28 results on '"Raynes K"'
Search Results
2. An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol
- Author
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Connor, C., MBH, Yap, Warwick, J., Birchwood, M., De Valliere, N, Madan, J., Melvin, G. A., Padfield, E., Patterson, P., Petrou, S., Raynes, K., Stewart-Brown, S., and Thompson, A.
- Published
- 2022
- Full Text
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3. An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol
- Author
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Connor, C, Yap, MBH, Warwick, J, Birchwood, M, De Valliere, N, Madan, J, Melvin, GA, Padfield, E, Patterson, P, Petrou, S, Raynes, K, Stewart-Brown, S, Thompson, A, Connor, C, Yap, MBH, Warwick, J, Birchwood, M, De Valliere, N, Madan, J, Melvin, GA, Padfield, E, Patterson, P, Petrou, S, Raynes, K, Stewart-Brown, S, and Thompson, A
- Abstract
BACKGROUND: Adolescent depression can place a young person at high risk of recurrence and a range of psychosocial and vocational impairments in adult life, highlighting the importance of early recognition and prevention. Parents/carers are well placed to notice changes in their child's emotional wellbeing which may indicate risk, and there is increasing evidence that modifiable factors exist within the family system that may help reduce the risk of depression and anxiety in an adolescent. A randomised controlled trial (RCT) of the online personalised 'Partners in Parenting' programme developed in Australia, focused on improving parenting skills, knowledge and awareness, showed that it helped reduce depressive symptoms in adolescents who had elevated symptom levels at baseline. We have adapted this programme and will conduct an RCT in a UK setting. METHODS: In total, 433 family dyads (parents/carers and children aged 11-15) will be recruited through schools, social media and parenting/family groups in the UK. Following completion of screening measures of their adolescent's depressive symptoms, parents/carers of those with elevated scores will be randomised to receive either the online personalised parenting programme or a series of online factsheets about adolescent development and wellbeing. The primary objective will be to test whether the personalised parenting intervention reduces depressive symptoms in adolescents deemed at high risk, using the parent-reported Short Mood & Feelings Questionnaire. Follow-up assessments will be undertaken at 6 and 15 months and a process evaluation will examine context, implementation and impact of the intervention. An economic evaluation will also be incorporated with cost-effectiveness of the parenting intervention expressed in terms of incremental cost per quality-adjusted life year gained. DISCUSSION: Half of mental health problems emerge before mid-adolescence and approximately three-quarters by mid-20s, highlighting the need
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- 2022
4. An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol (vol 23, 655, 2022)
- Author
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Connor, C, Yap, MBH, Warwick, J, Birchwood, M, De Valliere, N, Madan, J, Melvin, GA, Padfeld, E, Patterson, P, Petrou, S, Raynes, K, Stewart-Brown, S, Thompson, A, Connor, C, Yap, MBH, Warwick, J, Birchwood, M, De Valliere, N, Madan, J, Melvin, GA, Padfeld, E, Patterson, P, Petrou, S, Raynes, K, Stewart-Brown, S, and Thompson, A
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- 2022
5. Additional file 1 of An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol
- Author
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Connor, C., Yap, M. B. H., Warwick, J., Birchwood, M., De Valliere, N, Madan, J., Melvin, G. A., Padfield, E., Patterson, P., Petrou, S., Raynes, K., Stewart-Brown, S., and Thompson, A.
- Abstract
Additional file 1. Trial information leaflets (for schools, parents/carers and young people) and trial poster.
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- 2022
- Full Text
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6. Additional file 4 of An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol
- Author
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Connor, C., Yap, M. B. H., Warwick, J., Birchwood, M., De Valliere, N, Madan, J., Melvin, G. A., Padfield, E., Patterson, P., Petrou, S., Raynes, K., Stewart-Brown, S., and Thompson, A.
- Abstract
Additional file 4. Parent consent form and young person assent form.
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- 2022
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7. Additional file 2 of An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol
- Author
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Connor, C., Yap, M. B. H., Warwick, J., Birchwood, M., De Valliere, N, Madan, J., Melvin, G. A., Padfield, E., Patterson, P., Petrou, S., Raynes, K., Stewart-Brown, S., and Thompson, A.
- Abstract
Additional file 2. Process evaluation focus group question frameworks.
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- 2022
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8. Additional file 3 of An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol
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Connor, C., MBH, Yap, Warwick, J., Birchwood, M., De Valliere, N, Madan, J., Melvin, G. A., Padfield, E., Patterson, P., Petrou, S., Raynes, K., Stewart-Brown, S., and Thompson, A.
- Abstract
Additional file 3. Process evaluation family interview question framework.
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- 2022
- Full Text
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9. Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial
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Atkin, C, Iqbal, G, Planche, T, Pratt, G, Yong, K, Wood, J, Raynes, K, Low, E, Higgins, H, Neal, RD, Dunn, J, Drayson, MT, Bowcock, S, TEAMM Trial Management Group, and Trial Investigators
- Abstract
Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P
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- 2021
10. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
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Kolokathis F, Kostakou P, Lekakis J, Manolis A, Mantas I, Megalou A, Milkas A, Nanas J, Olympios CD, Patsilinakos S, Perperis A, Poulimenos L, Saloustros I, Tsioufis K, Tsorbatzoglou K, Vardas P, Zarifis I, Aguilar M, Arango JL, Borrayo NA, Corona V, Guerrero A, Guzman I, Haase F, De Krumbach L, Montenegro P, Munoz R, Munoz N, Paniagua A, Solares A, Vogel M, Anita S, Blazsek Z, Decsi K, Fulop T, Hangyal T, Hegedus V, Kalina A, Karakai H, Katona A, Kiss RG, Kovacs A, Laszlo Z, Lupkovics G, Medvegy M, Merkely B, Mihaly N, Nagy AC, Dékány JN, Nikoletta P, Noori E, Penzes J, Poor F, Sarszegi Z, Simay A, Simon J, Szakal I, Szatmarine V, Szocs A, Zilahi Z, Karsai XZ, Andersen K, Sigurdadottir E, Skuladottir F, Abdullakutty J, Abhaichand R, Abhyankar A, Agarwal DK, Aggarwal RK, Ahire N, Awasthi AK, Babu R, Bai A, Bali HK, Banker D, Bhadade S, Bisne V, Bohra P, Raghu C, Chauhan D, Chauhan H, Chavada J, Chaware G, Chella S, Chintala P, Dash D, Desai D, Devasia T, Dhanak R, Dobariya H, Dudhatra 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Y, Sakurada M, Sasaki S, Seki S, Shimomura H, Shinozaki T, Sugimoto N, Suzuki A, Taguchi S, Takahashi J, Takase S, Tanabe K, Tanaka A, Tani S, Tomioka J, Tsuboi H, Tsuji M, Tsujita K, Tsujiyama S, Umesu A, Yamada T, Yamaguchi E, Yamamoto H, Yamamoto T, Yamane M, Yanase T, Yasuoka S, Yasutake M, Yokoyama M, Yoshida M, Yoshimoto E, Yunoki C, Balode A, Dormidontova G, Flaksa I, Nagele-Luse I, Rancane G, Sime I, Bartuseviciene S, Cepinskiene L, Dobilas V, Grigaraviciene I, Marcinkeviciene J, Mazutavicius R, Miliuniene R, Motiejuniene R, Norkiene S, Norkute-Macijauske U, Rudys A, Slapikas R, Stonkute K, Strazdiene D, Tijuneliene E, Urbonas G, Vanagiene S, Viezelis M, Aguilar M, Arenas Leon JL, Bayram E, Carrillo J, Davalos C, De Los Rios M, Delgadillo T, Hernández N, Leon S, Mendoza N, Muñoz W, Ramos G, Anneveldt A, Bakker H, Brouwer M, Bunschoten P, De Boer P, De Jong C, De Vos A, Den Hartog F, Doesborg L, Dommerholt R, Drost I, Ellenbroek D, Engelen W, Folkeringa RJ, Hamer BJB, Herrman JP, Hoogslag PAM, Jansen M, Jerzewski A, Joosten C, Kalkman C, Kietselaer B, Kok M, Kooiman E, Kose V, Lardinois R, Lenderink T, Lok DJA, Lousberg A, Meijlis P, Mulder R, Singerling M, Smeele F, Stroes E, Swart HP, Ten Holt W, Van Der Wal M, Van Der Zwaan C, Van Kempen WW, Van Maarseveen M, Van Stein I, Viergever EP, Visseren FLJ, Voors C, Nugteren SKZ, Ata B, Berulfsen A, Rønnevik TD, Dickstein K, Furuseth B, Grundtvig M, Hansen H, Hofsoey K, Høivik HO, Bøen RH, Hurtig U, Pettersen KI, Johansen E, Kleve R, Kolleroy C, Moen S, Nilsen V, Norin V, Otterstad JE, Risberg K, Rønnevik P, Sirnes PA, Skjelvan G, Strand S, Szacinski G, Vegsundvåg J, Alcalde JM, Gomez Sanchez J, Rodriguez J, Rodriguez A, Zena N, Baszak J, Cymerman K, Czerski T, Fratczak M, Jaguszewska G, Kawka-Urbanek T, Koba M, Kopaczewski J, Kopczyńska M, Laniec M, Lysek R, Sciborski R, Szpajer M, Torun A, Wujkowski M, Zielinski M, Ahn Y, Baek C, Bang SA, Chang K, Choi AJ, Han S, Hong T, Hyun K, Kim M, Kim KS, Kim B, Lee SH, 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Skopets I, Skuratova M, Smolenskaya O, Solovev O, Trofimov V, Vasiliev M, Vezikova N, Vozzhaev A, Yakushin S, Zadionchenko V, Apostolovic S, Adjic NC, Ilic I, Ilic S, Nikolic L, Pupic L, Stokuca-Korac N, Antalik L, Bugan V, Csala L, Dokupilova A, Dzupina A, Forgon T, Fulop P, Gonsorcik J, Gyorgyova E, Holoubek D, Horvat P, Kamensky G, Kolikova V, Krupciakova B, Lenner E, Lennerova J, Lukac J, Majercak I, Mancikova I, Micko K, Nociar J, Pales J, Palka J Jr, Poliacik P, Ruffini L, Sabo L, Skubova K, Slanina M, Smik R, Srdos V, Stitova M, Stofkova D, Strbova J, Such S, Toth P, Urgeova L, Vinanska D, Zareczky P, Flezar M, Kovacic D, Marcun R, Zagozen P, Bolsmann C, Commerford P, Conradie C, Dawood SY, Decsi KL, Ebrahim I, Henley L, Horak A, Kapp I, Komati S, Lock E, Maboyi S, Makotoko E, Manga P, Page A, Ramdas S, Ranjith N, Roos J, Talliard C, Ajax K, Al-Khalili F, Assarsson E, Bergholtz T, Blom KB, Boman K, Boström PÅ, Curiac D, Jensen ED, Dahlen G, Davidsson