406 results on '"Farrell, Helen"'
Search Results
202. Schizophrenia and the Art of the Possible.
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FARRELL, HELEN M., BALICK, DEBORAH MAYER, OSCHAROFF, RUTH, and FROSCH, ALLAN
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LETTERS to the editor , *SCHIZOPHRENIA - Abstract
Several letters to the editor are presented in response to the article "Successful and Schizophrenic," by Elyn R. Saks in the January 27, 2013 issue.
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- 2013
203. The Mouse Cytomegalovirus G Protein-Coupled Receptor Homolog, M33, Coordinates Key Features of In Vivo Infection via Distinct Components of Its Signaling Repertoire.
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Jiawei Ma, Bruce, Kimberley, Davis-Poynter, Nicholas, Stevenson, Philip G., and Farrell, Helen E.
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CYTOMEGALOVIRUS diseases , *G protein coupled receptors , *CYTOMEGALOVIRUSES , *CYCLIC adenylic acid , *PHOSPHOLIPASE C , *CARRIER proteins , *MICE - Abstract
Common to all cytomegalovirus (CMV) genomes analyzed to date is the presence of G protein-coupled receptors (GPCR). Animal models of CMV provide insights into their role in viral fitness. The mouse cytomegalovirus (MCMV) GPCR, M33, facilitates dendritic cell (DC)-dependent viremia, the extravasation of blood-borne infected DCs to the salivary gland, and the frequency of reactivation events from latently infected tissue explants. Constitutive G protein-coupled M33 signaling is required for these phenotypes, although the contribution of distinct biochemical pathways activated by M33 is unknown. M33 engages Gq/11 to constitutively activate phospholipase C b (PLCb) and downstream cyclic AMP response-element binding protein (CREB) in vitro. Identification of a MCMV M33 mutant (M33DC38) for which CREB signaling was disabled but PLCb activation was preserved provided the opportunity to investigate their relevance in vivo. Following intranasal infection with MCMV M33DC38, the absence of M33 CREB Gq/11-dependent signaling correlated with reduced mobilization of lytically-infected DCs to the draining lymph node high endothelial venules (HEVs) and reduced viremia compared with wild type MCMV. In contrast, M33ΔC38-infected DCs within the vascular compartment extravasated to the salivary glands via a pertussis toxin-sensitive, Gi/o-dependent, and CREB-independent mechanism. In the context of MCMV latency, spleen explants from M33ΔC38-infected mice were markedly attenuated for reactivation. Taken together, these data demonstrate that key features of the MCMV life cycle are coordinated in diverse tissues by distinct pathways of the M33 signaling repertoire. IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular "switches" that regulate the cellular response to environmental stimuli. All cytomegalovirus (CMV) genomes analyzed to date possess GPCR homologs with phylogenetic evidence for independent gene capture events, signifying important in vivo roles. The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and the establishment and/or reactivation of latent MCMV infection. The signaling repertoire of M33 is distinct from cellular GPCRs and little is known of the relevance of component signaling pathways for in vivo M33 function. In this report, we showed that temporal and tissue-specific M33 signaling was required to facilitate in vivo infection. Understanding the relevance of the viral GPCR signaling profiles for in vivo function will provide opportunities for future targeted interventions. [ABSTRACT FROM AUTHOR]
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- 2022
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204. Surface Bonding Effects in Compound Semiconductor Nanoparticles: II
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Farrell, Helen
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- 2008
205. Catalytic Activity of Supported Metal Particles for Sulfuric Acid Decomposition Reaction
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Farrell, Helen
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- 2007
206. Catalyst Activity and Post-operation Analyses of Pt/TiO2 (Rutile) Catalysts Used in the Sulfuric Acid Decomposition Reaction
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Farrell, Helen
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- 2007
207. BOOK REVIEW. Developing a Forensic Practice: Operations and Ethics for Experts.
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Farrell, Helen M.
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PSYCHIATRIC practice , *NONFICTION , *FORENSIC psychiatry , *MEDICAL practice - Published
- 2016
208. Arts Governance: People, Passion, Performance.
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Farrell, Helen J.
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ARTS management ,NONFICTION - Published
- 2016
209. Local community in the era of social media technologies: a global approach.
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Farrell, Helen
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- 2014
210. Correction: Cross-presentation of a spread-defective MCMV is sufficient to prime the majority of virus-specific CD8+ T cells.
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Snyder, Christopher M., Davis-Poynter, Nicholas, Farrell, Helen E., Allan, Jane E., Bonnett, Elizabeth L., Doom, Carmen M., and Hill, Ann B.
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T cells , *MOLECULAR microbiology - Published
- 2019
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211. Improvisation: Methods and Techniques for Music Therapy Clinicians, Educators and Students.
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Farrell, Helen
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MUSIC improvisation ,NONFICTION - Abstract
The article reviews the book "Improvisation: Methods and Techniques for Music Therapy Clinicians, Educators and Students," by T. Wigram.
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- 2009
212. Music in Special Education.
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Farrell, Helen
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MUSIC in education ,NONFICTION - Abstract
The article reviews the book "Music in Special Education," by M. S. Adamek and A.-A. Darrow.
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- 2009
213. CHAPTER 5 - Electron Diffraction: Low Energy (LEED)
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Farrell, Helen H.
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- 1974
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214. Self-Assembled CoAs Nanostructures
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Farrell, Helen
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- 2003
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215. Catalytic activity of supported metal particles for sulfuric acid decomposition reaction
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Rashkeev, Sergey N., Ginosar, Daniel M., Petkovic, Lucia M., and Farrell, Helen H.
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METAL catalysts , *SULFURIC acid , *CHEMICAL decomposition , *CHEMICAL reactions , *HYDROGEN production , *DENSITY functionals , *PLATINUM group catalysts - Abstract
Abstract: Production of hydrogen by splitting of water in the thermochemical sulfur-based cycles that employs the catalytic decomposition of sulfuric acid into SO2 and O2 is of considerable interest. However, all of the known catalytic systems studied to date that consist of metal particles on oxide substrates deactivate with time on stream. To develop an understanding of the factors that are responsible for catalyst activity, we investigate the fresh activity of several platinum group metals (PGM) catalysts, including Pd, Pt, Rh, Ir, and Ru supported on titania at 850°C and perform an extensive theoretical study (density-functional-theory-based first-principles calculations and computer simulations) of the activity of the PGM nanoparticles of different size and shape positioned on TiO2 (rutile and anatase) and Al2O3 (γ- and η-alumina) surfaces. The activity and deactivation of the catalytic systems are defined by (i) the energy barrier for the detachment of O atoms from the SO n (n =1, 2, 3) species, and (ii) the removal rate of the products of the sulfuric acid decomposition (atomic O, S, and the SO n species) from metal nanoparticles. We show that these two nanoscale features collectively result in the observed experimental behavior. The removal rate of the reaction products is always lower than the SO n decomposition rates. The relation between these two rates explains why the “softer” PGM nanoparticles (Pd and Pt) exhibit the highest initial catalytic activity. [Copyright &y& Elsevier]
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- 2009
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216. Critical care admission following elective surgery was not associated with survival benefit
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Kahan, Brennan C., Desponia, Koulenti, Kostoula, Arvaniti, Vanessa, Beavis, Douglas, Campbell, Matthew, Chan, Rui, Moreno, Pearse, Rupert M., Scott, Beattie, Pierre-Alain, Clavien, Nicolas, Demartines, Lee, A Fleisher, Mike, Grocott, James, Haddow, Andreas, Hoeft, Peter, Holt, Naomi, Pritchard, Andrew, Rhodes, Duminda, Wijeysundera, Matt, Wilson, Tahania, Ahmed, Kirsty, Everingham, Russell, Hewson, Marta, Januszewska, Rupert, M Pearse, Mandeep-Kaur, Phull, Richard, Halliwell, Mark, Shulman, Paul, Myles, Werner, Schmid, Michael, Hiesmayr, Patrick, Wouters, Stefan de Hert, Suzana, Lobo, Xiangming, Fang, Lars, Rasmussen, Emmanuel, Futier, Matthieu, Biais, Aurélien, Venara, Karem, Slim, Michael, Sander, Despoina, Koulenti, Mathew, Chan, Atul, Kulkarni, Susilo, Chandra, Aida, Tantri, Emad, Geddoa, Muntadhar, Abbas, Giorgio Della Rocca, Datin, Sivasakthi, Marzida, Mansor, Pastor, Luna, Arthur, Bouwman, Wolfgang, Buhre, Tim, Short, Tunde, Osinaike, Ricardo, Matos, Ioana, Grigoras, Mikhail, Kirov, Denis, Protsenko, Bruce, Biccard, Cesar, Aldecoa, Michelle, Chew, Christoph, Hofer, Martin, Hubner, James, Ditai, Tamas, Szakmany, Lee, Fleisher, Marissa, Ferguson, Michael, Macmahon, Ritchie, Cherian, Helen, Currow, Kathirgamanathan, Kanathiban, David, Gillespie, Edward, Pathmanathan, Katherine, Phillips, Jenifer, Reynolds, Joanne, Rowley, Jeanene, Douglas, Ross, Kerridge, Sameer, Garg, Michael, Bennett, Megha, Jain, David, Alcock, Nico, Terblanche, Rochelle, Cotter, Kate, Leslie, Marcelle, Stewart, Nicolette, Zingerle, Antony, Clyde, Oliver, Hambidge, Adam, Rehak, Sharon, Cotterell, Wilson Binh Quan Huynh, Timothy, Mcculloch, Erez, Ben-Menachem, Thomas, Egan, Jennifer, Cope, Paul, Fellinger, Simone, Haselberger, Caroline, Holaubek, Paul, Lichtenegger, Florian, Scherz, Franz, Hoffer, Veronika, Cakova, Andreas, Eichwalder, Norbert, Fischbach, Reinhold, Klug, Elisabeth, Schneider, Martin, Vesely, Reinhart, Wickenhauser, Karl Gernot Grubmueller, Marion, Leitgeb, Friedrich, Lang, Nancy, Toro, Marlene, Bauer, Friedrich, Laengle, Thomas, Mayrhofer, Christian, Buerkle, Karin, Forstner, Reinhard, Germann, Harald, Rinoesl, Elke, Schindler, Ernst, Trampitsch, Gerhard, Fritsch, Christian, Szabo, Jawad, Bidgoli, Hans, Verdoodt, Patrice, Forget, David, Kahn, Fernande, Lois, Mona, Momeni, Caroline, Prégardien, Audrey, Pospiech, Arnaud, Steyaert, Laurent, Veevaete, Dirk De Kegel, Karen De Jongh, Luc, Foubert, Carine, Smitz, Marcel, Vercauteren, Jan, Poelaert, Veerle Van Mossevelde, Jacques, Abeloos, Stefaan, Bouchez, Marc, Coppens, Luc De Baerdemaeker, Isabel, Deblaere, Ann De Bruyne, Stefan De Hert, Kristine, Fonck, Bjorn, Heyse, Tom, Jacobs, Koen, Lapage, Anneliese, Moerman, Martine, Neckebroek, Aliaksandra, Parashchanka, Nathalie, Roels, Nancy Van Den Eynde, Michael, Vandenheuvel, Jurgen Van Limmen, Ann, Vanluchene, Caroline, Vanpeteghem, Piet, Wyffels, Christel, Huygens, Punitha, Vandenbempt, Marc Van de Velde, Dimitri, Dylst, Bruno, Janssen, Evelien, Schreurs, Fábia Berganton Aleixo, Keulle, Candido, Hugo Dias Batista, Mario, Guimarães, Jaqueline, Guizeline, João, Hoffmann, Suzana, M Lobo, Francisco Ricardo Lobo, Vinícius, Nascimento, Katia, Nishiyama, Lucas, Pazetto, Daniela, Souza, Rodrigo Souza Rodrigues, Ana Maria Vilela Dos Santos, Jaquelline, Jardim, Joao, Silva, Paulo do Nascimento Junior, Thalissa Hermínia Baio, Gabriel Isaac Pereira de Castro, Henri Roger Watanabe Oliveira, Cristina Prata Amendola, Gutemberg, Cardoso, Daniela, Ortega, Ana Flavia Brotto, Mirella Cristine De Oliveira, Álvaro, Réa-Neto, Fernando, Dias, Pedro, Azambuja, Marcos Freitas Knibel, Antonio, Martins, William, Almeida, Calim Neder Neto, Maria Angela Tardelli, Eliana, Caser, Marcio, Machado, Crisitiano, Aguzzoli, Sérgio, Baldisserotto, Fernanda Beck Tabajara, Fernanda, Bettega, La Hore Correa Rodrigues Júnior, Julia de Gasperi, Lais, Faina, Marcos Farias Nolasco, Bruna Ferreira da Costa Fischer, Mariana Fosch de Campos Ferreira, Cristina, Hartmann, Marta, Kliemann, Gustavo Luis Hubert Ribeiro, Julia Merladete Fraga, Thiago Motta Netto, Laura Valduga Pozza, Paulo Rafael Wendling, Caroline, Azevedo, Juliana, Garcia, Marcel, Lopes, Bernardo, Maia, Paula, Maselli, Ralph, Melo, Weslley, Mendes, Matheus, Neves, Jacqueline, Ney, Claudio, Piras, Christopher, Applewhaite, Adrienne, Carr, Lorraine, Chow, Kaylene, Duttchen, Julena, Foglia, Michael, Greene, Ashley, Hinther, Kendra, Houston, Thomas Jared McCormick, Jennifer, Mikhayel, Sam, Montasser, Alex, Ragan, Andrew, Suen, Adrianna, Woolsey, Hai Chuan Yu, Duane, Funk, Stephen, Kowalski, Regina, Legaspi, Heather, Mcdonald, Faisal, Siddiqui, Jeremy, Pridham, Bernadette, Rowe, Sonia, Sampson, Barton, Thiessen, Geoff, Zbitnew, Andre, Bernard, Ronald, George, Philip, Jones, Rita, Moor, Naveed, Siddiqui, Alexandra, Wolfer, Diem, Tran, Denyse, Winch, Gary, Dobson, Thomas, Mccormick, Osama, Montasser, Richard, Hall, Leyla, Baghirzada, Si Yuan Dai, Gregory, Hare, Esther, Lee, Uma, Shastri, Albert, Tsui, Anmol, Yagnik, Danielle, Alvares, Stephen, Choi, Heather, Dwyer, Kathrina, Flores, Colin, Mccartney, Priya, Somascanthan, Carroll, Jo, Janneth, Pazmino-Canizares, Noam, Ami, Vincent, Chan, Anahi, Perlas, Ruth, Argue, Katie, Lavis, Kelly, Mayson, Ying, Cao, Hong, Gao, Tingju, Hu, Jie, Lv, Jian, Yang, Yang, Yang, Zhong, Yi, Jing, Zhou, Xiaohua, Zou, Miao, He, Xiaoying, Li, Dihuan, Luo, Haiying, Wang, Tian, Yu, Liyong, Chen, Lijun, Wang, Yunfei, Cai, Zhongming, Cao, Yanling, Li, Jiaxin, Lian, Haiyun, Sun, Sheng, Wang, Zhipeng, Wang, Kenru, Wang, Zhu, Yi, Xindan, Du, Hao, Fan, Yunbin, Fu, Lixia, Huang, Yanming, Huang, Haifang, Hwan, Hong, Luo, Pi-Sheng, Qu, Fan, Tao, Zhen, Wang, Guoxiang, Wang, Shun, Wang, Yan, Zhang, Xiaolin, Zhang, Chao, Chen, Weixing, Wang, Zhengyuan, Liu, Lihua, Fan, Jing, Tang, Yijun, Chen, Yongjie, Chen, Yangyang, Han, Changshun, Huang, Guojin, Liang, Jing, Shen, Jun, Wang, Qiuhong, Yang, Jungang, Zhen, Haidong, Zhou, Junping, Chen, Zhang, Chen, Xiaoyu, Li, Meng, Bo, Haiwang, Ye, Xiaoyan, Zhang, Yanbing, Bi, Jianqiao, Cao, Fengying, Guo, Hong, Lin, Yang, Liu, Meng, Lv, Pengcai, Shi, Xiumei, Song, Chuanyu, Sun, Yongtao, Sun, Yuelan, Wang, Shenhui, Wang, Min, Zhang, Rong, Chen, Jiabao, Hou, Yan, Leng, Qing-Tao, Meng, Qian, Li, Zi-Ying, Shen, Zhong-Yuan, Xia, Rui, Xue, Yuan, Zhang, Zhao, Bo, Xian-Jin, Zhou, Qiang, Chen, Huinan, Guo, Yongqing, Guo, Yuehong, Qi, Zhi, Wang, Jianfeng, Wei, Weiwei, Zhang, Lina, Zheng, Bao, Qi, Yaqiu, Chen, Yijiao, Chen, Yue, Fei, Nianqiang, Hu, Xuming, Hu, Min, Lei, Xiaoqin, Li, Xiaocui, Lv, Fangfang, Miao, Lingling, Ouyang, Qian, Lu, Conyu, Shen, Sun, Yu, Yuting, Wang, Dong, Wang, Chao, Wu, Liyuan, Xu, Jiaqi, Yuan, Lina, Zhang, Huan, Zhang, Yapping, Zhang, Jinning, Zhao, Chong, Zhao, Lei, Zhao, Tianzhao, Zheng, Dachun, Zhou, Haiyan, Zhou, Zhou, Ce, Kaizhi, Lu, Ting, Zhao, Changlin, He, Hong, Chen, Shasha, Chen, Baoli, Cheng, Jie, He, Lin, Jin, Caixia, Li, Hui, Li, Yuanming, Pan, Yugang, Shi, Xiao