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1. Can plethysmographic capillary refill time predict lactate during sepsis? An observational study from Morocco

Author: Chadi Rahmani, Ayoub Belhadj, and Younes Aissaoui
Subjects: Sepsis, Septic shock, Plethysmography, Capillary refill time, Lactate, Low-income setting, Medicine, Medicine (General), R5-920
Abstract: Introduction: Blood lactate is a marker of tissue hypoxia while capillary refill time (CRT) is a surrogate of tissue perfusion. Measuring these parameters is recommended for assessing circulatory status and guiding resuscitation. However, blood lactate is not widely available in African emergency departments. Additionally, CRT assessment faces challenges related to its precision and reproducibility. This study aims to evaluate the accuracy of visual CRT(V-CRT) compared to plethysmographic CRT (P-CRT) in predicting lactate levels among septic patients. Methods: This prospective observational study enrolled consecutive patients with sepsis or septic shock over a 6-month period from a tertiary hospital in Marrakech, Morroco. V-CRT and P-CRT were evaluated upon admission, and simultaneous measurements of arterial lactate levels were obtained. The precision of V-CRT and P-CRT in predicting arterial lactate was assessed using ROC curve analysis. Results: Forty-three patients aged of 64±15 years, of whom 70 % were male, were included in the study. Of these, 23 patients (53 %) had sepsis, and 20 patients (47 %) experienced septic shock. Both V-CRT and P-CRT demonstrated statistically significant correlations with arterial lactate, with correlation coefficients of 0.529 (p < 0.0001) and 0.517 (p = 0.001), respectively. ROC curve analysis revealed that V-CRT exhibited satisfactory accuracy in predicting arterial lactate levels >2 mmol/l, with an area under the curve (AUC) of 0.8 (95 % CI=0.65 – 0.93; p < 0.0001). The prediction ability of P-CRT was lower than V-CRT with an AUC of 0.73 (95 % CI: 0.57–0.89; p = 0.043). The optimal thresholds were determined as 3.4 s for V-CRT (sensitivity = 90 %, specificity = 58 %) and 4.1 s for P-CRT (sensitivity = 85 %, specificity = 62 %). Conclusion: These findings suggest that the plethysmographic evaluation did not improve the accuracy of CRT for predicting lactate level. However, V-CRT may still serve as a viable surrogate for lactate in septic patients in low-income settings.
Published: 2024
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2. Domestic and External Drivers of Inflation in Oil Importing Developing Countries

Author: Younes Ait Hmadouch
Subjects: Inflation Drivers, Oil-importing Developing Countries, Dumitrescu and Hurlin Panel Causality, Monetary Policy, Oil Prices, Environmental sciences, GE1-350, Energy industries. Energy policy. Fuel trade, HD9502-9502.5
Abstract: This paper explores inflation drivers in 12 oil-importing developing economies, focusing on domestic and external drivers, such as monetary policy rate, government expenditure, global oil prices, exchange rate, imports, global food prices, and other factors. The study aims to establish a hierarchy of these drivers from the most to the least significant, which is essential for a better implementation of anti-inflationary policies in oil-importing developing countries. Using Seemingly Unrelated Regression (SUR) model and second-generation panel unit root test to handle cross-sectional dependence, and applying Dumitrescu-Hurlin panel Granger causality approach to confirm SUR outcomes, this research paper revealed for the period between 2000Q1, and 2023Q2 that lagged inflation is the most important driver of current inflation, supporting the theoretical concept of inertial inflation. Unexpectedly, this study showed that monetary policy rate is positively impacting inflation, confirming the presence of the price puzzle. Additionally, monetary base doesn’t have any significant impact on aggregate price level, meaning that the inflation is not a monetary phenomenon for the studied countries. Producer prices, used as a proxy for domestic supply shocks, seemed to have a positive and significant effect on inflation. Government expenditure, trade openness, and global oil prices have notable effects. Even if all the studied countries are oil importers, the impact of oil prices on inflation is mitigated by subsidies and price controls. Finally, inflation is negatively affected by imports and exchange rate. The study underscores the necessity for new central bank tools adapted to these countries context, monetary and fiscal policies coordination, a strategic use of subsidies, and an integrated policy to improve market competition.
Published: 2024
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3. Long Covid: a global health issue – a prospective, cohort study set in four continents

Author: Synne Jenum, Renaud Tamisier, Clark D Russell, Rachel Evans, Piero Valentini, Sylvain Diamantis, Dominique Deplanque, Jordi Rello, Agnes Meybeck, Maxime Hentzien, Clotilde Allavena, André Cabié, Firouzé Bani-Sadr, Patrick Rossignol, Lionel Piroth, Mathieu Blot, Marie-Pierre Debray, François Angoulvant, Marc Leone, Ewen M Harrison, Maria Zambon, Michael Edelstein, Florentia Kaguelidou, Marc Lambert, Olivier Lairez, Tom Solomon, Carrol Gamble, Laura Marsh, Christiana Kartsonaki, Natalie Wright, Behzad Nadjm, Srinivas Murthy, Gail Carson, Jake Dunning, Laura Merson, Peter Horby, Timothy M Uyeki, Piero Olliaro, Guillermo Maestro de la Calle, Stephen R Knight, Thomas M Drake, Marlene Murris, Aurore Bousquet, Kenneth A McLean, Hugues Cordel, Marc Fabre, Laurence Bouillet, Katrina Hann, Xavier Duval, James Lee, Christian Rabaud, Paul Klenerman, Jean-Christophe Lucet, Jean-François Timsit, Jennifer Lee, David J Lowe, Nicolas Terzi, Saad Nseir, Gwenhaël Colin, Steve Webb, Kalynn Kennon, Caroline Mudara, Diana Hernández, Yazdan Yazdanpanah, Jean-François Payen, Samreen Ijaz, Joanne McPeake, Meera Chand, Catherine A Shaw, Cameron J Fairfield, Bruno Levy, Eric D'ortenzio, Pierre Delobel, Tiphaine Goulenok, Bronner P Gonçalves, Arnaud Scherpereel, Danilo Buonsenso, Mark G Pritchard, Susanne Dudman, Adrien Auvet, Caterina Caminiti, Debby Bogaert, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Merce Jourdain, Sue Smith, Jia Wei, Antoine Khalil, Clément Le Bihan, Nathalie Pansu, Vincent Le Moing, Victor Fomin, Christophe Fraser, Daniel Munblit, William Greenhalf, François-Xavier Lescure, Nicolas Carlier, Saye Khoo, Annemarie B Docherty, Christopher A Green, Riinu Pius, Louise Sigfrid, Sophie Halpin, Clare Jackson, Antonia Ho, Malcolm G Semple, Andrew Dagens, Carlo Palmieri, Lance Turtle, Zeno Bisoffi, Thomas Flament, Julie Mankikian, Romain Basmaci, Peter Openshaw, Rob Fowler, Tom Fletcher, Adrien Lemaignen, Pierre Tattevin, Christelle Delmas, Hélène Espérou, Claire Lévy-Marchal, Olivier Picone, Jeanne Sibiude, Cecile Yelnik, Michelle Girvan, Piero L Olliaro, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Graham S Cooke, Ana da Silva Filipe, Alexander J Mentzer, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, David L Robertson, Vanessa Sancho-Shimizu, Janet T Scott, Shiranee Sriskandan, David Stuart, Charlotte Summers, Emma C Thomson, Ryan S Thwaites, Lance C W Turtle, Hayley Hardwick, Wilna Oosthuyzen, Fiona Griffiths, Jo Dalton, Egle Saviciute, Stephanie Roberts, Janet Harrison, Marie Connor, Gary Leeming, Ross Hendry, Victoria Shaw, Jade Ghosn, Lucille Blumberg, Nicolas Benech, Odile Launay, Yoan Lavie-Badie, Minh Le, Elise Artaud-Macari, Muge Cevik, Nicola Latronico, Mylène Maillet, Didier Laureillard, Ben Morton, Claire Hastie, Nicholas Sedillot, Anne-Sophie Boureau, Laurent Abel, Guillaume Martin-Blondel, Valérie Garrait, Isabelle Delacroix, Andrea Cortegiani, Jean-Benoît Arlet, Raphaël Borie, Kévin Bouiller, Vincent Langlois, Mélanie Roriz, Vincent Dubée, John H Amuasi, Madiha Hashmi, Edwin Jesudason, Jan Cato Holter, Anders Benjamin Kildal, Luis Felipe Reyes, Anna Beltrame, Sulaiman Lakoh, Stéphanie Fry, Lynsey Goodwin, Laurent Plantier, Anna Casey, Denis Malvy, Nina Jamieson, François Dubos, Jean-Sébastien Hulot, Paola Rodari, Frank Bloos, Cécile Tromeur, Paul Loubet, Marina Esposito-Farèse, France Mentré, Valérie Gaborieau, Cécile Goujard, Vincent Thibault, Adam Ali, Sadie Kelly, Fernando A Bozza, Bertrand Dussol, Marion Schneider, Marielle Buisson, Yves Levy, Carine Roy, Walter Picard, Olivier Sanchez, Nazir Lone, Antoine Kimmoun, Roberto Roncon-Albuquerque, Nathan Peiffer-Smadja, Julien Poissy, Lila Bouadma, Bruno Lina, Maude Bouscambert, Alexandre Gaymard, Gilles Peytavin, Jeremie Guedj, Claire Andrejak, Cedric Laouenan, Anissa Chair, Samira Laribi, Marie-Capucine Tellier, Sandrine Couffin-Cadiergues, Ventzislava Petrov-Sanchez, Alpha Diallo, Sarah Tubiana, Patrick Imbert, Emmanuelle Mercier, Waasila Jassat, Arsene Kpangon, Dominique Luton, Simone Piva, Sophie Mahy, Pierre-Adrien Bolze, Sarah Moore, Raphael Favory, Andrea Angheben, Andrea Rossanese, Matthew Hall, Johann Auchabie, Christophe Rapp, Vincent Peigne, Fredrik Müller, Christl A Donnelly, François Goehringer, Elodie Curlier, Catherine Chirouze, Vegard Skogen, Stéphane Jaureguiberry, Laurent Bitker, Hodane Yonis, Laurent Mandelbrot, Jérémie Pasquier, Bato Hammarström, Thushan de Silva, Polina Bugaeva, Julie Chas, Dario Sinatti, Arne Søraas, Murray Wham, Sara Clohisey, Seán Keating, Thibault Chiarabini, Agnes Sommet, Hugues Aumaître, Charlotte Charpentier, Sylvie LeGac, Sarah E McDonald, Jeanne Truong, Anne-Hélène Boivin, Mariachiara Ippolito, Ellen Pauley, Diane Descamps, Sérgio Gaião, Stéphane Lasry, Amanda Rojek, Charlotte Salmon Gandonniere, Sebastien Preau, Benoit Thill, Karine Faure, Denis Garot, Grégory Corvaisier, Elsa Nyamankolly, Merete Ellingjord-Dale, Eva Geraud, Barbara Wanjiru Citarella, Kévin Alexandre, Nathalie Allou, Séverine Ansart, Laurène Azemar, Cecile Azoulay, Delphine Bachelet, Claudine Badr, Valeria Balan, Marie Bartoli, Joaquín Baruch, Jules Bauer, Alexandra Bedossa, Husna Begum, Marine Beluze, Delphine Bergeaud, Giulia Bertoli, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Krishna Bhavsar, Laetitia Bodenes, Isabela Bolaños, Olivier Bouchaud, Sabelline Bouchez, Camile Bouisse, Marielle Boyer-Besseyre, Axelle Braconnier, Ingrid G Bustos, Denis Butnaru, Eder Caceres, Cyril Cadoz, Valentine Campana, Pauline Caraux-Paz, Thierry Carmoi, Marie-Christine Carret, Maire-Laure Casanova, Guylaine Castor-Alexandre, François-Xavier Catherine, Minerva Cervantes-Gonzalez, Catherine Chakveatze, Jean-Marc Chapplain, Antoine Cheret, Bernard Cholley, Marie-Charlotte Chopin, Roxane Courtois, Stéphanie Cousse, Alexa Debard, Nathalie DeCastro, Romain Decours, Eve Defous, Karen Delavigne, Elisa Demonchy, Emmanuelle Denis, Mathilde Desvallées, Kévin Didier, Jean-Luc Diehl, Vincent Dinot, Fara Diop, Alphonsine Diouf, Félix Djossou, Céline Dorival, Nathalie Dournon, Murray Dryden, Alexandre Ducancelle, Paul Dunand, Brigitte Elharrar, Philippine Eloy, Isabelle Enderle, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Manuel Etienne, Isabelle Fabre, François-Xavier Ferrand, Eglantine Ferrand Devouge, Nicolas Ferriere, Céline Ficko, Erwan Fourn, Rostane Gaci, Jean-Charles Gagnard, Esteban Garcia-Gallo, Tristan Gigante, Guillermo Giordano, Valérie Gissot, Petr Glybochko, Marie Gominet, Isabelle Gorenne, Laure Goubert, Pascal Granier, Segolène Greffe, Martin Guego, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Thomas Guimard, Ali Hachemi, Nadir Hadri, Rebecca Hamidfar, Lars Heggelund, Rupert Higgins, Hikombo Hitoto, Alexandre Hoctin, Isabelle Hoffmann, Ikram Houas, Margaux Isnard, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Florence Jego, Cédric Joseph, Ouifiya Kafif, Sabina Kali, Younes Kerroumi, Marie Lachatre, Marie Lacoste, Marie Lagrange, Fabrice Laine, Antonio Lalueza, Marie Langelot-Richard, Delphine Lariviere, Andy Law, Laurent Lefebvre, Bénédicte Lefebvre, Benjamin Lefèvre, Jean-Daniel Lelievre, Véronique Lemee, Anthony Lemeur, Quentin Lepiller, Olivier Lesens, Mathieu Lesouhaitier, Geoffrey Liegeon, Guillaume Lingas, Sylvie Lion-Daolio, Marine Livrozet, Bouchra Loufti, Guillame Louis, Liem Luong, Moïse Machado, Gabriel Macheda, Rafael Mahieu, Thomas Maitre, Victoria Manda, Aldric Manuel, Samuel Markowicz, Martin Martinot, Mathieu Mattei, Laurence Maulin, Thierry Mazzoni, Cécile Mear-Passard, Antoine Merckx, Mayka Mergeay-Fabre, Vanina Meysonnier, Mehdi Mezidi, Isabelle Michelet, Lucia Moro, Julien Moyet, Jimmy Mullaert, Nadège Neant, Nikita Nekliudov, Anthony Nghi, Duc Nguyen, Nadia Ouamara, Rachida Ouissa, Eric Oziol, Justine Pages Maïder Pagadoy, Aurélie Papadopoulos, Bruno Pastene, Christelle Paul, Florent Peelman, Daniel Perez, Thomas Perpoint, Vincent Pestre, Ryadh Pokeerbux, Diane Ponscarme, Marie Rafiq, Blandine Rammaert, Stanislas Rebaudet, Sarah Redl, Anne-Sophie Resseguier, Matthieu Revest, Laurent Richier, Patrick Rispal, Karine Risso, Olivier Robineau, Manuel Rosa-Calatrava, Benoît Roze, Hélène Salvator, Pierre-François Sandrine, Benjamine Sarton, Eric Senneville, Albert Sotto, Sarah Stabler, Andrey Svistunov, Coralie Tardivon, François Téoulé, Olivier Terrier, Simon-Djamel Thiberville, Peter S Timashev, Noémie Tissot, Tiffany Trouillon, Christelle Tual, Noémie Vanel, Charline Vauchy, Aurélie Veislinger, Fanny Vuotto, Aurélie Wiedemann, Marion Zabbe, David Zucman, Silvio Hamacher, Ekaterina Pazukhina, Allegra Chatterjee, Kyle Gomez, Matteo Puntoni, Oksana Kruglova, Yock Ping Chow, Yash Doshi, Sara Isabel Duque Vallejo, Elsa D Ibáñez-Prada, Yuli V Fuentes, Margaret E O'Hara, Tigist Menkir, Amal Abrous, Younes Ait Tamlihat, Aliya Mohammed Alameen, Marta Alessi, Kazali Enagnon Alidjnou, Jean Baptiste Assie, Eyvind W Axelsen, John Kenneth Baillie, José Luis Bernal Sobrino, Sonja Hjellegjerde Brunvoll, Roar Bævre-Jensen, Jose Andres Calvache, Léo Chenard, Juan Luis Cruz Bermúdez, Jaime Cruz Rojo, Charlene Da Silveira, John Arne Dahl, Etienne De Montmollin, Cristina De Rose, Fernanda Dias Da Silva, Thomas Drake, Amiel A Dror, Anne Margarita Dyrhol-Riise, Linn Margrete Eggesbø, Mohammed El Sanharawi, William Finlayson, Aline-Marie Florence, Linda Gail Skeie, Noelia García Barrio, Anatoliy Gavrylov, Louis Gerbaud Morlaes, Yanay Gorelik, Mette Stausland Istre, Silje Bakken Jørgensen, Karl Trygve Kalleberg, Beathe Kiland Granerud, Eyrun Floerecke Kjetland Kjetland, Gry Kloumann Bekken, Galyna Kutsyna, Nadhem Lafhej, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Hervé Le Nagard, Sophie Letrou, Wei Shen Lim, Andreas Lind, Carlos Lumbreras Bermejo, Miles Lunn, Olga Martynenko, Roberta Meta, Lina Morales Cely, Clara Mouton Perrot, Alamin Mustafa, Karl Erik Müller, Ebrahim Ndure, Anders Benteson Nygaard, Claudia Milena Orozco-Chamorro, Paul Otiku, Miguel Pedrera Jiménez, Frank Olav Pettersen, Chiara Piubelli, Víctor Quirós González, Else Quist-Paulsen, Dag Henrik Reikvam, Antonia Ricchiuto, Aleksander Rygh Holten, Nadia Saidani, Pablo Serrano Balazote, Nassima Si Mohammed, Lene Bergendal Solberg, Edouard Soum, Elisabetta Spinuzza, Trude Steinsvik, Birgitte Stiksrud, Mathew Thorpe, Vadim Tieroshyn, Kristian Tonby, Anders Tveita, Sylvie Van Der Werf, Paul Henri Wicky, Ibrahim Richard Bangura, Leonardo Bastos, Daniel Cassaglia, Barbara Citarella, Sarah Duque, Anne Margarita Dyrhol Riise, Annelies Gillesen, Bronner P Goncalvez, Margareta O’Hara, Lars Hegelund, Aquiles Henriquez Trujillo, Elsa D Ibañez, Jane Ireson, Oksana Krugalova, Sam Lissaeur, Sinnadurai Manohan, Prasan K Panda, Daniel R Plotkin, Liliana Resende, Sergio Ruiz Saltana, Steffi Ryckaert, Girish Sindhwani Pulm, and Caroline Vika
Subjects: Medicine (General), R5-920, Infectious and parasitic diseases, RC109-216
Abstract: Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to
Published: 2024
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4. Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms

