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1. Common coding variant in SERPINA1 increases the risk for large artery stroke

Author

Genetic International Stroke Consortium, Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J., Edeleva, Evgeniia V., Götzfried, Jessica, van der Laan, Sander W., Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Steve, Lincz, Lisa F., Holliday, Elizabeth G., Burgess, Annette I., Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M., Levi, Christopher, Attia, John, Sudlow, Cathie L. M., Braun, Dieter, Markus, Hugh S., Wintrode, Patrick L., Berger, Klaus, Jenne, Dieter E., and Dichgans, Martin

Published
2017

3. Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease

Author

Smid, Dionne E., Franssen, Frits M.E., Gonik, Maria, Miravitlles, Marc, Casanova, Ciro, Cosio, Borja G., de Lucas-Ramos, Pilar, Marin, Jose M., Martinez, Cristina, Mir, Isabel, Soriano, Joan B., de Torres, Juan P., Agusti, Alvar, Atalay, Nart B., Billington, Julia, Boutou, Afroditi K., Brighenti-Zogg, Stefanie, Chaplin, Emma, Coster, Samantha, Dodd, James W., Dürr, Selina, Fernandez-Villar, Alberto, Groenen, Miriam T.J., Guimarães, Miguel, Hejduk, Karel, Higgins, Victoria, Hopkinson, Nicholas S., Horita, Nobuyuki, Houben-Wilke, Sarah, Janssen, Daisy J.A., Jehn, Melissa, Joerres, Rudolf, Karch, Annika, Kelly, Julia L., Kim, Yu-Il, Kimura, Hiroshi, Koblizek, Vladimir, Kocks, Janwillem H., Kon, Samantha S.C., Kwon, Namhee, Ladeira, Inês, Lee, Sang-Do, Leuppi, Joerg D., Locantore, Nicholas, Lopez-Campos, José L., D-C Man, William, Maricic, Lana, Mendoza, Laura, Miedinger, David, Mihaltan, Florin, Minami, Seigo, van der Molen, Thys, Murrells, Trevor J., Nakken, Nienke, Nishijima, Yu, Norman, Ian J., Novotna, Barbora, O'Donnell, Denis E., Ogata, Yoshitaka, Pereira, Eanes D., Piercy, James, Price, David, Pothirat, Chaicharn, Raghavan, Natya, Ringbaek, Thomas, Sajkov, Dimitar, Sigari, Naseh, Singh, Sally, Small, Mark, da Silva, Guilherme F., Tanner, Rebecca J., Tsiligianni, Ioanna G., Tulek, Baykal, Tzanakis, Nikolaos, Vanfleteren, Lowie E.G.W., Watz, Henrik, Webb, Katherine A., Wouters, Emiel F.M., Xie, Guogang G., Yoshikawa, Masanori, and Spruit, Martijn A.

Published
2017
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8. Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease

Author

Smid, Dionne E., Gonik, Maria, Atalay, Nart Bedin, Raghavan, Natya, Pothirat, Chaicharn, Price, David, Piercy, James, Miravitlles, Marc, Casanova, Ciro, Pereira, Eanes D., Ogata, Yoshitaka, O'Donnell, Denis E., Novotna, Barbora, Norman, Ian J., Nishijima, Yu, Nakken, Nienke, Murrells, Trevor J., van der Molen, Thys, Minami, Seigo, Mihaltan, Florin, Miedinger, David, Mendoza, Laura, Maricic, Lana, Man, William D-C, Lopez-Campos, Jose L., Franssen, Frits M. E., Ringbaek, Thomas, Soriano, Joan B., Locantore, Nicholas, Leuppi, Joerg D., Sajkov, Dimitar, Lee, Sang-Do, Ladeira, Ines, Cosio, Borja G., Kwon, Namhee, Mir, Isabel, Martinez, Cristina, Kon, Samantha S. C., Kocks, Janwillem H., Koblizek, Vladimir, Kimura, Hiroshi, Kim, Yu-Il, Kelly, Julia L., Karch, Annika, Joerres, Rudolf, Jehn, Melissa, Janssen, Daisy J. A., Houben-Wilke, Sarah, Sigari, Naseh, Horita, Nobuyuki, Hopkinson, Nicholas S., Higgins, Victoria, Singh, Sally, Small, Mark, Hejduk, Karel, Guimaraes, Miguel, Groenen, Miriam T. J., Fernandez-Villar, Alberto, Durr, Selina, Dodd, James W., Coster, Samantha, Chaplin, Emma, Brighenti-Zogg, Stefanie, Boutou, Afroditi K., Billington, Julia, Agusti, Alvar, de Torres, Juan P., da Silva, Guilherme F., Tanner, Rebecca J., Tsiligianni, Ioanna G., Marin, Jose M., de Lucas-Ramos, Pilar, Tülek, Baykal, Tzanakis, Nikolaos, Vanfleteren, Lowie E. G. W., Spruit, Martijn A., Watz, Henrik, Yoshikawa, Masanori, Webb, Katherine A., Xie, Guogang G., Wouters, Emiel F. M., Smid, Dionne E., Gonik, Maria, Atalay, Nart Bedin, Raghavan, Natya, Pothirat, Chaicharn, Price, David, Piercy, James, Miravitlles, Marc, Casanova, Ciro, Pereira, Eanes D., Ogata, Yoshitaka, O'Donnell, Denis E., Novotna, Barbora, Norman, Ian J., Nishijima, Yu, Nakken, Nienke, Murrells, Trevor J., van der Molen, Thys, Minami, Seigo, Mihaltan, Florin, Miedinger, David, Mendoza, Laura, Maricic, Lana, Man, William D-C, Lopez-Campos, Jose L., Franssen, Frits M. E., Ringbaek, Thomas, Soriano, Joan B., Locantore, Nicholas, Leuppi, Joerg D., Sajkov, Dimitar, Lee, Sang-Do, Ladeira, Ines, Cosio, Borja G., Kwon, Namhee, Mir, Isabel, Martinez, Cristina, Kon, Samantha S. C., Kocks, Janwillem H., Koblizek, Vladimir, Kimura, Hiroshi, Kim, Yu-Il, Kelly, Julia L., Karch, Annika, Joerres, Rudolf, Jehn, Melissa, Janssen, Daisy J. A., Houben-Wilke, Sarah, Sigari, Naseh, Horita, Nobuyuki, Hopkinson, Nicholas S., Higgins, Victoria, Singh, Sally, Small, Mark, Hejduk, Karel, Guimaraes, Miguel, Groenen, Miriam T. J., Fernandez-Villar, Alberto, Durr, Selina, Dodd, James W., Coster, Samantha, Chaplin, Emma, Brighenti-Zogg, Stefanie, Boutou, Afroditi K., Billington, Julia, Agusti, Alvar, de Torres, Juan P., da Silva, Guilherme F., Tanner, Rebecca J., Tsiligianni, Ioanna G., Marin, Jose M., de Lucas-Ramos, Pilar, Tülek, Baykal, Tzanakis, Nikolaos, Vanfleteren, Lowie E. G. W., Spruit, Martijn A., Watz, Henrik, Yoshikawa, Masanori, Webb, Katherine A., Xie, Guogang G., and Wouters, Emiel F. M.

Abstract

Background: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. Methods: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, post-bronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. Main outcomes: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. Findings: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. Conclusions: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed. (C) 2017 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Published
2019

9. Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease

Author

Yoshikawa, Masanori, Spruit, Martijn A., Agusti, Alvar, Nishijima, Yu, Kimura, Hiroshi, Koblizek, Vladimir, Norman, Ian J., Kocks, Janwillem H., Novotna, Barbora, O'Donnell, Denis E., Groenen, Miriam T. J., Ogata, Yoshitaka, Pereira, Eanes D., Mendoza, Laura, Piercy, James, Price, David, Marin, Jose M., Pothirat, Chaicharn, Raghavan, Natya, Ringbaek, Thomas, Sajkov, Dimitar, Maricic, Lana, Sigari, Naseh, Singh, Sally, Kon, Samantha S. C., Small, Mark, da Silva, Guilherme F., Tanner, Rebecca J., Man, William D-C, Casanova, Ciro, Martinez, Cristina, Tsiligianni, Ioanna G., Miravitlles, Marc, Tülek, Baykal, Tzanakis, Nikolaos, Vanfleteren, Lowie E. G. W., Watz, Henrik, Webb, Katherine A., Wouters, Emiel F. M., Xie, Guogang G., Atalay, Nart Bedin, Lopez-Campos, Jose L., Fernandez-Villar, Alberto, de Lucas-Ramos, Pilar, de Torres, Juan P., Cosio, Borja G., Locantore, Nicholas, Jehn, Melissa, Horita, Nobuyuki, Houben-Wilke, Sarah, Kwon, Namhee, Soriano, Joan B., Franssen, Frits M. E., Ladeira, Ines, Leuppi, Joerg D., Boutou, Afroditi K., Hejduk, Karel, Dodd, James W., Coster, Samantha, Billington, Julia, Brighenti-Zogg, Stefanie, Lee, Sang-Do, Chaplin, Emma, Karch, Annika, Durr, Selina, Mihaltan, Florin, Miedinger, David, Gonik, Maria, Hopkinson, Nicholas S., Smid, Dionne E., Minami, Seigo, Janssen, Daisy J. A., Joerres, Rudolf, Guimaraes, Miguel, van der Molen, Thys, Higgins, Victoria, Murrells, Trevor J., Nakken, Nienke, Kelly, Julia L., Kim, Yu-Il, Mir, Isabel, Yoshikawa, Masanori, Spruit, Martijn A., Agusti, Alvar, Nishijima, Yu, Kimura, Hiroshi, Koblizek, Vladimir, Norman, Ian J., Kocks, Janwillem H., Novotna, Barbora, O'Donnell, Denis E., Groenen, Miriam T. J., Ogata, Yoshitaka, Pereira, Eanes D., Mendoza, Laura, Piercy, James, Price, David, Marin, Jose M., Pothirat, Chaicharn, Raghavan, Natya, Ringbaek, Thomas, Sajkov, Dimitar, Maricic, Lana, Sigari, Naseh, Singh, Sally, Kon, Samantha S. C., Small, Mark, da Silva, Guilherme F., Tanner, Rebecca J., Man, William D-C, Casanova, Ciro, Martinez, Cristina, Tsiligianni, Ioanna G., Miravitlles, Marc, Tülek, Baykal, Tzanakis, Nikolaos, Vanfleteren, Lowie E. G. W., Watz, Henrik, Webb, Katherine A., Wouters, Emiel F. M., Xie, Guogang G., Atalay, Nart Bedin, Lopez-Campos, Jose L., Fernandez-Villar, Alberto, de Lucas-Ramos, Pilar, de Torres, Juan P., Cosio, Borja G., Locantore, Nicholas, Jehn, Melissa, Horita, Nobuyuki, Houben-Wilke, Sarah, Kwon, Namhee, Soriano, Joan B., Franssen, Frits M. E., Ladeira, Ines, Leuppi, Joerg D., Boutou, Afroditi K., Hejduk, Karel, Dodd, James W., Coster, Samantha, Billington, Julia, Brighenti-Zogg, Stefanie, Lee, Sang-Do, Chaplin, Emma, Karch, Annika, Durr, Selina, Mihaltan, Florin, Miedinger, David, Gonik, Maria, Hopkinson, Nicholas S., Smid, Dionne E., Minami, Seigo, Janssen, Daisy J. A., Joerres, Rudolf, Guimaraes, Miguel, van der Molen, Thys, Higgins, Victoria, Murrells, Trevor J., Nakken, Nienke, Kelly, Julia L., Kim, Yu-Il, and Mir, Isabel

Abstract

Background: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. Methods: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, post-bronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. Main outcomes: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. Findings: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. Conclusions: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed. (C) 2017 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Published
2019

10. Common coding variant in SERPINA1 increases the risk for large artery stroke

Author

Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J, Edeleva, Evgeniia V, Götzfried, Jessica, van der Laan, Sander W, Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Steve, Lincz, Lisa F, Holliday, Elizabeth G, Burgess, Annette I, Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M, Levi, Christopher, Attia, John, Sudlow, Cathie L M, Braun, Dieter, Markus, Hugh S, Wintrode, Patrick L, Berger, Klaus, Jenne, Dieter E, Dichgans, Martin, International Stroke Genetics Consortium, Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J, Edeleva, Evgeniia V, Götzfried, Jessica, van der Laan, Sander W, Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Steve, Lincz, Lisa F, Holliday, Elizabeth G, Burgess, Annette I, Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M, Levi, Christopher, Attia, John, Sudlow, Cathie L M, Braun, Dieter, Markus, Hugh S, Wintrode, Patrick L, Berger, Klaus, Jenne, Dieter E, Dichgans, Martin, and International Stroke Genetics Consortium