Hong Wen, Shuijing, Wu, Guohao, Xie, Kai, Zhang, Bing, Zhao, Xianfu, Lu, Feifei, Chen, Qisheng, Liang, Xuewu, Lin, Yunzhi, Ling, Gang, Liu, Jing, Tao, Yang, Lu, Jialong, Zhou, Fumei, Chen, Yunlin, Feng, Benchao, Hou, Jiamei, Lin, Mei, Liu, Foquan, Luo, Xiaoyun, Shi, Yingfen, Xiong, Lin, Xu, Shuangjia, Yang, Qin, Zhang, Huaigen, Zhang, Weihong, Zhao, Weilu, Zhao, Yun, Bai, Linbi, Chen, Sijia, Chen, Qinxue, Dai, Wujun, Geng, Kunyuan, Han, Xin, He, Luping, Huang, Binbin, Ji, Danyun, Jia, Shenhui, Jin, Qianjun, Li, Dongdong, Liang, Shan, Luo, Lulu, Lwang, Yunchang, Mo, Yuanyuan, Pan, Xinyu, Qi, Meizi, Qian, Jinling, Qin, Yelong, Ren, Yiyi, Shi, Junlu, Wang, Junkai, Wang, Leilei, Wang, Junjie, Xie, Yixiu, Yan, Yurui, Yao, Mingxiao, Zhang, Jiashi, Zhao, Xiuxiu, Zhuang, Yanqiu, Ai, Fang, Du, Long, He, Ledan, Huang, Zhisong, Li, Huijuan, Li, Yetong, Li, Liwei, Li, Meng, Su, Yazhuo, Yuan, Enman, Zhang, Jie, Zhang, Shuna, Zhao, Zhenrong, Ji, Ling, Pei, Wang, Li, Chen, Chen, Beibei, Dong, Jing, Li, Ziqiang, Miao, Hongying, Mu, Chao, Qin, Lin, Su, Zhiting, Wen, Keliang, Xie, Yonghao, Yu, Fang, Yuan, Xianwen, Hu, Zhang, Ye, Wangpin, Xiao, Zhipeng, Zhu, Qingqing, Dai, Kaiwen, Fu, Rong, Hu, Xiaolan, Hu, Song, Huang, Yaqi, Li, Yingping, Liang, Shuchun, Yu, Zheng, Guo, Yan, Jing, Tang, Na, Jie, Wu, Dajiang, Yuan, Ruilin, Zhang, Xiaoying, Zhao, Yuhong, Li, Hui-Ping, Bai, Chun-Xiao, Liu, Fei-Fei, Liu, Wei, Ren, Xiu-Li, Wang, Guan-Jie, Xu, Na, Hu, Bo, Li, Yangwen, Ou, Yongzhong, Tang, Shanglong, Yao, Shihai, Zhang, Cui-Cui, Kong, Bei, Liu, Tianlong, Wang, Wei, Xiao, Bo, Lu, Yanfei, Xia, Jiali, Zhou, Fang, Cai, Pushan, Chen, Shuangfei, Hu, Hongfa, Wang, Qiong, Xu, Liu, Hu, Liang, Jing, Bin, Li, Qiang, Liu, Yuejiang, Liu, Xinjian, Lu, Zhen Dan Peng, Xiaodong, Qiu, Quan, Ren, Youliang, Tong, Jin, Wang, Yazhou, Wen, Qiong, Wu, Jiangyan, Xia, Jue, Xie, Xiapei, Xiong, Shixia, Xu, Tianqin, Yang, Hui, Ye, Ning, Yin, Jing, Yuan, Qiuting, Zeng, Baoling, Zhang, Kang, Zheng, Jing, Cang, Shiyu, Chen, Fan, Yu, Shuying, Fu, Xiaodong, Ge, Baolei, Guo, Wenhui, Huang, Linghui, Jiang, Xinmei, Jiang, Liu, Yi, Yan, Pan, Yun, Ren, Shan, Qi, Jiaxing, Wang, Fei, Wang, Chi, Wu, Xiaoguang, Zhang, Ida Cecilie Christiansen, Simon Nørgaard Granum, Bodil Steen Rasmussen, Morten, Daugaard, Rajiv, Gambhir, Guðný Erla Steingrímsdóttir, Peter, Jensen-Gadegaard, Karsten Skovgaard Olsen, Hanna, Siegel, Katrine Zwicky Eskildsen, Mona Ring Gätke, Ida, Wibrandt, Simon Bisgaard Heintzelmann, Kai Henrik Wiborg Lange, Rune Sarauw Lundsgaard, Louise, Amstrup-Hansen, Claus, Hovendal, Michael, Larsen, Mette, Lenstrup, Tina, Kobborg, Jens Rolighed Larsen, Anette Barbre Pedersen, Søren Hübertz Smith, Rebecca Monett Oestervig, Arash, Afshari, Cheme, Andersen, Kim, Ekelund, Erik Lilja Secher, Birgitte, Brandsborg, Helene, Beloeil, Sigismond, Lasocki, Alexandre, Ouattara, Marlene, Sineus, Serge, Molliex, Marie Lim Legouge, Florent, Wallet, Antoine, Tesniere, Christophe, Gaudin, Paul, Lehur, Emma, Forsans, Stéphane de Rudnicki, Valerie Serra Maudet, Didier, Mutter, Ghassan, Sojod, Mehdi, Ouaissi, Jean-Marc, Regimbeau, Jacques, Desbordes, Nicolas, Comptaer, Diae El Manser, Sabine, Ethgen, Gilles, Lebuffe, Patrick, Auer, Christine, Härtl, Maria, Deja, Kirill, Legashov, Susanne, Sonnemann, Carola, Wiegand-Loehnert, Elke, Falk, Marit, Habicher, Stefan, Angermair, Beatrix, Laetsch, Katrin, Schmidt, Christian Von Heymann, Axel, Ramminger, Florian, Jelschen, Svenja, Pabel, Andreas, Weyland, Elke, Czeslick, Jochen, Gille, Michael, Malcharek, Armin, Sablotzki, Katharina, Lueke, Peter, Wetzel, Joerg, Weimann, Franz-Peter, Lenhart, Florian, Reichle, Frederike, Schirmer, Michael, Hüppe, Karl, Klotz, Carla, Nau, Julika, Schön, Thomas, Mencke, Christina, Wasmund, Carla, Bankewitz, Georg, Baumgarten, Andreas, Fleischer, Vera, Guttenthaler, Yvonne, Hack, Katharina, Kirchgaessner, Olja, Männer, Marlen, Schurig-Urbaniak, Rafael, Struck, Rebekka van Zyl, Maria, Wittmann, Ulrich, Goebel, Sarah, Harris, Siegfried, Veit, Evangelia, Andreadaki, Flora, Souri, Ioannis, Katsiadramis, Anthi, Skoufi, Maria, Vasileiou, Eleni, Aimoniotou-Georgiou, Anastasios, Katsourakis, Fotini, Veroniki, Glyceria, Vlachogianni, Konstantina, Petra, Dimitra, Chlorou, Eirini, Oloktsidou, Vasileios, Ourailoglou, Konstantinos, Papapostolou, Georgia, Tsaousi, Panagoula, Daikou, Georgia, Dedemadi, Ioannis, Kalaitzopoulos, Christos, Loumpias, Sotirios, Bristogiannis, Nikolaos, Dafnios, Georgios, Gkiokas, Elissaios, Kontis, Dimitra, Kozompoli, Aspasia, Papailia, Theodosios, Theodosopoulos, Christol, Bizios, Anastasia, Koutsikou, Aleaxandra, Moustaka, Ioannis, Plaitakis, Apostolos, Armaganidis, Theodora, Christodoulopoulou, Mihail, Lignos, Maria, Theodorakopoulou, Andreas, Asimakos, Eleni, Ischaki, Angeliki, Tsagkaraki, Spyros, Zakynthinos, Eleni, Antoniadou, Ioannis, Koutelidakis, Dimitrios, Lathyris, Irene, Pozidou, Nikolaos, Voloudakis, Maria, Dalamagka, Elena, Gkonezou, Christos, Chronis, Dimitra, Manolakaki, Dimitris, Mosxogiannidis, Tatiana, Slepova, Isaia-Sissy, Tsakiridou, Claire Lampiri Lampiri, Anastasia Vachlioti Vachlioti, Christos Panagiotakis Panagiotakis, Dimitrios Sfyras Sfyras, Fotios Tsimpoukas Tsimpoukas, Athanasia, Tsirogianni, Elena, Axioti, Andreas, Filippopoulos, Elli, Kalliafa, George, Kassavetis, Petros, Katralis, Ioannis, Komnos, Georgios, Pilichos, Ifigenia, Ravani, Antonis, Totis, Eymorfia, Apagaki, Andromachi, Efthymiadi, Nikolaos, Kampagiannis, Theoniki, Paraforou, Agoritsa, Tsioka, Georgios, Georgiou, Aristeidis, Vakalos, Aggeliki, Bairaktari, Efthimios, Charitos, George, Markou, Panagiota, Niforopoulou, Nikolaos, Papakonstantinou, Evdoxia, Tsigou, Archontoula, Xifara, Menelaos, Zoulamoglou, Panagiota, Gkioni, Stylianos, Karatzas, Aikaterini, Kyparissi, Efstratios, Mainas, Ioannis, Papapanagiotou, Theonymfi, Papavasilopoulou, George, Fragandreas, Eleni, Georgopoulou, Eleni, Katsika, Kyriakos, Psarras, Eirini, Synekidou, Maria, Verroiotou, Evangelia, Vetsiou, Donika, Zaimi, Athina, Anagnou, Konstantinos, Apostolou, Theodora, Melissopoulou, Theophilos, Rozenberg, Christos, Tsigris, Georgios, Boutsikos, Vasileios, Kalles, Nikolaos, Kotsalas, Christina, Lavdaiou, Fotini, Paikou, Georgia-Laura, Panagou, Anna, Spring, Ioannis, Botis, Maria, Drimala, Georgios, Georgakakis, Ellada, Kiourtzieva, Panagiota, Ntouma, Apostolos, Prionas, Kyriakos, Xouplidis, Eleftheria, Dalampini, Chrysavgi, Giannaki, Christina, Iasonidou, Orestis, Ioannidis, Athina, Lavrentieva, Athena, Lavrentieva, George, Papageorgiou, Maria, Kokkinoy, Maria, Stafylaraki, Stylianos, Gaitanakis, Periclis, Karydakis, Josef, Paltoglou, Panagiotis, Ponireas, Panagiotis, Chaloulis, Athanasios, Provatidis, Anisoglou, Sousana, Varvara Vanessa Gardikou, Maria, Konstantivelli, Olga, Lataniotou, Elisavet, Lisari, Maria, Margaroni, Konstantinos, Stamatiou, Edouardos, Nikolaidis, Ioannis, Pnevmatikos, Eleni, Sertaridou, Alexandros, Andreou, Eleni, Arkalaki, Elias, Athanasakis, Fotini, Chaniotaki, Aikaterini, Chatzimichali, Maria, Christofaki, Despina, Dermitzaki, Klara, Fiorentza, Georgios, Frantzeskos, Elisavet, Geromarkaki, Kalliopi, Kafkalaki, Marina, Kalogridaki, Konstyllia, Karydi, Sofia, Kokkini, Georgios, Kougentakis, Tatiana, Lefaki, Emmanouhl, Lilitsis, Aikaterini, Makatounaki, Polychronis, Malliotakis, Dimosthenis, Michelakis, Maria, Neonaki, Vasileia, Nyktari, Iliana, Palikyra, Eleftherios, Papadakis, Alexandra, Papaioannou, Konstantinos, Sfakianakis, Maria, Sgouraki, Xenia, Souvatzis, Anastasia, Spartinou, Nefeli, Stefanidou, Paulina, Syrogianni, Georgia, Tsagkaraki, Elena, Arnaoutoglou, Christina, Arnaoutoglou, Christina, Bali, Vasilios, Bouris, Rodamanthos, Doumos, Konstantia-Paraskevi, Gkini, Clio, Kapaktsi, Vasilios, Koulouras, Arian, Lena, Dimitra, Lepida, Evangelos, Michos, Dimitrios, Papadopoulos, Minas, Paschopoulos, Vaia Aliki Rompou, Ioanna, Siouti, Stavros, Tsampalas, Ourania, Ververidou, Georgios, Zilis, Alexandra, Charlalampidoy, Gregory, Christodoulidis, Andreas, 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Biccard, Bruce M., Biyase, Thuli, Buccimazza, Ine, Cardosa, Jorge, Chen, Jame, Daya, Bhavika, Drummond, Leanne, Elabib, Ali, Goad, Ehab Helmy Abdel, Goga, Ismail E., Goga, Riaz, Harrichandparsad, R., Hodgson, Richard E., Jordaan, J., Kalafatis, Nicky, Kampik, Christian, Landers, At, Loots, Emil, Madansein, Rajhmum, Madaree, Anil, Madiba, Thandinkosi E., Manzini, Vukani T., Mbuyisa, Mbali, Moodley, Rajan, Msomi, Mduduzi, Mukama, Innocent, Naidoo, Desigan, Naidoo, Rubeshan, Naidu, Tesuven K., Ntloko, Sindiswa, Padayachee, Eneshia, Padayachee, Lucelle, Phaff, Martijn, Pillay, Bala, Pillay, Desigan, Pillay, Lutchmee, Ramnarain, Anupa, Ramphal, Suren R., Ryan, Paul, Saloojee, Ahmed, Sebitloane, Motshedisi, Sigcu, Noluyolo, Taylor, Jenna L., Torborg, Alexandra, Visser, Linda, Anderson, Philip, Conradie, Alae, de Swardt, Mathew, de Villiers, Martin, Eikman, Johan, Liebenberg, Riaan, Mouton, Johan, Paton, Abbey, van der Merwe, Louwrence, Wilscott-Davids, Candice, Barrett, Wendy Joan, Bester, Marlet, de Beer, Johan, Geldenhuys, Jacque, Gouws, Hanni, Potgieter, Jan-Hendrik, Strydom, Magdel, Wilberforce-Turton, Edwin, Chetty, Rubendraj R., Chirkut, Subash, Cronje, Larissa, de Vasconcellos, Kim, Dube, Nokukhanya Z., Sibusiso Gama, N., Green, Garyth M., Green-Thompson, Randolph, Kinoo, Suman Mewa, Kistnasami, Prenolin, Maharaj, Kapil, Moodley, Manogaran S., Mothae, Sibongile J., Naidoo, Ruvashni, Aslam, M., Noorbhai, F., Rughubar, Vivesh, Reddy, Jenendhiran, Singh, Avesh, Skinner, David L., Smith, Murray J., Singh, Bhagwan, Misra, Ravi, Naidoo, Maheshwar, Ramdharee, Pireshin, Selibea, Yvonne, Sewpersad, Selina, Sham, Shailendra, Wessels, Joseph D., Africander, Cucu, Bejia, Tarek, Blakemore, Stephen P., Botes, Marisa, Bunwarie, Bimalshakth, Hernandez, Carlos B., Jeeraz, Mohammud A., Legutko, Dagmara A., Lopez, Acela G., De Meyer, Jenine N., Muzenda, Tanaka, Naidoo, Noel, Patel, Maryam, Pentela, Rao, Junge, Marina, Mansoor, Naj, Rademan, Lana, Scislowski, Pawel, Seedat, Ismail, van den Berg, Bianca, van der Merwe, Doreen, van Wyk, Steyn, Govender, Komalan, Naicker, Darshan, Ramjee, Rajesh, Saley, Mueen, Kuhn, Warren Paul, Matos-Puig, Roel, Moolla, Zaheer, Lisi, Alberto, Perez, Gisela, Valle Beltran, Anna, Lozano, Angel, Delgado Navarro, Carlo, Duca, Alejandro, Pastor Martinez, Ernesto, Ferrando, Carlo, Fuentes, Isabel, García-Pérez, Maria Luisa, Gracia, Estefania, Izquierdo Palomares, Ana, Katime, Antonio, Miñana, Amanda, Incertis, Raul, Romero, Esther, Romero Garcia, Carolina Soledad, Rubio, Concepcion, Socorro Artiles, Tania, Soro, Marina, Valls, Paola, Laguarda, Gisela Alaman, Benavent, Pau, Cuenca, Vicente Chisbert, Cueva, Andreu, Lafuente, Matilde, Parra, Asuncion Marque, Rodrigo, Alejandra Romero, Sanchez-Morcillo, Silvia, Tormo, Sergi, Redondo, Francisco Javier, De Andres, Jose, Gómez Diago, Lorena, Hernández Cádiz, Maria José, Manuel, Granell Gil, Peris, Raquel, Saiz, Cristina, Tatay, Jose, Tebar Soto, Maria Teresa, Brunete, Tamara, Cancho, David, Delgado García, David R., Zamudio, Diana, Garcia Del Valle, Santiago, Luz Serrano, M., Alonso, Eduardo, Anillo, Victor, Maseda, Emilio, Salgado, Patricia, Suarez, Lui, Suarez-de-la-Rica, Alejandro, Villagrán, María José, Alonso, José Ignacio, Cabezuelo, Estefania, Garcia-Saiz, Irene, Lopez del Moral, Olga, Martín, Silvia, Perez Gonzalez, Alba, Tovar Doncel, Sherezade, Vera, Martin Agüero, Ávila Sánchez, Francisco José, Castaño, Beatriz, Castaño Moreira, Beatriz, Flores Risco, Sahely, Paz Martín, Daniel, Pérez Martín, Fernando, Poza, Paloma, Ruiz, Adela, Serna Martínez, Wilson Fabio, Vicente, Bárbara Vázquez, Dominguez, Saul Velaz, Fernández, Salvador, Munoz-López, Alfonso, Bernat, Maria Jose, Mas, Arantxa, Planas, Kenneth, Jawad, Monir, Saeed, Yousif, Hedin, Annika, Levander, Helena, Holmström, Sandra, Lönn, David, Zoerner, Frank, Åkring, Irene, Widmark, Carl, Zettergren, Jan, Liljequist, Victor Aspelund, Nystrom, Lena, Odeberg-Wernerman, Suzanne, Oldner, Ander, Reje, Patrik, Lyckner, Sara, Sperber, Jesper, Adolfsson, Anne, Klarin, Bengt, Ögren, Katrin, Barras, Jean-Pierre, Bührer, Thoma, Despotidis, Vasileio, Helmy, Naeder, Holliger, Stephan, Raptis, Dimitri Aristotle, Schmid, Roger, Meyer, Antoine, Jaquet, Yve, Kessler, Ulf, Muradbegovic, Mirza, Nahum, Solange R., Rotunno, Teresa, Schiltz, Bori, Voruz, Françoi, Worreth, Marc, Christoforidis, Dimitri, Popeskou, Sotirios Georgio, Furrer, Marku, Prevost, Gian Andrea, Stocker, Andrea, Lang, Klau, Breitenstein, Stefan, Ganter, Michael T., Geisen, Martin, Soll, Christopher, Korkmaz, Michelle, Lubach, Iri, Schmitz, Michael, Meyer zu Schwabedissen, Moritz, Zingg, Ur, Hillermann, Thoma, Wildi, Stefan, Pinto, Bernardo Bollen, Walder, Bernhard, Hübner, Martin, Mariotti, Giustina, Slankamenac, Ksenija, Namuyuga, Mirioce, Kyomugisha, Edward, Kituuka, Olivia, Wesonga Shikanda, Anne, Kakembo, Nasser, Otim Tom, Charle, Webombesa, Antonina, Bua, Emmanuel, Ssettabi, Eden Michael, Epodoi, Joseph, Kabagenyi, Fiona, Kirya, Fred, Dempsey, Ged, Seasman, Colette, Basit Nawaz Khan, Raja, Kurasz, Claire, Macgregor, Mark, Shawki, Burhan, Hariharan, Vimal, Chau, Simon, Ellis, Kate, Butt, Georgina, Chicken, Dennis-Wayne, Christmas, Natasha, Allen, Samantha, Daniel, Gayatri Daniel, Dempster, Angie, Kemp, Juliette, Matthews, Lewi, Mcglone, Philip, Tambellini, Joanne, Trodd, Dawn, Freitas, Katie, Garg, Atul, Karpate, Shilpaja, Kulkarni, Aditi, O’Hara, Chloe, Troko, Jtroko, Angus, Kirsty, Bradley, Jacqueline, Brennan, Emma, Brooks, Carolyn, Brown, Janette, Brown, Gemma, Finch, Amanda, Gratrix, Karen, Hesketh, Sue, Hill, Gillian, Jeffs, Carol, Morgan, Maureen, Pemberton, Chri, Slawson, Nicola, Spickett, Helen, Swarbrick, Gemma, Thomas, Megan, Van Duyvenvoorde, Greta, Brennan, Andrew, Briscoe, Richard, Cooper, Sarah, Lawton, Tom, Northey, Martin, Senaratne, Rashmi, Stanworth, Helen, Burrows, Lorna, Cain, Helen, Craven, Rachael, Davies, Keith, Jonas, Attila, Pachucki, Marcin, Walkden, Graham, Davies, Helen, Gudaca, Mariethel, Hobrok, Maria, Arawwawala, Dilshan, Fergey, Lauren, Gardiner, Matthew, Gunn, Jacqueline, Johnson, Lyndsay, Lofting, Amanda, Lyle, Amanda, Mc Neela, Fiona, Smolen, Susan, Topliffe, Joanne, Williams, Sarah, Bland, Martin, Kaura, Vika, Lanka, Prasad, Naylor, Chardé, Smith, Neil, Ahmed, Ahmed, Myatt, John, Shenoy, Ravikiran, Soon, Wai Cheong, Tan, Jessica, Karadia, Sunny, Self, Jame, Durant, Emma, Tripathi, Shiva, Bullock, Clare, Campbell, Debbie, Ghosh, Alison, Hughes, Thoma, Zsisku, Lajo, Bengeri, Sheshagiri, Cowton, Amanda, Khalid, Mohammed Shazad, Limb, Jame, McAdam, Colin, Porritt, Mandy, Rafi, M. Amir, Shekar, Priya, Harden, Catherine, Hollands, Heidi, King, Angela, March, Linda, Minto, Gary, Patrick, Abigail, Waugh, Darren, Kumara, Paramesh, Simeson, Karen, Yarwood, Jamie, Browning, Julie, Hatton, Jonathan, Julian, Howe, Mitra, Atideb, Newton, Maria, Pernu, Pawan, Wilson, Alison, Commey, Thelma, Foot, Helen, Glover, Lyn, Gupta, Ajay, Lancaster, Nicola, Levin, Jill, Mackenzie, Felicity, Mestanza, Claire, Nofal, Emma, Pout, Lauren, Varden, Rosanna, Wild, Jonathan, Jones, Stephanie, Moreton, Sarah, Pulletz, Mark, Davies, Charlotte, Martin, Matthew, Thomas, Sian, Burns, Karen, McArthur, Carol, Patel, Panna, Lau, Gary, Rich, Natalie, Davis, Fiona, Lyons, Rachel, Port, Beth, Prout, Rachel, Smith, Christopher, Adelaja, Yemi, Bennett, Victoria, Bidd, Heena, Dumitrescu, Alexandra, Murphy, Jacqui