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10. Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany

Author

Alessandra Solari, Ambra Mara Giovannetti, Andrea Giordano, Carla Tortorella, Valentina Torri Clerici, Giampaolo Brichetto, Franco Granella, Alessandra Lugaresi, Francesco Patti, Marco Salvetti, Ilaria Pesci, Eugenio Pucci, Diego Centonze, Maura Chiara Danni, Simona Bonavita, Diana Ferraro, Antonio Gallo, Alberto Gajofatto, Viviana Nociti, Luigi Grimaldi, Monica Grobberio, Roberta Lanzillo, Rachele Di Giovanni, Silvia Gregori, Alessia Manni, Erika Pietrolongo, Sarah Bertagnoli, Marco Ronzoni, Laura Compagnucci, Roberta Fantozzi, Beatrice Allegri, Sebastiano Arena, Maria Chiara Buscarinu, Loredana Sabattini, Maria Esmeralda Quartuccio, Elena Tsantes, Paolo Confaloneri, Andrea Tacchino, Insa Schiffmann, Anne Christin Rahn, Ingo Kleiter, Michele Messmer Uccelli, Anna Barabasch, Christoph Heesen, and the ManTra Project

Subjects
multiple sclerosis, conversion, secondary progressive multiple sclerosis, online survey, patient needs, patient-physician communication, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders.Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified.Methods: Participants were consenting adults with SPMS since ≤5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs.Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28–35% obtained second opinions, and 48–56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001).Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13–0.78 for Central Italy; OR 0.21, 95% CI 0.08–0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47–41.37 for dependent vs. autonomous patients).All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: “physiotherapy” and “active patient care involvement.” The other two differed across countries: “an individualized health care plan” and “information on social rights and policies” in Italy, and “psychological support” and “cognitive rehabilitation” in Germany.Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries.

Published
2019
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12. Long-term follow-up (up to 11 years) of an Italian pediatric MS cohort treated with natalizumab: a multicenter, observational study

Author

Damiano, Baroncini, Angelo, Ghezzi, Clara, Guaschino, Lucia, Moiola, Massimo, Filippi, Antonio, Ianniello, Carlo, Pozzilli, Roberta, Lanzillo, Vincenzo, Brescia-Morra, Monica, Margoni, Paolo, Gallo, Graziella, Callari, Luigi, Grimaldi, Giacomo, Lus, Massimiliano, Calabrese, Marta, Simone, Girolama Alessandra, Marfia, Sarah, Rasia, Daniela, Cargnelutti, Giancarlo, Comi, Mauro, Zaffaroni, Gabriella, Coniglio, Baroncini, Damiano, Ghezzi, Angelo, Guaschino, Clara, Moiola, Lucia, Filippi, Massimo, Ianniello, Antonio, Pozzilli, Carlo, Lanzillo, Roberta, Brescia-Morra, Vincenzo, Margoni, Monica, Gallo, Paolo, Callari, Graziella, Grimaldi, Luigi, Lus, Giacomo, Calabrese, Massimiliano, Simone, Marta, Marfia, Girolama Alessandra, Rasia, Sarah, Cargnelutti, Daniela, Comi, Giancarlo, and Zaffaroni, Mauro

Subjects
Pediatric, Adult, Multiple Sclerosis, treatment, Natalizumab, Dermatology, General Medicine, multiple sclerosis, natalizumab, pediatric, Settore MED/26, Treatment, Psychiatry and Mental health, Multiple Sclerosis, Relapsing-Remitting, Recurrence, Multiple Sclerosi, Humans, Immunologic Factors, Female, Neurology (clinical), Child, Follow-Up Studies, Retrospective Studies
Abstract

Background Natalizumab (NAT) has a strong impact on disease activity of aggressive pediatric multiple sclerosis (MS), with no difference in safety profile compared to adult MS. However, available data are limited by short follow-up. Our aim was to report long-term follow-up data (up to 11 years) of a large Italian pediatric MS cohort treated with NAT. Materials and methods We retrospectively collected data of pediatric MS patients treated with NAT included in a previous study and prospectively followed in Italian MS centers. We compared disease activity pre, during, and post-NAT and we performed survival analyses of time to evidence of disease activity (EDA) during NAT, time to reach EDA post-NAT, and time to NAT discontinuation. Results Ninety-two patients were included from 19 MS centers in Italy. At NAT initiation, cohort's characteristics were as follows: 55 females; 14.7 +/- 2.4 (mean +/- SD) years of age; 34 naive to disease modifying therapies; 1-year pre-NAT annualized relapse rate (ARR): 2.2 +/- 1.2; EDSS (median [IQR]): 2.5 [2.0-3.0]; gadolinium-enhancing lesions: 2 [1-5]; 41 JCV positives. During NAT treatment (61.9 +/- 35.2 mean infusions), ARR lowered to 0.08 +/- 0.23 (p < 0.001), EDSS score to 1.5 [1.0-2.5] at last infusion (p < 0.001), and 51% patients had EDA (21% after 6 months of rebaseline). No serious adverse events were reported. Forty-nine patients discontinued NAT, mainly due to PML concern; the majority (29/49) had disease reactivation in the subsequent 12 months, of which three with a clinical rebound. Conclusion NAT treatment maintains its high efficacy for a long time in pediatric MS patients, with no new safety issues.

Published
2022

13. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial

Author

John F Foley, Gilles Defer, Lana Zhovtis Ryerson, Jeffrey A Cohen, Douglas L Arnold, Helmut Butzkueven, Gary Cutter, Gavin Giovannoni, Joep Killestein, Heinz Wiendl, Karen Smirnakis, Shan Xiao, George Kong, Robert Kuhelj, Nolan Campbell, Anneke van der Walt, Christopher Dwyer, Katherine Buzzard, Judith Spies, John Parratt, Vincent van Pesch, Barbara Willekens, Gaetano Perrotta, Emmanuel Bartholomé, Francois Grand'Maison, Francois Jacques, Paul Giacomini, Reza Vosoughi, Jean-Marc Girard, Jerome de Seze, Christine Lebrun Frenay, Aurelie Ruet, David-Axel Laplaud, Gerd Reifschneider, Bert Wagner, Sebastian Rauer, Refik Pul, Maria Seipelt, Achim Berthele, Luisa Klotz, Boris-Alexander Kallmann, Friedemann Paul, Anat Achiron, Giacomo Lus, Diego Centonze, Francesco Patti, Luigi Grimaldi, Raymond Hupperts, Stephan Frequin, Jiske Fermont, Sara Eichau Madueno, Ana Maria Alonso Torres, Lucienne Costa-Frossard França, Jose Eustasio Meca-Lallana, Luis Brieva Ruiz, Owen Pearson, David Rog, Nikolaos Evangelou, Azza Ismail, Ellen Lathi, Edward Fox, Thomas Leist, Jacob Sloane, Gregory Wu, Bhupendra Khatri, Brian Steingo, Ben Thrower, Mark Gudesblatt, Jonathan Calkwood, Daniel Bandari, John Scagnelli, Christopher Laganke, Derrick Robertson, Lucas Kipp, Martin Belkin, Stanley Cohan, Lawrence Goldstick, Ardith Courtney, Wendy Vargas, Andrew Sylvester, Jayshri Srinivasan, Meena Kannan, Maryann Picone, Jeffrey English, Salvatore Napoli, Roumen Balabanov, Islam Zaydan, Jacqueline Nicholas, Jeffrey Kaplan, Fred Lublin, Emily Riser, Tamara Miller, Enrique Alvarez, Sibyl Wray, Jeffrey Gross, Siddharama Pawate, Carrie Hersh, Lucas McCarthy, Heidi Crayton, Jennifer Graves, NOVA study investigators, Neurology, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Double-Blind Method, Natalizumab, Leukoencephalopathy, Progressive Multifocal, Humans, Neurology (clinical), Human medicine, Settore MED/26, Magnetic Resonance Imaging
Abstract

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Funding: Biogen.