Author: Barbara Wanjiru Citarella, Christiana Kartsonaki, Elsa D. Ibáñez-Prada, Bronner P. Gonçalves, Joaquin Baruch, Martina Escher, Mark G. Pritchard, Jia Wei, Fred Philippy, Andrew Dagens, Matthew Hall, James Lee, Demetrios James Kutsogiannis, Evert-Jan Wils, Marília Andreia Fernandes, Bharath Kumar Tirupakuzhi Vijayaraghavan, Prasan Kumar Panda, Ignacio Martin-Loeches, Shinichiro Ohshimo, Arie Zainul Fatoni, Peter Horby, Jake Dunning, Jordi Rello, Laura Merson, Amanda Rojek, Michel Vaillant, Piero Olliaro, Luis Felipe Reyes, S.A. Moharam, Sabriya Abdalasalam, Alaa Abdalfattah Abdalhadi, Naana Reyam Abdalla, Walaa Abdalla, Almthani Hamza Abdalrheem, Ashraf Abdalsalam, Saedah Abdeewi, Esraa Hassan Abdelgaum, Mohamed Abdelhalim, Mohammed Abdelkabir, Israa Abdelrahman, Sheryl Ann Abdukahil, Lamees Adil Abdulbaqi, Salaheddin Abdulhamid, Widyan Abdulhamid, Nurul Najmee Abdulkadir, Eman Abdulwahed, Rawad Abdunabi, Ryuzo Abe, Laurent Abel, Ahmed Mohammed Abodina, Amal Abrous, Lara Absil, Kamal Abu Jabal, Nashat Abu Salah, Abdurraouf Abusalama, Tareg Abdallah Abuzaid, Subhash Acharya, Andrew Acker, Elisabeth Adam, Safia Adem, Manuella Ademnou, Francisca Adewhajah, Diana Adrião, Anthony Afum-Adjei Awuah, Melvin Agbogbatey, Saleh Al Ageel, Aya Mustafa Ahmed, Musaab Mohammed Ahmed, Shakeel Ahmed, Zainab Ahmed Alaraji, Abdulrahman Ahmed Elhefnawy Enan, Reham Abdelhamid Ahmed Khalil, Ali Mostafa Ahmed Mohamed Abdelaziz, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Aisha, Bugila Aisha, Ali Ait Hssain, Younes Ait Tamlihat, Takako Akimoto, Ernita Akmal, Chika Akwani, Eman Al Qasim, Ahmed Alajeeli, Ahmed Alali, Razi Alalqam, Aliya Mohammed Alameen, Mohammed Al-Aquily, Zinah A. Alaraji, Khalid Albakry, Safa Albatni, Angela Alberti, Osama Aldabbourosama, Tala Al-dabbous, Amer Aldhalia, Abdulkarim Aldoukali, Senthilkumar Alegesan, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman Al-Fares, Asil Alflite, Huda Alfoudri, Qamrah Alhadad, Hoda Salem Alhaddad, Maali Khalid Mohamed Abdalla Alhasan, Ahmad Nabil Alhouri, Hasan Alhouri, Adam Ali, Imran Ali, Maha TagElser Mohammed Ali, Syed Ali Abbas, Yomna Ali Abdelghafar, Naseem Ali Sheikh, Kazali Enagnon Alidjnou, Mahmoud Aljadi, Sarah Aljamal, Mohammed Alkahlout, Akram Alkaseek, Qabas Alkhafajee, Clotilde Allavena, Nathalie Allou, Lana Almasri, Abdulrahman Almjersah, Raja Ahmed Alqandouz, Walaa Alrfaea, Moayad Alrifaee, Rawan Alsaadi, Yousef Al-Saba'a, Entisar Alshareea, Eslam Alshenawy, Aneela Altaf, João Melo Alves, João Alves, Rita Alves, Joana Alves Cabrita, Maria Amaral, Amro Essam Amer, Nur Amira, Amos Amoako Adusei, John Amuasi, Roberto Andini, Claire Andrejak, Andrea Angheben, François Angoulvant, Sophia Ankrah, Séverine Ansart, Sivanesen Anthonidass, Massimo Antonelli, Carlos Alexandre Antunes de Brito, Ardiyan Apriyana, Yaseen Arabi, Irene Aragao, Francisco Arancibia, Carolline Araujo, Antonio Arcadipane, Patrick Archambault, Lukas Arenz, Jean-Benoît Arlet, Christel Arnold-Day, Lovkesh Arora, Rakesh Arora, Elise Artaud-Macari, Diptesh Aryal, Angel Asensio, Elizabeth A. Ashley, Muhammad Ashraf, Muhammad Sheharyar Ashraf, Abir Ben Ashur, Franklin Asiedu-Bekoe, Namra Asif, Mohammad Asim, Grace Assi, Jean Baptiste Assie, Amirul Asyraf, Fouda Atangana, Ahmed Atia, Minahel Atif, Asia Atif Abdelrhman Abdallahrs, Anika Atique, Moad Atlowly, AM Udara Lakshan Attanyake, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Abdelmalek Awad Ali Mohammed, Eyvind W. Axelsen, Ared Ayad, Ahmed Ayman Hassan Helmi, Laurène Azemar, Mohammed Azizeldin, Cecile Azoulay, Hakeem Babatunde, Benjamin Bach, Delphine Bachelet, Claudine Badr, Roar Bævre-Jensen, Nadia Baig, John Kenneth Baillie, J Kevin Baird, Erica Bak, Agamemnon Bakakos, Nazreen Abu Bakar, Hibah Bileid Bakeer, Ashraf Bakri, Andriy Bal, Mohanaprasanth Balakrishnan, Irene Bandoh, Firouzé Bani-Sadr, Renata Barbalho, Nicholas Yuri Barbosa, Wendy S. Barclay, Saef Umar Barnett, Michaela Barnikel, Helena Barrasa, Cleide Barrigoto, Marie Bartoli, Joaquín Baruch, Romain Basmaci, Muhammad Fadhli Hassin Basri, AbdAlkarim Batool, Denise Battaglini, Jules Bauer, Diego Fernando Bautista Rincon, Denisse Bazan Dow, Abigail Beane, Alexandra Bedossa, Ker Hong Bee, Husna Begum, Sylvie Behilill, Albertus Beishuizen, Aleksandr Beljantsev, David Bellemare, Anna Beltrame, Beatriz Amorim Beltrão, Marine Beluze, Nicolas Benech, Lionel Eric Benjiman, Suzanne Bennett, Luís Bento, Jan-Erik Berdal, Lamis Berdeweel, Delphine Bergeaud, Hazel Bergin, Giulia Bertoli, Lorenzo Bertolino, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Amar Bhatt, Krishna Bhavsar, Isabella Bianchi, Claudia Bianco, Sandra Bichoka, Farah Nadiah Bidin, Felwa Bin Humaid, Mohd Nazlin Bin Kamarudin, Muhannud Binnawara, Zeno Bisoffi, Patrick Biston, Laurent Bitker, Mustapha Bittaye, Jonathan Bitton, Pablo Blanco-Schweizer, Catherine Blier, Frank Bloos, Mathieu Blot, Filomena Boccia, Laetitia Bodenes, Debby Bogaert, Anne-Hélène Boivin, Ariel Bolanga, Isabela Bolaños, Pierre-Adrien Bolze, François Bompart, Aurelius Bonifasius, Joe Bonney, Diogo Borges, Raphaël Borie, Hans Martin Bosse, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Damien Bouhour, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Latsaniphone Bountthasavong, Anne-Sophie Boureau, John Bourke, Maude Bouscambert, Aurore Bousquet, Marielle Boyer-Besseyre, Maria Boylan, Fernando Augusto Bozza, Axelle Braconnier, Cynthia Braga, Timo Brandenburger, Filipa Brás Monteiro, Luca Brazzi, Dorothy Breen, Patrick Breen, David Brewster, Kathy Brickell, Tessa Broadley, Helen Brotherton, Alex Browne, Nicolas Brozzi, Sonja Hjellegjerde Brunvoll, Marjolein Brusse-Keizer, Petra Bryda, Nina Buchtele, Polina Bugaeva, Marielle Buisson, Danilo Buonsenso, Erlina Burhan, Donald Buri, Aidan Burrell, Ingrid G. Bustos, Denis Butnaru, André Cabie, Susana Cabral, Joana Cabrita, Eder Caceres, Cyril Cadoz, Rui Caetano Garcês, Kate Calligy, Jose Andres Calvache, João Camões, Valentine Campana, Paul Campbell, Josie Campisi, Cecilia Canepa, Mireia Cantero, Janice Caoili, Pauline Caraux-Paz, Sheila Cárcel, Filipa Cardoso, Filipe Cardoso, Nelson Cardoso, Sofia Cardoso, Simone Carelli, Nicolas Carlier, Thierry Carmoi, Gayle Carney, Inês Carqueja, Marie-Christine Carret, François Martin Carrier, Ida Carroll, Gail Carson, Maire-Laure Casanova, Mariana Cascão, Siobhan Casey, José Casimiro, Bailey Cassandra, Silvia Castañeda, Nidyanara Castanheira, Guylaine Castor-Alexandre, Ivo Castro, Ana Catarino, François-Xavier Catherine, Paolo Cattaneo, Roberta Cavalin, Giulio Giovanni Cavalli, Alexandros Cavayas, Adrian Ceccato, Masaneh Ceesay, Shelby Cerkovnik, Minerva Cervantes-Gonzalez, Muge Cevik, Anissa Chair, Catherine Chakveatze, Adrienne Chan, Meera Chand, Jean-Marc Chapplain, Charlotte Charpentier, Julie Chas, Muhammad Mobin Chaudry, Jonathan Samuel Chávez Iñiguez, Anjellica Chen, Yih-Sharng Chen, Léo Chenard, Matthew Pellan Cheng, Antoine Cheret, Thibault Chiarabini, Julian Chica, Suresh Kumar Chidambaram, Leong Chin Tho, Catherine Chirouze, Davide Chiumello, Sung-Min Cho, Bernard Cholley, Danoy Chommanam, Marie-Charlotte Chopin, Yock Ping Chow, Ting Soo Chow, Nathaniel Christy, Hiu Jian Chua, Jonathan Chua, Jose Pedro Cidade, José Miguel Cisneros Herreros, Anna Ciullo, Jennifer Clarke, Rolando Claure-Del Granado, Sara Clohisey, Cassidy Codan, Caitriona Cody, Jennifer Coles, Megan Coles, Gwenhaël Colin, Michael Collins, Pamela Combs, Jennifer Connolly, Marie Connor, Anne Conrad, Elaine Conway, Graham S. Cooke, Hugues Cordel, Amanda Corley, Sabine Cornelis, Alexander Daniel Cornet, Arianne Joy Corpuz, Andrea Cortegiani, Grégory Corvaisier, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Juthaporn Cowan, Rachel Cregan, Gloria Crowl, Jonathan Crump, Claudina Cruz, Marc Csete, Ailbhe Cullen, Matthew Cummings, Gerard Curley, Elodie Curlier, Colleen Curran, Paula Custodio, Ana da Silva Filipe, Charlene Da Silveira, Al-Awwab Dabaliz, John Arne Dahl, Darren Dahly, Umberto D'Alessandro, Peter Daley, Zaina Dalloul, Heidi Dalton, Jo Dalton, Seamus Daly, Juliana Damas, Joycelyn Dame, Cammandji Damien, Nick Daneman, Jorge Dantas, Frédérick D'Aragon, Gillian de Loughry, Diego de Mendoza, Etienne De Montmollin, Rafael Freitas de Oliveira França, Ana Isabel de Pinho Oliveira, Rosanna De Rosa, Cristina De Rose, Thushan de Silva, Peter de Vries, Jillian Deacon, David Dean, Alexa Debard, Bianca DeBenedictis, Marie-Pierre Debray, Nathalie DeCastro, William Dechert, Romain Decours, Eve Defous, Isabelle Delacroix, Alexandre Delamou, Eric Delaveuve, Karen Delavigne, Nathalie M. Delfos, Ionna Deligiannis, Andrea Dell'Amore, Christelle Delmas, Pierre Delobel, Corine Delsing, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Pieter Depuydt, Diane Descamps, Mathilde Desvallées, Santi Dewayanti, Pathik Dhangar, Alpha Diallo, Souleymane Taran Diallo, Sylvain Diamantis, André Dias, Fernanda Dias Da Silva, Rodrigo Diaz, Juan Jose Diaz, Priscila Diaz, Bakary K. Dibba, Kévin Didier, Jean-Luc Diehl, Wim Dieperink, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Yael Dishon, Cedric Djadda, Félix Djossou, Annemarie B. Docherty, Helen Doherty, Arjen M. Dondorp, Christl A. Donnelly, Yoann Donohue, Sean Donohue, Peter Doran, Céline Dorival, Eric D'Ortenzio, Yash Doshi, Phouvieng Douangdala, James Joshua Douglas, Renee Douma, Nathalie Dournon, Joanne Downey, Mark Downing, Thomas Drake, Aoife Driscoll, Ibrahim Kwaku Duah, Claudio Duarte Fonseca, Vincent Dubee, François Dubos, Audrey Dubot-Pérès, Alexandre Ducancelle, Toni Duculan, Susanne Dudman, Abhijit Duggal, Paul Dunand, Mathilde Duplaix, Emanuele Durante-Mangoni, Lucian Durham, III, Bertrand Dussol, Juliette Duthoit, Xavier Duval, Anne Margarita Dyrhol-Riise, Sim Choon Ean, Ada Ebo, Marco Echeverria-Villalobos, Michael Edelstein, Siobhan Egan, Linn Margrete Eggesbø, Khadeja Ehzaz, Carla Eira, Mohammed El Sanharawi, Marwan El Sayed, Mohammed Elabid, Mohamed Bashir Elagili, Subbarao Elapavaluru, Mohammad Elbahnasawy, Sohail Elboshra, Brigitte Elharrar, Jacobien Ellerbroek, Merete Ellingjord-Dale, Hamida ELMagrahi, Mohammad Muatasm Elmubark, Loubna Elotmani, Lauren Eloundou, Philippine Eloy, Basma Elshaikhy, Tarek Elshazly, Wafa Elsokni, Aml Ahmed Eltayeb, Iqbal Elyazar, Zarief Kamel Emad, Hussein Embarek, Isabelle Enderle, Tomoyuki Endo, Gervais Eneli, Chan Chee Eng, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Haneen Esaadi, Mariano Esperatti, Hélène Esperou, Catarina Espírito Santo, Marina Esposito-Farese, Rachel Essaka, Lorinda Essuman, João Estevão, Manuel Etienne, Anna Greti Everding, Mirjam Evers, Isabelle Fabre, Marc Fabre, Ismaila Fadera, Asgad Osman Abdalla Fadlalla, Amna Faheem, Arabella Fahy, Cameron J. Fairfield, Zul Fakar, Komal Fareed, Pedro Faria, Ahmed Farooq, Hanan Fateena, Mohamed Fathi, Salem Fatima, Karine Faure, Raphaël Favory, Mohamed Fayed, Niamh Feely, Jorge Fernandes, Susana Fernandes, François-Xavier Ferrand, Eglantine Ferrand Devouge, Joana Ferrão, Mário Ferraz, Benigno Ferreira, Isabel Ferreira, Bernardo Ferreira, Sílvia Ferreira, Nicolas Ferriere, Céline Ficko, Claudia Figueiredo-Mello, William Finlayson, Thomas Flament, Tom Fletcher, Aline-Marie Florence, Letizia Lucia Florio, Brigid Flynn, Deirdre Flynn, Jean Foley, Victor Fomin, Tatiana Fonseca, Patricia Fontela, Karen Forrest, Simon Forsyth, Denise Foster, Giuseppe Foti, Berline Fotso, Erwan Fourn, Robert A. Fowler, Marianne Fraher, Diego Franch-Llasat, Christophe Fraser, John F. Fraser, Marcela Vieira Freire, Ana Freitas Ribeiro, Craig French, Caren Friedrich, Ricardo Fritz, Stéphanie Fry, Nora Fuentes, Masahiro Fukuda, G. Argin, Valérie Gaborieau, Rostane Gaci, Massimo Gagliardi, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Abdou Gai, Sérgio Gaião, Linda Gail Skeie, Adham Mohamed Galal Mohamed Ramadan, Phil Gallagher, Carrol Gamble, Yasmin Gani, Arthur Garan, Rebekha Garcia, Julia Garcia-Diaz, Esteban Garcia-Gallo, Navya Garimella, Denis Garot, Valérie Garrait, Basanta Gauli, Anatoliy Gavrylov, Alexandre Gaymard, Johannes Gebauer, Eva Geraud, Louis Gerbaud Morlaes, Nuno Germano, Malak Ghemmeid, Praveen Kumar Ghisulal, Jade Ghosn, Marco Giani, Tristan Gigante, Elaine Gilroy, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Gezy Giwangkancana, Daniel Glikman, Petr Glybochko, Eric Gnall, Geraldine Goco, François Goehringer, Siri Goepel, Jean-Christophe Goffard, Jin Yi Goh, Brigitta Golács, Jonathan Golob, Kyle Gomez, Joan Gómez-Junyent, Marie Gominet, Alicia Gonzalez, Patricia Gordon, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Margarite Grable, Jeronimo Graf, Edward Wilson Grandin, Pascal Granier, Giacomo Grasselli, Lorenzo Grazioli, Christopher A. Green, Courtney Greene, William Greenhalf, Segolène Greffe, Domenico Luca Grieco, Matthew Griffee, Fiona Griffiths, Ioana Grigoras, Albert Groenendijk, Fassou Mathias Grovogui, Heidi Gruner, Yusing Gu, Jérémie Guedj, Martin Guego, Anne-Marie Guerguerian, Daniela Guerreiro, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Maisa Guimarães de Castro, Thomas Guimard, Marieke Haalboom, Daniel Haber, Ali Hachemi, Abdurrahman Haddud, Nadir Hadri, Wael Hafez, Fakhir Raza Haidri, Fatima Mhd Rida Hajij, Sheeba Hakak, Adam Hall, Sophie Halpin, Shaher Hamdan, Abdelhafeez Hamdi, Jawad Hameed, Ansley Hamer, Raph L. Hamers, Rebecca Hamidfar, Bato Hammarström, Naomi Hammond, Terese Hammond, Lim Yuen Han, Matly Hanan, Rashan Haniffa, Kok Wei Hao, Hayley Hardwick, Ewen M. Harrison, Janet Harrison, Samuel Bernard Ekow Harrison, Alan Hartman, Sulieman Hasan, Mohammad Ali Nabil Hasan, Mohd Shahnaz Hasan, Junaid Hashmi, Madiha Hashmi, Amoni Hassan, Ebtisam Hassanin, Muhammad Hayat, Ailbhe Hayes, Leanne Hays, Jan Heerman, Lars Heggelund, Ahmed Helmi, Ross Hendry, Martina Hennessy, Aquiles Rodrigo Henriquez-Trujillo, Maxime Hentzien, Diana Hernandez, Andrew Hershey, Liv Hesstvedt, Astarini Hidayah, Eibhlin Higgins, Rupert Higgins, Samuel Hinton, Hiroaki Hiraiwa, Haider Hirkani, Hikombo Hitoto, Antonia Ho, Yi Bin Ho, Alexandre Hoctin, Isabelle Hoffmann, Wei Han Hoh, Oscar Hoiting, Rebecca Holt, Jan Cato Holter, Juan Pablo Horcajada, Ikram Houas, Mabrouka Houderi, Catherine L. Hough, Stuart Houltham, Jimmy Ming-Yang Hsu, Jean-Sébastien Hulot, Abby Hurd, Iqbal Hussain, Aliae Mohamed Hussein, Mahmood Hussein, Fatima Ibrahim, Bashir Ibran, Samreen Ijaz, M. Arfan Ikram, Carlos Cañada Illana, Patrick Imbert, Muhammad Imran Ansari, Rana Imran Sikander, Hugo Inácio, Carmen Infante Dominguez, Yun Sii Ing, Mariachiara Ippolito, Vera Irawany, Sarah Isgett, Tiago Isidoro, Nadiah Ismail, Margaux Isnard, Mette Stausland Istre, Junji Itai, Daniel Ivulich, Danielle Jaafar, Salma Jaafoura, Hamza Jaber, Julien Jabot, Clare Jackson, Abubacarr Jagne, Stéphane Jaureguiberry, Denise Jaworsky, Florence Jego, Anilawati Mat Jelani, Synne Jenum, Ruth Jimbo-Sotomayor, Ong Yiaw Joe, Ruth Noemí Jorge García, Silje Bakken Jørgensen, Cédric Joseph, Mark Joseph, Swosti Joshi, Mercé Jourdain, Philippe Jouvet, Anna Jung, Hanna Jung, Dafsah Juzar, Ouifiya Kafif, Florentia Kaguelidou, Neerusha Kaisbain, Thavamany Kaleesvran, Sabina Kali, Karl Trygve Kalleberg, Smaragdi Kalomoiri, Muhammad Aisar Ayadi Kamaluddin, Armand Saloun Kamano, Zul Amali Che Kamaruddin, Nadiah Kamarudin, Kavita Kamineni, Darshana Hewa Kandamby, Kong Yeow Kang, Darakhshan Kanwal, Dyah Kanyawati, Mohamed Karghul, Pratap Karpayah, Todd Karsies, Daisuke Kasugai, Kevin Katz, Christy Kay, Lamees Kayyali, Seán Keating, Pulak Kedia, Andrea Kelly, Aoife Kelly, Claire Kelly, Niamh Kelly, Sadie Kelly, Yvelynne Kelly, Maeve Kelsey, Kalynn Kennon, Sommay Keomany, Maeve Kernan, Younes Kerroumi, Sharma Keshav, Shams Khail, Sarah Khaled, Imrana Khalid, Antoine Khalil, Irfan Khan, Quratul Ain Khan, Sushil Khanal, Abid Khatak, Krish Kherajani, Michelle E. Kho, Denisa Khoo, Ryan Khoo, Saye Khoo, Muhammad Nasir Khoso, Amin Khuwaja, Khor How Kiat, Yuri Kida, Peter Kiiza, Beathe Kiland Granerud, Anders Benjamin Kildal, Jae Burm Kim, Antoine Kimmoun, Detlef Kindgen-Milles, Nobuya Kitamura, Eyrun Floerecke Kjetland Kjetland, Paul Klenerman, Rob Klont, Gry Kloumann Bekken, Stephen