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1. Imaging Evaluation of Plexiform Neurofibromas in Neurofibromatosis Type 1

Author: Johannes Salamon, Dale J. Berg, Shivani Ahlawat, Michael Fisher, Dusica Babovic-Vuksanovic, Jaishri O. Blakeley, K. Ina Ly, Gordon J. Harris, Andrés J. Lessing, Laura M. Fayad, Scott R. Plotkin, Eva Dombi, and Victor-Felix Mautner
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Neurofibromatosis 1, Skin Neoplasms, Adolescent, Neurofibromatoses, MEDLINE, Asymptomatic, Imaging, Young Adult, Surveys and Questionnaires, Humans, Medicine, Clinical care, Neurofibromatosis, Child, Schwannomatosis, Neurofibroma, Plexiform, High prevalence, business.industry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Patient population, Neurology (clinical), medicine.symptom, business, Neurilemmoma
Abstract: ObjectiveTo assess imaging utilization practices across clinical specialists in neurofibromatosis type 1 (NF1) for the evaluation of symptomatic and asymptomatic children and adults with or without plexiform neurofibromas (PN).MethodsAn institutional review board–exempt survey was administered to medical practitioners caring for individuals with NF1 at the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) meeting in September 2019. The survey included questions on respondent demographic data (9 questions), type of imaging obtained for asymptomatic (4 questions) and symptomatic (4 questions) people with and without PN, and utilization of diffusion-weighted imaging (2 questions).ResultsThirty practitioners participated in the survey. Most were academic neuro-oncologists at high-volume (>10 patients/week) NF1 centers. Of 30 respondents, 26 had access to whole-body MRI (WB-MRI). The most common approach to an asymptomatic person without PN was no imaging (adults: 57% [17/30]; children: 50% [15/30]), followed by a screening WB-MRI (adults: 20% [6/30]; children: 26.7% [8/30]). The most common approach to a person with symptoms or known PN was regional MRI (adults: 90% [27/30]; children: 93% [28/30]), followed by WB-MRI (adults: 20% [6/30]; children: 36.7% [11/30]). WB-MRI was most often obtained to evaluate a symptomatic child with PN (37% [11/30]).ConclusionsMore than 90% of practitioners indicated they would obtain a regional MRI in a symptomatic patient without known or visible PN. Otherwise, there was little consensus on imaging practices. Given the high prevalence of PN and risk of malignant conversion in this patient population, there is a need to define imaging-based guidelines for optimal clinical care and the design of future clinical trials.
Published: 2021
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2. Outcome of acute hypoxaemic respiratory failure: insights from the LUNG SAFE Study

Author: Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andres, Gattinoni, Luciano, Larsson, Anders, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andre, Gattinoni, Luciano, Larsson, Ander, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, 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Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo 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C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Intensive Care Medicine, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Pham, T, Pesenti, A, Bellani, G, Rubenfeld, G, Fan, E, Bugedo, G, Lorente, J, Fernandes, A, Van Haren, F, Bruhn, A, Rios, F, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Thompson, B, Wrigge, H, Brochard, L, Laffey, J, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), St. Michael's Hospital, University of Toronto, Groupe de recherche clinique CARMAS, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano [Milano] (UNIMI), University of Milan, San Gerardo Hospital, Sunnybrook Health Sciences Center, Mount Sinai Hospital [Toronto, Canada] (MSH), Pontificia Universidad Católica de Chile (UC), University Hospital of Getafe, CIBER Enfermedades Respiratorias (CIBERES), Universidad Europea de Madrid, Hospital Garcia de Orta (EPE), Canberra Hospital, Medical School [Australian National University - ANU], Australian National University (ANU), University of Canberra, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Göttingen - Georg-August-Universität Göttingen, Uppsala University, Queen's University [Belfast] (QUB), Royal Victoria Hospital, McGill University Health Center [Montreal] (MUHC), Università degli Studi di Bologna, Massachusetts General Hospital [Boston], University Hospital Leipzig, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, 06112, Halle, National University of Ireland [Galway] (NUI Galway), Bayer GlaxoSmithKline, GSK Baxter International Boehringer Ingelheim Wellcome Trust, WT National Institute for Health Research, NIHR Queen's University Belfast, QUB Medical Research Council Canada, MRC European Society of Intensive Care Medicine, ESICM, Support statement: This work was supported by the European Society of Intensive Care Medicine. Funding information for this article has been deposited with the Crossref Funder Registry., Conflict of interest: T. Pham has nothing to disclose. A. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, Gilead and Boehringer Ingelheim, outside the submitted work. G. Bellani reports grants and personal fees from Draeger Medical, personal fees from Getinge, Hamilton, GE Healthcare, Dimar SRL, Intersurgical and Flowmeter SPA, outside the submitted work. G. Rubenfeld has nothing to disclose. E. Fan reports personal fees from ALung Technologies, Getinge and MC3 Cardiopulmonary, grants, personal fees and non-financial support from Fresenius Medical Care, outside the submitted work. G. Bugedo has nothing to disclose. J.A. Lorente has nothing to disclose. A.D. V. Fernandes has nothing to disclose. F. Van Haren has nothing to disclose. A. Bruhn has nothing to disclose. F. Rios has nothing to disclose. A. Esteban has nothing to disclose. L. Gattinoni has nothing to disclose. A. Larsson reports grants from the Swedish Heart and Lung Foundation, during the conduct of the study. D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work, in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, NI HSC R&D Division, NI Chest Heart and Stroke, and MRC, is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen’s University of Belfast (http://www.google.com/patents/US8962032), and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. M. Ranieri has nothing to disclose. B.T. Thompson reports personal fees from Bayer, Thetis and Novartis, outside the submitted work. H. Wrigge reports personal fees for consultancy from Dräger Medical, personal fees for advisory board work from Liberate Medical, grants and personal fees for lectures from InfectoPharm, personal fees for lectures from MSD and GE, outside the submitted work. L.J. Brochard reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec and Philips, other (patent) from General Electric, outside the submitted work. J.G. Laffey reports grants and personal fees from Baxter, grants and non-financial support from Aerogen and Factor Biosciences, outside the submitted work., LUNG SAFE Investigators and the European Society of Intensive Care Medicine Trials Group: Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J 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Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, and UCL - (SLuc) Service de soins intensifs
Subjects: Pulmonary and Respiratory Medicine, ARDS, Unidades de cuidados intensivos, [SDV]Life Sciences [q-bio], medicine.medical_treatment, mechanical ventilation, NO, law.invention, 03 medical and health sciences, Tratamiento médico, 0302 clinical medicine, law, Settore MED/41 - ANESTESIOLOGIA, Insuficiencia respiratoria, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Lung, Mechanical ventilation, Respiratory Distress Syndrome, business.industry, Respiration, Incidence (epidemiology), medicine.disease, Intensive care unit, Respiration, Artificial, 3. Good health, Intensive Care Units, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], medicine.anatomical_structure, 030228 respiratory system, Respiratory failure, Heart failure, Anesthesia, Artificial, ards, business, Respiratory Insufficiency, Enfermedad
Abstract: BackgroundCurrent incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).MethodsAn international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared.Findings12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved.InterpretationMore than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.
Published: 2021
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3. Structure-Based Design of a Selective Class I Histone Deacetylase (HDAC) Near-Infrared (NIR) Probe for Epigenetic Regulation Detection in Triple-Negative Breast Cancer (TNBC)

Author: Dale J. Hamilton, Zhiyi Liu, Sheng Jiang, Dong Chen, Yatao Qiu, Kuojun Zhang, Yiwu Yao, Feng Li, and Zheng Li
Subjects: Poor prognosis, Lung Neoplasms, Mice, Nude, Triple Negative Breast Neoplasms, Cyclic depsipeptide, 01 natural sciences, Histone Deacetylases, Epigenesis, Genetic, Malignant transformation, 03 medical and health sciences, Breast cancer, Cell Line, Tumor, Depsipeptides, Drug Discovery, Biomarkers, Tumor, medicine, Animals, Humans, Fluorometry, Epigenetics, Triple-negative breast cancer, 030304 developmental biology, Vorinostat, 0303 health sciences, Chemistry, Carbocyanines, medicine.disease, 0104 chemical sciences, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, 010404 medicinal & biomolecular chemistry, Cancer research, Heterografts, Molecular Medicine, Structure based, Female, Histone deacetylase
Abstract: Abnormally high levels of class I histone deacetylases (HDACs) are associated with triple-negative breast cancer (TNBC) proliferation, malignant transformation, and poor prognosis of patients. Herein, we report a near-infrared imaging probe for TNBC detection via visualizing class I HDACs. Conjugating Cy5.5 to a cyclic depsipeptide inhibitor, we obtained the probe (20-Cy5.5) that retained desirable class I HDAC affinity and selectivity. Then, this probe could visualize epigenetic changes by class I HDACs in TNBC MDA-MB-231 cells and in xenograft tumor models in real time. Treatment with suberoylanilide hydroxamic acid (SAHA) significantly reduced the uptake of the probe in tumors, suggesting its potential use in evaluation of therapeutic responses of HDACi-mediated therapy. Moreover, 20-Cy5.5 could detect class I HDAC expression in TNBC lung metastasis. This novel NIR probe that achieves tumor class I HDAC imaging not only leads to a better understanding of epigenetic regulation in tumors but also has great potential for improving the TNBC diagnosis and treatment.
Published: 2021
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4. Relationship Between Post-Traumatic Stress Disorder Symptoms and Chronic Pain-Related Symptom Domains Among Military Active Duty Service Members

Author: Ardith Z. Doorenbos, Dale J. Langford, Hongjin Li, Diane M Flynn, Krista B. Highland, and Patricia K Barr
Subjects: Active duty, media_common.quotation_subject, Anxiety, Anger, Stress Disorders, Post-Traumatic, mental disorders, medicine, Humans, Special Populations Section, Depression (differential diagnoses), Pain Measurement, Social functioning, media_common, business.industry, Traumatic stress, Chronic pain, General Medicine, Service member, medicine.disease, Military Personnel, Anesthesiology and Pain Medicine, Neurology (clinical), Chronic Pain, medicine.symptom, business, Clinical psychology
Abstract: Objective This study examined the relationships between symptom domains relevant to post-traumatic stress disorder (PTSD) diagnosis, PTSD screening, and chronic pain-related symptoms (pain intensity, pain interference, physical function, fatigue, depression, anxiety, anger, satisfaction with social roles) experienced by active duty military service members with chronic pain. Design ross-sectional study. Setting This study was conducted at the Interdisciplinary Pain Management Center (IPMC) at Madigan Army Medical Center between 2014 and 2018. Subjects Active duty service members receiving care at IPMC (n = 2745) were included in this study. Methods Independent sample t test was conducted to compare pain intensity and pain-related measures of physical, emotional, and social functioning among patients with and without a PTSD diagnosis or PTSD positive screen (≥3 symptoms). Relative weight analysis was used to identify the relative importance of each PTSD symptom cluster (e.g., intrusion, avoidance, hyperarousal, emotional numbness) to pain and related domains. Results Approximately 27.9% of the patients had a positive screen for PTSD, and 30.5% of the patients had a PTSD diagnosis. Patients with PTSD diagnosis and positive screening had higher pain interference and lower physical function and social satisfaction scores (P Conclusion To improve treatment effectiveness and overall functioning for active duty military patients, integrated treatment and therapies targeted to reducing chronic pain and PTSD symptoms (focus on emotional numbness and avoidance) are recommended.
Published: 2021
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5. Pain Intensity as a Lagging Indicator of Patient Improvement: Longitudinal Relationships With Sleep, Psychiatric Distress, and Function in Multidisciplinary Care