Published
2017

11. Common coding variant in SERPINA1 increases the risk for large artery stroke

Author

Experimentele Afd. Cardiologie 1, Circulatory Health, CDL Cluster Onderzoek en Onderwijs, Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J, Edeleva, Evgeniia V, Götzfried, Jessica, van der Laan, Sander W, Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Steve, Lincz, Lisa F, Holliday, Elizabeth G, Burgess, Annette I, Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M, Levi, Christopher, Attia, John, Sudlow, Cathie L M, Braun, Dieter, Markus, Hugh S, Wintrode, Patrick L, Berger, Klaus, Jenne, Dieter E, Dichgans, Martin, International Stroke Genetics Consortium, Experimentele Afd. Cardiologie 1, Circulatory Health, CDL Cluster Onderzoek en Onderwijs, Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J, Edeleva, Evgeniia V, Götzfried, Jessica, van der Laan, Sander W, Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Steve, Lincz, Lisa F, Holliday, Elizabeth G, Burgess, Annette I, Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M, Levi, Christopher, Attia, John, Sudlow, Cathie L M, Braun, Dieter, Markus, Hugh S, Wintrode, Patrick L, Berger, Klaus, Jenne, Dieter E, Dichgans, Martin, and International Stroke Genetics Consortium

Published
2017

16. Insecticidal Bt Crops Under Massive Bt-resistant Pest Invasion: Mathematical Simulation.

Author

Alt, Wolfgang, Adler, Fred, Chaplain, Mark, Deutsch, Andreas, Dress, Andreas, Krakauer, David, Tranquillo, Robert T., Hosking, Roger J., Venturino, Ezio, Medvinsky, Alexander B., Gonik, Maria M., Tyutyunov, Yuri V., Li, Bai-Lian, Rusakov, Alexey V., and Malchow, Horst

Abstract

There is growing public concern that pests may develop resistance to Bt toxins produced by genetically modified Bt plants. We develop and analyse a conceptual reaction-diffusion model of the agricultural ecosystem, to simulate the Bt-resistant insect massive invasion when the insect fecundity rate is limited by the number of females rather than by the mating frequency. We show by computer simulations that reproduction of Bt-resistant pests is a factor that significantly affects the Bt plant biomass under the Bt-resistant pest invasion. We demonstrate that periodical Bt plant sowing can lead to both regular and irregular oscillations in Bt plant and Bt-resistant insect biomass. The character of the oscillations (regular or irregular) is shown to be dependent on local insect fluxes, which are characterised by the diffusion number Ξ. The oscillations are irregular if Ξ ≥ 0.02, but otherwise the oscillations of the plant and insect biomass are regular. [ABSTRACT FROM AUTHOR]

Published
2008
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21. Confinement of Dynamical Chaos Expansion in Rotifer Populations Inhabiting Heterogeneous Environments: An Effect of Attractor Size Invariance.

Author

Gonik, Maria M. and Medvinsky, lexander B.

Subjects
CHAOS theory, ROTIFERA reproduction, WORMS, ANIMAL population density, POPULATION biology, HABITATS, REPRODUCTION
Abstract

We study the impact of inter-habitat interactions in rotifer populations with intrinsically different types of dynamics: chaotic and regular. For this purpose we use a modified version of the Consensus model. The Consensus model has been shown to be realistic enough to reproduce distinguishing features of the rotifer species dynamics. Being uncoupled, a habitat with chaotic dynamics and habitats with regular oscillations of the rotifer density do not affect each other. Migration of the rotifers between the habitats leads to the invasion of chaos into neighboring habitats, that is chaotic rotifer oscillations replace regular oscillations of the rotifer density in neighboring habitats. The invasion of chaos distorts spatial borders of the rotifer oscillations synchronization clusters. We show that the invasion of chaos is spatially confined. Invariance of the attractor size under transformation of regular oscillations into chaotic ones is demonstrated to be responsible for the chaos confinement. [ABSTRACT FROM AUTHOR]

Published
2007

22. MODELING INVASION OF PESTS RESISTANT TO Bt TOXINS PRODUCED BY GENETICALLY MODIFIED PLANTS: RECESSIVE VS. DOMINANT INVADERS.

Author

Medvinsky, Alexander B., Gonik, Maria M., Velkov, Vassili V., Bai-Lian Li, and Malchow, Horst

Subjects
PLANT ecology, GENETICS, INSECTS, PLANT biomass, SEX (Biology), SIMULATION methods & models, PLANT populations
Abstract

There is a growing public concern about the ecological and evolutionary consequence of the use of genetically modified organisms. We study the impact of Bt resistant pests on genetically modified Bt crops and compare exposure of Bt plants to recessive and dominant Bt resistant invaders. To simulate pest invasion we develop a conceptual react ion-diffusion model of the Bt crop-Bt susceptible insects-Bt resistant insects for both the recessive and dominant pests. We show by means of computer simulations that there is a key parameter which we define as the growth number that characterizes the insects' fitness. We also show that the Bt resistant insects' invasion can lead to inhomogeneity in plant and insect spatial distributions. The plant and insect spatial patterns resulting from the Bt resistant insects' invasion are found to be dependent on the duration of the Bt resistant insect reproduction period. We compare averaged plant biomass resulting from the invasion of the dominant insects with the averaged plant biomass resulting from the invasion of the recessive insects. As a result, we show that in contrast to the recessive insects, the dominant ones initiate destruction of the plant population if the inflow of Bt susceptible insects is more than a critical value. In this case the plant biomass decays to zero. Otherwise, the plant biomass under the invasion of both the dominant and recessive insects depends on the duration of the insect reproduction period. We conclude that under invasion of dominant Bt resistant pests, the refuge strategy which has received wide acceptance in agricultural practice may not be scientifically sound practice. [ABSTRACT FROM AUTHOR]