R. Knight, Robin Kobbe, Paa Kobina Forson, Chamira Kodippily, Malte Kohns Vasconcelos, Sabin Koirala, Mamoru Komatsu, Franklina Korkor Abebrese, Volkan Korten, Stephanie Kouba, Mohamed Lamine Kourouma, Karifa Kourouma, Arsène Kpangon, Karolina Krawczyk, Ali Kredan, Vinothini Krishnan, Sudhir Krishnan, Oksana Kruglova, Anneli Krund, Pei Xuan Kuan, Ashok Kumar, Deepali Kumar, Ganesh Kumar, Mukesh Kumar, Dinesh Kuriakose, Ethan Kurtzman, Demetrios Kutsogiannis, Galyna Kutsyna, Ama Kwakyewaa Bedu-Addo, Sylvie Kwedi, Konstantinos Kyriakoulis, Marie Lachatre, Marie Lacoste, John G. Laffey, Nadhem Lafhej, Marie Lagrange, Fabrice Laine, Olivier Lairez, Sanjay Lakhey, Marc Lambert, François Lamontagne, Marie Langelot-Richard, Vincent Langlois, Eka Yudha Lantang, Marina Lanza, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Sakshi Lath, Naveed Latif, Youssef Latifeh, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Cassie Lawrence, Teresa Lawrence, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Ema Leal, Marta Leal Santos, Biing Horng Lee, Heng Gee Lee, Su Hwan Lee, Jennifer Lee, Todd C. Lee, Yi Lin Lee, Gary Leeming, Bénédicte Lefebvre, Laurent Lefebvre, Benjamin Lefèvre, Sylvie LeGac, Merili-Helen Lehiste, Jean-Daniel Lelievre, François Lellouche, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Gretchen Lemmink, Ha Sha Lene, Jenny Lennon, Rafael León, Marc Leone, Tanel Lepik, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Amy Lester-Grant, Andrew Letizia, Sophie Letrou, Bruno Levy, Yves Levy, Claire Levy-Marchal, Katarzyna Lewandowska, Erwan L'Her, Gianluigi Li Bassi, Janet Liang, Ali Liaquat, Geoffrey Liegeon, Kah Chuan Lim, Wei Shen Lim, Chantre Lima, Bruno Lina, Lim Lina, Andreas Lind, Maja Katherine Lingad, Guillaume Lingas, Sylvie Lion-Daolio, Keibun Liu, Marine Livrozet, Patricia Lizotte, Antonio Loforte, Navy Lolong, Leong Chee Loon, Diogo Lopes, Dalia Lopez-Colon, Anthony L. Loschner, Paul Loubet, Bouchra Loufti, Guillame Louis, Silvia Lourenco, Lara Lovelace-Macon, Lee Lee Low, Marije Lowik, Jia Shyi Loy, Jean Christophe Lucet, Carlos M. Luna, Olguta Lungu, Miles Lunn, Liem Luong, Nestor Luque, Dominique Luton, Olavi Maasikas, Moïse Machado, Sara Machado, Gabriel Macheda, Mustafa Magzoub, Rafael Mahieu, Sophie Mahy, Ana Raquel Maia, Lars S. Maier, Oumou Maiga Ascofare, Mylène Maillet, Thomas Maitre, Nimisha Abdul Majeed, Maximilian Malfertheiner, Nadia Malik, Paddy Mallon, Fernando Maltez, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Frank Manetta, Julie Mankikian, Edmund Manning, Aldric Manuel, Veronika Maráczi, Ceila Maria Sant′Ana Malaque, Flávio Marino, Samuel Markowicz, Ana Marques, Catherine Marquis, Laura Marsh, Brian Marsh, Megan Marshal, John Marshall, Celina Turchi Martelli, Dori-Ann Martin, Emily Martin, Guillaume Martin-Blondel, Alessandra Martinelli, F. Eduardo Martinez, Martin Martinot, Alejandro Martín-Quiros, Ana Martins, João Martins, Nuno Martins, Caroline Martins Rego, Gennaro Martucci, Olga Martynenko, Eva Miranda Marwali, Marsilla Marzukie, David Maslove, Sabina Mason, Sobia Masood, Fatma Masoud, Moise Massoma, Palmer Masumbe, Mohd Basri Mat Nor, Moshe Matan, Henrique Mateus Fernandes, Meghena Mathew, Christina Mathew, Mathieu Mattei, Laurence Maulin, Juergen May, Javier Maynar, Mayfong Mayxay, Thierry Mazzoni, Lisa Mc Sweeney, Colin McArthur, Naina McCann, Peter McCanny, Aine McCarthy, Anne McCarthy, Colin McCloskey, Rachael McConnochie, Sherry McDermott, Sarah E. McDonald, Aine McElroy, Samuel McElwee, Natalie McEvoy, Allison McGeer, Kenneth A. McLean, Paul McNally, Bairbre McNicholas, Edel Meaney, Cécile Mear-Passard, Maggie Mechlin, Nastia Medombou, Omar Mehkri, Ferruccio Mele, Luis Melo, Kashif Ali Memon, João João Mendes, Ogechukwu Menkiti, Kusum Menon, France Mentré, Alexander J. Mentzer, Emmanuelle Mercier, Noémie Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Blake Mergler, António Mesquita, Roberta Meta, Osama Metwally, Agnès Meybeck, Dan Meyer, Alison M. Meynert, Vanina Meysonnier, Mehdi Mezidi, Céline Michelanglei, Isabelle Michelet, Efstathia Mihelis, Vladislav Mihnovit, Duha Milad Abdullah, Jennene Miller, Hugo Miranda-Maldonado, Nor Arisah Misnan, Nik Nur Eliza Mohamed, Nouralsabah Mohamed, Tahira Jamal Mohamed, Alaa Mohamed Ads, Ahmed Reda Mohamed Elsayed Abdelhalim, Libya Mohammed, Shrouk Fawze Mohammed Mostafa, Manahil Omer Abdelrahman Mohammedahmed, Omer Abdullah Mohammedelhassan, Asma Moin, Walaa Mokhtar, Elena Molinos, Brenda Molloy, Mary Mone, Agostinho Monteiro, Claudia Montes, Giorgia Montrucchio, Sarah Moore, Shona C. Moore, Lina Morales Cely, Marwa Morgom, Lucia Moro, Catherine Motherway, Ana Motos, Hugo Mouquet, Clara Mouton Perrot, Julien Moyet, Suleiman Haitham Mualla, Mohamed Muftah, Aisha Kalsoom Mufti, Ng Yong Muh, Mo'nes Muhaisen, Dzawani Muhamad, Jimmy Mullaert, Fredrik Müller, Karl Erik Müller, Daniel Munblit, Syed Muneeb Ali, Nadeem Munir, Laveena Munshi, Aisling Murphy, Patrick Murray, Marlène Murris, Srinivas Murthy, Himed Musaab, Alamin Mustafa, Mus'ab Mustafa, Dana Mustafa, Himasha Muvindi, Dimitra Melia Myrodia, Farah Nadia Mohd-Hanafiah, Behzad Nadjm, Dave Nagpal, Alex Nagrebetsky, Blanka Nagybányai-Nagy, Herwin Nanda Boudoin, Mangala Narasimhan, Nageswaran Narayanan, Prashant Nasa, Rashid Nasim Khan, Ahmad Nasrallah, Adel Gerges Nassif Metri, Alasdair Nazerali-Maitland, Nadège Neant, Holger Neb, Nikita Nekliudov, Matthew Nelder, Erni Nelwan, Raul Neto, Emily Neumann, Wing Yiu Ng, Pauline Yeung Ng, Anthony Nghi, Duc Nguyen, Orna Ni Choileain, Niamh Ni Leathlobhair, Nerissa Niba, Alistair D. Nichol, Prompak Nitayavardhana, Stephanie Nonas, Nurul Amani Mohd Noordin, Nurul Faten Izzati Norharizam, Anita North, Alessandra Notari, Mahdad Noursadeghi, Adam Nowinski, Saad Nseir, Leonard Numfor, Nurnaningsih Nurnaningsih, Dwi Utomo Nusantara, Elsa Nyamankolly, Anders Benteson Nygaard, Fionnuala O. Brien, Annmarie O. Callaghan, Annmarie O'Callaghan, Giovanna Occhipinti, Derbrenn OConnor, Max O'Donnell, Lawrence Ofori-Boadu, Tawnya Ogston, Takayuki Ogura, Tak-Hyuk Oh, Sophie O'Halloran, Katie O'Hearn, Sally-Ann Ohene, João Oliveira, Larissa Oliveira, Piero L. Olliaro, Cinderella Omar Rageh Elnaggar, Alsarrah Ali Mohammed Omer, Pierre Ondobo, David S.Y. Ong, Jee Yan Ong, Wilna Oosthuyzen, Anne Opavsky, Peter Openshaw, Saijad Orakzai, Claudia Milena Orozco-Chamorro, Jamel Ortoleva, Mohamed Osama Elsayed Soliman, Javier Osatnik, Linda O'Shea, Miriam O'Sullivan, Eman Othman, Siti Zubaidah Othman, Nadia Ouamara, Rachida Ouissa, Micheal Owusu, Ama Akyampomaa Owusu-Asare, Eric Oziol, Maïder Pagadoy, Justine Pages, Amanda Palacios, Massimo Palmarini, Giovanna Panarello, Hem Paneru, Lai Hui Pang, Mauro Panigada, Nathalie Pansu, Aurélie Papadopoulos, Rachael Parke, Melissa Parker, Jérémie Pasquier, Bruno Pastene, Fabian Patauner, Drashti Patel, Mohan Dass Pathmanathan, Luís Patrão, Patricia Patricio, Lisa Patterson, Rajyabardhan Pattnaik, Christelle Paul, Mical Paul, Jorge Paulos, William A. Paxton, Jean-François Payen, Sandra L. Peake, Kalaiarasu Peariasamy, Giles J. Peek, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Mare Pejkovska, Paolo Pelosi, Ithan D. Peltan, Rui Pereira, Daniel Perez, Thomas Perpoint, Antonio Pesenti, Vincent Pestre, Lenka Petrou, Michele Petrovic, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Richard Odame Philips, Ooyanong Phonemixay, Soulichanya Phoutthavong, Michael Piagnerelli, Walter Picard, Olivier Picone, Maria de Piero, Djura Piersma, Carlos Pimentel, Raquel Pinto, Catarina Pires, Lionel Piroth, Ayodhia Pitaloka, Chiara Piubelli, Riinu Pius, Simone Piva, Laurent Plantier, Hon Shen Png, Julien Poissy, Ryadh Pokeerbux, Sergio Poli, Georgios Pollakis, Diane Ponscarme, Diego Bastos Porto, Andra-Maris Post, Douwe F. Postma, Pedro Povoa, Diana Póvoas, Jeff Powis, Sofia Prapa, Viladeth Praphasiri, Sébastien Preau, Christian Prebensen, Jean-Charles Preiser, Anton Prinssen, Gamage Dona Dilanthi Priyadarshani, Lucia Proença, Sravya Pudota, Bambang Pujo Semedi, Mathew Pulicken, Peter Puplampu, Gregory Purcell, Luisa Quesada, Vilmaris Quinones-Cardona, Else Quist-Paulsen, Mohammed Quraishi, Fadi Qutishat, Maia Rabaa, Christian Rabaud, Ebenezer Rabindrarajan, Aldo Rafael, Marie Rafiq, Abdelrahman Ragab, Mutia Rahardjani, Arslan Rahat Ullah, Ahmad Kashfi Haji Ab Rahman, Rozanah Abd Rahman, Fernando Rainieri, Giri Shan Rajahram, Pratheema Ramachandran, Nagarajan Ramakrishnan, José Ramalho, Ahmad Afiq Ramli, Blandine Rammaert, Grazielle Viana Ramos, Asim Rana, Rajavardhan Rangappa, Ritika Ranjan, Christophe Rapp, Aasiyah Rashan, Thalha Rashan, Ghulam Rasheed, Menaldi Rasmin, Indrek Rätsep, Cornelius Rau, Tharmini Ravi, Ali Raza, Andre Real, Stanislas Rebaudet, Sarah Redl, Brenda Reeve, Attaur Rehman, Muhammad Osama Rehman Khalid, Dag Henrik Reikvam, Renato Reis, Jonathan Remppis, Martine Remy, Hongru Ren, Hanna Renk, Anne-Sophie Resseguier, Matthieu Revest, Oleksa Rewa, Maria Ines Ribeiro, Antonia Ricchiuto, David Richardson, Denise Richardson, Laurent Richier, Siti Nurul Atikah Ahmad Ridzuan, Ana L. Rios, Asgar Rishu, Patrick Rispal, Karine Risso, Maria Angelica Rivera Nuñez, Chiara Robba, André Roberto, Stephanie Roberts, Charles Roberts, David L. Robertson, Olivier Robineau, Anna Roca, Ferran Roche-Campo, Paola Rodari, Simão Rodeia, Bernhard Roessler, Claire Roger, Pierre-Marie Roger, Roberto Roncon-Albuquerque, Jr., Mélanie Roriz, Manuel Rosa-Calatrava, Michael Rose, Dorothea Rosenberger, Andrea Rossanese, Matteo Rossetti, Patrick Rossignol, Carine Roy, Benoît Roze, Desy Rusmawatiningtyas, Clark D. Russell, Maeve Ryan, Steffi Ryckaert, Aleksander Rygh Holten, Isabela Saba, Sairah Sadaf, Musharaf Sadat, Valla Sahraei, Abdurraouf Said, Nadia Saidani, Pranya Sakiyalak, Fodé Bangaly Sako, Moamen Salah, Ali Alaa Salah Eldin Mohamed Abbas, Nawal Salahuddin, Leonardo Salazar, Jodat Saleem, Mohammed Saleh Alyasiri, Talat Ahmed Abu Salem, Gabriele Sales, Charlotte Salmon Gandonniere, Hélène Salvator, Dana Samardali, Shaden Samardali, Yehia Samir Shaaban Aly Orabi, Emely Sanchez, Olivier Sanchez, Kizy Sanchez de Oliveira, Angel Sanchez-Miralles, Vanessa Sancho-Shimizu, Gyan Sandhu, Zulfiqar Sandhu, Pierre-François Sandrine, Oana Săndulescu, Marlene Santos, Shirley Sarfo-Mensah, Bruno Sarmento Banheiro, Iam Claire E. Sarmiento, Benjamine Sarton, Ankana Satya, Sree Satyapriya, Rumaisah Satyawati, Egle Saviciute, Yen Tsen Saw, Justin Schaffer, Tjard Schermer, Arnaud Scherpereel, Marion Schneider, János Schnur, Stephan Schroll, Michael Schwameis, Gary Schwartz, Janet T. Scott, James Scott-Brown, Nicholas Sedillot, Tamara Seitz, Jaganathan Selvanayagam, Mageswari Selvarajoo, Malcolm G. Semple, Rasidah Bt Senian, Eric Senneville, Claudia Sepulveda, Filipa Sequeira, Tânia Sequeira, Ary Serpa Neto, Ellen Shadowitz, Syamin Asyraf Shahidan, Hamza Shahla, Laila Shalabi, Haitam Shames, Anuraj Shankar, Shaikh Sharjeel, Pratima Sharma, Catherine A. Shaw, Victoria Shaw, John Robert Sheenan, Dr. Rajesh Mohan Shetty, Rohan Shetty, Mohiuddin Shiekh, Nobuaki Shime, Keiki Shimizu, Sally Shrapnel, Shubha Kalyan Shrestha, Pramesh Sundar Shrestha, Hoi Ping Shum, Nassima Si Mohammed, Ng Yong Siang, Moses Siaw-Frimpong, Jeanne Sibiude, Bountoy Sibounheuang, Nidhal Siddig, Atif Siddiqui, Maqsood Ahmed Siddiqui, Louise Sigfrid, Fatoumata Sillah, Piret Sillaots, Catarina Silva, Maria Joao Silva, Rogério Silva, Benedict Sim Lim Heng, Wai Ching Sin, Dario Sinatti, Mahendra Singh, Punam Singh, Pompini Agustina Sitompul, Karisha Sivam, Vegard Skogen, Sue Smith, Benjamin Smood, Coilin Smyth, Morgane Snacken, Dominic So, Tze Vee Soh, Lene Bergendal Solberg, Joshua Solomon, Tom Solomon, Emily Somers, Agnès Sommet, Myung Jin Song, Rima Song, Tae Song, Jack Song Chia, Arne Søraas, Albert Sotto, Edouard Soum, Ana Chora Sousa, Marta Sousa, Maria Sousa Uva, Vicente Souza-Dantas, Mamadou Saliou Sow, Alexandra Sperry, Elisabetta Spinuzza, B. P. Sanka Ruwan Sri Darshana, Shiranee Sriskandan, Sarah Stabler, Thomas Staudinger, Stephanie-Susanne Stecher, Trude Steinsvik, Ymkje Stienstra, Birgitte Stiksrud, Eva Stolz, Amy Stone, Anca Streinu-Cercel, Adrian Streinu-Cercel, Geoff Strong, Ami Stuart, David Stuart, Richa Su, Decy Subekti, Gabriel Suen, Jacky Y. Suen, Prasanth Sukumar, Asfia Sultana, Charlotte Summers, Dubravka Supic, Deepashankari Suppiah, Magdalena Surovcová, Atie Suwarti, Andrey Svistunov, Sarah Syahrin, Augustina Sylverken, Konstantinos Syrigos, Jaques Sztajnbok, Konstanty Szuldrzynski, Shirin Tabrizi, Fabio S. Taccone, Lysa Tagherset, Shahdattul Mawarni Taib, Sara Taleb, Cheikh Talla, Jelmer Talsma, Renaud Tamisier, Maria Lawrensia Tampubolon, Kim Keat Tan, Yan Chyi Tan, Hiroyuki Tanaka, Taku Tanaka, Hayato Taniguchi, Huda Taqdees, Arshad Taqi, Coralie Tardivon, Yousef Tarek Kamal Mostafa, Ali Tarhabat, Pierre Tattevin, M Azhari Taufik, Hassan Tawfik, Tze Yuan Tee, João Teixeira, Sofia Tejada, Marie-Capucine Tellier, Sze Kye Teoh, Vanessa Teotonio, François Téoulé, Olivier Terrier, Nicolas Terzi, Hubert Tessier-Grenier, Adrian Tey, Alif Adlan Mohd Thabit, Anand Thakur, Zhang Duan Tham, Suvintheran Thangavelu, Elmi Theron, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Jananee Thirumanickam, Niamh Thompson, Shaun Thompson, Emma C. Thomson, David Thomson, Mathew Thorpe, Surain Raaj Thanga Thurai, Ryan S. Thwaites, Paul Tierney, Vadim Tieroshyn, Peter S. Timashev, Jean-François Timsit, Noémie Tissot, Fiona Toal, Jordan Zhien Yang Toh, Maria Toki, Kristian Tonby, Sia Loong Tonnii, Marta Torre, Antoni Torres, Margarida Torres, Rosario Maria Torres Santos-Olmo, Hernando Torres-Zevallos, Aboubacar Tounkara, Michael Towers, Fodé Amara Traoré, Tony Trapani, Cécile Tromeur, Ioannis Trontzas, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Helen Tuite, Alexis F. Turgeon, Jean-Marie Turmel, Lance C.W. Turtle, Anders Tveita, Pawel Twardowski, Makoto Uchiyama, PG Ishara Udayanga, Andrew Udy, Roman Ullrich, Alberto Uribe, Asad Usman, Effua Usuf, Timothy M. Uyeki, Cristinava Vajdovics, Piero Valentini, Luís Val-Flores, Stijn Van de Velde, Marcel van den Berge, Machteld van der Feltz, Job van der Palen, Paul van der Valk, Nicky Van Der Vekens, Peter Van der Voort, Sylvie Van Der Werf, Laura van Gulik, Jarne Van Hattem, Carolien van Netten, Ilonka van Veen, Noémie Vanel, Henk Vanoverschelde, Michael Varrone, Shoban Raj Vasudayan, Charline Vauchy, Pavan Kumar Vecham, Shaminee Veeran, Aurélie Veislinger, Sebastian Vencken, Sara Ventura, Annelies Verbon, José Ernesto Vidal, César Vieira, Deepak Vijayan, Judit Villar, Pierre-Marc Villeneuve, Andrea Villoldo, Gayatri Vishwanathan, Benoit Visseaux, Hannah Visser, Chiara Vitiello, Manivanh Vongsouvath, Harald Vonkeman, Fanny Vuotto, Suhaila Abdul Wahab, Noor Hidayu Wahab, Nadirah Abdul Wahid, Marina Wainstein, Laura Walsh, Wan Fadzlina Wan Muhd Shukeri, Chih-Hsien Wang, Steve Webb, Katharina Weil, Tan Pei Wen, Hassi Wesam, Sanne Wesselius, T. Eoin West, Murray Wham, Bryan Whelan, Nicole White, Paul Henri Wicky, Aurélie Wiedemann, Surya Otto Wijaya, Keith Wille, Sue Willems, Bailey Williams, Patricia J. Williams, Virginie Williams, Jessica Wittman, Calvin Wong, Xin Ci Wong, Yew Sing Wong, Teck Fung Wong, Natalie Wright, Lim Saio Xian, Ioannis Xynogalas, Siti Rohani Binti Mohd Yakop, Masaki Yamazaki, Elizabeth Yarad, Yazdan Yazdanpanah, Nicholas Yee Liang Hing, Abdelrahman Yehia Mahmoud Abdelaal, Cécile Yelnik, Chian Hui Yeoh, Stephanie Yerkovich, Touxiong Yiaye, Toshiki Yokoyama, Hodane Yonis, Obada Yousif, Saptadi Yuliarto, Akram Zaaqoq, Marion Zabbe, Gustavo E. Zabert, Kai Zacharowski, Masliza Zahid, Maram Zahran, Nor Zaila Binti Zaidan, Maria Zambon, Miguel Zambrano, Alberto Zanella, Nurul Zaynah, Hiba Zayyad, Alexander Zoufaly, and David Zucman
Subjects: COVID-19, Non-respiratory symptoms, Respiratory symptoms, Risk factors, Mortality, Science (General), Q1-390, Social sciences (General), H1-99
Abstract: Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.
Published: 2024
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5. Chest tube placement in trauma patients: please use sonography