Author: John A. Sturgeon, Dale J. Langford, David J. Tauben, and Mark Sullivan
Subjects: Adult, Sleep Wake Disorders, medicine.medical_specialty, Comorbidity, Anxiety, Severity of Illness Index, Stress Disorders, Post-Traumatic, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Outcome Assessment, Health Care, medicine, Numeric Rating Scale, Humans, Pain Management, Longitudinal Studies, Prospective cohort study, Depression (differential diagnoses), Retrospective Studies, Sleep disorder, Depression, business.industry, Chronic pain, Models, Theoretical, medicine.disease, Psychosocial Functioning, Distress, Anesthesiology and Pain Medicine, Neurology, Physical therapy, Neurology (clinical), Chronic Pain, medicine.symptom, business, Psychosocial, 030217 neurology & neurosurgery
Abstract: Despite a common assumption that reductions in chronic pain intensity must precede improvements in other pain-relevant domains, there has been limited empirical inquiry into the temporal ordering of improvements in chronic pain treatment. Cross-lagged models using retrospective clinical data examined relationships between average pain intensity and symptoms of psychological distress, difficulties with sleep initiation and maintenance, and disability in 666 treatment-seeking patients with chronic pain who demonstrated improvement in pain intensity (≥1-point reduction on 0-10 numeric rating scale) over a 1-year span. Results indicated that decreased difficulties with sleep initiation, depressive and anxious symptoms, and disability predicted later improvement in pain intensity, whereas greater pain intensity predicted only later difficulties in sleep initiation and maintenance. A combined lagged model highlighted fewer baseline symptoms of post-traumatic stress disorder and lower levels of baseline disability as significant predictors of later improvements in pain. Overall, our results indicate that reductions in pain intensity may not be the first factors to change in effective chronic pain management. The current findings should be replicated using prospective studies utilizing structured approaches to maximize data capture, as well as uniform interventional approaches to permit greater inferences regarding causal and temporal aspects of the model. Perspective This study demonstrates that pain intensity scores are not robust predictors of psychosocial outcomes longitudinally. Instead, other factors such as sleep initiation, psychological distress and disability appear to be important targets for intervention that may promote effective pain reduction.
Published: 2021
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6. 64Cu/177Lu-DOTA-diZD, a Small-Molecule-Based Theranostic Pair for Triple-Negative Breast Cancer

Author: Chun Li, Dale J. Hamilton, Hong Zhao, Zhen Yang, Nam C. Yu, Zheng Li, Yuqian Huang, and Feng Li
Subjects: medicine.diagnostic_test, Chemistry, Angiogenesis, medicine.medical_treatment, Immunotherapy, medicine.disease, chemistry.chemical_compound, Breast cancer, Positron emission tomography, Drug Discovery, Radionuclide therapy, medicine, Cancer research, Molecular Medicine, DOTA, Receptor, Triple-negative breast cancer
Abstract: Despite advances in targeted therapies, the prognosis for patients with triple-negative breast cancer (TNBC) is poor because there are few actionable molecular targets. The dependence of solid tumor growth on angiogenesis prompted our development of angiogenic-receptor-targeted radionuclide therapy (TRT) to treat TNBC by targeted delivery of therapeutic doses of ionizing radiation to tumors. A high-affinity vascular endothelial growth factor receptor (VEGFR)-targeted agent, diZD, was synthesized and labeled with 177Lu and 64Cu by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator giving the TRT agent, 177Lu-DOTA-diZD, and PET imaging agent, 64Cu-DOTA-diZD. We showed that "64Cu/177Lu"-DOTA-diZD radiotracers are a promising theranostic pair for TNBC. 4T1-bearing mice treated with 177Lu-DOTA-diZD-based TRT survived with a median of 28 days, which was significantly longer than that of control mice as 18 days. Anti-PD1 immunotherapy resulted in a shorter median survival of 16 days. This work presents for the first time that small-molecule VEGFR-oriented TRT is a promising therapeutic option to treat "immunogenic cold" TNBC.
Published: 2021
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7. The relationship between abdominal fat and change in left ventricular ejection fraction in cancer patients

Author: Sujethra Vasu, W. Gregory Hundley, Khristine Ghemigian, Dale J. Langford, Giselle C. Meléndez, Kerryn W. Reding, Ralph B. D'Agostino, Alexandra Thomas, Jennifer H. Jordan, Heidi D. Klepin, Zanetta S. Lamar, and Salvatore Carbone
Subjects: 0301 basic medicine, medicine.medical_specialty, lcsh:Internal medicine, Endocrinology, Diabetes and Metabolism, visceral fat, 030209 endocrinology & metabolism, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Medicine, Prospective cohort study, lcsh:RC31-1245, body composition, 030109 nutrition & dietetics, Nutrition and Dietetics, Ejection fraction, business.industry, Confounding, Cancer, Original Articles, medicine.disease, Heart failure, Cardiology, Original Article, Sarcoma, business, Body mass index
Abstract: Objectives Prior studies have identified a relationship between body mass index (BMI) and intraperitoneal (IP) fat with heart failure; however, in prior studies of cancer patients receiving potentially cardiotoxic chemotherapy, elevations in BMI have not necessarily been associated with decrements in heart function. This study tested the hypothesis that IP fat may be associated with left ventricular ejection fraction (LVEF) decline among cancer patients receiving potentially cardiotoxic chemotherapy. Methods In this prospective study of 61 cancer patients (23 breast cancer, 32 lymphoma, and 6 sarcoma), IP fat and other assessments of body composition, and changes in LVEF from pre‐ to postcancer treatment using noninvasive magnetic resonance imaging was ascertained. Results After accounting for age, baseline LVEF, and confounding variables, pre‐ to 24‐month post‐treatment LVEF changes were inversely correlated with IP fat (r = −0.33; p = 0.02) and positively correlated with measures of subcutaneous (SQ) fat (r = 0.33; p = 0.01). These LVEF changes were not correlated with BMI (r = 0.12; p = 0.37). Conclusion Among patients receiving potentially cardiotoxic chemotherapy, pretreatment IP fat was associated with subsequent declines in LVEF. There was no association between BMI and LVEF decline. These findings may be related to a potential protective effect of SQ fat.
Published: 2021

8. Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth

Author: Tanya Parish, Lindsay Flint, Anuradha Kumar, Lisa M. Massoudi, Paul Scullion, Gregory T. Robertson, Shilah A. Bonnett, Simon Green, Nicola Caldwell, Jennifer Riley, Gail M. Freiberg, Philip Arthur Hipskind, Michael Mathieson, Thierry Masquelin, Laste Stojanovski, Curtis A. Engelhart, Margaret Huggett, Dinakaran Murugesan, Abraham Lopez Moure, Fabio Zuccotto, Julie V. Early, Ola Epemolu, Paul G. Wyatt, Dale J. Kempf, Kevin D. Read, Susan Davis, Laura A. T. Cleghorn, James Johnson, Steven Mullen, Malcolm Taylor, Anne J. Lenaerts, Penelope A. Turner, Peter C. Ray, Joshua Odingo, Dirk Schnappinger, Aaron Korkegian, and Douglas Joerss
Subjects: 0303 health sciences, Tuberculosis, biology, 030306 microbiology, Chemistry, General Chemical Engineering, Phenotypic screening, hERG, General Chemistry, Pharmacology, medicine.disease, biology.organism_classification, In vitro, Article, 3. Good health, Mycobacterium tuberculosis, 03 medical and health sciences, Minimum inhibitory concentration, In vivo, biology.protein, medicine, Cytotoxicity, QD1-999, 030304 developmental biology
Abstract: With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-a-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.
Published: 2021

9. Prior exercise enhances skeletal muscle microvascular blood flow and mitigates microvascular flow impairments induced by a high‐glucose mixed meal in healthy young men

Author: Glenn D. Wadley, Katherine Roberts-Thomson, Lewan Parker, Michelle A. Keske, Christopher S. Shaw, Gunveen Kaur, Dale J. Morrison, and Andrew C. Betik
Subjects: Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, Physiology, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Endurance training, Internal medicine, medicine, Humans, Insulin, Ingestion, Muscle, Skeletal, Meal, business.industry, Microcirculation, digestive, oral, and skin physiology, Skeletal muscle, Blood flow, Postprandial Period, medicine.disease, Glucose, 030104 developmental biology, Postprandial, medicine.anatomical_structure, Endocrinology, Heart failure, business, 030217 neurology & neurosurgery
Abstract: KEY POINTS Exercise, insulin-infusion and low-glucose mixed-nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high-glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism. We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high-glucose mixed-nutrient meal ingested 3 and 24 h post-exercise. Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high-glucose mixed meal ingested 3 h post-exercise, and to a lesser extent 24 h post-exercise. High-glucose ingestion 3 h post-exercise leads to greater postprandial blood glucose, non-esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control. Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. ABSTRACT Exercise, insulin-infusion and low-glucose mixed-nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high-glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high-glucose mixed-nutrient meal ingestion. In a randomized cross-over design, eight healthy young men ingested a high-glucose mixed-nutrient meal (1.1 g glucose/kg body weight; 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no-exercise control) and 3 h and 24 h after moderate-intensity cycling exercise (1 h at 70-75% VO2peak ). Skeletal muscle MBF, measured directly by contrast-enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions (P
Published: 2020
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10. Clinical care and therapeutic trials in PLS

Author: Sabrina Paganoni, Hiroshi Mitsumoto, James Wymer, Mary Kay Floeter, Deborah L. Warden, and Dale J. Lange
Subjects: medicine.medical_specialty, Degenerative Disorder, Article, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary approach, Humans, Medicine, Spasticity, Motor Neuron Disease, Amyotrophic lateral sclerosis, Intensive care medicine, Disease burden, Primary Lateral Sclerosis, Motor Neurons, business.industry, Upper motor neuron, Amyotrophic Lateral Sclerosis, medicine.disease, Clinical trial, medicine.anatomical_structure, Neurology, Muscle Spasticity, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Primary lateral sclerosis (PLS) is an extremely rare central nervous system degenerative disorder characterized by slowly progressive upper motor neuron loss leading to severe limb and bulbar dysfunction and disability. Although not necessarily life-shortening, PLS disease burden is substantial and improved symptomatic treatments are a major unmet need, especially for the often refractory spasticity that is a core feature of the syndrome. In Section 1, we describe clinical care needs and emphasize a highly personalized approach that can be best attained through multidisciplinary management. In Section 2, we describe progress in clinical trials in PLS that includes advances in symptomatic treatment, disease-modifying therapy, and emerging innovative trials.
Published: 2020
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11. Mitochondria and chronic effects of cancer therapeutics: The clinical implications

Author: Dale J. Hamilton, Jun Ichi Abe, and Abishai Dominic
Subjects: Senescence, Cell cycle checkpoint, DNA damage, 030204 cardiovascular system & hematology, Mitochondrion, DNA, Mitochondrial, Article, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Neoplasms, Humans, Medicine, 030212 general & internal medicine, Cellular Senescence, business.industry, Cancer, Hematology, Cell cycle, medicine.disease, Mitochondria, Cancer research, Reactive Oxygen Species, Cardiology and Cardiovascular Medicine, business, Reprogramming
Abstract: One of the major mechanisms of action of chemo-radiation is to induce cellular senescence, which exerts crucial roles in age-related pathology. The concept of senescence is evolved, and the novel understanding of senescence-associated reprogramming/stemness has emerged. This new concept emphasizes senescence as not only cell cycle arrest but describes that subsets of senescent cells induced by chemotherapy can re-enter cell cycles, proliferate rapidly, and acquire “stemness” status. Cancer therapeutics, including chemo-radiation triggers toxicity effects through damaging mitochondria, primarily through the upregulation of mtROS production leading to subsequent mtDNA and telomeric DNA damage elicitng DNA damage responses (DDR). . The ultimate goal of this review is to highlight the new concept of senescence-associated stemnessthat is induced by cancer treatment and its adverse effects on the vascular system. . We will describe how chemo-radiation exerts toxicity effects by simultaneously producing reactive oxygen species in mitochondria and promoting DDR in the nucleus. We discuss the potential of clinical targeting poly (ADP-ribose) polymerase which might prevent downstream mitochondrial dysfunction and confer protection to cancer survivors. Overall we emphasize the importance of recognizing the consequences of cardio-toxic effects of several cancer treatments and therefore developing personalized therapeutic approaches to screen for inflammatory and cardiac testing for better patient survival.
Published: 2020
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12. Risk of Breast Cancer Associated with Estrogen DNA Adduct Biomarker

Author: Dale Whittington, Eleanor G. Rogan, Dale J. Langford, Wendy E. Barrington, Lesley F. Tinker, Thomas E. Rohan, Tongguang Cheng, Kerryn W. Reding, Rowan T. Chlebowski, Muhammad Zahid, and Claire J. Han
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, medicine.drug_class, Estrogen receptor, Breast Neoplasms, Urine, Logistic regression, Article, DNA Adducts, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, DNA adduct, Biomarkers, Tumor, Humans, Medicine, business.industry, Estrogens, Odds ratio, Middle Aged, medicine.disease, 030104 developmental biology, Estrogen, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, business
Abstract: Background: It is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women. Methods: In postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs. Results: EDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71–1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer. Conclusions: Despite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC. Impact: This analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.
Published: 2020
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13. Optimizing telehealth pain care after COVID-19

Author: Cara Towle, David J. Tauben, Dale J. Langford, Sean D. Rundell, Michael K. Nicholas, C. Bockman, and John A. Sturgeon
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, Clinical Neurology, Pain, Telehealth, medicine.disease_cause, Betacoronavirus, Behavior Therapy, Pandemic, medicine, Humans, Pain Management, Topical Review, Pandemics, Physical Therapy Modalities, Coronavirus, biology, SARS-CoV-2, Viral Epidemiology, business.industry, COVID-19, medicine.disease, biology.organism_classification, Virology, Telemedicine, Pneumonia, Anesthesiology and Pain Medicine, Neurology, Neurology (clinical), Coronavirus Infections, business
Published: 2020
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14. Postdiagnosis Physical Activity: Association With Long-Term Fatigue and Sleep Disturbance in Older Adult Breast Cancer Survivors

