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51. A factor score reflecting cognitive functioning in patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF)

Author

Springer, Anne, Monsch, Andreas U, Dutilh, Gilles, Coslovsky, Michael, Kievit, Rogier A, Bonati, Leo H, Conen, David, Aeschbacher, Stefanie, Beer, Juerg H, Schwenkglenks, Matthias, Fischer, Urs, Meyer-Zuern, Christine S, Conte, Giulio, Moutzouri, Elisavet, Moschovitis, Giorgio, Kühne, Michael, Osswald, Stefan, University of Zurich, and Springer, Anne

Subjects
1000 Multidisciplinary, 1300 General Biochemistry, Genetics and Molecular Biology, 360 Social problems & social services, 610 Medicine & health, 10060 Epidemiology, Biostatistics and Prevention Institute (EBPI), 1100 General Agricultural and Biological Sciences, 11171 Cardiocentro Ticino
Abstract

BACKGROUND Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is considered as risk factor for the development of mild cognitive impairment (MCI) and dementia. However, dynamics of cognitive functions are subtle, and neurocognitive assessments largely differ in detecting these changes. We aimed to develop and evaluate a score which represents the common aspects of the cognitive functions measured by validated tests (i.e., "general cognitive construct"), while reducing overlap between tests and be more sensitive to identify changes in overall cognitive functioning. METHODS We developed the CoCo (cognitive construct) score to reflect the cognitive performance obtained by all items of four neurocognitive assessments (Montreal Cognitive Assessment (MoCA); Trail Making Test; Semantic Fluency, animals; Digital Symbol Substitution Test). The sample comprised 2,415 AF patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF), 87% aged at least 65 years. Psychometric statistics were calculated for two cognitive measures based on (i) the full set of items from the neurocognitive test battery administered in the Swiss-AF study (i.e., CoCo item set) and (ii) the items from the widely used MoCA test. For the CoCo item set, a factor score was derived based on a principal component analysis, and its measurement properties were analyzed. RESULTS Both the MoCA item set and the full neurocognitive test battery revealed good psychometric properties, especially the full battery. A one-factor model with good model fit and performance across time and groups was identified and used to generate the CoCo score, reflecting for each patient the common cognitive skill performance measured across the full neurocognitive test battery. The CoCo score showed larger effect sizes compared to the MoCA score in relation to relevant clinical variables. CONCLUSION The derived factor score allows summarizing AF patients' cognitive performance as a single score. Using this score in the Swiss-AF project increases measurement sensitivity and decreases the number of statistical tests needed, which will be helpful in future studies addressing how AF affects the risk of developing cognitive impairment.

Published
2020
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52. A significant increase in exercise test performance with virtual group motivation: a randomised open-label controlled trial.

Author

Wilzeck, Verena C, Hufschmid, Janik, Bischof, Louis, Hansi, Christopher, Nägele, Matthias P, Beer, Juerg H, Hufschmid, Urs, Wilzeck, Verena C, Hufschmid, Janik, Bischof, Louis, Hansi, Christopher, Nägele, Matthias P, Beer, Juerg H, and Hufschmid, Urs

Abstract

AIMS Exercise stress testing is frequently used for the assessment of coronary artery disease. As the validity of the test result is highly dependent on the patient’s cooperation and motivation, we hypothesised that virtual group motivation would result in a higher exercise capacity and may increase the test’s validity. METHODS 108 patients at a Swiss teaching hospital with an indication for exercise testing were included in a controlled, open-label trial and randomised 1:1 to treadmill exercise testing whilst either watching a video of a walking group (video group, n = 43), or watching a static image of flowers (image group, n = 43). The video showed a group of five amateur runners, giving the patients the impression of running within the group. As primary outcomes, the performance achieved and the perceived level of comfort during the test were analysed. RESULTS The video group achieved significantly higher percentages of their age-predicted METs (149 ± 32% vs 135 ± 29%, p = 0.041) and longer exercise durations (11:12 ± 2:54 min vs 08:54 ± 02:39 min, p <0.001). Levels of comfort (8.4 ± 1.4 vs 7.5 ± 1.7 analogue scale, p = 0.011) and closeness to their physical limits (8.9 ± 0.8 vs 8.1 ± 1.5, p = 0.005) were rated significantly higher by patients in the video group. CONCLUSIONS Patients watching a video of a running group achieved significantly higher maximum exercise levels and longer test durations. This may have implications for the test’s validity. Furthermore, the virtual setting enhanced patient comfort. (This trial was formally registered at clinicaltrials.gov: trial ID NCT03704493.).

Published
2020

53. A factor score reflecting cognitive functioning in patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF)

Author

Springer, Anne; https://orcid.org/0000-0002-4829-1041, Monsch, Andreas U, Dutilh, Gilles, Coslovsky, Michael, Kievit, Rogier A; https://orcid.org/0000-0003-0700-4568, Bonati, Leo H, Conen, David, Aeschbacher, Stefanie, Beer, Juerg H, Schwenkglenks, Matthias; https://orcid.org/0000-0001-7217-1173, Fischer, Urs, Meyer-Zuern, Christine S, Conte, Giulio, Moutzouri, Elisavet, Moschovitis, Giorgio, Kühne, Michael, Osswald, Stefan; https://orcid.org/0000-0002-9240-6731, Springer, Anne; https://orcid.org/0000-0002-4829-1041, Monsch, Andreas U, Dutilh, Gilles, Coslovsky, Michael, Kievit, Rogier A; https://orcid.org/0000-0003-0700-4568, Bonati, Leo H, Conen, David, Aeschbacher, Stefanie, Beer, Juerg H, Schwenkglenks, Matthias; https://orcid.org/0000-0001-7217-1173, Fischer, Urs, Meyer-Zuern, Christine S, Conte, Giulio, Moutzouri, Elisavet, Moschovitis, Giorgio, Kühne, Michael, and Osswald, Stefan; https://orcid.org/0000-0002-9240-6731

Abstract

BACKGROUND Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is considered as risk factor for the development of mild cognitive impairment (MCI) and dementia. However, dynamics of cognitive functions are subtle, and neurocognitive assessments largely differ in detecting these changes. We aimed to develop and evaluate a score which represents the common aspects of the cognitive functions measured by validated tests (i.e., "general cognitive construct"), while reducing overlap between tests and be more sensitive to identify changes in overall cognitive functioning. METHODS We developed the CoCo (cognitive construct) score to reflect the cognitive performance obtained by all items of four neurocognitive assessments (Montreal Cognitive Assessment (MoCA); Trail Making Test; Semantic Fluency, animals; Digital Symbol Substitution Test). The sample comprised 2,415 AF patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF), 87% aged at least 65 years. Psychometric statistics were calculated for two cognitive measures based on (i) the full set of items from the neurocognitive test battery administered in the Swiss-AF study (i.e., CoCo item set) and (ii) the items from the widely used MoCA test. For the CoCo item set, a factor score was derived based on a principal component analysis, and its measurement properties were analyzed. RESULTS Both the MoCA item set and the full neurocognitive test battery revealed good psychometric properties, especially the full battery. A one-factor model with good model fit and performance across time and groups was identified and used to generate the CoCo score, reflecting for each patient the common cognitive skill performance measured across the full neurocognitive test battery. The CoCo score showed larger effect sizes compared to the MoCA score in relation to relevant clinical variables. CONCLUSION The derived factor score allows summarizing AF patients' cognitive performance as a single score. Using this s

Published
2020

54. Elevated HbA1c is not associated with recurrent venous thromboembolism in the elderly, but with all-cause mortality- the SWEETCO 65+ study

Author

Mathis, Alexandra, Villiger, Lukas, Reiner, Martin F, Egloff, Michael, Schmid, Hans Ruedi, Stivala, Simona; https://orcid.org/0000-0003-1549-8932, Limacher, Andreas, Mean, Marie, Aujesky, Drahomir, Rodondi, Nicolas, Angelillo-Scherrer, Anna, Righini, Marc, Staub, Daniel, Aschwanden, Markus, Frauchiger, Beat, Osterwalder, Joseph, Kucher, Nils, Matter, Christian M, Banyai, Martin, Hugli, Oliver; https://orcid.org/0000-0003-2312-1625, Beer, Juerg H, Mathis, Alexandra, Villiger, Lukas, Reiner, Martin F, Egloff, Michael, Schmid, Hans Ruedi, Stivala, Simona; https://orcid.org/0000-0003-1549-8932, Limacher, Andreas, Mean, Marie, Aujesky, Drahomir, Rodondi, Nicolas, Angelillo-Scherrer, Anna, Righini, Marc, Staub, Daniel, Aschwanden, Markus, Frauchiger, Beat, Osterwalder, Joseph, Kucher, Nils, Matter, Christian M, Banyai, Martin, Hugli, Oliver; https://orcid.org/0000-0003-2312-1625, and Beer, Juerg H

Abstract

The association of glycated hemoglobin (HbA1c) with venous thromboembolism (VTE) and death in the elderly is unknown. In the SWEETCO 65+ study we analyzed prospectively a Swiss Cohort of Elderly Patients with Venous Thromboembolism (SWITCO 65+). 888 patients were enrolled for the SWEETCO 65+ analysis. HbA1c was determined at baseline and divided into three categories (HbA1c < 5.7%, normal range; 5.7-6.49%, pre-diabetic range; and >6.5%, diabetic range). Median follow-up was 2.5 years. The primary endpoint was recurrent VTE. Secondary endpoints included all-cause mortality and major bleeds. The total prevalence of diabetes was 22.1%. The risk of recurrent VTE was similar in patients with HbA1c with pre-diabetes (adjusted subhazard ratio (aSHR) 1.07 [0.70 to 1.63]) and diabetes (aSHR 0.73 [0.39 to 1.37]) as compared to those with a HbA1c in the normal range. However, a HbA1c ≥ 6.5% (median IQ range 7.0 [6.70;7.60]) was significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.83 [1.21 to 2.75]). In summary we found no association between HbA1c and major bleeding. Elevated HbA1c levels are not associated with recurrent VTE but with increased all-cause mortality in an elderly population with acute VTE.