Author: Fatimaezzahra Saroukh, Ayoub Bouchama, Ayoub Belhadj, and Younes Aissaoui
Subjects: Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published: 2024
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6. Paediatric COVID-19 mortality: a database analysis of the impact of health resource disparity

Author: Nick Daneman, John Marshall, Vinod Kumar, Aasiyah Rashan, Jérôme Dimet, Sylvain Diamantis, John F Fraser, Dominique Deplanque, Anne Conrad, François Lellouche, Heidi Gruner, Detlef Kindgen-Milles, Agnes Meybeck, Maxime Hentzien, Clotilde Allavena, André Cabié, Firouzé Bani-Sadr, Patrick Rossignol, Arjen M Dondorp, Rashan Haniffa, Harald Vonkeman, Lionel Piroth, Mathieu Blot, Yaseen Arabi, Marie-Pierre Debray, François Angoulvant, Marc Leone, Maria Zambon, Florentia Kaguelidou, Marc Lambert, Olivier Lairez, Tom Solomon, Carrol Gamble, Laura Marsh, David Richardson, Christiana Kartsonaki, Philippe Jouvet, Asgar Rishu, Eman Al Qasim, Rachael Parke, Srinivas Murthy, Alistair Nichol, Calum Semple, Colin McArthur, Gail Carson, Jake Dunning, Laura Merson, Peter Horby, David Maslove, Nadia Malik, Stephen R Knight, Annelies Verbon, Oana Sândulescu, Patrick Archambault, Paul McNally, Marlene Murris, Aurore Bousquet, Kenneth A McLean, Hugues Cordel, Marc Fabre, Laurence Bouillet, Melissa Parker, Xavier Duval, Amanda Corley, James Lee, Kusum Menon, Christian Rabaud, Paul Klenerman, Jean-François Timsit, Jennifer Lee, Nicolas Terzi, Saad Nseir, Gwenhaël Colin, Steve Webb, Kalynn Kennon, Caroline Mudara, Diana Hernández, Yazdan Yazdanpanah, Elias Iosifidis, Emmanuel Roilides, Yi Lin Lee, Pieter Depuydt, Jean-François Payen, Ana Martins, Samreen Ijaz, Meera Chand, Wei Shen Lim, Bruno Levy, Eric D'ortenzio, Jean-Charles Preiser, Pierre Delobel, Claudia Figueiredo-Mello, Jaques Sztajnbok, Ana Freitas Ribeiro, Tiphaine Goulenok, Bronner P Gonçalves, Arnaud Scherpereel, Chloe Donohue, Carlo Giaquinto, Karolina Nowicka, Adrien Auvet, Debby Bogaert, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Merce Jourdain, Anne McCarthy, Todd C Lee, António Mesquita, Sue Smith, Jia Wei, Jenny Lennon, Antoine Khalil, Nathalie Pansu, Victor Fomin, Audrey Barrelet, Christophe Fraser, Daniel Munblit, Robert A Fowler, William Greenhalf, François-Xavier Lescure, Nicolas Carlier, Saye Khoo, Riinu Pius, Lisa Norman, Louise Sigfrid, Sophie Halpin, Clare Jackson, Antonia Ho, Andrew Dagens, Thomas Flament, Julie Mankikian, Romain Basmaci, Peter Openshaw, Mary Copland, Brenda Reeve, William Dechert, Patricia Lizotte, Felwa Bin Humaid, Tom Fletcher, Adrien Lemaignen, Pierre Tattevin, Christelle Delmas, Hélène Espérou, Claire Lévy-Marchal, Olivier Picone, Jeanne Sibiude, Cecile Yelnik, Olivia V Swann, Michelle Girvan, Piero L Olliaro, Beatrice Alex, Benjamin Bach, Alexander J Mentzer, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, Georgios Pollakis, Vanessa Sancho-Shimizu, Shiranee Sriskandan, David Stuart, Charlotte Summers, Ryan S Thwaites, Hayley Hardwick, Wilna Oosthuyzen, Fiona Griffiths, Jo Dalton, Egle Saviciute, Stephanie Roberts, Janet Harrison, Marie Connor, Gary Leeming, Ross Hendry, Victoria Shaw, Jade Ghosn, Lucille Blumberg, Nicolas Benech, James Scott-Brown, Odile Launay, Todd Karsies, Yoan Lavie-Badie, Minh Le, Elise Artaud-Macari, Mylène Maillet, Huda Alfoudri, Djura Piersma, Didier Laureillard, Graham S. 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Russell, Musharaf Sadat, Valla Sahraei, Maximilien Saint-Gilles, Stéphane Sallaberry, Charlotte Salmon Gandonniere, Hélène Salvator, Zulfiqar Sandhu, Pierre-François Sandrine, Shirley Sarfo-Mensah, Benjamine Sarton, Parthena Savvidou, Yen Tsen Saw, Janet T. Scott, Jaganathan Selvanayagam, Mageswari Selvarajoo, Malcolm G. Semple, Rasidah Bt Senian, Eric Senneville, Tânia Sequeira, Pablo Serrano Balazote, Ellen Shadowitz, Syamin Asyraf Shahidan, Mohammad Shamsah, Shaikh Sharjeel, Catherine A. Shaw, Ashraf Sheharyar, Mohiuddin Shiekh, Nassima Si Mohammed, Ng Yong Siang, Benedict Sim Heng, Karisha Sivam, Morgane Snacken, Tze Vee Soh, Rima Song, Azlan Mat Soom, Albert Sotto, B. P Edouard Soum, Sanka Sri Darshana, Sarah Stabler, Ymkje Stienstra, Jacky Y. Suen, Deepashankari Suppiah, Andrey Svistunov, Sarah Syahrin, Shirin Tabrizi, Fabio S. Taccone, Lysa Tagherset, Shahdattul Mawarni Taib, Ewa Talarek, Kim Keat Tan, Yan Chyi Tan, Coralie Tardivon, M Azhari Taufik, Richard S. Tedder, Tze Yuan Tee, João Teixeira, Sze Kye Teoh, François Téoulé, Olivier Terrier, Hubert Tessier-Grenier, Alif Adlan Thabit, Zhang Duan Tham, Suvintheran Thangavelu, Simon-Djamel Thiberville, Jananee Thirumanickam, Emma C. Thomson, Surain Raaj Thurai, Peter S Timashev, Noémie Tissot, Jordan Zhien Toh, Sia Loong Tonnii, Marta Torre, Margarida Torres, Théo Treoux, Tiffany Trouillon, Christelle Tual, Lance C.W. Turtle, PG Ishara Udayanga, Timothy M. Uyeki, Luís Val-Flores, Amélie Valran, Marcel van den Berge, Job van der Palen, Paul van der Valk, Peter Van der Voort, Jarne Van Hattem, Carolien van Netten, Ilonka van Veen, Noémie Vanel, Shoban Raj Vasudayan, Charline Vauchy, Shaminee Veeran, Aurélie Veislinger, James Vickers, José Ernesto Vidal, César Vieira, Benoit Visseaux, Fanny Vuotto, Noor Hidayu Wahab, Suhaila Abdul Wahab, Nadirah Abdul Wahid, Tan Pei Wen, Sanne Wesselius, Nicole White, Paul Henri Wicky, Aurélie Wiedemann, Calvin Wong, Xin Ci Wong, Yew Sing Wong, Teck Fung Wong, Gan Ee Xian, Lim Saio Xian, Kuan Pei Xuan, Siti Rohani Yakop, Nicholas Yee Hing, Chian Hui Yeoh, Obada Yousif, Marion Zabbe, Masliza Zahid, Maram Zahran, Nor Zaila Zaidan, Konrad Zawadka, Nurul Zaynah, Hiba Zayyad, and David Zucman
Subjects: Pediatrics, RJ1-570
Abstract: Background The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.Methods The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.Results A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).Conclusion Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities.
Published: 2022
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7. Modeling of Microwave Cavities Based on SIBC-FDTD Method for EM Wave Focalization by TR Technique