Author: Dale J. Langford, Di Wang, Oleg Zaslavsky, Elizabeth M. Cespedes Feliciano, Alexi Vasbinder, Wendy E. Barrington, Electra D. Paskett, Claire J. Han, and Kerryn W. Reding
Subjects: Gerontology, Breast Neoplasms, Logistic regression, Article, Breast cancer, Cancer Survivors, Surveys and Questionnaires, Intervention (counseling), Humans, Medicine, Prospective Studies, Association (psychology), Prospective cohort study, Exercise, Fatigue, Aged, General Environmental Science, Sleep disorder, Cancer survivor, business.industry, Cancer, medicine.disease, General Earth and Planetary Sciences, Female, Sleep, business
Abstract: Background Physical activity is frequently proposed as an intervention to reduce fatigue and sleep disturbance in cancer survivors; however, the long-term effects of physical activity are often not reported, and older adults are typically excluded from these intervention studies. Objectives This article aimed to examine if postdiagnosis physical activity is associated with lower long-term fatigue and sleep disturbance in older adult breast cancer survivors. Methods Data were analyzed of a prospective cohort of 440 breast cancer survivors aged 65 years or older from the Women's Health Initiative study. Multiple linear and logistic regression models were used to examine associations of physical activity with fatigue and sleep disturbance. Findings Higher postdiagnosis physical activity was associated with lower long-term fatigue but was not associated with lower sleep disturbance after adjusting for demographics, cancer characteristics, and baseline measures.
Published: 2020
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15. Distinct Stress Profiles Among Oncology Patients Undergoing Chemotherapy

Author: Bruce A. Cooper, Dale J. Langford, Janice Humphreys, Fay Wright, Laura B. Dunn, Marilyn J. Hammer, Steven M. Paul, Christine Miaskowski, Yvette P. Conley, and Jon D. Levine
Subjects: Male, media_common.quotation_subject, Perceived Stress Scale, Context (language use), Comorbidity, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Humans, Medicine, 030212 general & internal medicine, Socioeconomic status, General Nursing, media_common, business.industry, Stressor, Resilience, Psychological, medicine.disease, Anesthesiology and Pain Medicine, 030220 oncology & carcinogenesis, Normative, Female, Neurology (clinical), Psychological resilience, business, Psychosocial, Stress, Psychological, Clinical psychology
Abstract: Context Cancer and its treatment are inherently stressful and stress impacts important patient outcomes. Patients vary considerably in their response to stress. Understanding this variability requires a patient-centered multidimensional approach. Objectives The objectives of this study were to identify and characterize patient subgroups with distinct multidimensional stress profiles (stress appraisal, exposure, and adaptation) during cancer treatment. Methods Among 957 patients undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer, latent profile analysis was performed to identify patient subgroups using concurrent evaluations of global (Perceived Stress Scale) and cancer-specific (Impact of Events Scale–Revised) stress, lifetime stress exposure (Life Stressor Checklist–Revised), and resilience (Connor-Davidson Resilience Scale-10). Results Three latent classes were identified: “Normative” (54.3%; intermediate global stress and resilience, lower cancer-related stress, lowest life stress); “Stressed” (39.9%; highest global and cancer-specific stress scores, lowest resilience, most life stress); and “Resilient” (5.7%; lowest global stress, cancer-specific stress comparable to Normative class, highest resilience, intermediate life stress). Characteristics that distinguished the Stressed from the Normative class included the following: younger age, female gender, lower socioeconomic status, unmarried/partnered, living alone, poorer functional status, and higher comorbidity burden. Compared to Stressed patients, Resilient patients were more likely to be partnered, to not live alone, and had a higher functional status. No demographic or clinical characteristics differentiated Normative from Resilient patients. Exposure to specific life stressors differed significantly among the classes. Conclusion A subset of patients warrants intensive psychosocial intervention to reduce stress and improve adaptation to cancer. Intervention efforts may be informed by further study of Resilient patients.
Published: 2020
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16. Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: Insights from the LUNG SAFE study

Author: Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Fernando Rios, T Sottiaux, P Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Uhc Mother Theresa, Hektor Sula, Lordian Nunci, Alma Cani, Villa Maria, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E Mckenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Suresh Shindhe, Dk Maizatul Aiman B Pg Hj Ismail, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E Solis-Quesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Miguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tai Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, Pierre-Louis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, Hans-Bernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Sara Sher, Anna Rossi, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin-Nunomiya Kansuke-Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Dulce M Dector, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra-Rinia, Monique Raaijmakers, Hellen M Van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin Mcarthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L Ruiz-Aguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam-Prieto-González, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran Roche-Campo, Marcos Ibañez-Santacruz, Susana-Temprano, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier-Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel Gonz Á Lez, D Á Cil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Richard O Adamsson, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R JhaMatthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla O'Neill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz De Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C O'Kane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Matt P Wise, Jade M Cole, Caroline C MacFie, Anna T 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L., Schomer, A., Bumbasirevic, V., Jovanovic, B., Surbatovic, M., Veljovic, M., UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, UCL - (SLuc) Service de soins intensifs, Graduate School, Intensive Care Medicine, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Madotto, F, Rezoagli, E, Pham, T, Schmidt, M, Mcnicholas, B, Protti, A, Panwar, R, Bellani, G, Fan, E, Van Haren, F, Brochard, L, Laffey, J, Pesenti, A, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Rubenfeld, G, Thompson, B, Wrigge, H, Slutsky, A, Rios, F, Sottiaux, T, Depuydt, P, Lora, F, Azevedo, L, Bugedo, G, Qiu, H, Gonzalez, M, Silesky, J, Cerny, V, Nielsen, J, Jibaja, M, Matamis, D, Ranero, J, Amin, P, Hashemian, S, Clarkson, K, Kurahashi, K, Villagomez, A, Zeggwagh, A, Heunks, L, Laake, J, Palo, J, Do Vale Fernandes, A, Sandesc, D, Arabi, Y, Bumbasierevic, V, Nin, N, Lorente, J, 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Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin-Nunomiya, Kansuke-Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Dulce M Dector, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra-Rinia, Monique Raaijmakers, Hellen M Van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin Mcarthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L Ruiz-Aguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam-Prieto-González, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran Roche-Campo, Marcos Ibañez-Santacruz, Susana-Temprano, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier-Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel Gonz Á Lez, D Á Cil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Richard O Adamsson, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R JhaMatthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla O'Neill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz De Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C O'Kane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Matt P Wise, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, Jarone Lee, Tomaz Mesar, John O Shinn 3rd, Dina Gomaa, Christopher Tainter, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, and LUNG SAFE Investigators and the ESICM Trials Group, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Renaud M Gueret, Aiman Tulaimat, Shazia Choudry, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Rebecca M Baron, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Vesna Bumbasirevic, Bojan Jovanovic, Maja Surbatovic, Milic Veljovic
Subjects: ARDS, medicine.medical_treatment, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Hyperoxemia, Hypoxemia, law.invention, 0302 clinical medicine, law, Fraction of inspired oxygen, Oxygen therapy, Prevalence, Medicine, Hypoxia, Acute respiratory distress syndrome, Hyperoxia, Invasive mechanical ventilation, Mortality, Respiratory Distress Syndrome, Hyperbaric Oxygenation, Respiration, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Intensive care unit, Intensive Care Units, Anesthesia, Artificial, medicine.symptom, Human, Artificial ventilation, Intensive Care Unit, NO, 03 medical and health sciences, Intensive care, Settore MED/41 - ANESTESIOLOGIA, Humans, business.industry, Research, Respiratory Distress Syndrome, Adult, lcsh:RC86-88.9, medicine.disease, Respiration, Artificial, respiratory tract diseases, Oxygen, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030228 respiratory system, business
Abstract: Background Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55–100 mmHg) patients (P = 0.47). Conclusions Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073
Published: 2020

17. Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice

Author: Varsha M. Prahaladan, Suchismita Acharya, Alison J. Carey, Shadi N. Malaeb, Vineet Bhandari, Dale J. Christensen, Sumita Behera, Ogan K. Kumova, Beamon Agarwal, and Pragnya Das
Subjects: medicine.medical_specialty, Neonatal intensive care unit, QH301-705.5, Hypertension, Pulmonary, Drug Evaluation, Preclinical, Neovascularization, Physiologic, Chitin, Gastroenterology, Catalysis, Article, Pulmonary function testing, Inorganic Chemistry, Mice, Pharmacokinetics, Internal medicine, bronchopulmonary dysplasia, medicine, Animals, Physical and Theoretical Chemistry, Biology (General), Molecular Biology, QD1-999, Spectroscopy, Lung, business.industry, BPD-associated pulmonary hypertension, Organic Chemistry, General Medicine, medicine.disease, Pulmonary hypertension, Computer Science Applications, Rats, Pulmonary Alveoli, Chemistry, Disease Models, Animal, medicine.anatomical_structure, Bronchopulmonary dysplasia, Animals, Newborn, inflammation, Toxicity, AVR-48, chitohexaose, Complication, business
Abstract: Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton’s Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts, total inflammatory cells were decreased in the BALF, Fulton’s Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.
Published: 2021

18. A cross-sectional study of retired Great British Olympians (Berlin 1936 - Sochi 2014):Olympic career injuries, joint health in later life, and reasons for retirement from Olympic sport

Author: Debbie Palmer, Dale J. Cooper, Mark E Batt, and Mary S O'Hanlon
Subjects: musculoskeletal diseases, medicine.medical_specialty, Sports medicine, Cross-sectional study, Joint replacement, injury, medicine.medical_treatment, education, prevalence, Prevalence, Pain, Injury, Physical Therapy, Sports Therapy and Rehabilitation, Osteoarthritis, Logistic regression, Olympians, RC1200, 03 medical and health sciences, 0302 clinical medicine, RA0421, Medicine, Orthopedics and Sports Medicine, pain, Original Research Article, 030212 general & internal medicine, biology, Athletes, business.industry, 030229 sport sciences, Odds ratio, biology.organism_classification, medicine.disease, R1, osteoarthritis, Physical therapy, business, RA, human activities
Abstract: Abstract Background The relationship between Olympic career sport injury and the long-term musculoskeletal health of the elite athlete remains unclear. This study describes the lifetime prevalence of medical attention injuries that occurred during training and/or competition as part of the athlete’s Olympic career, reasons for retirement from Olympic sport, and the point prevalence of pain and osteoarthritis (OA) among retired Great Britain’s (GB) Olympians. Methods This cross-sectional study involved distributing a questionnaire to retired GB Olympians who had competed at 36 Olympic Games between Berlin 1936 and Sochi 2014. The questionnaire captured Olympic career injury history (lasting ≥ 1 month), sport exposure, musculoskeletal pain (last 4 weeks), physician-diagnosed OA, and joint replacement. Injury prevalence was calculated for sports with a minimal of 15 respondents. Adjusted odds ratios (aOR) were estimated in logistic regression for pain, OA, and joint replacement. Models were adjusted for age, sex, BMI, and career duration. Results Six hundred fifty (57.8% male; 42.2% female) retired athletes representing 40 sports (29 summer; 11 winter), aged 60.5 years (range 23–97), completed the questionnaire. Overall, 721 injuries (368 athletes) were self-reported equating to a lifetime Olympic career injury prevalence of 56.6%. Injury prevalence was highest in field athletics (81.0%), gymnastics (75.0%), and track athletics (67.7%). Injuries most frequently occurred at the knee (19.0%), lower back (15.4%), and shoulder (11.5%). Of those injured, 19.5% retired from sport due to injury. Pain was most prevalent at the lumbar spine (32.8%), knee (25.3%), and hip (22.5%), and OA at the knee (13.4%), hip (10.4%), and lumbar spine (4.6%). Injury was associated with pain at the hip (aOR 4.88; 95% CI, 1.87–12.72, p = 0.001), knee (aOR 2.35; 95% CI, 1.45–3.81, p = 0.001), and lumbar spine (aOR 2.53; 95% CI, 1.63–3.92, p < 0.001); OA at the hip (aOR 5.97; 95% CI, 1.59–22.47, p = 0.008) and knee (aOR 3.91; 95% CI, 2.21–6.94, p < 0.001); and joint replacement at the hip (aOR 8.71; 95% CI, 2.13–35.63, p = 0.003) and knee (aOR 5.29; 95% CI, 2.39–11.74, p < 0.001). Conclusion The lifetime prevalence of Olympic career injury was 56.6%, with those injured more likely to self-report current pain and/or OA at the hip, knee, and lumbar spine and joint replacement at the hip and knee.
Published: 2021
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19. The Tuberculosis Drug Accelerator at year 10: what have we learned?