Published
2022

14. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Author

Alison Halliday, Richard Bulbulia, Leo H Bonati, Johanna Chester, Andrea Cradduck-Bamford, Richard Peto, Hongchao Pan, John Potter, Hans Henning Eckstein, Barbara Farrell, Marcus Flather, Averil Mansfield, Boby Mihaylova, Kazim Rahimi, David Simpson, Dafydd Thomas, Peter Sandercock, Richard Gray, Andrew Molyneux, Cliff P Shearman, Peter Rothwell, Anna Belli, Will Herrington, Parminder Judge, Peter Leopold, Marion Mafham, Michael Gough, Piergiorgio Cao, Sumaira MacDonald, Vasha Bari, Clive Berry, S Bradshaw, Wojciech Brudlo, Alison Clarke, Robin Cox, Susan Fathers, Kamran Gaba, Mo Gray, Elizabeth Hayter, Constance Holliday, Rijo Kurien, Michael Lay, Steffi le Conte, Jessica McManus, Zahra Madgwick, Dylan Morris, Andrew Munday, Sandra Pickworth, Wiktor Ostasz, Michiel Poorthuis, Sue Richards, Louisa Teixeira, Sergey Tochlin, Lynda Tully, Carol Wallis, Monique Willet, Alan Young, Renato Casana, Chiara Malloggi, Andrea Odero Jr, Vincenzo Silani, Gianfranco Parati, Giuseppe Malchiodi, Giovanni Malferrari, Francesco Strozzi, Nicola Tusini, Enrico Vecchiati, Gioacchino Coppi, Antonio Lauricella, Roberto Moratto, Roberto Silingardi, Jessica Veronesi, Andrea Zini, Emanuele Ferrero, Michelangelo Ferri, Andrea Gaggiano, Carmelo Labate, Franco Nessi, Daniele Psacharopulo, Andrea Viazzo, Giovanni Malacrida, Daniela Mazzaccaro, Giovanni Meola, Alfredo Modafferi, Giovanni Nano, Maria Teresa Occhiuto, Paolo Righini, Silvia Stegher, Stefano Chiarandini, Filippo Griselli, Sandro Lepidi, Fabio Pozzi Mucelli, Marcello Naccarato, Mario D'Oria, Barbara Ziani, Andrea Stella, Mortalla Dieng, Gianluca Faggioli, Mauro Gargiulo, Sergio Palermo, Rodolfo Pini, Giovanni Maria Puddu, Andrea Vacirca, Domenico Angiletta, Claudio Desantis, Davide Marinazzo, Giovanni Mastrangelo, Guido Regina, Raffaele Pulli, Paolo Bianchi, Lea Cireni, Elisabetta Coppi, Rocco Pizzirusso, Filippo Scalise, Giovanni Sorropago, Valerio Tolva, Valeria Caso, Enrico Cieri, Paola DeRango, Luca Farchioni, Giacomo Isernia, Massimo Lenti, Gian Battista Parlani, Guglielmo Pupo, Grazia Pula, Gioele Simonte, Fabio Verzini, Federico Carimati, Maria Luisa Delodovici, Federico Fontana, Gabriele Piffaretti, Matteo Tozzi, Efrem Civilini, Giorgio Poletto, Bernhard Reimers, Barbara Praquin, Sonia Ronchey, Laura Capoccia, Wassim Mansour, Enrico Sbarigia, Francesco Speziale, Pasqualino Sirignano, Danilo Toni, Roberto Galeotti, Vincenzo Gasbarro, Francesco Mascoli, Tiberio Rocca, Elpiniki Tsolaki, Giulia Bernardini, Ester DeMarco, Alessia Giaquinta, Francesco Patti, Massimiliano Veroux, Pierfrancesco Veroux, Carla Virgilio, Nicola Mangialardi, Matteo Orrico, Vincenzo Di Lazzaro, Nunzio Montelione, Francesco Spinelli, Francesco Stilo, Carlo Cernetti, Sandro Irsara, Giuseppe Maccarrone, Diego Tonello, Adriana Visonà, Beniamino Zalunardo, Emiliano Chisci, Stefano Michelagnoli, Nicola Troisi, Maela Masato, Massimo Dei Negri, Andrea Pacchioni, Salvatore Saccà, Giovanni Amatucci, Alfredo Cannizzaro, Federico Accrocca, Cesare Ambrogi, Renzo Barbazza, Giustino Marcucci, Andrea Siani, Guido Bajardi, Giovanni Savettieri, Angelo Argentieri, Riccardo Corbetta, Attilio Odero, Pietro Quaretti, Federico Z Thyrion, Alessandro Cappelli, Domenico Benevento, Gianmarco De Donato, Maria Agnese Mele, Giancarlo Palasciano, Daniela Pieragalli, Alessandro Rossi, Carlo Setacci, Francesco Setacci, Domenico Palombo, Maria Cecilia Perfumo, Edoardo Martelli, Aldo Paolucci, Santi Trimarchi, Viviana Grassi, Luigi Grimaldi, Giuliana La Rosa, Domenico Mirabella, Matteo Scialabba, Leonildo Sichel, Costantino L D'Angelo, Gian Franco Fadda, Holta Kasemi, Mario Marino, Francesco Burzotta, Francesco Alberto Codispoti, Angela Ferrante, Giovanni Tinelli, Yamume Tshomba, Claudio Vincenzoni, Deborah Amis, Dawn Anderson, Martin Catterson, Mike Clarke, Michelle Davis, Anand Dixit, Alexander Dyker, Gary Ford, Ralph Jackson, Sreevalsan Kappadath, David Lambert, Tim Lees, Stephen Louw, James McCaslin, Noala Parr, Rebecca Robson, Gerard Stansby, Lucy Wales, Vera Wealleans, Lesley Wilson, Michael Wyatt, Hardeep Baht, Ibrahim Balogun, Ilse Burger, Tracy Cosier, Linda Cowie, Gunaratnam Gunathilagan, David Hargroves, Robert Insall, Sally Jones, Hannah Rudenko, Natasha Schumacher, Jawaharlal Senaratne, George Thomas, Audrey Thomson, Tom Webb, Ellen Brown, Bernard Esisi, Ali Mehrzad, Shane MacSweeney, Norman McConachie, Alison Southam, Wayne Sunman, Ahmed Abdul-Hamiq, Jenny Bryce, Ian Chetter, Duncan Ettles, Raghuram Lakshminarayan, Kim Mitchelson, Christopher Rhymes, Graham Robinson, Paul Scott, Alison Vickers, Ray Ashleigh, Stephen Butterfield, Ed Gamble, Jonathan Ghosh, Charles N McCollum, Mark Welch, Sarah Welsh, Leszek Wolowczyk, Mary Donnelly, Stephen D'Souza, Anselm A Egun, Bindu Gregary, Thomas Joseph, Christine Kelly, Shuja Punekar, M Asad Rahi, Sonia Raj, Dare Seriki, George Thomson, James Brown, Ragunath Durairajan, Iris Grunwald, Paul Guyler, Paula Harman, Matthew Jakeways, Christopher Khuoge, Ashish Kundu, Thayalini Loganathan, Nisha Menon, Raji O Prabakaran, Devesh Sinha, Vicky Thompson, Sharon Tysoe, Dennis Briley, Chris Darby, Linda Hands, Dominic Howard, Wilhelm Kuker, Ursula Schulz, Rachel Teal, David Barer, Andrew Brown, Susan Crawford, Paul Dunlop, Ramesh Krishnamurthy, Nikhil Majmudar, Duncan Mitchell, Min P Myint, Richard O'Brien, Janice O'Connell, Naweed Sattar, Shanmugam Vetrivel, Jonathan Beard, Trevor Cleveland, Peter Gaines, John Humphreys, Alison Jenkins, Craig King, Daniel Kusuma, Ralph Lindert, Robbie Lonsdale, Raj Nair, Shah Nawaz, Faith Okhuoya, Douglas Turner, Graham Venables, Paul Dorman, Andrea Hughes, Deborah Jones, David Mendelow, Helen Rodgers, Aidas Raudoniitis, Peter Enevoldson, Hans Nahser, Imelda O'Brien, Francesco Torella, Dave Watling, Richard White, Pauline Brown, Dipankar Dutta, Lorraine Emerson, Paula Hilltout, Sachin Kulkarni, Jackie Morrison, Keith Poskitt, Fiona Slim, Sarah Smith, Amanda Tyler, Joanne Waldron, Mark Whyman, Milda Bajoriene, Lucy Baker, Amanda Colston, Bekky Eliot-Jones, Gita Gramizadeh, Catherine Lewis-Clarke, Laura McCafferty, Deborah Oliver, Debbie Palmer, Abhijeet Patil, Suzannah Pegler, Gopi Ramadurai, Aisling Roberts, Tracey Sargent, Shivaprasad Siddegowda, Ravi Singh-Ranger, Akintunde Williams, Lucy Williams, Steve Windebank, Tadas Zuromskis, Lanka Alwis, Jane Angus, Asaipillai Asokanathan, Caroline Fornolles, Diana Hardy, Sophy Hunte, Frances Justin, Duke Phiri, Marie Mitabouana-Kibou, Lakshmanan Sekaran, Sakthivel Sethuraman, Margaret L Tate, Joyce Akyea-Mensah, Stephen Ball, Angela Chrisopoulou, Elizabeth Keene, Alison Phair, Steven Rogers, John V Smyth, Colin Bicknell, Jeremy Chataway, Nicholas Cheshire, Andrew Clifton, Caroline Eley, Richard Gibbs, Mohammad Hamady, Beth Hazel, Alex James, Michael Jenkins, Nyma Khanom, Austin Lacey, Maz Mireskandari, Joanna O'Reilly, Antony Pereira, Tina Sachs, John Wolfe, Philip Davey, Gill Rogers, Gemma Smith, Gareth Tervit, Ian Nichol, Andrew Parry, Gavin Young, Simon Ashley, James Barwell, Francis Dix, Azlisham M Nor, Chris Parry, Angela Birt, Paul Davies, Jim George, Anne Graham, Leon Jonker, Nicci Kelsall, Caroline Potts, Toni Wilson, Jamie Crinnion, Larissa Cuenoud, Nikola Aleksic, Srdan Babic, Nenad Ilijevski, Đorde Radak, Dragan Sagic, Slobodan Tanaskovic, Momcilo Colic, Vladimir Cvetic, Lazar Davidovic, Dejana R Jovanovic, Igor Koncar, Perica Mutavdžic, Miloš Sladojevic, Ivan Tomic, Eike S Debus, Ulrich Grzyska, Dagmar Otto, Götz Thomalla, Jessica Barlinn, Johannes Gerber, Kathrin Haase, Christian Hartmann, Stefan Ludwig, Volker Pütz, Christian Reeps, Christine Schmidt, Norbert Weiss, Sebastian Werth, Simon Winzer, Janine Gemper, Albrecht Günther, Bianka Heiling, Elisabeth Jochmann, Panagiota Karvouniari, Carsten Klingner, Thomas Mayer, Julia Schubert, Friederike Schulze-Hartung, Jürgen Zanow, Yvonne Bausback, Franka Borger, Spiridon Botsios, Daniela Branzan, Sven Bräunlich, Henryk Hölzer, Janin Lenzer, Christopher Piorkowski, Nadine Richter, Johannes Schuster, Dierk Scheinert, Andrej Schmidt, Holger Staab, Matthias Ulrich, Martin Werner, Hermann Berger, Gábor Biró, Hans-Henning Eckstein, Michael Kallmayer, Kornelia Kreiser, Alexander Zimmermann, Bärbel Berekoven, Klaus Frerker, Vera Gordon, Giovanni Torsello, Sebastian Arnold, Cora Dienel, Martin Storck, Bernhard Biermaier, Hans Martin Gissler, Christof Klötzsch, Tomas Pfeiffer, Ralph Schneider, Leander Söhl, Michael Wennrich, Angelika Alonso, Michael Keese, Christoph Groden, Andreas Cöster, Andreas Engelhardt, Christoph-Maria Ratusinski, Bengt Berg, Martin Delle, Johan Formgren, Peter Gillgren, Lotta Jarl, Torbjörn B Kall, Peter Konrad, Niklas Nyman, Claes Skiöldebrand, Johnny Steuer, Rabbe Takolander, Jonas Malmstedt, Stefan Acosta, Katarina Björses, Kerstin Brandt, Nuno Dias, Anders Gottsäter, Jan Holst, Thorarinn Kristmundsson, Tobias Kühme, Tilo Kölbel, Bengt Lindblad, Mats Lindh, Martin Malina, Tomas Ohrlander, Tim Resch, Viola Rönnle, Björn Sonesson, Margareta Warvsten, Zbigniew Zdanowski, Erik Campbell, Per Kjellin, Hans Lindgren, Johan Nyberg, Björn Petersen, Gunnar Plate, Håkan Pärsson, Peter Qvarfordt, Pavel Ignatenko, Andrey Karpenko, Vladimir Starodubtsev, Mikhail A Chernyavsky, Maria S Golovkova, Boris B Komakha, Nikolay N Zherdev, Andrey Belyasnik, Pavel Chechulov, Dmitry Kandyba, Igor Stepanishchev, Csaba Csobay-Novák, Edit Dósa, László Entz, Balázs Nemes, Zoltán Szeberin, Pál Barzó, Mihaly Bodosi, Eniko Fákó, Béla Fülöp, Tamás Németh, Szilárd Pazdernyik, Krisztina Skoba, Erika Vörös, Eleni Chatzinikou, Athanasios Giannoukas, Christos Karathanos, Stylianos Koutsias, Georgios Kouvelos, Miltiadis Matsagkas, Styliani Ralli, Christos Rountas, Nikolaos Rousas, Konstantinos Spanos, Elias Brountzos, John D Kakisis, Andreas Lazaris, Konstantinos G Moulakakis, Leonidas Stefanis, Georgios Tsivgoulis, Spyros Vasdekis, Constantine N Antonopoulos, Ion Bellenis, Dimitrios Maras, Antonios Polydorou, Victoria Polydorou, Antonios Tavernarakis, Nikolaos Ioannou, Maria Terzoudi, Miltos Lazarides, Michalis Mantatzis, Kostas Vadikolias, Lukasz Dzieciuchowicz, Marcin Gabriel, Zbigniew Krasinski, Grzegorz Oszkinis, Fryderyk Pukacki, Maciej Slowinski, Michal-Goran Stanišic, Ryszard Staniszewski, Jolanta Tomczak, Maciej Zielinski, Piotr Myrcha, Dorota Rózanski, Stanislaw Drelichowski, Wojciech Iwanowski, Katarzyna Koncewicz, Pawel Bialek, Zbigniew Biejat, Wojciech Czepel, Anna Czlonkowska, Anatol Dowzenko, Julia Jedrzejewska, Adam Kobayashi, Jerzy Leszczynski, Andrzej Malek, Jerzy Polanski, Robert Proczka, Maciej Skorski, Mieczyslaw Szostek, Piotr Andziak, Maciej Dratwicki, Robert Gil, Miroslaw Nowicki, Jaroslaw Pniewski, Jaroslaw Rzezak, Piotr Seweryniak, Pawel Dabek, Michal Juszynski, Grzegorz Madycki, Bartosz Pacewski, Witold Raciborski, Piotr Slowinski, Walerian Staszkiewicz, Martin Bombic, Vladimír Chlouba, Jirí Fiedler, Karel Hes, Petr Koštál, Jindrich Sova, Zdenek Kríž, Mojmír Prívara, Michal Reif, Robert Staffa, Robert Vlachovský, Bohuslav Vojtíšek, Tomáš Hrbác, Martin Kuliha, Václav Procházka, Martin Roubec, David Školoudík, David Netuka, Anna Šteklácová, Vladimír Beneš III, Pavel Buchvald, Ladislav Endrych, Miroslav Šercl, Walter Campos Jr, Ivan B Casella, Nelson de Luccia, André E V Estenssoro, Calógero Presti, Pedro Puech-Leão, Celso R B Neves, Erasmo S da Silva, Cid J Sitrângulo Jr, José A T Monteiro, Gisela Tinone, Marcelo Bellini Dalio, Edwaldo E Joviliano, Octávio M Pontes Neto, Mauricio Serra Ribeiro, Patrick Cras, Jeroen M H Hendriks, Mieke Hoppenbrouwers, Patrick Lauwers, Caroline Loos, Laetitia Yperzeele, Mia Geenens, Dimitri Hemelsoet, Isabelle van Herzeele, Frank Vermassen, Parla Astarci, Frank Hammer, Valérie Lacroix, André Peeters, Robert Verhelst, Silvana Cirelli, Pol Dormal, Annelies Grimonprez, Bart Lambrecht, Philipe Lerut, Eddy Thues, Guy De Koster, Quentin Desiron, Alain Maertens de Noordhout, Danielle Malmendier, Mireille Massoz, Georges Saad, Marc Bosiers, Joren Callaert, Koen Deloose, Estrella Blanco Cañibano, Beatriz García Fresnillo, Mercedes Guerra Requena, Pilar C Morata Barrado, Miguel Muela Méndez, Antonio Yusta Izquierdo, Fernando Aparici Robles, Paula Blanes Orti, Luis García Dominguez, Rafael Martínez López, Manuel Miralles Hernández, José I Tembl Ferrairo, Ángel Chamorro, Juan Macho, Víctor Obach, Vincent Riambau, Luis San Román, Frank J Ahlhelm, Kristine Blackham, Stefan Engelter, Thomas Eugster, Henrik Gensicke, Lorenz Gürke, Philippe Lyrer, Luigi Mariani, Marina Maurer, Edin Mujagic, Mandy Müller, Marios Psychogios, Peter Stierli, Christoph Stippich, Christopher Traenka, Thomas Wolff, Benjamin Wagner, Martina M Wiegert, Sandra Clarke, Michael Diepers, Ernst Gröchenig, Philipp Gruber, Andrej Isaak, Timo Kahles, Regula Marti, Krassen Nedeltchev, Luca Remonda, Nadir Tissira, Martina Valença Falcão, Gert J de Borst, Rob H Lo, Frans L Moll, Raechel Toorop, Bart H van der Worp, Evert J Vonken, Jaap L Kappelle, Ommid Jahrome, Floris Vos, Wouter Schuiling, Hendrik van Overhagen, Rudolf W M Keunen, Bob Knippenberg, Jan J Wever, Jan W Lardenoije, Michel Reijnen, Luuk Smeets, Steven van Sterkenburg, Gustav Fraedrich, Elke Gizewski, Ingrid Gruber, Michael Knoflach, Stefan