Published
2020

55. Towards personalized antithrombotic management with drugs and devices across the cardiovascular spectrum.

Author

Lüscher, Thomas F, Davies, Allan, Beer, Juerg H, Valgimigli, Marco, Nienaber, Christoph A, Camm, John A, Baumgartner, Iris, Diener, Hans-Christoph, and Konstantinides, Stavros V

Subjects
BLOOD coagulation disorders, THROMBOSIS, ATRIAL fibrillation, VITAMIN K, PLATELET aggregation inhibitors
Abstract

Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow's triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article. [ABSTRACT FROM AUTHOR]

Published
2022
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57. Elevated HbA1c is not associated with recurrent venous thromboembolism in the elderly, but with all-cause mortality– the SWEETCO 65+ study

Author

Mathis, Alexandra, primary, Villiger, Lukas, additional, Reiner, Martin F., additional, Egloff, Michael, additional, Schmid, Hans Ruedi, additional, Stivala, Simona, additional, Limacher, Andreas, additional, Mean, Marie, additional, Aujesky, Drahomir, additional, Rodondi, Nicolas, additional, Angelillo-Scherrer, Anna, additional, Righini, Marc, additional, Staub, Daniel, additional, Aschwanden, Markus, additional, Frauchiger, Beat, additional, Osterwalder, Joseph, additional, Kucher, Nils, additional, Matter, Christian M., additional, Banyai, Martin, additional, Hugli, Oliver, additional, and Beer, Juerg H., additional

Published
2020
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58. Whole blood omega-3 fatty acid concentrations are inversely associated with blood pressure in young, healthy adults

Author

Filipovic, Mark G, Aeschbacher, Stefanie, Reiner, Martin F, Stivala, Simona, Gobbato, Sara, Bonetti, Nicole, Risch, Martin, Risch, Lorenz, Camici, Giovanni G, Luescher, Thomas F, von Schacky, Clemens, Conen, David, Beer, Juerg H, University of Zurich, and Beer, Juerg H

Subjects
11459 Center for Molecular Cardiology, 2724 Internal Medicine, 610 Medicine & health, 1314 Physiology, 2705 Cardiology and Cardiovascular Medicine
Published
2018

59. Relationships of Overt and Silent Brain Lesions With Cognitive Function in Patients With Atrial Fibrillation

Author

Conen, David, Rodondi, Nicolas, Müller, Andreas, Beer, Juerg H, Ammann, Peter, Moschovitis, Giorgio, Auricchio, Angelo, Hayoz, Daniel, Kobza, Richard, Shah, Dipen, Novak, Jan, Schläpfer, Jürg, Di Valentino, Marcello, Aeschbacher, Stefanie, Blum, Steffen, Meyre, Pascal, Sticherling, Christian, Bonati, Leo H, Ehret, Georg, Moutzouri, Elisavet, Fischer, Urs, Monsch, Andreas U, Stippich, Christoph, Wuerfel, Jens, Sinnecker, Tim, Coslovsky, Michael, Schwenkglenks, Matthias, Kühne, Michael, and Osswald, Stefan

Subjects
610 Medicine & health, 360 Social problems & social services
Abstract

BACKGROUND Patients with atrial fibrillation (AF) have an increased risk of cognitive decline, potentially resulting from clinically unrecognized vascular brain lesions. OBJECTIVES This study sought to assess the relationships between cognitive function and vascular brain lesions in patients with AF. METHODS Patients with known AF were enrolled in a multicenter study in Switzerland. Brain magnetic resonance imaging (MRI) and cognitive testing using the Montreal Cognitive Assessment (MoCA) were performed in all participants. Large noncortical or cortical infarcts (LNCCIs), small noncortical infarcts (SNCIs), microbleeds, and white matter lesions were quantified by a central core laboratory. Clinically silent infarcts were defined as infarcts on brain MRI in patients without a clinical history of stroke or transient ischemic attack. RESULTS The study included 1,737 patients with a mean age of 73 ± 8 years (28% women, 90% taking oral anticoagulant agents). On MRI, LNCCIs were found in 387 patients (22%), SNCIs in 368 (21%), microbleeds in 372 (22%), and white matter lesions in 1715 (99%). Clinically silent infarcts among the 1,390 patients without a history of stroke or transient ischemic attack were found in 201 patients with LNCCIs (15%) and 245 patients with SNCIs (18%). The MoCA score was 24.7 ± 3.3 in patients with and 25.8 ± 2.9 in those without LNCCIs on brain MRI (p < 0.001). The difference in MoCA score remained similar when only clinically silent LNCCIs were considered (24.9 ± 3.1 vs. 25.8 ± 2.9; p < 0.001). In a multivariable regression model including all vascular brain lesion parameters, LNCCI volume was the strongest predictor of a reduced MoCA (β = -0.26; 95% confidence interval: -0.40 to -0.13; p < 0.001). CONCLUSIONS Patients with AF have a high burden of LNCCIs and other brain lesions on systematic brain MRI screening, and most of these lesions are clinically silent. LNCCIs were associated with worse cognitive function, even among patients with clinically silent infarcts. Our findings raise the question of MRI screening in patients with AF.

Published
2019
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61. Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