Author: H. Michael Petrassi, Gregory T. Robertson, Carl Nathan, Clifton E. Barry, Kelly Chibale, Dale J. Kempf, Helena I. Boshoff, Joël Lelièvre, Ken Duncan, Bree B. Aldridge, Jeremy M. Rock, Betsy Russell, Peter Warner, Fabian Gusovsky, Michael R. Schrimpf, Véronique Dartois, James C. Sacchettini, Nader Fotouhi, Anne J. Lenaerts, Robert H. Bates, Anna Upton, David B. Olsen, Dirk Schnappinger, David G. Russell, Case W. McNamara, David Barros-Aguirre, Tanya Parish, Kyu Y. Rhee, Philip Arthur Hipskind, Valerie Mizrahi, Paul G. Wyatt, Steven Joseph Berthel, Alexander Pym, Xin-Jie Chu, Eric J. Rubin, Ying Yuan, and Christopher B. Cooper
Subjects: Drug, Medical education, Tuberculosis, Time Factors, Drug discovery, media_common.quotation_subject, MEDLINE, Antitubercular Agents, General Medicine, Intellectual property, Research management, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Drug development, Political science, Drug Design, medicine, Humans, Learning, media_common
Abstract: The Tuberculosis Drug Accelerator, an experiment designed to facilitate collaboration in tuberculosis drug discovery by breaking down barriers among competing labs and institutions, has reached a 10-year landmark. We review the consortium’s achievements, advantages and limitations and advocate for the application of similar models to other diseases.
Published: 2021

20. Lightning NO x Production in the Tropics as Determined Using OMI NO 2 Retrievals and WWLLN Stroke Data

Author: Nickolay A. Krotkov, Kenneth E. Pickering, Dale J. Allen, Robert H. Holzworth, and Eric Bucsela
Subjects: Atmospheric Science, Geophysics, Meteorology, Space and Planetary Science, Earth and Planetary Sciences (miscellaneous), medicine, Tropics, Environmental science, medicine.disease, Stroke, Lightning
Published: 2019
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21. An Acute Pain Service experience initiating methadone for opioid use disorder in hospitalized patients with acute pain

Author: C. Bockman, Dale J. Langford, Katherin A Peperzak, Rebecca Dale, Michelle C. Accardi-Ravid, Andrea K Breuner, Daniel Krashin, Carol L Metcalf, I. Lesnik, and Debra B. Gordon
Subjects: Adult, Male, medicine.medical_specialty, Sedation, Analgesic, Heroin, Clinical pathway, medicine, Humans, Pharmacology (medical), Retrospective Studies, business.industry, Retrospective cohort study, Opioid use disorder, General Medicine, Opioid-Related Disorders, medicine.disease, Acute Pain, Analgesics, Opioid, Anesthesiology and Pain Medicine, Pain Clinics, Emergency medicine, Female, medicine.symptom, business, Methadone, medicine.drug
Abstract: Objective: Inform readers of the use of a clinical pathway that includes initiation of methadone in hospitalized patients with acute pain who have untreated opioid use disorder (OUD). Design: A retrospective chart review with frequency distributions and descriptive statistics calculated to describe demographic and clinical characteristics of the sample. Setting: Urban academic hospital. Patients: One hundred twenty consecutive patients with untreated OUD cared for by the Acute Pain Service (APS). Interventions: APS leadership spearheaded development of a clinical pathway to standardize pain management and optimize outcomes. The authors outline pathway development and describe 120 patients managed using this pathway, initiated on methadone for OUD. Results: The sample included patients, average age 40 years, predominantly non-Hispanic white (74.2 percent), male (61.7 percent), unemployed (88.2 percent), and on Medicaid (84.2 percent). 96.7 percent had a history of heroin use, and 52.1 percent had engaged in previous medication-assisted treatment (MAT). Methadone or other opioids were held for signs of intoxication/sedation in 10.9 percent or for prolonged corrected QT interval in 1.7 percent. The majority received at least one other analgesic agent. For those prescribed opioids upon discharge, the average maximum morphine equivalent dose was 68.2 mg/day for approximately 3 days. 68.3 percent agreed to schedule post-discharge MAT, and of these, 68 percent attended their intake appointment. A small percentage (4.7 percent) left the hospital against medical advice. Conclusion: This pathway provides an example of an effective and safe response to address the opioid epidemic and provide quality care to patients with OUD and pain.
Published: 2019
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22. How Theory Can Help Facilitate Implementing Relaxation as a Complementary Pain Management Approach

Author: Linda H. Eaton, Dale J. Langford, Jennifer P. Hulett, and Ardith Z. Doorenbos
Subjects: Complementary Therapies, Advanced and Specialized Nursing, 030504 nursing, Relaxation (psychology), Diffusion of innovation theory, business.industry, Chronic pain, Complementary therapy, Relaxation Therapy, Pain management, Research findings, medicine.disease, humanities, Research utilization, 03 medical and health sciences, 0302 clinical medicine, Nursing Theory, Nursing, medicine, Humans, Pain Management, 030212 general & internal medicine, 0305 other medical science, business
Abstract: Complementary therapies provide cancer survivors and clinicians with options for managing chronic pain. Recent published clinical guidelines and research findings support the use of relaxation therapy for managing chronic pain in cancer survivors. However, translating research findings into clinical practice remains a challenge. Using theory to guide implementation of a new practice can increase the likelihood of successful adoption. This article uses relaxation therapy for cancer survivors to describe how clinicians could use Rogers’ Diffusion of Innovation Theory and the related Collaborative Research Utilization Model to implement a complementary therapy and ensure that it becomes standard practice.
Published: 2019
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23. Variability in endocrine cell identity in patients with chronic pancreatitis undergoing islet autotransplantation

Author: Christine A. Beamish, Solmaz F. Afshar, Omaima M. Sabek, A. Osama Gaber, Dale J. Hamilton, and Daniel W. Fraga
Subjects: Adult, Male, endocrine system, medicine.medical_specialty, medicine.medical_treatment, Islets of Langerhans Transplantation, 030209 endocrinology & metabolism, Type 2 diabetes, 030230 surgery, Transplantation, Autologous, Islets of Langerhans, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Pancreatitis, Chronic, Internal medicine, Diabetes mellitus, medicine, Humans, Immunology and Allergy, Pharmacology (medical), Transplantation, geography, geography.geographical_feature_category, business.industry, Insulin, Middle Aged, Prognosis, medicine.disease, Islet, Endocrinology, medicine.anatomical_structure, Pancreatectomy, Pancreatitis, Female, Endocrine Cells, Pancreas, business, Biomarkers
Abstract: Beta-cell dedifferentiation as shown by cellular colocalization of insulin with glucagon and/or vimentin, and decreased expression of MAFA and/or urocortin3 has been suggested to contribute to metabolic decompensation in type 2 diabetes, and was recently described postimplantation in islet allotransplant patients. Dysglycaemia and diabetes mellitus are often encountered preoperatively in patients undergoing pancreatectomy and islet autotransplantation (PIAT). In this series of case reports, we document variation in islet phenotypic identity in three patients with chronic pancreatitis (CP) without diabetes or significant insulin resistance who subsequently underwent PIAT. Pancreas histology was examined using colocalization of endocrine hormones, mesenchymal and pan-endocrine markers in islets, and the relative expression of MAFA and urocortin3 in insulin-expressing cells as compared to that of nondiabetic and type 2 diabetic donors. We present results of pre- and posttransplant clinical metabolic testing. Varying degrees of islet-cell dedifferentiation are identified in nondiabetic patients with CP at the time of PIAT, and may need further investigation.
Published: 2019
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24. Management of primary cardiac paraganglioma

Author: Juan P. Umana, Duc T. Nguyen, Edward A. Graviss, Michael J. Reardon, Edward Y. Chan, Areeba Ali, Thomas E. MacGillivray, Vinod Ravi, and Dale J. Hamilton
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, 030204 cardiovascular system & hematology, Heart Neoplasms, Paraganglioma, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, medicine.artery, medicine, Humans, Heart Atria, Retrospective Studies, Intra-aortic balloon pump, Paraganglioma, Extra-Adrenal, Aorta, medicine.diagnostic_test, business.industry, Cardiac Paraganglioma, Magnetic resonance imaging, medicine.disease, Surgery, 030228 respiratory system, Pulmonary artery, Patent foramen ovale, Cardiology and Cardiovascular Medicine, business
Abstract: Objective Cardiac paraganglioma is a rare tumor that most surgeons have limited experience treating. The objective of this study is to examine the management and outcomes for cardiac paraganglioma treatment when cared for by a multidisciplinary cardiac tumor team. Methods We reviewed our institutionally approved cardiac tumor database from March 2004 to June 2020 for cardiac paraganglioma. These prospectively collected data were retrospectively reviewed. Patient characteristics were presented for individual patients and as summary statistics. Demographic and clinical data were also reported as median and interquartile range for continuous variables and frequencies and proportions for categoric variables. Kaplan–Meier curves were used to depict the patient survival from surgery. Results There were 21 cases of primary cardiac paraganglioma, 19 of whom had surgical resection with 3 refusing offered surgery. Of 19 resected tumors, 13 originated from the left atrium and 6 originated from the roots of the pulmonary artery and the aorta. Complex procedures were required, including aortic and pulmonary root replacement and 8 autotransplants. All tumors had complete gross resection with no identifiable disease left behind, but 4 of these had microscopically positive margins. None of the patients had local recurrence of disease. There was 1 case of metastatic paraganglioma with death at 4 years postsurgery. Operative mortality was 10.6%. Survival from surgery was 88.2%, 71.8%, and 71.8% and 1, 5, and 10 years, respectively. Conclusions Cardiac paraganglioma presents a surgical challenge. Mortality and long-term survival after surgical resection are acceptable but may require complex resection and reconstruction.
Published: 2022
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25. First experience in clinical application of hyperspectral endoscopy for evaluation of colonic polyps

Author: Sarah Diamond, Vassiliki L. Tsikitis, Charlie Borzy, Kyla Siemens, Sarah E. Bohndiek, James Joseph, Jonghee Yoon, and Dale J. Waterhouse
Subjects: medicine.medical_specialty, Endoscope, Colorectal cancer, Colonic Polyps, General Physics and Astronomy, Early detection, Colonoscopy, General Biochemistry, Genetics and Molecular Biology, Adenomatous Polyps, medicine, Humans, General Materials Science, Spectral data, neoplasms, Early Detection of Cancer, medicine.diagnostic_test, Crc screening, business.industry, General Engineering, Hyperspectral imaging, General Chemistry, medicine.disease, digestive system diseases, Endoscopy, Radiology, Colorectal Neoplasms, business
Abstract: Early detection and resection of adenomatous polyps prevents their progression to colorectal cancer (CRC), significantly improving patient outcomes. Polyps are typically identified and removed during white-light colonoscopy. Unfortunately, the rate of interval cancers that arise between CRC screening events remains high, linked to poor visualization of polyps during screening and incomplete polyp removal. Here, we sought to evaluate the potential of a hyperspectral endoscope (HySE) to enhance polyp discrimination for detection and resection. We designed, built and tested a new compact HySE in a proof-of-concept clinical study. We successfully collected spectra from three tissue types in seven patients undergoing routine colonoscopy screening. The acquired spectral data from normal tissue and polyps, both pre- and post- resection, were subjected to quantitative analysis using spectral angle mapping and machine learning, which discriminated the data by tissue type, meriting further investigation of HySE as a clinical tool.
Published: 2021
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26. Plumbagin Elicits Cell-Specific Cytotoxic Effects and Metabolic Responses in Melanoma Cells