Kiechl, Barbara Rantner, Timur Abdulamit, Patrice Bergeron, Raymond Padovani, Jean-Christophe Trastour, Jean-Marie Cardon, Anne Le Gallou-Wittenberg, Eric Allaire, Jean-Pierre Becquemin, Frédéric Cochennec-Paliwoda, Pascal Desgranges, Hassan Hosseini, Hicham Kobeiter, Jean Marzelle, Mohammed A Almekhlafi, Simerpreet Bal, Phillip A Barber, Shelagh B Coutts, Andrew M Demchuk, Muneer Eesa, Michelle Gillies, Mayank Goyal, Michael D Hill, Mark E Hudon, Anitha Jambula, Carol Kenney, Gary Klein, Marie McClelland, Alim Mitha, Bijoy K Menon, William F Morrish, Steven Peters, Karla J Ryckborst, Greg Samis, Supriya Save, Eric E Smith, Peter Stys, Suresh Subramaniam, Garnette R Sutherland, Tim Watson, John H Wong, L Zimmel, Vojko Flis, Jože Matela, Kazimir Miksic, Franko Milotic, Božidar Mrdja, Barbara Stirn, Erih Tetickovic, Mladen Gasparini, Anton Grad, Ingrid Kompara, Zoren Miloševic, Veronika Palmiste, Toomas Toomsoo, Balzhan Aidashova, Nursultan Kospanov, Roman Lyssenko, Daulet Mussagaliev, Rafi Beyar, Aaron Hoffman, Tony Karram, Arthur Kerner, Eugenia Nikolsky, Samy Nitecki, Silva Andonova, Chavdar Bachvarov, Vesko Petrov, Ivan Cvjetko, Vinko Vidjak, Damir Halužan, Mladen Petrunic, Bao Liu, Chang-Wei Liu, Daniel Bartko, Peter Beno, František Rusnák, Kamil Zelenák, Masayuki Ezura, Takashi Inoue, Naoto Kimura, Ryushi Kondo, Yasushi Matsumoto, Hiroaki Shimizu, Hidenori Endo, Eisuke Furui, Søren Bakke, Kristen Krohg-Sørensen, Terje Nome, Mona Skjelland, Bjørn Tennøe, João Albuquerque e Castro, Gonçalo Alves, Frederico Bastos Gonçalves, José de Aragão Morais, Ana C Garcia, Hugo Valentim, Leonor Vasconcelos, Fernando Belcastro, Fernando Cura, Patricio Zaefferer, Foad Abd-Allah, Mohamed H Eldessoki, Hussein Heshmat Kassem, Haytham Soliman Gharieb, Mary P Colgan, Syed N Haider, Joe Harbison, Prakash Madhavan, Dermot Moore, Gregor Shanik, Viviane Kazan, Munier Nazzal, Vicki Ramsey-Williams, ACST-2 Collaborative Group, Group, ACST-2 Collaborative, Halliday A., Bulbulia R., Bonati L.H., Chester J., Cradduck-Bamford A., Peto R., Pan H., Potter J., Henning Eckstein H., Farrell B., Flather M., Mansfield A., Mihaylova B., Rahimi K., Simpson D., Thomas D., Sandercock P., Gray R., Molyneux A., Shearman C.P., Rothwell P., Belli A., Herrington W., Judge P., Leopold P., Mafham M., Gough M., Cao P., MacDonald S., Bari V., Berry C., Bradshaw S., Brudlo W., Clarke A., Cox R., Fathers S., Gaba K., Gray M., Hayter E., Holliday C., Kurien R., Lay M., le Conte S., McManus J., Madgwick Z., Morris D., Munday A., Pickworth S., Ostasz W., Poorthuis M., Richards S., Teixeira L., Tochlin S., Tully L., Wallis C., Willet M., Young A., Casana R., Malloggi C., Odero A., Silani V., Parati G., Malchiodi G., Malferrari G., Strozzi F., Tusini N., Vecchiati E., Coppi G., Lauricella A., Moratto R., Silingardi R., Veronesi J., Zini A., Ferrero E., Ferri M., Gaggiano A., Labate C., Nessi F., Psacharopulo D., Viazzo A., Malacrida G., Mazzaccaro D., Meola G., Modafferi A., Nano G., Occhiuto M.T., Righini P., Stegher S., Chiarandini S., Griselli F., Lepidi S., Pozzi Mucelli F., Naccarato M., D'Oria M., Ziani B., Stella A., Dieng M., Faggioli G., Gargiulo M., Palermo S., Pini R., Puddu G.M., Vacirca A., Angiletta D., Desantis C., Marinazzo D., Mastrangelo G., Regina G., Pulli R., Bianchi P., Cireni L., Coppi E., Pizzirusso R., Scalise F., Sorropago G., Tolva V., Caso V., Cieri E., DeRango P., Farchioni L., Isernia G., Lenti M., Parlani G.B., Pupo G., Pula G., Simonte G., Verzini F., Carimati F., Delodovici M.L., Fontana F., Piffaretti G., Tozzi M., Civilini E., Poletto G., Reimers B., Praquin B., Ronchey S., Capoccia L., Mansour W., Sbarigia E., Speziale F., Sirignano P., Toni D., Galeotti R., Gasbarro V., Mascoli F., Rocca T., Tsolaki E., Bernardini G., DeMarco E., Giaquinta A., Patti F., Veroux M., Veroux P., Virgilio C., Mangialardi N., Orrico M., Di Lazzaro V., Montelione N., Spinelli F., Stilo F., Cernetti C., Irsara S., Maccarrone G., Tonello D., Visona A., Zalunardo B., Chisci E., Michelagnoli S., Troisi N., Masato M., Dei Negri M., Pacchioni A., Sacca S., Amatucci G., Cannizzaro A., Accrocca F., Ambrogi C., Barbazza R., Marcucci G., Siani A., Bajardi G., Savettieri G., Argentieri A., Corbetta R., Quaretti P., Thyrion F.Z., Cappelli A., Benevento D., De Donato G., Mele M.A., Palasciano G., Pieragalli D., Rossi A., Setacci C., Setacci F., Palombo D., Perfumo M.C., Martelli E., Paolucci A., Trimarchi S., Grassi V., Grimaldi L., La Rosa G., Mirabella D., Scialabba M., Sichel L., D'Angelo C.L., Fadda G.F., Kasemi H., Marino M., Burzotta F., Codispoti F.A., Ferrante A., Tinelli G., Tshomba Y., Vincenzoni C., Amis D., Anderson D., Catterson M., Clarke M., Davis M., Dixit A., Dyker A., Ford G., Jackson R., Kappadath S., Lambert D., Lees T., Louw S., McCaslin J., Parr N., Robson R., Stansby G., Wales L., Wealleans V., Wilson L., Wyatt M., Baht H., Balogun I., Burger I., Cosier T., Cowie L., Gunathilagan G., Hargroves D., Insall R., Jones S., Rudenko H., Schumacher N., Senaratne J., Thomas G., Thomson A., Webb T., Brown E., Esisi B., Mehrzad A., MacSweeney S., McConachie N., Southam A., Sunman W., Abdul-Hamiq A., Bryce J., Chetter I., Ettles D., Lakshminarayan R., Mitchelson K., Rhymes C., Robinson G., Scott P., Vickers A., Ashleigh R., Butterfield S., Gamble E., Ghosh J., McCollum C.N., Welch M., Welsh S., Wolowczyk L., Donnelly M., D'Souza S., Egun A.A., Gregary B., Joseph T., Kelly C., Punekar S., Rahi M.A., Raj S., Seriki D., Thomson G., Brown J., Durairajan R., Grunwald I., Guyler P., Harman P., Jakeways M., Khuoge C., Kundu A., Loganathan T., Menon N., Prabakaran R.O., Sinha D., Thompson V., Tysoe S., Briley D., Darby C., Hands L., Howard D., Kuker W., Schulz U., Teal R., Barer D., Brown A., Crawford S., Dunlop P., Krishnamurthy R., Majmudar N., Mitchell D., Myint M.P., O'Brien R., O'Connell J., Sattar N., Vetrivel S., Beard J., Cleveland T., Gaines P., Humphreys J., Jenkins A., King C., Kusuma D., Lindert R., Lonsdale R., Nair R., Nawaz S., Okhuoya F., Turner D., Venables G., Dorman P., Hughes A., Jones D., Mendelow D., Rodgers H., Raudoniitis A., Enevoldson P., Nahser H., O'Brien I., Torella F., Watling D., White R., Brown P., Dutta D., Emerson L., Hilltout P., Kulkarni S., Morrison J., Poskitt K., Slim F., Smith S., Tyler A., Waldron J., Whyman M., Bajoriene M., Baker L., Colston A., Eliot-Jones B., Gramizadeh G., Lewis-Clarke C., McCafferty L., Oliver D., Palmer D., Patil A., Pegler S., Ramadurai G., Roberts A., Sargent T., Siddegowda S., Singh-Ranger R., Williams A., Williams L., Windebank S., Zuromskis T., Alwis L., Angus J., Asokanathan A., Fornolles C., Hardy D., Hunte S., Justin F., Phiri D., Mitabouana-Kibou M., Sekaran L., Sethuraman S., Tate M.L., Akyea-Mensah J., Ball S., Chrisopoulou A., Keene E., Phair A., Rogers S., Smyth J.V., Bicknell C., Chataway J., Cheshire N., Clifton A., Eley C., Gibbs R., Hamady M., Hazel B., James A., Jenkins M., Khanom N., Lacey A., Mireskandari M., O'Reilly J., Pereira A., Sachs T., Wolfe J., Davey P., Rogers G., Smith G., Tervit G., Nichol I., Parry A., Young G., Ashley S., Barwell J., Dix F., Nor A.M., Parry C., Birt A., Davies P., George J., Graham A., Jonker L., Kelsall N., Potts C., Wilson T., Crinnion J., Cuenoud L., Aleksic N., Babic S., Ilijevski N., Radak, Sagic D., Tanaskovic S., Colic M., Cvetic V., Davidovic L., Jovanovic D.R., Koncar I., Mutavdzic P., Sladojevic M., Tomic I., Debus E.S., Grzyska U., Otto D., Thomalla G., Barlinn J., Gerber J., Haase K., Hartmann C., Ludwig S., Putz V., Reeps C., Schmidt C., Weiss N., Werth S., Winzer S., Gemper J., Gunther A., Heiling B., Jochmann E., Karvouniari P., Klingner C., Mayer T., Schubert J., Schulze-Hartung F., Zanow J., Bausback Y., Borger F., Botsios S., Branzan D., Braunlich S., Holzer H., Lenzer J., Piorkowski C., Richter N., Schuster J., Scheinert D., Schmidt A., Staab H., Ulrich M., Werner M., Berger H., Biro G., Eckstein H.-H., Kallmayer M., Kreiser K., Zimmermann A., Berekoven B., Frerker K., Gordon V., Torsello G., Arnold S., Dienel C., Storck M., Biermaier B., Gissler H.M., Klotzsch C., Pfeiffer T., Schneider R., Sohl L., Wennrich M., Alonso A., Keese M., Groden C., Coster A., Engelhardt A., Ratusinski C.-M., Berg B., Delle M., Formgren J., Gillgren P., Jarl L., Kall T.B., Konrad P., Nyman N., Skioldebrand C., Steuer J., Takolander R., Malmstedt J., Acosta S., Bjorses K., Brandt K., Dias N., Gottsater A., Holst J., Kristmundsson T., Kuhme T., Kolbel T., Lindblad B., Lindh M., Malina M., Ohrlander T., Resch T., Ronnle V., Sonesson B., Warvsten M., Zdanowski Z., Campbell E., Kjellin P., Lindgren H., Nyberg J., Petersen B., Plate G., Parsson H., Qvarfordt P., Ignatenko P., Karpenko A., Starodubtsev V., Chernyavsky M.A., Golovkova M.S., Komakha B.B., Zherdev N.N., Belyasnik A., Chechulov P., Kandyba D., Stepanishchev I., Csobay-Novak C., Dosa E., Entz L., Nemes B., Szeberin Z., Barzo P., Bodosi M., Fako E., Fulop B., Nemeth T., Pazdernyik S., Skoba K., Voros E., Chatzinikou E., Giannoukas A., Karathanos C., Koutsias S., Kouvelos G., Matsagkas M., Ralli S., Rountas C., Rousas N., Spanos K., Brountzos E., Kakisis J.D., Lazaris A., Moulakakis K.G., Stefanis L., Tsivgoulis G., Vasdekis S., Antonopoulos C.N., Bellenis I., Maras D., Polydorou A., Polydorou V., Tavernarakis A., Ioannou N., Terzoudi M., Lazarides M., Mantatzis M., Vadikolias K., Dzieciuchowicz L., Gabriel M., Krasinski Z., Oszkinis G., Pukacki F., Slowinski M., Stanisic M.-G., Staniszewski R., Tomczak J., Zielinski M., Myrcha P., Rozanski D., Drelichowski S., Iwanowski W., Koncewicz K., Bialek P., Biejat Z., Czepel W., Czlonkowska A., Dowzenko A., Jedrzejewska J., Kobayashi A., Leszczynski J., Malek A., Polanski J., Proczka R., Skorski M., Szostek M., Andziak P., Dratwicki M., Gil R., Nowicki M., Pniewski J., Rzezak J., Seweryniak P., Dabek P., Juszynski M., Madycki G., Pacewski B., Raciborski W., Slowinski P., Staszkiewicz W., Bombic M., Chlouba V., Fiedler J., Hes K., Kostal P., Sova J., Kriz Z., Privara M., Reif M., Staffa R., Vlachovsky R., Vojtisek B., Hrbac T., Kuliha M., Prochazka V., Roubec M., Skoloudik D., Netuka D., Steklacova A., Benes III V., Buchvald P., Endrych L., Sercl M., Campos W., Casella I.B., de Luccia N., Estenssoro A.E.V., Presti C., Puech-Leao P., Neves C.R.B., da Silva E.S., Sitrangulo C.J., Monteiro J.A.T., Tinone G., Bellini Dalio M., Joviliano E.E., Pontes Neto O.M., Serra Ribeiro M., Cras P., Hendriks J.M.H., Hoppenbrouwers M., Lauwers P., Loos C., Yperzeele L., Geenens M., Hemelsoet D., van Herzeele I., Vermassen F., Astarci P., Hammer F., Lacroix V., Peeters A., Verhelst R., Cirelli S., Dormal P., Grimonprez A., Lambrecht B., Lerut P., Thues E., De Koster G., Desiron Q., Maertens de Noordhout A., Malmendier D., Massoz M., Saad G., Bosiers M., Callaert J., Deloose K., Blanco Canibano E., Garcia Fresnillo B., Guerra Requena M., Morata Barrado P.C., Muela Mendez M., Yusta Izquierdo A., Aparici Robles F., Blanes Orti P., Garcia Dominguez L., Martinez Lopez R., Miralles Hernandez M., Tembl Ferrairo J.I., Chamorro A., Macho J., Obach V., Riambau V., San Roman L., Ahlhelm F.J., Blackham K., Engelter S., Eugster T., Gensicke H., Gurke L., Lyrer P., Mariani L., Maurer M., Mujagic E., Muller M., Psychogios M., Stierli P., Stippich C., Traenka C., Wolff T., Wagner B., Wiegert M.M., Clarke S., Diepers M., Grochenig E., Gruber P., Isaak A., Kahles T., Marti R., Nedeltchev K., Remonda L., Tissira N., Valenca Falcao M., de Borst G.J., Lo R.H., Moll F.L., Toorop R., van der Worp B.H., Vonken E.J., Kappelle J.L., Jahrome O., Vos F., Schuiling W., van Overhagen H., Keunen R.W.M., Knippenberg B., Wever J.J., Lardenoije J.W., Reijnen M., Smeets L., van Sterkenburg S., Fraedrich G., Gizewski E., Gruber I., Knoflach M., Kiechl S., Rantner B., Abdulamit T., Bergeron P., Padovani R., Trastour J.-C., Cardon J.-M., Le Gallou-Wittenberg A., Allaire E., Becquemin J.-P., Cochennec-Paliwoda F., Desgranges P., Hosseini H., Kobeiter H., Marzelle J., Almekhlafi M.A., Bal S., Barber P.A., Coutts S.B., Demchuk A.M., Eesa M., Gillies M., Goyal M., Hill M.D., Hudon M.E., Jambula A., Kenney C., Klein G., McClelland M., Mitha A., Menon B.K., Morrish W.F., Peters S., Ryckborst K.J., Samis G., Save S., Smith E.E., Stys P., Subramaniam S., Sutherland G.R., Watson T., Wong J.H., Zimmel L., Flis V., Matela J., Miksic K., Milotic F., Mrdja B., Stirn B., Tetickovic E., Gasparini M., Grad A., Kompara I., Milosevic Z., Palmiste V., Toomsoo T., Aidashova B., Kospanov N., Lyssenko R., Mussagaliev D., Beyar R., Hoffman A., Karram T., Kerner A., Nikolsky E., Nitecki S., Andonova S., Bachvarov C., Petrov V., Cvjetko I., Vidjak V., Haluzan D., Petrunic M., Liu B., Liu C.-W., Bartko D., Beno P., Rusnak F., Zelenak K., Ezura M., Inoue T., Kimura N., Kondo R., Matsumoto Y., Shimizu H., Endo H., Furui E., Bakke S., Krohg-Sorensen K., Nome T., Skjelland M., Tennoe B., Albuquerque e Castro J., Alves G., Bastos Goncalves F., de Aragao Morais J., Garcia A.C., Valentim H., Vasconcelos L., Belcastro F., Cura F., Zaefferer P., Abd-Allah F., Eldessoki M.H., Heshmat Kassem H., Soliman Gharieb H., Colgan M.P., Haider S.N., Harbison J., Madhavan P., Moore D., Shanik G., Kazan V., Nazzal M., Ramsey-Williams V., and Gargiulo M