Author

Butler, Amy, Elmersson, Micael, Egilsson, Arnor, Borjesson, Ulf, Svard, Gunnar, Liu, Bo, Lindh, Anders, Olsson, Lars-Bertil, Gustaysson, Mikael, Andersson, Lars, Benson, Lars, Bothin, Claes, Hajimirsadeghi, Ali, Martinsson, Bjorn, Ericsson, Marianne, Ohlsson, Ake, Lindvall, Hakan, Svensson, Peter, Thorne, Katarina, Handel, Hans, Platonov, Pyotr, Bernsten, Fredrik, Timberg, Ingar, Crisby, Milita, Karlsson, Jan-Erik, Andersson, Agneta, Malmqvist, Lennart, Engdahl, Johan, Thulin, Jorgen, Hot-Bjelak, Aida, Jensen, Steen, Debrunner, Johann, Beer, Juerg H., Shah, Dipen, Rudyk, Iurii, Tseluyko, Vira, Karpenko, Oleksandr, Zhurba, Svitlana, Kraiz, Igor, Parkhomenko, Oleksandr, Kupnovytska, Iryna, Seredyuk, Nestor, Mostovoy, Yuriy, Ushakov, Oleksiy, Koval, Olena, Kovalskiy, Igor, Svyshchenko, Yevgeniya, Sychov, Oleg, Stanislavchuk, Mykola, Tykhonova, Susanna, Fushtey, Ivan, Murdoch, Will, Chauhan, Naresh, Goodwin, Daryl, Lumley, Louise, Patel, Ramila, Saunders, Philip, Wong, Bennett, Patel, Niranjan, Jhittay, P., Ross, Andrew, Kainth, M. S., Ladha, Karim, Douglas, Kevin, Pickavance, Gill, McDonnell, Joanna, Handscombe, Laura, Gooding, Trevor, Wagner, Helga, Bradshaw, Colin, Bromham, Catherine, Jones, Kevin, Suryani, Shoeb, Coates, Richard, Sarai, Bhupinder, Willcock, W., Sircar, S., Cairns, John, Gilliand, A., Bilas, Roman, Strieder, E., Hutchinson, Peter, Wakeman, Anne, Stokes, Michael, Kirby, Graham, Vishwanathan, Bhaskhar, Vormann, Reinhold, Mueller, Thomas, Mayer, Peter, Horstmeier, Uwe, Eissing, Volker, Hey, Heinz, Leuchtgens, Heinz, Lilienweiss, Volker, Mueller, Heiner, Schubert, Christian, Lauer, Hellmann, Buchner, Thomas, Brauer, Gunter, Kamin, Susanne, Mueller, Karsten, Baumbach, Sylvia, Abdel-Qader, Muwafeg, Ebert, Hans-Holger, Schwencke, Carsten, Bernhardt, Peter, Karolyi, Laszlo, Sievers, Britta, Haverkamp, Wilhelm, Roehnisch, Jens-Uwe, Vertes, Andras, Szantai, Gabor, Menke, Holger, Matoltsy, Andras, Kanakaridisz, Nikosz, Boda, Zoltan, Kis, Erno, Gaszner, Balazs, Juhasz, Ferenc, Kamogawa, Yasuyuki, Fournier, Pierre-Yves, Muller, Jean-Joseph, Marquand, Andre, Delarche, Nicolas, Bantwal, Ganapathi, Faes, Dirk, Verstraete, Stefan, Dominguez, Helena, Topsakal, Ramazan, Centurion, Nestor, Alfredo Sinisi, Victor, Minc, Piotr, Nagy, Andras, Bilo, Grzegorz, Bongiorni, Maria Grazia, Bird, Nigel, Paul, Carolyn, Wadeson, Paul, Hargreaves, Nick, Kostenko, Victor, Tercedor Sanchez, Luis, Tranche Iparraguirre, Salvador, Jimenez Gonzalez, Mercedes, Herreros Melenchon, Juan, Stalby, Per, Yagensky, Andriy, Cameron, Alex, Jacobs, Polly, Juhasz, Gizella, Kancz, Sandor, Laszlo, Zoltan, May, Zsolt, Astridge, Penny, Loghdey, Rehana, Quick, Annette, Yang, Ping, Chen, Yingmin, He, Shenghu, Wang, Yong, Fu, Guosheng, Li, Xin, Wu, Tongguo, Cheng, Xiaoshu, Yan, Xiaowei, Zhao, Ruiping, Chen, Moshui, Xiong, Longgen, Chen, Ping, Jiao, Yang, Guo, Ying, Xue, Li, Yang, Zhiming, Jadhavm, Praveen, Merkely, Bela, Noon, Ebrahim, Habon, Tamas, Polgar, Peter, Szalai, Gabriella, Vangel, Sandor, Sarma, Raghava, Kulkarni, Govind, Engelthaler, Gabriella, Ferenczi, Judit, Chandwani, Prakash, Pothiwala, Rasesh Atulbhai, Purayil, Mohanan Padinhare, Chawla, Kamaldeep, Verheugt, Freek W. A., Ambrosio, Giuseppe, Atar, Dan, Bassand, Jean-Pierre, Costabel, Juan Pablo, Goldhaber, Samuel Z., Goto, Shinya, Egyutt, Mihaly, Martini, Giuliana, Cristina, Leone Maria, Tirafern, Eros, Santoro, Rita, Testa, Sophie, Di Minno, Giovanni, Moia, Marco, Caimi, Teresa Maria, Tessitori, Maria, Cappelli, Roberto, Accogli, Michele, Mariani, Antonio, Feola, Mauro, Raisaro, Arturo, Fattore, Luciano, Mauric, Andrea, Germini, Fabrizio, Tedeschi, Luca, Settimi, Maria, Nicoli, Sergio, Ricciarini, Paolo, Argena, Antonio, Ronchini, Paolo, Bulla, Claudio, Tradati, Filippo, Volpe, Massimo, Avino, Maria D., Seven, Silva, Capucci, Alessandro, Lodigiani, Corrado, Salomone, Enrico, Serviddio, Gaetano, Tondo, Claudio, Golino, Paolo, Mazzone, Carmine, Iacopino, Saverio, Ruiter, J. H., Lucassen, Andreas, Adriaansen, Henk, Bongaerts, Maarten, Pieterse, Mathijs, van Guldener, Coen, Herrman, Johannes, Nierop, S. H. K. P. R., Hoogslag, Pieter, Hermans, Walter, Groenemeijer, B. E., Terpstra, W., Buiks, Cees, Boersma, L. V. A., Berge, Eivind, Sirnes, Per Anton, Gjertsen, Erik, Hole, Torstein, Erga, Knut, Hallaraker, Arne, Skjelvan, Gunnar, Ostrem, Anders, Ghezai, Beraki, Svilaas, Arne, Christersson, Peter, Oien, Torbjorn, Henrichsen, Svein Hoegh, Otterstad, Jan Erik, Berg-Johansen, Jan, Gieroba, Andrzej, Biedrzycka, Malgorzata, Ogorek, Michal, Wozakowska-Kaplon, Beata, Loboz-Grudzien, Krystyna, Jaroslaw, Jaroslaw, Supinski, Wieslaw, Kuzniar, Jerzy, Zaluska, Roman, Hiczkiewicz, Jaroslaw, Swiatkowska-Byczynska, Lucyna, Kucharski, Lech, Gruchala, Marcin, Olszewski, Maciej, Kania, Grzegorz, Krzciuk, Malgorzata, Lajkowski, Zbigniew, Ostrowska-Pomian, Bozenna, Lewczuk, Jerzy, Zinka, Elzbieta, Karczmarczyk, Agnieszka, Chmielnicka-Pruszczynska, Malgorzata, Wozniak-Skowerska, Iwona, Opolski, Grzegorz, Bronisz, Marek, Ogorek, Marcin, Glanowska, Grazyna, Ruszkowski, Piotr, Skonieczny, Grzegorz, Sciborski, Ryszard, Okopien, Boguslaw, Kukla, Piotr, Galbas, Krzysztof, Cymerman, Krzysztof, Jurowiecki, Jaroslaw, Miekus, Pawel, Myszka, Waldemar, Mazur, Stanislaw, Lysek, Roman, Baszak, Jacek, Rusicka-Piekarz, Teresa, Raczak, Grzegorz, Domanska, Ewa, Nessler, Jadwiga, Catanchin, Andrei, Colquhoun, David, Kiat, Hosen, Eccleston, David, French, John, Ayres, Bronte, Blombery, Peter, Phan, Thanh, Rogers, James, O'Donnell, David, Cheol, Sang, Carroll, Patrick, Starmer, Greg, Arstall, Margaret, Binnekamp, Maurits, Lee, Astin, Luton, Robert, Gupta, Milan, Pandey, Amritanshu Shekhar, Cheung, Stephen, Leader, Rolland, Beaudry, Philippe, Ayala-Paredes, Felix, Berlingieri, Joseph, Heath, John, Poirier, Germain, du Preez, Miranda, Schweitzer, Bradley, Nadeau, Reginald, Dhillon, Ripple, Hruczkowski, Tomasz, Lavoie, Andrea, Parkash, Ratika, Cha, James, Coutu, Benoit, MacDonald, Paul, Ramjattan, Brian, Bonet, Jorge, Vizel, Saul, Angaran, Paul, Fikry, Sameh, Mowafy, Ahmed, Katta, Azza, Tawfik, Mazen, Nawar, Moustafa, Sobhy, Mohamed, Abou Seif, Seif Kamal, Khairy, Tarek, Abd El-Aziz, Ahmed, Taha, Nasser, Reda, Ashraf, Elbahry, Atef, Setiha, Mohamed, El Din, Mohamed Gamal, Elkhadem, Magdi, El-Etreby, Adel, Kettles, David, Bayat, Junaid, Siebert, Heidi, Horak, Adrian, Kelfkens, Ynez, Garda, Riaz, Pillay, Thayabran, Guerra, Michele, van Zyl, Louis, Theron, Hendrik, Murray, Andrew, Louw, Rikus, Greyling, Deon, Mntla, Pindile, Ismail, Siddique, Ahmed, Fayzal, Engelbrecht, Johannes, Maharajh, Shambu, Oosthuysen, Wessel, Ueckermann, Veronica, Al Naeemi, Abdullah, Yousef, Ghazi, Bazargani, Nooshin, Alomairi, Munther, Maruthanayagam, Rajan, Singh, Rupesh, Naguib, Ahmed, Ibrahim, Mohamed, Agrawal, Amrish, Nathani, Mukesh, Esheiba, Ehab M., Wassef, Adel, Gupta, Rajeev, Cox, Michael, Beach, Scott, Duffy, Peter, Falkowski, Stephen, Ferrick, Kevin, Franco, Miguel, Kutayli, W. Michael, Sharma, Niraj, Wilson, Vance, Miller, Stephen, Alberts, Mark, Blumberg, Edwin, Canosa, Roddy, Gutowski, Ted, Ison, Rodney, Garcia, Jorge, Mullen, Paul, Noveck, Howard, Rama, Pamela, Reddy, Rajneesh, Williams, Marcus, Nishijima, Daniel, Ferdinand, Keith, Hague, Ihsan, Mendelson, Robert, Pitta, Sridevi, Theodoro, Daniel, Treasure, Charles, Moustafa, Moustafa, Cader, Cas, Pharr, Walter, Oropallo, Alisha, Platt, George, Gujral, Jaspal, Welker, James, Koura, Firas, Lesnik, Jozef, Eltishcheva, Vera, Libis, Roman, Kamalov, Gadel, Belenky, Dmitry, Egorova, Liudmila, Khokhlov, Alexander, Yakupov, Eduard, Zateyshchikov, Dmitry, Barbarash, Olga, Miller, Olga, Mazur, Evgeniy, Zrazhevskiy, Konstantin, Novikova, Tatyana, Moiseeva, Yulia, Polkanova, Elena, Sobolev, Konstantin, Rossovskaya, Maria, Shapovalova, Yulia, Kolesnikova, Alla, Nikolaev, Konstantin, Zemlianskaia, Oksana, Zateyshchikova, Anna, Popov, Sergey, Poltayskaya, Maria, Edin, Anton, Aleksandrova, Elena, Drapkina, Oksana, Vishnevsky, Alexander, Nagibovich, Oleg, Chizhov, Petr, Rachkova, Svetlana, Sergeev, Mikhail, Kurylo, Borys, Ushakov, Alexey, Alvarez Garcia, Pere, Lopez Fernandez, Maria Fernanda, Toran Monserrat, Pere, Marquez Contreras, Emilio, Isart Rafecas, Jordi, Motero Carrasco, Juan, Garcia Pavia, Pablo, Gomez Pajuelo, Casimiro, Rincon Diaz, Luis Miguel, Iglesias Alonso, Luis Fernando, Grande Ruiz, Angel, Merce Klein, Jordi, Gonzalez Juanatey, Jose Ramon, Monte Collado, Ines, Palacin Piquero, Herminia, Brotons Cuixart, Carles, Fernandez Escobar, Esther, Bayo i Llibre, Joan, Corros Vicente, Cecilia, Vida