Author: Anisha A. Gupte, Aijun Zhang, Dale J. Hamilton, and Haoran Zhang
Subjects: Pharmaceutical Science, Oxidative phosphorylation, Mitochondrion, Article, Cell membrane, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacy and materia medica, medicine, melanoma, Cytotoxic T cell, Respiratory function, plumbagin, 030304 developmental biology, chemistry.chemical_classification, reactive oxygen species, 0303 health sciences, Reactive oxygen species, Melanoma, Plumbagin, medicine.disease, RS1-441, mitochondria, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer research, cytotoxic effect, metabolism
Abstract: Melanoma is one of the most malignant skin cancers that require comprehensive therapies, including chemotherapy. A plant-derived drug, plumbagin (PLB), exhibits an anticancer property in several cancers. We compared the cytotoxic and metabolic roles of PLB in A375 and SK-MEL-28 cells, each with different aggressiveness. In our results, they were observed to have distinctive mitochondrial respiratory functions. The primary reactive oxygen species (ROS) source of A375 can be robustly attenuated by cell membrane permeabilization. A375 cell viability and proliferation, migration, and apoptosis induction are more sensitive to PLB treatment. PLB induced metabolic alternations in SK-MEL-28 cells, which included increasing mitochondrial oxidative phosphorylation (OXPHOS), mitochondrial ATP production, and mitochondrial mass. Decreasing mitochondrial OXPHOS and total ATP production with elevated mitochondrial membrane potential (MMP) were observed in PLB-induced A375 cells. PLB also induced ROS production and increased proton leak and non-mitochondria respiration in both cells. This study reveals the relationship between metabolism and cytotoxic effects of PLB in melanoma. PLB displays stronger cytotoxic effects on A375 cells, which exhibit lower respiratory function than SK-MEL-28 cells with higher respiratory function, and triggers cell-specific metabolic changes in accordance with its cytotoxic effects. These findings indicate that PLB might serve as a promising anticancer drug, targeting metabolism.
Published: 2021

27. Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)

Author: Dale J. Christensen, Vineet Bhandari, Stella M. Robertson, Beamon Agarwal, Suchismita Acharya, Pragnya Das, and Dilip Shah
Subjects: Lipopolysaccharides, Male, 0301 basic medicine, ARDS, Lipopolysaccharide, Chitin, Pharmacology, Rats, Sprague-Dawley, sepsis, lcsh:Chemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Lung, lcsh:QH301-705.5, Spectroscopy, Hyperoxia, Respiratory Distress Syndrome, General Medicine, respiratory system, Pulmonary edema, Computer Science Applications, medicine.anatomical_structure, AVR-25, Female, medicine.symptom, Inflammation, Lung injury, Article, Catalysis, Small Molecule Libraries, Inorganic Chemistry, Sepsis, 03 medical and health sciences, Animals, Immunologic Factors, pulmonary edema, Physical and Theoretical Chemistry, Molecular Biology, business.industry, Organic Chemistry, lung inflammation, Pneumonia, medicine.disease, Rats, respiratory tract diseases, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, acute lung injury, lcsh:Biology (General), lcsh:QD1-999, AVR-48, business, 030215 immunology
Abstract: Background: Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary process triggered by a variety of insults including sepsis, viral or bacterial pneumonia, and mechanical ventilator-induced trauma. Currently, there are no effective therapies available for ARDS. We have recently reported that a novel small molecule AVR-25 derived from chitin molecule (a long-chain polymer of N-acetylglucosamine) showed anti-inflammatory effects in the lungs. The goal of this study was to determine the efficacy of two chitin-derived compounds, AVR-25 and AVR-48, in multiple mouse models of ALI/ARDS. We further determined the safety and pharmacokinetic (PK) profile of the lead compound AVR-48 in rats. Methods: ALI in mice was induced by intratracheal instillation of a single dose of lipopolysaccharide (LPS, 100µg) for 24h or exposed to hyperoxia (100% oxygen) for 48h or undergoing cecal ligation and puncture (CLP) procedure and observation for 10 days. Results: Both chitin derivatives, AVR-25 and AVR-48, showed decreased neutrophil recruitment and reduced inflammation in the lungs of ALI mice. Further, AVR-25 and AVR-48 mediated diminished lung inflammation was associated with reduced expression of lung adhesion molecules with improvement in pulmonary endothelial barrier function, pulmonary edema, and lung injury. Consistent with these results, CLP-induced sepsis mice treated with AVR-48 showed a significant increase in survival of the mice (80%) and improved lung histopathology in the treated CLP group. AVR-48, the lead chitin derivative compound, demonstrated a good safety profile. Conclusion: Both AVR-25 and AVR-48 demonstrate the potential to be developed as therapeutic agents to treat ALI/ARDS.
Published: 2021

28. Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

Author: Geert Vandeweyer, Ellen Elinck, Dale J Annear, Courtney E. French, R. Frank Kooy, Lucy Raymond, Alba Sanchis-Juan, and Apollo - University of Cambridge Repository
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Candidate gene, Ataxia, Bioinformatics, Science, Disease, Biology, Genome, Article, Genomic Instability, Human disease, Trinucleotide Repeats, medicine, Humans, Genetic Predisposition to Disease, DNA sequencing, Alleles, Genetic Association Studies, Disease gene, Genetics, Polymorphism, Genetic, Multidisciplinary, Genome, Human, Medical genetics, Computational Biology, Molecular Sequence Annotation, medicine.disease, nervous system diseases, Fragile X syndrome, Neurodevelopmental Disorders, Medicine, Microsatellite Instability, Human genome, Nervous System Diseases, medicine.symptom, Trinucleotide Repeat Expansion, Engineering sciences. Technology
Abstract: Funder: Marguerite-Marie Delacroix foundation, Funder: Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO), Funder: NIHR BioResource, Funder: Rosetrees Trust, Newton Trust, National Institute for Health Research (NIHR) for the Cambridge Biomedical Research Centre, Funder: Methusalem-OEC grant – “GENOMED”, Expanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.
Published: 2021
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29. Research productivity and collaboration of the NIH-funded HIV vaccine trials network: A bibliometric analysis

Author: Jonathan Nye, Dale J. Hu, Dolan Ghosh, and M. Patricia D'Souza
Subjects: 0301 basic medicine, Bibliometric analysis, HIV vaccine, Human immunodeficiency virus (HIV), Library science, Outcomes, Bibliometrics, medicine.disease_cause, Original research, Scientific productivity, 03 medical and health sciences, 0302 clinical medicine, Acquired immunodeficiency syndrome (AIDS), Political science, Global network, medicine, lcsh:Social sciences (General), lcsh:Science (General), Productivity, Medical education, Multidisciplinary, HIV, medicine.disease, Clinical trial, 030104 developmental biology, lcsh:H1-99, Citation, 030217 neurology & neurosurgery, Research Article, lcsh:Q1-390
Abstract: The HIV Vaccine Trials Network (HVTN) is the world's largest publicly funded, multi-disciplinary international collaboration facilitating the development of vaccines to prevent HIV/AIDS and has conducted the vast majority of HIV/AIDS clinical trials since its inception in 1999. Although scientific findings from the program have been published in scholarly journals, the impact of a large scientific research network such as the HVTN on the HIV/AIDS vaccine field has not been assessed. This paper describes and elucidates the productivity, influence, and collaboration among HVTN researchers over the last two decades. Our analyses indicate that the HVTN has funded a large number of HIV/AIDS vaccine safety and efficacy clinical trials through a strong global network of clinical sites. In addition, several metrics indicate HVTN researchers also published original research articles that are influential in the HIV vaccine field. Scientific research collaboration is critically important in a complex and multidisciplinary field such as HIV vaccine development as it allows improved sharing of knowledge and expertise as well as the pooling of resources and data. We found that collaboration in the HIV vaccine field increased during this time period and collaboration among HVTN authors increased even more. Combining these productivity, influence, and collaboration metrics with research outcomes can provide a comprehensive assessment of large complex programs such as the HVTN., Bibliometrics; Outcomes; HIV vaccine; HIV
Published: 2021

30. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author: Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract: Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
Published: 2020
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31. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Author: Armineuza Evora, Eric A. Macklin, Adel Marei, P. Davila-Pérez, Seward B. Rutkove, Brian J. Wainger, William S. David, Courtney E. McIlduff, James D. Berry, Joan A. Camprodon, Clifford J. Woolf, Bjorn Oskarsson, Nicholas J. Maragakis, Nazem Atassi, Richard A. Lewis, Richard Bedlack, Sean K. Meehan, Evangelos Kiskinis, Shafeeq Ladha, Alvaro Pascual-Leone, Karissa L. Gable, Matthew C. Kiernan, Aura Hurtado, João D. Pereira, Elizabeth A. Mauricio, Zachary Simmons, Divpreet Kaur, Nicolas Phielipp, Sylvia Baedorf Kassis, Robert H. Baloh, Michael D. Weiss, Kevin Eggan, Merit Cudkowicz, Pablo Celnik, David Klements, Peter B. Rosenquist, Lindsay Pothier, Thuong La, Joan Koh, Meghan Hall, Namita Goyal, Sabrina Paganoni, Steve Vucic, Dale J. Lange, Jeremy M. Shefner, Vern C. Juel, Vinay Chaudhry, Stephen A. Goutman, and Michael H. Rivner
Subjects: Male, medicine.medical_treatment, Phenylenediamines, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Motor system, medicine, Humans, 030212 general & internal medicine, Amyotrophic lateral sclerosis, Aged, Original Investigation, Cerebral Cortex, Motor Neurons, Dose-Response Relationship, Drug, business.industry, Amyotrophic Lateral Sclerosis, Motor neuron, Middle Aged, medicine.disease, Transcranial magnetic stimulation, Clinical trial, medicine.anatomical_structure, Treatment Outcome, Spinal Cord, Anesthesia, Pharmacodynamics, Anticonvulsants, Female, Neurology (clinical), Carbamates, business, 030217 neurology & neurosurgery
Abstract: IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI(−1) was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. RESULTS: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI(−1) increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI(−1) did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P
Published: 2020

32. Abstract 13885: Phenotyping Risk Profiles for Heart Failure With Preserved and Reduced Ejection Fraction Among Breast Cancer Survivors

Author: Dale J. Langford, Michael S. Simon, Garnet L. Anderson, Abu Taiyab Nazmus Saquib, Kerryn W. Reding, Mary Branch, Bette J. Caan, Alexi Vasbinder, Richard Cheng, Ana Barac, Aladdin H. Shadyab, and Roberta M. Ray
Subjects: education.field_of_study, medicine.medical_specialty, Ejection fraction, business.industry, Population, medicine.disease, Risk profile, Increased risk, Breast cancer, Physiology (medical), Heart failure, Internal medicine, medicine, Cardiology, Cardio oncology, Cardiology and Cardiovascular Medicine, education, business
Abstract: Introduction: Breast cancer (BC) survivors (BCS) are at increased risk for incident heart failure (HF). In this population, the risk for HF with preserved ejection fraction (HFpEF) has been understudied compared to HF with reduced EF (HFrEF). The purpose of this study was to estimate 1) the incidence of HFpEF and HFrEF, and 2) the phenotypic profiles conferring risk for incident HFpEF and HFrEF in BCS. Methods: This Women’s Health Initiative analysis was conducted in women with invasive BC stages I-IV in the Medical Records Cohort (MRC). Those with pre-existing HF were excluded. Exposures of interest were lifestyle factors [e.g. body mass index (BMI)], comorbidities [e.g. hypertension, diabetes, and myocardial infarction (MI)], and BC treatment. Lifestyle factors and comorbidities most proximal and prior to BC diagnosis were assessed. In the MRC, BC and HF as well as left ventricular EF (LVEF) were ascertained through chart review and physician-adjudication. LVEF ≥50% was classified as HFpEF; and Results: In 2,250 BCS, 153 developed HF after BC during a median follow-up of 7.3 years. Of those, 49 had HFrEF and 75 had HFpEF. The cumulative incidences of HFrEF and HFpEF over follow-up were 7.3% and 4.6%, respectively. Diabetes and MI were associated with both HFpEF and HFrEF (Table). Smoking, BMI ≥30, and hypertension were associated with HFpEF. Anthracycline use was associated with HFrEF but not HFpEF (p=0.03). Conclusions: In BCS, lifestyle factors were associated with incident HFpEF, whereas anthracycline use was associated with a higher risk for HFrEF. Understanding risk factors associated with incident HFpEF and HFrEF in BCS is important to guide the implementation of risk profile-specific preventative measures and interventions.
Published: 2020
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33. Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

