analysis, Cognitive function, addiction, dimensions, Longitudinal study, age at onset, post-traumatic, MESH: Sex Characteristics, medicine.medical_specialty, Data set, Methylation, MESH: Sulfurtransferases, Clusters, 03 medical and health sciences, PSQI, Bipolar I disorder, LITHIUM USE, Functioning, Misperception of sleep, Transcriptomics, Genotype-by-sex interaction, MESH: Humans, variability, patient experience, Modifiers, transferability, biomarkers, MESH: Adult, MESH: Retrospective Studies, Precision medicine, Psychosis, Pharmacodynamics, antecedents, major depression, MESH: Female, Cohorts, Youth, patient satisfaction, Seasonal variation, Response variability, Practice guidelines, Trajectories, activity rhythms, Argument, quality of care, Suicide attempt, pain, Sequence of onset, bipolar disorder, Psychiatry, Maintenance treatment, MESH: Suicidal Ideation, outcome studies, MESH: Depression, Postpartum, Alda scale, Clinical Practice, Phenotype, biological rhythms, Tolerability, radiomics, biomarker, affective symptoms, circadian genes, medicine.drug, mood recurrence, Validity of diagnosis, DSM-5, health care workers, severe mental illness, medicine, Bipolar disorders, morningness, Unsupervised machine learning, Neurokinetics, Sleep duration, business.industry, illness trajectories, COVID-19, Delirium, clinical cohort, meta-analysis, Treatment, chronotype, Bipolar, Systematic review, eveningness, Delayed early intervention, Sleep, chronobiology, Prediction, chronic kidney disease, qualitative research, actigraphy, Lithium (medication), MS-HRM, CKD-chronic kidney disease, 0302 clinical medicine, Cognition, circadian gene, MESH: Bipolar Disorder, Confusion, Children, DNA methylation, MESH: Middle Aged, High risk, Metabolic syndrome, health services research, 3. Good health, Adolescence, Psychiatry and Mental health, Transporters, Sunlight, Infectious diseases, light, CRP, Personality, MESH: Cross-Sectional Studies, Polygenicity, Memory, MESH: Sleep Initiation and Maintenance Disorders, Polygenic score, Sex differences, Circadian rhythms, mediation, Intensive care medicine, resilience, Medication adherence, Biological Psychiatry, Pleiotropy, Lifestyle, Metabolic abnormalities, 030227 psychiatry, clinical severity, 030217 neurology & neurosurgery, Sleep efficiency, clock gene, Neurodevelopment, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, impulsiveness, Subtype, Alcohol use disorder, Cocaine, Recurrence, MESH: Risk Factors, Mood stabilizers, magnetic resonance imaging, rest, Handedness, Blood-brain barrier, sanitary crisis, nephrotoxicity, Circadian, Cohort, Sleep quality, animal models, side effects, serious suicide attempt, Mania, lithium, antidepressants, Solar insolation, Domains, Mood disorders, Language disorders, MESH: Suicide, Attempted, patient-reported experience measures, lithium response, Genetic correlation, Genome-wide association study, prevalence, Family history, early life stress, Major depressive disorder, Follow-up studies, comorbidities, ICD-11, kidney microcysts, Obesity, MESH: Patient Acuity, First episode, Clinical trajectory, suicide, Plexus choroid, childhood trauma, outbreak, Predictors, Hierarchical agglomerative clustering, MESH: Quantitative Trait Loci, Evidence map, MESH: France, antipsychotics, physical abuse, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Longitudinal, Schizophrenia, gene expression, expert centres, polarity at onset, Course, business, depressive disorders, bipolar affective disorders
Abstract: Background Despite its pivotal role in prophylaxis for bipolar-I-disorders (BD-I), variability in lithium (Li) response is poorly understood and only a third of patients show a good outcome. Converging research strands indicate that rest–activity rhythms can help characterize BD-I and might differentiate good responders (GR) and non-responders (NR). Methods Seventy outpatients with BD-I receiving Li prophylaxis were categorized as GR or NR according to the ratings on the retrospective assessment of response to lithium scale (Alda scale). Participants undertook 21 consecutive days of actigraphy monitoring of sleep quantity (SQ), sleep variability (SV) and circadian rhythmicity (CR). Results Twenty-five individuals were categorized as GR (36%). After correcting statistical analysis to minimize false discoveries, four variables (intra-daily variability; median activity level; amplitude; and relative amplitude of activity) significantly differentiated GR from NR. The odds of being classified