Gutierrez, Manuel, Evans, Paul, Clark, M., Bisatt, John, Litchfield, Jennifer, Fisher, E., Fooks, Tim, Kelsall, Richard, Paul, Neil, Alborough, Elizabeth, Aziz, Michael, Ramesh, C., Wilson, Pete, Franklin, Simon, Fairhead, Sue, Thompson, Julian, Chowan, Hasan, Taylor, Gary, Tragen, Dawn, Parfitt, Matt, Seamark, Claire, Richardson, Mark, Jefferies, Angus, Sharp, Helen, Jones, Hywel, Giles, Claire, Bramley, Matthew, Williams, Philip, Aldegather, Jehad, Wetherell, Simon, Lumb, William, Evans, Phil, Scouller, Frances, Macey, Neil, Rogers, Stephen, Stipp, Yvette, West, Richard, Pinney, Philip, Matthews, John, Pandya, Preeti, Gallagher, Andrew, Railton, T., Davies, Emyr, McClure, Jonathan, Jacobs, Marc, Hutton, Claire, Thompson, R., Sinha, Bijoy, Butter, Keith, Barrow, Susan, Little, Helen, Russell, David, Choudhary, Ulka, Haq, Ikram, Ainsworth, Paul, Jones, Claire, Weeks, Phil, Eden, Jane, Gibbons, Lisa, Glencross, Janet, MacLeod, Alison, Poland, K., Mulolland, Conor, Warke, A., Conn, Paul, Burns, D., Smith, R., Kamath, R., Webster, Jonathan, Hodgins, Ian, Vercoe, Stephen, Roome, Paul, Pinnock, Hilary, Patel, Jayesh, Ali, Amar, Hart, Nigel, Davies, Richard, De-Sousa, Nigel, Neden, Catherine, Danielsen, Mark, Sharma, Purnima, Galloway, Sophia, Hawkins, Charlotte, Oliver, Raife, Aylward, Martin, Pattni, Mira, Irvine, Gordon, Ahmad, Shahid, Rothwell, Catherine, Choudhary, Fiaz, Khalaque, Sabrina, Short, Stephanie, Peters, Sharon, Coulson, Warwick, Roberts, Neil, Coates, Steven, Ward, Ben, Jackson, Daniel, Walton, Steve, Shepherd, Diane, Wong, Toh, Boon, Mark, Deacon, Melanie, Cornelius, David, Davies, Sarah, Ben Frankel, Ben Frankel, Choi, Henry, Sumner, Jon, Myhill, Tim, Estifanos, Salah, Geatch, Diane, Wilkinson, Justin, Veale, Richard, Forshaw, Karen, Hirst, Rob, Zaman, Kashif, Liley, Catherine, Wastling, Rebecca, McEleny, Paul, Beattie, Andre, Cooke, Philip, Wong, Mike, Pugsley, Mark, Dooldeniya, Chaminda, Rogers, Greg, Bennett, James, Muvva, Rajesh, Adam, Matthew, Fox, Robin, Thomas, Nicolas, Cartwright, Simon, Reed, Rory, Randfield, Simon, ACourt, Christine, Flynn, Ann, Halpin, Andrew, Dobson, Simon, Lomax, Louise, Nadaph, Minnal, Goram, Jane, Stoddart, Helen, Simmons, Phil, Shewring, John, Bowen-Simpkins, Emma, Rickenbach, Mark, Munro, Iain, Blenkhorn, Adam, Singh, Bhuwanendu, van Gaal, William, Abhayaratna, Walter, Thomson, Philip, Lehman, Ron, Kilian, Jens, Coulshed, David, Camm, A. John, Fitzmaurice, David A., Illingworth, Laura, Kayani, Gloria, Kakkar, Ajay K., YILMAZ, MEHMET BİRHAN, Taga, Kuniaki, Techigawara, Masaaki, Igarashi, Mono, Watanabe, Hiroshi, Seo, Toshihiko, Hiramitsu, Shinya, Hosokawa, Hiroaki, Hoshiai, Mitsumoto, Hibino, Michitaka, Miyagawa, Koichi, Horie, Hideki, Turpie, Alexander G. G., van Eickels, Martin, Hacke, Werner, Mantovani, Lorenzo G., Misselwitz, Frank, Pieper, Karen S., Kayani, Glo-ria, Fox, Keith A. A., Gersh, Bernard J., Lucas Luciardi, Hector, Gibbs, Harry, Brodmann, Marianne, Cools, Frank, Pereira Barrett, Antonio Carlos, Connolly, Stuart J., Spyropoulos, Alex, Eikelboom, John, Corbalan, Ramon, Hu, Dayi, Nielsen, JOrn Dalsgaard, Ragy, Hany, Raatikainen, Pekka, Le Heuzey, Jean-Yves, Darius, Harald, Keltai, Matyas, Kakkar, Sanjay, Sawhney, Jitendra Pal Singh, Agnelli, Giancarlo, Koretsune, Yukihiro, Sanchez Diaz, Carlos Jerjes, Ten Cate, Hugo, Panchenko, Elizaveta, Lim, Toon Wei, Jacobson, Barry, Oh, Seil, Vinolas, Xavier, Rosenqvist, Marten, Steffel, Jan, Angchaisuksiri, Pantep, Oto, Ali, Parkhomenko, Alex, Al Mahmeed, Wael, Fitzmaurice, David, Chen, Kangning, Zhao, Yusheng, Zhang, Huaiqin, Chen, Jiyan, Cao, Shiping, Wang, Daowen, Yang, Yuejin, Li, Weihua, Li, Hui, Yin, Yuehui, Tao, Guizhou, Kothiwale, Veerappa Annasaheb, Kimura, Teruaki, Raghuraman, Bagirath, Vijan, Vinod Madan, Sawhney, Jitendra, Khan, Aziz, Meena, Ramdhan, Okuda, Fumio, Mizuguchi, Masato, Mukawa, Hiroaki, Chopada, Manojkumar, Abraham, Sunitha, Bisne, Vikas, Vijayaraghavan, Govindan, Roy, Debabrata, Durgaprasad, Rajashekhar, Shankar, A. G. Ravi, Kumar, Sunil, Jain, Dinesh, Bhargava, Kartikeya, Kumar, Vinay, Nagamalesh, Udigala Madappa, Rajput, Rajeeve Kumar, Kanamori, Seishu, Wada, Masamichi, Minagawa, Taro, Ishiguro, Motoyuki, Yamamoto, Kenichi, Kumagai, Koichiro, Katsuda, Yosuke, Yoshida, Keiki, Toyota, Fumitoshi, Mizuno, Yuji, Misumi, Ikuo, Noguchi, Hiroo, Ando, Shinichi, Suetsugu, Tetsuro, Minamoto, Masahiro, Oda, Hiroyuki, Adachi, Susumu, Chiba, Kei, Norita, Hiroaki, Tsuruta, Makoto, Koyanagi, Takeshi, Matsuta, Masahiro, Ito, Kenichiro, Nakano, Masayuki, Shibuya, Mitsuhiro, Stepinska, Janina, Jansky, Petr, Yamamoto, Kunihiko, Haas, Sylvia, Ando, Hiroshi, Higashi, Takayuki, Okada, Megumi, Azakami, Shiro, Komaki, Shinichiro, Kumeda, Kenshi, Murayama, Takashi, Matsumura, Jun, Oba, Yurika, Sonoda, Ryuji, Goto, Kazuo, Minoda, Kotaro, Haraguchi, Yoshikuni, Suefuji, Hisakazu, Miyagi, Hiroo, Kato, Hitoshi, Nakamura, Tsugihiro, Nakamura, Tadashi, Nandate, Hidekazu, Zaitsu, Ryuji, Fujiura, Yoshihisa, Yoshimura, Akira, Numata, Hiroyuki, Ogawa, Jun, Murakami, Kinshiro, Wakasa, Yutaka, Yamasawa, Masanori, Maekawa, Hiromitsu, Abe, Sumihisa, Kihara, Hajime, Tsunoda, Satoru, Saito, Katsumi, Tachibana, Hiroki, Oba, Ichiro, Kuwahata, Takashi, Higa, Satoshi, Gushiken, Masamichi, Eto, Takuma, Chibana, Hidetoshi, Fujisawa, Kazuaki, Shiga, Yuhei, Sumi, Hirokuni, Nagatomo, Toshihisa, Atsuchi, Yoshihiko, Nagoshi, Toshiro, Sanno, Kazuhisa, Hoshino, Fumihiro, Yokota, Naoto, Kameko, Masahiro, Tabuchi, Toshifumi, Ishizawa, Munesumi, Fujiura, Yoshitake, Ikeda, Daisuke, Seto, Taku, Iwao, Tetsu, Ishioka, Norio, Oshiro, Koichi, Tsuchida, Keizo, Hatori, Yutaka, Takeuchi, Motoshi, Takezawa, Hiroto, Kira, Tetsuya, Tada, Masato, Tsuzaki, Ken, Miura, Naoya, Fujisawa, Yasuaki, Furumoto, Wataru, Suzuki, Susumu, Fujisawa, Akinori, Nakamura, Ryosai, Komatsu, Hiroyasu, Fujiki, Rei, Kawano, Shuichi, Nishizawa, Keijiro, Kato, Yoji, Azuma, Junya, Yasui, Kiyoshi, Amano, Toshio, Sekine, Yasuhiro, Honzawa, Tatsuo, Koshibu, Yuichiro, Sakamoto, Yasuhide, Seta, Yukihiro, Miyaguchi, Shingo, Morishita, Kojuro, Samejima, Yasuko, Sasaki, Toyoshi, Iseki, Fumiko, Kobayashi, Toshiyuki, Kano, Hiroshi, Kim, Jaeyoung, Yamaguchi, Hiroshi, Takagi, Yoichi, Pearce, Yoko Onuki, Suzuki, Yasuyuki, Fukui, Takayuki, Nakayama, Toni, Kanai, Hideaki, Kawano, Yoshiyuki, Ino, Tetsuji, Miyoshi, Hironori, Miyamoto, Yasufumi, Shigekiyo, Masahito, Ono, Shimato, Okamoto, Yutaka, Ubukata, Satoshi, Kodera, Kojiro, Oriuchi, Tatsuo, Matsumoto, Naoki, Nagano, Shinjiro, Iwaki, Masaaki, Nakamura, Yuichiro, Miyamoto, Naomasa, Taguchi, Toshifumi, Ashida, Ko, Yoshizawa, Naoto, Agata, Jun, Matsukawa, Seishiro, Arasaki, Osamu, Fukuoka, Shuji, Murakami, Hirofumi, Mishima, Kazuya, Hata, Yoshiki, Sakuma, Ichiro, Obunai, Kotaro, Takamura, Ichiro, Akutsu, Mitsuyuki, Unoki, Toshihide, Go, Yoshinori, Ikemura, Makoto, Morii, Shoji, Marusaki, Shigem, Doi, Hideo, Tanaka, Mitsuru, Kusu-moto, Takaaki, Kakinoki, Shigeo, Ogurusu, Chiga, Murata, Kazuya, Shimoyama, Masaki, Nakatsuka, Masami, Kitami, Yutaka, Nakamura, Yoichi, Oda, Hiroshi, Oyama, Rikimaru, Ageta, Masato, Mita, Teruaki, Nagao, Kazuhiko, Mito, Takafumi, Minami, Junichi, Abe, Mitsunori, Fujii, Masako, Okawa, Makoto, Fujito, Tsuneo, Taniguchi, Toshiya, Ko, Tenei, Kubo, Hiroshi, Imamaki, Mizuho, Akiyama, Masahiro, Ueda, Takashi, Odakura, Hironori, Inagaki, Masahiko, Katsube, Yoshiki, Nakata, Atsuyuki, Tomimoto, Shinobu, Sugishita, Nobuyoshi, Shiga, Yukio, Soma, Akira, Neya, Kazuo, Yoshida, Tetsuro, Akahane, Kunio, Adachi, Sen, Takanaka, Chiei, Matsui, Saori, Kanda, Hirofumi, Kaneko, Masanori, Nagasaka, Shiro, Taguchi, Atsushi, Toru, Shuta, Saito, Kazuyuki, Miyashita, Akiko, Sasaguri, Hiroki, Nariyama, Jin, Hatsuno, Taketo, Iwase, Takash, Sato, Kazuki, Kawai, Kazuya, Kotani, Tomobumi, Tsuji, Tsuyoshi, Sakai, Hirosumi, Nishino, Kiyoshi, Ikeda, Kenichi, Maeda, Kazuo, Shinozuka, Tomohiro, Inoue, Takeshi, Kawakami, Koichi, Kitazumi, Hiromichi, Takagi, Tsutomu, Hamaoka, Mamoru, Kojima, Jisho, Sasaki, Akitoshi, Tsuchiya, Yoshihiro, Bet-suyaku, Tetsuo, Higuchi, Koji, Honda, Masaaki, Hasegawa, Koichi, Baba, Takao, Mineoi, Kazuaki, Koeda, Toshihiko, Hirasawa, Kunihiko, Kumazaki, Toshihide, Nakagomi, Akira, Otaki, Eiji, Shindo, Takashi, Hirayama, Hiroyoshi, Sugimoto, Chikako, Yamagishi, Takashi, Mizuguchi, Ichiro, Sezaki, Kazunori, Niwa, Isamu, Takenaka, Ken, Iiji, Osamu, Taya, Koichi, Kitazawa, Hitoshi, Ueda, Samu, Kakuda, Hirokazu, Ono, Takuya, Oriso, Seizo, Kamata, Junya, Nanke, Toshihiko, Maeda, Itaru, Matsuura, Yoshifusa, Teragawa, Hiroki, Maruyama, Yasuyuki, Takei, Kazuo, Hone, Hajime, Kito, Tetsu-taro, Asano, Hiroshi, Matsushita, Koji, Nakamura, Masaichi, Washizuka, Takashi, Yoshida, Tomoki, Sawano, Masato, Arima, Shinichi, Arai, Hidekazu, Shinohara, Hisanori, Takai, Hiroyuki, Furukawa, Nobufusa, Ota, Akira, Yamamoto, Kentaro, Aoki, Kenji, Yamamoto, Taku, Kasai, Takeaki, Suzuki, Shunji, Suzuki, Shu, Shibata, Nitaro, Watanabe, Masayuki, Nishihata, Yosuke, Arino, Torn, Okuyama, Masaki, Wakiyama, Tetsushi, Kato, Tomoko, Sasagawa, Yasuo, Tana, Takeshi, Tumelero, Rogerio Tadeu, Maia, Lilia, de Almeida, Roberto Simoes, Carmo Borges, Ney Carter, Gomes