Author: Martin Stangel, K. George, Inna Rubanovits, A. Kutschenko, Michael Schroeter, Juliane Klehmet, Tsugio Akutsu, Robert D. Henderson, S. Mumfrey, Takuya Ohkubo, Helmar C. Lehmann, Mari Auranen, Paul Bassett, Giuseppe Lauria, A. Di Muzio, Kenichi Kaida, David Yarnitsky, S. Larue, R. Gold, Fabian Klostermann, Karissa L. Gable, Ivo N. van Schaik, Gens Sobue, A Schenone, U. Sorro, Jeffrey A. Allen, S. Attarian, A. Algom, U. Chyrchel-Paszkiewicz, J. Haas, Jens Ejbye Schmidt, I. N. van Schaik, Jasper M. Morrow, Ingemar S. J. Merkies, R. Carne, C. Marquez Infante, Michael P. Lunn, Khema Sharma, E. Chi Ho Lai, Billie L. Durn, Satoshi Kuwabara, D. Kramer, David Gosal, P. MacDonald, Janneke G. J. Hoeijmakers, Giovanni Antonini, Senda Ajroud-Driss, S. Muley, Takanori Yokota, Tim Hagenacker, Eroboghene E. Ubogu, M. Kawai, Maria Salvado, Jean Pouget, Mika Saarela, John T. Kissel, Alexander Shtilbans, K. Kanai, B. Murinson, Olaf Hoffmann, Claudia Sommer, Sandro Sorbi, P. Berlit, Norman Latov, Nora A. Visser, C. G. Faber, A. Wielanek, J. Demeestere, Ericka Simpson, Ginna Gonzalez, Konrad Rejdak, C. Casanovas Pons, Alessandro Testori, Orell Mielke, T. Kalous, Alexa Cleasby, Vera Bril, J. Sussova, D. Mueller, Katrin Gross-Paju, Dale J. Lange, Nicolette C. Notermans, Florian Then Bergh, R. Talab, Kazumasa Yokoyama, M. Zibetti, C. Trebst, Marina Grandis, Miriam Freimer, E. Delmon, David R. Cornblath, Masahiro Mori, H. Onoue, Richard J. Barohn, D. Liebetanz, M. Chatzopoulos, J. Oechtering, F. Ciccocioppo, T. Rao, P. Van Damme, A. Sabet, Takashi Kanda, J. Zschuentzsch, Hans-Peter Hartung, S. Benitez, D. Aufauvre, M. Bednar, M. Tomiyama, G. Le Masson, C. D'Amour, Richard A. Lewis, Anne D. Sperfeld, I. Melamed, Lisa D. Hobson-Webb, Stefan Blum, Dario Cocito, K. Nishiyama, Daniele Cazzato, F. Bethke, Toomas Toomsoo, Said R. Beydoun, Leslie Roberts, David Walk, Josep Gamez, Masahiro Iijima, A. Jaspert-Grehl, Israel V. Drory, P. Kunc, John-Philip Lawo, C. Goerlitz, H. Johl, R. Yoon, Daniela M. Menichella, T. Lavin, Stefania Morino, K. Ohyama, Masayuki Baba, M. Antonia, Shafeeq Ladha, Claude Desnuelle, Pierre Clavelou, Andreas Meisel, Martin Vališ, Filip Eftimov, P. Baum, Sabrina Matà, Russell L. Chin, Mazen M. Dimachkie, ANS - Neuroinfection & -inflammation, Neurology, and AII - Inflammatory diseases
Subjects: Research design, CIDP, immunoglobulin, non-relapse, placebo, relapse, Humans, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Immunologic Factors, Outcome Assessment, Health Care, Placebo Effect, Randomized Controlled Trials as Topic, Research Design, Research Report, medicine.medical_specialty, Outcome Assessment, SUBCUTANEOUS IMMUNOGLOBULIN, Polyradiculoneuropathy, non‐relapse, Severe disease, PLASMA-EXCHANGE, Chronic inflammatory demyelinating polyneuropathy, Placebo, THERAPY, Immunoglobulin G, 03 medical and health sciences, DOUBLE-BLIND, 0302 clinical medicine, Internal medicine, Clinical endpoint, Medicine, Chronic Inflammatory Demyelinating, biology, business.industry, General Neuroscience, INTRAVENOUS IMMUNOGLOBULIN TREATMENT, Research Reports, medicine.disease, Health Care, INTERFERON BETA-1A, 030220 oncology & carcinogenesis, biology.protein, TRIAL, Neurology (clinical), business, Polyneuropathy, 030217 neurology & neurosurgery
Abstract: The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.
Published: 2020

34. A specific biomarker for amyotrophic lateral sclerosis: Quantitative susceptibility mapping

Author: Beiyi Shen, Kathryn E. Dean, Andrew D. Schweitzer, Yi Wang, Gulce Askin, Apostolos John Tsiouris, Dale J. Lange, and Mona Shahbazi
Subjects: medicine.medical_specialty, Optimal cutoff, Imaging biomarker, business.industry, Amyotrophic Lateral Sclerosis, Leukoaraiosis, Motor Cortex, Retrospective cohort study, Quantitative susceptibility mapping, medicine.disease, Magnetic Resonance Imaging, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Biomarker (medicine), Humans, Radiology, Nuclear Medicine and imaging, Radiology, Amyotrophic lateral sclerosis, Medical diagnosis, business, Biomarkers, Retrospective Studies
Abstract: Accurate and timely diagnosis of amyotrophic lateral sclerosis (ALS) is a diagnostic challenge given the lack of specific diagnostic and imaging biomarkers as well as the significant clinic overlap with mimic syndromes. We hypothesize that MR quantitative susceptibility mapping (QSM) can help differentiate ALS from mimic diagnoses.In a blinded retrospective study of MRIs with QSM from 2015 to 2018, we compared motor cortex susceptibility along the hand and face homunculi in ALS patients and patients with similar clinical presentations. Inclusion required a confirmed ALS or a mimic diagnosis. Comparative groups included age-matched patients with MRIs performed for non-motor neuron symptoms that were reported as normal or demonstrated leukoaraiosis. Quantitative susceptibility values were compared with ANOVA and Tukey-Kramer (post-hoc). ROC analysis and Youden's index were used to identify optimal cutoff values.Fifty ALS, 35 mimic, and 70 non-motor neuron symptom patients (35 normal, 35 leukoaraiosis) were included. Hand and face homunculus mean susceptibility values were significantly higher in the ALS group compared to the mimic (p=0.001, p=0.004), leukoaraiosis (p0.001, p=0.003), and normal (p0.001, p0.001) groups. ROC curve analysis comparing ALS to mimics resulted in an area under the curve of 0.71 and 0.67 for the hand and face homunculus measurements, respectively. In differentiating ALS from mimics, Youden's index showed 100% specificity and 36% sensitivity for hand homunculus measurements.QSM has diagnostic potential in the assessment of suspected ALS patients, demonstrating very high specificity in differentiating ALS from mimic diagnoses.
Published: 2020

35. High-glucose mixed-nutrient meal ingestion impairs skeletal muscle microvascular blood flow in healthy young men

Author: Michelle A. Keske, Christopher S. Shaw, Lewan Parker, Katherine Roberts-Thomson, Glenn D. Wadley, Gunveen Kaur, Dale J. Morrison, and Andrew C. Betik
Subjects: Adult, Blood Glucose, Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Blood volume, Microcirculation, Young Adult, Insulin resistance, Heart Rate, Physiology (medical), Internal medicine, medicine, Ingestion, Humans, Insulin, Muscle, Skeletal, Meals, Ultrasonography, business.industry, Area under the curve, Blood flow, medicine.disease, Postprandial Period, Healthy Volunteers, Femoral Artery, Endocrinology, Postprandial, Glucose, Thigh, Regional Blood Flow, Hyperglycemia, business, Blood Flow Velocity
Abstract: Oral glucose ingestion leads to impaired muscle microvascular blood flow (MBF), which may contribute to acute hyperglycemia-induced insulin resistance. We investigated whether incorporating lipids and protein into a high-glucose load would prevent postprandial MBF dysfunction. Ten healthy young men (age, 27 yr [24, 30], mean with lower and upper bounds of the 95% confidence interval; height, 180 cm [174, 185]; weight, 77 kg [70, 84]) ingested a high-glucose (1.1 g/kg glucose) mixed-nutrient meal (10 kcal/kg; 45% carbohydrate, 20% protein, and 35% fat) in the morning after an overnight fast. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh MBF was measured via contrast-enhanced ultrasound, before meal ingestion and 1 h and 2 h postprandially. Blood glucose and plasma insulin were measured at baseline and every 15 min throughout the 2-h postprandial period. Compared with baseline, thigh muscle microvascular blood volume, velocity, and flow were significantly impaired at 60 min postprandial (−25%, −27%, and −46%, respectively; all P < 0.05) and to a greater extent at 120 min postprandial (−37%, −46%, and −64%; all P < 0.01). Heart rate and femoral arterial diameter, blood velocity, and blood flow were significantly increased at 60 min and 120 min postprandial (all P < 0.05). Higher blood glucose area under the curve was correlated with greater MBF dysfunction ( R2 = 0.742; P < 0.001). Ingestion of a high-glucose mixed-nutrient meal impairs MBF in healthy individuals for up to 2 h postprandial.
Published: 2020

36. Evaluating the Relationship Between Initial Injury, Referral to A Pain Clinic, and Medical Retirement from the Army: A Retrospective Analysis

Author: Honor McQuinn, Justin J. Stewart, Dale J. Langford, Diane M Flynn, Ardith Z. Doorenbos, and Alana Steffen
Subjects: Adult, medicine.medical_specialty, Referral, 0211 other engineering and technologies, 02 engineering and technology, Logistic regression, Odds, 03 medical and health sciences, 0302 clinical medicine, Outcome variable, medicine, Retrospective analysis, Humans, Referral and Consultation, Retrospective Studies, 021110 strategic, defence & security studies, Retirement, business.industry, Public Health, Environmental and Occupational Health, Chronic pain, General Medicine, Pain management, medicine.disease, Pain Clinics, Military Personnel, Physical therapy, Supplement Article, business, 030217 neurology & neurosurgery
Abstract: Introduction Soldiers are expected to deploy worldwide and must be medically ready in order to accomplish their mission. Soldiers unable to deploy for an extended period of time because of chronic pain or other conditions undergo an evaluation for medical retirement. A retrospective analysis of existing longitudinal data from an Interdisciplinary Pain Management Center (IPMC) was used to evaluate the temporal relationship between the time of initial duty restriction and referral for comprehensive pain care to being evaluated for medical retirement. Methods Patients were adults (>18 years old) and were cared for in an IPMC at least once between May 1, 2014 and February 28, 2018. A total of 1,764 patients were included in the final analysis. Logistic regression was used to evaluate the impact of duration between date of first duty restriction documentation and IPMC referral to the outcome variable of establishment of a permanent 3 (P3) profile. Results The duration between date of first duty restriction and IPMC referral showed a curvilinear relationship to probability of a P3 profile. According to our model, a longer duration before referral is associated with an increased probability of a subsequent P3 profile with the highest probability peaking at 19 months. The probability of P3 declines gradually for those who were referred later. Discussion This is the first time the relationship between time of initial duty restriction, referral to an IPMC, and subsequent P3 or higher profile has been tested. Future research is needed to examine medical conditions listed on the profile to see how they might contribute to the cause of referral to the IPMC. Conclusion A longer duration between initial duty restriction and referral to IPMC was associated with higher odds of subsequent P3 status for up to 19 months. Referral to an IPMC for comprehensive pain care early in the course of chronic pain conditions may reduce the likelihood of P3 profile and eventual medical retirement of soldiers.
Published: 2020

37. MP51-13 ENHANCED MITOCHONDRIAL COMPLEX II FLUX IN HUMAN PROSTATE CANCER

Author: Alberto G. Ayala, Brian J. Miles, Aijun Zhang, Dale J. Hamilton, Anisha A. Gupte, Somik Chatterjeee, and Indira Vedula
Subjects: business.industry, Urology, Cancer research, Medicine, Cancer, Mitochondrial Complex II, business, medicine.disease, Flux (metabolism), Human prostate
Published: 2020
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38. Development of a clinically translatable hyperspectral endoscopy (HySE) system and analysis methods for the improved diagnosis of gastrointestinal disease (Conference Presentation)

Author: Wladyslaw Januszewicz, Jonghee Yoon, Siri Luthman, James Joseph, Rebecca C. Fitzgerald, Dale J. Waterhouse, Sarah E. Bohndiek, George S. D. Gordon, Massimiliano di Pietro, and Alexandru Grigoroiu
Subjects: CMOS sensor, medicine.diagnostic_test, business.industry, Computer science, Machine vision, Hyperspectral imaging, Iterative reconstruction, medicine.disease, Endoscopy, Gastrointestinal disease, Distortion, medicine, Computer vision, Artificial intelligence, business, Spectrograph
Abstract: Hyperspectral imaging techniques measure spatial and spectral information, which enables discrimination between healthy tissue and lesions. Hyperspectral imaging applications in endoscopy for clinical diagnostic applications are still limited due to image distortion challenges that arise when working with a flexible endoscope, for example in the gastrointestinal tract. Here, we developed a hyperspectral endoscopy (HySE) system by exploiting a line-scanning spectrograph to measure spectral information at high spectral resolution and combining it with a CMOS camera that records wide-field images for hyperspectral image reconstruction. Moreover, we developed an image normalisation method using near-infrared light to obtain accurate hyperspectral signals by correcting uneven illumination conditions during clinical endoscopy. Our next step is to apply HySE to patients to identify abnormal features in the gastrointestinal tract in vivo.
Published: 2020
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39. Telementoring for improving primary care provider knowledge and competence in managing chronic pain: A randomised controlled trial