K, Duckert A, Hansson A, Härstedt N, Henriksson A, Olsson GH, Johansson K, Jonsson JE, Knutsson A, Lindholm CJ, Liu B, Lönnberg I, Lundqvist M, Mellberg L, Moodh J, Mooe T, Olofsson M, Risenfors M, Rönndahl M, Sundelin R, Suorra I, Torgersruud M, Torstensson I, Chang KC, Chen CP, Chen ZC, Chen MH, Cheng SM, Cheng JJ, Fang CY, Ho CJ, Hsieh IC, Huang PH, Huang A, Hwang JJ, Kuo JY, Lai WT, Lee SC, Li YH, Lin T, Liu HM, Tsai MC, Tsao HM, Tzong L, Ueng KC, Wang YL, Wang HC, Wang CP, Yang CC, Abaci F, Birdane A, Yilmaz MB, Asim Oktay AO, Kan G, Koldas N, Ozcan IT, Sahin M, Sahin T, Saka B, Tekten T, Ucar N, Uresin S, Yigit Z, Arif I, Bakhai A, Baksi A, Blagdon M, Brickman T, Brown N, Burton M, Burton J, Chaggar S, Chung A, Collier D, Covell W, Crawford G, Davies N, Davies M, Dayer M, Doughty A, Duff J, Dwenger E, Fisher J, Fitzpatrick L, Garner K, Glover J, Haughton G, Ilsley M, Ivan P, Voyzey EJ, Keenan S, Kelt T, Knight J, Kondagunta V, Lang C, Lee K, Lim L, Macdonald J, Mathew A, Mckenzie A, Mckibbin A, Michalska A, Pagett K, Pogson A, Price R, Price D, Procter K, Pye M, Redfearn H, Rewbury J, Ryding A, Sattar N, Sharp A, Shaw P, Simpson H, Smith W, Squire I, Storey R, Teenan M, Thomas H, Townend J, Trevelyan J, Wakeling J, Walukiewicz P, Wilkinson S, Zaman A, Acevedo L, Benton J, Abbate A, Aboufakher R, Acampora M, Acampora D, Aceto L, Acevedo B, Acheatel R, Adams M, Adams A, Ahmad I, Ahmed SH, Aish B, Akyea-Djamson A, Al Joundi T, Alcide P, Alfieri A, Alfonso T, Alfrey A, Allen J, Alllison DC, Almaliky T, Amos A, Angiolillo D, Antolick A, Ara M, Aragorn L, Arevalo S, Armas E, Arthur A, Asafu-Adjaye N, Ashcom T, Ashford M, Aslam A, Ather N, Atieh M, Aull L, Ayala M, Azizad M, Backer T, Baehl S, Bailey S, Bair S, Baker C, Ballmajo M, Pieretti HB, Baquero A, Barnett S, Baron S, Bartkowiak A, Bashir K, Beall K, Beauregard LA, Sarah S, Beckett L, Belejchak P, Bendelow T, Bender D, Benjamin S, Berdoff R, Berger V, Bergeron P, Berk M, Bernstein M, Binns Y, Bitzer V, Blahey M, Bloch S, Bluemel J, Boffetti P, Boley K, Bonner J, Boudreaux R, Boulanger K, Bradley A, Bramlet D, Bredlau C, Briggs S, Brousalis L, Brown S, Brown C, Buchannan C, Burke W, Burley T, Burton C, Burtt D, Byars W, Caballero-Valiente B, Carr K, Halliwell TC, Castillo J, Cei L, Cerda L, Chambers J, Chamblee T, Chattin W, Chee L, Chen YC, Cherlin R, Cheung D, Chiodi L, Christensen L, Christenson S, Cislowski D, Clavier-Firmin C, Colfer H, Colvin T, Cosgrove N, Covert C, Cox B, Cox R, Craig W, Crandall L, Crepps K, Cromer M, Cruz H, Cruz H, Cruz M, Cucher F, Damron M, Dave K, Dave B, Davis M, Davis B, Dawkins-Hughes S, Dean J, Debnam S, Defosse C, Dehning M, Dela Llana A, Dellorso M, Denham D, Desalle D, Dettmer M, Dhawan M, Diago M, Dicken T, Diederich C, Diederich M, Diehl R, Digangi D, Diller P, Dimattia M, Dodds G, Doggett J, Donahue K, Doughty L, Dragutksy B, Dreese M, Dunhurst F, Dunn D, Dutka C, Earl J, Eaton C, Eaves W, Ebeling K, Eder F, Edgerton L, Edillo C, Edwards J, Edwards T, Einhorn D, El Hafi S, Ellis M, Erickson B, Ervin W, Eskridge L, Fail P, Falcon D, Fang C, Fattal P, Fawson A, Felix L, Ferdinand K, Fien E, Fintel D, Firek C, Fitz-Patrick D, Flores E, Flores E, Flores H, Floro T, Forker A, Foster M, Foucauld J, Lehman KF, Fox B, Francoeur L, Frandsen B, Frandsen B, Frivold G, Fruchter G, Fullerton D, Gabriel J, Gacioch G, Garas S, Garcia N, Garcia Rinaldi R, Garcia-Fragoso V, Garcia-Portela M, Gelb R, George F, Ghali J, Gilbert J, Gilley J, Glancy R, Goff R, Goldberg N, Gonzales D, Gonzales V, Gonzalez E, Gorges R, Gould R, Grabeau R, Grable M, Graham JA, Graif J, Green E, Greener R, Greenway F, Grieshaber V, Griffin S, Gros C, Gudipati RVC, Guillinta P, Gupta V, Gutmann J, Gwyn M, El Hachem M, Hage F, Hageman T, Haidar A, Hakas J, Haldis T, Hall L, Hall C, Hall S, Halpern S, Hamud-Socoro A, Hardee L, Harrell W, Harrington A, Hartwell J, Hasan F, Hattler B, Haught H, Haynes E, Haywood A, Heaney L, Hecht J, Hernandez I, Herzog W, Hess E, Hill H, Hilton T, Hinderaker P, Hodnett P, Hoffman M, Hogan C, Holmes Z, Rees DH, Hotchkiss D, Huang P, Humbert J, Hutchens E, Iachini K, Ibarra M, Igbokidi O, Ilahi T, Imbrognio M, Ipp E, Iteld B, Jacques G, Jafri A, Jafry B, Jardula M, Jefferson D, Jenkins R, Johnson E, Johnson J, Jones S, Kawahara M, Kelehan S, Kelly R, Kendall T, Kereiakes D, Khan M, Khan S, Kick J, Kimmel M, King T, King A, Kirkland S, Kissel S, Kitchens D, Klein P, Klugherz B, Korban E, Koren M, Korte M, Kostis J, Kotek L, Kozak M, Kreutter F, Kusnick B, Labovitz R, Lail J, Lamance J, Lamas G, Lambert J, Lambert C, Landzberg J, Langdon J, Lavoie W, Ledger G, Lee T, Lee K, Lehman R, Leimbach W, Lennard M, Lepor N, Lester F, Levin P, Levinson L, Lewis D, Lillo J, Link L, Long C, Longaker R, Lorch G, Lucksinger G, Lynd S, Rhudy JM, Madder R, Magness K, Maheshwari A, Alan A, Malek M, Maletz L, Malhotra V, Malhotra S, Mandviwala M, Mani CK, Manuel J, Marchelletta N, Marshall L, Marsters M, Martin L, Martinez E, Mavromatis K, Maynard R, Mays M, Mays B, Mbulaiteye A, Mcalister R, Mccoy C, Mccrary D Jr, Mccullough-O'Brien H, Mcdonald M, Mcgill J, Mcgrew F, Mckenzie C, Mclaurin B, Mclellan BA, Mcneil D, Mcneill R, Mehrle A, Melbie K, Melliza T, Messina T, Meyer R, Michel K, Mikdadi G, Miller C, Miller R, Miller A, Miller G, Miller W, Mitchell J, Moats DJR, Mody F, Moffat J, Molk B, Molter D, Monroe T, Montero H, Montgomery R, Mookherjee D, Moran J, Moriarty P, Morrison J, Morton D, Moshayedi P, Mosley J, Moustafa M, Munshi K, Murray A, Mustafa J, Nadar V, Naidu R, Nalley J, Navy S, Neil L, Neutel JM, Niblack P, Nicely V, Nicolai M, Nijmeh G, Nikas A, Nikyar A, Nixon S, Norman L, Noto G, Nour K, Nugent A, Ocman B, Odegard A, Olsen S, Ortiz-Carrasquillo R, Ossino N, Paez H, Palchick B, Paliwal Y, Pannell R, Parfait V, Partridge J, Patel B, Patel R, Patel M, Patel S, Paysor C, Pena A, Pereira S, Perez M, Perez A, Perkins H, Perry B, Peters P, Phillippi C, Phillips A, Phillips A, Piacente R, Pintado M, Pish R, Pitt W, Poling T, Pomposini D, Poock J, Potts J, Poudrier R, Prior J, Pritchard C, Purighalla R, Quddusi K, Quinones J, Quinton D, Radin M, Radojcsics B, Rajput B, Rama B, Ramos M, Rauch R, Raynes K, Reber AM, Reddy J, Reeves M, Reilly K, Renaud K, Resnick H, Reyes R, Richardson M, Riethof M, Riser J, Rodero M, Rodriguez Araya E, Roper L, Rozeman P, Ruder D, Runquist L, Sack G, Saint-Jacques H, Salfity M, Sall N, Sam K, Samal A, Sanchez D, Santiago J Jr, Savignano C, Saylor R, Scheffel M, Schifferdecker B, Schindler E, Schneider P, Schneider R, Schnitzler R, Schrager B, Schwartz A, Scott R, Seals A, Shah AV, Shah A, Shatsky K, Shayani S, Shealy N, Sheets L, Shelley J, Shepard P, Shetty S, Silver K, Simon M, Singh K, Singh N, Sizemore BC, Skatrud L, Slayton C, Slimak V, Sloane G, Smallwood B, Smith P, Smith M, Smith T, Smith G, Smith B, Smith W, Smith M, Smith J, Smith J, Soca Y, Sofley C, Sopko K, Sosa-Padilla M, Sotolongo R, Sprinkle B, Srivastava S, Starzec M, Steinhoff J, Stelly L, Stinson J, Stoddard M, Stoltz S, Stone B, Stover T, Strain J, Strugatsky S, Stys T, Suleman A, Sullivan P, Tamez W, Tandon N, Teltser M, Terry PS, Terry K, Tessmar C, Thekkoott D, Thomas D, Thomas DM, Thompson E, Thompson J, Thornton A, Tjaden T, Tobias C, Topper J, Tran A, Treasure C, Trenkamp P, Trevino M, Tsou L, Tuholske C, Uy W, Vahtel M, Vaid B, Valenzuela M, Vance A, Vandam J, Vanhecke T, Vanness WC III, Vargas R, Vaz S, Vazquez Tanus J, Veerina K, Vega J, Vento A, Vijay N, Voelker F, Vogt E, Vold D, Vora K, Wade RD, Wadell C, Waksman R, Walker K, Walker K, Wallace K, Warren M, Washam M, Watson B, Webel R, Wells T, West M, Whitaker J, White J, White C, White A, White A, Wilhoit G, Wilkins M, Willingham K, Wilson S, Wilson V, Wise J, Woodall S, Woods A, Wright J, Wu J, Xu ZJ, Yarows S, Young A, Younis L, Zarate J, Zebrack J, Zhang W, Zieve F, Zineldine A, Ridker, P. M., Everett, B. M., Thuren, T., Macfadyen, J. G., Chang, W. H., Ballantyne, C., FONSECA E PIRES, CARLOS EDUARDO, Nicolau, J., Koenig, W., Anker, S. D., Kastelein, J. J. P., Cornel, J. H., Pais, P., Pella, D., Genest, J., Cifkova, R., Lorenzatti, A., Forster, T., Kobalava, Z., Vida-Simiti, L., Flather, M., Shimokawa, H., Ogawa, H., Dellborg, M., Rossi, P. R. F., Troquay, R. P. T., Libby, P., Glynn R., J, CANTOS Trial, Group, Perrone, Filardi, P, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
0301 basic medicine ,030204 cardiovascular system & hematology ,law.invention ,0302 clinical medicine ,c-reactive protein ,Randomized controlled trial ,law ,Cardiovascular Disease ,middle aged ,double-blind method ,antibodies ,Myocardial infarction ,humans ,Stroke ,interleukin-1beta ,biology ,Antibodies, Monoclonal ,drug ,General Medicine ,Lipid ,Aged ,anti-inflammatory agents ,monoclonal ,humanized ,atherosclerosis ,cardiovascular diseases ,dose-response relationship ,female ,incidence ,infections ,lipids ,male ,myocardial infarction ,neutropenia ,secondary prevention ,stroke ,Anti-Inflammatory Agent ,aged ,Editorial ,Atherosclerosi ,Monoclonal ,Human ,medicine.drug ,medicine.medical_specialty ,Neutropenia ,Antibodies, Monoclonal, Humanized ,Infections ,Placebo ,antibodies, monoclonal ,dose-response relationship, drug ,infection ,medicine (all) ,03 medical and health sciences ,Internal medicine ,medicine ,Dose-Response Relationship, Drug ,business.industry ,Antiinflammatory Therapy, Canakinumab, for Atherosclerotic Disease ,C-reactive protein ,medicine.disease ,Surgery ,Canakinumab ,030104 developmental biology ,biology.protein ,business - Abstract
Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.)
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- 2017
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11. Major changes in levels of regulatory cytokines and functional antibodies contribute to severe immunodeficiency of myeloma patients and persist at one year post diagnosis
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Chicca, IJ, Heaney, JLJ, Iqbal, G, Bowcock, S, Planche, T, Wood, J, Raynes, K, Hawkey, P, Pratt, G, Yong, K, Dunn, JA, and Drayson, MT
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- 2018
12. ChemInform Abstract: A Carbonyl Oxide Route to Antimalarial Yingzhaosu A Analogues: Synthesis and Antimalarial Activity.