Subjects
Male, medicine.medical_specialty, Time Factors, Time Factor, medicine.medical_treatment, Carotid Stenosi, MEDLINE, Carotid endarterectomy, Rate ratio, Risk Assessment, Asymptomatic, law.invention, Randomized controlled trial, law, Risk Factors, carotid artery stenting (CAS), carotid endarterectomy (CEA), Stent, medicine, Humans, Carotid Stenosis, Stroke, Endarterectomy, Aged, Endarterectomy, Carotid, business.industry, carotid artery, Risk Factor, Articles, General Medicine, trial, medicine.disease, Settore MED/22 - CHIRURGIA VASCOLARE, Surgery, Stenosis, Treatment Outcome, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Female, Stents, Human medicine, medicine.symptom, business, Human
Abstract

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Published
2021

15. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY)

Author

Diego Cadavid, Michelle Mellion, Raymond Hupperts, Keith R Edwards, Peter A Calabresi, Jelena Drulović, Gavin Giovannoni, Hans-Peter Hartung, Douglas L Arnold, Elizabeth Fisher, Richard Rudick, Sha Mi, Yi Chai, Jie Li, Yiwei Zhang, Wenting Cheng, Lei Xu, Bing Zhu, Susan M Green, Ih Chang, Aaron Deykin, Sarah I Sheikh, Eduardo Agüera Morales, Abdullatif Al Khedr, Radek Ampapa, Rafael Arroyo, Martin Belkin, Robert Bonek, Alexey Boyko, Ruggero Capra, Diego Centonze, Pierre Clavelou, Marc Debouverie, Jelena Drulovic, Keith Edwards, Nikos Evangelou, Evgeniy Evdoshenko, Oscar Fernández, Victoria Fernández Sánchez, Mark Freedman, Steven Freedman, Waldemar Fryze, Antonio Garcia-Merino, Mira Gavric-Kezic, Angel Ghezzi, Olivier Gout, Luigi Grimaldi, Barry Hendin, Hanka Hertmanowska, Rogier Hintzen, Pavel Hradilek, Jan Ilkowski, Evelina Ivashinenkova, Guillermo Izquierdo, Francois Jacques, Gabor Jakab, Farit Khabirov, Gabriela Klodowska-Duda, Samuel Komoly, Smiljana Kostic, Ivana Kovarova, Marcelo Kremenchuzky, Christopher Laganke, Yves LaPierre, Maciej Maciejowski, Francois Grand Maison, Girolama Alessandra Marfia, Sergio Martínez Yélamos, Eva Meluzinova, Xavier Montalban, Ronald Murray, Robert Naismith, Scott Newsome, Viet Nguyen, Delia Oreja, Gabriel Pardo, Elena Pasechnik, Francesco Patti, Andrzej Potemkowski, Semen Prokopenko, Peiqing Qian, Alfredo Rodríguez-Antigüedad, Howard Rossman, Csilla Rozsa, Fernando Sánchez López, Krzysztof Selmaj, Eli Silber, Adam Stepien, Anna Stepniewska, Maciej Swiat, Gordana Toncev, Ayman Tourbah, Tatyana Trushnikova, Antonio Uccelli, Marta Vachova, Martin Valis, Laszlo Vecsei, Sandrine Wiertlewski, Mauro Zaffaroni, Tomasz Zielinski, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
0301 basic medicine, EXPRESSION, medicine.medical_specialty, Paced Auditory Serial Addition Test, Phases of clinical research, Placebo, Settore MED/26, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, SPINAL-CORD REMYELINATION, 10. No inequality, Adverse effect, Expanded Disability Status Scale, medicine.diagnostic_test, business.industry, Multiple sclerosis, CENTRAL-NERVOUS-SYSTEM, Oligodendrocyte differentiation, medicine.disease, 3. Good health, 030104 developmental biology, Neurology (clinical), CNS, business, OLIGODENDROCYTE DIFFERENTIATION, 030217 neurology & neurosurgery, LINGO-1
Abstract

Summary Background Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. Methods We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18–58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov , number NCT01864148 . Findings Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. Interpretation Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. Funding Biogen.

