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1. Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status

Author

Alcantara-Neves, N., Almeida, P.C.A., Amorim, L., Araujo, M.I., Barnes, K.C., Barreto, M.L., Belitardo, E., Bião-Lima, V., Cardoso, L., Camargos, P.A., Chatkin, J.M., Costa, R.S., Coelho, A.C.C., Cooper, P.J., Cruz, A.A., Cruz, C.S., Cunha, J., de Jesus, J.V., Fernandes, J., Franco, R.A., Gomes-Filho, I., Lima-Matos, A., Figueiredo, C.A., Lessa, M.A., Lins, L., Mello, L.M., Moura-Santos, P., Muniz, I.S., Paixao-Araujo, I., Pinheiro, G.P., Ponte, E.V., Rodrigues, L.C., Santana, C.V.N., Santos-Lima, G., Souza, T.M.O., Souza-Machado, A., Souza-Machado, C., Stelmach, R., Vasquez, V.S., Adcock, I.M., Ahmed, H., Auffray, C., Bakke, P., Baribaud, F., Bel, E.H., Bigler, J., Bisgaard, H., Boedigheimer, M.J., Bønnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Caruso, M., Chaiboonchoe, A., Chanez, P., Compton, C.H., Corfield, J., D'Amico, A., Dahlén, B., Dahlén, S.E., De Meulder, B., Djukanovic, R., Erpenbeck, V.J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L.J., Formaggio, E., Fowler, S.J., Frey, U., Gahlemann, M., Geiser, T., Goss, V., Guo, Y.-K., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P.W., Higenbottam, T., Hohlfeld, J.M., Holweg, C., Horváth, I., Howarth, P., James, A.J., Knowles, R.G., Knox, A.J., Krug, N., Lefaudeux, D., Loza, M.J., Lutter, R., Manta, A., Masefield, S., Matthews, J.G., Mazein, A., Meiser, A., Middelveld, R.J.M., Miralpeix, M., Montuschi, P., Mores, N., Murray, C.S., Musial, J., Myles, D., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Praticò, G., Puig Valls, M., Rao, N., Roberts, A., Roberts, G., Rowe, A., Sandström, T., Schofield, J.P.R., Seibold, W., Selby, A., Shaw, D.E., Sigmund, R., Singer, F., Skipp, P.J., Sousa, A.R., Sterk, P.J., Sun, K., Thornton, B., van Aalderen, W.M., van Geest, M., Vestbo, J., Vissing, N.H., Wagener, A.H., Wagers, S.S., Weiszhart, Z., Wheelock, C.E., Wilson, S.J., Cruz, Alvaro A., Riley, John H., Bansal, Aruna T., Ponte, Eduardo V., Souza-Machado, Adelmir, Almeida, Paula C.A., Biao-Lima, Valmar, Davis, Maggie, Bates, Stewart, Adcock, Ian M., Sterk, Peter J., and Chung, Kian Fan

Published
2020
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2. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M.S. Kolmert, J. Andersson, L.I. Östling, J. Knowles, R.G. Gómez, C. Ericsson, M. Thörngren, J.-O. Khoonsari, P.E. Dahlén, B. Kupczyk, M. de Meulder, B. Auffray, C. Bakke, P.S. Beghe, B. Bel, E.H. Caruso, M. Chanez, P. Chawes, B. Fowler, S.J. Gaga, M. Geiser, T. Gjomarkaj, M. Horváth, I. Howarth, P.H. Johnston, S.L. Joos, G. Krug, N. Montuschi, P. Musial, J. Niżankowska-Mogilnicka, E. Olsson, H.K. Papi, A. Rabe, K.F. Sandström, T. Shaw, D.E. Siafakas, N.M. Uhlén, M. Riley, J.H. Bates, S. Middelveld, R.J.M. Wheelock, C.E. Chung, K.F. Adcock, I.M. Sterk, P.J. Djukanovic, R. Nilsson, P. Dahlén, S.-E. James, A. Ahmed, H. Balgoma, D. Bansal, A.T. Baribaud, F. Bigler, J. Billing, B. Bisgaard, H. Boedigheimer, M.J. Bønnelykke, K. Brandsma, J. Brinkman, P. Bucchioni, E. Burg, D. Bush, A. Chaiboonchoe, A. Checa, T. Compton, C.H. Corfield, J. Cunoosamy, D. D’Amico, A. Emma, R. Erpenbeck, V.J. Erzen, D. Fichtner, K. Fitch, N. Fleming, L.J. Formaggio, E. Frey, U. Gahlemann, M. Goss, V. Guo, Y.-K. Hashimoto, S. Haughney, J. Hedlin, G. Hekking, P.-P.W. Higenbottam, T. Hohlfeld, J.M. Holweg, C.T.J. Knox, A.J. Konradsen, J. Lazarinis, N. Lefaudeux, D. Li, T. Loza, M.J. Lutter, R. Manta, A. Masefield, S. Matthews, J.G. Mazein, A. Meiser, A. Miralpeix, M. Mores, N. Murray, C.S. Myles, D. Naz, S. Nordlund, B. Pahus, L. Pandis, I. Pavlidis, S. Postle, A. Powel, P. Rao, N. Reinke, S. Roberts, A. Roberts, G. Rowe, A. Schofield, J.P.R. Seibold, W. Selby, A. Sigmund, R. Singer, F. Sjödin, M. Skipp, P.J. Sousa, A.R. Sun, K. Thornton, B. Uddin, M. van Aalderen, W.M. van Geest, M. Vestbo, J. Vissing, N.H. Wagener, A.H. Wagers, S.S. Weiszhart, Z. Wheelock, C.E. Wheelock, Å. Wilson, S.J. Yasinska, V. Brusselle, G.G. Campbell, D.A. Contoli, M. Damm, K. de Rudder, I. Delin, I. Devautour, C. Duplaga, M. Eduards, M. Ek, A. Ekström, T. Figiel, E. Gaber, F. Gauw, S. Gawlewicz-Mroczka, A. Gerding, D. Haque, S. Hewitt, L. Hiemstra, P.S. Holgate, S.T. Holloway, J. Kania, A. Kanniess, F. Karlsson, Ö. Kips, J.C. Kumlin, M. Lantz, A.-S. Lazarinis, N. Magnussen, H. Mallia, P. Martling, I. Meziane, L. Oikonomidou, E. Olsson, M. Pace, E. Papadopouli, E. Papadopoulos, N. Plataki, M. Profita, M. Reinius, L.E. Richter, K. Robinson, D.S. Romagnoli, M. Samara, K. Schelfhout, V. Skedinger, M. Stamataki, E. ten Brinke, A. Vachier, I. Wallén-Nielsen, E. van Veen, I. Weersink, E. Wilson, S.J. Yasinska, V. Zervas, E. Ziolkowska-Graca, B. U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group BIOAIR (Longitudinal Assessment of Clinical Course Biomarkers in Severe Chronic Airway Disease) Consortium