Published
2005

23. Common coding variant in SERPINA1 increases the risk for large artery stroke

Author

Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J., Edeleva, Evgeniia V., Götzfried, Jessica, van der Laan, Sander W., Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Stephen, Lincz, Lisa F., Holliday, Elizabeth G., Burgess, Annette I., Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M., Levi, Christopher, Attia, John, Sudlow, Cathie L. M., Braun, Dieter, Markus, Hugh S., Wintrode, Patrick L., Berger, Klaus, Jenne, Dieter E., Dichgans, Martin, Malik, Rainer, Dau, Therese, Gonik, Maria, Sivakumar, Anirudh, Deredge, Daniel J., Edeleva, Evgeniia V., Götzfried, Jessica, van der Laan, Sander W., Pasterkamp, Gerard, Beaufort, Nathalie, Seixas, Susana, Bevan, Stephen, Lincz, Lisa F., Holliday, Elizabeth G., Burgess, Annette I., Rannikmäe, Kristiina, Minnerup, Jens, Kriebel, Jennifer, Waldenberger, Melanie, Müller-Nurasyid, Martina, Lichtner, Peter, Saleheen, Danish, Rothwell, Peter M., Levi, Christopher, Attia, John, Sudlow, Cathie L. M., Braun, Dieter, Markus, Hugh S., Wintrode, Patrick L., Berger, Klaus, Jenne, Dieter E., and Dichgans, Martin

Abstract

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3'-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.

24. Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease

Author

Masanori Yoshikawa, Daisy J.A. Janssen, Selina Dürr, Rudolf Joerres, Julia Billington, Nicholas Locantore, Florin Mihaltan, Sally Singh, Dimitar Sajkov, Thys van der Molen, Borja G. Cosío, Guilherme F. da Silva, Sarah Houben-Wilke, Ian Norman, Baykal Tulek, Jose M. Marin, David Miedinger, Samantha Coster, Janwillem W. H. Kocks, Sang Do Lee, Karel Hejduk, Juan P. de Torres, Maria Gonik, Mark Small, Samantha S.C. Kon, Nobuyuki Horita, Katherine A. Webb, Naseh Sigari, Ioanna Tsiligianni, Natya Raghavan, Yoshitaka Ogata, William D.-C. Man, Afroditi K. Boutou, Cristina Martínez, Marc Miravitlles, Lowie E.G.W. Vanfleteren, Miriam T.J. Groenen, Barbora Novotna, Isabel Mir, Miguel Guimaraes, Alvar Agusti, Nart Bedin Atalay, Dionne E. Smid, Trevor Murrells, Stefanie Brighenti-Zogg, Henrik Watz, Seigo Minami, José Luis López-Campos, Frits M.E. Franssen, Nicholas S Hopkinson, Pilar de Lucas-Ramos, Emiel F.M. Wouters, James Piercy, Melissa Jehn, Emma Chaplin, Vladimir Koblizek, Ciro Casanova, Nikolaos Tzanakis, Rebecca Tanner, Hiroshi Kimura, Lana Maricic, Nienke Nakken, David Price, Alberto Fernández-Villar, Denis E. O'Donnell, Annika Karch, Martijn A. Spruit, Yu-Il Kim, Joan B. Soriano, Ines Ladeira, Yu Nishijima, Namhee Kwon, Victoria Higgins, Laura Mendoza, Eanes Delgado Barros Pereira, Julia L. Kelly, Thomas Ringbaek, Guogang G. Xie, Chaicharn Pothirat, James W. Dodd, Joerg D. Leuppi, RS: NUTRIM - R3 - Respiratory & Age-related Health, Pulmonologie, Afdeling Onderwijs FHML, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, Promovendi NTM, MUMC+: MA Longziekten (3), [Smid, Dionne E.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Franssen, Frits M. E.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Groenen, Miriam T. J.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Houben-Wilke, Sarah] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Janssen, Daisy J. A.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Nakken, Nienke] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Vanfleteren, Lowie E. G. W.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Wouters, Emiel F. M.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Spruit, Martijn A.] CIRO, Dept Res & Educ, Hornerheide 1, NL-6085 NM Horn, Netherlands, [Franssen, Frits M. E.] Maastricht Univ, Med Ctr, Dept Resp Med, Maastricht, Netherlands, [Vanfleteren, Lowie E. G. W.] Maastricht Univ, Med Ctr, Dept Resp Med, Maastricht, Netherlands, [Wouters, Emiel F. M.] Maastricht Univ, Med Ctr, Dept Resp Med, Maastricht, Netherlands, [Gonik, Maria] Biomax Informat AG, Planegg, Germany, [Miravitlles, Marc] Hosp Univ Hebron, CIBER Enfermedades Resp CIBERES, Pneumol Dept Hosp, Barcelona, Spain, [Casanova, Ciro] Hosp Univ NS Candelaria, Pulmonaty Dept, Santa Cruz de Tenerife, Spain, [Casanova, Ciro] Hosp Univ NS Candelaria, Res Unit, Santa Cruz de Tenerife, Spain, [Cosio, Borja G.] Hosp Son Espases IdISPa CIBERES, Dept Resp Med, Islas Baleares, Spain, [de Lucas-Ramos, Pilar] Hosp Gen Univ Gregorio Maranon, Pulm Dept, Madrid, Spain, [Marin, Jose M.] Hosp Univ Miguel Servet, IISAragon, CIBER Enfermedades Resp, Zaragoza, Spain, [Martinez, Cristina] Hosp Univ Cent Asturias, Inst Nacl Silicosis, Pneumol Serv, Oviedo, Spain, [Mir, Isabel] Hosp Gen Univ Gregorio Maranon, Pulm Dept, Madrid, Spain, [Soriano, Joan B.] Univ Autonoma Madrid, Hosp Univ Princesa, Inst Invest, IISP, Madrid, Spain, [de Torres, Juan P.] Clin Univ Navarra, Pulm Dept, Pamplona, Spain, [Agusti, Alvar] Univ Barcelona, Hosp Clin, Resp Inst, Barcelona, Spain, [Agusti, Alvar] CIBERES, Madrid, Spain, [Atalay, Nart B.] TOBB Univ Econ & Technol, Dept Psychol, Ankara, Turkey, [Billington, Julia] Surbiton Hlth Ctr, Cent Surg, Surrey, England, [Boutou, Afroditi K.] G Gennimats Gen Hosp, Intens Care Unit, Thessaloniki, Greece, [Boutou, Afroditi K.] Aristotle Univ Thessaloniki, Resp Failure Unit, Thessaloniki, Greece, [Brighenti-Zogg, Stefanie] Univ Clin Med, Cantonal Hosp Baselland, Liestal, Switzerland, [Durr, Selina] Univ Clin Med, Cantonal Hosp Baselland, Liestal, Switzerland, [Leuppi, Joerg D.] Univ Clin Med, Cantonal Hosp Baselland, Liestal, Switzerland, [Miedinger, David] Univ Clin Med, Cantonal Hosp