Published
2019

16. A Background Calibration Technique to Control the Bandwidth of Digital PLLs

Author

Salvatore Levantino, Luca Bertulessi, Carlo Samori, Andrea L. Lacaita, Luigi Grimaldi, and Mario Mercandelli

Subjects
Automatic control, Computer science, Oscillation, 020208 electrical & electronic engineering, Bandwidth (signal processing), 020206 networking & telecommunications, Hardware_PERFORMANCEANDRELIABILITY, 02 engineering and technology, Transfer function, Phase-locked loop, CMOS, Phase noise, Hardware_INTEGRATEDCIRCUITS, 0202 electrical engineering, electronic engineering, information engineering, Electronic engineering, Electrical and Electronic Engineering, Jitter, Loop gain
Abstract

This paper presents a technique to regulate the bandwidth of digital phase-locked loops (PLLs), where a fully digital automatic control circuit, running in background, is used to desensitize loop gain from analog parameters. The method that is based on an adaptive least-mean-squares algorithm requires no injection of a training sequence, potentially degrading phase noise performance, and is suitable in particular for bang-bang PLLs, where the bandwidth depends on the input noise. The operating principle is first introduced and discussed with the help of an intuitive time-domain model, and the algorithm extension addressing the practical implementation issues associated with loop latency is then presented. The calibration circuit is embedded in a 65-nm CMOS digital PLL that achieves 400-fs integrated rms jitter with a power consumption of 4.5 mW. The algorithm enables digital programmability of loop bandwidth from 100 kHz to 2 MHz with an error below 1 dB between the theoretical and measured PLL noise transfer functions.

Published
2018

17. Analysis of Spurs Impact in PLL-Based FMCW Radar Systems

Author

Roberto Nonis, Luigi Grimaldi, Dmytro Cherniak, and Werner Grollitsch

Subjects
Continuous-wave radar, Phase-locked loop, Computer science, law, Phase noise, DPLL algorithm, Spur, Electronic engineering, Chirp, Radar, Frequency modulation, law.invention
Abstract

Performance of FMCW generators based on DPLLs are significantly affected by the presence of spurs. The latter may originate from the inherent operation of the DPLL itself, when operated in Fractional-N mode, or by external aggressors via coupling paths. Moreover, non-linearities of the loop can result in a worsening of the spur level thus in a degradation of the generated frequency modulation. This paper provides an insight on spurs impact in PLL-based chirp generators for radar sensors. Three different scenarios are taken into account: fractional spurs arising from non linearities, spurs coupling to the output of the DPLL and coupling of the digital activity of the divider to the DCO. The analysis is performed by means of a time-domain model of the FMCW Radar transceiver for target detection, and the effect on the range FFT and on Doppler shift of the base-band signal is presented.

Published
2020

18. A 250Mb/s Direct Phase Modulator with -42.4dB EVM Based on a 14GHz Digital PLL

Author

Mario Mercandelli, Luigi Grimaldi, Alessio Santiccioli, Michael Aichner, Salvatore Levantino, Fabio Padovan, Dmytro Cherniak, Luca Bertulessi, and Carlo Samori

Subjects
Computer science, Bang-bang, Energy consumption, Power (physics), Phase-locked loop, Adaptive filter, Root mean square, Modulation, Direct phase modulation, Digital phase-locked loop, Electronic engineering, Adaptive filters, QPSK, Electrical and Electronic Engineering, PSK, Phase modulation, Phase-shift keying
Abstract

This letter presents a 14-GHz digital-intensive phase modulator circuit, which is able to enforce an arbitrary carrier phase change in one sample of a 200-MHz clock. The architecture is based on a fractional-N bang–bang digital PLL exploiting an adaptive DCO-tuning requantizer, which mitigates the segmentation-induced nonlinearity of the DCO, and a novel deskewing circuit, which improves the EVM at high bit rates. The modulation error, expressed in terms of RMS value of the EVM, is below −42 dB for a 250-Mb/s 32-PSK modulated carrier. The phase modulator, integrated in a 28-nm CMOS process, consumes 31.5-mW power, achieving 0.13-nJ/bit energy consumption.

Published
2020

19. Reduced Admissions for Cerebrovascular Events during COVID-19 Outbreak in Italy

Author

Simona Sacco, Stefano Ricci, Raffaele Ornello, Paolo Eusebi, Luca Petraglia, Danilo Toni, Eugenia Rota, Gianluca Bruzzone, Lucia Testa, Roberta Bongioanni, Mara Rosso, Carmelo Labate, Roberto Tarletti, Roberto Cantello, Thomas Fleetwood, Fabio Melis, Daniele Imperiale, Salvatore Amarù, Monica Reggiani, Luigi Ruiz, Elia Cipriano, Delfina Ferrandi, Patrizia Julita, Liana Africa, Piero Meinieri, Maria Federica Grasso, Serena Servo, Roberto Cavallo, Gigliola Chianale, Andrea Naldi, Paolo Cerrato, Elisa Rubino, Alessia Giossi, Valentina Puglisi, Luisa Vinciguerra, Ignazio Santilli, Bianca Maria Bordo, Simona Marcheselli, Julia Bottini, Caterina Mariotto D’Alessandro, Giuseppe Micieli, Anna Cavallini, Isabella Canavero, Francesco Muscia, Graziamaria Nuzzaco, Alfonso Ciccone, Giorgio Silvestrelli, Andrea Salmaggi, Davide Sangalli, Carla Zanferrari, Simona Fanucchi, Michela Ranieri, Simone Beretta, Carlo Ferrarese, Francesco Pasini, Francesco Santangelo, Nicoletta Checcarelli, Sandro Beretta, Paola Bazzi, Massimo Camerlingo, Marcello Tognozzi, Giorgio Caneve, Alessandro Adami, Rocco Quatrale, Adriana Critelli, Luigi Bartolomei, Maela Masato, Francesco Perini, Antonella De Boni, Caterina Disco, Claudio Baracchini, Alessio Pieroni, Roberto Lerario, Monia Russo, Alberto Polo, Alessandra Danese, Luca Valentinis, Antonio Baldi, Simone Tonello, Francesco Paladin, Agnese Tonon, Bruno Bonetti, Manuel Cappellari, Francesco Teatini, Roberto Currò Dossi, Enrica Franchini, Bruno Giometto, Valeria Bignamini, Paolo Manganotti, Marcello Naccarato, Gian Luigi Gigli, Simone Lorenzut, Giovanni Merlino, Mariarosaria Valente, Michele Rana, Carolina Gentile, Tiziana Tassinari, Annalisa Sugo, Valentina Saia, Maurizio Balestrino, Alberto Coccia, Cinzia Finocchi, Franco Valzania, Maria Luisa Zedde, Giulia Toschi, Marco Longoni, Matteo Paolucci, Valeria Tugnoli, Pietro Querzani, Marina Padroni, Stefano Meletti, Guido Bigliardi, Maria Luisa Dall’Acqua, Andrea Zini, Mauro Gentile, Ludovica Migliaccio, Alberto Chiti, Rossana Tassi, Giuseppe Martini, Patrizia Nencini, Maria Lamassa, Michelangelo Mancuso, Giovanni Orlandi, Elena Ferrari, Roberto Marconi, Simone Gallerini, Vincenzo Groggia, Gino Volpi, Chiara Menichetti, Stefano Spolveri, Mauro Silvestrini, Giovanna Viticchi, Laura Buratti, Giuseppe Pelliccioni, Eleonora Potente, Tatiana Mazzoli, Erica Marsili, Silvia Cenciarelli, Antonella Picchioni, Franco Costantini, Carlo Colosimo, Maurizio Paciaroni, Valeria Caso, Maurizia Rasura, Mario Beccia, Nicola Falcone, Marisa Di Stefano, Emanuela Cecconi, Sabrina Anticoli, Francesca Romana Pezzella, Marilena Mangiardi, Maurizio Plocco, Maria Magarelli, Carlo Emanuele Saggese, Irene Berto, Maria Concetta Altavista, Cinzia Roberti, Marina Diomedi, Fabrizio Sallustio, Alessandro Rocco, Letizia Maria Cupini, Novella Bonaffini, Maria Vittoria De Angelis, Anna Digiovanni, Marianna Rispoli, Berardino Orlandi, Federica De Santis, Enrico Colangeli, Francesco Di Blasio, Caterina Di Carmine, Pierluigi Tocco, Maurizio Melis, Jessica Moller, Valeria Saddi, Antonio Manca, Antonio Baule, Antonello Caddeo, Nicola Iorio, Rosa Napoletano, Maria di Gregorio, Giampiero Volpe, Florindo D’Onofrio, Daniele Spitaleri, Leonardo Barbarini, Gaetano Barbagallo, Marcella Caggiula, Bonaventura Ardito, Domenico Di Noia, Pietro Di Viesti, Maurizio Angelo Leone, Vincenzo Inchingolo, Marco Petruzzellis, Federica Rizzo, Mariantonietta Savarese, Alfredo Petrone, Franco Galati, Luciano Arcudi, Damiano Branca, Paolo Aridon, Valentina Arnao, Rosa Musolino, Cristina Dell’Aera, Isabella Francalanza, Luigi Grimaldi, Matilde Gammino, Antonello Giordano, Giuseppe Zelante, Enzo Sanzaro, Antonio Gasparro, Sacco, Simona, Ricci, Stefano, Ornello, Raffaele, Eusebi, Paolo, Petraglia, Luca, Toni, Danilo, and paolo, aridon

Subjects
disease outbreak, Male, medicine.medical_treatment, 030204 cardiovascular system & hematology, Italy, cerebral hemorrhage, disease outbreaks, incidence, ischemic attack, transient, 0302 clinical medicine, Epidemiology, 80 and over, Medicine, Thrombolytic Therapy, Acute ischemic stroke, Thrombectomy, Aged, 80 and over, Ischemic Attack, Transient, Incidence (epidemiology), Endovascular Procedures, Middle Aged, Hospitalization, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Settore MED/26 - Neurologia, Female, Cardiology and Cardiovascular Medicine, Aged, COVID-19, Cerebral Hemorrhage, Humans, Ischemic Attack, Transient, Ischemic Stroke, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Revascularization, Settore MED/26, 03 medical and health sciences, Advanced and Specialized Nursing, business.industry, Outbreak, Emergency medicine, Brief Reports, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Supplemental Digital Content is available in the text., Background and Purpose: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. Methods: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). Results: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71–0.80] P

Published
2020

21. 16.7 A 30GHz Digital Sub-Sampling Fractional-N PLL with 198fsrms Jitter in 65nm LP CMOS

Author

Alessandro Garghetti, Salvatore Levantino, Luca Bertulessi, Luigi Grimaldi, Dmytro Cherniak, Carlo Samori, Andrea L. Lacaita, and Saleh Karman

Subjects
Phase-locked loop, CMOS, Computer science, 020208 electrical & electronic engineering, 0202 electrical engineering, electronic engineering, information engineering, Electronic engineering, 020206 networking & telecommunications, 02 engineering and technology, Noise (electronics), Phase detector, Sub-sampling, Power (physics), Jitter
Abstract

Digital phase-locked loops (DPLLs) have been demonstrated to achieve excellent performance as fractional-N frequency synthesizers in the sub-6GHz range, but, when used in the mm-wave range, at 30GHz and above, they typically feature poor jitter-power trade-off. This paper presents a 30GHz fractional-N DPLL in 65nm low-power (LP) CMOS achieving 198fs integrated jitter at 35mW power. The DPLL based on a digital-to-time converter (DTC) combines: (i) sub-sampling bang-bang phase detection to reduce power consumption, (ii) a digital error correction to reduce DTC noise contribution, and (iii) a low-power wide-lock-range divide-by-six circuit to allow operation up to 34GHz.

Published
2019

22. A 15.6-18.2 GHz Digital Bang-Bang PLL with −63dBc in-Band Fractional Spur

Author

Roberto Nonis, Fabio Padovan, Matteo Bassi, Luigi Grimaldi, Salvatore Levantino, Carlo Samori, and Dmytro Cherniak

Subjects
Physics, fractional-N PLL, 020208 electrical & electronic engineering, spurs, nonlinearity, 02 engineering and technology, Predistortion, pre-distortion, law.invention, Phase-locked loop, Bang-bang phase detector, Nonlinear system, Capacitor, Engineering (all), CMOS, Modulation, law, digital PLL, 0202 electrical engineering, electronic engineering, information engineering, Spur, Electronic engineering, Bang bang
Abstract

This paper describes a 15.6-18.2GHz fractional-N bang-bang digital PLL fabricated in 28nm CMOS. To compensate for the nonlinearity of the digital-to-time converter and reduce the level of fractional spurs, two alternative predistortion techniques are introduced. The adoption of those algorithms operating continuously in background is demonstrated to reduce the level of the in-band fractional spur at 300kHz from −20dBc to −57dBc and −63dBc, respectively. The fabricated PLL achieves FoM of −237.2dB.