Author: Zhigang Li, Younes Aimer, and Tayeb H. C. Bouazza
Subjects: curvilinear modeling, EM waves focalization, SIBCFDTD method, TR technique, Telecommunication, TK5101-6720, Information technology, T58.5-58.64
Abstract: The time reversal (TR) techniques used in electromagnetics have been limited for a variety of reasons, including extensive computations, complex modeling and simulation, processes as well as, large-scale numerical analysis. In this paper, the SIBC-FDTD method is applied to address these issues and to efficiently model TR systems. An original curvilinear modeling method is also proposed for constructing various obstacles in a 2D microwave cavity and for processing the corners of the cavity. The EM waves’ spatio-temporal focalization has been realized, and results of the simulations further prove the accuracy and effectiveness of this modeling method. Furthermore, they demonstrate that the microwave cavity processes may significantly improve the focalization quality in terms of SSLL enhancement.
Published: 2022
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8. Shaping code in conjunction with DCT for PAPR reduction in multicarrier system

Author: Younes Aimer, Boubakar Seddik Bouazza, Smail Bachir, and Claude Duvanaud
Subjects: Nonlinear power amplifier, PAPR reduction, DCT technique, Shaping code, OFDM systems, WLAN 802.11y applications, Telecommunication, TK5101-6720, Electronics, TK7800-8360
Abstract: Abstract Nonlinear behavior and power efficiency of the Power Amplifier (PA) contradictorily depend on the input signal amplitude distribution. The transmitted signal in multi-carrier modulation exhibits high Peak-to-Average Power Ratio (PAPR) and large bandwidths, leading to the degradation of the radio link and additional generation out-of-band interferences, which degrade the quality of the transmission. Practical solutions exist, like a power back-off, but with unacceptable efficiency performances of the transmitter. This paper deals with efficiency and linearity improvement using a new PAPR reduction method based on the combination of Discrete Cosine Transform and shaping technique. The main principle is to determine an optimal coding scheme according to a trade-off between coding complexity and performance benefits in the presence of PA nonlinearities. Simulation and experimental results in the context of OFDM signal and using a 20 W–3.7 GHz Radio-Frequency Power Amplifier show an improvement on PAPR reduction of about 3.25 dB. Also, the communication criteria like Bit Error Rate and Error Vector Magnitude are improved by about one decade and a half and $$8\%$$ 8 % , respectively.
Published: 2021
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9. Éventuelles implications de la sortie de la fixité du régime de change sur le choix d’une nouvelle stratégie monétaire : recommandations aux autorités monétaires marocaines

Author: Younes Ait Hmadouch
Subjects: Stratégie monétaire, Régime de change, Mandat dual, Ciblage du PIB Nominal, Economics as a science, HB71-74, Finance, HG1-9999, Business, HF5001-6182
Abstract: En analysant les interactions entre stratégie de politique monétaire et régimes de change adoptés au Maroc, la particularité du présent article est qu’il n’étudie pas l’impact de la politique de change et/ou de la politique monétaire sur un ou des indicateurs économiques, mais il étudie plutôt l’implication de la réforme touchant la politique de change sur la nécessité de mener une autre réforme touchant la politique monétaire. Je montre ainsi sur cet article que le ciblage d’inflation, que Bank Al-Maghrib envisage d’adopter suite à l’abandon graduel de l’ancrage du taux de change, n’est pas adapté à la nature des chocs économiques au Maroc et ne ferait que pénaliser l’économie marocaine. Je recommande alors comme stratégie alternative, une éventuelle adoption du ciblage du PIB nominal au lieu du ciblage d’inflation, afin d’améliorer la transmission de la politique monétaire à l’activité économique.
Published: 2022

10. Possible implications of the exit from the fixed exchange rate regime on the choice of a new monetary strategy: recommendations to Moroccan monetary authorities

Author: Younes Ait Hmadouch
Subjects: Monetary strategy, exchange rate regime, dual mandate, Nominal GDP targeting, Economics as a science, HB71-74, Finance, HG1-9999, Business, HF5001-6182
Abstract: Through the analysis of the interactions between monetary policy strategy and exchange rate regimes adopted in Morocco, the particularity of this article is that it does not study the impact of exchange rate policy and/or monetary policy on economic indicators, but rather to that, it analyzes the implication of the reform affecting exchange rate policy on the need for another reform affecting monetary policy. I thus show in this article that inflation targeting, which Bank Al-Maghrib plans to adopt following the gradual abandonment of the exchange rate anchor, is not adapted to the nature of economic shocks in Morocco and would only penalize the Moroccan economy. I therefore recommend as an alternative strategy, the possible adoption of nominal GDP targeting instead of inflation targeting, in order to improve the transmission of monetary policy to economic activity.
Published: 2022
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11. What happened during COVID-19 in African ICUs? An observational study of pulmonary co-infections, superinfections, and mortality in Morocco

Author: Younes Aissaoui, Youssef Ennassimi, Ismail Myatt, Mohammed El Bouhiaoui, Mehdi Nabil, Mohammed Bahi, Lamiae Arsalane, Mouhcine Miloudi, and Ayoub Belhadj
Subjects: Medicine, Science
Abstract: Background There is a growing literature showing that critically ill COVID-19 patients have an increased risk of pulmonary co-infections and superinfections. However, studies in developing countries, especially African countries, are lacking. The objective was to describe the prevalence of bacterial co-infections and superinfections in critically ill adults with severe COVID-19 pneumonia in Morocco, the micro-organisms involved, and the impact of these infections on survival. Methods This retrospective study included severe COVID-19 patients admitted to the intensive care unit (ICU) between April 2020 and April 2021. The diagnosis of pulmonary co-infections and superinfections was based on the identification of pathogens from lower respiratory tract samples. Co-infection was defined as the identification of a respiratory pathogen, diagnosed concurrently with SARS-Cov2 pneumonia. Superinfections include hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). A multivariate regression analysis was performed to identify factors independently associated with mortality. Results Data from 155 patients were analyzed. The median age was 68 years [62–72] with 87% of patients being male. A large proportion of patients (68%) received antibiotics before ICU admission. Regarding ventilatory management, the majority of patients (88%) underwent non-invasive ventilation (NIV). Sixty-five patients (42%) were placed under invasive mechanical ventilation, mostly after failure of NIV. The prevalence of co-infections, HAP and VAP was respectively 4%, 12% and 40% (64 VAP/1000 ventilation days). The most isolated pathogens were Enterobacterales for HAP and Acinetobacter sp. for VAP. The proportion of extra-drug resistant (XDR) bacteria was 78% for Acinetobacter sp. and 24% for Enterobacterales. Overall ICU mortality in this cohort was 64.5%. Patients with superinfection showed a higher risk of death (OR = 6.4, 95% CI: 1.8–22; p = 0.004). Conclusions In this single-ICU Moroccan COVID-19 cohort, bacterial co-infections were relatively uncommon. Conversely, high rates of superinfections were observed, with an increased frequency of antimicrobial resistance. Patients with superinfections showed a higher risk of death.
Published: 2022

12. QUELS ARGUMENTS POUR L'ADOPTION D'UN MANDAT DUAL DE POLITIQUE MONETAIRE AU MAROC ?

Author: Younes AIT HMADOUCH
Subjects: monetary policy, central bank, dual mandate, nominal gdp targeting., Management. Industrial management, HD28-70, Economics as a science, HB71-74
Abstract: By studying monetary authorities’ missions and analyzing the oretical contributions on the role of monetary policy, this paper brings critical analysis of central banks’ mandates that’s werve full employment objective from their main missions and that place the price stability on top of their objectives. These so-called "hierarchical" mandates, which predominate both in practice and in the literature, have shown their weakness since the financial crisis of 2008. Wethen develop in this article, arguments drawn both from the economic and monetary reality and from the litterature, in favor of the adoption of a "dual" mandate which gives the goal of full employment the same weight as the control of inflation within the the central bank’s statutes in general, and within Bank Al-Maghrib statutes in particular.
Published: 2020
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13. Optimal Fault Tolerant Control of Large-Scale Wind Turbines in the Case of the Pitch Actuator Partial Faults