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O'NEILL, P. M., primary, SEARLE, N. L., additional, RAYNES, K. J., additional, MAGGS, J. L., additional, WARD, S. A., additional, STORR, R. C., additional, PARK, B. K., additional, and POSNER, G. H., additional
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- 1998
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13. Laboratory-based investigation into the potential for algal proliferation in Lake Coleman, Victoria
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Haynes, D, primary, Rayment, P, additional, Raynes, K, additional, and Mosse, PRL, additional
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- 1994
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14. Novel Short Chain Chloroquine Analogues Retain Activity Against Chloroquine Resistant K1 Plasmodium falciparum
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Stocks, P. A., Raynes, K. J., Bray, P. G., Park, B. K., O'Neill, P. M., and Ward, S. A.
- Abstract
A series of short chain chloroquine (CQ) derivatives have been synthesized in one step from readily available starting materials. The diethylamine function of CQ is replaced by shorter alkylamine groups (
4 −9 ) containing secondary or tertiary terminal nitrogens. Some of these derivatives are significantly more potent than CQ against a CQ resistant strain of Plasmodium falciparum in vitro. We conclude that the ability to accumulate at higher concentrations within the food vacuole of the parasite is an important parameter that dictates their potency against CQ sensitive and the chloroquine resistant K1 P. falciparum.- Published
- 2002
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15. Novel, Potent, Semisynthetic Antimalarial Carba Analogues of the First-Generation 1,2,4-Trioxane Artemether
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O'Neill, P. M., Searle, N. L., Kan, K.-W., Storr, R. C., Maggs, J. L., Ward, S. A., Raynes, K., and Park, B. K.
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Ten novel, second-generation, fluorinated ether and ester analogues of the potent first-generation analogues artemether (
4a ) and arteether (4b ) have been designed and synthesized. All of the compounds demonstrate high antimalarial potency in vitro against the chloroquine-sensitive HB3 and -resistant K1 strains of Plasmodium falciparum. The most potent derivative8 was 15 times more potent than artemisinin (2 ) against the HB3 strain of P. falciparum. In vivo, versus Plasmodium berghei in the mouse, selected derivatives were generally less potent than dihydroartemisinin with ED50 values of between 5 and 8 mg/kg. On the basis of the products obtained from the in vitro biomimetic Fe(II)-mediated decomposition of8 , the radical mediator of biological activity of this series may be different from that of the parent drug, artemisinin (2 ).- Published
- 1999
16. New 4-Aminoquinoline Mannich Base Antimalarials. 1. Effect of an Alkyl Substituent in the 5-Position of the 4-Hydroxyanilino Side Chain
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Raynes, K. J., Stocks, P. A., O'Neill, P. M., Park, B. K., and Ward, S. A.
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A new series of 4-aminoquinoline Mannich base derivatives have been synthesized, in which the 3-diethylamino function of amodiaquine (AQ) is replaced by a 3-tert-butylamino group and an aliphatic hydrocarbon entity is incorporated into the 5-position of the 4-hydroxyanilino side chain. Seven alkyl Mannich base derivatives were screened and found to be active against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. The propyl and isopropyl alkyl derivatives were found to be the most active; consequently these derivatives were tested against a nonsensitive strain of Plasmodium berghi in vivo and found to be 3-fold more active than AQ, irrespective of the route of administration (oral or intraperitoneal).
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- 1999
17. Novel bisquinoline antimalarials: synthesis, antimalarial activity, and inhibition of haem polymerisation
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Raynes, K., Foley, M., Tilley, L., and Deady, L. W.
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- 1996
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18. Bisquinoline antimalarials: their role in malaria chemotherapy
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Raynes, K.
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- 1999
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19. Antiinflammatory therapy with canakinumab for atherosclerotic disease
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Ridker P.M., Everett B.M., Thuren T., MacFadyen J.G., Chang W.H., Ballantyne C., Fonseca F., Nicolau J., Koenig W., Anker S.D., Kastelein J.J.P., Cornel J.H., Pais P., Pella D., Genest J., Cifkova R., Lorenzatti A., Forster T., Kobalava Z., Vida-Simiti L., Flather M., Shimokawa H., Ogawa H., Dellborg M., Rossi P.R.F., Troquay R.P.T., Libby P., Glynn R.J., Krum H., Varigos J., Siostrzonek P., Sinnaeve P., Gotcheva N., Yong H., Urina-Triana M., Milicic D., Vettus R., Manolis A.J., Wyss F., Sigurdsson A., Fucili A., Veze I., Petrauskiene B., Salvador L., Klemsdal T.O., Medina F., Budaj A., Otasevic P., Lainscak M., Seung K.B., Commerford P., Donath M., Hwang J.J., Kultursay H., Bilazarian S., East C., Forgosh L., Harris B., Ligueros M., Bohula E., Charmarthi B., Cheng S., Chou S., Danik J., McMahon G., Maron B., Ning M., Olenchock B., Pande R., Perlstein T., Pradhan A., Rost N., Singhal A., Taqueti V., Wei N., Burris H., Cioffi A., Dalseg A.M., Ghosh N., Gralow J., Mayer T., Rugo H., Fowler V., Limaye A.P., Cosgrove S., Levine D., Lopes R., Scott J., Hilkert R., Tamesby G., Mickel C., Manning B., Woelcke J., Tan M., Manfreda S., Ponce T., Kam J., Saini R., Banker K., Salko T., Nandy P., Tawfik R., O’Neil G., Manne S., Jirvankar P., Lal S., Nema D., Jose J., Collins R., Bailey K., Blumenthal R., Colhoun H., Gersh B., Abreu M., Actis M.V., Aiub J., Aiub F., Albisu J., Alvarisqueta A., Avalos V., Barreto M., Berli M.A., Blumberg C., Bocanera M., Botta C., Bowen L., Budassi N., Buhlman S., Westberg J.C., Carabajal T., Caruso G., Casala J., Cendali G., Coloma G., Berra F.C., Cuneo C., Degennaro N., Dellasa M., Diaz M., Dos Santos P., Espinosa V., Facello A., Facello M., Farias E., Fernandez A.A., Ferrari V., Pacora F.F., Flores G.S., Franco M., Gabito A., Viola H.G., Garcia F., Garcia Duran R., Garcia Pinna J., Glenny J., Godoy Sanchez M., Grosse A., Guzman P., Hasbani E., Hominal M., Ibañez J., Jure H., Jure D., Vico M.L., Liniado G., Luciardi H., Luquez H., Maehara G., Maffei L., Majul C., Mallagray M., Marinaro S., Martinez J., Massaccesi R., De Los Milagros Had M., Azize G.M., Montana O., Montenegro E., Morell Y., Muntaner J., Navarrete S., Olmedo M., Paganini M., Paz S., Perez Manghi F., Piskorz D., Polato C., Recoaro R., Romano A., Salinger M., Sanchez A., Saravia M.A., Sarjanovich R., Scaro G., Schiavi L.B., Soler J., Tinnirello V., Tomassi A., Valle M., Vallejo M.A., Venturini C., Marcela Wenetz L.M., Yossen M., Zaidman C., Zalazar L., Zangroniz P., Amerena J., Brady L., Colquhoun D., Eccleston D., Ferreira-Jardim A., French J., Jayasinghe R., Mcintosh C., Ord M., Plotz M., Purnell P., Roberts-Thomson P., Schultz C., Shanahan T., Tan R., Taverner P., Turner F., Vibert J., Vorster M., William M., Youssef G., Bergler-Klein J., Brath H., Brodmann M., Fliesser-Goerzer E., Haider K., Heeren G., Hiden C., Mandic L., Paulweber B., Ploechl A., Prenner A., Steringer-Mascherbauer R., Strohner-Kaestenbauer H., Barbato E., Bouvy C., Briké C., Charlier F., Cools F., De Knijf K., De Wolf L., Delforge M., Deweerdt N., Gits F., Goffinet C., Hermans K., Hollanders G., Mestdagh I., Pirenne B., Servaes V., Simons N., Tahon S., Theunissen E., Van Genechten G., Vervoort G., Vissers C., Vranckx P., Vrolix M., Abib E.Jr., Abrantes J., Araujo Fonseca M., Barbosa E., Barroso W., Barroso A., Bodanese L., Botelho R., Costa Amorim R., Da Costa F., Da Silva A., Da Silva O.Jr., Da Silva D.Jr., Ferreira Dos Santos T., Dos Santos F., Dos Santos A., Duda N., Feitosa G., Felario Junior GA., Ferraz R., Filho P., Fonseca A., Wanderley F.F., Freitas E., Fucci F., Marengo Garcia De Carvalho L., Hernandez M., Hettwer Magedanz E., Julião K., Kormann A., Lameira A., Lima F., Lino E., Maia L., Manenti E., Marchi A.L., Fischer S.M., Michalaros Y., Moraes J.Jr., Moreira L., Pagnan M., Pesce F., Pinheiro L., Rassi S., Reis G., Reis H., Resende I., Roel A., Ruschel K., Saporito W., Saraiva J.F., Seroqui M., Silva R., Unterkircher B., Vicente C., Vieira N., Xavier J.P., Zucchetti C., Angelova I., Dimitrov G., Genova D., Gospodinov K., Goudev A., Grigorova V., Hristova K., Makedonska J.J., Katova T., Kostov K., Lazov P., Manov E., Manukov I., Manukov D., Milanova M., Kabakchieva V.M., Petrov D., Petrusheva T., Pramatarova I., Raev D., Runev N., Sirakova-Taseva A., Tisheva-Gospodinova S., Todorova A., Tzekova M., Yakovova S., Yanev T., Abulencia K., Arora S., Baker A., Bata I.R., Beaudry M., Belle Isle J., Bilodeau N., Boivin M.C., Bolduc H., Bourgeois S., Brons S., Cantor W., Chaussé I., Chhabra A., Chouinard G., Cleveland T., Dattani D., Deslongchamps F., Diodati J., Drouin K., Duchesne L., Fontaine S., D'Amours D.G., Gervais B., Gosselin G., Graham J., Grover A., Gupta A., Haldane H., Hartleib M., Hickey L., Huynh T., Johnston J., Julien V.E., Lachance P., Lake J., Lamontagne C., Lauzon C., Lepage S., Maheux K., Manyari D., Martin E., McPherson C., Mehta S., Michaud N., Kouz S.M., Murphy G., OKeefe D., Otis R., Ouimet F., Pandey S., Peck C., Perkins L., Richert L., Robbins K., Robinson S., Cabau J.R., Ross B., Roy C., Roy M., Roy A., Rupka D., Affaki G.S., Saunders K., Savard D., Soucy D., St Amour E., Thiessen S., Vertes G., Vezina M., Vincelli G., Weisnagel S.J., Zadra R., Chen J., Chen Y., Dong X., Feng Y., Feng Z., Fu G., Han B., Hao Y., He Y., He Z., Hong T., Jia Z., Jiang T., Jiang J., Jiang X., Ke Y., Li Y., Li Z., Li W., Li X., Liu P., Liu Y., Liu