Published
2018

23. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND)

Author

Raju Kapoor, Pei-Ran Ho, Nolan Campbell, Ih Chang, Aaron Deykin, Fiona Forrestal, Nisha Lucas, Bei Yu, Douglas L Arnold, Mark S Freedman, Myla D Goldman, Hans-Peter Hartung, Eva Kubala Havrdová, Douglas Jeffery, Aaron Miller, Finn Sellebjerg, Diego Cadavid, Dan Mikol, Deborah Steiner, Emmanuel Bartholomé, Marie D'Hooghe, Massimo Pandolfo, Bart Van Wijmeersch, Virender Bhan, Gregg Blevins, Donald Brunet, Virginia Devonshire, Pierre Duquette, Mark Freedman, François Grand'Maison, François Jacques, Yves Lapierre, Liesly Lee, Sarah Morrow, Michael Yeung, Michal Dufek, Petr Kanovsky, Ivana Stetkarova, Marika Talabova, Jette Frederiksen, Matthias Kant, Thor Petersen, Mads Ravnborg, Laura Airas, Irina Elovaara, Juha-Pekka Eralinna, Taneli Sarasoja, Abdullatif Al Khedr, David Brassat, Bruno Brochet, William Camu, Marc Debouverie, David Laplaud, Christine Lebrun Frenay, Jean Pelletier, Patrick Vermersch, Sandra Vukusi, Karl Baum, Achim Berthele, Juergen Faiss, Peter Flachenecker, Reinhard Hohlfeld, Markus Krumbholz, Christoph Lassek, Mathias Maeurer, Sven Meuth, Tjalf Ziemssen, Orla Hardiman, Christopher McGuigan, Anat Achiron, Dimitrios Karussis, Roberto Bergamaschi, Vincenzo Brescia Morra, Giancarlo Comi, Salvatore Cottone, Luigi Grimaldi, Giovanni Luigi Mancardi, Luca Massacesi, Ugo Nocentini, Marco Salvetti, Elio Scarpini, Patrizia Sola, Gioacchino Tedeschi, Maria Trojano, Mauro Zaffaroni, Stephan Frequin, Raymond Hupperts, Joep Killestein, Hans Schrijver, Ronald Van Dijl, Erik van Munster, Maciej Czarnecki, Wieslaw Drozdowski, Waldemar Fryze, Hanka Hertmanowska, Jan Ilkowski, Anna Kaminska, Gabriela Klodowska-Duda, Maciej Maciejowski, Ewa Motta, Ryszard Podemski, Andrzej Potemkowski, Teresa Rog, Krzysztof Selmaj, Zbigniew Stelmasiak, Adam Stepien, Andrzej Tutaj, Jacek Zaborski, Alexey Boyko, Zanna Chefranova, Evgeny Evdoshenko, Farit Khabirov, Stella Sivertseva, Eduard Yakupov, Jose Carlos Alvarez Cermeño, Antonio Escartin, Oscar Fernandez Fernandez, Antonio Garcia-Merino, Miguel Angel Hernandez Perez, Guillermo Izquierdo Ayuso, José Meca Lallana, Xavier Montalban Gairin, Celia Oreja-Guevara, Albert Saiz Hinarejos, Martin Gunnarsson, Jan Lycke, Claes Martin, Fredrik Piehl, Homayoun Roshanisefat, Peter Sundstrom, Martin Duddy, Bruno Gran, Timothy Harrower, Jeremy Hobart, Martin Lee, Paul Mattison, Richard Nicholas, Owen Pearson, Waqar Rashid, David Rog, Basil Sharrack, Eli Silber, Ben Turner, Anna Williams, John Woolmore, Carolyn Young, Daniel Bandari, Joseph Berger, Ann Camac, Stanley Cohan, Jill Conway, Keith Edwards, Michelle Fabian, Jack Florin, Steven Freedman, Dennis Garwacki, Myla Goldman, Daniel Harrison, Craig Herrman, Deren Huang, Adil Javed, Stephen Kamin, George Katsamakis, Bhupendra Khatri, Annette Langer-Gould, Sharon Lynch, David Mattson, Tamara Miller, Augusto Miravalle, Harold Moses, Suraj Muley, James Napier, Allen Nielsen, Andrew Pachner, Gabriel Pardo, MaryAnn Picone, Derrick Robertson, Walter Royal, Christopher Sheppard, Ben Thrower, Cary Twyman, Emmanuelle Waubant, Jeanette Wendt, Vijayshree Yadav, Rana Zabad, Greg Zarelli, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), Biogen Inc. [Cambridge, MA, USA], Montreal Neurological Institute, Montreal, QC, Canada, NeuroRx Research, Montreal, QC, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, University of Virginia, Charlottesville, VA, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], First Faculty of Medicine-Charles University in Prague and General University Hospital in Prague, Piedmont HealthCare, Mooresville, NC, Icahn School of Medicine at Mount Sinai, New York, NY, University of Copenhagen = Københavns Universitet (UCPH), AP-HM, CHU Timone, Pole de Neurosciences Cliniques, Department of Neurology, Marseille, France., Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Outcome Assessment, secondary progressive multiple sclerosis, natalizumab, Placebo-controlled study, multicenter, Severity of Illness Index, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Natalizumab, Randomized controlled trial, law, Outcome Assessment, Health Care, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Progressive multifocal leukoencephalopathy, Multiple Sclerosis, Chronic Progressive, Middle Aged, Chronic Progressive, Research Design, Disease Progression, Female, Settore MED/26 - Neurologia, medicine.drug, Adult, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Population, Clinical Neurology, Double-Blind Method, Hand, Humans, Immunologic Factors, Young Adult, interferon beta 1b, 03 medical and health sciences, Internal medicine, medicine, education, Expanded Disability Status Scale, business.industry, Multiple sclerosis, ms, medicine.disease, Health Care, 030104 developmental biology, Siponimod, chemistry, brain atrophy, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Published
2018

24. A 23-GHz Low-Phase-Noise Digital Bang-Bang PLL for Fast Triangular and Sawtooth Chirp Modulation

Author

Roberto Nonis, Dmytro Cherniak, Luigi Grimaldi, Salvatore Levantino, Carlo Samori, and Luca Bertulessi

Subjects
PLL, Computer science, 020208 electrical & electronic engineering, CMOS, nonlinearity, 020206 networking & telecommunications, 02 engineering and technology, LMS, CMOS, radar, PLL, LMS, nonlinearity, Phase-locked loop, Voltage-controlled oscillator, Duty cycle, Modulation, Phase noise, 0202 electrical engineering, electronic engineering, information engineering, Electronic engineering, Chirp, Digitally controlled oscillator, Electrical and Electronic Engineering, Frequency modulation, radar
Abstract

Frequency-modulated continuous-wave (FMCW) radars with high resolution require the generation of low-phase-noise, low-spurs, and highly linear chirp signals with large peak-to-peak value (chirp bandwidth) and a short period of the modulation signal [1]. In radar systems, the spot phase noise of the chirp generator is converted to the intermediate frequency of the receiver making it difficult to detect two close targets, while spurs cause the detection of false targets. For those reasons, medium-range radar applications in the 77-to-81GHz band typically specify spot phase noise lower than −90dBc/Hz at 1MHz offset and spur level below −50dBc. Unlike triangular chirps, saw-tooth chirps allow for a reduced dead time for range detection. However, any practical modulator needs a finite time (idle time) to make a large frequency jump at the end of the saw-tooth, and this limits the duty cycle of the saw-tooth. For instance, a fast saw-tooth chirp with 200kHz rate and 95% duty cycle leaves the idle time of only 250ns. Fractional-N PLLs can be used as chirp modulators. Unfortunately, low phase noise and spur levels require a narrow PLL bandwidth, while short idle time demands for a wide one. The two-point injection of the modulation signal, both from the modulus control of the divider and the tuning input of the voltage-controlled oscillator (VCO), is a known method to simultaneously achieve a narrow PLL bandwidth and fast modulation. However, even in that scheme, a frequency modulation error is mainly limited by gain mismatch between the two injection paths and by the linearity of the VCO [2]. In this work, a 20-to-24GHz digital bang-bang PLL, which uses the two-point modulation scheme to generate triangular and saw-tooth chirp signals, is presented. Unlike previous works [1-4], this architecture is able to generate fast saw-tooth chirps with the slope up to 173MHz/js, the idle time below 200ns, and the rms frequency error of better than 0.06%. The gain mismatch between the two modulation paths are automatically calibrated by a digital algorithm [5], and the input of the digitally controlled oscillator (DCO) is pre-distorted via an automatic background correction scheme, which compensates for the DCO nonlinearity.