Author: Dale J. Langford, Tessa Rue, Daniel S. Godfrey, Linda H. Eaton, David J. Tauben, and Ardith Z. Doorenbos
Subjects: Adult, Male, Health Knowledge, Attitudes, Practice, medicine.medical_specialty, 020205 medical informatics, Health Personnel, Health Informatics, 02 engineering and technology, Primary care, Telehealth, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, 0202 electrical engineering, electronic engineering, information engineering, medicine, Humans, Pain Management, 030212 general & internal medicine, Competence (human resources), Aged, Primary Health Care, business.industry, Professional development, Chronic pain, Middle Aged, Pain management, medicine.disease, Telemedicine, Physical therapy, Female, Clinical Competence, Chronic Pain, Tele education, business
Abstract: Introduction Primary care providers are frequently unprepared to manage chronic pain adequately due in part to insufficient professional training. This study evaluated the effect of a telementoring intervention on knowledge and perceived competence related to chronic pain management. Methods The study design was a cluster randomised controlled trial. Primary care clinics that were part of the University of Washington Medicine Telehealth network were the unit of randomization. Primary care providers comprised the intervention group ( n = 23) and the control group ( n = 18). Providers in the intervention group attended telementoring sessions through the TelePain programme and presented patient cases at the beginning and end of their enrolled patients’ 12-week study period. TelePain sessions included a didactic presentation and telementoring for specific patient cases by a panel of pain specialists from the disciplines of pain medicine, internal medicine, anaesthesiology, rehabilitation medicine, psychiatry, addiction medicine, nursing and complementary and integrative pain management. Providers’ baseline and end-of-study knowledge and perceived competence in managing chronic pain were assessed by three questionnaires: Knowledge and Attitudes Survey Regarding Pain, the KnowPain-12 and the Perceived Competence Scale. Results Knowledge (Z = –0.34, p = 0.97 (Knowledge and Attitudes Survey Regarding Pain) and Z = 0.49, p = 0.62 (KnowPain-12)) and perceived competence (Z = –0.74, p = 0.46) did not increase for providers in the intervention group compared with providers in the control group. These providers attended on average 12.5 sessions (range 0–31) while participating in the study. Discussion Further research is recommended to establish the effectiveness of this telementoring intervention.
Published: 2018
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40. Emerging optical methods for endoscopic surveillance of Barrett's oesophagus

Author: Sarah E. Bohndiek, Massimiliano di Pietro, Catherine R. M. Fitzpatrick, and Dale J. Waterhouse
Subjects: medicine.medical_specialty, Standard of care, Esophageal Neoplasms, Oesophageal adenocarcinoma, Adenocarcinoma, Malignancy, Sensitivity and Specificity, Barrett Esophagus, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Medicine, New device, Early Detection of Cancer, Curative intent, Hepatology, business.industry, Optical Imaging, Gastroenterology, medicine.disease, digestive system diseases, Highly sensitive, 030220 oncology & carcinogenesis, White light endoscopy, Barrett's oesophagus, 030211 gastroenterology & hepatology, Esophagoscopy, Radiology, business
Abstract: Barrett's oesophagus is an acquired metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma, prompting the use of surveillance regimes to detect early malignancy for endoscopic therapy with curative intent. The currently accepted surveillance regime uses white light endoscopy together with random biopsies, but has poor sensitivity and discards information from numerous light-tissue interactions that could be exploited to probe structural, functional, and molecular changes in the tissue. Advanced optical methods are now emerging that are highly sensitive to these changes and hold potential to improve surveillance of Barrett's oesophagus if they can be applied endoscopically. The next decade will see some of these exciting new methods applied to surveillance of Barrett's oesophagus in new device architectures for the first time, potentially leading to a long-awaited improvement in the standard of care.
Published: 2018
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41. Number and Type of Post-Traumatic Stress Disorder Symptom Domains Are Associated With Patient-Reported Outcomes in Patients With Chronic Pain

Author: David J. Tauben, Ardith Z. Doorenbos, Christine Tran, Mark Sullivan, Dale J. Langford, Danica Balsiger, and Brian R. Theodore
Subjects: Adult, Male, Adolescent, media_common.quotation_subject, Context (language use), behavioral disciplines and activities, Article, Stress Disorders, Post-Traumatic, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Quality of life, mental disorders, medicine, Humans, Patient Reported Outcome Measures, 030212 general & internal medicine, Aged, Pain Measurement, media_common, Aged, 80 and over, business.industry, Chronic pain, Traumatic stress, Middle Aged, medicine.disease, Substance abuse, Cross-Sectional Studies, Anesthesiology and Pain Medicine, Mood, Pain Clinics, Neurology, Feeling, Female, Neurology (clinical), Chronic Pain, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Post-Traumatic Stress Disorder (PTSD) commonly accompanies complex chronic pain, yet PTSD is often overlooked in chronic pain management. Using the 4-item Primary Care (PC)-PTSD screening tool, we evaluated the relationship between the number and type of PC-PTSD symptoms endorsed and a set of patient-reported outcomes, including: pain intensity and interference; function; mood; quality of life; and substance abuse risk in a consecutive sample of patients with chronic pain (n=4,402). Patients completed PainTracker(™), a web-based patient-reported outcome tool that provides a multidimensional evaluation of chronic pain, as part of their intake evaluation at a specialty pain clinic in a community setting. Twenty-seven percent of the sample met PC-PTSD screening criteria for PTSD by endorsing three of the four symptom domains. Significant ordinal trends were observed between increasing number of PTSD symptoms and all outcomes evaluated. The occurrence of even one PTSD symptom was associated with overall poorer outcomes, suggesting that subsyndromal PTSD is clinically significant in the context of chronic pain. Among the four PTSD domains assessed, “numbness/detachment” was most strongly associated with negative pain outcomes by relative weight analysis. Results from this cross-sectional study suggest that a range of pain-related outcomes may be significantly related to co-morbid PTSD. PERSPECTIVE: We present evidence that PTSD symptoms are significantly related to a broad set of pain-related patient-reported outcomes. These findings highlight the need to evaluate for PTSD symptoms in patients with chronic pain, especially feelings of numbness or detachment from others, in order to improve understanding and management of chronic pain.
Published: 2018
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42. Treat the Patient, Not the Pain: Using a Multidimensional Assessment Tool to Facilitate Patient-Centered Chronic Pain Care

Author: Daniel S. Godfrey, Mark Sullivan, Dale J. Langford, David J. Tauben, Ardith Z. Doorenbos, and John A. Sturgeon
Subjects: medicine.medical_specialty, MEDLINE, Multidimensional assessment, 03 medical and health sciences, 0302 clinical medicine, Patient-Centered Care, Internal Medicine, medicine, Humans, Pain Management, Patient Reported Outcome Measures, 030212 general & internal medicine, Concise Research Reports, Pain Measurement, Primary Health Care, Extramural, business.industry, Chronic pain, Patient-centered care, Pain management, medicine.disease, Physical therapy, Chronic Pain, business, 030217 neurology & neurosurgery, Patient centered
Published: 2018
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43. Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation

Author: Masaki Imanishi, Ying H. Shen, Eugenie S. Kleinerman, Yisang Yoon, Sevinj Isgandarova, Tamlyn N. Thomas, Elena McBeath, Sunil Krishnan, Anisha A. Gupte, Sarah A. Milgrom, Zarana S. Patel, Sanjay B. Maggirwar, Jared K. Burks, Nhat-Tu Le, Diana N Amaya, Mark L. Entman, Jose Banchs, Kyung Ae Ko, John P. Cooke, Sivareddy Kotla, Jun Ichi Abe, Margie Moczygemba, Aijun Zhang, Keri Schadler, Giovanni Schifitto, Dale J. Hamilton, Steven H. Lin, Joerg Herrmann, Keigi Fujiwara, Young Jin Gi, Paul S. Brookes, Anita Deswal, Syed Wamique Yusuf, Caroline Chung, and Huifang Guo
Subjects: Ionizing radiation, Medicine (General), Programmed cell death, QH301-705.5, Ribose, Poly ADP ribose polymerase, Clinical Biochemistry, Population, Poly (ADP-Ribose) Polymerase-1, Coronary Artery Disease, Mitochondrion, Biochemistry, Antioxidants, Feedback, Mice, R5-920, medicine, Animals, Humans, Phosphorylation, Biology (General), Efferocytosis, education, Mitogen-Activated Protein Kinase 7, chemistry.chemical_classification, Reactive oxygen species, education.field_of_study, Telomere length, Organic Chemistry, Cancer, Atherosclerosis, medicine.disease, Mitochondrial stunning, Mitochondria, Adenosine Diphosphate, Phenotype, ERK5, chemistry, Senescence-associated secretory phenotype (SASP), Poly (ADP-Ribose) polymerase, Cancer research, Poly(ADP-ribose) Polymerases, p90RSK, Research Paper
Abstract: The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors., Graphical abstract Image 1, Highlights • High-throughput screening detects chemo-radiation as p90RSK-ERK5 modulator, which induces senescence-associated secretory phenotype (SASP). • Chemo-radiation instigates mitochondrial (mt) stunning (reversible mt dysfunction without showing any cell death under ATP depletion). • Mt stunning is provoked by p90RSK-ERK5 modulation and PARP activation, which forms a nucleus-mitochondria positive feedback loop. • This feedback loop reprogramed myeloid cells (MCs) to induce a sustained SASP state, and ultimately prime MCs to be more sensitive to reactive oxygen species. • When PARP activity is transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis are all eradicated.
Published: 2021
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44. Abstract 642: Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer

Author: Andrew Thrasher, Samuel W. Brady, Yu Liu, Brent A. Orr, Roya Mostafavi, Scott G. Foy, Mark C. Wilkinson, Liza-Marie Johnson, Jinghui Zhang, Antonina Silkov, Lynn W. Harrison, David A. Wheeler, Elizabeth M Azzato, Chimene Kesserwan, Lu Wang, Armita Bahrami, Alberto S. Pappo, Stacy Hines-Dowell, Leslie Taylor, Regina Nuccio, Charles G. Mullighan, Manish Kubal, Yanling Liu, Joy Nakitandwe, Jay Knight, David W. Ellison, Elsie L. Gerhardt, Rose B. McGee, Scott Newman, Kim E. Nichols, Jeffery M. Klco, Jing Wang, Michael R. Clay, Michael N. Edmonson, James R. Downing, Xin Zhou, Sheila A. Shurtleff, Delaram Rahbarinia, Dale J. Hedges, Giles W. Robinson, Emily Quinn, Jamie L. Maciaszek, Jessica M. Valdez, Jiali Gu, Ching-Hon Pui, Kayla V. Hamilton, Michael Rusch, Zhaojie Zhang, and Annastasia A. Ouma
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Context (language use), medicine.disease, Pediatric cancer, DNA sequencing, Germline, MUTYH, Internal medicine, PMS2, Medicine, business, Exome
Abstract: Clinical genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. In the Genomes for Kids study (NCT02530658) we used a three-platform sequencing approach, including whole genome (WGS), whole exome (WES) and RNA sequencing, to examine tumor and paired germline genomes from prospectively identified children with cancer. The goal of the study was to assess the potential of comprehensive next generation sequencing to elucidate the molecular mechanisms underlying tumor formation and investigate the potential of this information to influence clinical decision-making.The cohort, with a median age of 6 yrs, range 0 - 26 yrs, included 301 patients with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type or stage. Patients with hematologic malignancies accounted for 41% of cases, 31% had CNS tumors, and 28% had other non-CNS solid tumors. This cohort also included 18 patients with very rare tumor types, defined here as occurring in less than 2 cases per million person per year.Two hundred fifty three patients (84%) had sufficient tumor for three-platform sequencing and all 301 had adequate paired germline samples. Following analysis, 86% of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer predisposing (18%) variants. The inclusion of WGS enabled detection of oncogenic gene fusions, as well as 22 cases in which oncogenes were activated through enhancer hijacking, a particularly frequent occurrence in hematologic malignancies. In addition, WGS effectively detected clinically relevant small intragenic deletions (15% of tumors) and a variety of mutational signatures, which were not detectable through analysis of whole exome data. Evaluation of 56 pathogenic germline variants in the context of paired tumor sequence data helped establish the disease relevance of several genes that are not typically associated with the cancer type in question, providing critical insights on a case-by-case basis. Examples include a pathogenic germline variant in MUTYH in a patient with retinoblastoma whose tumor exhibited a mutation signature associated with reactive oxygen species indicative of loss of MUTYH function; and conversely, a likely pathogenic variant in PMS2 in a rare brain cancer, which did not exhibit a mutation signature associated with microsatellite instability. This study successfully demonstrated the power of this three-platform approach to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. As a result of these findings, we have incorporated this three-platform approach into our routine real-time clinical service at St. Jude Children's Hospital. Citation Format: David A. Wheeler, Scott Newman, Joy Nakitandwe, Chimene A. Kesserwan, Elizabeth M. Azzato, Michael C. Rusch, Sheila Shurtleff, Armita Bahrami, Brent Orr, Jeffery M. Klco, Dale J. Hedges, Kayla V. Hamilton, Scott G. Foy, Michael N. Edmonson, Andrew Thrasher, Jiali Gu, Lynn W. Harrison, Lu Wang, Roya Mostafavi, Manish Kubal, Jamie Maciaszek, Michael Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W. Brady, Xin Zhou, Mark Wilkinson, Delaram Rahbarinia, Jay Knight, Jian Wang, Charles G. Mullighan, Rose B. McGee, Emily A. Quinn, Elsie L. Gerhardt, Leslie M. Taylor, Regina Nuccio, Jessica M. Valdez, Stacy J. Hines-Dowell, Alberto Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W. Ellison, James R. Downing, Jinghui Zhang, Kim E. Nichols. Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 642.
Published: 2021
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45. Evaluation of coping as a mediator of the relationship between stressful life events and cancer-related distress