B., Liu S., Liu L., Lu Z., Lv Y., Ma C., Ma G., Peng L., Qing L., Ren L., Sang X., Song M., Sun Z., Wang J., Wang Y., Wei J., Wu W., Wu J., Xu H., Yan J., Yang P., Yang K., Yao Z., Yaoqing H., Yuan Z., Zhai Z., Zhang J., Zhang Y., Zhao R., Zhou H., Accini Mendoza JL., Aparicio C.V., Castillo T., Chaverra I., Conrado Y., Coronel J., Cotes C., Cuentas I., Cuervo A., Dussan M.A., Echeverria L., Hernandez E., Ibarra J., Isaza D., Jimenez D., Lopez P., Manzur F., Mejia I., Mendoza Y., Molina D.I., Patino J.M., Rodriguez D., Rodriguez L.M., Rodriguez S.M., Sanchez Vallejo G., Luz Serrano H., Sotomayor A., Urina M., Vesga B., Yupanqui H., Akrap B., Busic N., Ciglenecki N., Cmrecnjak J., Fucak E., Gabor M., Jeric M., Jutrisa N., Kordic K., Planinc I., Popovic Z., Radeljic V., Sesto I., Sutalo K., Tusek S., Belohlavek J., Budkova J., Busak L., Capova L., Cech V., Cermak O., Coufalova Z., Cyprian R., Dedek V., Dedkova S., Ferkl R., Hanak P., Hanustiakova A., Homza M., Horackova K., Houra M., Iveta H., Kaiserova L., Kala P., Karel I., Kellnerova I., Koleckar P., Kreckova M., Krupicka J., Lorenc Z., Machova V., Malik J., Masarikova L., Matyasek I., Mikus M., Mikusova T., Ondrasik J., Otava M., Palubova L., Pavlickova L., Peterka M., Petrova I., Pokorna B., Povolny P., Radvan M., Reznakova S., Rickova Z., Roszkowska P., Rotreklova M., Samkova D., Skalicka H., Slechticka A., Sternthal P., Telekes P., Tesak M., Vesely P., Vesely J., Vins P., Vitovec M., Vodnansky P., Zidova M., Keba E., Laane E., Pool T., Randvee L., Ratnik E., Reimand M., Reinmets S., Rivis L., Siemann M., Stern M., Toom M., Vahula V., Apel T., Axthelm C., Ayasse D., Ayasse M., Baar M., Baeumer A., Bagi E.S., Becker B., Binder A., Blankenberg S., Braun P., Johansen B.B., Contzen C., Delfonso F., Denecke C., Dengler T., Donaubauer T., Eichinger G., Englmann E., Erhard M., Faghih M., Foerster A., Frankenstein L., Fuchs R., Furch G., Gaeb-Strasas B., Germann H., Giese C., Goette A., Gravenhorst-Muenter U., Haege R., Haenel T., Hagemann D., Hagenow A., Hanefeld M., Heider J., Heisters J., Hennig D., Hielscher S., Himpel-Boenninghoff A., Holscher A., Hornig M., Jeserich M., Kaczmarek N., Kanitz S., Kara Y.D., Khariouzov A., Kiefer R., Kiroglu K., Klamm M., Klein C., Korth-Wiemann B., Krapivsky A., Kuenzler J., Kuntzsch A., Landers B., Lappo M., Laube S., Leggewie S., Lehmann D., Lepp H., Lierse T., Lindner C., Luecke-Uzar M., Luedemann J., Marschke T., Maruzzo S., Mauersberger K., Maus O., Meinrich M., Meissner A., Moehring B., Muehlhaus J., Mueller S., Muenter K.C., Muenzel T., Naumann R., Nebel J., Neumann J., Nuding S., Overhoff U., Papke B., Pencz I., Peter Y., Peukert A.M., Radde I., Rau T., Regner S., Reichenbach D., Reimer D., Rinke A., Roettges R., Romanski A., Rummel R., Samer H., Sanuri M., Sarnighausen H.E., Schäfer B., Scheibner T., Schermaul K.H., Schindler A., Schlundt C., Schmidt E., Schmidt K., Schnabel A., Schoen N., Schorn K., Schroeder T., Schulenburg D., Schulz M., Schulze U., Schulze J., Schumacher M., Schwerin G., Schwerin M., Stadelmeier S., Stahl H.D., Stahl A., Stockhausen J., Stockhausen G., Stoessel J., Stolze K., Stratmann M., Szymanowski N., Teschner A.B., Teske A., Uecker C., Veit S., Voeller H., Walter I., Walter J., Walther I., Weber H.G., Weimer J., Wichterich K., Wiebusch A., Willmerdinger M., Willner C., Winkelmann B., Winkler J., Wistuba T., Woehrle J., Wohnlich T., Wolf S., Woyczak D., Wrage P., Zirlik A., Anadiotis A., Chachalis G., Dermitzakis A., Kafarakis P., Kaldara E., Kolokathis F., Kostakou P., Lekakis J., Manolis 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Bulashova O., Burova N., Churina S., Demidova M., Dorogova I., Dovgalevskiy Y., Dovgolis S., Dudarev M., Fitilev S., Gapon L., Gazizianova V., Gordeev I., Ivanov I., Izmozherova N., Kazanskay E., Khirmanov V., Khromtsova O., Konradi A., Kosmacheva E., Kozlova S., Kulibaba E., Kuzin A., Libov I., Lipchenko A., Lozhkina N., Malchikova S., Morozov E., Myslyaeva L., Onuchina E., Palatkina T., Panov A., Parmon E., Petelina T., Repin A., Reznik I., Sazonova E., Sergienko T., Shaposhnik I., Shapovalova Y., Shustov S., Shvarts Y., Skopets I., Skuratova M., Smolenskaya O., Solovev O., Trofimov V., Vasiliev M., Vezikova N., Vozzhaev A., Yakushin S., Zadionchenko V., Apostolovic S., Adjic N.C., Ilic I., Ilic S., Nikolic L., Pupic L., Stokuca-Korac N., Antalik L., Bugan V., Csala L., Dokupilova A., Dzupina A., Forgon T., Fulop P., Gonsorcik J., Gyorgyova E., Holoubek D., Horvat P., Kamensky G., Kolikova V., Krupciakova B., Lenner E., Lennerova J., Lukac J., Majercak I., Mancikova I., Micko K., 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S.C., Lin T., Liu H.M., Tsai M.C., Tsao H.M., Tzong L., Ueng K.C., Wang Y.L., Wang H.C., Wang C.P., Yang C.C., Abaci F., Birdane A., Yilmaz M.B., Asim Oktay AO., Kan G., Koldas N., Ozcan I.T., Sahin M., Sahin T., Saka B., Tekten T., Ucar N., Uresin S., Yigit Z., Arif I., Bakhai A., Baksi A., Blagdon M., Brickman T., Brown N., Burton M., Burton J., Chaggar S., Chung A., Collier D., Covell W., Crawford G., Davies N., Davies M., Dayer M., Doughty A., Duff J., Dwenger E., Fisher J., Fitzpatrick L., Garner K., Glover J., Haughton G., Ilsley M., Ivan P., Voyzey E.J., Keenan S., Kelt T., Knight J., Kondagunta V., Lang C., Lee K., Lim L., Macdonald J., Mathew A., Mckenzie A., Mckibbin A., Michalska A., Pagett K., Pogson A., Price R., Price D., Procter K., Pye M., Redfearn H., Rewbury J., Ryding A., Sattar N., Sharp A., Shaw P., Simpson H., Smith W., Squire I., Storey R., Teenan M., Thomas H., Townend J., Trevelyan J., Wakeling J., Walukiewicz P., Wilkinson S., Zaman A., Acevedo L., Benton J., 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W., Caballero-Valiente B., Carr K., Halliwell T.C., Castillo J., Cei L., Cerda L., Chambers J., Chamblee T., Chattin W., Chee L., Chen Y.C., Cherlin R., Cheung D., Chiodi L., Christensen L., Christenson S., Cislowski D., Clavier-Firmin C., Colfer H., Colvin T., Cosgrove N., Covert C., Cox B., Cox R., Craig W., Crandall L., Crepps K., Cromer M., Cruz H., Cruz M., Cucher F., Damron M., Dave K., Dave B., Davis M., Davis B., Dawkins-Hughes S., Dean J., Debnam S., Defosse C., Dehning M., Dela Llana A., Dellorso M., Denham D., Desalle D., Dettmer M., Dhawan M., Diago M., Dicken T., Diederich C., Diederich M., Diehl R., Digangi D., Diller P., Dimattia M., Dodds G., Doggett J., Donahue K., Doughty L., Dragutksy B., Dreese M., Dunhurst F., Dunn D., Dutka C., Earl J., Eaton C., Eaves W., Ebeling K., Eder F., Edgerton L., Edillo C., Edwards J., Edwards T., Einhorn D., El Hafi S., Ellis M., Erickson B., Ervin W., Eskridge L., Fail P., Falcon D., Fang C., Fattal P., Fawson A., Felix L., Ferdinand 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D.H., Hotchkiss D., Huang P., Humbert J., Hutchens E., Iachini K., Ibarra M., Igbokidi O., Ilahi T., Imbrognio M., Ipp E., Iteld B., Jacques G., Jafri A., Jafry B., Jardula M., Jefferson D., Jenkins R., Johnson E., Johnson J., Jones S., Kawahara M., Kelehan S., Kelly R., Kendall T., Kereiakes D., Khan M., Khan S., Kick J., Kimmel M., King T., King A., Kirkland S., Kissel S., Kitchens D., Klein P., Klugherz B., Korban E., Koren M., Korte M., Kostis J., Kotek L., Kozak M., Kreutter F., Kusnick B., Labovitz R., Lail J., Lamance J., Lamas G., Lambert J., Lambert C., Landzberg J., Langdon J., Lavoie W., Ledger G., Lee T., Lehman R., Leimbach W., Lennard M., Lepor N., Lester F., Levin P., Levinson L., Lewis D., Lillo J., Link L., Long C., Longaker R., Lorch G., Lucksinger G., Lynd S., Rhudy J.M., Madder R., Magness K., Maheshwari A., Alan A., Malek M., Maletz L., Malhotra V., Malhotra S., Mandviwala M., Mani C.K., Manuel J., Marchelletta N., Marshall L., Marsters M., Martin L., Martinez E., Mavromatis K., Maynard R., Mays M., Mays B., Mbulaiteye A., Mcalister R., Mccoy C., Mccrary D.Jr., Mccullough-O'Brien H., Mcdonald M., Mcgill J., Mcgrew F., Mckenzie C., Mclaurin B., Mclellan B.A., Mcneil D., Mcneill R., Mehrle A., Melbie K., Melliza T., Messina T., Meyer R., Michel K., Mikdadi G., Miller C., Miller R., Miller A., Miller G., Miller W., Mitchell J., Moats DJR., Mody F., Moffat J., Molk B., Molter D., Monroe T., Montero H., Montgomery R., Mookherjee D., Moran J., Moriarty P., Morrison J., Morton D., Moshayedi P., Mosley J., Moustafa M., Munshi K., Murray A., Mustafa J., Nadar V., Naidu R., Nalley J., Navy S., Neil L., Neutel J.M., Niblack P., Nicely V., Nicolai M., Nijmeh G., Nikas A., Nikyar A., Nixon S., Norman L., Noto G., Nour K., Nugent A., Ocman B., Odegard A., Olsen S., Ortiz-Carrasquillo R., Ossino N., Paez H., Palchick B., Paliwal Y., Pannell R., Parfait V., Partridge J., Patel B., Patel M., Patel S., Paysor C., Pena A., Pereira S., Perez M., Perez A., Perkins 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Smith G., Smith B., Smith J., Soca Y., Sofley C., Sopko K., Sosa-Padilla M., Sotolongo R., Sprinkle B., Srivastava S., Starzec M., Steinhoff J., Stelly L., Stinson J., Stoddard M., Stoltz S., Stone B., Stover T., Strain J., Strugatsky S., Stys T., Suleman A., Sullivan P., Tamez W., Tandon N., Teltser M., Terry P.S., Terry K., Tessmar C., Thekkoott D., Thomas D., Thomas D.M., Thompson E., Thompson J., Thornton A., Tjaden T., Tobias C., Topper J., Tran A., Treasure C., Trenkamp P., Trevino M., Tsou L., Tuholske C., Uy W., Vahtel M., Vaid B., Valenzuela M., Vance A., Vandam J., Vanhecke T., Vanness WC III., Vargas R., Vaz S., Vazquez Tanus J., Veerina K., Vega J., Vento A., Vijay N., Voelker F., Vogt E., Vold D., Vora K., Wade R.D., Wadell C., Waksman R., Walker K., Wallace K., Warren M., Washam M., Watson B., Webel R., Wells T., West M., Whitaker J., White J., White C., White A., Wilhoit G., Wilkins M., Willingham K., Wilson S., Wilson V., Wise J., Woodall S., Woods A., Wright J., Xu 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Taqueti V., Wei N., Burris H., Cioffi A., Dalseg A.M., Ghosh N., Gralow J., Mayer T., Rugo H., Fowler V., Limaye A.P., Cosgrove S., Levine D., Lopes R., Scott J., Hilkert R., Tamesby G., Mickel C., Manning B., Woelcke J., Tan