Fox, Keen, Abigail, Mguni, Nhlanhla, Ong, Cheng, Adams, George, Boshier, Pier, Brown, Richard, Butryn, Izabella, Chatterjee, Jayanta, Freethy, Alexander, Lockwood, Geoffrey, Tsakok, Maria, Tsiligiannis, Sophia, Peat, William, Stephenson, Lorraine, Bradburn, Mike, Pick, Sara, Cunha, Pedro, Olagbaiye, Olufemi, Tayeh, Salim, Abernethy, Caroline, Balasubramaniam, Madhu, Bennett, Rachael, Bolton, David, Martinson, Victoria, Naylor, Charde, Bell, Stephanie, Heather, Blaylock, Kushakovsky, Vlad, Alcock, Liam, Alexander, Hazel, Anderson, Colette, Baker, Paul, Brookes, Morag, Cawthorn, Louise, Cirstea, Emanuel, Colling, Kerry, Coulter, Ian, Das, Suparna, Haigh, Kathryn, Hamdan, Alhafidz, Hugill, Keith, Kottam, Lucksy, Lisseter, Emily, Mawdsley, Matthew, McGivern, Julie, Padala, Krishnaveni, Phelps, Victoria, kumar, Vineshykaa Ramesh, Stewart, Kirsten, Towse, Kayley, Tregonning, Julie, Vahedi, Ali, Walker, Alycon, Baines, Duncan, Bilolikar, Anjali, Chande, Shiv, Copley, Edward, Dunk, Nigel, Kulkarni, Raghavendra, Kumar, Pawan, Metodiev, Yavor, Ncomanzi, Dumisani, Raithatha, Bhavesh, Raymode, Parizade, Szafranski, Jan, Twohey, Linda, Watt, Philip, Weatherall, Lucie, Weatherill, J., Whitman, Zoe, Wighton, Elinor, Abayasinghe, Chamika, Chan, Alexander, Darwish, Sharif, Gill, Jame, Glasgow, Emma, Hadfield, Daniel, Harris, Clair, Kochhar, Arun, Mellis, Clare, Pool, Andrew, Riozzi, Paul, Selman, Andrew, Smith, Emma-Jane, Vele, Liana, Gercek, Yuksel, Guy, Kramer, Holden, Dougla, Watson, Nichola, Whysall, Karen, Andreou, Prematie, Hales, Dawn, Thompson, Jonathan, Bowrey, Sarah, McDonald, Shara, Gilmore, Jemma, Hills, Vicky, Kelly, Chan, Kelly, Sinead, Lloyd, Geraint, Abbott, Tom, Gall, Lewi, Torrance, Hew, Vivian, Mark, Berntsen, Emer, Nolan, Tracey, Turner, Angu, Vohra, Akbar, Brown, Andrew, Clark, Richard, Coughlan, Elaine, Daniel, Conway, Patvardhan, Chinmay, Pearson, Rachel, Predeep, Sheba, Saad, Hesham, Shanmugam, Mohanakrishnan, Varley, Simon, Wylie, Katharine, Cooper, Lucy, Makowski, Arystarch, Misztal, Beata, Moldovan, Eliza, Pegg, Claire, Donovan, Andrew, Foot, Jayne, Large, Simon, Claxton, Andrew, Netke, Bhagyashree, Armstrong, Richard, Calderwood, Claire, Kwok, Andy, Mohr, Otto, Oyeniyi, Peter, Patnaik, Lisa, Post, Benjamin, Ali, Sarah, Arshad, Homa, Baker, Gerard, Brenner, Laura, Brincat, Maximilian, Brunswicker, Annemarie, Cox, Hannah, Cozar, Octavian Ionut, Durst, Alexander, Fengas, Lior, Flatt, Jim, Glister, Georgina, Narwani, Vishal, Photi, Evangelo, Rankin, Adeline, Rosbergen, Melissa, Tan, Mark, Beaton, Ceri, Horn, Rachel, Hunt, Jane, Rousseau, Guy, Stancombe, Lucia, Absar, Mohammed, Allsop, Joanne, Drinkwater, Zoe, Hodgkiss, Tracey, Smith, Kirsty, Brown, Jamie, Alexander-Sefre, Farhad, Campey, Lorraine, Dudgeon, Lucy, Hall, Kathryn, Hitchcock, Rachael, James, Lynne, Smith, Kate, Winstone, Ulrika, Ahmad, Norfaizan, Bauchmuller, Kri, Harrison, Jonathan, Jeffery, Holly, Miller, Duncan, Pinder, Angela, Pothuneedi, Sailaja, Rosser, Jonathan, Sanghera, Sumayer, Swift, Diane, Walker, Rachel, Bester, Delia, Cavanagh, Sarah, Cripps, Heather, Daniel, Harvey, Lynch, Julie, Paton, Alison, Pyke, Shirley, Scholefield, John, Whitworth, Helen, Bottrill, Fiona, Ramalingam, Ganesh, Webb, Stephen, Akerman, Nik, Antill, Philip, Bourner, Lynsey, Buckley, Sarah, Castle, Gail, Charles, Rob, Eggleston, Christopher, Foster, Rebecca, Gill, Satwant, Lindley, Kate, Lklouk, Mohamed, Lowery, Tracey, Martin, Oliver, Milne, David, O’Connor, Patrick, Ratcliffe, Andrew, Rose, Alastair, Smith, Annie, Varma, Sandeep, Ward, Jackie, Barcraft-Barnes, Helena, Camsooksai, Julie, Colvin, Carolyn, Reschreiter, Henrik, Tbaily, Lee, Venner, Nicola, Hamilton, Caroline, Kelly, Lewi, Toth-Tarsoly, Piroska, Dodsworth, Kerry, Foord, Denise, Gordon, Paul, Hawes, Elizabeth, Lamb, Nikki, Mouland, Johanna, Nightingale, Jeremy, Rose, Steve, Schrieber, Joe, Al ‘Amri, Khalid, Aladin, Hafiz, Arshad, Mohammed Asif, Barraclough, Jame, Bentley, Conor, Bergin, Colin, Carrera, Ronald, Clarkson, Aisling, Collins, Michelle, Cooper, Lauren, Denham, Samuel, Griffiths, Ewen, Ip, Peter, Jeyanthan, Somasundaram, Joory, Kavita, Kaur, Satwant, Marriott, Paul, Mitchell, Natalie, Nagaiah, Sukumar, Nilsson, Annette, Parekh, Nilesh, Pope, Martin, Seager, Joseph, Serag, Hosam, Tameem, Alifia, Thomas, Anna, Thunder, Joanne, Torrance, Andrew, Vohra, Ravinder, whitehouse, Arlo, Wong, Tony, Blunt, Mark, Wong, Kate, Giles, Julian, Reed, Isabelle, Weller, Debbie, Bell, Gillian, Birch, Julie, Damant, Rose, Maiden, Jane, Mewies, Clare, Prince, Claire, Radford, Jane, Balain, Birender, Banerjee, Robin, Barnett, Andrew, Burston, Ben, Davies, Kirsty, Edwards, Jayne, Evans, Chri, Ford, David, Gallacher, Pete, Hill, Simon, Jaffray, David, Karlakki, Sudheer, Kelly, Cormac, Kennedy, Julia, Kiely, Nigel, Lewthwaite, Simon, Marquis, Chri, Ockendon, Matthew, Phillips, Stephen, Pickard, Simon, Richardson, Jame, Roach, Richard, Smith, Tony, Spencer-Jones, Richard, Steele, Niall, Steen, Julie, Van Liefland, Marck, White, Steve, Faulds, Matthew, Harris, Meredyth, Kelly, Carrie, Nicol, Scott, Pearson, Sally Anne, Chukkambotla, Srikanth, Andrew, Alyson, Attrill, Elizabeth, Campbell, Graham, Datson, Amanda, Fouracres, Anna, Graterol, Juan, Graves, Lynne, Hong, Bosun, Ishimaru, Alexander, Karthikeyan, Arvind, King, Helen, Lawson, Tom, Lee, Gregory, Lyons, Saoirse, Macalister Hall, Andrew, Mathoulin, Sophie, Mcintyre, Eilidh, Mclaughlin, Danny, Mulcahy, Kathleen, Ratcliffe, Anna, Robbins, Jame, Sung, Weilin, Tayo, Adeoluwa, Trembath, Lisa, Venugopal, Suneetha, Walker, Robert, Wigmore, Geoffrey, Boereboom, Catherine, Downes, Charlotte, Humphries, Ryan, Melbourne, Susan, Smith, Coral, Tou, Samson, Ullah, Shafa, Batchelor, Nick, Boxall, Leigh, Broomby, Rupert, Deen, Tariq, Hellewell, Alistair, Helliwell, Laurence, Hutchings, Melanie, Hutchins, David, Keenan, Samantha, Mackie, Donna, Donna, Alison, Smith, France, Stone, Lucy, Thorpe, Kevin, Wassall, Richard, Woodgate, Andrew, Baillie, Shelley, Campbell, Tara, James, Sarah, King, Chri, Marques de Araujo, Daniela, Martin, Daniel, Morkane, Clare, Neely, Julia, Rajendram, Rajkumar, Burton, Megan, James, Kathryn, Keevil, Edward, Minik, Orsolya, Morgan, Jenna, Musgrave, Anna, Rajanna, Harish, Roberts, Tracey, Adamson, Michael, Jumbe, Sandra, Kendall, Jennie, Muthuswamy, Mohan Babu, Anderson, Charlotte, Cruikshanks, Andrew, Wrench, Ian, Zeidan, Lisa, Ardern, Diane, Harris, Benjamin, Hellstrom, Johanna, Martin, Jane, Thomas, Richard, Varsani, Nimu, Wrey Brown, Caroline, Docherty, Philip, Gillies, Michael, McGregor, Euan, Usher, Helen, Craig, Jayne, Smith, Andrew, Ahmad, Tahania, Bodger, Phoebe, Creary, Thai, Fowler, Alexander, Hewson, Ru, Ijuo, Eke, Jones, Timothy, Kantsedikas, Ilya, Lahiri, Sumitra, McLean, Aaron Lawson, Niebrzegowska, Edyta, Phull, Mandeep, Wang, Difei, Wickboldt, Nadine, Baldwin, Jacqueline, Doyle, Donna, Mcmullan, Sean, Oladapo, Michelle, Owen, Thoma, Williams, Alexandra, Daniel, Hull, Gregory, Peter, Husain, Tauqeer, Kirk-Bayley, Justin, Mathers, Edward, Montague, Laura, White, Stuart, Avis, Joanne, Cook, Tim, Dali-Kemmery, Lola, Kerslake, Ian, Lambourne, Victoria, Pearson, Annabel, Boyd, Christine, Callaghan, Mark, Lawson, Cathy, McCrossan, Roopa, Nesbitt, Vanessa, O’connor, Laura, Scott, Julia, Sinclair, Rhona, Farid, Nahla, Morgese, Ciro, Bhatia, Kailash, Karmarkar, Swati, Ahmed, Jamil, Branagan, Graham, Hutton, Monica, Swain, Andrew, Brookes, Jamie, Cornell, Jonathan, Dolan, Rachael, Hulme, Jonathan, Jansen van Vuuren, Amanda, Jowitt, Tom, Kalashetty, Gunasheela, Lloyd, Fran, Patel, Kiran, Sherwood, Nichola, Brown, Lynne, Chandler, Ben, Deighton, Kerry, Emma, Temlett, Haunch, Kirsty, Cheeseman, Michelle, Dent, Kathy, Garg, Sanjeev, Gray, Carol, Hood, Marion, Jones, Dawn, Juj, Joanne, Rao, Roshan, Walker, Tara, Al Anizi, Mashel, Cheah, Clarissa, Cheing, Yushio, Coutinho, Francisco, Gondo, Prisca, Hadebe, Bernard, Onie Hove, Mazvangu, khader, Ahamed, Krishnachetty, Bobby, Rhodes, Karen, Sokhi, Jagdish, Baker, Katie-Anne, Bertram, Wendy, Looseley, Alex, Mouton, Ronelle, Arnold, Glenn, Arya, Shobhit, Balfoussia, Danai, Baxter, Linden, Harris, Jame, Jones, Craig, Knaggs, Alison, Markar, Sheraz, Perera, Anisha, Scott, Alasdair, Shida, Asako, Sirha, Ravneet, Wright, Sally, Frost, Victoria, Gray, Catherine, MacGregor, Mark, Andrews, Emma, Arrandale, Lindsay, Barrett, Stephen, Cifra, Elna, Cooper, Mariese, Dragnea, Drago, Elna, Cifra, Maclean, Jennifer, Meier, Sonja, Milliken, Donald, Munns, Christopher, Ratanshi, Nadir, Salvana, Abegail, Watson, Anthony, Ali, Hani, Campbell, Gill, Critchley, Rebecca, Hicks, Catherine, Liddle, Alison, Pass, Marc, Ritchie, Charlotte, Thomas, Charlotte, Too, Lingxi, Welsh, Sarah, Gill, Talvinder, Johnson, Joanne, Reed, Joanne, Davis, Edward, Papadopoullos, Sam, Attwood, Clare, Biffen, Andrew, Boulton, Kerenza, Gray, Sophie, Hay, David, Mills, Sarah, Montgomery, Jane, Riddell, Rory, Simpson, Jame, Bhardwaj, Neeraj, Paul, Elaine, Uwubamwen, Nosakhare, Alexander, Maini, Arrich, Jame, Arumugam, Swarna, Blackwood, Dougla, Boggiano, Victoria, Brown, Robyn, Lam Chan, Yik, Chatterjee, Devnandan, Chhabra, Ashok, Christian, Rachel, Costelloe, Hannah, Coxwell Matthewman, Madeline, Dalton, Emma, Darko, Julia, Davari, Maria, Dave, Tejal, Deacon, Matthew, Deepak, Shantal, Edmond, Holly, Ellis, Jessica, El-Sayed, Ahmed, Eneje, Philip, English, Rose, Ewe, Renee, Foers, William, Franklin, John, Gallego, Laura, Garrett, Emily, Goldberg, Olivia, Goss, Harry, Greaves, Rosanna, Harris, Rudy, Hennings, Charle, Jones, Eleanor, Kamali, Nelson, Kokkinos, Naomi, Lewis, Cary, Lignos, Leda, Malgapo, Evaleen Victoria, Malik, Rizwana, Milne, Andrew, Mulligan, John-Patrick, Nicklin, Philippa, Palipane, Natasha, Parsons, Thoma, Piper, Rebecca, Prakash, Rohan, Ramesh, Byron, Rasip, Sarah, Reading, Jacob, Rela, Mariam, Reyes, Anna, Robert, Stephen, Rooms, Martin, Shah, Karishma, Simons, Henry, Solanki, Shalil, Spowart, Emma, Stevens, Amy, Thomas, Christopher, Waggett, Helena, Yassaee, Arrash, Kennedy, Anthony, Scott, Sara, Somanath, Sameer, Berg, Andrew, Hernandez, Miguel, Nanda, Rajesh, Tank, Ghanshyambhai, Wilson, Natalie, Wilson, Debbie, Al-Soudaine, Yassr, Baldwin, Matthew, Cornish, Julie, Davies, Zoe, Davies, Leigh, Edwards, Marc, Frewer, Natasha, Gallard, Sian, Glasbey, Jame, Harries, Rhiannon, Hopkins, Luke, Kim, Taeyang, Koompirochana, Vilavan, Lawson, Simon, Lewis, Megan, Makzal, Zaid, Scourfield, Sarah, Ahmad, Yousra, Bates, Sarah, Blackwell, Clare, Bryant, Helen, Coulter, Suzanne, Cruickshank, Ro, Daniel, Sonya, Daubeny, Thoma, Edwards, Mark, Golder, Kim, Hawkins, Lesley, Helen, Bryant, Hinxman, Honor, Levett, Denny, Skinner, Ben, Walsgrove, Joseph, Dickson, Jane, Constantin, Kathryn, Karen, Markwell, O’Brien, Peter, O’Donohoe, Lynn, Payne, Hannah, Sundayi, Saul, Walker, Elaine, Brooke, Jenny, Cardy, Jon, Humphreys, Sally, Kessack, Laura, Kubitzek, Christiane, Kumar, Suha, Cotterill, Donna, Hodzovic, Emil, Hosdurga, Gurunath, Miles, Edward, Saunders, Glenn, Campbell, Marta, Chan, Peter, Jemmett, Kim, Raj, Ashok, Naik, Aditi, Ramamoorthy, Rajarajan, Shah, Nimesh, Sylvan, Axel, Blyth, Katharine, Burtenshaw, Andrew, Freeman, David, Johnson, Emily, Lo, Philip, Martin, Terry, Plunkett, Emma, Wollaston, Julie, Allison, Joanna, Carroll, Christine, Craw, Nichola, Craw, Sarah, Pitt-Kerby, Tressy, Rowland-Axe, Rebecca, Spurdle, Katie, McDonald, Andrew, Simon, Davie, Sinha, Vivek, Smith, Thoma, Banner-Goodspeed, Valerie, Boone, Myle, Campbell, Kathleen, Lu, Fengxin, Scannell, Joseph, Sobol, Julia, Balajonda, Naraida, Clemmons, Karen, Conde, Carlo, Funk, Bonita, Hall, Roger, Hopkins, Thoma, Olaleye, Omowunmi, Omer, Omer, Pender, Michelle, Porto, Angelo, Stevens, Alice, Waweru, Peter, Yeh, Erlinda, Bodansky, Daniella, Evans, Adam, Kleopoulos, Steven, Maril, Robert, Mathney, Edward, Sanchez, Angela, Tinuoye, Elizabeth, Bateman, Brian, Eng, Kristen, Jiang, Ning, Ladha, Karim, Needleman, Joseph, Chen, Lee-lynn, Lane, Rondall, Robinowitz, David, Ghushe, Neil, Irshad, Mariam, Patel, Samir, Takemoto, Steven, Wallace, Art, Mazzeffi, Michael, Rock, Peter, Wallace, Karin, Zhu, Xiaomao, Chua, 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Male ,HSJ UCI ,Critical Care and Intensive Care Medicine ,law.invention ,Perioperative Care/methods ,0302 clinical medicine ,Surgical procedures ,030202 anesthesiology ,law ,Critical care/utilisation, Postoperative care/methods, Postoperative care/statistics and numerical data, Surgical procedures, operative/mortality ,statistics and numerical data ,Prospective Studies ,Postoperative Period ,Postoperative care/methods ,education.field_of_study ,Postoperative care/method ,Elective Surgical Procedures/mortality ,fluid output ,Middle Aged ,fluid administration ,Intensive care unit ,Hospitalization ,Length of Stay/statistics & numerical data ,operative/mortality ,Intensive Care Units/statistics & numerical data ,outcome ,Female ,Elective Surgical Procedure ,Human ,Adult ,medicine.medical_specialty ,Logistic Model ,Postoperative care/statistics and numerical data ,Critical care/utilisation ,Population ,Intensive Care Unit ,Elective Surgical Procedures/statistics & numerical data ,Hospitalization/statistics & numerical data ,Humans ,Logistic Models ,Surgical procedures, operative/mortality ,Postoperative care ,methods ,Perioperative Care ,NO ,03 medical and health sciences ,Anesthesiology ,Intensive care ,medicine ,Elective surgery ,Intensive care medicine ,education ,business.industry ,030208 emergency & critical care medicine ,Perioperative ,Length of Stay ,Clinical trial ,Prospective Studie ,septic shock ,business - Abstract
PURPOSE: As global initiatives increase patient access to surgical treatments, there is a need to define optimal levels of perioperative care. Our aim was to describe the relationship between the provision and use of critical care resources and postoperative mortality. METHODS: Planned analysis of data collected during an international 7-day cohort study of adults undergoing elective in-patient surgery. We used risk-adjusted mixed-effects logistic regression models to evaluate the association between admission to critical care immediately after surgery and in-hospital mortality. We evaluated hospital-level associations between mortality and critical care admission immediately after surgery, critical care admission to treat life-threatening complications, and hospital provision of critical care beds. We evaluated the effect of national income using interaction tests. RESULTS: 44,814 patients from 474 hospitals in 27 countries were available for analysis. Death was more frequent amongst patients admitted directly to critical care after surgery (critical care: 103/4317 patients [2%], standard ward: 99/39,566 patients [0.3%]; adjusted OR 3.01 [2.10-5.21]; p < 0.001). This association may differ with national income (high income countries OR 2.50 vs. low and middle income countries OR 4.68; p = 0.07). At hospital level, there was no association between mortality and critical care admission directly after surgery (p = 0.26), critical care admission to treat complications (p = 0.33), or provision of critical care beds (p = 0.70). Findings of the hospital-level analyses were not affected by national income status. A sensitivity analysis including only high-risk patients yielded similar findings. CONCLUSIONS: We did not identify any survival benefit from critical care admission following surgery. info:eu-repo/semantics/publishedVersion
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- 2017
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217. A mouse cytomegalovirus glycoprotein, gp34, forms a complex with folded class I MHC molecules in the ER which is not retained but is transported to the cell surface.