as a GR case were greatest for individuals showing more regular/stable CR (1.41; 95% confidence interval (CI) 1.08, 2.05; p < 0.04). Also, there was a trend for lower SV to be associated with GR (odds ratio: 0.56; 95% CI 0.31, 1.01; p < 0.06). Conclusions To our knowledge, this is the largest actigraphy study of rest–activity rhythms and Li response. Circadian markers associated with fragmentation, variability, amount and/or amplitude of day and night-time activity best-identified GR. However, associations were modest and future research must determine whether these objectively measured parameters, singly or together, represent robust treatment response biomarkers. Actigraphy may offer an adjunct to multi-platform approaches aimed at developing personalized treatments or stratification of individuals with BD-I into treatment-relevant subgroups., Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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49. Perspectives of the role of ICRP and the system of protection in meeting the United Nations sustainable development goals.

Author: Bryant PA, Clement C, Chapple CL, Martinez N, Lips M, and Dowds C
Subjects: Humans, International Agencies, Goals, Radiation Protection standards, Sustainable Development, United Nations
Abstract: Established in 2015 the United Nations (UN) sustainable development goals (SDGs) were agreed with the aim to balance the need to address social and ethical obligations such as ending poverty and other deprivations, while tackling climate change and the other planetary boundaries. In 2018 the International Commission on Radiological Protection (ICRP) initiated a review and revision of the System of Radiological Protection which will lay the foundation for Radiation Protection standards, regulations, guidance and practice worldwide for the next 40 years. Recognising the importance of the UN SDG's the ICRP has started to consider what the role of the revised system of protection should be in enabling delivery. On the 15 May 2024 the Society for Radiological Protection and World Nuclear Association ran a workshop exploring the intersection of the System of Radiological Protection and the SDG's. The outputs of the workshop are summarised in this paper showing the views from a variety of practitioners working across the radiation protection sectors on the key factors to be considered in the revision of the system of radiological protection to enable delivery of the UN SDG's., (Creative Commons Attribution license.)
Published: 2024
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50. Cerebellum and basal ganglia connectivity in isolated REM sleep behaviour disorder and Parkinson's disease: an exploratory study.

Author: Firbank MJ, Pasquini J, Best L, Foster V, Sigurdsson HP, Anderson KN, Petrides G, Brooks DJ, and Pavese N
Abstract: REM sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviour with loss of muscle atonia during REM sleep and is a prodromal feature of α-synucleinopathies like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Although cortical-to-subcortical connectivity is well-studied in RBD, cerebellar and subcortical nuclei reciprocal connectivity is less established. Nonetheless, it could be relevant since RBD pathology involves brainstem structures with an ascending gradient. In this study, we utilised resting-state functional MRI to investigate 13 people with isolated RBD (iRBD), 17 with Parkinson's disease and 16 healthy controls. We investigated the connectivity between the basal ganglia, thalamus and regions of the cerebellum. The cerebellum was segmented using a functional atlas, defined by a resting-state network-based parcellation, rather than an anatomical one. Controlling for age, we found a significant group difference (F 4,82 = 5.47, p FDR = 0.017) in cerebellar-thalamic connectivity, with iRBD significantly lower compared to both control and Parkinson's disease. Specifically, cerebellar areas involved in this connectivity reduction were related to the default mode, language and fronto-parietal resting-state networks. Our findings show functional connectivity abnormalities in subcortical structures that are specific to iRBD and may be relevant from a pathophysiological standpoint. Further studies are needed to investigate how connectivity changes progress over time and whether specific changes predict disease course or phenoconversion., (© 2024. The Author(s).)
Published: 2024
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