M., Manfreda S., Ponce T., Kam J., Saini R., Banker K., Salko T., Nandy P., Tawfik R., O’Neil G., Manne S., Jirvankar P., Lal S., Nema D., Jose J., Collins R., Bailey K., Blumenthal R., Colhoun H., Gersh B., Abreu M., Actis M.V., Aiub J., Aiub F., Albisu J., Alvarisqueta A., Avalos V., Barreto M., Berli M.A., Blumberg C., Bocanera M., Botta C., Bowen L., Budassi N., Buhlman S., Westberg J.C., Carabajal T., Caruso G., Casala J., Cendali G., Coloma G., Berra F.C., Cuneo C., Degennaro N., Dellasa M., Diaz M., Dos Santos P., Espinosa V., Facello A., Facello M., Farias E., Fernandez A.A., Ferrari V., Pacora F.F., Flores G.S., Franco M., Gabito A., Viola H.G., Garcia F., Garcia Duran R., Garcia Pinna J., Glenny J., Godoy Sanchez M., Grosse A., Guzman P., Hasbani E., Hominal M., Ibañez J., Jure H., Jure D., Vico M.L., Liniado G., Luciardi H., Luquez H., Maehara G., Maffei L., Majul C., Mallagray M., Marinaro S., Martinez J., Massaccesi R., De Los Milagros Had M., Azize G.M., Montana O., Montenegro E., Morell Y., Muntaner J., Navarrete S., Olmedo M., Paganini M., Paz S., Perez Manghi F., Piskorz D., Polato C., Recoaro R., Romano A., Salinger M., Sanchez A., Saravia M.A., Sarjanovich R., Scaro G., Schiavi L.B., Soler J., Tinnirello V., Tomassi A., Valle M., Vallejo M.A., Venturini C., Marcela Wenetz L.M., Yossen M., Zaidman C., Zalazar L., Zangroniz P., Amerena J., Brady L., Colquhoun D., Eccleston D., Ferreira-Jardim A., French J., Jayasinghe R., Mcintosh C., Ord M., Plotz M., Purnell P., Roberts-Thomson P., Schultz C., Shanahan T., Tan R., Taverner P., Turner F., Vibert J., Vorster M., William M., Youssef G., Bergler-Klein J., Brath H., Brodmann M., Fliesser-Goerzer E., Haider K., Heeren G., Hiden C., Mandic L., Paulweber B., Ploechl A., Prenner A., Steringer-Mascherbauer R., Strohner-Kaestenbauer H., Barbato E., Bouvy C., Briké C., Charlier F., Cools F., De Knijf K., De Wolf L., Delforge M., Deweerdt N., Gits F., Goffinet C., Hermans K., Hollanders G., Mestdagh I., Pirenne B., Servaes V., Simons N., Tahon S., Theunissen E., Van Genechten G., Vervoort G., Vissers C., Vranckx P., Vrolix M., Abib E.Jr., Abrantes J., Araujo Fonseca M., Barbosa E., Barroso W., Barroso A., Bodanese L., Botelho R., Costa Amorim R., Da Costa F., Da Silva A., Da Silva O.Jr., Da Silva D.Jr., Ferreira Dos Santos T., Dos Santos F., Dos Santos A., Duda N., Feitosa G., Felario Junior GA., Ferraz R., Filho P., Fonseca A., Wanderley F.F., Freitas E., Fucci F., Marengo Garcia De Carvalho L., Hernandez M., Hettwer Magedanz E., Julião K., Kormann A., Lameira A., Lima F., Lino E., Maia L., Manenti E., Marchi A.L., Fischer S.M., Michalaros Y., Moraes J.Jr., Moreira L., Pagnan M., Pesce F., Pinheiro L., Rassi S., Reis G., Reis H., Resende I., Roel A., Ruschel K., Saporito W., Saraiva J.F., Seroqui M., Silva R., Unterkircher B., Vicente C., Vieira N., Xavier J.P., Zucchetti C., Angelova I., Dimitrov G., Genova D., Gospodinov K., Goudev A., Grigorova V., Hristova K., Makedonska J.J., Katova T., Kostov K., Lazov P., Manov E., Manukov I., Manukov D., Milanova M., Kabakchieva V.M., Petrov D., Petrusheva T., Pramatarova I., Raev D., Runev N., Sirakova-Taseva A., Tisheva-Gospodinova S., Todorova A., Tzekova M., Yakovova S., Yanev T., Abulencia K., Arora S., Baker A., Bata I.R., Beaudry M., Belle Isle J., Bilodeau N., Boivin M.C., Bolduc H., Bourgeois S., Brons S., Cantor W., Chaussé I., Chhabra A., Chouinard G., Cleveland T., Dattani D., Deslongchamps F., Diodati J., Drouin K., Duchesne L., Fontaine S., D'Amours D.G., Gervais B., Gosselin G., Graham J., Grover A., Gupta A., Haldane H., Hartleib M., Hickey L., Huynh T., Johnston J., Julien V.E., Lachance P., Lake J., Lamontagne C., Lauzon C., Lepage S., Maheux K., Manyari D., Martin E., McPherson C., Mehta S., Michaud N., Kouz S.M., Murphy G., OKeefe D., Otis R., Ouimet F., Pandey S., Peck C., Perkins L., Richert L., Robbins K., Robinson S., Cabau J.R., Ross B., Roy C., Roy M., Roy A., Rupka D., Affaki G.S., Saunders K., Savard D., Soucy D., St Amour E., Thiessen S., Vertes G., Vezina M., Vincelli G., Weisnagel S.J., Zadra R., Chen J., Chen Y., Dong X., Feng Y., Feng Z., Fu G., Han B., Hao Y., He Y., He Z., Hong T., Jia Z., Jiang T., Jiang J., Jiang X., Ke Y., Li Y., Li Z., Li W., Li X., Liu P., Liu Y., Liu B., Liu S., Liu L., Lu Z., Lv Y., Ma C., Ma G., Peng L., Qing L., Ren L., Sang X., Song M., Sun Z., Wang J., Wang Y., Wei J., Wu W., Wu J., Xu H., Yan J., Yang P., Yang K., Yao Z., Yaoqing H., Yuan Z., Zhai Z., Zhang J., Zhang Y., Zhao R., Zhou H., Accini Mendoza JL., Aparicio C.V., Castillo T., Chaverra I., Conrado Y., Coronel J., Cotes C., Cuentas I., Cuervo A., Dussan M.A., Echeverria L., Hernandez E., Ibarra J., Isaza D., Jimenez D., Lopez P., Manzur F., Mejia I., Mendoza Y., Molina D.I., Patino J.M., Rodriguez D., Rodriguez L.M., Rodriguez S.M., Sanchez Vallejo G., Luz Serrano H., Sotomayor A., Urina M., Vesga B., Yupanqui H., Akrap B., Busic N., Ciglenecki N., Cmrecnjak J., Fucak E., Gabor M., Jeric M., Jutrisa N., Kordic K., Planinc I., Popovic Z., Radeljic V., Sesto I., Sutalo K., Tusek S., Belohlavek J., Budkova J., Busak L., Capova L., Cech V., Cermak O., Coufalova Z., Cyprian R., Dedek V., Dedkova S., Ferkl R., Hanak P., Hanustiakova A., Homza M., Horackova K., Houra M., Iveta H., Kaiserova L., Kala P., Karel I., Kellnerova I., Koleckar P., Kreckova M., Krupicka J., Lorenc Z., Machova V., Malik J., Masarikova L., Matyasek I., Mikus M., Mikusova T., Ondrasik J., Otava M., Palubova L., Pavlickova L., Peterka M., Petrova I., Pokorna B., Povolny P., Radvan M., Reznakova S., Rickova Z., Roszkowska P., Rotreklova M., Samkova D., Skalicka H., Slechticka A., Sternthal P., Telekes P., Tesak M., Vesely P., Vesely J., Vins P., Vitovec M., Vodnansky P., Zidova M., Keba E., Laane E., Pool T., Randvee L., Ratnik E., Reimand M., Reinmets S., Rivis L., Siemann M., Stern M., Toom M., Vahula V., Apel T., Axthelm C., Ayasse D., Ayasse M., Baar M., Baeumer A., Bagi E.S., Becker B., Binder A., Blankenberg S., Braun P., Johansen B.B., Contzen C., Delfonso F., Denecke C., Dengler T., Donaubauer T., Eichinger G., Englmann E., Erhard M., Faghih M., Foerster A., Frankenstein L., Fuchs R., Furch G., Gaeb-Strasas B., Germann H., Giese C., Goette A., Gravenhorst-Muenter U., Haege R., Haenel T., Hagemann D., Hagenow A., Hanefeld M., Heider J., Heisters J., Hennig D., Hielscher S., Himpel-Boenninghoff A., Holscher A., Hornig M., Jeserich M., Kaczmarek N., Kanitz S., Kara Y.D., Khariouzov A., Kiefer R., Kiroglu K., Klamm M., Klein C., Korth-Wiemann B., Krapivsky A., Kuenzler J., Kuntzsch A., Landers B., Lappo M., Laube S., Leggewie S., Lehmann D., Lepp H., Lierse T., Lindner C., Luecke-Uzar M., Luedemann J., Marschke T., Maruzzo S., Mauersberger K., Maus O., Meinrich M., Meissner A., Moehring B., Muehlhaus J., Mueller S., Muenter K.C., Muenzel T., Naumann R., Nebel J., Neumann J., Nuding S., Overhoff U., Papke B., Pencz I., Peter Y., Peukert A.M., Radde I., Rau T., Regner S., Reichenbach D., Reimer D., Rinke A., Roettges R., Romanski A., Rummel R., Samer H., Sanuri M., Sarnighausen H.E., Schäfer B., Scheibner T., Schermaul K.H., Schindler A., Schlundt C., Schmidt E., Schmidt K., Schnabel A., Schoen N., Schorn K., Schroeder T., Schulenburg D., Schulz M., Schulze U., Schulze J., Schumacher M., Schwerin G., Schwerin M., Stadelmeier S., Stahl H.D., Stahl A., Stockhausen J., Stockhausen G., Stoessel J., Stolze K., Stratmann M., Szymanowski N., Teschner A.B., Teske A., Uecker C., Veit S., Voeller H., Walter I., Walter J., Walther I., Weber H.G., Weimer J., Wichterich K., Wiebusch A., Willmerdinger M., Willner C., Winkelmann B., Winkler J., Wistuba T., Woehrle J., Wohnlich T., Wolf S., Woyczak D., Wrage P., Zirlik A., Anadiotis A., Chachalis G., Dermitzakis A., Kafarakis P., Kaldara E., Kolokathis F., Kostakou P., Lekakis J., Manolis A., Mantas I., Megalou A., Milkas A., Nanas J., Olympios C.D., Patsilinakos S., Perperis A., Poulimenos L., Saloustros I., Tsioufis K., Tsorbatzoglou K., Vardas P., Zarifis I., Aguilar M., Arango J.L., Borrayo N.A., Corona V., Guerrero A., Guzman I., Haase F., De Krumbach L., Montenegro P., Munoz R., Munoz N., Paniagua A., Solares A., Vogel M., Anita S., Blazsek Z., Decsi K., Fulop T., Hangyal T., Hegedus V., Kalina A., Karakai H., Katona A., Kiss R.G., Kovacs A., Laszlo Z., Lupkovics G., Medvegy M., Merkely B., Mihaly N., Nagy A.C., Dékány J.N., Nikoletta P., Noori E., Penzes J., Poor F., Sarszegi Z., Simay A., Simon J., Szakal I., Szatmarine V., Szocs A., Zilahi Z., Karsai X.Z., Andersen K., Sigurdadottir E., Skuladottir F., Abdullakutty J., Abhaichand R., Abhyankar A., Agarwal D.K., Aggarwal R.K., Ahire N., Awasthi A.K., Babu R., Bai A., Bali H.K., Banker D., Bhadade S., Bisne V., Bohra P., Raghu C., Chauhan D., Chauhan H., Chavada J., Chaware G., Chella S., Chintala P., Dash D., Desai D., Devasia T., Dhanak R., Dobariya H., Dudhatra N., Duhan S., Fulwani M., Ghondale N., Ghosh S., Gohel P., Govindaraj D., Goyal B., Goyal S., Gundala A.K., Gupta M., Hardas S., Iby M., Jagtap P., Jain A., Joshi U., Karpuram M., Kaur H., Khan A., Khan R., Kodem D.R., Koeitti P., Kulkarni L., Kullal P., Kumar K.S., Kumbla M., Latheef K., Lohkare M., Santosh M.J., Makhe B., Mandati M., Mehta A., Minocha G., Mittal A., Modi R., Mohan K., Oomman A., Pai R., Pai V., Palaniswami N., Pansheriya A., Parekh N., Patel J., Patel R., Patole T., Praveen M., Radhakrishnan V., Rajan B A., Rajasekhar D., Rao M., Rao M.B., Rao N.M., Rathnavel S., Rathore A., Rathore SRS., Rawat S., Reddy N.C., Sarma R., Sathe S., Shah J., Shaikh P., Sharma K., Sharma S., Sharma T., Shetty P., Sidhu G., Singh V., Sohi G.S., Srinath V.S., Raju S.S., Taran A., Thakkar B., Velusamy K., Vijan V., Vora V., Vuriya A.K., Agosta G.F., Antonicelli R., Ardissino D., Argiolas G., Baldin M.G., Benedetti G., Berti S., Bevilacqua M.T., Bolognesi M.G., Dessalvi C.C., Calabrese A., Campanale E.G., Candusso R., Caso P., Cosmi F., Crea F., Crocamo A., De Caterina R., De Rosa S., Destro M., Di Biase M., Dognini G.P., Eleuteri E., Fedele F., Ferrario M., Gabrielli D., Gamba C., Ganau