- Author
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Kleijnen, Maurits F., Huppa, Johannes B., Lucin, Pero, Mukherjee, Siddhartha, Farrell, Helen, Campbell, Ann E., Koszinowski, Ulrich H., Hill, Ann B., and Ploegh, Hidde L.
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CYTOMEGALOVIRUSES , *MAJOR histocompatibility complex , *ENDOPLASMIC reticulum , *GLYCOPROTEINS , *ANTIGEN presenting cells , *KILLER cells , *VIRUS diseases , *CANCER research - Abstract
Murine cytomegalovirus (MCMV) interferes with antigen presentation by means of retaining major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum (ER). Here we identify and characterize an MCMV-encoded glycoprotein, gp34, which tightly associates with properly conformed MHC class I molecules in the ER. Gp34 is synthesized in large quantities during MCMV infection and it leaves the ER only in association with MHC class I complexes. Many but not all class I molecules are retained in the ER during the early phase of MCMV infection, and we observe an inverse correlation between amounts of gp34 synthesized during the course of inflection and class I retention. An MCMV deletion mutant lacking several genes, including the gene encoding gp34, shows increased class I retention. Thus, MCMV gp34 may counteract class I retention, perhaps to decrease susceptibility of infected cells to recognition by natural killer cells. [ABSTRACT FROM AUTHOR]
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- 1997
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218. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries
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Ahmad, T, Bouwman, RA, Grigoras, I, Aldecoa, C, Hofer, C, Hoeft, A, Holt, P, Fleisher, LA, Buhre, W, Pearse, RM, Ferguson, M, MacMahon, M, Shulman, M, Cherian, R, Currow, H, Kanathiban, K, Gillespie, D, Pathmanathan, E, Phillips, K, Reynolds, J, Rowley, J, Douglas, J, Kerridge, R, Garg, S, Bennett, M, Jain, M, Alcock, D, Terblanche, N, Cotter, R, Leslie, K, Stewart, M, Zingerle, N, Clyde, A, Hambidge, O, Rehak, A, Cotterell, S, Huynh, WBQ, McCulloch, T, Ben-Menachem, E, Egan, T, Cope, J, Halliwell, R, Fellinger, P, Haisjackl, M, Haselberger, S, Holaubek, C, Lichtenegger, P, Scherz, F, Schmid, W, Hoffer, F, Cakova, V, Eichwalder, A, Fischbach, N, Klug, R, Schneider, E, Vesely, M, Wickenhauser, R, Grubmueller, KG, Leitgeb, M, Lang, F, Toro, N, Bauer, M, Laengle, F, Haberl, C, Mayrhofer, T, Trybus, C, Buerkle, C, Forstner, K, Germann, R, Rinoesl, H, Schindler, E, Trampitsch, E, Bogner, G, Dankl, D, Duenser, M, Fritsch, G, Gradwohl-Matis, I, Hartmann, A, Hoelzenbein, T, Jaeger, T, 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Amabra, Echem, Richard, Obasuyi, Bright, Onajin-Obembe, Bisola, Bandeira, Maria Expedito, Martins, Alda, Tomã©, Miguel, Costa, Ana Cristina Miranda Martin, Krystopchuk, Andriy, Branco, Teresa, Esteves, Simao, Melo, Marco António, Monte, Jãºlia, Rua, Fernando, Martins, Isabel, Pinho-Oliveira, VÃtor Miguel, Rodrigues, Carla Maria, Cabral, Raquel, Marques, Sofia, Rãªgo, Sara, Jesus, Joana Sofia Teixeira, Marques, Maria Conceição, Romao, Cristina, Dias, Sandra, Santos, Ana Margarida, Alves, Maria Joao, Salta, Cristina, Cruz, Salome, Duarte, Cã©lia, Paiva, António Armando Furtado, Do Nascimento Cabral, Tiago, Faria Maia, Dionisio, Correia Da Silva, Rui Freitas Mendonça, Langner, Anuschka, Resendes, Hernâni Oliveira, Da Conceição Soares, Maria, Abrunhosa, Alexandra, Faria, Filomena, Miranda, Lina, Pereira, Helena, Serra, Sofia, Ionescu, Daniela, Margarit, Simona, Mitre, Calin, Vasian, Horatiu, Manga, Gratiela, Stefan, Andreea, Tomescu, Dana, Filipescu, Daniela, Paunescu, Marilena-Alina, Stefan, Mihai, Stoica, Radu, Gavril, Laura, Pç trç å canu, Emilia, Ristescu, Irina, Rusu, Daniel, Diaconescu, Ciresica, Iosep, Gabriel Florin, Pulbere, Dorin, Ursu, Irina, Balanescu, Andreea, Grintescu, Ioana, Mirea, Liliana, Rentea, Irina, Vartic, Mihaela, Lupu, Mary-Nicoleta, Stanescu, Dorin, Streanga, Lavinea, Antal, Oana, Hagau, Natalia, Patras, Dumitru, Petrisor, Cristina, Tosa, Flaviu, Tranca, Sebastian, Copotoiu, Sanda Maria, Ungureanu, Liviu Lucian, Harsan, Cristian Remu, Papurica, Mariu, Cernea, Daniela Denisa, Dragoescu, Nicoleta Alice, Aflori, Laura, Vaida, Carmen, Ciobotaru, Oana Roxana, Aignatoaie, Mariana, Carp, Cristina Paula, Cobzaru, Isabelle, Mardare, Oana, Purcarin, Bianca, Tutunaru, Valentin, Ionita, Victor, Arustei, Mirela, Codita, Anisoara, Busuioc, Mihai, Chilinciuc, Ion, Ciobanu, Cristina, Belciu, Ioana, Tincu, Eugen, Blaj, Mihaela, Grosu, Ramona-Mihaela, Sandu, Gigel, Bruma, Dana, Corneci, Dan, Dutu, Madalina, Krepil, Adriana, Copaciu, Elena, Dumitrascu, Clementina Oana, Jemna, Ramona, Mihaescu, Florentina, Petre, Raluca, Tudor, Cristina, Ursache, Elena, Kulikov, Alexander, Lubnin, Andrey, Grigoryev, Evgeny, Pugachev, Stanislav, Protsenko, Deni, Tolmasov, Alexander, Hussain, Ayyaz, Ilyina, Yana, Kirov, Mikhail, Roshchina, Anna, Iurin, Aleksandr, Chazova, Elena, Dunay, Artem, Karelov, Alexey, Khvedelidze, Irina, Voldaeva, Olga, Belskiy, Vladislav, Dzhamullaev, Parvin, Grishkowez, Elena, Kretov, Vladimir, Levin, Valeriy, Molkov, Aleksandr, Puzanov, Sergey, Samoilenko, Aleksandr, Tchekulaev, Aleksandr, Tulupova, Valentina, Utkin, Ivan, Allorto, Nikki Leigh, Bishop, David Gray, Builu, Pierre Monji, Cairns, Carel, Dasrath, Ashish, De Wet, Jacque, Den Hoedt, Marielle, Grey, Ben, Hayes, Morgan Philip, Kã¼sel, Belinda Senta, Shangase, Nomcebo, Wise, Robert, Cacala, Sharon, Farina, Zane, Govindasamy, Vishendran, Kruse, Carl-Heinz, Lee, Carolyn, Marais, Leonard, Naidoo, Thinagrin Dhasarthun, Rajah, Chantal, Rodseth, Reitze Nil, Ryan, Lisa, Von Rhaden, Richard, Adam, Suwayba, Alphonsus, Christella, Ameer, Yusuf, Anderson, Frank, Basanth, Sujith, Bechan, Sudha, Bhula, Chettan, Biccard, Bruce M., Biyase, Thuli, Buccimazza, Ine, Cardosa, Jorge, Chen, Jame, Daya, Bhavika, Drummond, Leanne, Elabib, Ali, Goad, Ehab Helmy Abdel, Goga, Ismail E., Goga, Riaz, Harrichandparsad, R., Hodgson, Richard E., Jordaan, J., Kalafatis, Nicky, Kampik, Christian, Landers, A. T., Loots, Emil, Madansein, Rajhmum, Madaree, Anil, Madiba, Thandinkosi E., Manzini, Vukani T., Mbuyisa, Mbali, Moodley, Rajan, Msomi, Mduduzi, Mukama, Innocent, Naidoo, Desigan, Naidoo, Rubeshan, Naidu, Tesuven K., Ntloko, Sindiswa, Padayachee, Eneshia, Padayachee, Lucelle, Phaff, Martijn, Pillay, Bala, Pillay, Desigan, Pillay, Lutchmee, Ramnarain, Anupa, Ramphal, Suren R., Ryan, Paul, Saloojee, Ahmed, Sebitloane, Motshedisi, Sigcu, Noluyolo, Taylor, Jenna L., Torborg, Alexandra, Visser, Linda, Anderson, Philip, Conradie, Alae, De Swardt, Mathew, De Villiers, Martin, Eikman, Johan, Liebenberg, Riaan, Mouton, Johan, Paton, Abbey, Van Der Merwe, Louwrence, Wilscott-Davids, Candice, Barrett, Wendy Joan, Bester, Marlet, De Beer, Johan, Geldenhuys, Jacque, Gouws, Hanni, Potgieter, Jan-Hendrik, Strydom, Magdel, Wilberforceturton, Edwin, Chetty, Rubendraj R., Chirkut, Subash, Cronje, Larissa, De Vasconcellos, Kim, Dube, Nokukhanya Z., Gama, N. Sibusiso, Green, Garyth M., Green-Thompson, Randolph, Kinoo, Suman Mewa, Kistnasami, Prenolin, Maharaj, Kapil, Moodley, Manogaran S., Mothae, Sibongile J., Naidoo, Ruvashni, Noorbhai, M. Aslam F., Rughubar, Vivesh, Reddy, Jenendhiran, Singh, Avesh, Skinner, David L., Smith, Murray J., Singh, Bhagwan, Misra, Ravi, Naidoo, Maheshwar, Ramdharee, Pireshin, Selibea, Yvonne, Sewpersad, Selina, Sham, Shailendra, Wessels, Joseph D., Africander, Cucu, Bejia, Tarek, Blakemore, Stephen P., Botes, Marisa, Bunwarie, Bimalshakth, Hernandez, Carlos B., Jeeraz, Mohammud A., Legutko, Dagmara A., Lopez, Acela G., De Meyer, Jenine N., Muzenda, Tanaka, Naidoo, Noel, Patel, Maryam, Pentela, Rao, Junge, Marina, Mansoor, Naj, Rademan, Lana, Scislowski, Pawel, Seedat, Ismail, Van Den Berg, Bianca, Van Der Merwe, Doreen, Van Wyk, Steyn, Govender, Komalan, Naicker, Darshan, Ramjee, Rajesh, Saley, Mueen, Kuhn, Warren Paul, Matos-Puig, Roel, Moolla, Zaheer, Lisi, Alberto, Perez, Gisela, Beltran, Anna Valle, Lozano, Angel, Navarro, Carlos Delgado, Duca, Alejandro, Ernesto, Ernesto Pastor Martinez, Ferrando, Carlo, Fuentes, Isabel, GarcÃa-Pérez, Maria Luisa, Gracia, Estefania, Palomares, Ana Izquierdo, Katime, Antonio, Miã±ana, Amanda, Incertis, Raul Raul, Romero, Esther, Garcia, Carolina Soledad Romero, Rubio, Concepcion, Artiles, Tania Socorro, Soro, Marina, Valls, Paola, Laguarda, Gisela Alaman, Benavent, Pau, Cuenca, Vicente Chisbert, Cueva, Andreu, Lafuente, Matilde, Parra, Asuncion Marque, Rodrigo, Alejandra Romero, Sanchez-Morcillo, Silvia, Tormo, Sergi, Redondo, Francisco Javier, De Andres, Jose, Diago, Lorena Gómez, Cã¡diz, Maria José Hernández, Manuel, Granell Gil, Peris, Raquel, Saiz, Cristina, Tatay, Jose, Soto, Maria Teresa Tebar, Brunete, Tamara, Cancho, David, Garcãa, David R. 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Luz, Alonso, Eduardo, Anillo, Victor, Maseda, Emilio, Salgado, Patricia, Suarez, Lui, Suarez-De-La-Rica, Alejandro, Villagrã¡n, MarÃa José, Aldecoa, Cesar, Alonso, José Ignacio, Cabezuelo, Estefania, Garcia-Saiz, Irene, Del Moral, Olga Lopez, Martãn, Silvia, Gonzalez, Alba Perez, Doncel, Ma Sherezade Tovar, Vera, Martin Agüero, Sanchez, Francisco José à vila, Castaã±o, Beatriz, Moreira, Beatriz Castaño, Risco, Sahely Flore, Martãn, Daniel Paz, Martãn, Fernando Pérez, Poza, Paloma, Ruiz, Adela, Martãnez, Wilson Fabio Serna, Vicente, Bárbara Vázquez, Dominguez, Saul Velaz, Fernã¡ndez, Salvador, Munoz-López, Alfonso, Bernat, Maria Jose, Mas, Arantxa, Planas, Kenneth, Jawad, Monir, Saeed, Yousif, Hedin, Annika, Levander, Helena, Chew, Michelle, Holmstrã¶m, Sandra, Lonn, David, Zoerner, Frank, à kring, Irene, Widmark, Carl, Zettergren, Jan, Liljequist, Victor Aspelund, Nystrom, Lena, Odeberg-Wernerman, Suzanne, Oldner, Ander, Fagerlund, Malin Jonsson, Reje, Patrik, Lyckner, Sara, Sperber, Jesper, Adolfsson, Anne, Klarin, Bengt, à gren, Katrin, Barras, Jean-Pierre, Bã¼hrer, Thoma, Despotidis, Vasileio, Helmy, Naeder, Holliger, Stephan, Raptis, Dimitri Aristotle, Schmid, Roger, Meyer, Antoine, Jaquet, Yve, Kessler, Ulf, Muradbegovic, Mirza, Nahum, Solange R., Rotunno, Teresa, Schiltz, Bori, Voruz, Franã§oi, Worreth, Marc, Christoforidis, Dimitri, Popeskou, Sotirios Georgio, Furrer, Marku, Prevost, Gian Andrea, Stocker, Andrea, Lang, Klau, Breitenstein, Stefan, Ganter, Michael T., Geisen, Martin, Soll, Christopher, Korkmaz, Michelle, Lubach, Iri, Schmitz, Michael, Zu Schwabedissen, Moritz Meyer, Zu Schwabedissen Moritz, Meyer, Zingg, Ur, Hillermann, Thoma, Wildi, Stefan, Hofer, Christoph, Pinto, Bernardo Bollen, Walder, Bernhard, Hã¼bner, Martin, Mariotti, Giustina, Slankamenac, Ksenija, Namuyuga, Mirioce, Kyomugisha, Edward, Kituuka, Olivia, Shikanda, Anne Wesonga, Kakembo, Nasser, Tom, Charles Otim, Antonina, Webombesa, Bua, Emmanuel, Ditai, Jame, Ssettabi, Eden Michael, Epodoi, Joseph, Kabagenyi, Fiona, Kirya, Fred, Dempsey, Ged, Seasman, Colette, Khan, Raja Basit Nawaz, Kurasz, Claire, Macgregor, Mark, Shawki, Burhan, Francis, Daren, Hariharan, Vimal, Chau, Simon, Ellis, Kate, Butt, Georgina, Chicken, Dennis-Wayne, Christmas, Natasha, Allen, Samantha, Daniel, Gayatri Daniel, Dempster, Angie, Kemp, Juliette, Matthews, Lewi, Mcglone, Philip, Tambellini, Joanne, Trodd, Dawn, Freitas, Katie, Garg, Atul, Gupta, Janesh Kumar, Karpate, Shilpaja, Kulkarni, Aditi, O'Hara, Chloe, Troko, Jtroko, Angus, Kirsty, Bradley, Jacqueline, Brennan, Emma, Brooks, Carolyn, Brown, Janette, Brown, Gemma, Finch, Amanda, Gratrix, Karen, Hesketh, Sue, Hill, Gillian, Jeffs, Carol, Morgan, Maureen, Pemberton, Chri, Slawson, Nicola, Spickett, Helen, Swarbrick, Gemma, Thomas, Megan, Van Duyvenvoorde, Greta, Brennan, Andrew, Briscoe, Richard, Cooper, Sarah, Lawton, Tom, Northey, Martin, Senaratne, Rashmi, Stanworth, Helen, Burrows, Lorna, Cain, Helen, Craven, Rachael, Davies, Keith, Jonas, Attila, Pachucki, Marcin, Walkden, Graham, Davies, Helen, Gudaca, Mariethel, Hobrok, Maria, Arawwawala, Dilshan, Fergey, Lauren, Gardiner, Matthew, Gunn, Jacqueline, Johnson, Lyndsay, Lofting, Amanda, Lyle, Amanda, Mcneela, Fiona, Smolen, Susan, Topliffe, Joanne, Williams, Sarah, Bland, Martin, Balaji, Packianathaswamy, Kaura, Vika, Lanka, Prasad, Naylor, Charde, Smith, Neil, Ahmed, Ahmed, Myatt, John, Shenoy, Ravikiran, Soon, Wai Cheong, Tan, Jessica, Karadia, Sunny, Durant, Emma, Tripathi, Shiva, Bullock, Clare, Campbell, Debbie, Ghosh, Alison, Hughes, Thoma, Zsisku, Lajo, Bengeri, Sheshagiri, Cowton, Amanda, Khalid, Mohammed Shazad, Limb, Jame, Mcadam, Colin, Porritt, Mandy, Rafi, M. 