Baselland, Liestal, Switzerland, [Chaplin, Emma] Univ Hosp Leicester NHS Trust, NIHR Leicester Resp Biomed Res Unit, Ctr Exercise & Rehabil Sci, Leicester, Leics, England, [Singh, Sally] Univ Hosp Leicester NHS Trust, NIHR Leicester Resp Biomed Res Unit, Ctr Exercise & Rehabil Sci, Leicester, Leics, England, [Coster, Samantha] Kings Coll London, Florence Nightingale Fac Nursing & Midwifery, London, England, [Murrells, Trevor J.] Kings Coll London, Florence Nightingale Fac Nursing & Midwifery, London, England, [Norman, Ian J.] Kings Coll London, Florence Nightingale Fac Nursing & Midwifery, London, England, [Dodd, James W.] Univ Bristol, Southmead Hosp Bristol, North Bristol Lung Ctr, Acad Resp Unit, Bristol, Avon, England, [Fernandez-Villar, Alberto] Complexo Hosp Vigo, Inst Invest Biomed Vigo, Serv Neumol, Pontevedra, Spain, [Guimaraes, Miguel] Ctr Hosp Vila Nova Gaia Espinho, Pulmonol Dept, Vila Nova De Gaia, Portugal, [Ladeira, Ines] Ctr Hosp Vila Nova Gaia Espinho, Pulmonol Dept, Vila Nova De Gaia, Portugal, [Hejduk, Karel] Masaryk Univ, Fac Med, Inst Biostat & Analyses, Brno, Czech Republic, [Higgins, Victoria] Adelphi Real World, Bollington, England, [Piercy, James] Adelphi Real World, Bollington, England, [Small, Mark] Adelphi Real World, Bollington, England, [Hopkinson, Nicholas S.] Imperial Coll London, Royal Brompton & Harefield NHS Fdn Trust, NIHR Resp Biomed Res Unit, London, England, [Tanner, Rebecca J.] Imperial Coll London, Royal Brompton & Harefield NHS Fdn Trust, NIHR Resp Biomed Res Unit, London, England, [Horita, Nobuyuki] Yokohama City Univ, Grad Sch Med, Dept Pulmonol, Yokohama, Kanagawa, Japan, [Jehn, Melissa] Charite Univ Med Berlin, Arbeitsbereich Ambulante Pneumol, Berlin, Germany, [Joerres, Rudolf] Inst & Output Clin Occupat & Environm Med, Munich, Germany, [Karch, Annika] Hannover Med Sch, Inst Biostat, Hannover, Germany, [Kelly, Julia L.] Imperial Coll London, NIHR Resp Dis Biomed Res Unit Royal Brompton, Natl Heart & Lung Inst, Acad Unit Sleep & Ventilat, London, England, [Kelly, Julia L.] Harefield NHS Fdn Trust & Imperial Coll, London, England, [Kim, Yu-Il] Chonnam Natl Univ Hosp, Dept Internal Med, Div Pulmonol, Donggu, Gwangju, South Korea, [Kimura, Hiroshi] Nara Med Univ, Dept Internal Med 2, Nara, Japan, [Yoshikawa, Masanori] Nara Med Univ, Dept Internal Med 2, Nara, Japan, [Koblizek, Vladimir] Charles Univ Prague, Fac Med Hradec Kralove, Dept Pneumol, Hradec Kralove, Czech Republic, [Novotna, Barbora] Charles Univ Prague, Fac Med Hradec Kralove, Dept Pneumol, Hradec Kralove, Czech Republic, [Koblizek, Vladimir] Univ Hosp Hradec Kralove, Hradec Kralove, Czech Republic, [Novotna, Barbora] Univ Hosp Hradec Kralove, Hradec Kralove, Czech Republic, [Kocks, Janwillem H.] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma, Dept Primary Care, Groningen, Netherlands, [van der Molen, Thys] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma, Dept Primary Care, Groningen, Netherlands, [Tsiligianni, Ioanna G.] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma, Dept Primary Care, Groningen, Netherlands, [Kocks, Janwillem H.] Univ Groningen, Univ Med Ctr Groningen, GRIAC, COPD, Groningen, Netherlands, [van der Molen, Thys] Univ Groningen, Univ Med Ctr Groningen, GRIAC, COPD, Groningen, Netherlands, [Tsiligianni, Ioanna G.] Univ Groningen, Univ Med Ctr Groningen, GRIAC, COPD, Groningen, Netherlands, [Kon, Samantha S. C.] Hillingdon Hosp NHS Fdn Trust, Uxbridge, Middx, England, [Kon, Samantha S. C.] Royal Brompton & Harefield NHS Fdn Trust, NIHR Resp Biomed Res Unit, London, England, [Man, William D-C] Royal Brompton & Harefield NHS Fdn Trust, NIHR Resp Biomed Res Unit, London, England, [Kon, Samantha S. C.] Imperial Coll, London, England, [Man, William D-C] Imperial Coll, London, England, [Kwon, Namhee] GlaxoSmithICline GSK, Resp Franchise Med, London, England, [Lee, Sang-Do] Univ Ulsan, Coll Med, Clin Res Ctr Chron Obstruct Airway Dis, Asan Med Ctr,Dept Pulm & Critical Care Med, Seoul, South Korea, [Locantore, Nicholas] GlaxoSmithICline, King Of Prussia, PA USA, [Lopez-Campos, Jose L.] Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla, Unidad MedQuirarg Enfermedades Resp, Seville, Spain, [Lopez-Campos, Jose L.] Inst Salud Carlos III, CIBERES, CIBER Enfermedades Resp, Madrid, Spain, [Maricic, Lana] Univ JJ Strossmayer Osijek, Fac Med, Dept Internal Med, Univ Hosp Osijek, Osijek, Croatia, [Mendoza, Laura] Hosp Clin Univ Chile, Independencia, Region Metropol, Chile, [Mihaltan, Florin] Inst Pneumol Marius Nasta, Bucharest, Romania, [Minami, Seigo] Osaka Police Hosp, Dept Resp Med, Osaka, Japan, [Nishijima, Yu] Osaka Police Hosp, Dept Resp Med, Osaka, Japan, [Ogata, Yoshitaka] Osaka Police Hosp, Dept Resp Med, Osaka, Japan, [Nishijima, Yu] Osaka Univ, Grad Sch Med, Dept Resp Med Allergy & Rheumat Dis, Suita, Osaka, Japan, [O'Donnell, Denis E.] Queens Univ & Kingston Gen Hosp, Dept Med, Kingston, ON, Canada, [Webb, Katherine A.] Queens Univ & Kingston Gen Hosp, Dept Med, Kingston, ON, Canada, [Pereira, Eanes D.] Fed Univ Ceara Brazil, Fortaleza, Ceara, Brazil, [Price, David] Observat & Pragmat Res Inst, Singapore, Singapore, [Price, David] Univ Aberdeen, Aberdeen, Scotland, [Pothirat, Chaicharn] Chiang Mai Univ, Fac Med, Dept Internal Med, Div Pulm Crit Care & Allergy, Chiang Mai, Thailand, [Raghavan, Natya] McMaster Univ, Dept Med, Hamilton, ON, Canada, [Ringbaek, Thomas] Univ Copenhagen, Hvidovre Hosp, Dept Resp Med, Copenhagen, Denmark, [Sajkov, Dimitar] Flinders Med Ctr, Australian Resp & Sleep Med Inst, Adelaide, SA, Australia, [Sigari, Naseh] Kurdistan Univ Med Sci, Med Fac, Internal Med Dept, Sanandaj, Iran, [da Silva, Guilherme F.] Univ Fortaleza, UNIFOR, Fortaleza, Ceara, Brazil, [Tsiligianni, Ioanna G.] Agia Barbara Hlth Care Ctr, Iraklion, Greece, [Tulek, Baykal] Selcuk Univ, Fac Med, Dept Chest Dis, Konya, Turkey, [Tulek, Baykal] Univ Crete, Med Sch, Univ Hosp Herakl, Dept Thorac Med, Iraklion, Greece, [Watz, Henrik] German Ctr Lung Res, Pulm Res Inst, Lung Clin Grosshansdorf, Grosshansdorf, Germany, [Xie, Guogang G.] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Resp Med, Shanghai, Peoples R China, [Spruit, Martijn A.] Hasselt Univ, Fac Med & Life Sci, Biomed Res Inst, REVAL,Rehabil Res Ctr,BIOMED, Diepenbeek, Belgium, [Spruit, Martijn A.] Maastricht Univ, Med Ctr, NUTRIM Sch Nutr & Translat Res Metab, Dept Resp Med, Maastricht, Netherlands, MRC, National Institute for Health Research, Medical Research Council, Department of Health, Medical Research Council (MRC), EU/IMI Joint Undertaking, TOBB ETU, Faculty of Science and Literature, Department of Psychology, TOBB ETÜ, Fen Edebiyat Fakültesi, Psikoloji Bölümü, Atalay, Nart Bedin, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
ASSESSMENT TEST SCORE, Male, clinical significance, health status, HISTORY ASSESSMENT, Global Health, Severity of Illness Index, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Assessment test score, Quality of life, CLINICAL CHARACTERISTICS, QUALITY-OF-LIFE, Sickness Impact Profile, 030212 general & internal medicine, Prospective cohort study, Copd assessment test, General Nursing, POPULATION, COPD, education.field_of_study, HEALTH-STATUS, COPD ASSESSMENT TEST, Evidence-Based Medicine, medicine.diagnostic_test, Health Policy, Age Factors, Cat, CAT, General Medicine, Middle Aged, Obstructive lung disease, Health-status, 3. Good health, 1117 Public Health And Health Services, Practice Guidelines as Topic, Disease Progression, Female, Symptom Assessment, Research-council scale, Spirometry, medicine.medical_specialty, Population, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, Severity of illness, medicine, Humans, GOLD, education, Aged, Receiver operating characteristic, Clinical characteristics, business.industry, 1103 Clinical Sciences, medicine.disease, RESEARCH-COUNCIL SCALE, History assessment, PHYSICAL-ACTIVITY, 030228 respiratory system, Geriatrics, Physical therapy, Physical-activity, Quality-of-life, Geriatrics and Gerontology, business
Abstract

Background: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference.Methods: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, post-bronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores.Main outcomes: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points.Findings: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points.Conclusions: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed. (C) 2017 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Published
2017

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