Ferreira, Luis Gustavo, Stockins Fernandez, Benjamin Aleck Joseh, Montecinos, Humberto, Lanas, Fernando, Larico Gomez, Martin, Astudillo, Carlos, Conejeros, Carlos, Marin Cuevas, Patricio, Forero, Alejandro, Bugueno Gutierrez, Claudio, Aguilar, Juan, Potthoff Cardenas, Sergio, Eggers, German, Houzvic, Cesar, Rey, Carlos, Arriagada, German, Charme Vilches, Gustavo, Illescas Diaz, Jesus Jaime, Leal Cantu, Raul, Ramos Zavala, Maria Guadalupe, Cabrera Jardines, Ricardo, Espinola Zavaleta, Nilda, Lopez Rosas, Enrique, Llamas Esperon, Guillermo Antonio, Pozas, Gerardo, Cardona Munoz, Ernesto, Her-nandez, Norberto Matadamas, Leyva Rendon, Adolfo, Garcia Hernandez, Norberto, de los Rios Ibarra, Manuel, Virgen Carrillo, Luis Ramon, Lopez Villezca, David, Hernandez Herrera, Carlos, Lopez Prieto, Juan Jose, Gaona Rodriguez, Rodolfo, Villeda Espinosa, Efrain, Flores Martinez, David, Velasco Barcena, Jose, Fierro Fierro, Omar, Rodriguez Briones, Ignacio, Leiva Pons, Jose Luis, Alvarez Lopez, Humberto, Olvera Ruiz, Rafael, Cantu Brito, Carlos Gerardo, Chuquiure Valenzuela, Eduardo Julian Jose Roberto, Reyes Sanchez, Roxana, Bazzoni Ruiz, Alberto Esteban, Lopez Ruiz, Oscar Martin, Arriaga Nava, Roberto, Morales Cerda, Jesus David, Fajardo Campos, Pedro, Benavides Gonzalez, Mario, Lenz, Kurt, Hagn, Claus, Foechterle, Johannes, Drexel, Heinz, Huber, Kurt, Podczeck-Schweighofer, Andrea, Winkler, Michael, Schneeweiss, Bruno, Gegenhuber, Alfons, Lang, Wilfried, Eichinger-Hasenauer, Sabine, Kaserer, Peter, Sykora, Josef, Rasch, Heribert, Strohmer, Bernhard, Capiau, Luc, Vervoort, Geert, Wollaert, Bart, Hollanders, Geert, Vercammen, Jan, Balthazar, Yohan, Delforge, Marc, Xhaet, Olivier, Striekwold, Harry, Thoeng, John, Hermans, Kurt, Mairesse, Georges, Anne, Wim, Blankoff, Ivan, Beutels, Michel, Vandergoten, Peter, Purnode, Philippe, Godart, Pascal, Boussy, Tim, Desfontaines, Philippe, Heyse, Alex, Voet, Joeri, De Wolf, Axel, Zidkova, Eva, Spacek, Rudolf, Machova, Vilma, Ludka, Ondrej, Olsr, Josef, Kotik, Lubos, Racz, Blazej, Ferkl, Richard, Hubac, Jan, Kotik, Ilja, Monhart, Zdenek, Burianova, Hana, Jerabek, Ondrej, Pisova, Jana, Petrova, Iveta, Dedek, Vratislav, Honkova, Michaela, Podrazil, Petr, Reichert, Petr, Spinar, Jindrich, Novak, Miroslav, Durdil, Vaclav, Plocova, Katarina, Lastuvka, Jiri, Nielsen, Jorn, Hayashi, Yoshihito, Hirota, Shinichi, Abe, Yukihiko, Saito, Yoshihiro, Uchiyama, Hirohide, Takeda, Hiroshi, Ono, Hiroshi, Tohyo, Shuichi, Hanazono, Naoto, Miyajima, Seiichi, Shimono, Hisashi, Aoyama, Takuma, Shozawa, Yasunobu, Niijima, Yawara, Murai, Osamu, Inaba, Hideko, Nomura, Katsumasa, Nozoe, Masatsugu, Suzuki, Kazuo, Furukawa, Toshiyuki, Shiraiwa, Toshihiko, Ito, Nobuhisa, Nagai, Shunichi, Sato, Kiyoharu, Nakahara, Shiro, Shimoyama, Yujin, Ohara, Naoko, Kozuka, Teruhiko, Okita, Hideaki, Endo, Masato, Goto, Tsutomu, Hirose, Makoto, Nagata, Emiko, Nakanishi, Noriyuki, Mori, Toshizumi, Seki, Shuichi, Okamoto, Katsuhiro, Moriai, Osamu, Emura, Yoko, Fukuda, Tsuyoshi, Date, Haruhiko, Kawakami, Shuichi, Nagai, Sho, Ueyama, Yuya, Fudo, Tetsuro, Imaizumi, Mitsuru, Ogawa, Takuo, Take, Shunsuke, Ikeda, Hideo, Nishioka, Hiroaki, Sakamoto, Norihiko, Ikeoka, Kiyomitsu, Wakaki, Nobuo, Abe, Masatake, Doiuchi, Junji, Inagaki, Koichi, Iseki, Atsushi, Yoshida, Tomohiro, Goda, Toshihiro, Katsuki, Tsukasa, Sato, Atsushi, Mori, Etsuo, Tsubokura, Toshio, Shudo, Hiroshi, Fujimoto, Shunichi, Katsuya, Tomohiro, Furukawa, Yoshiyuki, Hosokawa, Hiroshi, Narumi, Jun, Yamamoto, Kiichiro, Owari, Masaki, Inakura, Takuya, Anno, Takafumi, Shirakawa, Kazuyuki, Ching, Chi Keong, Foo, David, Wong, Kelvin, Yuyang, Tan, Park, Hui Nam, Kim, Woo-Shik, Lee, HyeYoung, Jang, Sung-Won, Kim, Dae Hyeok, Kim, Jun, Ryu, DongRyeol, Shim, Jaemin, Kim, Dae-Kyeong, Choi, Dong Ju, Oh, Yong Seog, Cho, Myeong-Chan, Kim, Hack-Lyoung, Jeon, Hui-Kyung, Shin, Dong-Gu, Park, Sang Weon, Park, Hoon Ki, Han, Sang-Jin, Sung, Jung Hoon, Park, Hyung-Wook, Nam, Gi-Byoung, On, Young Keun, Lim, Hong Euy, Kwak, JaeJin, Cha, Tae-Joon, Hong, Taek Jong, Park, Seong Hoon, Yoon, Jung Han, Kim, Nam-Ho, Kim, Kee-Sik, Jung, Byung Chun, Hwang, Gyo-Seung, Kim, Chong-Jin, Rungaramsin, Sakda, Katekangplu, Peerapat, Khunrong, Porames, Bunyapipat, Thanita, Wongcharoen, Wanwarang, Kaewsuwanna, Pinij, Siriwattana, Khanchai, Tiyanon, Waraporn, Pattanaprichakul, Supalerk, Likittanasombat, Khanchit, Cholsaringkarl, Doungrat, Boonyapisit, Warangkana, Cheewatanakornkul, Sirichai, Silaruks, Songkwan, Hutayanon, Pisit, Chawanadelert, Seksan, Chattranukulchai, Pairoj, Chatlaong, Boonsert, Santanakorn, Yingsak, Kanokphatcharakun, Khompiya, Mongkolwongroj, Piya, Jai-Aue, Sasivimon, Komson, Ongkarn, Altun, Armagan, Aydinlar, Ali, Ongen, Zeki, Acikel, Sadik, Sahin, Durmus Yildiray, Yilmaz, Ozcan, Pekdemir, Hasan, Demir, Mesut, Sucu, Murat, Sahiner, Levent, Ersanli, Murat, Okuyan, Ertugrul, Aras, Dursun, Rolandi, Florencia, Cesar Ingaramo, Adrian, Alberto Sambadaro, Gustavo, Fernandez Caputi, Vanina, Luciardi, Hector, Graciela Berman, Sofia, Dragotto, Pablo, Poli, Daniela, Quintavalla, Roberto, Cosmi, Franco, Fanelli, Raffaele, Oriana, Vincenzo, Reggio, Raffaele, Anti, Roberto S., Pancaldi, Leonardo, De Cristofaro, Raimondo, Guazzaloca, Giuliana, De Blasio, Angelo, Uriate, Jorge Salerno, Lillo, Flavia, Pogliani, Enrico Maria, Javier Kleiban, Andres, Ahuad Guerrero, Rodolfo Andres, Adalberto Di Paola, Leonel, Dario Dran, Ricardo, Egido, Javier, Jose Fosco, Matias, Rodolfo Cartasegna, Luis, Gomez Vilamajo, Oscar, Luis Ramos, Jose, Sassone, Sonia, Zapata, Gerardo, Conde, Diego, Giacomi, Guillermo, Alfredo Fernandez, Alberto, Alberto Berli, Mario, Ferroni, Fabian, Sobral Filho, Dario Celestino, Jaber, Jefferson, Armaganijan, Luciana Vidal, Frack Costantini, Costantino Roberto, Steffens, Andre, Sebba Barroso de Souzaem, Weimar Kunz, de Souza Neto, Joao David, Ribeiro, Jose Marcio, Teixeira, Marcelo Silveira, Rossi, Paulo, Pires, Leonardo, Moreira, Daniel, Moura Jorge, Jose Carlos, Lorga Filho, Adalberto Menezes, Bodanese, Luiz, Montera, Marcelo Westerlund, Del Carlo, Carlos Henrique, Saad, Jamil Abdalla, Alves Costa, Fernando Augusto, Lopes, Renato, de Aranjo, Gilson Roberto, Manenti, Euler Roberto, Kerr Saraiva, Jose Francisco, Ferreira Braga, Joao Carlos, Negri, Alexandre, Moncada, Carlos, Precoma, Dalton, Roquette, Fernando, Reis, Gilmar, Ramos Filho, Roberto Alvaro, Figueiredo, Estevao Lanna, Botelho, Roberto Vieira, Fontoura Tavares, Claudio Munhoz, Finimundi, Helius Carlos, Kochi, Adriano, Broilo Franca, Cesar Cassio, Alban, Fabio, Aranha Rosito, Guido Bernardo, de Moura Xavier Moraes Junior, Joao Batista, Husted, Steen, Hintze, Ulrik, Rasmussen, Soren, Sygehus, Nwstved, Bremmelgaard, Arne, Markenvard, John, Borger, Jan, Solgaard, Jorgen, Eriksen, Ebbe, Lokkegaard, Thomas, Bruun, Michael, Mertz, Jacob, Schou, Morten, Olsen, Michael, Viitanen, Carmela, Paganelli, Franck, Ohayon, Joel, Casassus, Frederic, Galinier, Michel, Gottwalles, Yannick, Loiselet, Philippe, Koujan, Mohamed Bassel, Destrac, Sylvain, Piot, Olivier, Cebron, Jean-Pierre, Guenoun, Maxime, Guedj-Meynier, Dominique, Lokesh, A. G., Zuber, Mathieu, Amarenco, Pierre, Ellie, Emmanuel, Kadouch, James, Huberman, Jean-Pierre, Lemaire, Nestor, Rodier, Gilles, Vandamme, Xavier, Sibon, Igor, Neau, Jean-Philippe, Mahagne, Marie Helene, Mielot, Antoine, Bonnefoy, Marc, Churet, Jean-Baptiste, Navarre, Vincent, Sellem, Frederic, Monniot, Gilles, Boyes, Jean-Paul, Doucet, Bernard, Martelet, Michel, Obadia, Desire, Crousillat, Bernard, Mouallem, Joseph, Bearez, Etienne, Brugnaux, Jean Philippe, Fedorowsky, Alain, Nazeyrollas, Pierre, Berneau, Jean-Baptiste, Chemin, Frederic, Schellong, Sebastien, Koeniger, Georg, Kopf, Andreas, Gerbaulet, Uwe, Kellner, Bernd-Thomas, Schaefer, Thomas, Purr, Jan, Eissfeller, Enno, Zauzig, Heinz-Dieter, Riegel, Peter, Axthelm, Christoph, Heinz, Gerd-Ulrich, Pustelnik, Andreas, Zutz, Stefan, Eder, Wolfgang, Rehling, Guenter, Glatzel, Dirk, Ludwig, Norbert, Sandow, Petra, Wiswedel, Henning, Wildenauer, Cosmas, Schoen, Steffen, Schwarz, Toralf, Babyesiza, Adyeri, Kropp, Maximilian, Zimny, Hans-Hermann, Kahl, Friedhelm, Caspar, Andreas, Omankowsky, Sabine, Laessig, Torsten, Hartmann, Hermann-Josef, Lehmann, Gunter, Bindig, Hans-Walter, Hergdt, Gunter, Reimer, Dietrich, Hauk, Joachim, Michel, Holger, Dres, Praxis, Erdle, Werner, Dorsch, Wilfried, Dshabrailov, Janna, Rapp, Karl-Albrecht, Epelde Gonzalo, Francisco, Almeida Fernandez, Carlos Alexandre, Martinez Navarro, Encarnacion, Montero Alia, Juan Jose, Barreda Gonzalez, Maria, Moleiro Oliva, Maria Angels, Iglesias Sanmartin, Jose, Rodriguez Alvarez, Maria del Mar, Ripoll Vera, Tomas, Jimenez Navarro, Manuel, Vazquez Caamano, Maria, Arcocha Tones, Maria Fe, Marcos Gomez, Gonzalo, Iniguez Romo, Andres, Prieto Diaz, Miguel Angel, Wirdby, Alexander, Linden, Jan, and Henriksson, Kerstin