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Denham, Samuel, Griffiths, Ewen, Peter, Ip, Jeyanthan, Somasundaram, Joory, Kavita, Kaur, Satwant, Marriott, Paul, Mitchell, Natalie, Nagaiah, Sukumar, Nilsson, Annette, Parekh, Nilesh, Pope, Martin, Seager, Joseph, Serag, Hosam, Tameem, Alifia, Thomas, Anna, Thunder, Joanne, Torrance, Andrew, Vohra, Ravinder, Whitehouse, Arlo, Wong, Tony, Blunt, Mark, Wong, Kate, Giles, Julian, Reed, Isabelle, Weller, Debbie, Bell, Gillian, Birch, Julie, Damant, Rose, Maiden, Jane, Mewies, Clare, Prince, Claire, Radford, Jane, Reynolds, Tim, Balain, Birender, Banerjee, Robin, Barnett, Andrew, Burston, Ben, Davies, Kirsty, Edwards, Jayne, Evans, Chri, Ford, David, Gallacher, Pete, Hill, Simon, Jaffray, David, Karlakki, Sudheer, Kelly, Cormac, Kennedy, Julia, Kiely, Nigel, Lewthwaite, Simon, Marquis, Chri, Ockendon, Matthew, Phillips, Stephen, Pickard, Simon, Richardson, Jame, Roach, Richard, Smith, Tony, Spencer-Jones, Richard, Steele, Niall, Steen, Julie, Van Liefland, Marck, White, Steve, Faulds, Matthew, Harris, Meredyth, Kelly, Carrie, Nicol, Scott, Pearson, Sally Anne, Chukkambotla, Srikanth, Andrew, Alyson, Attrill, Elizabeth, Campbell, Graham, Datson, Amanda, Fouracres, Anna, Graterol, Juan, Graves, Lynne, Hong, Bosun, Ishimaru, Alexander, Karthikeyan, Arvind, King, Helen, Lawson, Tom, Lee, Gregory, Lyons, Saoirse, Hall, Andrew Macalister, Mathoulin, Sophie, Mcintyre, Eilidh, Mclaughlin, Danny, Mulcahy, Kathleen, Paddle, Jonathan, Ratcliffe, Anna, Robbins, Jame, Sung, Weilin, Tayo, Adeoluwa, Trembath, Lisa, Venugopal, Suneetha, Walker, Robert, Wigmore, Geoffrey, Boereboom, Catherine, Downes, Charlotte, Humphries, Ryan, Melbourne, Susan, Smith, Coral, Tou, Samson, Ullah, Shafa, Batchelor, Nick, Boxall, Leigh, Broomby, Rupert, Deen, Tariq, Hellewell, Alistair, Helliwell, Laurence, Hutchings, Melanie, Hutchins, David, Keenan, Samantha, Mackie, Donna, Potter, Alison, Smith, France, Stone, Lucy, Thorpe, Kevin, Wassall, Richard, Woodgate, Andrew, Baillie, Shelley, Campbell, 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Williams, Alexandra, Daniel, Hull, Gregory, Peter, Husain, Tauqeer, Kirk-Bayley, Justin, Mathers, Edward, Montague, Laura, Harper, Mark, White, Stuart, Jack, Jame, Ridley, Carrie, Avis, Joanne, Cook, Tim, Dali-Kemmery, Lola, Kerslake, Ian, Lambourne, Victoria, Pearson, Annabel, Boyd, Christine, Callaghan, Mark, Lawson, Cathy, Mccrossan, Roopa, Nesbitt, Vanessa, O'Connor, Laura, Scott, Julia, Sinclair, Rhona, Farid, Nahla, Morgese, Ciro, Bhatia, Kailash, Karmarkar, Swati, Ahmed, Jamil, Branagan, Graham, Hutton, Monica, Swain, Andrew, Brookes, Jamie, Cornell, Jonathan, Dolan, Rachael, Hulme, Jonathan, Van Vuuren, Amanda Jansen, Jowitt, Tom, Kalashetty, Gunasheela, Lloyd, Fran, Patel, Kiran, Sherwood, Nichola, Brown, Lynne, Chandler, Ben, Deighton, Kerry, Emma, Temlett, Haunch, Kirsty, Cheeseman, Michelle, Dent, Kathy, Garg, Sanjeev, Gray, Carol, Hood, Marion, Jones, Dawn, Juj, Joanne, Rao, Roshan, Walker, Tara, Al Anizi, Mashel, Cheah, Clarissa, Cheing, Yushio, Coutinho, Francisco, Gondo, Prisca, Hadebe, Bernard, Hove, Mazvangu Onie, Khader, Ahamed, Krishnachetty, Bobby, Rhodes, Karen, Sokhi, Jagdish, Baker, Katie-Anne, Bertram, Wendy, Looseley, Alex, Mouton, Ronelle, Hanna, George, Arnold, Glenn, Arya, Shobhit, Balfoussia, Danai, Baxter, Linden, Harris, Jame, Jones, Craig, Knaggs, Alison, Markar, Sheraz, Perera, Anisha, Scott, Alasdair, Shida, Asako, Sirha, Ravneet, Wright, Sally, Frost, Victoria, Gray, Catherine, Andrews, Emma, Arrandale, Lindsay, Barrett, Stephen, Cifra, Elna, Cooper, Mariese, Dragnea, Drago, Elna, Cifra, Maclean, Jennifer, Meier, Sonja, Milliken, Donald, Munns, Christopher, Ratanshi, Nadir, Ramessur, Suneil, Salvana, Abegail, Watson, Anthony, Hani, Ali, Campbell, Gill, Critchley, Rebecca, Endersby, Simon, Hicks, Catherine, Liddle, Alison, Pass, Marc, Ritchie, Charlotte, Thomas, Charlotte, Too, Lingxi, Welsh, Sarah, Gill, Talvinder, Johnson, Joanne, Reed, Joanne, Davis, Edward, Papadopoullos, Sam, Attwood, Clare, Biffen, Andrew, Boulton, Kerenza, Gray, Sophie, Hay, David, Mills, Sarah, Montgomery, Jane, Riddell, Rory, Simpson, Jame, Bhardwaj, Neeraj, Paul, Elaine, Uwubamwen, Nosakhare, Alexander, Maini, Arrich, Jame, Arumugam, Swarna, Blackwood, Dougla, Boggiano, Victoria, Brown, Robyn, Chan, Yik Lam, Chatterjee, Devnandan, Chhabra, Ashok, Christian, Rachel, Costelloe, Hannah, Matthewman, Madeline Coxwell, Dalton, Emma, Darko, Julia, Davari, Maria, Dave, Tejal, Deacon, Matthew, Deepak, Shantal, Edmond, Holly, Ellis, Jessica, El-Sayed, Ahmed, Eneje, Philip, English, Rose, Ewe, Renee, Foers, William, Franklin, John, Gallego, Laura, Garrett, Emily, Goldberg, Olivia, Goss, Harry, Greaves, Rosanna, Harris, Rudy, Hennings, Charle, Jones, Eleanor, Kamali, Nelson, Kokkinos, Naomi, Lewis, Cary, Lignos, Leda, Malgapo, Evaleen Victoria, Malik, Rizwana, Milne, Andrew, Mulligan, John-Patrick, Nicklin, Philippa, Palipane, Natasha, Parsons, Thoma, Piper, Rebecca, Prakash, Rohan, Ramesh, Byron, Rasip, Sarah, Reading, Jacob, Rela, Mariam, Reyes, Anna, Robert, Stephen, Rooms, Martin, Shah, Karishma, Simons, Henry, Solanki, Shalil, Spowart, Emma, Stevens, Amy, Thomas, Christopher, Waggett, Helena, Yassaee, Arrash, Kennedy, Anthony, Scott, Sara, Somanath, Sameer, Berg, Andrew, Miguel, Hernandez, Nanda, Rajesh, Tank, Ghanshyambhai, Wilson, Natalie, Wilson, Debbie, Al-Soudaine, Yassr, Baldwin, Matthew, Cornish, Julie, Davies, Zoe, Davies, Leigh, Edwards, Marc, Frewer, Natasha, Gallard, Sian, Glasbey, Jame, Harries, Rhiannon, Hopkins, Luke, Kim, Taeyang, Koompirochana, Vilavan, Lawson, Simon, Lewis, Megan, Makzal, Zaid, Scourfield, Sarah, Ahmad, Yousra, Bates, Sarah, Blackwell, Clare, Bryant, Helen, Collins, Hannah, Coulter, Suzanne, Cruickshank, Ro, Daniel, Sonya, Daubeny, Thoma, Edwards, Mark, Golder, Kim, Hawkins, Lesley, Helen, Bryant, Hinxman, Honor, Levett, Denny, Salmon, Karen, Seaward, Leanne, Skinner, Ben, Tyrell, Bryony, Wadams, Beverley, Walsgrove, Joseph, Dickson, Jane, Constantin, Kathryn, Karen, Markwell, O'Brien, Peter, O'Donohoe, Lynn, Payne, Hannah, Sundayi, Saul, Walker, Elaine, Brooke, Jenny, Cardy, Jon, Humphreys, Sally, Kessack, Laura, Kubitzek, Christiane, Kumar, Suha, Cotterill, Donna, Hodzovic, Emil, Hosdurga, Gurunath, Miles, Edward, Saunders, Glenn, Campbell, Marta, Chan, Peter, Jemmett, Kim, Raj, Ashok, Naik, Aditi, Oshowo, Ayo, Ramamoorthy, Rajarajan, Shah, Nimesh, Sylvan, Axel, Blyth, Katharine, Burtenshaw, Andrew, Freeman, David, Johnson, Emily, Philip, Lo, Martin, Terry, Plunkett, Emma, Wollaston, Julie, Allison, Joanna, Carroll, Christine, Craw, Nichola, Craw, Sarah, Pitt-Kerby, Tressy, Rowland-Axe, Rebecca, Spurdle, Katie, Mcdonald, Andrew, Simon, Davie, Sinha, Vivek, Smith, Thoma, Banner-Goodspeed, Valerie, Boone, Myle, Campbell, Kathleen, Fengxin, Lu, Scannell, Joseph, Sobol, Julia, Balajonda, Naraida, Clemmons, Karen, Conde, Carlo, Elgasim, Magdi, Funk, Bonita, Hall, Roger, Hopkins, Thoma, Olaleye, Omowunmi, Omer, Omer, Pender, Michelle, Porto, Angelo, Stevens, Alice, Waweru, Peter, Yeh, Erlinda, Bodansky, Daniella, Evans, Adam, Kleopoulos, Steven, Maril, Robert, Mathney, Edward, Sanchez, Angela, Tinuoye, Elizabeth, Bateman, Brian, Eng, Kristen, Jiang, Ning, Ladha, Karim, Needleman, Joseph, Chen, Lee-Lynn, Lane, Rondall, Robinowitz, David, Ghushe, Neil, Irshad, Mariam, O'Connor, John, Patel, Samir, Myles, Paul, Hiesmayr, Michael, Fang, Xiangming, Slim, Karem, Sander, Michael, Koulenti, Despoina, Chan, Mathew, Abbas, Muntadhar, Sivasakthi, Datin, Osinaike, Tunde, Matos, Ricardo, Grigoras, Ioana, Hubner, Martyn, Other departments, The International Surgical Outcomes Study, Group, Beretta, L, Landoni, G, and Zangrillo, A
- Subjects
Critical Care/utilization ,Postoperative Complications/epidemiology ,Male ,cohort studies, critical care/utilisation, operative/mortality, postoperative care/methods, postoperative care/statistics and numerical data, surgery, surgical procedures ,Global Health ,law.invention ,surgery ,Postoperative Complications ,0302 clinical medicine ,Correction Notice ,cohort studies ,Anesthesiology ,030202 anesthesiology ,law ,cohort studiescritical care/utilisationoperative/mortalitypostoperative care/methodspostoperative care/statistics and numerical datasurgerysurgical procedures ,80 and over ,Hospital Mortality ,Prospective Studies ,030212 general & internal medicine ,Prospective cohort study ,Aged, 80 and over ,International Surgical Outcomes Study group ,Elective Surgical Procedures/mortality ,HCC NEF ,Middle Aged ,Elective Surgical Procedures/adverse effects ,Intensive care unit ,surgical procedure ,3. Good health ,Treatment Outcome ,Length of Stay/statistics & numerical data ,operative/mortality ,Elective Surgical Procedures ,Female ,Elective Surgical Procedure ,Life Sciences & Biomedicine ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Critical Care ,critical care/utilisation ,postoperative care/methods ,postoperative care/statistics and numerical data ,surgical procedures ,Aged ,Humans ,Length of Stay ,Poverty ,Socioeconomic Factors ,Young Adult ,Anesthesiology and Pain Medicine ,NO ,Clinical Practice ,03 medical and health sciences ,Intensive care ,Journal Article ,medicine ,postoperative care/method ,Elective surgery ,Science & Technology ,business.industry ,Postoperative complication ,030208 emergency & critical care medicine ,1103 Clinical Sciences ,Surgery ,Global Health/statistics & numerical data ,Emergency medicine ,business ,cohort studie - Abstract
Background:As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. Methods:We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. Results:A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44814 patients with a median hospital stay of 4 (range 2–7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. Conclusions:Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. Study registration:ISRCTN51817007
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- 2016
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219. LETTERS.
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FISKE, HEIDI, KRATZ, RALPH HUESTON, TAUSTINE, GARY, SCHNEIDERMAN, HOWARD, TRUFELMAN, LLOYD, FARRELL, HELEN M., FURSTENBERG, FRANçOIS, OBERSCHALL, TONY, and STASCH, STANLEY F.
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- *
CASINO personnel , *MINIMUM wage , *TELEPHONE calls -- Law & legislation - Abstract
Several letters to the editor are presented in response to articles in the December 2013 issues including "Living Wage Ruling Gives Queens Casino Workers a Fighting Chance" in the December 23 issue, "A Judge Upholds N.S.A. Collection of Data on Calls" in the December 28 issue, and "12 Years of Mayor Bloomberg" in the Dece,ber 29 issue.
- Published
- 2013
220. Mouse cytomegalovirus lacking sgg1 shows reduced import into the salivary glands.
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Ma J, Bruce K, Stevenson PG, and Farrell HE
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- Animals, Mice, Viral Tropism, Myeloid Cells virology, Myeloid Cells metabolism, Viral Proteins genetics, Viral Proteins metabolism, Herpesviridae Infections virology, Chemokines, CC, Salivary Glands virology, Muromegalovirus genetics, Muromegalovirus physiology
- Abstract
Cytomegaloviruses (CMVs) transmit via chronic shedding from the salivary glands. How this relates to the broad cell tropism they exhibit in vitro is unclear. Human CMV (HCMV) infection presents only after salivary gland infection is established. Murine CMV (MCMV) is therefore useful to analyse early infection events. It reaches the salivary glands via infected myeloid cells. Three adjacent spliced genes designated as m131/129 (MCK-2), sgg1 and sgg1.1, positional homologues of the HCMV UL128/130/131 tropism determinants, are implicated. We show that a sgg1 null mutant is defective in infected myeloid cell entry into the salivary glands, a phenotype distinct from MCMV lacking MCK-2. These data point to a complex, multi-step process of salivary gland colonization.
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- 2024
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221. Indirect CD4 + T cell protection against persistent MCMV infection by NK cells requires IFNγ.
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Xie W, Bruce K, Stevenson PG, and Farrell HE
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- Mice, Animals, T-Lymphocytes, Cytoprotection, Killer Cells, Natural, CD4-Positive T-Lymphocytes, Mice, Inbred C57BL, Muromegalovirus, Cytomegalovirus Infections
- Abstract
Host control of mouse cytomegalovirus (MCMV) infection of MHCII
- salivary gland acinar cells is mediated by CD4+ T cells, but how they protect is unclear. Here, we show CD4+ T cells control MCMV indirectly in the salivary gland, via IFNγ engagement with uninfected, but antigen+ MHCII+ APC and recruitment of NK cells to infected cell foci. This immune mechanism renders direct contact of CD4+ T cells with infected cells unnecessary and may represent a host strategy to overcome viral immune evasion.- Published
- 2024
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222. Statement in Support of: "Virology under the Microscope-a Call for Rational Discourse".