A., Gravellone M., Iannopollo G., Indolfi C., Infusino F., Invitti C., Landolfi A., Lembo G., Liberato N.L., Mannucci E., Marino P., Mariottoni B., Marziali A., Mercuro G., Monti L., Mos L., Mureddu V., Musumeci M.B., Novo S., Panzarino C., Parente A., Perotti M., Filardi P.P., Petrillo C., Piatti P., Priori S., Racca V., Ragghianti B., Renda G., Righini V., Sarcone M., Senni M., Soro E., Tamburrini P., Vallone L., Villani G.Q., Volpe M., Ajioka M., Akai Y., Ashino K., Baden M., Doi M., Eki Y., Endo T., Fukuike C., Hagiwara Y., Hasegawa K., Higuchi Y., Higuchi T., Hioki M., Hirayama A., Hiroma J., Hosokawa S., Ichisawa M., Iijima T., Inada T., Inagaki M., Ito K., Kaigawa K., Kajihara S., Kamiya H., Kamiya J., Kaneno Y., Katahira K., Kataoka M., Kawai M., Kawasaki T., Kojima E., Komura Y., Kuramochi T., Kuruma T., Kyo E., Mani H., Miyamoto T., Morii I., Morinaga Y., Morisawa T., Nagai Y., Naka T., Nakamura Y., Nakamura S., Nakayoshi K., Nishibe A., Ogawa M., Okada Y., Okawa M., Sakamoto Y., Sakurada M., Sasaki S., Seki S., Shimomura H., Shinozaki T., Sugimoto N., Suzuki A., Taguchi S., Takahashi J., Takase S., Tanabe K., Tanaka A., Tani S., Tomioka J., Tsuboi H., Tsuji M., Tsujita K., Tsujiyama S., Umesu A., Yamada T., Yamaguchi E., Yamamoto H., Yamamoto T., Yamane M., Yanase T., Yasuoka S., Yasutake M., Yokoyama M., Yoshida M., Yoshimoto E., Yunoki C., Balode A., Dormidontova G., Flaksa I., Nagele-Luse I., Rancane G., Sime I., Bartuseviciene S., Cepinskiene L., Dobilas V., Grigaraviciene I., Marcinkeviciene J., Mazutavicius R., Miliuniene R., Motiejuniene R., Norkiene S., Norkute-Macijauske U., Rudys A., Slapikas R., Stonkute K., Strazdiene D., Tijuneliene E., Urbonas G., Vanagiene S., Viezelis M., Arenas Leon JL., Bayram E., Carrillo J., Davalos C., De Los Rios M., Delgadillo T., Hernández N., Leon S., Mendoza N., Muñoz W., Ramos G., Anneveldt A., Bakker H., Brouwer M., Bunschoten P., De Boer P., De Jong C., De Vos A., Den Hartog F., Doesborg L., Dommerholt R., Drost I., Ellenbroek D., Engelen W., Folkeringa R.J., Hamer BJB., Herrman J.P., Hoogslag PAM., Jansen M., Jerzewski A., Joosten C., Kalkman C., Kietselaer B., Kok M., Kooiman E., Kose V., Lardinois R., Lenderink T., Lok DJA., Lousberg A., Meijlis P., Mulder R., Singerling M., Smeele F., Stroes E., Swart H.P., Ten Holt W., Van Der Wal M., Van Der Zwaan C., Van Kempen W.W., Van Maarseveen M., Van Stein I., Viergever E.P., Visseren FLJ., Voors C., Nugteren SKZ., Ata B., Berulfsen A., Rønnevik T.D., Dickstein K., Furuseth B., Grundtvig M., Hansen H., Hofsoey K., Høivik H.O., Bøen R.H., Hurtig U., Pettersen K.I., Johansen E., Kleve R., Kolleroy C., Moen S., Nilsen V., Norin V., Otterstad J.E., Risberg K., Rønnevik P., Sirnes P.A., Skjelvan G., Strand S., Szacinski G., Vegsundvåg J., Alcalde J.M., Gomez Sanchez J., Rodriguez J., Rodriguez A., Zena N., Baszak J., Cymerman K., Czerski T., Fratczak M., Jaguszewska G., Kawka-Urbanek T., Koba M., Kopaczewski J., Kopczyńska M., Laniec M., Lysek R., Sciborski R., Szpajer M., Torun A., Wujkowski M., Zielinski M., Ahn Y., Baek C., Bang S.A., Chang K., Choi A.J., Han S., Hyun K., Kim M., Kim K.S., Kim B., Lee S.H., Lee J., Lee H.N., Lee J.H., Moon K., Park B., Park C., Tahk S., Yim K.H., Yim S., Tase T., Andor M., Aron G., Badea C., Casoinic F., Clocotan M., Coman S., Emil B., Imre B.S., Istratoaie O., Liviu C., Maximov D., Militaru C., Minescu B., Istvan K.P., Parepa I., Petrescu L., Podoleanu C., Pop C.F., Popa V., Popescu E., Radoi M., Sarbu I., Socoteanu E., Socoteanu G., Sorodoc L., Spiridon M., Stanciulescu G., Stefanescu M., Tanaseanu C., Tudoran M., Zdrenghea D., Agafina A., Akatova E., Avdonina N., Balukova E., Barbarash O.L., Bartosh L., Boyarkin M., Bulashova O., Burova N., Churina S., Demidova M., Dorogova I., Dovgalevskiy Y., Dovgolis S., Dudarev M., Fitilev S., Gapon L., Gazizianova V., Gordeev I., Ivanov I., Izmozherova N., Kazanskay E., Khirmanov V., Khromtsova O., Konradi A., Kosmacheva E., Kozlova S., Kulibaba E., Kuzin A., Libov I., Lipchenko A., Lozhkina N., Malchikova S., Morozov E., Myslyaeva L., Onuchina E., Palatkina T., Panov A., Parmon E., Petelina T., Repin A., Reznik I., Sazonova E., Sergienko T., Shaposhnik I., Shapovalova Y., Shustov S., Shvarts Y., Skopets I., Skuratova M., Smolenskaya O., Solovev O., Trofimov V., Vasiliev M., Vezikova N., Vozzhaev A., Yakushin S., Zadionchenko V., Apostolovic S., Adjic N.C., Ilic I., Ilic S., Nikolic L., Pupic L., Stokuca-Korac N., Antalik L., Bugan V., Csala L., Dokupilova A., Dzupina A., Forgon T., Fulop P., Gonsorcik J., Gyorgyova E., Holoubek D., Horvat P., Kamensky G., Kolikova V., Krupciakova B., Lenner E., Lennerova J., Lukac J., Majercak I., Mancikova I., Micko K., Nociar J., Pales J., Palka J.Jr., Poliacik P., Ruffini L., Sabo L., Skubova K., Slanina M., Smik R., Srdos V., Stitova M., Stofkova D., Strbova J., Such S., Toth P., Urgeova L., Vinanska D., Zareczky P., Flezar M., Kovacic D., Marcun R., Zagozen P., Bolsmann C., Conradie C., Dawood S.Y., Decsi K.L., Ebrahim I., Henley L., Horak A., Kapp I., Komati S., Lock E., Maboyi S., Makotoko E., Manga P., Page A., Ramdas S., Ranjith N., Roos J., Talliard C., Ajax K., Al-Khalili F., Assarsson E., Bergholtz T., Blom K.B., Boman K., Boström P.A., Curiac D., Jensen E.D., Dahlen G., Davidsson K., Duckert A., Hansson A., Härstedt N., Henriksson A., Olsson G.H., Johansson K., Jonsson J.E., Knutsson A., Lindholm C.J., Lönnberg I., Lundqvist M., Mellberg L., Moodh J., Mooe T., Olofsson M., Risenfors M., Rönndahl M., Sundelin R., Suorra I., Torgersruud M., Torstensson I., Chen C.P., Chen Z.C., Chen M.H., Cheng S.M., Cheng J.J., Fang C.Y., Ho C.J., Hsieh I.C., Huang P.H., Huang A., Kuo J.Y., Lai W.T., Lee S.C., Lin T., Liu H.M., Tsai M.C., Tsao H.M., Tzong L., Ueng K.C., Wang Y.L., Wang H.C., Wang C.P., Yang C.C., Abaci F., Birdane A., Yilmaz M.B., Asim Oktay AO., Kan G., Koldas N., Ozcan I.T., Sahin M., Sahin T., Saka B., Tekten T., Ucar N., Uresin S., Yigit Z., Arif I., Bakhai A., Baksi A., Blagdon M., Brickman T., Brown N., Burton M., Burton J., Chaggar S., Chung A., Collier D., Covell W., Crawford G., Davies N., Davies M., Dayer M., Doughty A., Duff J., Dwenger E., Fisher J., Fitzpatrick L., Garner K., Glover J., Haughton G., Ilsley M., Ivan P., Voyzey E.J., Keenan S., Kelt T., Knight J., Kondagunta V., Lang C., Lee K., Lim L., Macdonald J., Mathew A., Mckenzie A., Mckibbin A., Michalska A., Pagett K., Pogson A., Price R., Price D., Procter K., Pye M., Redfearn H., Rewbury J., Ryding A., Sattar N., Sharp A., Shaw P., Simpson H., Smith W., Squire I., Storey R., Teenan M., Thomas H., Townend J., Trevelyan J., Wakeling J., Walukiewicz P., Wilkinson S., Zaman A., Acevedo L., Benton J., Abbate A., Aboufakher R., Acampora M., Acampora D., Aceto L., Acevedo B., Acheatel R., Adams M., Adams A., Ahmad I., Ahmed S.H., Aish B., Akyea-Djamson A., Al Joundi T., Alcide P., Alfieri A., Alfonso T., Alfrey A., Allen J., Alllison D.C., Almaliky T., Amos A., Angiolillo D., Antolick A., Ara M., Aragorn L., Arevalo S., Armas E., Arthur A., Asafu-Adjaye N., Ashcom T., Ashford M., Aslam A., Ather N., Atieh M., Aull L., Ayala M., Azizad M., Backer T., Baehl S., Bailey S., Bair S., Baker C., Ballmajo M., Pieretti H.B., Baquero A., Barnett S., Baron S., Bartkowiak A., Bashir K., Beall K., Beauregard L.A., Sarah S., Beckett L., Belejchak P., Bendelow T., Bender D., Benjamin S., Berdoff R., Berger V., Bergeron P., Berk M., Bernstein M., Binns Y., Bitzer V., Blahey M., Bloch S., Bluemel J., Boffetti P., Boley K., Bonner J., Boudreaux R., Boulanger K., Bradley A., Bramlet D., Bredlau C., Briggs S., Brousalis L., Brown S., Brown C., Buchannan C., Burke W., Burley T., Burton C., Burtt D., Byars W., Caballero-Valiente B., Carr K., Halliwell T.C., Castillo J., Cei L., Cerda L., Chambers J., Chamblee T., Chattin W., Chee L., Chen Y.C., Cherlin R., Cheung D., Chiodi L., Christensen L., Christenson S., Cislowski D., Clavier-Firmin C., Colfer H., Colvin T., Cosgrove N., Covert C., Cox B., Cox R., Craig W., Crandall L., Crepps K., Cromer M., Cruz H., Cruz M., Cucher F., Damron M., Dave K., Dave B., Davis M., Davis B., Dawkins-Hughes S., Dean J., Debnam S., Defosse C., Dehning M., Dela Llana A., Dellorso M., Denham D., Desalle D., Dettmer M., Dhawan M., Diago M., Dicken T., Diederich C., Diederich M., Diehl R., Digangi D., Diller P., Dimattia M., Dodds G., Doggett J., Donahue K., Doughty L., Dragutksy B., Dreese M., Dunhurst F., Dunn D., Dutka C., Earl J., Eaton C., Eaves W., Ebeling K., Eder F., Edgerton L., Edillo C., Edwards J., Edwards T., Einhorn D., El Hafi S., Ellis M., Erickson B., Ervin W., Eskridge L., Fail P., Falcon D., Fang C., Fattal P., Fawson A., Felix L., Ferdinand K., Fien E., Fintel D., Firek C., Fitz-Patrick D., Flores E., Flores H., Floro T., Forker A., Foster M., Foucauld J., Lehman K.F., Fox B., Francoeur L., Frandsen B., Frivold G., Fruchter G., Fullerton D., Gabriel J., Gacioch G., Garas S., Garcia N., Garcia Rinaldi R., Garcia-Fragoso V., Garcia-Portela M., Gelb R., George F., Ghali J., Gilbert J., Gilley J., Glancy R., Goff R., Goldberg N., Gonzales D., Gonzales V., Gonzalez E., Gorges R., Gould R., Grabeau R., Grable M., Graham J.A., Graif J., Green E., Greener R., Greenway F., Grieshaber V., Griffin S., Gros C., Gudipati RVC., Guillinta P., Gupta V., Gutmann J., Gwyn M., El Hachem M., Hage F., Hageman T., Haidar A., Hakas J., Haldis T., Hall L., Hall C., Hall S., Halpern S., Hamud-Socoro A., Hardee L., Harrell W., Harrington A., Hartwell J., Hasan F., Hattler B., Haught H., Haynes E., Haywood A., Heaney L., Hecht J., Hernandez I., Herzog W., Hess E., Hill H., Hilton T., Hinderaker P., Hodnett P., Hoffman M., Hogan C., Holmes Z., Rees D.H., Hotchkiss D., Huang P., Humbert J., Hutchens E., Iachini K., Ibarra M., Igbokidi O., Ilahi T., Imbrognio M., Ipp E., Iteld B., Jacques G., Jafri A., Jafry B., Jardula M., Jefferson D., Jenkins R., Johnson E., Johnson J., Jones S., Kawahara M., Kelehan S., Kelly R., Kendall T., Kereiakes D., Khan M., Khan S., Kick J., Kimmel M., King T., King A., Kirkland S., Kissel S., Kitchens