Subjects
Male, medicine.medical_specialty, Acute coronary syndrome, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Hemorrhage, 030204 cardiovascular system & hematology, antiplatelet therapy, Coronary artery disease, Anticoagulation, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cause of Death, Internal medicine, Atrial Fibrillation, medicine, Humans, 030212 general & internal medicine, Acute Coronary Syndrome, bleeding, mortality, stroke, Stroke, Aged, Proportional Hazards Models, business.industry, Hazard ratio, Anticoagulants, Atrial fibrillation, General Medicine, Prognosis, medicine.disease, Blood pressure, Cardiovascular Diseases, Heart failure, Cardiology, Female, Liver function, business, Platelet Aggregation Inhibitors, Follow-Up Studies
Abstract

Item does not contain fulltext BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes. METHODS: Adults with newly diagnosed atrial fibrillation and >/=1 investigator-defined stroke risk factor were enrolled in GARFIELD-AF between March 2010 and September 2015. The association between prior acute coronary syndromes and long-term outcomes was determined using a Cox proportional hazards model, adjusting for baseline risk factors, oral anticoagulation (OAC) +/- antiplatelet (AP) therapy, and usual care. RESULTS: Of 39,679 patients, 10.5% had a history of acute coronary syndromes. At 2-year follow-up, patients with prior acute coronary syndromes had higher adjusted risks of stroke/systemic embolism (hazard ratio [HR] 1.39; 95% confidence interval [CI], 1.08-1.78), major bleeding (HR 1.30; 95% CI, 0.95 -1.79), all-cause mortality (HR 1.34; 95% CI, 1.21 -1.49), cardiovascular mortality (HR 1.85; 95% CI, 1.51-2.26), and new acute coronary syndromes (HR 3.42; 95% CI, 2.62-4.45). Comparing antithrombotic therapy in the acute coronary syndromes vs no acute coronary syndromes groups, most patients received OAC +/- AP: 60.8% vs 66.1%, but AP therapy was more likely in the acute coronary syndromes group (68.1% vs 32.9%), either alone (34.9% vs 20.8%) or with OAC (33.2% vs 12.1%). Overall, 17.8% in the acute coronary syndromes group received dual AP therapy with (5.3%) or without OAC (12.5%). Among patients with moderate/high risk for stroke/systemic embolism, fewer in the acute coronary syndromes group received OAC with or without AP therapy (Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke, TIA, or thromboembolism, Vascular disease, Age 65-74 years, Sex category [CHA2DS2-VASc] 2: 52.1% vs 64.6%; CHA2DS2-VASc >/=3: 62.0% vs 70.7%), and the majority with a Hypertension (uncontrolled systolic blood pressure >160 mm Hg), Abnormal renal or liver function, previous Stroke, Bleeding history or predisposition, Labile international normalized ratios, Elderly, and concomitant Drugs or alcohol excess (HAS-BLED) score >/=3 were on AP therapy (83.8% vs 65.5%). CONCLUSIONS: In GARFIELD-AF, previous acute coronary syndromes are associated with worse 2-year outcomes and a greater likelihood of under-treatment with OAC, while two-thirds of patients receive AP therapy. Major bleeding was more common with previous acute coronary syndromes, even after adjusting for all risk factors.

Published
2019

62. Risk stratification of elderly patients with acute pulmonary embolism

Author

Klingenberg, Roland, primary, Schlager, Oliver, additional, Limacher, Andreas, additional, Méan, Marie, additional, Vuilleumier, Nicolas, additional, Beer, Juerg H., additional, Staub, Daniel, additional, Frauchiger, Beat, additional, Aschwanden, Markus, additional, Lämmle, Bernhard, additional, Righini, Marc, additional, Egloff, Michael, additional, Osterwalder, Joseph, additional, Angelillo‐Scherrer, Anne, additional, Kucher, Nils, additional, Banyai, Martin, additional, Rodondi, Nicolas, additional, Eckardstein, Arnold, additional, Aujesky, Drahomir, additional, Husmann, Marc, additional, and Matter, Christian M., additional

Published
2019
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63. Relationships of Overt and Silent Brain Lesions With Cognitive Function in Patients With Atrial Fibrillation

Author

Conen, David, primary, Rodondi, Nicolas, additional, Müller, Andreas, additional, Beer, Juerg H., additional, Ammann, Peter, additional, Moschovitis, Giorgio, additional, Auricchio, Angelo, additional, Hayoz, Daniel, additional, Kobza, Richard, additional, Shah, Dipen, additional, Novak, Jan, additional, Schläpfer, Jürg, additional, Di Valentino, Marcello, additional, Aeschbacher, Stefanie, additional, Blum, Steffen, additional, Meyre, Pascal, additional, Sticherling, Christian, additional, Bonati, Leo H., additional, Ehret, Georg, additional, Moutzouri, Elisavet, additional, Fischer, Urs, additional, Monsch, Andreas U., additional, Stippich, Christoph, additional, Wuerfel, Jens, additional, Sinnecker, Tim, additional, Coslovsky, Michael, additional, Schwenkglenks, Matthias, additional, Kühne, Michael, additional, Osswald, Stefan, additional, Berger, Sebastian, additional, Bernasconi, Raffaele, additional, Fröhlich, Lorin, additional, Göldi, Tobias, additional, Gugganig, Rebecca, additional, Kofler, Thomas, additional, Krisai, Philipp, additional, Mongiat, Michel, additional, Pudenz, Christiane, additional, Repilado, Javier Ruperti, additional, Schweizer, Aleksandra, additional, Springer, Anne, additional, Stempfel, Samuel, additional, Szucs, Thomas, additional, van der Stouwe, Jan, additional, Voellmin, Gian, additional, Zwimpfer, Leon, additional, Aujesky, Drahomir, additional, Fuhrer, Juerg, additional, Roten, Laurent, additional, Jung, Simon, additional, Mattle, Heinrich, additional, Adam, Luise, additional, Aubert, Carole Elodie, additional, Feller, Martin, additional, Schneider, Claudio, additional, Loewe, Axel, additional, Flückiger, Tanja, additional, Groen, Cindy, additional, Schwab, Nathalie, additional, Beynon, Christopher, additional, Dillier, Roger, additional, Eberli, Franz, additional, Fontana, Simone, additional, Franzini, Christine, additional, Juchli, Isabel, additional, Liedtke, Claudia, additional, Nadler, Jacqueline, additional, Obst, Thayze, additional, Schneider, Xiaoye, additional, Studerus, Katrin, additional, Weishaupt, Dominik, additional, Kuest, Silke, additional, Scheuch, Karin, additional, Hischier, Denise, additional, Bonetti, Nicole, additional, Bello, Corina, additional, Isberg, Henriette, additional, Grau, Alexandra, additional, Villinger, Jonas, additional, Papaux, Mary-Monica, additional, Baumgartner, Philipp, additional, Filipovic, Mark, additional, Frick, Marcel, additional, Anesini, Adriana, additional, Camporini, Cristina, additional, Conte, Giulio, additional, Caputo, Maria Luce, additional, Regoli, Francois, additional, Moccetti, Tiziano, additional, Brenner, Roman, additional, Altmann, David, additional, Forrer, Manuela, additional, Gemperle, Michaela, additional, Firmann, Mathieu, additional, Foucras, Sandrine, additional, Berte, Benjamin, additional, Kaeppeli, Andrea, additional, Mehmann, Brigitta, additional, Pfeiffer, Markus, additional, Russi, Ian, additional, Schmidt, Kai, additional, Weberndoerfer, Vanessa, additional, Young, Mabelle, additional, Zbinden, Melanie, additional, Vicari, Luisa, additional, Frangi, Jane, additional, Terrot, Tatiana, additional, Gallet, Hervé, additional, Guillermet, Elise, additional, Lazeyras, Francois, additional, Lovblad, Karl-Olof, additional, Perret, Patrick, additional, Teres, Cheryl, additional, Lauriers, Nathalie, additional, Méan, Marie, additional, Salzmann, Sandrine, additional, Arenja, Nisha, additional, Grêt, Andrea, additional, Vitelli, Sandra, additional, Gallino, Augusto, additional, Schoenenberger-Berzins, Renate, additional, Witassek, Fabienne, additional, Radue, Ernst-Wilhelm, additional, Benkert, Pascal, additional, Fabbro, Thomas, additional, Simon, Patrick, additional, and Schmid, Ramun, additional

Published
2019
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68. Whole blood omega-3 fatty acid concentrations are inversely associated with blood pressure in young, healthy adults

Author

Filipovic, Mark G., primary, Aeschbacher, Stefanie, additional, Reiner, Martin F., additional, Stivala, Simona, additional, Gobbato, Sara, additional, Bonetti, Nicole, additional, Risch, Martin, additional, Risch, Lorenz, additional, Camici, Giovanni G., additional, Luescher, Thomas F., additional, von Schacky, Clemens, additional, Conen, David, additional, and Beer, Juerg H., additional

Published
2018
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70. Design of the Swiss Atrial Fibrillation Cohort Study (Swiss-AF): structural brain damage and cognitive decline among patients with atrial fibrillation