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Speck P, Mackenzie J, Bull RA, Slobedman B, Drummer H, Fraser J, Herrero L, Helbig K, Londrigan S, Moseley G, Prow N, Hansman G, Edwards R, Ahlenstiel C, Abendroth A, Tscharke D, Hobson-Peters J, Kriiger-Loterio R, Parry R, Marsh G, Harding E, Jacques DA, Gartner MJ, Lee WS, McAuley J, Vaz P, Sainsbury F, Tate MD, Sinclair J, Imrie A, Rawlinson S, Harman A, Carr JM, Monson EA, Hibma M, Mahony TJ, Tu T, Center RJ, Shrestha LB, Hall R, Warner M, Ward V, Anderson DE, Eyre NS, Netzler NE, Peel AJ, Revill P, Beard M, Legione AR, Spencer AJ, Idris A, Forwood J, Sarker S, Purcell DFJ, Bartlett N, Deerain JM, Brew BJ, Asgari S, Farrell H, Khromykh A, Enosi Tuipulotu D, Anderson D, Mese S, Tayyar Y, Edenborough K, Uddin JM, Hussain A, Daymond CJI, Agius J, Johnson KN, Shirmast P, Abedinzadeshahri M, MacDiarmid R, Ashley CL, Laws J, Furfaro LL, Burton TD, Johnson SMR, Telikani Z, Petrone M, Roby JA, Samer C, Suhrbier A, Van Der Kamp A, Cunningham A, Donato C, Mahar J, Black WD, Vasudevan S, Lenchine R, Spann K, Rawle DJ, Rudd P, Neil J, Kingston R, Newsome TP, Kim KW, Mak J, Lowry K, Bryant N, Meers J, Roberts JA, McMillan N, Labzin LI, Slonchak A, Hugo LE, Henzeler B, Newton ND, David CT, Reading PC, Esneau C, Briody T, Nasr N, McNeale D, McSharry B, Fakhri O, Horsburgh BA, Logan G, Howley P, and Young P
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- Humans, SARS-CoV-2, Microscopy, COVID-19
- Abstract
Competing Interests: The authors declare a conflict of interest. P Speck owns shares in DFU Solutions Pty Ltd. D Tscharke is a paid consultant of Sementis Ltd. A Spencer is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. P Howley is co-founder, shareholder and managing director of VAXMED Pty Ltd., and an inventor of intellectual property owned by Sementis Ltd and VAXMED Pty Ltd. N Prow is a paid consultant of VAXMED Pty Ltd.
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- 2023
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223. The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection.
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Bonavita CM, White TM, Francis J, Farrell HE, Davis-Poynter NJ, and Cardin RD
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- Humans, Animals, Mice, Receptors, Chemokine genetics, Viral Proteins metabolism, Cytomegalovirus physiology, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Muromegalovirus physiology, Myocarditis, Cytomegalovirus Infections, Heart Diseases
- Abstract
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects the majority of the world population and causes lifelong latent infection. HCMV has been shown to exacerbate cardiovascular diseases, including myocarditis, vascular sclerosis, and transplant vasculopathy. Recently, we have shown that murine CMV (MCMV) recapitulates the cardiovascular dysfunction observed in patients with HCMV-induced myocarditis. To understand the viral mechanisms involved in CMV-induced heart dysfunction, we further characterized cardiac function in response to MCMV and examined virally encoded G-protein-coupled receptor homologs (vGPCRs) US28 and M33 as potential factors that promote infection in the heart. We hypothesized that the CMV-encoded vGPCRs could exacerbate cardiovascular damage and dysfunction. Three viruses were used to evaluate the role of vGPCRs in cardiac dysfunction: wild-type MCMV, a M33-deficient virus (∆M33), and a virus with the M33 open reading frame (ORF) replaced with US28, an HCMV vGPCR (i.e., US28+). Our in vivo studies revealed that M33 plays a role in promoting cardiac dysfunction by increasing viral load and heart rate during acute infection. During latency, ΔM33-infected mice demonstrated reduced calcification, altered cellular gene expression, and less cardiac hypertrophy compared with wild-type MCMV-infected mice. Ex vivo viral reactivation from hearts was less efficient in ΔM33-infected animals. HCMV protein US28 expression restored the ability of the M33-deficient virus to reactivate from the heart. US28+ MCMV infection caused damage to the heart comparable with wild-type MCMV infection, suggesting that the US28 protein is sufficient to complement the function of M33 in the heart. Altogether, these data suggest a role for vGPCRs in viral pathogenesis in the heart and thus suggest that vGPCRs promote long-term cardiac damage and dysfunction.
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- 2023
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224. The CMV-encoded G protein-coupled receptors M33 and US28 play pleiotropic roles in immune evasion and alter host T cell responses.
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White TM, Bonavita CM, Stanfield BA, Farrell HE, Davis-Poynter NJ, and Cardin RD
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- Humans, Animals, Mice, Virus Latency physiology, Cytomegalovirus physiology, Receptors, G-Protein-Coupled, CD8-Positive T-Lymphocytes, Immune Evasion, Cytomegalovirus Infections genetics
- Abstract
Introduction: Human cytomegalovirus (HCMV) is a global health threat due to its ubiquity and lifelong persistence in infected people. During latency, host CD8
+ T cell responses to HCMV continue to increase in a phenomenon known as memory inflation. We used murine CMV (MCMV) as a model for HCMV to characterize the memory inflation response to wild-type MCMV (KP) and a latency-defective mutant (ΔM33stop ), which lacks M33, an MCMV chemokine receptor homolog. M33 is essential for normal reactivation from latency and this was leveraged to determine whether reactivation in vivo contributes to T cell memory inflation., Methods: Mice were infected with wild-type or mutant MCMV and T cell responses were analyzed by flow cytometry at acute and latent time points. Ex vivo reactivation and cytotoxicity assays were carried out to further investigate immunity and virus replication. Quantitative reverse-transcriptase polymerase chain reaction (q-RTPCR) was used to examine gene expression during reactivation. MHC expression on infected cells was analyzed by flow cytometry. Finally, T cells were depleted from latently-infected B cell-deficient mice to examine the in vivo difference in reactivation between wild-type and ΔM33stop ., Results: We found that ΔM33stop triggers memory inflation specific for peptides derived from the immediate-early protein IE1 but not the early protein m164, in contrast to wild-type MCMV. During ex vivo reactivation, gene expression in DM33stop-infected lung tissues was delayed compared to wild-type virus. Normal gene expression was partially rescued by substitution of the HCMV US28 open reading frame in place of the M33 gene. In vivo depletion of T cells in immunoglobulin heavy chain-knockout mice resulted in reactivation of wild-type MCMV, but not ΔM33stop , confirming the role of M33 during reactivation from latency. Further, we found that M33 induces isotype-specific downregulation of MHC class I on the cell surface suggesting previously unappreciated roles in immune evasion., Discussion: Our results indicate that M33 is more polyfunctional than previously appreciated. In addition to its role in reactivation, which had been previously described, we found that M33 alters viral gene expression, host T cell memory inflation, and MHC class I expression. US28 was able to partially complement most functions of M33, suggesting that its role in HCMV infection may be similarly pleotropic., Competing Interests: Author RC is employed by Pfizer, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 White, Bonavita, Stanfield, Farrell, Davis-Poynter and Cardin.)- Published
- 2022
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225. Recent Advancements in Understanding Primary Cytomegalovirus Infection in a Mouse Model.
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Bruce K, Ma J, Lawler C, Xie W, Stevenson PG, and Farrell HE
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- Animals, Antiviral Agents, Cytomegalovirus, Disease Models, Animal, Humans, Mice, Cytomegalovirus Infections, Herpesviridae Infections, Muromegalovirus
- Abstract
Animal models that mimic human infections provide insights in virus-host interplay; knowledge that in vitro approaches cannot readily predict, nor easily reproduce. Human cytomegalovirus (HCMV) infections are acquired asymptomatically, and primary infections are difficult to capture. The gap in our knowledge of the early events of HCMV colonization and spread limits rational design of HCMV antivirals and vaccines. Studies of natural infection with mouse cytomegalovirus (MCMV) have demonstrated the olfactory epithelium as the site of natural colonization. Systemic spread from the olfactory epithelium is facilitated by infected dendritic cells (DC); tracking dissemination uncovered previously unappreciated DC trafficking pathways. The olfactory epithelium also provides a unique niche that supports efficient MCMV superinfection and virus recombination. In this review, we summarize recent advances to our understanding of MCMV infection and spread and the tissue-specific mechanisms utilized by MCMV to modulate DC trafficking. As these mechanisms are likely conserved with HCMV, they may inform new approaches for preventing HCMV infections in humans.
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- 2022
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226. Increasing anticipated and anticipatory pleasure through episodic thinking.
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Hallford DJ, Farrell H, and Lynch E
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- Adult, Forecasting, Humans, Imagery, Psychotherapy, Memory, Episodic, Pleasure
- Abstract
Episodic future thinking for positive future events is known to evoke positive affect. We aimed to assess whether it specifically evokes anticipated and anticipatory pleasure for future events, and behavioral intention. As a secondary aim, we examined if this differed compared to a condition of thinking of positive past events. In two studies, participants nominated 5 upcoming positive events and 5 positive past events. They then completed guided episodic thinking of past events and guided episodic thinking of future events. After guided episodic thinking, they rated the nominated future events on detail/vividness, mental imagery, anticipated and anticipatory pleasure, and behavioral intention. In Study 1 ( N = 32, M age = 37.0, SD = 19.7), increases on all variables were found relative to baseline, although expected pleasure was at trend level. There were no significant differences between future and past conditions. In Study 2 ( N = 29, M age = 38.4, SD = 16.3), participants were asked to nominate future events that were not already planned, and perceived control was also assessed. Again, increases in detail/vividness, mental imagery, and anticipated and anticipatory pleasure were found, this time with stronger effects for the future condition. No change was found for perceived control or intention. In both studies, increases in detail/vividness, mental imagery, and anticipated and anticipatory pleasure were generally positively correlated with increases in behavioral intention. This study provides evidence that guided episodic thinking increases anticipated and anticipatory pleasure for positive future events. Clinical implications, particularly in depression and schizophrenia-spectrum disorders, are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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- 2022
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227. The Mouse Cytomegalovirus G Protein-Coupled Receptor Homolog, M33, Coordinates Key Features of In Vivo Infection via Distinct Components of Its Signaling Repertoire.
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Ma J, Bruce K, Davis-Poynter N, Stevenson PG, and Farrell HE
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- Animals, Cyclic AMP Response Element-Binding Protein metabolism, Dendritic Cells virology, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, Herpesviridae Infections metabolism, Lymph Nodes virology, Mice, Mice, Inbred BALB C, Muromegalovirus genetics, Muromegalovirus metabolism, Mutation, Phospholipase C beta metabolism, Receptors, G-Protein-Coupled genetics, Salivary Glands virology, Signal Transduction, Viral Proteins genetics, Viremia metabolism, Viremia virology, Virus Activation genetics, Herpesviridae Infections virology, Muromegalovirus physiology, Receptors, G-Protein-Coupled metabolism, Viral Proteins metabolism
- Abstract
Common to all cytomegalovirus (CMV) genomes analyzed to date is the presence of G protein-coupled receptors (GPCR). Animal models of CMV provide insights into their role in viral fitness. The mouse cytomegalovirus (MCMV) GPCR, M33, facilitates dendritic cell (DC)-dependent viremia, the extravasation of blood-borne infected DCs to the salivary gland, and the frequency of reactivation events from latently infected tissue explants. Constitutive G protein-coupled M33 signaling is required for these phenotypes, although the contribution of distinct biochemical pathways activated by M33 is unknown. M33 engages G
q/11 to constitutively activate phospholipase C β (PLCβ) and downstream cyclic AMP response-element binding protein (CREB) in vitro . Identification of a MCMV M33 mutant (M33ΔC38 ) for which CREB signaling was disabled but PLCβ activation was preserved provided the opportunity to investigate their relevance in vivo . Following intranasal infection with MCMV M33ΔC38 , the absence of M33 CREB Gq/11 -dependent signaling correlated with reduced mobilization of lytically-infected DCs to the draining lymph node high endothelial venules (HEVs) and reduced viremia compared with wild type MCMV. In contrast, M33ΔC38 -infected DCs within the vascular compartment extravasated to the salivary glands via a pertussis toxin-sensitive, Gi/o -dependent, and CREB-independent mechanism. In the context of MCMV latency, spleen explants from M33ΔC38 -infected mice were markedly attenuated for reactivation. Taken together, these data demonstrate that key features of the MCMV life cycle are coordinated in diverse tissues by distinct pathways of the M33 signaling repertoire. IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular "switches" that regulate the cellular response to environmental stimuli. All cytomegalovirus (CMV) genomes analyzed to date possess GPCR homologs with phylogenetic evidence for independent gene capture events, signifying important in vivo roles. The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and the establishment and/or reactivation of latent MCMV infection. The signaling repertoire of M33 is distinct from cellular GPCRs and little is known of the relevance of component signaling pathways for in vivo M33 function. In this report, we showed that temporal and tissue-specific M33 signaling was required to facilitate in vivo infection. Understanding the relevance of the viral GPCR signaling profiles for in vivo function will provide opportunities for future targeted interventions.- Published
- 2022
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228. Constitutive Signaling by the Human Cytomegalovirus G Protein Coupled Receptor Homologs US28 and UL33 Enables Trophoblast Migration In Vitro.
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Davis-Poynter N and Farrell HE
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- Cell Line, Chemokine CX3CL1 metabolism, Cytomegalovirus physiology, Humans, NF-kappa B metabolism, Protein Binding, Receptors, G-Protein-Coupled metabolism, Cytomegalovirus metabolism, Receptors, Chemokine metabolism, Signal Transduction, Trophoblasts metabolism, Viral Proteins metabolism
- Abstract
Human cytomegalovirus (HCMV) encodes four homologs of G protein coupled receptors (vGPCRs), of which two, designated UL33 and US28, signal constitutively. UL33 and US28 are also conserved with chemokine receptors: US28 binds numerous chemokine classes, including the membrane bound chemokine, fractalkine; whereas UL33 remains an orphan receptor. There is emerging data that UL33 and US28 each contribute to HCMV associated disease, although no studies to date have reported their potential contribution to aberrant placental physiology that has been detected with HCMV congenital infection. We investigated the signaling repertoire of UL33 and US28 and their potential to enable trophoblast mobilization in vitro. Results demonstrate the constitutive activation of CREB by each vGPCR in ACIM-88 and HTR-8SVneo trophoblasts; constitutive NF-kB activation was detected for US28 only. Constitutive signaling by each vGPCR enabled trophoblast migration. For US28, fractalkine exhibited inverse agonist activity and dampened trophoblast migration. UL33 stimulated expression of both p38 mitogen activated (MAP) and Jun N-terminal (JNK) kinases; while p38 MAP kinase stimulated CREB, JNK was inhibitory, suggesting that UL33 dependent CREB activation was regulated by p38/JNK crosstalk. Given that chemokines and their receptors are important for placental development, these data point to the potential of HCMV UL33 and US28 to interfere with trophoblast responses which are important for normal placental development.
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- 2022
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229. A Live Olfactory Mouse Cytomegalovirus Vaccine, Attenuated for Systemic Spread, Protects against Superinfection.
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Farrell HE, Bruce K, and Stevenson PG
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- Animals, Cytomegalovirus Infections immunology, Cytomegalovirus Vaccines administration & dosage, Female, Immunity, Innate, Mice, Mice, Inbred BALB C, Nose virology, Proof of Concept Study, Vaccination methods, Vaccines, Attenuated, Cytomegalovirus immunology, Cytomegalovirus Infections prevention & control, Cytomegalovirus Vaccines immunology, Muromegalovirus immunology, Olfactory Mucosa virology, Superinfection prevention & control, Superinfection virology
- Abstract
Vaccination against the betaherpesvirus, human cytomegalovirus (HCMV) is a public health goal. However, HCMV has proved difficult to vaccinate against. Vaccination against single HCMV determinants has not worked, suggesting that immunity to a wider antigenic profile may be required. Live attenuated vaccines provide the best prospects for protection, but the question remains as to how to balance vaccine virulence with safety. Animal models of HCMV infection provide insights into identifying targets for virus attenuation and understanding how host immunity blocks natural, mucosal infection. Here, we evaluated the vaccine potential of a mouse cytomegalovirus (MCMV) vaccine deleted of a viral G protein-coupled receptor (GPCR), designated M33, that renders it attenuated for systemic spread. A single noninvasive olfactory ΔM33 MCMV vaccine replicated locally, but as a result of the loss of the M33 GPCR, it failed to spread systemically and was attenuated for latent infection. Vaccination did not prevent host entry of a superinfecting MCMV but spread from the mucosa was blocked. This approach to vaccine design may provide a viable alternative for a safe and effective betaherpesvirus vaccine. IMPORTANCE Human cytomegalovirus (HCMV) is the most common cause of congenital infection for which a vaccine is not yet available. Subunit vaccine candidates have failed to achieve licensure. A live HCMV vaccine may prove more efficacious, but it faces safety hurdles which include its propensity to persist and to establish latency. Understanding how pathogens infect guide rational vaccine design. However, HCMV infections are asymptomatic and thus difficult to capture. Animal models of experimental infection provide insight. Here, we investigated the vaccine potential of a mouse cytomegalovirus (MCMV) attenuated for systemic spread and latency. We used olfactory vaccination and virus challenge to mimic its natural acquisition. We provide proof of concept that a single olfactory MCMV that is deficient in systemic spread can protect against wild-type MCMV superinfection and dissemination. This approach of deleting functional counterpart genes in HCMV may provide safe and effective vaccination against congenital HCMV disease.
- Published
- 2021
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230. Murine Cytomegalovirus MCK-2 Facilitates In Vivo Infection Transfer from Dendritic Cells to Salivary Gland Acinar Cells.