D., Klein P., Klugherz B., Korban E., Koren M., Korte M., Kostis J., Kotek L., Kozak M., Kreutter F., Kusnick B., Labovitz R., Lail J., Lamance J., Lamas G., Lambert J., Lambert C., Landzberg J., Langdon J., Lavoie W., Ledger G., Lee T., Lehman R., Leimbach W., Lennard M., Lepor N., Lester F., Levin P., Levinson L., Lewis D., Lillo J., Link L., Long C., Longaker R., Lorch G., Lucksinger G., Lynd S., Rhudy J.M., Madder R., Magness K., Maheshwari A., Alan A., Malek M., Maletz L., Malhotra V., Malhotra S., Mandviwala M., Mani C.K., Manuel J., Marchelletta N., Marshall L., Marsters M., Martin L., Martinez E., Mavromatis K., Maynard R., Mays M., Mays B., Mbulaiteye A., Mcalister R., Mccoy C., Mccrary D.Jr., Mccullough-O'Brien H., Mcdonald M., Mcgill J., Mcgrew F., Mckenzie C., Mclaurin B., Mclellan B.A., Mcneil D., Mcneill R., Mehrle A., Melbie K., Melliza T., Messina T., Meyer R., Michel K., Mikdadi G., Miller C., Miller R., Miller A., Miller G., Miller W., Mitchell J., Moats DJR., Mody F., Moffat J., Molk B., Molter D., Monroe T., Montero H., Montgomery R., Mookherjee D., Moran J., Moriarty P., Morrison J., Morton D., Moshayedi P., Mosley J., Moustafa M., Munshi K., Murray A., Mustafa J., Nadar V., Naidu R., Nalley J., Navy S., Neil L., Neutel J.M., Niblack P., Nicely V., Nicolai M., Nijmeh G., Nikas A., Nikyar A., Nixon S., Norman L., Noto G., Nour K., Nugent A., Ocman B., Odegard A., Olsen S., Ortiz-Carrasquillo R., Ossino N., Paez H., Palchick B., Paliwal Y., Pannell R., Parfait V., Partridge J., Patel B., Patel M., Patel S., Paysor C., Pena A., Pereira S., Perez M., Perez A., Perkins H., Perry B., Peters P., Phillippi C., Phillips A., Piacente R., Pintado M., Pish R., Pitt W., Poling T., Pomposini D., Poock J., Potts J., Poudrier R., Prior J., Pritchard C., Purighalla R., Quddusi K., Quinones J., Quinton D., Radin M., Radojcsics B., Rajput B., Rama B., Ramos M., Rauch R., Raynes K., Reber A.M., Reddy J., Reeves M., Reilly K., Renaud K., Resnick H., Reyes R., Richardson M., Riethof M., Riser J., Rodero M., Rodriguez Araya E., Roper L., Rozeman P., Ruder D., Runquist L., Sack G., Saint-Jacques H., Salfity M., Sall N., Sam K., Samal A., Sanchez D., Santiago J.Jr., Savignano C., Saylor R., Scheffel M., Schifferdecker B., Schindler E., Schneider P., Schneider R., Schnitzler R., Schrager B., Schwartz A., Scott R., Seals A., Shah A.V., Shah A., Shatsky K., Shayani S., Shealy N., Sheets L., Shelley J., Shepard P., Shetty S., Silver K., Simon M., Singh K., Singh N., Sizemore B.C., Skatrud L., Slayton C., Slimak V., Sloane G., Smallwood B., Smith P., Smith M., Smith T., Smith G., Smith B., Smith J., Soca Y., Sofley C., Sopko K., Sosa-Padilla M., Sotolongo R., Sprinkle B., Srivastava S., Starzec M., Steinhoff J., Stelly L., Stinson J., Stoddard M., Stoltz S., Stone B., Stover T., Strain J., Strugatsky S., Stys T., Suleman A., Sullivan P., Tamez W., Tandon N., Teltser M., Terry P.S., Terry K., Tessmar C., Thekkoott D., Thomas D., Thomas D.M., Thompson E., Thompson J., Thornton A., Tjaden T., Tobias C., Topper J., Tran A., Treasure C., Trenkamp P., Trevino M., Tsou L., Tuholske C., Uy W., Vahtel M., Vaid B., Valenzuela M., Vance A., Vandam J., Vanhecke T., Vanness WC III., Vargas R., Vaz S., Vazquez Tanus J., Veerina K., Vega J., Vento A., Vijay N., Voelker F., Vogt E., Vold D., Vora K., Wade R.D., Wadell C., Waksman R., Walker K., Wallace K., Warren M., Washam M., Watson B., Webel R., Wells T., West M., Whitaker J., White J., White C., White A., Wilhoit G., Wilkins M., Willingham K., Wilson S., Wilson V., Wise J., Woodall S., Woods A., Wright J., Xu Z.J., Yarows S., Young A., Younis L., Zarate J., Zebrack J., Zhang W., Zieve F., and Zineldine A.
- Abstract
BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83
20. Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.
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Atkin C, Iqbal G, Planche T, Pratt G, Yong K, Wood J, Raynes K, Low E, Higgins H, Neal RD, Dunn J, Drayson MT, and Bowcock S
- Subjects
- Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Male, Middle Aged, Multiple Myeloma therapy, Referral and Consultation, Severity of Illness Index, Multiple Myeloma diagnosis, Multiple Myeloma mortality
- Abstract
Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2021
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21. Stratifying risk of infection and response to therapy in patients with myeloma: a prognostic study
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Chicca IJ, Heaney JLJ, Iqbal G, Dunn JA, Bowcock S, Planche T, Pratt G, Yong K, Low E, Wood J, Raynes K, Higgins H, and Drayson MT
- Abstract
Background: Multiple myeloma is a cancer of plasma cells that is associated with severe immunodeficiency and increased numbers of bacterial infections. The Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial assessed the use of prophylactic levofloxacin in newly diagnosed multiple myeloma patients. Interactions between multiple myeloma disease activity, immunity and infection are central to the TEAMM trial. Active multiple myeloma suppresses immunity and infections delay administration of anti-multiple myeloma therapy. Furthermore, infection-derived inflammation nurtures multiple myeloma activity and resistance to anti-multiple myeloma therapy., Objectives: The aim of this study was to measure biomarkers of (1) immune competence to develop risk stratification of patients for infection to personalise the decision to prescribe antibiotics, (2) myeloma activity to sensitively measure speed and depth of myeloma response and (3) inflammation to identify patients who may be at risk of poor treatment responses., Method: Serum samples were collected from 977 TEAMM trial patients (aged 35–90 years) at randomisation, then every 4 weeks for 16 weeks and again at 1 year. Biomarker levels were compared with samples from healthy controls. Multiplex Luminex
® assays (R&D Systems, Minneapolis, MN, USA) and enzyme-linked immunosorbent assays were used for the analysis of biomarkers and anti-viral antibodies were measured by a haemagglutination assay., Results: At baseline, levels of both polyclonal immunoglobulins and anti-bacterial antibodies were below the normal range in most TEAMM trial patients. This immunoparesis was much more severe for antibodies against specific bacterial targets than for total immunoglobulin levels. Levels of anti-bacterial antibodies were below the threshold of protection for 18 of the 19 bacterial antigens tested. More patients aged < 65 years were protected against meningococcal serotypes, Haemophilus influenza type b and tetanus, whereas more patients aged ≥ 65 years were protected against pneumococcal serotypes but there was good protection in only 6% of the TEAMM trial patients. Higher levels of polyclonal immunoglobulins, but not specific anti-bacterial antibodies, were found to be associated with a lower risk of infection and a longer survival. At presentation, levels of neutrophil elastase, calprotectin and interleukin 10 were elevated in TEAMM trial patients, compared with healthy controls. Interleukin 10 levels were related to infection during the trial: patients with interleukin 10 levels ≥ 10 pg/ml had a greater risk of infection than patients with interleukin 10 levels < 10 pg/ml. Levels of soluble CD138 were elevated in 72% of TEAMM trial patients and were decreased in response to therapy, with a complete response seen in 40% of TEAMM trial patients by 16 weeks. Of the 76 TEAMM trial patients achieving a free light chain complete response at 16 weeks, only 30% had a soluble CD138 complete response. Overall, responses in the levels of soluble CD138 did not correlate with free light chain and myeloma monoclonal protein (also known as m-protein) responses, consistent with the fact that soluble CD138 responses reflect a separate aspect of disease activity and clonal size. Levels of procalcitonin were elevated in only 50% of patients who had febrile episodes during the TEAMM trial. Although levels of interleukins 6 and 8 at presentation were lower than in a heathy cohort of patients, lower levels of interleukin 6 were identified at baseline in poor responders than in good responders, and in patients who had febrile and non-febrile infections during the trial than in patients who had only non-febrile episodes., Conclusion: Information from this Efficacy and Mechanism Evaluation project can help inform risk stratification and patient identification strategies to be responsive to individual patient needs. Monitoring levels of free light chains and soluble CD138 can help identify non-responders early and monitoring interleukin 10 levels can help stratify patients for risk of infection. Furthermore, immunisation in remission should be tested., Limitations: The TEAMM trial administered prophylactic antibiotics or placebo for 12 weeks from a new diagnosis of myeloma. Patients were monitored for infections for 16 weeks post diagnosis, with a final set of clinical data gathered at 1 year. Infection data and efficacy of prophylactic antibiotics are available for only the first 16 weeks and survival for the first 52 weeks. This limits long-term data, particularly for progression-free and overall survival., Future Work: The TEAMM 2 trial (in preparation) will explore the benefit of prophylactic antibiotics up to 12 months following diagnosis and will explore infection risk post therapy and during remission. Furthermore, some of the key findings will be applied to investigate biomarkers in samples from other UK myeloma trials in which long-term outcome data are available., Trial Registration: Current Controlled Trials ISRCTN51731976., Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation ; Vol. 7, No. 10. See the NIHR Journals Library website for further project information., (Copyright © Queen’s Printer and Controller of HMSO 2020. This work was produced by Chicca et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.)- Published
- 2020
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22. Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.