Published
2018

25. Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting

Author

Maria Trojano, Helmut Butzkueven, Ludwig Kappos, Heinz Wiendl, Tim Spelman, Fabio Pellegrini, Yi Chen, Qunming Dong, Harold Koendgen, Shibeshih Belachew, Jorge Correale, Alejandro Caride, Norma H. Deri, Carlos Ballario, Simon Broadley, Chris Kneebone, Michael Barnett, John Pollard, Suzanne Hodgkinson, Allan Kermode, Richard Macdonell, John King, Jeannette Lechner-Scott, Noel Saines, Mark Slee, Chris Plummer, Barbara Willekens, Ludo Vanopdenbosch, Rémy Phan-Ba, Valérie Delvaux, Veronique Bissay, Jan Debruyne, Danny Decoo, Roeland Crols, Anoek Symons, Guy Nagels, Vincent Van Pesch, Christian Sindic, Benedicte Dubois, Robert Medaer, Marie D'Hooghe, Daniel Guillaume, Eric De Smet, Pierrette Seeldrayers, Andreas Lysandropoulos, Mathieu Vokaer, Karine Geens, Christina Willems, Pierre Denayer, Michel Bureau, Cecile Retif, Michel Dupuis, Olivier Bouquiaux, Patrick Vanderdonckt, William van Landegem, Jo Caekebeke, Erwin Van Ingelghem, Katelijne Peeters, Pascale Gerard, Alain Maertens de Noordhout, Philippe Desfontaines, Etienne Urbain, Inge Declercq, Bart Van Wijmeersch, Erwin Vanroose, Alain Wibail, Emmanuel Barthomolé, Melanie Ursell, Margaret Elizabeth Sweet, David Howse, Draga Jichici, Melad Shawush, Mike Namaka, Anthony Traboulsee, Stan Hashimoto, Raymond Lo, Paul Marchetti, Yves Lapierre, Francois Jacques, Gregg MacLean, Virender Bhan, Pierre Duquette, Bradley Stewart, John Paulseth, Marcelo Kremenchutzky, Galina Vorobeychik, Paul O'Connor, François Grand'Maison, Eva Havrdova, Eva Meluzinová, Martin Valis, Radomír Talab, Pavel Stourac, Olga Zapletalová, Michal Dufek, Vladimíra Sládková, Alena Novotna, Romana Vancurová, Libuse Lhotaková, Jiri Fiedler, Marta Vachova, David Dolezil, Ivana Stetkarova, Adela Rehankova, Petr Psenica, Veronika Ulehlova, Sona Feketova, Ondrej Skoda, Markus Färkkilä, Sarasoja Taneli, Keijo Koivisto, Juha Matti Seppä, Laura Airas, Irina Elovaara, Päivi Hartikainen, Tuula Pirttila, Pierre Louchart, Olivier Ille, Jean philippe Thenint, Etienne Godet, Marcel Maillet Vioud, Renato Colamarino, Michel Gugenheim, Jerome Grimaud, Audrey Kopf, Christophe Billy, Bernard Huttin, Jean paul Borsotti, Philippe Devos, Jean bertin N Kendjuo, Albert Verier, Stephane Chapuis, Nathalie Daluzeau, Gilles Angibaud, Marie-Sylvie Artaud Uriot, François Ziegler, François Sellal, Antoine Moulignier, Isabelle Lavenu, Samir Ismail, Richard Devy, Manuel Suceveanu, Marc Wagner, Sebastien Marcel, Faycal Derouiche, Sohrab Mostoufizadehghalamfarsa, Sophie Delalande, Irene Ruggieri, Catherine Bossu Van Nieuwenhuyse, Chantal Nifle, Basile Ondze, Carmen Gurau Vasilescu, Cyrille Vongsouthi, Marc Coustans, Olivier Anne, Josephine Amevigbe, Jerome Servan, Marc Merienne, Philippe Eck, Stephane Berroir, Philippe Busson, Bruno Barroso, Jean-Marc Larrieu, Catherine Louvet Giendaj, Imad Malkoun, Patrick Hautecoeur, Arnaud Kwiatkowski, Andre Pouliquen, Guillaume Garrigues, Olivier Delerue, Pierric Giraud, Julien Gere, Jean Vaunaize, Olivier Dereeper, Nicolas Seiller, Roger Alsassa, Mihaela Vlaicu, Veronique Neuville, Jean Marc Faucheux, Patricia Bernady, Guy Fanjaud, François Viallet, Michael Schroeter, Sylke Schlemilch-Paschen, Thomas Lange, Kin-Arno Bohr, Klaus Jendroska, Elisabeth Rehkopf, Arnfin Bergmann, Christoph Kleinschnitz, Thomas Postert, Peter Scholz, Uwe Mauz, Hubert Stratmann, Veneta Siefjediers, Martin Prantl, Klaus Gehring, Ruth Zellner, Kathrin Junge, Anton Zellner, Valerina Bacay, Eugen Schlegel, Udo Polzer, Erik Strauss, Andreas Link, Christoph Stenzel, Matthias Freidel, Joachim Drews, Christian Neudert, Frank Schmitz, Joachim Jaeger, Said Masri, Wolfgang Heuberger, Beate Trausch, Oliver Ruhnke, Serena Scarel, Kathlen Bach, Michael Ernst, Harald Landefeld, Nils Richter, Stephan Schmidt, Michaela Krause, Alezander Dressel, Roland Ruth, Kerstin Anvari, Jens Gossling, Christoph Schenk, Oliver Tiedge, Lutz Bode, Hans-Thomas Eder, Oliver Pfeffer, Reinhard Krug, Christoph Lassek, Eberhard Fleischer, Sven Meuth, Luisa Hildegard Klotz, Ines Peglau, Borries Kukowski, Birgit Herting, Kersten Guthke, Jurgen Schierenbeck, Bernd Brockmeier, Holger Albrecht, Matthias Wuttke, Regine Augspach-Hofmann, Stefan Gunther, Martin Redbrake, Christian Franke, Klaus Buchner, Thomas Gratz, Rolf Horn, Frank Doemges, Martin Schreiber, Thomas Brosch, Markus Horn, Matthias Kittlitz, Gabriele Vulturius, Paul Hinse, Rolf Malessa, Stephan Wiehler, Zaza Katsarava, Oliver Kastrup, Ulrich Kausch, Martin Gullekes, Markus Fickinger, Wilhelm Wenzel, Ingolf C. Botefur, Gerd Reifschneider, Sebastian Rauer, Michael Lang, Lutz Harms, Ulrich Eckhardt, Simone Cursiefen, Ralf Linker, Klemens Angstwurm, Judith Haas, Ivo Schuetze, Eva Rohm, H. Stienker-Fisse, Michael Sailer, Johannes Bohringer, Mathias Maurer, Eberhard Bause, Ronald Wersching, Reinhardt Dachsel, Sylke Domke, Frank Hoffman, Bjorn Tackenberg, Kerstin Roch, Uwe Ziebold, Boris Kallmann, Bernhard Buehler, Judith Faiss, Juergen Faiss, Sebastian Schimrigk, Christian Menges, Karl Christian Knop, Wolfgang Koehler, Arno Siever, Johannes Bufler, Georg Gramsl, Benedicta Kuhnler, Matthias Maschke, Florian Stogbauer, Lisa Staude, Florian Bethke, Andreas Bitsch, Arndt D. Harmjanz, Jorg Windsheimer, Bernd C. Kieseier, Ralf Berkenfeld, Hayrettin Tumani, Michael Kirsch, Brigitte Wildemann, Regina Daniels, Klaus Gottwald, Wolfgang-Gerhard Elias, Olaf Hoffmann, Matthias Schwab, Christopher Pilz, Fabian Klostermann, Kerstin Hellwig, Achim Berthele, Antonios Bayas, Daniel Molitor, Christoph Grothe, Bert Wagner, Klimentini Karageorgiou, Dimosthenis Mitsikostas, Antonios Kodounis, Andreas Plaitakis, Alexandros Papadimitriou, Nikolaos Grigoriadis, Nikolaos Vlaikidis, Evaggelos Koutlas, Athanassios Kyritsis, Panagiotis Papathanassopoulos, Nikolaos Makris, Antonios Tavernarakis, Elio Scarpini, Enrico Montanari, Maria Giovanna Marrosu, Maria Pia Amato, Mariarosa Rottoli, Alessandra Lugaresi, Ciro Florio, Claudio Gasperini, Luigi Grimaldi, Enrico Millefiorini, Tatiana Koudriavtseva, Franco Perla, Renato Mantegazza, Antonio Bertolotto, Angelo Ghezzi, Sandra Quinones Aguilar, Eli Skromne Eisenberg, Leondardo Llamas Lopez, Rocio Marquez Estudillo, H.M. Schrijver, M.C. Wittebol, J.C. Baart, A.E.L. van Golde, G.J.D. Hengstman, P.H.M. Pop, M. Bos (Geldrop), R. Medaer, Angelique Schyns-Soeterboek, A. van der Zwart, A.J.H. van Diepen, G.A.M. Verheul, W.I.M. Verhagen, M. Bos (Helmond), R.J.G.M. Witjes, L.G.F. Sinnige, E.Th.L. van Munster, E.A.C.M. Sanders, Ron van Dijl, R.M.M. Hupperts, S.T.F.M. Frequin, L.H. Visser, J.M.L. Henselmans, J.W.B. Moll, Rune Midgard, Kjell Morten Myhr, Astrid Edland, Wenche Telstad, Tone Hognestad, Christian Lund, Harald Hovdal, Kaur Kamaljit, Jan Schepel, Roelfien Ida Hogenesch, Stephan Schüler, Francis Odeh, Karl B. Alstadhaug, Olav Korsgaard, Elisabeth Farbu, Teis Barclay Ingvaldsen, Diana Soares (SCO), José Rente, José Manuel Costa Guerra, Armando Morganho, António Leitão, João de Sá, Maria José Sá, Pinto Marques, Mário Veloso, Miguel Viana Baptista, Jarmila Szilasiová, Daniela Copikova-Cudrakova, Lubica Prochazkova, Eleonóra Klimová, Vladimir Donath, Miroslav Brozman, Cristina Ramo, Domingo Pérez Ruiz, Carmen Calles Hernández, María Eugenia Marzo Sola, Roberto Suarez Moro, Jose Antonio Vidal, Ana Belén Caminero Rodríguez, Gisela Martin Ozaeta, Jordi Batlle Nadal, Amaya Alvarez de Arcaya Esquide, Javier Olascoaga Urtaza, Sergio Martínez-Yélamos, Txomin Arbizu, Lluis Ramio i Torrenta, Mike Boggild, Martin Wilson, Adnan Al-Araji, Richard Nicholas, Timothy Harrower, Ian Redmond, Tilo Wolf, Michael Osei-Bonsu, Gordon Mazibrada, David Rog, David Cottrell, Cris Constantinescu, Orla Gray, Mohamed Belhag, Abdullah Shehu, Waqar Rashid, Martin Duddy, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Clinical sciences, Neurology, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, medicine.medical_specialty, Disability worsening, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, immune system diseases, Internal medicine, Medicine, Humans, Immunologic Factors, In patient, Disability progression, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Medicine(all), Natalizumab/therapeutic use, Expanded Disability Status Scale, business.industry, Multiple sclerosis, General Medicine, Multiple Sclerosis, Relapsing-Remitting/drug therapy, medicine.disease, Immunologic Factors/therapeutic use, Clinical Practice, Treatment Outcome, Neurology, Disease Progression, Observational study, Female, Relapsing-remitting multiple sclerosis, Neurology (clinical), business, EDSS milestones, 030217 neurology & neurosurgery, medicine.drug, Follow-Up Studies
Abstract

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Published
2018

26. Adaptive Digital Pre-Emphasis for PLL-Based FMCW Modulators

Author

Salvatore Levantino, Luigi Grimaldi, Dmytro Cherniak, and Carlo Samori

Subjects
Computer science, 020208 electrical & electronic engineering, Emphasis (telecommunications), Equalization (audio), 020206 networking & telecommunications, 02 engineering and technology, Filter (signal processing), Signal, Transfer function, Phase-locked loop, Modulation, 0202 electrical engineering, electronic engineering, information engineering, Chirp, Electronic engineering, Frequency modulation
Abstract

The direct frequency modulation of a phase locked loop suffers from limited modulation bandwidth. To overcome this limitation, the modulation signal can be pre-emphasized by means of a high-pass filter. Unfortunately, the incorrect equalization of the PLL transfer function causes modulation error. This paper introduces a new method to adaptively match the transfer functions of the PLL and the pre-emphasis filter over environmental and process variations. The technique is verified using a time-domain model of a digital PLL designed for the generation of chirp signals for FMCW radar sensors. The new adaptive digital pre-emphasis technique enables the generation of highly-linear fast chirps with significant reduction of the idle time.

Published
2018

27. A low-phase-noise digital bang-bang PLL with fast lock over a wide lock range

Author

Luigi Grimaldi, Luca Bertulessi, Carlo Samori, Dmytro Cherniak, and Salvatore Levantino

Subjects
Record locking, sezele, Computer science, 020208 electrical & electronic engineering, CMOS, 02 engineering and technology, Phase-locked loop, Noise, Phase noise, 0202 electrical engineering, electronic engineering, information engineering, Electronic engineering, Digitally controlled oscillator, Electrical and Electronic Engineering, Electronic circuit
Abstract

Digital phase-locked loops (DPLLs) based on binary phase detectors (BPDs) avoid power-hungry high-resolution time/digital converters (TDCs) while demonstrating advantages in area, power consumption, and design complexity. The introduction of digital/time converters (DTCs) enables fractional-N resolution at high spectral purity [1]. The design of a bang-bang digital PLL for wireless standards has two main challenges: quantization noise must be kept below the tolerable spot phase noise and fast lock must be guaranteed even for wide frequency steps. However, the overload of the BPD causes bang-bang PLLs to fail lock or to exhibit extremely long transients. A similar issue appears in the design of sub-sampling PLLs. This problem is exacerbated when the bang-bang PLL is designed for low phase noise for the tight resolution required of the digitally controlled oscillator (DCO). Fast locking techniques are usually based on the use of lookup tables [2], finite state machine [3], or gear shifting techniques, mostly in the field of clock-and-data recovery circuits (CDR) where spot noise performance is less of a concern. High-performance bang-bang PLLs (or subsampling PLLs) also include a frequency-aid circuit running in background [4], but its settling performance is seldom discussed.

Published
2018

28. PSO-based Search mechanism in dynamic environments: Swarms in Vector Fields

Author

Luigi Grimaldi, Palina Bartashevich, and Sanaz Mostaghim

Subjects
Structure (mathematical logic), Mathematical optimization, MathematicsofComputing_NUMERICALANALYSIS, Particle swarm optimization, 020206 networking & telecommunications, 02 engineering and technology, ComputingMethodologies_ARTIFICIALINTELLIGENCE, Mechanism (engineering), Search algorithm, Complete information, 0202 electrical engineering, electronic engineering, information engineering, Robot, 020201 artificial intelligence & image processing, Vector field, Algorithm, Mathematics, Interpolation
Abstract

This paper presents the Vector Field Map PSO (VFM-PSO) as a collective search algorithm for aerial micro-robots in environments with unknown external dynamics (such as wind). The proposed method is based on a multi-swarm approach and allows to cope with unknown disturbances arising by the vector fields in which the positions and the movements of the particles are highly affected. VFM-PSO requires gathering the information regarding the vector fields and one of our goals is to investigate the amount of the required information for a successful search mechanism. The experiments show that VFM-PSO can reduce the drift and improves the performance of the PSO algorithm despite incomplete information (awareness) about the structure of considered vector fields.