Author: Younes Ait El Maati and Lhoussain El Bahir
Subjects: Electronic computers. Computer science, QA75.5-76.95
Abstract: In this paper, an adaptive fault tolerant control strategy is proposed to deal with the three pitch actuator faults in the large-scale wind turbines. Firstly, a simultaneous state and fault estimation was performed through a suitable LMI (linear matrix inequality) based optimal strategy. Hereafter, the new control law is designed using the previously estimated fault information. The actuator efficiency estimator uses as design parameters, respectively, the performance index γ against the wind and the learning rate Ξ. of the fault estimation algorithm. The study shows that the choice of the previous two parameters impacts the response time of the fault estimation and the correlation of the tracking error with the wind. The aim is to choose a small fault estimation response time while keeping a weak correlation between the tracking error and the wind turbulence noise. Finally, a tuning strategy is elaborated to choose the suitable γ and Ξ to match the reconfiguration objective.
Published: 2020
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14. Interleaving Technique Implementation to Reduce PAPR of OFDM Signal in Presence of Nonlinear Ampliﬁcation with Memory Eﬀects

Author: Younes Aimer, Boubakar Seddik Bouazza, Smail Bachir, and Claude Duvanaud
Subjects: downward compatibility, interleaving technique, interleaver key, OFDM systems, PAPR reduction, Telecommunication, TK5101-6720, Information technology, T58.5-58.64
Abstract: In OFDM systems, peak-to-average power ratio (PAPR) reduction of the signal is one of the main challenges that need to be overcome in order to use the transmitter in an eﬃcient manner. As one of attractive techniques, interleaving can be used in PAPR reduction for multicarrier signals without spectrum distortion. In this paper, the authors propose to extend the possibilities of interleaving to improve PAPR reduction, to use a new coding of interleaver keys at the transmitter and a robust decoding procedure at the receiver. In order not to degrade the data rate, the use of null subcarriers to transmit side information to the receiver is proposed and evaluated. Simulation results in the context of the WLAN 802.11a standard in the presence of a nonlinear power ampliﬁer model with memory, show a reduction of PAPR of approximately 5.2 dB, and an improvement of bit error rate and error vector magnitude of about 2 decades and 4% respectively, while respecting the spectral mask speciﬁcation.
Published: 2018
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15. Fault Tolerant Control of Internal Faults in Wind Turbine: Case Study of Gearbox Efficiency Decrease

Author: Younes Ait El Maati, Lhoussain El Bahir, and Khalid Faitah
Subjects: Engineering (General). Civil engineering (General), TA1-2040
Abstract: This paper presents a method to control the rotor speed of wind turbines in presence of gearbox efficiency fault. This kind of faults happens due to lack of lubrication. It affects the dynamic of the principal shaft and thus the rotor speed. The principle of the fault tolerant control is to find a bloc that equalizes the dynamics of the healthy and faulty situations. The effectiveness decrease impacts on not only the dynamics but also the steady state value of the rotor speed. The last reason makes it mandatory to add an integral term on the steady state error to cancel the residual between the measured and operating point rotor speed. The convergence of the method is proven with respect to the rotor parameters and its effectiveness is evaluated through the rotor speed.
Published: 2018
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16. Syndrome de choc toxique staphylococcique chez un hémodialysé chronique

Author: Hassan Alaoui, Ayoub Belhadj, Younes Aissaoui, Rachid Seddiki, Mohamed Zoubir, and Mohamed Bougalem
Subjects: syndrome de choc toxique staphylococcique, staphylocoque doré, hémodialyse, fistule artério-veineuse, Medicine
Abstract: Le syndrome de choc toxique staphylococcique est un syndrome infectieux aigu et systémique lié à l'activité super-antigénique des toxines staphylococciques. C'est une pathologie qui est assez rare mais reste grevée d'une mortalité considérable malgré la prise en charge thérapeutique. La porte d'entrée est le plus souvent cutanée avec dissémination bactériémique secondaire pourrait être sujet de mesures préventives. Nous rapportons le cas d'un choc toxique à staphylocoque doré d'évolution rapidement mortelle, développé chez un hémodialysé chronique dont la porte d'entrée à partir de la fistule artério-veineuse était soupçonnée.
Published: 2017
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17. Une intoxication peut en cacher une autre plus grave. Exemple d'une intoxication fatale à l'éthylène glycol masquée par une intoxication à un insecticide pyréthrinoïde

Author: Younés Aissaoui, Hicham Kechna, Mohammed Boughalem, and Noureddine Drissi Kamili
Subjects: intoxication, insecticide, pyréthrinoïde, cyperméthrine, éthylène glycol, solvant, Medicine
Abstract: Les pyréthrinoïdes sont des insecticides largement utilisés du fait de leur efficacité et de leur relative sécurité chez l'homme. Les intoxications mortelles liées à ces agents restent exceptionnelles. Leur métabolisme hépatique rapide limite considérablement leur toxicité chez l'homme. Cette observation relate une intoxication grave à un pyréthrinoïde (la cyperméthrine) dont le solvant était l'éthylène glycol. Ce dernier est un toxique nettement plus dangereux pour l'homme. Le tableau clinique consistait en une atteinte multiviscérale avec prédominance de la défaillance cardiovasculaire et neurologique. Le faible potentiel toxique des pyréthrinoïdes suggère l'implication évidente de l'éthylène glycol dans la gravité de cette intoxication. La prise en charge thérapeutique, essentiellement symptomatique, na pas pris en compte la présence d'éthylène glycol dans la formulation de l'insecticide. L'évolution clinique était défavorable. Devant toute intoxication grave à un insecticide pyréthrinoïde une intoxication associée au solvant tel que l'éthylène glycol doit être recherchée et traitée.
Published: 2013
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18. Les accidents aux AVK: étude rétrospective à propos de 30 cas

Author: Issam Serghini, Younés Aissaoui, Youssef Quamouss, Rachid Sedikki, Nourredine Taj, Jaafar Salim Alaoui, Mohamed Zoubir, and Mohamed Boughanem
Subjects: anti-vitamine k, hémorragie, surveillance, maroc, Medicine
Abstract: Les accidents hémorragiques sous AVK (antivitamines K) sont la première cause d'hospitalisation iatrogène. Le but de cette étude est de ressortir les caractéristiques des patients présentant des accidents hémorragiques graves sous AVK et de mettre le point sur la prise en charge. Nous avons réalisé une étude rétrospective portant sur 30 malades, réalisée au service de réanimation de l'Hôpital militaire Avicenne de Marrakech. L'âge moyen de nos patients est de 59, 6 avec un sexe ratio de 1,5 (18 femmes et 12 femmes). On note dans notre série le terrain multi-taré des patients sous AVK avec plusieurs antécédents en cause. La fibrillation auriculaire était la principale indication recensée. Plus que la moitié ne bénéficiaient pas d'une bonne surveillance biologique à base d'INR (international normalized ratio). Le saignement d'origine gastro-intestinal était le plus fréquent. La conduite était différente en fonction des cas mais axée sur l'arrêt des AVK, l'administration de vit K, la transfusion de culots globulaires et plasma frais congelé. Plus du quart des patients admis sont décédés. L'index de Landefeld s'est avéré utile, il permet de classer les patients selon le risque prédictif de saignement (élevé moyen ou faible), ce qui concordait avec les résultats de notre étude. Son importance est d' autant plus quéil est facile à mesurer et à appliquer par le médecin en ambulatoire et permet de définir les patients nécessitant une surveillance accrue. La polymédication et les antécédents de saignement digestif sont apparus comme facteur de risque de saignement sous AVK. La prévention de la survenue de ces accidents est le pilier de la prise en charge, d'où l'mportance de l'information et de l'éducation des différents intervenants dans cette complication iatrogène potentiellement mortelle.
Published: 2012
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19. Médiastinite compliquant une cellulite cervicale à porte d’entrée dentaire: à propos d’un cas et revue de la littérature

Author: Issam Serghini, Younés Aissaoui, Youssef Quamouss, Rachid Sedikki, Karim Filali, Mohamed Zoubir, and Mohamed Boughanem
Subjects: Cellulite cervicale, infection dentaire, infections à germes anaérobies, retard diagnostic, médiastinite, Medicine
Abstract: Les cellulites cervicales ou fasciites cervicales nécrosantes sont des infections des parties molles développées à partir de foyer dentaire ou pharyngé dont le risque, si elles ne sont pas reconnues précocement, est l’extension vers le médiastin. Les premiers signes cliniques sont parfois frustres et peuvent conduire à un retard diagnostique. L’examen clé est la tomodensitométrie cervicale et thoracique. Le traitement consiste en des excisions tissulaires larges et répétées associées une antibiothérapie dirigée contre les germes aréo- et anaérobies. Nous rapportons le cas d’un homme connu diabétique présentant une cellulite cervicale d’origine dentaire compliquée de médiastinite.
Published: 2011

20. Choc anaphylactique au cours de la chirurgie de kyste hydatique du foie : à propos d’un cas

Author: Mohame Boughalem, Younes Aissawi, Karim Filali, Youssef Qamouss, and Rachid Seddiqui
Subjects: Choc anaphylactique, kyste hydatique, Maroc, Medicine
Abstract: Nous rapportons l’observation d’un choc anaphylactique survenue au cours d’une chirurgie de kystes hydatiques hépatiques multiples. Il s’agit d’un enfant de 13 ans, de sexe féminin, sans antécédents pathologiques notables, en particulier allergique, programmé pour cure chirurgicale de kystes hydatiques hépatiques multiples. L’examen préopératoire est strictement normal. La patiente est classée ASA (American Society of Anaesthesiologists) I. L’intervention est réalisée sous anesthésie générale. Au moment de la manipulation du deuxième kyste, une augmentation des pressions d’insufflation apparaît, avec des râles sibilants au niveau des deux champs pulmonaires et une désaturation, suivi d’un collapsus vasculaire avec hypotension artérielle 50/30. La prise en charge est débutée aussitôt par un remplissage vasculaire par du sérum salé 9%, suivi par des bolus d’adrénaline de 0,1mg à trois reprises, puis d’une perfusion continue à raison. L’adrénaline est arrêtée au bout de 48 heures et la patiente est adressée au service de chirurgie à j+4 de l’intervention. Le choc anaphylactique est une complication connue de la rupture intra péritonéale spontanée ou post-traumatique du kyste hydatique du foie. Sa survenue en peropératoire est devenue exceptionnelle, grâce aux mesures de prévention chirurgicale entretenues en peropératoire par l’éviction de manipulation du kyste, de le vider avant d’injecter le scolicide, et de ne pas l’administrer sous forte pression.
Published: 2010

21. GLI1 -Rearranged Enteric Tumors: Updates on Clinicopathologic and Molecular Genetics Features.

Author: Younes AI and Mejbel HA
Subjects: Humans, Prognosis, Zinc Finger Protein GLI1 genetics, Gene Rearrangement genetics
Abstract: Recent advances in molecular genetics, particularly in identifying and characterizing genetic abnormalities within mesenchymal neoplasms, have led to a more comprehensive and evolving classification system. Modern technological developments in cytogenetics and next-generation sequencing have enabled the analysis of small clinical samples, expanded our understanding of tumor biology, and improved the diagnostic, prognostic, and predictive precision by identifying targeted genetic alterations, confirming the presence of fusion transcripts, and/or revealing the overexpression of specific genes and their targets. In this review, we focus specifically on the GLI1 -rearranged enteric tumor, a recent clinicopathological entity that has emerged within the expanding classification of mesenchymal tumors. Herein, we aim to explore the histopathological features, molecular genetic characteristics, and clinical outcomes in these tumors. Due to their rarity and the extensive overlapping in their histopathological and molecular features with other neoplasms, continued research and systematic documentation of GLI1 -rearranged enteric tumors is necessary to better understand their biological behavior, develop more accurate prognostic indicators, and establish optimal treatment strategies.
Published: 2025
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22. Delayed Pembrolizumab-Associated Sarcoidosis.

Author: Valasapalli S, Aslam H, Younes AI, and Muzaffar M
Subjects: Humans, Antineoplastic Agents, Immunological adverse effects, Melanoma drug therapy, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized therapeutic use, Sarcoidosis chemically induced, Sarcoidosis drug therapy
Abstract: Competing Interests: The authors have no conflicts of interest to declare.
Published: 2024
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23. A Rare Case of a Pancreatic Intraductal Oncocytic Papillary Neoplasm Associated With Invasive Adenocarcinoma Presenting as a Gastric Mass.

Author: Younes AI, Hu X, Peng L, and Chi Z
Abstract: The World Health Organization recently recognized intraductal oncocytic papillary neoplasms of the pancreas (IOPNs) as distinct, pre-malignant pancreatic neoplasms. Due to their unique macroscopic and microscopic features, IOPNs are typically easy to diagnose and yield an indolent prognostic outcome. The diagnosis may be more complicated, and the prognosis may differ if an associated invasive carcinoma is present. Owing to the rarity of this entity, the available data is severely limited. Herein, we report a diagnostically challenging case of an IOPN associated with invasive carcinoma, initially presenting as a gastric mass with distinctive radiological and histopathological features., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Younes et al.)
Published: 2023
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24. A Quantitative and Qualitative Assessment of Frozen Section Diagnosis Accuracy and Deferral Rate Across Organ Systems.

Author: Mohamed A, Hassan MM, Zhong W, Kousar A, Takeda K, Donthi D, Rizvi A, Majeed M, Younes AI, Ali A, Sutton A, Murray G, Thayyil A, Fallon J, and Geisinger K
Subjects: Female, Humans, Intraoperative Period, Retrospective Studies, Diagnostic Errors prevention & control, Frozen Sections methods, Pathology, Surgical methods
Abstract: Objectives: Monitoring of frozen section diagnostic performance provides an important quality improvement measure., Methods: Surgical specimens involving a frozen section diagnosis over a 3-year period were retrospectively reviewed. Glass slides were reviewed on cases with discordance. Discordance and deferral rates were calculated., Results: Of 3,675 frozen section diagnoses included, 96 (2.7%) were discordant with the final diagnosis. Additionally, 114 frozen section diagnoses (3.1%) were deferred. The organ-specific discordance rates were lowest in breast and genitourinary specimens and highest for pancreas, lymph node, and gynecologic specimens. Deferral rates were highest in musculoskeletal, breast, and hepatobiliary cases and lowest in thyroid, parathyroid, and neuropathology cases. Discordance was explained by block-sampling error (45%), specimen-sampling error (27%), or interpretation error (27%). Discordant frozen section diagnoses from gynecologic specimens were responsible for 81% of specimen-sampling errors; frozen section diagnoses of lymph nodes, head and neck, and pancreas were responsible for 54% of interpretation errors; 51% of block-sampling errors involved lymph node evaluation for metastatic carcinoma., Conclusions: Careful gross evaluation and microscopic examination of multiple levels should minimize specimen-sampling error and block-sampling error, respectively. Periodic review of accuracy and deferral rates may help reduce errors and improve the overall performance of this essential procedure., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Published: 2022
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25. A Rare Case of Synchronous Oncocytoma and Angiomyolipoma of the Kidney.

Author: Younes AI, Jackson M, and Dal Zotto VL
Subjects: Aged, Female, Humans, Kidney pathology, Tomography, X-Ray Computed, Adenoma, Oxyphilic diagnostic imaging, Adenoma, Oxyphilic pathology, Adenoma, Oxyphilic surgery, Angiomyolipoma diagnostic imaging, Angiomyolipoma surgery, Kidney Neoplasms diagnostic imaging, Kidney Neoplasms surgery
Abstract: BACKGROUND The co-occurrence of renal oncocytoma and angiomyolipoma is exceedingly rare. To date, 17 such cases have been reported in the literature. This report describes a unique case of that association that presented as a single renal mass on imaging. CASE REPORT A 75-year-old woman presented with epigastric discomfort. A CT scan of the abdomen revealed a 6.6×5.7×4.7 cm enhancing right renal mass. Gross examination revealed a nodular, well-circumscribed, tan-brown mass located in the lower pole of the kidney that was abutting the renal capsule. Interestingly, superior to this mass, there was an adjacent, pale tan-white, firm, well-circumscribed nodule in the mid-pole, which was not detected on the CT scan and grossly extended to 1.1 cm of the overlying renal capsule. Histologically, the larger tumor showed characteristic features of oncocytoma. The smaller tumor had an admixture of mature adipose tissue, smooth muscle, and vessels, consistent with a renal angiomyolipoma. CONCLUSIONS We present a new case of synchronous renal angiomyolipoma and oncocytoma, which were uniquely adjacent and coexisted with minimal intermingling renal parenchyma. Other "eosinophilic renal tumors" are significant differential diagnosis considerations. Due to the close proximity of these lesions, this association can present clinically and radiologically as a single renal mass. Careful examination of the nephrectomy specimen is essential for the proper detection of small-sized tumors.
Published: 2022
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26. High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses.