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Earl H, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Rea D, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mahler-Araujo B, Provenzano E, Chhabra A, Gasson S, Balmer C, Abraham JE, Caldas C, Hall P, Shinkins B, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, and Dunn JA
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- Antineoplastic Agents, Immunological adverse effects, Cost-Benefit Analysis, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Middle Aged, Quality-Adjusted Life Years, Time Factors, Trastuzumab adverse effects, Antineoplastic Agents, Immunological administration & dosage, Breast Neoplasms drug therapy, Chemotherapy, Adjuvant, Receptor, ErbB-2 genetics, Trastuzumab administration & dosage
- Abstract
Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority., Objectives: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival., Design: This was a Phase III randomised controlled non-inferiority trial., Setting: The setting was 152 NHS hospitals., Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part., Intervention: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment., Main Outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model., Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently., Limitations: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered., Conclusions: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events., Future Work: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned., Trial Registration: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 40. See the NIHR Journals Library website for further project information., Competing Interests: Helena Earl reports grants from Roche (Basel, Switzerland) and Sanofi-Aventis (Paris, France), personal fees and travel expenses from Daiichi Sankyo (Tokyo, Japan), AstraZeneca plc (Cambridge, UK) and Intas Pharmaceuticals (Ahmedabad, India), travel expenses from Pfizer Inc. (New York, NY, USA) and Amgen Inc. (Thousand Oaks, CA, USA) and personal fees from prIME Oncology (Atlanta, GA, USA), all outside the submitted work. Karen McAdam reports grants from Roche and personal fees from Roche, Novartis International AG (Basel, Switzerland), Pfizer and Eisai Co., Ltd (Tokyo, Japan), all outside the submitted work. Daniel Rea reports personal fees and grants from Roche during the conduct of the study, as well as personal fees from Novartis, Pfizer, Genomic Health (Redwood City, CA, USA) and Daiichi Sankyo, and grants from Celgene Corporation (Summit, NJ, USA), all outside the submitted work. Chris Plummer reports personal fees and non-financial support from Roche Products Limited, Novartis UK Limited, Pfizer UK Limited, Celgene and Incyte Corporation (Wilmington, DE, USA) for attending education meetings. He also reports personal fees and non-financial support from Amgen Limited for attending education meetings and advisory boards, all outside the submitted work. Jean Abraham reports fees to her institution, and accommodation and travel expenses from AstraZeneca for session boards and advisory chairs, as well as fees to her institution, and accommodation and travel expenses from Pfizer for a lecture, all outside the submitted work. Carlos Caldas reports grants from Genentech, Inc. (South San Francisco, CA, USA), Roche, Servier Laboratories (Suresnes, France) and AstraZeneca outside the submitted work, and that he is a member of the AstraZeneca iMED External Science Panel. Peter Hall reports grants from Roche, Pfizer, AstraZeneca, Novartis, Eisai and Daiichi Sankyo outside the submitted work. Christopher McCabe’s institution holds research contracts with Roche and reports grants from Roche, all outside the submitted work. David Miles reports personal fees from Roche/Genetech, outside the submitted work. Claire Hulme reports that she is a member of the National Institute for Health Research (NIHR) Health Technology Assessment Commissioning Board. Andrew M Wardley reports personal fees from Roche, Napp Pharmaceuticals Ltd (Cambridge, UK), Amgen, Merck Sharp & Dohme (Hoddesdon, UK), Novartis, Pfizer, AstraZeneca, Laboratoires Pierre Fabre (Paris, France), Accord (Barnstaple, UK), Athenex (Buffalo, NY, USA), Gerson Lehrman Group (New York, NY, USA), Coleman Research Expert Network Group (New York, NY, USA) and Guidepoint Global (New York, NY, USA). He also reports personal fees and other from Eli Lilly and Company (Indianapolis, IN, USA) and Daiichi Sankyo, all outside the submitted work. He is leading the National Cancer Research Institute Breast Group Initiative to develop the next de-escalation trial for HER2-positive breast cancer. David A Cameron reports funds to his institution from Novartis, Astrazeneca, Pfizer, Roche, Eli Lilly and Company, Puma Biotechnology (Los Angeles, CA, USA), Daiichi Sankyo, Synthon (Nijmegen, the Netherlands), SeaGen International GmbH (Zug, Switzerland), Zymeworks (Vancouver, BC, Canada), Elsevier (Amsterdam, the Netherlands), European Cancer Organisation (Brussels, Belgium), Celgene Corporation, Succinct Medical Communications (Wilmington, DE, USA), Immutep (Sydney, NSW, Australia), Oncolytics Biotech (U.S) Inc. (San Diego, CA, USA), Celldex Therapeutics Inc. (Hampton, NJ, USA), San Antonio Breast Cancer Consortium (TX, USA), Highfield Communication (Oxford, UK), Samsung Bioepis Co. Ltd (Incheon, South Korea), prIME Oncology, Merck Sharp & Dohme Ltd, Prima Biomed Ltd, RTI Health Solutions (Research Triangle, NC, USA) and Eisai, all outside the submitted work. Janet A Dunn reports that she is a member of the NIHR Efficacy and Mechanism Evaluation funding board and an NIHR senior investigator.
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- 2020
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23. Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.
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Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, Wood J, Raynes K, Higgins H, Dawkins B, Meads D, Hulme CT, Monahan I, Karunanithi K, Dignum H, Belsham E, Neilson J, Harrison B, Lokare A, Campbell G, Hamblin M, Hawkey P, Whittaker AC, Low E, and Dunn JA
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- Aged, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma pathology, Prognosis, Prospective Studies, Anti-Bacterial Agents therapeutic use, Antibiotic Prophylaxis methods, Febrile Neutropenia prevention & control, Infections drug therapy, Levofloxacin therapeutic use, Multiple Myeloma drug therapy
- Abstract
Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma., Methods: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35., Findings: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group., Interpretation: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy., Funding: UK National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2019
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24. Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT.
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Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, Wood J, Raynes K, Higgins H, Dawkins B, Meads D, Hulme CT, Whittaker AC, Hawkey P, Low E, and Dunn JA
- Subjects
- Antibiotic Prophylaxis, Clostridioides difficile, Cost-Benefit Analysis, Cross Infection prevention & control, England, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Northern Ireland, Technology Assessment, Biomedical, Wales, Anti-Bacterial Agents therapeutic use, Levofloxacin therapeutic use, Multiple Myeloma drug therapy
- Abstract
Background: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile . There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial., Objectives: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients., Design: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio., Setting: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales., Participants: A total of 977 patients with newly diagnosed symptomatic myeloma., Intervention: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year., Main Outcome Measures: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond., Results: In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p -trend of 0.06). There was no difference in new acquisitions of C. difficile , methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival ( p = 0.94)., Limitations: Short duration of prophylactic antibiotics and cost-effectiveness., Conclusions: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04)., Trial Registration: Current Controlled Trials ISRCTN51731976., Funding Details: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 62. See the NIHR Journals Library website for further project information., Competing Interests: Mark T Drayson reports personal fees from Abingdon Health (Abingdon Health, York, UK) outside the submitted work. Stella Bowcock reports personal fees from Amgen (Amgen, CA, USA) and Celgene (Celgene, NJ, USA) outside the submitted work, non-financial support to attend educational meetings and has a patent issued for a device broadly related to the work. Tim Planche reports personal fees from Pfizer (Pfizer, CT, USA), Actellion (Actellion, Allschnil, Switzerland) and Astellas (Astellas Pharma, Tokyo, Japan) outside the submitted work. Kwee Yong reports grants from Janssen (Janssen Pharmaceutica, Beerse, Belgium), Celgene and Chugai (Chugai Pharmaceutical Co Tokyo, Japan) outside the submitted work. David Meads is a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) European Economic and Social Committee (EESC) Methods Group and the NIHR HTA EESC Panel. Claire T Hulme is a member of the NIHR HTA Commissioning Board. Janet A Dunn is a member of the NIHR Efficacy and Mechanism Evaluation board.
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- 2019
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25. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.
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Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, and Dunn JA
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological adverse effects, Breast Neoplasms metabolism, Chemotherapy, Adjuvant, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Injections, Subcutaneous, Middle Aged, Prospective Studies, Receptor, ErbB-2 metabolism, Trastuzumab adverse effects, Treatment Outcome, United Kingdom, Young Adult, Antineoplastic Agents, Immunological administration & dosage, Breast Neoplasms drug therapy, Trastuzumab administration & dosage
- Abstract
Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival., Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140)., Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001)., Interpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial., Funding: UK National Institute for Health Research, Health Technology Assessment Programme., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2019
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26. Action video game training reduces the Simon Effect.
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Hutchinson CV, Barrett DJ, Nitka A, and Raynes K
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- Adult, Humans, Young Adult, Attention physiology, Executive Function physiology, Practice, Psychological, Psychomotor Performance physiology, Video Games
- Abstract
A number of studies have shown that training on action video games improves various aspects of visual cognition including selective attention and inhibitory control. Here, we demonstrate that action video game play can also reduce the Simon Effect, and, hence, may have the potential to improve response selection during the planning and execution of goal-directed action. Non-game-players were randomly assigned to one of four groups; two trained on a first-person-shooter game (Call of Duty) on either Microsoft Xbox or Nintendo DS, one trained on a visual training game for Nintendo DS, and a control group who received no training. Response times were used to contrast performance before and after training on a behavioral assay designed to manipulate stimulus-response compatibility (the Simon Task). The results revealed significantly faster response times and a reduced cost of stimulus-response incompatibility in the groups trained on the first-person-shooter game. No benefit of training was observed in the control group or the group trained on the visual training game. These findings are consistent with previous evidence that action game play elicits plastic changes in the neural circuits that serve attentional control, and suggest training may facilitate goal-directed action by improving players' ability to resolve conflict during response selection and execution.
- Published
- 2016
- Full Text
- View/download PDF
27. Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum.
- Author
-
Bray PG, Janneh O, Raynes KJ, Mungthin M, Ginsburg H, and Ward SA
- Subjects
- Amiloride analogs & derivatives, Animals, Antimalarials blood, Antimalarials pharmacokinetics, Bicarbonates pharmacology, Biological Transport drug effects, Chloroquine blood, Erythrocyte Membrane drug effects, Erythrocyte Membrane physiology, Humans, Hydrogen-Ion Concentration, Kinetics, Leupeptins pharmacology, Plasmodium falciparum drug effects, Verapamil pharmacology, Amiloride pharmacology, Chloroquine pharmacokinetics, Erythrocytes parasitology, Hemin metabolism, Hemoglobins metabolism, Plasmodium falciparum physiology, Sodium-Hydrogen Exchangers metabolism
- Abstract
Here we provide definitive evidence that chloroquine (CQ) uptake in Plasmodium falciparum is determined by binding to ferriprotoporphyrin IX (FPIX). Specific proteinase inhibitors that block the degradation of hemoglobin and stop the generation of FPIX also inhibit CQ uptake. Food vacuole enzymes can generate cell-free binding, using human hemoglobin as a substrate. This binding accounts for CQ uptake into intact cells and is subject to identical inhibitor specificity. Inhibition of CQ uptake by amiloride derivatives occurs because of inhibition of CQ-FPIX binding rather than inhibition of the Na+/H+ exchanger (NHE). Inhibition of parasite NHE using a sodium-free medium does not inhibit CQ uptake nor does it alter the ability of amilorides to inhibit uptake. CQ resistance is characterized by a reduced affinity of CQ-FPIX binding that is reversible by verapamil. Diverse compounds that are known to disrupt lysosomal pH can mimic the verapamil effect. These effects are seen in sodium-free medium and are not due to stimulation of the NHE. We propose that these compounds increase CQ accumulation and overcome CQ resistance by increasing the pH of lysosomes and endosomes, thereby causing an increased affinity of binding of CQ to FPIX.
- Published
- 1999
- Full Text
- View/download PDF
28. Synthesis and activity of some antimalarial bisquinolines.
- Author
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Raynes K, Galatis D, Cowman AF, Tilley L, and Deady LW
- Subjects
- Animals, Chloroquine analogs & derivatives, Plasmodium falciparum drug effects, Antimalarials chemical synthesis, Antimalarials pharmacology, Quinolines chemical synthesis, Quinolines pharmacology
- Abstract
A new type of bisquinoline antimalarial, in which the basic side chain of chloroquine is retained, has been evaluated. Nine bisamides were prepared from aliphatic diacids with 6-amino- and 8-amino-((4-(diethylamino)-1-methylbutyl)amino)quinoline, and screened against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. The resistance indices for all compounds were lower than for chloroquine. The position of attachment and length of the linker chain markedly affected activity. The most active (IC50 = 120 nM against the chloroquine-resistant FAC8 strain) was the -(O)C(CH2)4C(O)- linked 8-amino compound.
- Published
- 1995
- Full Text
- View/download PDF
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