- Author
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Ma J, Bruce K, Stevenson PG, and Farrell HE
- Subjects
- Acinar Cells metabolism, Animals, Chemokines, CC genetics, Dendritic Cells metabolism, Female, Herpesviridae Infections genetics, Herpesviridae Infections metabolism, Macrophages, Alveolar metabolism, Macrophages, Alveolar virology, Mice, Mice, Inbred BALB C, Salivary Glands metabolism, Viral Proteins genetics, Virion, Virus Internalization, Acinar Cells virology, Chemokines, CC metabolism, Dendritic Cells virology, Herpesviridae Infections virology, Muromegalovirus physiology, Salivary Glands virology, Viral Proteins metabolism, Virus Replication
- Abstract
The cytomegaloviruses (CMVs) spread systemically via myeloid cells and demonstrate broad tissue tropism. Human CMV (HCMV) UL128 encodes a component of the virion pentameric complex (PC) that is important for entry into epithelial cells and cell-cell spread in vitro . It possesses N-terminal amino acid sequences similar to those of CC chemokines. While the species specificity of HCMV precludes confirmation of UL128 function in vivo , UL128-like counterparts in experimental animals have demonstrated a role in salivary gland infection. How they achieve this has not been defined, although effects on monocyte tropism and immune evasion have been proposed. By tracking infected cells following lung infection, we show that although the UL128-like protein in mouse CMV (MCMV) (designated MCK-2) facilitated entry into lung macrophages, it was dispensable for subsequent viremia mediated by CD11c
+ dendritic cells (DCs) and extravasation to the salivary glands. Notably, MCK-2 was important for the transfer of MCMV infection from DCs to salivary gland acinar epithelial cells. Acinar cell infection of MCMVs deleted of MCK-2 was not rescued by T-cell depletion, arguing against an immune evasion mechanism for MCK-2 in the salivary glands. In contrast to lung infection, peritoneal MCMV inoculation yields mixed monocyte/DC viremia. In this setting, MCK-2 again promoted DC-dependent infection of salivary gland acinar cells, but it was not required for monocyte-dependent spread to the lung. Thus, the action of MCK-2 in MCMV spread was specific to DC-acinar cell interactions. IMPORTANCE Cytomegaloviruses (CMVs) establish myeloid cell-associated viremias and persistent shedding from the salivary glands. In vitro studies with human CMV (HCMV) have implicated HCMV UL128 in epithelial tropism, but its role in vivo is unknown. Here, we analyzed how a murine CMV (MCMV) protein with similar physical properties, designated MCK-2, contributes to host colonization. We demonstrate that MCK-2 is dispensable for initial systemic spread from primary infection sites but within the salivary gland facilitates the transfer of infection from dendritic cells (DCs) to epithelial acinar cells. Virus transfer from extravasated monocytes to the lungs did not require MCK-2, indicating a tissue-specific effect. These results provide new information about how persistent viral tropism determinants operate in vivo .- Published
- 2021
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231. Defining a new model of interdisciplinary cancer cachexia care in regional Victoria, Australia.
- Author
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Vaughan VC, Farrell H, Lewandowski PA, McCoombe SG, and Martin P
- Subjects
- Adult, Aged, Aged, 80 and over, Ambulatory Care Facilities, Appointments and Schedules, Cachexia mortality, Cachexia pathology, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neoplasms metabolism, Neoplasms mortality, Quality of Life, Retrospective Studies, Self Care, Victoria epidemiology, Cachexia therapy, Neoplasms pathology, Patient Care Team organization & administration
- Abstract
Purpose: Cachexia is a wasting condition affecting approximately 50% of cancer patients, associated with decreased quality of life and survival. Barwon Health's Cachexia and Nutrition Support Service provides person-centred interdisciplinary care to assist the management of cachexia symptoms. This study describes a novel and effective service model established in a regional cachexia clinic and the patient population it serves., Methods: A descriptive, retrospective longitudinal study was conducted of records from patients attending Barwon Health between 2008 and 2013 (n = 175), alongside the description of service refinement over this time. Patients with ≥ 2 attendance dates were assessed for anthropometric measures, follow-up intervals, and muscle function outcomes to describe patient trajectory during clinic involvement., Results: This is the first detailed description of a successful interdisciplinary clinic specific to cancer cachexia management, where patients are seen outside established 8- to 12-week structured programs which prevail in other cachexia clinics. Seventy-five patients (43%) attended one appointment only, with almost half of these (n = 33) first attending within 60 days of death. Of the 99 patients with two or more appointments, 49% displayed positive outcomes with > 2-kg weight gain between two consecutive appointments, and > 50% improved functional strength between two consecutive appointments., Conclusions: The majority of patients attending clinic multiple times maintained or increased weight and functional status during their involvement with the service. However, successes of care provision were muted by high attrition, primarily due to delayed referral and expected high mortality within the study cohort. Planned future analyses with greater patient numbers and cancer stratification will establish cachectic populations most likely to benefit from this novel mode of interdisciplinary care. The Cachexia and Nutrition Support Service provides an effective and efficient service model for the provision of specialist cachexia care to community-dwelling patients in regional Australia.
- Published
- 2020
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232. Murine cytomegalovirus disseminates independently of CX3CR1, CCL2 or its m131/m129 chemokine homologue.
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Farrell HE, Bruce K, Redwood AJ, and Stevenson PG
- Subjects
- Animals, CX3C Chemokine Receptor 1 genetics, Dendritic Cells metabolism, Dendritic Cells virology, Mice, Mice, Knockout, Monocytes metabolism, Monocytes virology, Protein Binding, Virus Replication, CX3C Chemokine Receptor 1 metabolism, Chemokine CCL2 metabolism, Chemokines, CC metabolism, Herpesviridae Infections metabolism, Herpesviridae Infections virology, Host-Pathogen Interactions, Muromegalovirus physiology, Viral Proteins metabolism
- Abstract
Cytomegaloviruses (CMVs) use myeloid cells to move within their hosts. Murine CMV (MCMV) colonizes the salivary glands for long-term shedding, and reaches them via CD11c
+ infected cells. A need to recruit patrolling monocytes for systemic spread has been proposed, based on poor salivary gland infection in fractalkine receptor (CX3CR1)-deficient mice. We found no significant CX3CR1 dependence of salivary gland infection. CCL2 and the viral m131/m129 chemokine homologue were also redundant for acute MCMV spread, arguing against a need for inflammation or infection to recruit additional monocytes to the entry site. M131/m129 promoted salivary gland infection, but only after the initial seeding of infected cells to this site. Our data support the idea that MCMV disseminates by infecting and mobilizing tissue-resident dendritic cells.- Published
- 2019
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233. Murine Cytomegalovirus Spread Depends on the Infected Myeloid Cell Type.
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Farrell HE, Bruce K, Lawler C, and Stevenson PG
- Subjects
- Animal Structures virology, Animals, Body Fluids virology, Disease Models, Animal, Disease Transmission, Infectious, Humans, Mice, Cytomegalovirus Infections virology, Dendritic Cells virology, Muromegalovirus growth & development, Myeloid Cells virology
- Abstract
Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells. Murine CMV (MCMV) spreads from the lungs via infected CD11c
+ cells, consistent with an important role for dendritic cells (DC). We show here that MCMV entering via the olfactory epithelium, a natural transmission portal, also spreads via infected DC. They reached lymph nodes, entered the blood via high endothelial venules, and then entered the salivary glands, driven by constitutive signaling of the viral M33 G protein-coupled receptor (GPCR). Intraperitoneal infection also delivered MCMV to the salivary glands via DC. However, it also seeded F4/80+ infected macrophages to the blood; they did not enter the salivary glands or require M33 for extravasation. Instead, they seeded infection to a range of other sites, including brown adipose tissue (BAT). Peritoneal cells infected ex vivo then adoptively transferred showed similar cell type-dependent differences in distribution, with abundant F4/80+ cells in BAT and CD11c+ cells in the salivary glands. BAT colonization by CMV-infected cells was insensitive to pertussis toxin inhibition of the GPCR signaling through Gi/o substrate, whereas salivary gland colonization was sensitive. Since salivary gland infection required both M33 and Gi/o -coupled signaling, whereas BAT infection required neither, these migrations were mechanistically distinct. MCMV spread from the lungs or nose depended on DC, controlled by M33. Infecting other monocyte populations resulted in unpredictable new infections. IMPORTANCE Cytomegaloviruses (CMVs) spread through the blood by infecting monocytes, and this can lead to disease. With murine CMV (MCMV) we can track infected myeloid cells and so understand how CMVs spread. Previous experiments have injected MCMV into the peritoneal cavity. MCMV normally enters mice via the olfactory epithelium. We show that olfactory infection spreads via dendritic cells, which MCMV directs to the salivary glands. Peritoneal infection similarly reached the salivary glands via dendritic cells. However, it also infected other monocyte types, and they spread infection to other tissues. Thus, infecting the "wrong" monocytes altered virus spread, with potential to cause disease. These results provide a basis for understanding how the monocyte types infected by human CMV might promote different infection outcomes., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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234. Cytomegalovirus host entry and spread.
- Author
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Farrell HE and Stevenson PG
- Subjects
- Animals, Cytomegalovirus genetics, Cytomegalovirus Infections genetics, Cytomegalovirus Infections metabolism, Dendritic Cells metabolism, Dendritic Cells virology, Humans, Lymph Nodes metabolism, Lymph Nodes virology, Receptors, Chemokine genetics, Receptors, Chemokine metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Viral Proteins genetics, Viral Proteins metabolism, Cytomegalovirus physiology, Cytomegalovirus Infections virology, Virus Internalization
- Abstract
Cytomegaloviruses (CMVs) are large, complex pathogens that persistently and systemically colonize most mammals. Human cytomegalovirus (HCMV) causes congenital harm, and has proved hard to control. One problem is that key vaccine targets - virus entry and spread in naive hosts - remain ill-defined. As CMVs predate human speciation, those of other mammals can provide new insight. Murine CMV (MCMV) enters new hosts via olfactory neurons. Like HCMV it binds to heparan, which is lacking from most differentiated apical epithelia but is displayed on olfactory neuronal cilia. It then spreads via infected dendritic cells (DCs), which migrate to draining lymph nodes (LNs), rejoin the circulation by entering high endothelial venules (HEVs), and extravasate into other tissues. This migration depends quantitatively on M33, a constitutively active viral G protein-coupled receptor (GPCR). The homologous US28 GPCR of HCMV can substitute for M33 in allowing MCMV-infected DCs to leave LNs via HEVs, so HCMV could potentially use the same route. The capacity of DCs to seed MCMV to tissues, and for other DCs to collect it for redistribution, suggest that DC recirculation chronically maintains and links diverse CMV reservoirs through lytic exchange.
- Published
- 2019
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235. Murine Cytomegalovirus Glycoprotein O Promotes Epithelial Cell Infection In Vivo .
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Yunis J, Farrell HE, Bruce K, Lawler C, Wyer O, Davis-Poynter N, Brizić I, Jonjić S, Adler B, and Stevenson PG
- Subjects
- Animals, Cells, Cultured, Epithelial Cells metabolism, Fibroblasts metabolism, Herpesviridae Infections metabolism, Lung metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Virus Internalization, Epithelial Cells virology, Fibroblasts virology, Herpesviridae Infections virology, Lung virology, Membrane Glycoproteins metabolism, Muromegalovirus pathogenicity, Viral Envelope Proteins metabolism, Virus Replication
- Abstract
Cytomegaloviruses (CMVs) establish systemic infections across diverse cell types. Glycoproteins that alter tropism can potentially guide their spread. Glycoprotein O (gO) is a nonessential fusion complex component of both human CMV (HCMV) and murine CMV (MCMV). We tested its contribution to MCMV spread from the respiratory tract. In vitro , MCMV lacking gO poorly infected fibroblasts and epithelial cells. Cell binding was intact, but penetration was delayed. In contrast, myeloid infection was preserved, and in the lungs, where myeloid and type 2 alveolar epithelial cells are the main viral targets, MCMV lacking gO showed a marked preference for myeloid infection. Its poor epithelial cell infection was associated with poor primary virus production and reduced virulence. Systemic spread, which proceeds via infected CD11c
+ myeloid cells, was initially intact but then diminished, because less epithelial infection led ultimately to less myeloid infection. Thus, the tight linkage between peripheral and systemic MCMV infections gave gO-dependent infection a central role in host colonization. IMPORTANCE Human cytomegalovirus is a leading cause of congenital disease. This reflects its capacity for systemic spread. A vaccine is needed, but the best viral targets are unclear. Attention has focused on the virion membrane fusion complex. It has 2 forms, so we need to know what each contributes to host colonization. One includes the virion glycoprotein O. We used murine cytomegalovirus, which has equivalent fusion complexes, to determine the importance of glycoprotein O after mucosal infection. We show that it drives local virus replication in epithelial cells. It was not required to infect myeloid cells, which establish systemic infection, but poor local replication reduced systemic spread as a secondary effect. Therefore, targeting glycoprotein O of human cytomegalovirus has the potential to reduce both local and systemic infections., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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236. The Effectiveness of Technology-Mediated Dance Interventions and Their Impact on Psychosocial Factors in Older Adults: A Systematic Review and Meta-Analysis.
- Author
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Silva PA, Cochrane A, and Farrell H
- Subjects
- Aged, Aged, 80 and over, Dance Therapy methods, Geriatrics instrumentation, Geriatrics methods, Humans, Dance Therapy standards, Psychology methods
- Abstract
Background: Engaging in physical activity contributes to healthy aging; however, adherence to exercise programs is often low among older adults. Technology-mediated dance systems, which can be used at home, and dance as a way of keeping physically active have been receiving attention as a means of not only enabling physical activity among older people but may also address key psychosocial factors that are amenable to change., Objectives: To assess the effectiveness of technology-mediated dance interventions and their impact on psychosocial factors in older adults (aged 65 or older)., Methods: A systematic review of randomized controlled trials from January 2000 to February 2017 using key search terms. Two independent reviewers screened articles using predetermined selection criteria. Risk of bias of selected articles was assessed in accordance with the Cochrane guidelines., Results: From an overall 264 articles, six articles (five studies) were found, which assessed the impact of technology-mediated dance interventions on psychosocial factors in older adults. Studies' quality ratings were low, with exception of one study that was considered of moderate quality. None of the studies considered psychosocial factors as primary outcomes. Secondary outcomes assessed fear of falling, depression, and training enjoyment, but no study showed evidence of an effective impact on these variables. The meta-analysis revealed low quality evidence that there was little or no difference above that of the comparison groups for fear of falling (standardized mean difference [SMD] -0.02, 95% confidence interval [CI] -0.37 to 0.33; P = 0.91; five trials). Similarly, there was little or no difference on depression (SMD -0.06, 95% CI -0.59 to 0.47; P = 0.83; three trials)., Conclusion: Existing evidence to support the effectiveness of technology-mediated dance interventions and their impact on psychosocial factors in older adults is weak and with a high risk for bias. The findings of this review may inform future, more rigorous research in the area.
- Published
- 2018
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237. Human cytomegalovirus US28 allows dendritic cell exit from lymph nodes.
- Author
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Farrell HE, Bruce K, Ma J, Davis-Poynter N, and Stevenson PG
- Subjects
- Animal Structures virology, Animals, Cells, Cultured, Cytomegalovirus growth & development, Cytomegalovirus Infections immunology, Cytomegalovirus Infections veterinary, Dendritic Cells immunology, Humans, Lymph Nodes immunology, Mice, Inbred BALB C, Muromegalovirus growth & development, Cell Movement, Cytomegalovirus pathogenicity, Cytomegalovirus Infections virology, Dendritic Cells virology, Host-Pathogen Interactions, Lymph Nodes virology, Receptors, Chemokine metabolism, Viral Proteins metabolism
- Abstract
Human cytomegalovirus (HCMV) colonizes blood-borne dendritic cells (DCs). They express US28, a viral G protein-coupled receptor (GPCR). In vitro functions have been described for US28, but how it contributes to host colonization has been unclear. The murine CMV (MCMV) M33 GPCR promotes DC recirculation. We show that US28 shares this function. Thus, DC recirculation is also available to HCMV via US28, and inhibiting US28 G protein-dependent signalling has the potential to reduce systemic infection. We show that M33 also promotes systemic infection through infected DC extravasation.
- Published
- 2018
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238. Murine cytomegalovirus degrades MHC class II to colonize the salivary glands.
- Author
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Yunis J, Farrell HE, Bruce K, Lawler C, Sidenius S, Wyer O, Davis-Poynter N, and Stevenson PG
- Subjects
- Animals, BALB 3T3 Cells, Cells, Cultured, Cricetinae, Embryo, Mammalian, HEK293 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Muromegalovirus immunology, NIH 3T3 Cells, Salivary Glands metabolism, Salivary Glands pathology, Histocompatibility Antigens Class II metabolism, Immune Evasion, Muromegalovirus physiology, Proteolysis, Salivary Glands immunology, Salivary Glands virology
- Abstract
Cytomegaloviruses (CMVs) persistently and systemically infect the myeloid cells of immunocompetent hosts. Persistence implies immune evasion, and CMVs evade CD8+ T cells by inhibiting MHC class I-restricted antigen presentation. Myeloid cells can also interact with CD4+ T cells via MHC class II (MHC II). Human CMV (HCMV) attacks the MHC II presentation pathway in vitro, but what role this evasion might play in host colonization is unknown. We show that Murine CMV (MCMV) down-regulates MHC II via M78, a multi-membrane spanning viral protein that captured MHC II from the cell surface and was necessary although not sufficient for its degradation in low pH endosomes. M78-deficient MCMV down-regulated MHC I but not MHC II. After intranasal inoculation, it showed a severe defect in salivary gland colonization that was associated with increased MHC II expression on infected cells, and was significantly rescued by CD4+ T cell loss. Therefore MCMV requires CD4+ T cell evasion by M78 to colonize the salivary glands, its main site of long-term shedding.
- Published
- 2018
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239. Palliative radiotherapy utilization within a regional Australian palliative care unit.
- Author
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Eastman P, Dowd A, Goonan J, Farrell H, and Pitson G
- Subjects
- Adult, Aged, Aged, 80 and over, Analgesics, Opioid therapeutic use, Cancer Pain mortality, Cancer Pain prevention & control, Female, Hospices statistics & numerical data, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasms mortality, Neoplasms radiotherapy, Pain Management mortality, Pain Management statistics & numerical data, Radiotherapy mortality, Retrospective Studies, Victoria epidemiology, Palliative Care statistics & numerical data, Radiotherapy statistics & numerical data
- Abstract
Background: Palliative radiotherapy has been demonstrated to be efficacious for symptom management in advanced malignancy however there are limited data investigating its use for inpatient palliative care patients. The aim of the current paper was to evaluate the utilization of radiotherapy amongst patients admitted to a regional Australian palliative care unit (PCU)., Methods: A retrospective cohort study was undertaken involving all Barwon Health PCU patients who received radiotherapy whilst an inpatient. A range of clinico-demographic, radiotherapy-specific and outcome measures were evaluated. Changes in opioid consumption were used as a surrogate for radiotherapy effectiveness. Demographic variables were analyzed descriptively and Wilcoxon Signed Rank Tests were used to compare opioid consumption before and after radiotherapy at time points one week, two weeks and three weeks., Results: Sixty episodes of radiotherapy were provided to 51 PCU patients during the study period with 54 admissions included in the final analysis. Pain management was the commonest reason for radiotherapy treatment and most courses were multi-fractionated. Using the proportion of patients whose opioid dose decreased following radiotherapy as a marker for response, response rates ranged from 32-42%. Fortyeight percent of patients died during their PCU admission and the median survival from radiotherapy commencement was 36 days., Conclusions: A small proportion of all patients admitted to PCU received radiotherapy. Almost half of patients died during their admission and radiotherapy response rates were lower than have been reported for all-comers. More research is needed to optimize the stratification of PCU patients for radiotherapy.
- Published
- 2017
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240. Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation.