Author

Conen, David, Rodondi, Nicolas, Mueller, Andreas, Beer, Juerg H, Auricchio, Angelo, Ammann, Peter, Hayoz, Daniel, Kobza, Richard, Moschovitis, Giorgio, Shah, Dipen, Schlaepfer, Juerg, Novak, Jan, di Valentino, Marcello, Erne, Paul, Sticherling, Christian, Bonati, Leo H; https://orcid.org/0000-0003-1163-8133, Ehret, Georg, Roten, Laurent, Fischer, Urs, Monsch, Andreas, Stippich, Christoph, Wuerfel, Jens, Schwenkglenks, Matthias, Kuehne, Michael, Osswald, Stefan, Conen, David, Rodondi, Nicolas, Mueller, Andreas, Beer, Juerg H, Auricchio, Angelo, Ammann, Peter, Hayoz, Daniel, Kobza, Richard, Moschovitis, Giorgio, Shah, Dipen, Schlaepfer, Juerg, Novak, Jan, di Valentino, Marcello, Erne, Paul, Sticherling, Christian, Bonati, Leo H; https://orcid.org/0000-0003-1163-8133, Ehret, Georg, Roten, Laurent, Fischer, Urs, Monsch, Andreas, Stippich, Christoph, Wuerfel, Jens, Schwenkglenks, Matthias, Kuehne, Michael, and Osswald, Stefan

Abstract

BACKGROUND: Several studies found that patients with atrial fibrillation (AF) have an increased risk of cognitive decline and dementia over time. However, the magnitude of the problem, associated risk factors and underlying mechanisms remain unclear. METHODS: This article describes the design and methodology of the Swiss Atrial Fibrillation (Swiss-AF) Cohort Study, a prospective multicentre national cohort study of 2400 patients across 13 sites in Switzerland. Eligible patients must have documented AF. Main exclusion criteria are the inability to provide informed consent and the presence of exclusively short episodes of reversible forms of AF. All patients undergo extensive phenotyping and genotyping, including repeated assessment of cognitive functions, quality of life, disability, electrocardiography and cerebral magnetic resonance imaging. We also collect information on health related costs, and we assemble a large biobank. Key clinical outcomes in Swiss-AF are death, stroke, systemic embolism, bleeding, hospitalisation for heart failure and myocardial infarction. Information on outcomes and updates on other characteristics are being collected during yearly follow-up visits. RESULTS: Up to 7 April 2017, we have enrolled 2133 patients into Swiss-AF. With the current recruitment rate of 15 to 20 patients per week, we expect that the target sample size of 2400 patients will be reached by summer 2017. CONCLUSION: Swiss-AF is a large national prospective cohort of patients with AF in Switzerland. This study will provide important new information on structural and functional brain damage in patients with AF and on other AF related complications, using a large variety of genetic, phenotypic and health economic parameters.

Published
2017

71. In response to the comment by Hechler et al .: Amotosalen/UVA pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance.

Author

Stivala, Simona, primary, Gobbato, Sara, additional, Infanti, Laura, additional, Reiner, Martin F., additional, Bonetti, Nicole, additional, Meyer, Sara C., additional, Camici, Giovanni G., additional, Lüscher, Thomas F., additional, Buser, Andreas, additional, and Beer, Juerg H., additional

Published
2017
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73. Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

Author

Reiner, Martin F., primary, Akhmedov, Alexander, additional, Stivala, Simona, additional, Keller, Stephan, additional, Gaul, Daniel S., additional, Bonetti, Nicole R., additional, Savarese, Gianluigi, additional, Glanzmann, Martina, additional, Zhu, Cuicui, additional, Ruf, Wolfram, additional, Yang, Zhihong, additional, Matter, Christian M., additional, Lüscher, Thomas F., additional, Camici, Giovanni G., additional, and Beer, Juerg H., additional

Published
2016
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74. Corrigendum to ‘Sirtuin 5 as a novel target to blunt blood–brain barrier damage induced by cerebral ischemia/reperfusion injury’ [Int. J. Cardiol. 260 (2018) 148–155]

Author

Diaz-Cañestro, Candela, Merlini, Mario, Bonetti, Nicole R., Liberale, Luca, Wüst, Patricia, Briand-Schumacher, Sylvie, Klohs, Jan, Costantino, Sara, Miranda, Melroy, Schoedon-Geiser, Gabriele, Kullak-Ublick, Gerd A., Akhmedov, Alexander, Paneni, Francesco, Beer, Jürg H., Lüscher, Thomas F., and Camici, Giovanni G.

Published
2018
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87. Dietary α-linolenic acid increases the platelet count in ApoE−/−mice by reducing clearance

Author

Stivala, Simona, Reiner, Martin F., Lohmann, Christine, Lüscher, Thomas F., Matter, Christian M., and Beer, Juerg H.

Abstract

Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces atherogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE−/−) mice were fed a 0.21g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein Ib (GPIb) shedding, exposure of P-selectin, and activated integrin αIIbβ3upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-α–converting enzyme and reduced platelet activation/expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders.

Published
2013
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88. Collagen-Platelet Interactions: Evidence for a Direct Interaction of Collagen With Platelet GPIa/IIa and an Indirect Interaction With Platelet GPIIb/IIIa Mediated by Adhesive Proteins

Author

Coller, Barry S., Beer, Juerg H., Scudder, Lesley E., and Steinberg, Mark H.

Abstract

Using intact human platelets as the immunogen and a functional, collagen-coated bead agglutination assay, we have produced a murine monoclonal antibody (6F1) that blocks the interaction between platelets and collagen in the presence of Mg++. 6F1 affinity-purified the platelet glycoprotein la/Ila complex, and approximately 800 molecules of 6F1 bound per platelet at saturation. 6F1 nearly completely inhibited collagen-induced platelet aggregation and inhibited platelet adhesion to collagen by >95% when plasma proteins were absent. Antibody 10E5, which blocks the binding of adhesive glycoproteins to GPIIb/IIIa, produced only minor inhibition (~25%) of adhesion under the same circumstances. In contrast, when tested in plateletrich plasma (PRP), 6F1 had only a minor effect on collagen- induced platelet aggregation, prolonging the lag phase but not the slope or maximum aggregation. Similarly, when collagen was precoated with plasma, 6F1 caused less inhibition of platelet adhesion (53%) than without the precoating (>95%). Antibody 10E5 inhibited this adhesion by 32%, and the combination of 6F1 and 10E5 was more effective than either alone, inhibiting it by 90%. Time course studies of platelet agglutination of collagen-coated beads using PRP containing physiologic concentrations of divalent cations showed early inhibition by 6F1, indicating that the GPIa/IIa receptor operates in this environment. With more prolonged incubation, however, 6F1 was less effective; this later agglutination could be partially prevented by adding 10E5 or PGE1to the 6F1. These data support a model wherein collagen can directly interact with GPIa/IIa and can indirectly interact with GPIIb/IIIa via intermediary adhesive proteins. The physiological significance of these interactions, and potential interactions with other receptors, remains to be established.

Published
1989
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90. Elevated HbA1c is not associated with recurrent venous thromboembolism in the elderly, but with all-cause mortality- the SWEETCO 65+ study

Author

Mathis, Alexandra, Villiger, Lukas, Reiner, Martin F, Egloff, Michael, Schmid, Hans Ruedi, Stivala, Simona, Limacher, Andreas, Méan, Marie, Aujesky, Drahomir, Rodondi, Nicolas, Angelillo, Anne, Righini, Marc, Staub, Daniel, Aschwanden, Markus, Frauchiger, Beat, Osterwalder, Joseph, Kucher, Nils, Matter, Christian M, Banyai, Martin, Hugli, Oliver, and Beer, Juerg H

Subjects
endocrine system diseases, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

The association of glycated hemoglobin (HbA1c) with venous thromboembolism (VTE) and death in the elderly is unknown. In the SWEETCO 65+ study we analyzed prospectively a Swiss Cohort of Elderly Patients with Venous Thromboembolism (SWITCO 65+). 888 patients were enrolled for the SWEETCO 65+ analysis. HbA1c was determined at baseline and divided into three categories (HbA1c 6.5%, diabetic range). Median follow-up was 2.5 years. The primary endpoint was recurrent VTE. Secondary endpoints included all-cause mortality and major bleeds. The total prevalence of diabetes was 22.1%. The risk of recurrent VTE was similar in patients with HbA1c with pre-diabetes (adjusted subhazard ratio (aSHR) 1.07 [0.70 to 1.63]) and diabetes (aSHR 0.73 [0.39 to 1.37]) as compared to those with a HbA1c in the normal range. However, a HbA1c ≥ 6.5% (median IQ range 7.0 [6.70;7.60]) was significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.83 [1.21 to 2.75]). In summary we found no association between HbA1c and major bleeding. Elevated HbA1c levels are not associated with recurrent VTE but with increased all-cause mortality in an elderly population with acute VTE.

91. Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

Author

Reiner, Martin F., Akhmedov, Alexander, Stivala, Simona, Keller, Stephan, Gaul, Daniel S., Bonetti, Nicole R., Savarese, Gianluigi, Glanzmann, Martina, Zhu, Cuicui, Ruf, Wolfram, Yang, Zhihong, Matter, Christian M., Lüscher, Thomas F., Camici, Giovanni G., Beer, Juerg H., Reiner, Martin F., Akhmedov, Alexander, Stivala, Simona, Keller, Stephan, Gaul, Daniel S., Bonetti, Nicole R., Savarese, Gianluigi, Glanzmann, Martina, Zhu, Cuicui, Ruf, Wolfram, Yang, Zhihong, Matter, Christian M., Lüscher, Thomas F., Camici, Giovanni G., and Beer, Juerg H.

Abstract

The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-α-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries.Conclusion: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor.