Published
2017

29. Natalizumab-Related Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: Findings from an Italian Independent Registry

Author

Prosperini, Luca, De Rossi, Nicola, Scarpazza, Cristina, Moiola, Lucia, Cosottini, Mirco, Gerevini, Simonetta, Capra, Ruggero, the Italian PML study group, Maria Pia Amato, Artusi, Carlo Alberto, Fabio, Bandini, Antonio, Bertolotto, Vincenzo, Bresciamorra, Guido, Cavaletti, Paolacavalla, Marco, Capobianco, Clerico, Marinella, Eleonora, Cocco, Giangaetano, D'Aleo, Marilena de Riz, Luciano, Deotto, Durelli, Luca, Mario, Falcini, Eugenio, Ferrari, Maria Luisa Fusco, Claudio, Gasperini, Simonetta, Gerevini, Angelo, Ghezzi, Luigi, Grimaldi, Mario, Guidotti, Alessandra, Lugaresi, Maria Giovanna Marrosu, Lucia, Moiola, Paola, Naldi, Patrizia, Perrone, Matteo, Pizzorno, Carlo, Pozzilli, Monica, Rezzonico, Marco, Rovaris, Giuseppe, Salemi, Marco, Salvetti, Giuseppe, Santuccio, Elio, Scarpini, Edoardo, Sessa, Claudio, Solaro, Giulia, Tabiadon, Carla, Tortorella, Maria, Trojano, and Paola, Valentino

Subjects
Male, Central Nervous System, Genetics and Molecular Biology (all), 0301 basic medicine, Pathology, Physiology, viruses, JC virus, lcsh:Medicine, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Pathology and Laboratory Medicine, medicine.disease_cause, Nervous System, Biochemistry, Diagnostic Radiology, Leukoencephalopathy, 0302 clinical medicine, Natalizumab, Medicine and Health Sciences, Ethnicities, lcsh:Science, Immune Response, Cerebrospinal Fluid, Multidisciplinary, Cognitive Neurology, Radiology and Imaging, Progressive multifocal leukoencephalopathy, Leukoencephalopathy, Progressive Multifocal, Middle Aged, JC Virus, Magnetic Resonance Imaging, Body Fluids, Italian People, Survival Rate, Neurology, Female, Anatomy, medicine.symptom, Research Article, medicine.drug, Adult, medicine.medical_specialty, Multiple Sclerosis, Imaging Techniques, Cognitive Neuroscience, Immunology, Progressive Multifocal, Research and Analysis Methods, Asymptomatic, Disease-Free Survival, Humans, Retrospective Studies, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Internal medicine, medicine, Survival rate, Inflammation, Expanded Disability Status Scale, business.industry, Multiple sclerosis, lcsh:R, Biology and Life Sciences, medicine.disease, 030104 developmental biology, People and Places, Lesions, Cognitive Science, Population Groupings, lcsh:Q, business, 030217 neurology & neurosurgery, Neuroscience
Abstract

Background The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). Objective To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. Methods An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. Results Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values

Published
2016

30. Analysis of adaptive pre-distortion in DTC-based digital fractional-N PLLs

Author

Luigi Grimaldi, Salvatore Levantino, and Carlo Samori

Subjects
PLL, Computer science, 020208 electrical & electronic engineering, CMOS, PLL, CMOS, Hardware_PERFORMANCEANDRELIABILITY, 02 engineering and technology, Converters, Phase-locked loop, Reduction (complexity), Nonlinear system, Control theory, Linearization, PLL multibit, Hardware_INTEGRATEDCIRCUITS, 0202 electrical engineering, electronic engineering, information engineering, Electronic engineering, sezelee, Jitter, Pre distortion
Abstract

The adoption of digital-to-time converters (DTCs) along with coarse, or even single-bit, time-to-digital converters (TDCs) is known to substantially reduce jitter and power consumption of digital fractional-N PLLs. Beside these advantages, DTC-based PLLs enable an adaptive pre-distortion algorithm which mitigates the nonlinearity of the DTC and the nonlinearity-induced fractional spurs. This paper provides a novel analytical framework of this linearization algorithm and demonstrates a reduction of fractional-N in-band spurs by 25 dB in a 3.6-GHz digital PLL.

Published
2016

31. Hodgkin's disease

Author

Pier Luigi Grimaldi, Pietro Torricelli, Renato Romagnoli, Massimo Federico, and Federica Fiocchi

Subjects
Hodgkin s, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Follow up studies, Tumor burden, Retrospective cohort study, Computed tomography, Disease, Sex factors, medicine, Radiology, Nuclear Medicine and imaging, Radiology, Stage (cooking), Nuclear medicine, business
Abstract

A direct method for the evaluation by computed tomography (CT) of the neoplastic mass (tumor burden [TB]) has been adopted in 34 patients diagnosed with Hodgkin's disease in the early stage. Stressed are its prognostic value, and its correlation with the clinical and laboratory parameters usually adopted in the staging of the disease and in its follow-up. It is concluded that the CT-calculated TB is a reliable index showing good correlation with other commonly used prognostic parameters.

Published
2004

32. Guidelines for the diagnosis of dementia and Alzheimer's disease

Author

Nicola Pugliese, Laura Bracco, Alessandro Padovani, Vincenzo Mascia, Francesco Valluzzi, Francesco Iemolo, Sandro Sorbi, Roberto Gallassi, Giorgio Giaccone, Pasquale Alfieri, Andrea Stracciari, Graziella D'Achille, Francesco Redi, Gabriella Marcon, M. Gasparini, S. Latorraca, Rudolf Schoenuber, Rosa Maria Ruggieri, Gilberto Pizzolato, Roberta Pantieri, Bruno Bergamasco, Bernardino Ghetti, Massimo Musicco, Antonio Daniele, Carlo Piccolini, Antonietta Citterio, Patrizia Ferrero, Antonio Carolei, Michela Morbin, Serena Amici, Guido Gainotti, Silvia Piacentini, Lucilla Parnetti, Biancamaria Guarnieri, Orso Bugiani, Vito Toso, Serenella Grioli, Margherita Alberoni, E. Farina, Stefano Grottoli, Antonella Bartoli, Claudio Mariani, Federico Piccoli, Ildebrando Appollonio, Emanuela Galante, Paolo Gabriele, Bruno Passerella, Simonetta Mearelli, Luigi Grimaldi, Luciana Ciannella, Maria Caterina Silveri, Stefano Avanzi, Maria Morante, Carla Pettenati, Amalia C. Bruni, Daniele Durante, Carlo Caltagirone, Giuseppe Sorrentino, Anna De Rosa, Marco Paganini, Ettore Nardelli, Paolo Forleo, Massimo Tabaton, Francesco Le Pira, Marco Saetta, Pietro Parisen, Gian Luigi Lenzi, Leandro Provinciali, Paolo Frigio Nichelli, Sebastiano Lorusso, Patrizia Sucapane, Grazia Dell'Agnello, Giuseppe Del Curatolo, Daniele Antana, Fabrizio Tagliavini, Umberto Ruggiero, Paolo Caffarra, Floriano Girotti, Virgilio Gallai, Sorbi, S, Alberoni, M, Alfieri, P, Amici, S, Antana, D, Appollonio, I, Avanzi, S, Bartoli, A, Bergamasco, B, Bracco, L, Bruni, A, Bugiani, O, Caffarra, P, Caltagirone, C, Carolei, A, Rosa, A, Ciannella, L, Citterio, A, Daniele, A, D'Achille, G, Del Curatolo, G, Dell'Agnello, G, Durante, D, Farina, E, Ferrero, P, Forleo, P, Gainotti, G, Gabriele, P, Galante, E, Gallai, V, Gallassi, R, Gasparini, M, Ghetti, B, Giaccone, G, Girotti, F, Grimaldi, L, Grioli, S, Guarnieri, B, Grottoli, S, Iemolo, F, Latorraca, S, Le Pira, F, Lenzi, G, Lorusso, S, Mariani, C, Marcon, G, Mascia, V, Mearelli, S, Morante, M, Morbin, M, Musicco, M, Nardelli, E, Nichelli, P, Padovani, A, Paganini, M, Pantieri, R, Parisen, P, Parnetti, L, Passerella, B, Pettenati, C, Piacentini, S, Piccoli, F, Piccolini, C, Pizzolato, G, Provinciali, L, Pugliese, N, Redi, F, Ruggieri, R, Ruggiero, U, Saetta, M, Schoenuber, R, Silveri, M, Sorrentino, G, Sucapane, P, Stracciari, A, Tabaton, M, Tagliavini, F, Toso, V, and Valluzzi, F

Subjects
MED/26 - NEUROLOGIA, Psychiatry and Mental health, media_common.quotation_subject, Neurology (clinical), Dermatology, General Medicine, Art, MED/09 - MEDICINA INTERNA, M-PSI/02 - PSICOBIOLOGIA E PSICOLOGIA FISIOLOGICA, Humanities, Guideline, dementia, Alzheimer's disease, diagnosis, media_common
Abstract

SIN DOCUMENT*The Dementia Study Group is co-ordinated by Sandro Sorbi andincludes: Margherita Alberoni, Milan; Pasquale Alfieri, SommaVesuviana (NA); Serena Amici, Perugia; Daniele Antana, Rome;Ildebrando Appollonio, Monza (MI); Stefano Avanzi,Castelgoffredo (MN); Antonella Bartoli, Pescara; BrunoBergamasco, Turin; Laura Bracco, Florence; Amalia Bruni,Lamezia Terme (CZ); Orso Bugiani, Milan; Paolo Caffarra, Parma;Carlo Caltagirone, Rome; Antonio Carolei, L’Aquila; Anna RosaCasini, Rome; Luciana Ciannella, Benevento; Antonietta Citterio,Pavia; Antonio Daniele, Rome; Graziella D’Achille, Isernia;Giuseppe Del Curatolo, Grosseto; Grazia Dell’Agnello, Pisa;Daniele Durante, Parma; Elisabetta Farina, Milan; Patrizia Ferrero,Turin; Paolo Forleo, Florence; Guido Gainotti, Rome; PaoloGabriele, Cassino (FR); Emanuela Galante, Castelgoffredo (MN);Virgilio Gallai, Perugia; Roberto Gallassi, Bologna; MaddalenaGasparini, Milan; Bernardino Ghetti, Indianapolis (USA); GiorgioGiaccone, Milan; Floriano Girotti, Milan; Luigi Grimaldi, Milanand Caltanisetta; Serenella Grioli, Catania; Bianca MariaGuarnieri, Pescara; Stefano Grottoli, Fossombrone (PS); FrancescoIemolo, Ragusa; Stefania Latorraca, Florence; Francesco Le Pira,Catania; Gian Luigi Lenzi, Rome; Sebastiano Lorusso, Rimini;Claudio Mariani, Milan; Gabriella Marcon, Udine; VincenzoMascia, Carbonia (CA); Simonetta Mearelli, L’Aquila; MariaMorante, Senigallia (AN); Michela Morbin, Milan; MassimoMusicco, Segrate (MI); Ettore Nardelli, Verona; Paolo Nichelli,Modena; Alessandro Padovani, Brescia; Marco Paganini, Florence;Roberta Pantieri, Bologna; Pietro Parisen, Vicenza; LucillaParnetti, Perugia; Bruno Passerella, Brindisi; Carla Pettenati, Rho(MI); Silvia Piacentini, Florence; Federico Piccoli, Palermo; CarloPiccolini, Perugia; Gilberto Pizzolato, Padova; LeandroProvinciali, Ancona; Nicola Pugliese, Salerno; Francesco Redi,Arezzo; Rosa Maria Ruggieri, Palermo; Umberto Ruggiero,Naples; Marco Saetta, Siracusa; Rudolf Schoenuber, Bolzano;Maria Caterina Silveri, Rome; Sandro Sorbi, Florence; GiuseppeSorrentino, Naples; Patrizia Sucapane, L’Aquila; Andrea Stracciari,Bologna; Massimo Tabaton, Genova; Fabrizio Tagliavini, Milan;Vito Toso, Vicenza; Francesco Valluzzi, Putignano Noci (BA)S. Sorbi ( )Department of Neurological and Psychiatric SciencesUniversity of FlorenceViale Morgagni 85, I-50131 Florence, Italy

Published
2000

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