- Author
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Farrell HE, Bruce K, Lawler C, Oliveira M, Cardin R, Davis-Poynter N, and Stevenson PG
- Subjects
- Animals, Dendritic Cells physiology, Herpesviridae Infections blood, Herpesviridae Infections virology, Host-Pathogen Interactions, Humans, Lung immunology, Lung virology, Lymph Nodes immunology, Lymph Nodes virology, Mice, Mice, Inbred BALB C, Receptors, Chemokine metabolism, Salivary Glands immunology, Salivary Glands virology, Viremia, Virus Replication, Dendritic Cells virology, Muromegalovirus physiology
- Abstract
Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. However, poor CMV transfer by stem cell transplantation argues against this being the main reservoir. To identify alternative pathways for CMV spread, we tracked murine CMV (MCMV) colonization after mucosal entry. We show that following intranasal MCMV infection, lung CD11c
+ dendritic cells (DC) migrated sequentially to lymph nodes (LN), blood, and then salivary glands. Replication-deficient virus followed the same route, and thus, DC infected peripherally traversed LN to enter the blood. Given that DC are thought to die locally following their arrival and integration into LN, recirculation into blood represents a new pathway. We examined host and viral factors that facilitated this LN traverse. We show that MCMV-infected DC exited LN by a distinct route to lymphocytes, entering high endothelial venules and bypassing the efferent lymph. LN exit required CD44 and the viral M33 chemokine receptor, without which infected DC accumulated in LN and systemic spread was greatly reduced. Taken together, our studies provide the first demonstration of virus-driven DC recirculation. As viruses follow host-defined pathways, high endothelial venules may normally allow DC to pass from LN back into blood. IMPORTANCE Human cytomegalovirus (HCMV) causes devastating disease in the unborn fetus and in the immunocompromised. There is no licensed vaccine, and preventive measures are impeded by our poor understanding of early events in host colonization. HCMV and murine CMV (MCMV) both infect blood-borne myeloid cells. HCMV-infected blood cells are thought to derive from infected bone marrow stem cells. However, infected stem cells have not been visualized in vivo nor shown to produce virus ex vivo , and hematopoietic transplants poorly transfer infection. We show that MCMV-infected dendritic cells in the lungs reach the blood via lymph nodes, surprisingly migrating into high endothelial venules. Dissemination did not require viral replication. It depended on the constitutively active viral chemokine receptor M33 and on the host hyaluronan receptor CD44. Thus, viral chemokine receptors are a possible target to limit systemic CMV infections., (Copyright © 2017 Farrell et al.)- Published
- 2017
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241. When and How Should Clinicians Share Details from a Health Record with Patients with Mental Illness?
- Author
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Thom RP and Farrell HM
- Subjects
- Beneficence, Humans, Personal Autonomy, Social Justice, Social Stigma, Stereotyping, Vulnerable Populations, Disclosure, Ethics, Medical, Health Records, Personal ethics, Language, Mental Disorders, Patient Rights, Physician-Patient Relations ethics
- Abstract
Stigma associated with mental illness-a public health crisis-is perpetuated by the language used to describe and document it. Psychiatric pathology and how it can be perceived among clinicians contribute to the marginalization of patients, which exacerbates their vulnerability. Clinical documentation of mental illness has long been mired in pejorative language that perpetuates negative assumptions about those with mental illness. Although patients have the legal right to view their health record, sharing mental health notes with patients remains a sensitive issue, largely due to clinicians' fears that review of this content might cause harm, specifically psychiatric destabilization. However, the ethical principles of justice, beneficence, and autonomy as well as nonmaleficence must be considered by clinicians in determining when and how to share psychiatric details from a health record with their patients., (© 2017 American Medical Association. All Rights Reserved.)
- Published
- 2017
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242. Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus.
- Author
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Farrell HE, Bruce K, Lawler C, Cardin RD, Davis-Poynter NJ, and Stevenson PG
- Subjects
- Animals, Lymph Nodes virology, Macrophages virology, Mice, Muromegalovirus immunology, Herpesviridae Infections immunology, Immunity, Innate immunology, Interferon Type I immunology, Killer Cells, Natural immunology, Lymph Nodes immunology
- Abstract
Cytomegaloviruses (CMVs) establish chronic, systemic infections. Peripheral infection spreads via lymph nodes, which are also a focus of host defence. Thus, this is a point at which systemic infection spread might be restricted. Subcapsular sinus macrophages (SSM) captured murine CMV (MCMV) from the afferent lymph and poorly supported its replication. Blocking the type I interferon (IFN-I) receptor (IFNAR) increased MCMV infection of SSM and of the fibroblastic reticular cells (FRC) lining the subcapsular sinus, and accelerated viral spread to the spleen. Little splenic virus derived from SSM, arguing that they mainly induce an anti-viral state in the otherwise susceptible FRC. NK cells also limited infection, killing infected FRC and causing tissue damage. They acted independently of IFN-I, as IFNAR blockade increased NK cell recruitment, and NK cell depletion increased infection in IFNAR-blocked mice. Thus SSM restricted MCMV infection primarily though IFN-I, with NK cells providing a second line of defence. The capacity of innate immunity to restrict MCMV escape from the subcapsular sinus suggested that enhancing its recruitment might improve infection control., Competing Interests: The authors have declared no competing interests exist.
- Published
- 2016
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243. Luciferase-tagged wild-type and tropism-deficient mouse cytomegaloviruses reveal early dynamics of host colonization following peripheral challenge.
- Author
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Farrell H, Oliveira M, Macdonald K, Yunis J, Mach M, Bruce K, Stevenson P, Cardin R, and Davis-Poynter N
- Subjects
- Animals, Cytomegalovirus genetics, Cytomegalovirus growth & development, Female, Genes, Reporter, Humans, Luciferases metabolism, Mice, Mice, Inbred BALB C, Molecular Imaging, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Viral Proteins genetics, Viral Proteins metabolism, Cytomegalovirus physiology, Cytomegalovirus Infections virology, Luciferases genetics, Viral Tropism
- Abstract
Cytomegaloviruses (CMVs) establish persistent, systemic infections and cause disease by maternal-foetal transfer, suggesting that their dissemination is a key target for antiviral intervention. Late clinical presentation has meant that human CMV (HCMV) dissemination is not well understood. Murine CMV (MCMV) provides a tractable model. Whole mouse imaging of virus-expressed luciferase has proved a useful way to track systemic infections. MCMV, in which the abundant lytic gene M78 was luciferase-tagged via a self-cleaving peptide (M78-LUC), allowed serial, unbiased imaging of systemic and peripheral infection without significant virus attenuation. Ex vivo luciferase imaging showed greater sensitivity than plaque assay, and revealed both well-known infection sites (the lungs, lymph nodes, salivary glands, liver, spleen and pancreas) and less explored sites (the bone marrow and upper respiratory tract). We applied luciferase imaging to tracking MCMV lacking M33, a chemokine receptor conserved in HCMV and a proposed anti-viral drug target. M33-deficient M78-LUC colonized normally in peripheral sites and local draining lymph nodes but spread poorly to the salivary gland, suggesting a defect in vascular transport consistent with properties of a chemokine receptor.
- Published
- 2016
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244. The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types.
- Author
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Davis-Poynter N, Yunis J, and Farrell HE
- Subjects
- Animals, Cell Line, HeLa Cells, Humans, Mice, Protein Domains, Protein Structure, Secondary, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled genetics, Sequence Deletion, Viral Proteins chemistry, Viral Proteins genetics, Virus Replication, Endocytosis, Macrophages, Alveolar virology, Muromegalovirus physiology, Receptors, G-Protein-Coupled metabolism, Viral Proteins metabolism
- Abstract
Virus homologues of seven-transmembrane receptors (7TMR) are encoded by all beta- and gammaherpesviruses, suggesting important functional roles. M78 of mouse cytomegalovirus (MCMV) is representative of a family of 7TMR conserved in all betaherpesviruses. M78 family members have been found to exhibit cell-type specific effects upon virus replication in tissue culture and to affect virus pathogenesis in vivo. We reported previously that M78, for which no ligands are known, undergoes rapid, constitutive endocytosis. In this study, we have investigated the role of the M78 cytoplasmic C-tail in mediating endocytosis and consequences of C-tail deletion upon replication and pathogenesis. Mutations of M78 (C-tail truncations or point mutations) and CCR5-M78 chimeras identified two distinct regions affecting endocytosis. The first was a classical acidic di-leucine motif (DDxxxLL), located close to the C-terminus. The second region, the activity of which was suppressed by downstream sequences, included the putative 8th helix, located close to the 7th transmembrane domain. A recombinant MCMV expressing an endocytosis-deficient M78, lacking most of the C-tail (M78_CΔ155), had a cell-type specific replication phenotype. M78_CΔ155 had restricted replication in bone marrow macrophages, indistinguishable from an M78-null recombinant. In contrast, M78_CΔ155 replicated normally or with enhanced titres to wild type virus in other tested cell-types, whereas M78-null was attenuated. Distinct phenotypes for M78_CΔ155 and M78-null suggest that the C-tail deletion resulted in M78 dysfunction, rather than complete loss of function; furthermore, they highlight a cell-type specific role of M78 during replication. Infection of mice (intranasal) demonstrated that M78_CΔ155, similar to M78-null, was cleared more rapidly from the lungs than wild type virus and was severely attenuated for replication in salivary glands. It may be speculated that attenuation of both M78_CΔ155 and M78-null for replication in macrophages may have contributed to their similar pathogenic phenotypes., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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245. Murine Cytomegalovirus Exploits Olfaction To Enter New Hosts.
- Author
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Farrell HE, Lawler C, Tan CS, MacDonald K, Bruce K, Mach M, Davis-Poynter N, and Stevenson PG
- Subjects
- Animals, Cytomegalovirus Infections virology, Humans, Mice, Muromegalovirus genetics, Salivary Glands virology, Smell, Virus Internalization, Cytomegalovirus Infections veterinary, Muromegalovirus physiology, Nose virology, Rodent Diseases virology
- Abstract
Unlabelled: Viruses transmit via the environmental and social interactions of their hosts. Herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. Cytomegaloviruses (CMVs) are assumed to enter new hosts orally, but no site has been identified. We show by live imaging that murine CMV (MCMV) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. Replication-deficient virions revealed the primary target as olfactory neurons. Local, nasal replication by wild-type MCMV was not extensive, but there was rapid systemic spread, associated with macrophage infection. A long-term, transmissible infection was then maintained in the salivary glands. The viral m131/m129 chemokine homolog, which influences tropism, promoted salivary gland colonization after nasal entry but was not required for entry per se The capacity of MCMV to transmit via olfaction, together with previous demonstrations of experimental olfactory infection by murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1), suggest that this is a common, conserved route of mammalian herpesvirus entry., Importance: Cytomegaloviruses (CMVs) infect most mammals. Human CMV (HCMV) harms people with poor immune function and can damage the unborn fetus. It infects approximately 1% of live births. We lack a good vaccine. One problem is that how CMVs first enter new hosts remains unclear. Oral entry is often assumed, but the evidence is indirect, and no infection site is known. The difficulty of analyzing HCMV makes related animal viruses an important source of insights. Murine CMV (MCMV) infected not orally but nasally. Specifically, it targeted olfactory neurons. Viral transmission was also a nasal infection. Like HCMV, MCMV infected cells by binding to heparan, and olfactory surfaces display heparan to incoming viruses, whereas most other mucosal surfaces do not. These data establish a new understanding of CMV infections and a basis for infection control., (Copyright © 2016 Farrell et al.)
- Published
- 2016
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246. Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs.
- Author
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Farrell HE, Lawler C, Oliveira MT, Davis-Poynter N, and Stevenson PG
- Subjects
- Animals, Epithelial Cells virology, Herpesvirus 1, Human physiology, Mice, Inbred BALB C, Mice, Inbred C57BL, Rhadinovirus physiology, Lung virology, Macrophages, Alveolar virology, Muromegalovirus physiology
- Abstract
Unlabelled: Cytomegaloviruses (CMVs) infect the lungs and cause pathological damage there in immunocompromised hosts. How lung infection starts is unknown. Inhaled murine CMV (MCMV) directly infected alveolar macrophages (AMs) and type 2 alveolar epithelial cells (AEC2s) but not type 1 alveolar epithelial cells (AEC1s). In contrast, herpes simplex virus 1 infected AEC1s and murid herpesvirus 4 (MuHV-4) infected AEC1s via AMs. MCMV-infected AMs prominently expressed viral reporter genes from a human CMV IE1 promoter; but most IE1-positive cells were AEC2s, and CD11c-cre mice, which express cre in AMs, switched the fluorochrome expression of <5% of floxed MCMV in the lungs. In contrast, CD11C-cre mice exhibited fluorochrome switching in >90% of floxed MuHV-4 in the lungs and 50% of floxed MCMV in the blood. AM depletion increased MCMV titers in the lung during the acute phase of infection. Thus, the influence of AMs was more restrictive than permissive. Circulating monocytes entered infected lungs in large numbers and became infected, but not directly; infection occurred mainly via AEC2s. Mice infected with an MCMV mutant lacking its m131/m129 chemokine homolog, which promotes macrophage infection, showed levels of lung infection equivalent to those of wild-type MCMV-infected mice. The level of lung infiltration by Gr-1-positive cells infected with the MCMV m131/m129-null mutant was modestly different from that for wild-type MCMV-infected lungs. These results are consistent with myeloid cells mainly disseminating MCMV from the lungs, whereas AEC2s provide local amplification., Importance: Cytomegaloviruses (CMVs) chronically and systemically infect most mammals. Human CMV infection is usually asymptomatic but causes lung disease in people with poor immune function. As human infection is hard to analyze, studies with related animal viruses provide important insights. We show that murine CMV has two targets in the lungs: macrophages and surfactant-secreting epithelial cells. Acute virus replication occurred largely in epithelial cells. Macrophages had an important defensive role, as their removal increased the level of infection. These results establish the dual nature of lung infection, with local virus replication occurring in epithelial cells and spread occurring via quiescently infected macrophages. Distinct therapies may be needed to target these contrasting events., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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247. Lymph Node Macrophages Restrict Murine Cytomegalovirus Dissemination.
- Author
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Farrell HE, Davis-Poynter N, Bruce K, Lawler C, Dolken L, Mach M, and Stevenson PG
- Subjects
- Animals, Disease Models, Animal, Leukocyte Reduction Procedures, Mice, Salivary Glands virology, Spleen virology, Herpesviridae Infections immunology, Herpesviridae Infections virology, Lymph Nodes immunology, Lymph Nodes virology, Macrophages immunology, Macrophages virology, Muromegalovirus immunology
- Abstract
Unlabelled: Cytomegaloviruses (CMVs) establish chronic infections that spread from a primary entry site to secondary vascular sites, such as the spleen, and then to tertiary shedding sites, such as the salivary glands. Human CMV (HCMV) is difficult to analyze, because its spread precedes clinical presentation. Murine CMV (MCMV) offers a tractable model. It is hypothesized to spread from peripheral sites via vascular endothelial cells and associated monocytes. However, viral luciferase imaging showed footpad-inoculated MCMV first reaching the popliteal lymph nodes (PLN). PLN colonization was rapid and further spread was slow, implying that LN infection can be a significant bottleneck. Most acutely infected PLN cells were CD169(+) subcapsular sinus macrophages (SSM). Replication-deficient MCMV also reached them, indicating direct infection. Many SSM expressed viral reporter genes, but few expressed lytic genes. SSM expressed CD11c, and MCMV with a cre-sensitive fluorochrome switch showed switched infected cells in PLN of CD11c-cre mice but yielded little switched virus. SSM depletion with liposomal clodronate or via a CD169-diphtheria toxin receptor transgene shifted infection to ER-TR7(+) stromal cells, increased virus production, and accelerated its spread to the spleen. Therefore, MCMV disseminated via LN, and SSM slowed this spread by shielding permissive fibroblasts and poorly supporting viral lytic replication., Importance: HCMV chronically infects most people, and it can cause congenital disability and harm the immunocompromised. A major goal of vaccination is to prevent systemic infection. How this is established is unclear. Restriction to humans makes HCMV difficult to analyze. We show that peripheral MCMV infection spreads via lymph nodes. Here, MCMV infected filtering macrophages, which supported virus replication poorly. When these macrophages were depleted, MCMV infected susceptible fibroblasts and spread faster. The capacity of filtering macrophages to limit MCMV spread argued that their infection is an important bottleneck in host colonization and might be a good vaccine target., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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248. Virus-encoded 7 transmembrane receptors.
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Mølleskov-Jensen AS, Oliveira MT, Farrell HE, and Davis-Poynter N
- Subjects
- Amino Acid Sequence, Animals, Evolution, Molecular, Humans, Molecular Sequence Data, Receptors, Chemokine chemistry, Viral Proteins chemistry, Cell Membrane metabolism, Receptors, Chemokine metabolism, Viral Proteins metabolism
- Abstract
Herpesviruses are an ancient group which have exploited gene capture of multiple cellular modulators of the immune response. Viral homologues of 7 transmembrane receptors (v7TMRs) are a consistent feature of beta- and gammaherpesviruses; the majority of the v7TMRs are homologous to cellular chemokine receptors (CKRs). Conserved families of v7TMRs distinguish between beta- versus gammaherpesviruses; furthermore, significant divisions within these subfamilies, such as between genera of the gammaherpesviruses or between the primate and rodent cytomegaloviruses, coincide with specific v7TMR gene families. Divergence of functional properties between the viral 7TMR and their cellular counterparts is likely, therefore, to reflect adaptation supporting various aspects of the viral lifecycle with concomitant effects upon viral pathogenesis. Consistent with their long evolutionary history, the v7TMRs have acquired a range of distinctive characteristics. This chapter reviews key features of the v7TMRs which are likely to impact upon their functional roles: trafficking properties, ligand specificity, and signaling capacity. Rapid, constitutive endocytosis, reminiscent of cellular "scavenger" receptors, may provide a mechanism for immune evasion, or alternatively relate to virion assembly, including incorporation of v7TMRs within the virion envelope. Some v7TMRs display relatively broad chemokine-binding specificity, whereas others remain "orphan" and may be completely independent of ligand activation. Indeed, many of the v7TMRs have been shown to signal constitutively, associated in some cases with notable divergence of highly conserved regulatory elements such as the "DRY" motif of TMIII. The availability of rodent models for v7TMR functional studies has provided evidence for important biological roles, including cellular transformation, tissue tropism, and viral persistence. Recent studies addressing signaling pathways critical to these phenotypes will be discussed, with reference to both beta- and gammaherpesviruses., (© 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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249. Lithium-induced nephrogenic diabetes insipidus after gastric banding.
- Author
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Leo JR, Farrell HM, and Friedman R
- Subjects
- Adult, Diabetes Insipidus, Nephrogenic urine, Female, Fluid Therapy methods, Gastroplasty psychology, Humans, Hypernatremia etiology, Kidney Concentrating Ability drug effects, Obesity, Morbid surgery, Postoperative Care methods, Postoperative Period, Psychomotor Agitation etiology, Referral and Consultation, Antimanic Agents adverse effects, Delirium etiology, Diabetes Insipidus, Nephrogenic chemically induced, Gastroplasty adverse effects, Lithium Compounds adverse effects, Polydipsia etiology
- Published
- 2013
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250. A piece of my mind. A house built out of madness.
- Author
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Farrell HM
- Subjects
- Forensic Psychiatry, Humans, Ireland, Residential Facilities, Mental Disorders psychology, Physician-Patient Relations
- Published
- 2011
- Full Text
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