92. Elevated HbA1c is not associated with recurrent venous thromboembolism in the elderly, but with all-cause mortality– the SWEETCO 65+ study

Author

Nils Kucher, Daniel Staub, Lukas Villiger, Andreas Limacher, Alexandra Mathis, Hans Ruedi Schmid, Martin F Reiner, Anna Angelillo-Scherrer, Markus Aschwanden, Marc Philip Righini, Juerg H. Beer, Nicolas Rodondi, Martin Banyai, Beat Frauchiger, Christian M. Matter, Simona Stivala, Oliver Hugli, Joseph Osterwalder, Marie Méan, Michael Egloff, Drahomir Aujesky, University of Zurich, and Beer, Juerg H

Subjects
Male, lcsh:Medicine, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Clinical endpoint, 80 and over, Medicine, 030212 general & internal medicine, lcsh:Science, ddc:616, Aged, 80 and over, Multidisciplinary, Aged, Biomarkers/blood, Female, Glycated Hemoglobin A/metabolism, Humans, Mortality/trends, Venous Thromboembolism/blood, Venous Thromboembolism/epidemiology, Hazard ratio, Venous Thromboembolism, 3. Good health, Cohort, 10209 Clinic for Cardiology, Venous Thromboembolism/blood/epidemiology, medicine.medical_specialty, 610 Medicine & health, Article, 03 medical and health sciences, Medical research, 360 Social problems & social services, Internal medicine, Diabetes mellitus, Mortality, Glycated Hemoglobin, 1000 Multidisciplinary, business.industry, 10031 Clinic for Angiology, lcsh:R, medicine.disease, chemistry, Elevated HbA1c, lcsh:Q, Glycated hemoglobin, business, Venous thromboembolism, All cause mortality, Biomarkers
Abstract

The association of glycated hemoglobin (HbA1c) with venous thromboembolism (VTE) and death in the elderly is unknown. In the SWEETCO 65+ study we analyzed prospectively a Swiss Cohort of Elderly Patients with Venous Thromboembolism (SWITCO 65+). 888 patients were enrolled for the SWEETCO 65+ analysis. HbA1c was determined at baseline and divided into three categories (HbA1c 6.5%, diabetic range). Median follow-up was 2.5 years. The primary endpoint was recurrent VTE. Secondary endpoints included all-cause mortality and major bleeds. The total prevalence of diabetes was 22.1%. The risk of recurrent VTE was similar in patients with HbA1c with pre-diabetes (adjusted subhazard ratio (aSHR) 1.07 [0.70 to 1.63]) and diabetes (aSHR 0.73 [0.39 to 1.37]) as compared to those with a HbA1c in the normal range. However, a HbA1c ≥ 6.5% (median IQ range 7.0 [6.70;7.60]) was significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.83 [1.21 to 2.75]). In summary we found no association between HbA1c and major bleeding. Elevated HbA1c levels are not associated with recurrent VTE but with increased all-cause mortality in an elderly population with acute VTE.

Published
2020

93. Dietary α-linolenic acid increases the platelet count in ApoE-/- mice by reducing clearance.

Author

Stivala, Simona, Reiner, Martin F., Lohmann, Christine, Luscher, Thomas F., Matter, Christian M., and Beer, Juerg H.

Subjects
*LINOLENIC acids, *PLATELET count, *LABORATORY mice, *APOLIPOPROTEIN E, *INTEGRINS
Abstract

Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces ath-erogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE)-/- mice were fed a 0.21 g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein lb (GPIb) shedding, exposure of P-selectin, and activated integrin αllbβ3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-a-converting enzyme and reduced platelet activation/ expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders. [ABSTRACT FROM AUTHOR]

Published
2013
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94. Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

Author

Juerg H. Beer, Gianluigi Savarese, Zhihong Yang, Cuicui Zhu, Daniel S. Gaul, Stephan Keller, Christian M. Matter, Wolfram Ruf, Alexander Akhmedov, Nicole R. Bonetti, Martina Glanzmann, Thomas F. Lüscher, Simona Stivala, Giovanni G. Camici, Martin F Reiner, University of Zurich, and Beer, Juerg H

Subjects
0301 basic medicine, Male, Ticagrelor, Adenosine, Time Factors, Physiology, 030204 cardiovascular system & hematology, 2737 Physiology (medical), 0302 clinical medicine, P2Y12, Antithrombotic, Cells, Cultured, Clopidogrel, Receptors, Purinergic P2Y12, 3. Good health, medicine.anatomical_structure, Coagulation, 10209 Clinic for Cardiology, Cardiology, Cardiology and Cardiovascular Medicine, medicine.drug, Blood Platelets, Acute coronary syndrome, medicine.medical_specialty, Proteasome Endopeptidase Complex, Ticlopidine, Endothelium, Down-Regulation, 610 Medicine & health, 2705 Cardiology and Cardiovascular Medicine, Thromboplastin, Equilibrative Nucleoside Transporter 1, 03 medical and health sciences, Tissue factor, Fibrinolytic Agents, Physiology (medical), Internal medicine, medicine, Animals, Humans, cardiovascular diseases, Blood Coagulation, business.industry, Tumor Necrosis Factor-alpha, Endothelial Cells, Thrombosis, 1314 Physiology, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Proteolysis, Purinergic P2Y Receptor Antagonists, business, Carotid Artery Injuries, Platelet Aggregation Inhibitors
Abstract

The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-α-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries.Conclusion: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor.

Published
2017

95. A factor score reflecting cognitive functioning in patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF).

Author

Springer A, Monsch AU, Dutilh G, Coslovsky M, Kievit RA, Bonati LH, Conen D, Aeschbacher S, Beer JH, Schwenkglenks M, Fischer U, Meyer-Zuern CS, Conte G, Moutzouri E, Moschovitis G, Kühne M, and Osswald S

Subjects
Aged, Aged, 80 and over, Atrial Fibrillation epidemiology, Cognition, Cognitive Dysfunction epidemiology, Female, Humans, Male, Psychometrics methods, Psychometrics standards, Atrial Fibrillation complications, Cognitive Dysfunction diagnosis, Neuropsychological Tests standards
Abstract

Background: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is considered as risk factor for the development of mild cognitive impairment (MCI) and dementia. However, dynamics of cognitive functions are subtle, and neurocognitive assessments largely differ in detecting these changes. We aimed to develop and evaluate a score which represents the common aspects of the cognitive functions measured by validated tests (i.e., "general cognitive construct"), while reducing overlap between tests and be more sensitive to identify changes in overall cognitive functioning., Methods: We developed the CoCo (cognitive construct) score to reflect the cognitive performance obtained by all items of four neurocognitive assessments (Montreal Cognitive Assessment (MoCA); Trail Making Test; Semantic Fluency, animals; Digital Symbol Substitution Test). The sample comprised 2,415 AF patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF), 87% aged at least 65 years. Psychometric statistics were calculated for two cognitive measures based on (i) the full set of items from the neurocognitive test battery administered in the Swiss-AF study (i.e., CoCo item set) and (ii) the items from the widely used MoCA test. For the CoCo item set, a factor score was derived based on a principal component analysis, and its measurement properties were analyzed., Results: Both the MoCA item set and the full neurocognitive test battery revealed good psychometric properties, especially the full battery. A one-factor model with good model fit and performance across time and groups was identified and used to generate the CoCo score, reflecting for each patient the common cognitive skill performance measured across the full neurocognitive test battery. The CoCo score showed larger effect sizes compared to the MoCA score in relation to relevant clinical variables., Conclusion: The derived factor score allows summarizing AF patients' cognitive performance as a single score. Using this score in the Swiss-AF project increases measurement sensitivity and decreases the number of statistical tests needed, which will be helpful in future studies addressing how AF affects the risk of developing cognitive impairment., Competing Interests: DC has received consultant/speaker fees from Servier Canada outside of the submitted work; GC reports a research grant from the Swiss National Science Foundation, and research grants from Boston Scientific Inc., outside of this work; JHB reports grants from the Swiss National Foundation of Science, The Swiss Heart Foundation, grants from Bayer, lecture fees from Sanofi Aventis and Amgen, to the institution outside of this work; LHB received grants from the Swiss National Science Foundation, The Swiss Heart Foundation, an unrestricted research grant from AstraZeneca, and consultancy or advisory board fees or speaker’s honoraria from Amgen, Bayer, Bristol-Myers Squibb, and Claret Medical, and travel grants from AstraZeneca and Bayer, all outside of this work; MK reports personal fees from Bayer, personal fees from Böhringer Ingelheim, personal fees from Pfizer BMS, personal fees from Daiichi Sankyo, personal fees from Medtronic, personal fees from Biotronik, personal fees from Boston Scientific, personal fees from Johnson & Johnson, grants from Bayer, grants from Pfizer BMS, grants from Boston Scientific, all outside of this work. CSZ reports a research grant from Medtronic and speaker fees from Vifor Pharma and Novartis, outside of this work. RS of the study group Swiss-AF Study Investigators is employed by Schiller AG Baar. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Published
2020
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97. Platelet receptor gain-of-function single nucleotide polymorphisms in carotid and vertebral stenosis patients.

Author

Lugli AK, Brown MM, Steffel J, Büchi L, Förnzler D, Dupont A, Gaussem P, Forestier M, and Beer JH

Subjects
Age Factors, Aged, Carotid Stenosis therapy, Female, Humans, Male, Middle Aged, Risk Factors, Sex Factors, United Kingdom, Vertebrobasilar Insufficiency therapy, Carotid Stenosis genetics, Epistasis, Genetic, Platelet Membrane Glycoproteins genetics, Polymorphism, Single Nucleotide, Vertebrobasilar Insufficiency genetics
Abstract

The role of platelet receptor gain-of-function single nucleotide polymorphisms (SNP) in cardiovascular disease is controversial. We hypothesised that certain SNPs may accelerate the development of carotid artery stenosis. The intronic PAR-1 receptor intervening sequence-14 A/T (IVSn-14 A/T) polymorphism and three additional platelet receptor polymorphisms, i.e. GPIa (807C/T), GPIbα (5T/C) and HPA-1a/HPA-1b (Pl (A1/A2)) of GPIIIa were studied. The interaction of SNPs with conventional risk factors including male gender, hypertension, high cholesterol, diabetes, advanced age and smoking were investigated. The hypothesis was tested in 114 well-characterised patients with symptomatic carotid or vertebral stenosis from the British CAVATAS population and compared the results with 97 unrelated controls. The allele frequency of the platelet gain-of-function SNP was not significantly different in the CAVATAS population as compared to controls (PAR-1A/T (P = 0.13), GPIa C/T (P = 0.25), GPIIIa HPA-1a/HPA-1b (PlA1/A2) (P = 0.66) and GPIb T/C (P = 0.20)). In the subgroup of smokers, however, the prothrombotic GPIbα C mutated allele was found in a significantly higher frequency in the patient as compared to the control group (P = 0.04). Contrary to the primary hypothesis, the PAR-1A/T SNP as well as the other SNPs tested were not over- or underrepresented in the CAVATAS population. However, a significantly increased prevalence of GPIb-α (5C/T) was found in the subgroup of smokers and may represent an important cofactor in this patient group of our hypothesis-generating study.

Published
2011
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98. [To prevent myocardial infarction with a tooth brush?].

Author

Beer JH

Subjects
C-Reactive Protein metabolism, Fibrinogen metabolism, Humans, Male, Middle Aged, Periodontitis prevention & control, Risk Factors, Scotland, Socioeconomic Factors, Myocardial Infarction prevention & control, Periodontitis complications, Toothbrushing
Abstract

Unlabelled: The association of periodontal disease and cardiovascular events is discussed. Low grade inflammation, with elevated CRP and elevated fibrinogen might contribute. A recent study from Scotland in which the dental brushing was evaluated found a relative risk for a cardiovascular event of 1.69 associated with rare tooth brushing. However, there was a bias with elderly patients, male gender and low socioeconomic status., Conclusion: The common risk factor is smoking; active "dentogenic" inflammation should be checked before surgery, particularly before surgery with implants.

Published
2010
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