Author: Christine Miaskowski, Janice Humphreys, Dale J. Langford, Bruce A. Cooper, Steven M. Paul, Michelle E. Melisko, Fay Wright, Carolyn D. Keagy, Laura B. Dunn, Marilyn J. Hammer, Yvette P. Conley, and Jon D. Levine
Subjects: Male, Coping (psychology), PsycINFO, Stress, chemotherapy, Medical and Health Sciences, Article, Structural equation modeling, Education, law.invention, Life Change Events, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Clinical Research, law, Neoplasms, Behavioral and Social Science, Prevalence, medicine, cancer, Humans, 030212 general & internal medicine, Disengagement theory, Applied Psychology, life stressors, business.industry, Psychology and Cognitive Sciences, Stressor, distress, Middle Aged, medicine.disease, Survival Analysis, Comorbidity, coping, Psychiatry and Mental health, Distress, Mental Health, 030220 oncology & carcinogenesis, Psychological, Female, Public Health, business, Mind and Body, Stress, Psychological, Clinical psychology
Abstract: OBJECTIVE Lifetime stressful life events (SLEs) may predispose oncology patients to cancer-related distress (i.e., intrusive thoughts, hyperarousal, avoidance). Coping may influence cancer-related distress by mediating this relationship. This study sought to (a) determine the prevalence and impact of lifetime SLEs among oncology outpatients receiving chemotherapy and (b) examine the relationship between SLEs and cancer-related distress and the mediating role of coping on this relationship. METHOD Patients (n = 957), with breast, gastrointestinal, gynecologic or lung cancer, who were undergoing chemotherapy, completed the Life Stressor Checklist-Revised (LSC-R), a measure of lifetime SLEs. Cancer-related distress was assessed with the Impact of Event Scale-Revised. Coping strategies since beginning chemotherapy were assessed with the Brief COPE; 2 latent variables (engagement and disengagement coping) were identified based on these scores. LSC-R scores (number of SLEs and perceived impact during the prior year) were evaluated in relation to demographic and clinical characteristics. Structural equation modeling was used to evaluate the relationship between LSC-R and Impact of Event Scale-Revised scores and the mediating role of engagement and disengagement coping on this relationship. RESULTS On average, patients reported 6.1 (SD = 4.0; range = 0-23 out of 30) SLEs. Patients who were not married/partnered, had incomes
Published: 2017
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46. SPX-101 Is a Novel Epithelial Sodium Channel–targeted Therapeutic for Cystic Fibrosis That Restores Mucus Transport

Author: William M. Abraham, Dale J. Christensen, Juan R. Sabater, David W. Scott, Matthew P. Walker, Bryant Wu, Timothy J. Stuhlmiller, Juliana I. Sesma, Robert Tarran, and Timothy M. Crowder
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Epithelial sodium channel, medicine.medical_specialty, Mucociliary clearance, media_common.quotation_subject, Pharmacology, Critical Care and Intensive Care Medicine, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Internalization, media_common, Lung, Hyperactivation, biology, urogenital system, business.industry, respiratory system, medicine.disease, Mucus, Cystic fibrosis transmembrane conductance regulator, respiratory tract diseases, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, 030228 respiratory system, biology.protein, business, hormones, hormone substitutes, and hormone antagonists
Abstract: Rationale: Cystic fibrosis (CF) lung disease is caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) combined with hyperactivation of the epithelial sodium channel (ENaC). In the lung, ENaC is responsible for movement of sodium. Hyperactivation of ENaC, which creates an osmotic gradient that pulls fluid out of the airway, contributes to reduced airway hydration, causing mucus dehydration, decreased mucociliary clearance, and recurrent acute bacterial infections. ENaC represents a therapeutic target to treat all patients with CF independent of their underlying CFTR mutation.Objectives: To investigate the in vitro and in vivo efficacy of SPX-101, a peptide mimetic of the natural regulation of ENaC activity by short palate, lung, and nasal epithelial clone 1, known as SPLUNC1.Methods: ENaC internalization by SPX-101 in primary human bronchial epithelial cells from healthy and CF donors was assessed by surface biotinylation and subsequent Western blot analysis. SPX-...
Published: 2017
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47. Nonclinical safety assessment of SPX-101, a novel peptide promoter of epithelial sodium channel internalization for the treatment of cystic fibrosis

Author: Phillip Barley, Timothy M. Crowder, Dale J. Christensen, Matt Cowlen, Matthew P. Walker, and Mutsumi Miyamoto
Subjects: Male, 0301 basic medicine, Epithelial sodium channel, ERG1 Potassium Channel, Cystic Fibrosis, Health, Toxicology and Mutagenesis, media_common.quotation_subject, hERG, Inhalation Toxicology, Pharmacology, Toxicology, Cystic fibrosis, Rats, Sprague-Dawley, 03 medical and health sciences, Dogs, 0302 clinical medicine, Administration, Inhalation, Animals, Humans, Medicine, Respiratory system, Epithelial Sodium Channels, Adverse effect, Internalization, Lung, Glycoproteins, media_common, biology, business.industry, Safety pharmacology, Phosphoproteins, medicine.disease, HEK293 Cells, Toxicity Tests, Subacute, 030104 developmental biology, 030228 respiratory system, biology.protein, Female, Peptides, business
Abstract: ENaC inhibition has long been an attractive therapeutic target for the treatment of cystic fibrosis. However, previous attempts at developing ENaC inhibitors have been unsuccessful due to complications arising from systemic circulation of the compounds. Here, we describe the preclinical toxicology assessment of a new inhaled peptide promoter of ENaC internalization delivered as a nebulized aerosol.Preclinical assessment of SPX-101 safety was determined using an in vitro hERG assay, bolus injection of SPX-101 in a canine cardiovascular and respiratory safety pharmacology model and 28-day inhalation toxicology studies of nebulized drug in rats and dogs.SPX101 had no effects on the respiratory, cardiac or central nervous systems. The 28-day inhalation toxicology studies of nebulized SPX-101 in rats and dogs revealed no drug-related adverse events. Plasma levels of SPX-101 peaked less than 1 h after the end of treatment in rats and were below the limit of detection in canine models.SPX-101, a novel peptide promoter of ENaC internalization, elicited no adverse effects at doses up to the MFD and in excess of the highest preclinical efficacious and expected clinical doses. In contrast to channel blockers like amiloride and derivative small molecules, SPX-101 does not achieve significant systemic circulation, thus doses are not limited due to toxic side effects like hyperkalemia and weight loss.
Published: 2017
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48. Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients withSOD1mutations

Author: Senda Ajroud-Driss, Claudia Morelli, Peter M. Andersen, Mona Shahbazi, Rahul Remanan, Stanley H. Appel, Kara G. Fields, Vincenzo Silani, Alberto Doretti, Luca Maderna, Ulrike Weiland, Stefan L. Marklund, Stefano Messina, Dale J. Lange, Jochen H. Weishaupt, and Albert C. Ludolph
Subjects: 0301 basic medicine, animal diseases, SOD1, Pharmacology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Antisense Oligonucleotide Therapy, Zn superoxide dismutase, medicine, Amyotrophic lateral sclerosis, Mutation, Chemistry, Cu-Zn Superoxide Dismutase, nutritional and metabolic diseases, medicine.disease, nervous system diseases, 030104 developmental biology, Pyrimethamine, nervous system, Neurology, Immunology, Neurology (clinical), 030217 neurology & neurosurgery, medicine.drug
Abstract: Objective: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous p ...
Published: 2017
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49. Crystal structure of full-lengthZika virusNS5 protein reveals a conformation similar toJapanese encephalitis virusNS5

Author: Anup K. Upadhyay, Dale J. Kempf, Rakesh Tripathi, Kenton L. Longenecker, Chaohong Sun, and Matthew Cyr
Subjects: Models, Molecular, Protein Conformation, alpha-Helical, 0301 basic medicine, Methyltransferase, NS5, Cations, Divalent, Viral protein, viruses, Amino Acid Motifs, 030106 microbiology, Biophysics, Gene Expression, Viral Nonstructural Proteins, Crystallography, X-Ray, medicine.disease_cause, Biochemistry, Virus, Research Communications, Zika virus, 03 medical and health sciences, chemistry.chemical_compound, Structural Biology, Health hazard, nonstructural protein 5, RNA polymerase, Escherichia coli, Genetics, medicine, Protein Interaction Domains and Motifs, Cloning, Molecular, Encephalitis Virus, Japanese, Binding Sites, Protein molecules, biology, Zika Virus, Japanese encephalitis, Condensed Matter Physics, biology.organism_classification, medicine.disease, Virology, Recombinant Proteins, Zinc, 030104 developmental biology, chemistry, Structural Homology, Protein, Protein Conformation, beta-Strand, Plasmids, Protein Binding
Abstract: The recent epidemic of Zika virus (ZIKV) has created a major global health concern. Here, the crystal structure of the full-length ZIKV NS5 protein at 3.05 Å resolution is presented to facilitate the structure-based design of antiviral agents against ZIKV., The rapid spread of the recent Zika virus (ZIKV) epidemic across various countries in the American continent poses a major health hazard for the unborn fetuses of pregnant women. To date, there is no effective medical intervention. The nonstructural protein 5 of Zika virus (ZIKV-NS5) is critical for ZIKV replication through the 5′-RNA capping and RNA polymerase activities present in its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent RNA polymerase (RdRp) domains, respectively. The crystal structure of the full-length ZIKV-NS5 protein has been determined at 3.05 Å resolution from a crystal belonging to space group P21212 and containing two protein molecules in the asymmetric unit. The structure is similar to that reported for the NS5 protein from Japanese encephalitis virus and suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.
Published: 2017
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50. Preface: promoting research in PLS: current knowledge and future challenges

Author: Vincenzo Silani, Omar Jawdat, Sheena Chew, Annemarie Hübers, Jerome E. Kurent, Leonard H. van den Berg, Kourosh Rezania, Raghav Govindarajan, Osamu Kano, Teepu Siddique, Juan Marcos Solano Atehortua, Bjorn Oskarsson, Matthew B. Harms, John K. Fink, David Walk, Orla Hardiman, Senda Ajroud-Driss, Stephen N. Scelsa, Vivian E. Drory, Bryan Hill, Jose Americo M. Fernandes, Richard J. Barohn, Hiroshi Mitsumoto, Jennifer Murphy, Pam Factor-Litvak, and Family, James Wymer, Volkan Granit, Mitsuya Morita, Patricia L. Andres, Michael Benatar, Terry Heiman-Patterson, Frank Davis, Albert C. Ludolph, Philippe Corcia, Georg Haase, Nailah Siddique, Angela Genge, Justin Kwan, Dominic A. Ferrey, Christina Fournier, Bryan J. Traynor, Ian R. A. Mackenzie, Jinsy Andrews, Marka van Blitterswijk, David Pellerin, Ghazala Hayat, Dale J. Lange, John Ravits, Sabrina Paganoni, Edward D. Huey, Yasushi Kisanuki, Estela Area Gomez, Mamede de Carvalho, Mary Kay Floeter, Jeffrey Statland, Deborah L. Warden, Merit Cudkowicz, Giovanni Manfredi, Kristen Kau, Lauren Elman, Martin R Turner, Matthew C. Kiernan, Guy A. Rouleau, Sharon P. Nations, Robin Conwit, David Marren, Zachary Simmons, Suma Babu, Eoin Finegan, and Peter Bede
Subjects: medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, MEDLINE, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Humans, Medicine, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, Primary Lateral Sclerosis
Abstract: Primary lateral sclerosis (PLS) is a condition that most neurologists will never personally diagnose. For the estimated several thousand people living with PLS globally, while it may not be life-sh...
Published: 2020
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