Author: Barsoumian HB, Sezen D, Menon H, Younes AI, Hu Y, He K, Puebla-Osorio N, Wasley M, Hsu E, Patel RR, Yang L, Cortez MA, and Welsh JW
Abstract: Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT + exhausted T-cells and TIGIT + regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control.
Published: 2022
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27. Radiation Therapy Enhanced by NBTXR3 Nanoparticles Overcomes Anti-PD1 Resistance and Evokes Abscopal Effects.

Author: Hu Y, Paris S, Barsoumian H, Abana CO, He K, Wasley M, Younes AI, Masrorpour F, Chen D, Yang L, Dunn JD, Zhang J, Gandhi S, Nguyen QN, Cortez MA, and Welsh J
Subjects: Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Female, Humans, Mice, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell, Tumor Microenvironment, Antineoplastic Agents, Lung Neoplasms radiotherapy, Nanoparticles
Abstract: Purpose: Radiation combined with PD1 blockade offers significant treatment benefits in several tumor types; however, anti-PD1 resistance precludes such benefits in many cases. Here we attempted to overcome anti-PD1 resistance by combining localized radiation with a radioenhancing nanoparticle (NBTXR3) and systemic anti-PD1 treatment to achieve abscopal effects in an anti-PD1-resistant mouse model of lung cancer., Methods and Materials: Female 129Sv/Ev mice were inoculated with 344SQ anti-PD1-resistant (344SQR) or anti-PD1-sensitive (344SQP) metastatic lung cancer cells in the right leg on day 0 ("primary" tumor) and the left leg on day 4 ("secondary" tumor). Primary tumors were injected intratumorally with NBTXR3 on day 7 and were irradiated with 12 Gy on days 8, 9, and 10. Mice were given 6 intraperitoneal injections of anti-PD1. T cell receptor repertoire was analyzed in tumor samples with RNA sequencing, infiltration of CD8 T cells with immunohistochemical staining, and activities of various immune pathways with NanoString analysis., Results: The triple combination of NBTXR3 with localized radiation and systemic anti-PD1 significantly delayed the growth of both irradiated and unirradiated tumors in both 344SQP and 344SQR tumor models. NBTXR3 remodeled the immune microenvironment of unirradiated tumors by triggering the activation of various immune pathways, increasing the number of CD8 + T cells, and modifying the T cell receptor repertoire in the 344SQR tumor model., Conclusions: The ability of NBTXR3 to evoke significant abscopal effects in both anti-PD1-sensitive and anti-PD1-resistant lung cancers could open the possibility of its use for treating patients with metastatic lung cancer regardless of sensitivity (or resistance) to immunotherapies., (Copyright © 2021. Published by Elsevier Inc.)
Published: 2021
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28. An unusual presentation of chronic lymphocytic leukemia/small lymphocytic lymphoma on mammography: Case report.

Author: Mohamed A, Younes AI, Stalls S, Kousar A, and Li T
Abstract: Although rare, breast CLL/SLL should be considered in the differential diagnosis of a breast mass. A high index of suspicion is needed to differentiate this neoplasm from more common breast carcinomas like solid variant of invasive lobular carcinoma., Competing Interests: All authors declare no conflict of interest., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)
Published: 2021
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29. Primary malignant melanoma of the gastric antrum: A case report.

Author: Younes AI, Mohamed A, Rizvi AH, and Prenshaw K
Abstract: Primary melanoma of the antrum is a rare and aggressive disease. Diagnosis requires a correlation between the patient's history, tumor histopathology, and immunohistochemistry. Surgery and mutation-targeted treatments may improve overall survival., Competing Interests: None declared., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)
Published: 2021
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30. Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity.

Author: Younes AI, Barsoumian HB, Sezen D, Verma V, Patel R, Wasley M, Hu Y, Dunn JD, He K, Chen D, Menon H, Masrorpour F, Gu M, Yang L, Puebla-Osorio N, Cortez MA, and Welsh JW
Abstract: Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b + myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4 + and CD8 + T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease., Competing Interests: Declaration of competing Interest Dr. Welsh serves on the science advisory board for RefleXion Medical, Checkmate Pharmaceuticals, and Alpine Immune Sciences; he is the founder of Healios Oncology, Molecular Match, and OncoResponse; and has research support in collaborations with BMS, Merck, Mavu Pharma, Checkmate Pharmaceuticals, and Nanobiotix. All other authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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31. Role of Mitochondria in Cancer Immune Evasion and Potential Therapeutic Approaches.

Author: Klein K, He K, Younes AI, Barsoumian HB, Chen D, Ozgen T, Mosaffa S, Patel RR, Gu M, Novaes J, Narayanan A, Cortez MA, and Welsh JW
Subjects: Animals, Humans, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mitochondria drug effects, Mitochondria pathology, Mitochondria radiation effects, Molecular Targeted Therapy, Neoplasms immunology, Neoplasms pathology, Neoplasms therapy, Signal Transduction, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Hypoxia, Tumor Microenvironment, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism, Energy Metabolism drug effects, Energy Metabolism radiation effects, Mitochondria metabolism, Neoplasms metabolism, Tumor Escape drug effects
Abstract: The role of mitochondria in cancer formation and progression has been studied extensively, but much remains to be understood about this complex relationship. Mitochondria regulate many processes that are known to be altered in cancer cells, from metabolism to oxidative stress to apoptosis. Here, we review the evolving understanding of the role of mitochondria in cancer cells, and highlight key evidence supporting the role of mitochondria in cancer immune evasion and the effects of mitochondria-targeted antitumor therapy. Also considered is how knowledge of the role of mitochondria in cancer can be used to design and improve cancer therapies, particularly immunotherapy and radiation therapy. We further offer critical insights into the mechanisms by which mitochondria influence tumor immune responses, not only in cancer cells but also in immune cells. Given the central role of mitochondria in the complex interactions between cancer and the immune system, high priority should be placed on developing rational strategies to address mitochondria as potential targets in future preclinical and clinical studies. We believe that targeting mitochondria may provide additional opportunities in the development of novel antitumor therapeutics., (Copyright © 2020 Klein, He, Younes, Barsoumian, Chen, Ozgen, Mosaffa, Patel, Gu, Novaes, Narayanan, Cortez and Welsh.)
Published: 2020
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32. Author Correction: Bone morphogenetic protein 7 promotes resistance to immunotherapy.

Author: Cortez MA, Masrorpour F, Ivan C, Zhang J, Younes AI, Lu Y, Estecio MR, Barsoumian HB, Menon H, da Silva Caetano M, Ramapriyan R, Schoenhals JE, Wang X, Skoulidis F, Wasley MD, Calin G, Hwu P, and Welsh JW
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020
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33. Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma.

Author: Barsoumian HB, Ramapriyan R, Younes AI, Caetano MS, Menon H, Comeaux NI, Cushman TR, Schoenhals JE, Cadena AP, Reilly TP, Chen D, Masrorpour F, Li A, Hong DS, Diab A, Nguyen QN, Glitza I, Ferrarotto R, Chun SG, Cortez MA, and Welsh J
Subjects: Aged, Animals, Female, Humans, Male, Mice, Neoplasms immunology, Tumor Microenvironment, Immunity immunology, Immunotherapy methods, Neoplasms radiotherapy
Abstract: Background: Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes., Methods: We bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect., Results: Through our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to 'prime' T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to 'modulate the stroma'. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4 + T cells and NK cells abrogated the observed antitumor effect., Conclusion: Our data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors., Competing Interests: Competing interests: JW serves on the science advisory boards for Alpine Immune Sciences, RefleXion Medical, Mavu Pharma, MolecularMatch and Checkmate Pharmaceuticals, and he is the founder of Healios Oncology, MolecularMatch, and OncoResponse companies. MD Anderson Cancer Center has a trademark for RadScopal (TM). JW has research support collaborations with Bristol Myers Squibb, Checkmate Pharmaceuticals, Mavu pharma, Merck, and Nanobiotix. AD is an advisory board member for Nektar Therapeutics. IG is a consultant for Bristol Myers Squibb and Array Biopharma. DSH has consulting/advisory role in Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics. DSH has research/grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda. DSH's ownership interests include MolecularMatch (Advisor), OncoResponse (founder), Presagia Inc (Advisor)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2020
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34. Bone morphogenetic protein 7 promotes resistance to immunotherapy.

Author: Cortez MA, Masrorpour F, Ivan C, Zhang J, Younes AI, Lu Y, Estecio MR, Barsoumian HB, Menon H, Caetano MDS, Ramapriyan R, Schoenhals JE, Wang X, Skoulidis F, Wasley MD, Calin G, Hwu P, and Welsh JW
Subjects: Animals, Antibodies, Monoclonal, Humanized pharmacology, CD4-Positive T-Lymphocytes, Cell Line, Tumor, Female, Follistatin metabolism, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mice, Mitogen-Activated Protein Kinase 14 genetics, Mitogen-Activated Protein Kinase 14 metabolism, Programmed Cell Death 1 Receptor drug effects, RAW 264.7 Cells, Smad1 Protein metabolism, Transcriptome, Tumor Microenvironment drug effects, Bone Morphogenetic Protein 7 genetics, Bone Morphogenetic Protein 7 metabolism, Drug Resistance, Neoplasm drug effects, Immunotherapy methods, Neoplasms metabolism
Abstract: Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4 + T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.
Published: 2020
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35. SHP-2 and PD-L1 Inhibition Combined with Radiotherapy Enhances Systemic Antitumor Effects in an Anti-PD-1-Resistant Model of Non-Small Cell Lung Cancer.

Author: Chen D, Barsoumian HB, Yang L, Younes AI, Verma V, Hu Y, Menon H, Wasley M, Masropour F, Mosaffa S, Ozgen T, Klein K, Cortez MA, and Welsh JW
Subjects: Animals, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, Chemoradiotherapy, Drug Resistance, Neoplasm, Female, Lung Neoplasms immunology, Lung Neoplasms metabolism, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Antineoplastic Agents, Immunological pharmacology, B7-H1 Antigen antagonists & inhibitors, Carcinoma, Non-Small-Cell Lung therapy, Lung Neoplasms therapy, Piperidines pharmacology, Protein Tyrosine Phosphatase, Non-Receptor Type 6 antagonists & inhibitors, Pyrimidines pharmacology
Abstract: Immune checkpoint inhibitors, such as anti-PD-1/PD-L1, have emerged as promising therapies for advanced non-small cell lung cancer (NSCLC). However, approximately 80% of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance. Radiotherapy (XRT) can overcome PD-1 resistance and improve treatment outcomes, but its efficacy remains suboptimal. The tyrosine phosphatase SHP-2, expressed in some cancers and in immune cells, has been shown to negatively affect antitumor immunity. Our hypothesis was that SHP-2 inhibition in combination with anti-PD-L1 would enhance immune-mediated responses to XRT and synergistically boost antitumor effects in an anti-PD-1-resistant mouse model. We treated 129Sv/Ev mice with anti-PD-1-resistant 344SQ NSCLC adenocarcinoma with oral SHP099 (a SHP-2 inhibitor) combined with XRT and intraperitoneal anti-PD-L1. Primary tumors were treated with XRT (three fractions of 12 Gy each), whereas abscopal (out-of-field) tumors were observed but not treated. XRT in combination with SHP099 and anti-PD-L1 promoted local and abscopal responses, reduced lung metastases, and improved mouse survival. XRT also increased SHP-2 + M1 tumor-associated macrophages in abscopal tumors ( P = 0.019). The addition of SHP099 also associated with a higher M1/M2 ratio, greater numbers of CD8 + T cells, and fewer regulatory T cells. This triple-combination therapy had strong antitumor effects in a mouse model of anti-PD-1-resistant NSCLC and may be a novel therapeutic approach for anti-PD-1-resistant NSCLC in patients., (©2020 American Association for Cancer Research.)
Published: 2020
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36. Combination treatment with radiotherapy and a novel oxidative phosphorylation inhibitor overcomes PD-1 resistance and enhances antitumor immunity.

Author: Chen D, Barsoumian HB, Fischer G, Yang L, Verma V, Younes AI, Hu Y, Masropour F, Klein K, Vellano C, Marszalek J, Davies M, Cortez MA, and Welsh J
Subjects: Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor transplantation, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm radiation effects, Drug Screening Assays, Antitumor, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms immunology, Lung Neoplasms pathology, Mice, Oxadiazoles therapeutic use, Oxidative Phosphorylation drug effects, Piperidines therapeutic use, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung therapy, Chemoradiotherapy methods, Lung Neoplasms therapy, Oxadiazoles pharmacology, Piperidines pharmacology
Abstract: Background: Despite outstanding responses to anti-PD-1 agents in a subset of non-small cell lung cancer (NSCLC) patients, approximately 80% of patients fail to have prolonged favorable response. Recent studies show that tumor cell oxidative metabolism is a barrier to PD-1 immunotherapy and radiotherapy could overcome PD-1 resistance, so it is urgent to determine if combination treatment with radiotherapy and a novel oxidative phosphorylation (OXPHOS) inhibitor (IACS-010759) is an effective strategy against PD-1 resistance in NSCLC., Methods: The antitumor effect of this combinational treatment was evaluated in vitro and in vivo. For in vivo experiments, we treated 129Sv/Ev mice with anti-PD1-sensitive and anti-PD1-resistant 344SQ NSCLC adenocarcinoma xenografts with oral IACS-010759 combined with radiotherapy (XRT). In vitro experiments included PCR, seahorse bioenergetic profiling, flow cytometry phenotyping, and clonogenic survival assay., Results: In the current study, we found that our PD-1-resistant model utilized OXPHOS to a significantly greater extent than the PD-1-sensitive model and XRT increased OXPHOS in vitro and in vivo. Thus, we explored the effect of the novel OXPHOS inhibitor IACS-010759 on PD-1-resistant NSCLC in an effort to overcome XRT-induced immunosuppression and maximize response to PD-1. Additionally, combined XRT and IACS-010759 promoted antitumor effects in the PD-1-resistant model, but not in the sensitive model. After elucidation of the most optimal dose/fractionation scheme of XRT with IACS-010759, the combinatorial therapy with this regimen did not increase the abscopal antitumor effect, although IACS-010549 did not decrease CD45+, CD4+, and CD8+ immune cells. Finally, triple therapy with IACS-010759, XRT, and anti-PD-1 promoted abscopal responses and prolonged survival time., Conclusion: OXPHOS inhibition as part of a combinatorial regimen with XRT is a promising strategy to address PD-1-resistant NSCLC, and this combination is being tested clinically., Competing Interests: Competing interests: JW has received research support from GlaxoSmithKline (GSK), Bristol-Meyers Squibb, Merck, Nanobiotix, Mavu Pharmaceuticals, and Checkmate Pharmaceuticals; served on the scientific advisory board for RefleXion Medical, MolecularMatch, OncoResponse, CheckMate, Mavu Pharmaceuticals, and Alpine Immune Sciences; was cofounder of Helios Oncology, MolecularMatch, and OncoResponse; served as an advisor to AstraZeneca, Merck, MolecularMatch, Incyte, Aileron, and Nanobiotix; and holds patents for MP470 (amuvatinib), MRX34 regulation of PD-L1, and the use of radiotherapy to overcome immune resistance (The University of Texas MD Anderson Cancer Center has a trademark for RadScopal). MD has served on advisory committees for Roche/Genentech, BMS, Novartis, GSK, Sanofi-Aventis, and Vaccinex and has been the PI of funded research grants to his institution by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. Durg, IACS-010759, was developed from MD Anderson cancer center., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
Published: 2020
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37. Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

Author: Caetano MS, Younes AI, Barsoumian HB, Quigley M, Menon H, Gao C, Spires T, Reilly TP, Cadena AP, Cushman TR, Schoenhals JE, Li A, Nguyen QN, Cortez MA, and Welsh JW
Subjects: Animals, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Cell Line, Tumor, Combined Modality Therapy, Female, Lung Neoplasms pathology, Lung Neoplasms therapy, Mice, Tumor Microenvironment drug effects, Antibodies, Monoclonal pharmacology, Carcinoma, Non-Small-Cell Lung immunology, Lung Neoplasms immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Radiosurgery methods, c-Mer Tyrosine Kinase antagonists & inhibitors
Abstract: Purpose: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy., Experimental Design: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response., Results: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8 + and NK cells populations measured by granzyme B expression with upregulation of CD8 + CD103 + tissue-resident memory cells (T RM ) within the abscopal tumor microenvironment relative to radiation only., Conclusions: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of T RM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients., (©2019 American Association for Cancer Research.)
Published: 2019
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38. Thymic Mucoepidermoid Carcinoma: A Systematic Review and Meta-analysis.

Author: Hamza A, Younes AI, and Kalhor N
Subjects: DNA-Binding Proteins genetics, Humans, Neoplasm Staging, Nuclear Proteins genetics, Transcription Factors genetics, Carcinoma, Mucoepidermoid pathology, Carcinoma, Mucoepidermoid surgery, Oncogene Proteins, Fusion genetics, Trans-Activators genetics
Abstract: Thymic mucoepidermoid carcinoma is a rare tumor that remains poorly characterized and a diagnostic challenge. The aim of this review is to characterize this tumor in a larger cohort of patients using all the available cases in the literature. We systematically searched the PubMed and Scopus database for primary thymic mucoepidermoid carcinoma. A total of 24 studies were included in the final analysis. A total of 41 patients were identified; 23 (56.1%) were male and 18 (43.9%) were female. Mean age was 49.8±21.3 years. Mean tumor size was 7.6±3.5 cm. Twenty (66.7%) were low grade and 8 (26.7%) were high grade. In total, 20 (55.6%) patients were treated with surgery alone. Nodal dissection was performed in 4 cases only. Two patients had MAML2 gene rearrangement and 2 were negative. Follow-up time varied from 2 to 93 months. A total of 13 (44.8%) patients died of disease with a median survival of 12 months. There seems to be a bimodal age distribution with peaks between second and third decades of life, and between sixth and eight decades. Lymph node sampling is frequently not performed; however, we recommend performing it, as it may lead to more accurate staging. There is limited data regarding the utility of MAML2 gene rearrangement in the thymic location. Histologic grade and tumor stage/resectability are the main prognostic factors.
Published: 2019
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39. Results of a Phase 1/2 Trial of Chemoradiotherapy With Simultaneous Integrated Boost of Radiotherapy Dose in Unresectable Locally Advanced Esophageal Cancer.

Author: Chen D, Menon H, Verma V, Seyedin SN, Ajani JA, Hofstetter WL, Nguyen QN, Chang JY, Gomez DR, Amini A, Swisher SG, Blum MA, Younes AI, Barsoumian HB, Erasmus JJ, Lee JH, Bhutani MS, Hess KR, Minsky BD, and Welsh JW
Subjects: Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Capecitabine adverse effects, Capecitabine therapeutic use, Chemoradiotherapy adverse effects, Docetaxel adverse effects, Docetaxel therapeutic use, Female, Fluorouracil adverse effects, Fluorouracil therapeutic use, Humans, Male, Middle Aged, Proton Therapy adverse effects, Radiotherapy Dosage, Radiotherapy, Intensity-Modulated adverse effects, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemoradiotherapy methods, Esophageal Neoplasms therapy, Proton Therapy methods, Radiotherapy, Intensity-Modulated methods
Abstract: Importance: Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high., Objective: To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer., Design, Setting, and Participants: A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019., Interventions: Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil., Main Outcomes and Measures: Toxic effects, local (in-field) control, and overall survival rates., Results: All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost., Conclusions and Relevance: These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study., Trial Registration: ClinicalTrials.gov identifier: NCT01102088.
Published: 2019
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40. Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy.

Author: Menon H, Chen D, Ramapriyan R, Verma V, Barsoumian HB, Cushman TR, Younes AI, Cortez MA, Erasmus JJ, de Groot P, Carter BW, Hong DS, Glitza IC, Ferrarotto R, Altan M, Diab A, Chun SG, Heymach JV, Tang C, Nguyen QN, and Welsh JW
Subjects: Adult, Aged, Aged, 80 and over, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Combined Modality Therapy, Dose-Response Relationship, Radiation, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasms immunology, Neoplasms pathology, Prognosis, Prospective Studies, Randomized Controlled Trials as Topic, Retrospective Studies, Survival Rate, Young Adult, Immunotherapy mortality, Neoplasms therapy, Radiosurgery mortality
Abstract: Background: Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting., Methods: A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1-20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types., Results: The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1-19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.0001). The median change for longest diameter size for low-dose lesions was - 38.5% compared to 8% in no-dose lesions (P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (P = 0.0004)., Conclusions: Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.
Published: 2019
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41. IDO1 Inhibition Overcomes Radiation-Induced "Rebound Immune Suppression" by Reducing Numbers of IDO1-Expressing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.

Author: Li A, Barsoumian HB, Schoenhals JE, Caetano MS, Wang X, Menon H, Valdecanas DR, Niknam S, Younes AI, Cortez MA, and Welsh JW
Subjects: Animals, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung pathology, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Mice, Mice, Inbred C57BL, Myeloid-Derived Suppressor Cells metabolism, Radiation Dose Hypofractionation, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory radiation effects, Up-Regulation radiation effects, Carcinoma, Lewis Lung radiotherapy, Immune Tolerance, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Myeloid-Derived Suppressor Cells cytology, Oximes pharmacology, Radiation Tolerance immunology, Sulfonamides pharmacology, Tumor Microenvironment immunology
Abstract: Purpose: The limitation of hypofractionated radiation efficacy is due partly to the immunosuppressive tumor microenvironment. Indoleamine 2,3-dioxygenase 1 (IDO1) is an important regulator of tumor immune suppression. We evaluated the effects of IDO1 in hypofractionated radiation using a Lewis lung carcinoma (LLC) mouse model and tested whether IDO1 inhibition could sensitize those tumors to hypofractionated radiation., Methods and Materials: Bilateral LLC tumors were established in C57BL/6 mice. Primary tumors were treated with 3 fractions of either 12 Gy or 6 Gy, and the IDO1 inhibitor INCB023843 was given starting on the first day of radiation. Plasma tryptophan and kynurenine levels were quantified by liquid chromatography and tandem mass spectrometry. Tumor-infiltrating immune cells were isolated from the tumors, stained, and quantified by flow cytometry., Results: The combination of INCB023843 and three 12-Gy fractions led to better tumor control and survival than radiation alone; INCB023843 plus three 6-Gy fractions had no benefit. IDO1 expression by tumor-infiltrating immune cells was increased by three 12-Gy doses and inhibited by the addition of INCB023843. Nearly all IDO1 + immune cells were also F4/80 + . Percentages of IDO1 + F4/80 + immune cells were drastically increased by three 12-Gy fractions and by three 6-Gy fractions, but only INCB023843 combined with three 12-Gy fractions reduced those percentages. IDO1 + F4/80 + immune cells were further found to be CD11b + , Gr1-intermediate-expressing, CD206 - , and CD11c - (ie, myeloid-derived suppressor cells). Three 12-Gy fractions also increased the percentages of tumor-infiltrating T regulatory cells and CD8 + T cells, but adding INCB023843 did not affect those percentages., Conclusions: In addition to its immune activation effects, hypofractionated radiation induced "rebound immune suppression" in the tumor microenvironment by activating and recruiting IDO1-expressing myeloid-derived suppressor cells in a dose-dependent manner. Adding an IDO1 inhibitor to hypofractionated radiation reduced the percentages of these cells, overcame the immune suppression, and sensitized LLC tumors to hypofractionated radiation., (Copyright © 2019. Published by Elsevier Inc.)
Published: 2019
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42. Radiation Followed by OX40 Stimulation Drives Local and Abscopal Antitumor Effects in an Anti-PD1-Resistant Lung Tumor Model.

Author: Niknam S, Barsoumian HB, Schoenhals JE, Jackson HL, Yanamandra N, Caetano MS, Li A, Younes AI, Cadena A, Cushman TR, Chang JY, Nguyen QN, Gomez DR, Diab A, Heymach JV, Hwu P, Cortez MA, and Welsh JW
Subjects: Animals, Cell Line, Tumor, Chemoradiotherapy, Disease Models, Animal, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Female, Humans, Lung Neoplasms pathology, Lung Neoplasms therapy, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating radiation effects, Mice, Receptors, OX40 antagonists & inhibitors, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological pharmacology, Lung Neoplasms metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors, Receptors, OX40 metabolism
Abstract: Purpose: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system has increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti-PD1-resistant lung tumors. Experimental Design: We established a bilateral tumor model in 129Sv/Ev mice using an anti-PD1-resistant lung tumor cell line. Primary tumors were treated with intratumoral injection of an OX40 agonist antibody, given as adjuvant therapy after XRT (36 Gy in three 12-Gy fractions), whereas secondary tumors were left untreated to investigate abscopal outcomes. Results: The combination of XRT followed by OX40 stimulation effectively inhibited local and systemic antitumor growth, limited lung metastases, and improved survival rates. This treatment regimen augmented CD4 + and CD8 + T-cell expansion. XRT induced the expression of OX40 on T cells in tumors and spleens and increased the percentages of splenic CD103 + dendritic cells. Conclusions: Our data extend the benefits of radiation to systemic disease control, especially when combined with anti-OX40 agonist to promote immunologically mediated abscopal effects. Moreover, this study provides a rational treatment approach and sequence to overcome anti-PD1-resistant poorly immunogenic tumors. Clin Cancer Res; 24(22); 5735-43. ©2018 AACR ., (©2018 American Association for Cancer Research.)
Published: 2018
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43. Anti-glucocorticoid-induced Tumor Necrosis Factor-Related Protein (GITR) Therapy Overcomes Radiation-Induced Treg Immunosuppression and Drives Abscopal Effects.

Author: Schoenhals JE, Cushman TR, Barsoumian HB, Li A, Cadena AP, Niknam S, Younes AI, Caetano MDS, Cortez MA, and Welsh JW
Subjects: Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor transplantation, Chemoradiotherapy adverse effects, Chemoradiotherapy methods, Disease Models, Animal, Drug Screening Assays, Antitumor, Glucocorticoid-Induced TNFR-Related Protein agonists, Glucocorticoid-Induced TNFR-Related Protein immunology, Humans, Lung Neoplasms immunology, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Mice, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Survival Analysis, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory radiation effects, Treatment Outcome, Tumor Burden drug effects, Tumor Burden radiation effects, Tumor Escape drug effects, Tumor Escape radiation effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung therapy, Glucocorticoid-Induced TNFR-Related Protein antagonists & inhibitors, Lung Neoplasms therapy, T-Lymphocytes, Regulatory immunology, Tumor Escape immunology
Abstract: Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono- or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.
Published: 2018
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44. Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells.

Author: Li A, Barsoumian HB, Schoenhals JE, Cushman TR, Caetano MS, Wang X, Valdecanas DR, Niknam S, Younes AI, Li G, Woodward WA, Cortez MA, and Welsh JW
Subjects: Animals, Cell Line, Tumor, Enzyme Inhibitors pharmacology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Immunosuppression Therapy, Immunosuppressive Agents pharmacology, Kynurenine chemistry, Mice, Neoplasm Transplantation, Tryptophan chemistry, Tumor Microenvironment, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Lung Neoplasms drug therapy, Lung Neoplasms enzymology, Myeloid-Derived Suppressor Cells drug effects
Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80 + Gr1 int CD11b + myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8 + T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy., (Copyright © 2018. Published by Elsevier B.V.)
Published: 2018
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45. Radiation therapy and immunotherapy: what is the optimal timing or sequencing?

Author: Aliru ML, Schoenhals JE, Venkatesulu BP, Anderson CC, Barsoumian HB, Younes AI, K Mahadevan LS, Soeung M, Aziz KE, Welsh JW, and Krishnan S
Subjects: Animals, Clinical Protocols, Disease Models, Animal, Humans, Mice, Neoplasms immunology, Neoplasms radiotherapy, Immunotherapy methods, Neoplasms therapy
Abstract: Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.
Published: 2018
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46. Uncovering the immune tumor microenvironment in non-small cell lung cancer to understand response rates to checkpoint blockade and radiation.

Author: Schoenhals JE, Seyedin SN, Anderson C, Brooks ED, Li YR, Younes AI, Niknam S, Li A, Barsoumian HB, Cortez MA, and Welsh JW
Abstract: The study of immunology has led to breakthroughs in treating non-small cell lung cancer (NSCLC). The recent approval of an anti-PD1 checkpoint drug for NSCLC has generated much interest in novel combination therapies that might provide further benefit for patients. However, a better understanding of which combinations may (or may not) work in NSCLC requires understanding the lung immune microenvironment under homeostatic conditions and the changes in that microenvironment in the setting of cancer progression and with radiotherapy. This review provides background information on immune cells found in the lung and the prognostic significance of these cell types in lung cancer. It also addresses current clinical directions for the combination of checkpoint inhibitors with radiation for NSCLC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
Published: 2017
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47. Local Control and Toxicity of a Simultaneous Integrated Boost for Dose Escalation in Locally Advanced Esophageal Cancer: Interim Results from a Prospective Phase I/II Trial.

Author: Welsh JW, Seyedin SN, Allen PK, Hofstetter WL, Ajani JA, Chang JY, Gomez DR, Amini A, Swisher SG, Blum MA, Younes AI, Nguyen QN, Minsky BD, Erasmus JJ, Lee JH, Bhutani M, and Komaki RU
Subjects: Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Carcinoma, Neuroendocrine pathology, Carcinoma, Squamous Cell pathology, Esophageal Neoplasms pathology, Female, Follow-Up Studies, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Prognosis, Prospective Studies, Radiotherapy Dosage, Radiotherapy Planning, Computer-Assisted, Survival Rate, Adenocarcinoma therapy, Carcinoma, Neuroendocrine therapy, Carcinoma, Squamous Cell therapy, Chemoradiotherapy, Esophageal Neoplasms therapy, Neoplasm Recurrence, Local therapy, Radiotherapy, Intensity-Modulated methods
Abstract: Introduction: Approximately 50% of recurrences after standard-dose chemoradiation for locally advanced esophageal cancer occur within the gross tumor volume (GTV). In this prospective phase I/II clinical trial, we explored the use of a simultaneous integrated boost (SIB) dose to the GTV., Methods: Forty-four patients with unresectable esophageal cancer received chemoradiation with an SIB of 58.8 to 63 Gy to the GTV and 50.4 Gy to the planning target volume, all in 28 fractions, with 5 weeks of concurrent docetaxel and fluorouracil or capecitabine. The end points were maximum tolerated dose, time to local failure, and clinical response., Results: Excluding those with less than 6 months of follow-up, 38 patients were evaluated at the time of analysis. The median age was 65 years (range 37-84). Most patients (71%) were men; 84% had T3 disease, 37% had N1 disease, 26% had N2 disease, 13% had M1 disease, and 50% had adenocarcinoma. The maximum tolerated SIB dose was 63 Gy. None experienced Common Terminology Criteria for Adverse Events grade 4 or 5 toxicity. At a median follow-up time of 13.3 months (range 1.2-36.2), 11 (29%) had local failure (median time to local failure 2.5 months [range 1.5-23.9]). A comparison with 97 similar patients who received 50.4 Gy without an SIB showed that the SIB reduced the local failure rate for patients with node-positive disease (13% versus 56%, p = 0.04), adenocarcinoma (26% versus 59%, p = 0.02), or stage III-IV disease (29% versus 55%, p = 0.04)., Conclusions: SIB intensity-modulated radiation therapy to gross primary disease may improve local control for patients with unresectable locally advanced esophageal cancer, especially those with adenocarcinoma., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
Published: 2017
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