Abstract

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA. © 2022 European Respiratory Society. All rights reserved.

Published
2022

4. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Author

Mikus, M. S., Kolmert, J., Andersson, L. I., Ostling, J., Knowles, R. G., Gomez, C., Ericsson, M., Thorngren, J. -O., Khoonsari, P. E., Dahlen, B., Kupczyk, M., de Meulder, B., Auffray, C., Bakke, P. S., Beghe, Bianca, Bel, E. H., Caruso, M., Chanez, P., Chawes, B., Fowler, S. J., Gaga, M., Geiser, T., Gjomarkaj, M., Horvath, I., Howarth, P. H., Johnston, S. L., Joos, G., Krug, N., Montuschi, P., Musial, J., Nizankowska-Mogilnicka, E., Olsson, H. K., Papi, A., Rabe, K. F., Sandstrom, T., Shaw, D. E., Siafakas, N. M., Uhlen, M., Riley, J. H., Bates, S., Middelveld, R. J. M., Wheelock, C. E., Chung, K. F., Adcock, I. M., Sterk, P. J., Djukanovic, R., Nilsson, P., Dahlen, S. -E., James, A., Ahmed, H., Balgoma, D., Bansal, A. T., Baribaud, F., Bigler, J., Billing, B., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Chaiboonchoe, A., Checa, T., Compton, C. H., Corfield, J., Cunoosamy, D., D'Amico, A., Emma, R., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L. J., Formaggio, E., Frey, U., Gahlemann, M., Goss, V., Guo, Y. -K., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. -P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C. T. J., Knox, A. J., Konradsen, J., Lazarinis, N., Lefaudeux, D., Li, T., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Miralpeix, M., Mores, N., Murray, C. S., Myles, D., Naz, S., Nordlund, B., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Rao, N., Reinke, S., Roberts, A., Roberts, G., Rowe, A., Schofield, J. P. R., Seibold, W., Selby, A., Sigmund, R., Singer, F., Sjodin, M., Skipp, P. J., Sousa, A. R., Sun, K., Thornton, B., Uddin, M., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, A., Wilson, S. J., Yasinska, V., Brusselle, G. G., Campbell, D. A., Contoli, M., Damm, K., de Rudder, I., Delin, I., Devautour, C., Duplaga, M., Eduards, M., Ek, A., Ekstrom, T., Figiel, E., Gaber, F., Gauw, S., Gawlewicz-Mroczka, A., Gerding, D., Haque, S., Hewitt, L., Hiemstra, P. S., Holgate, S. T., Holloway, J., Kania, A., Kanniess, F., Karlsson, O., Kips, J. C., Kumlin, M., Lantz, A. -S., Magnussen, H., Mallia, P., Martling, I., Meziane, L., Oikonomidou, E., Olsson, M., Pace, E., Papadopouli, E., Papadopoulos, N., Plataki, M., Profita, M., Reinius, L. E., Richter, K., Robinson, D. S., Romagnoli, M., Samara, K., Schelfhout, V., Skedinger, M., Stamataki, E., ten Brinke, A., Vachier, I., Wallen-Nielsen, E., van Veen, I., Weersink, E., Zervas, E., and Ziolkowska-Graca, B.

Subjects
Blood Proteins, Humans, Inflammation, Proteomics, Severity of Illness Index, Steroids, Asthma, Quality of Life
Published
2022

6. Patrones de progresión de la actividad física en pacientes con EPOC

Author

Koreny, M, Demeyer, H, Benet, M, Arbillaga-Etxarri, A, Balcells, E, Barberan-Garcia, A, Gimeno-Santos, E, Hopkinson, NS, De Jong, C, Karlsson, N, Louvaris, Z, Polkey, MI, Puhan, MA, Rabinovich, RA, Rodríguez-Roisin, R, Vall-Casas, P, Vogiatzis, I, Troosters, T, Garcia-Aymerich, J, Urban Training Study Group and PROactive Consortium members, Urban Training Study Group, Delgado, A, Torrent-Pallicer, J, Vilaró, J, Chiaradía, DAR, Marín, A, Ortega, P, Celorrio, N, Teagudo, MM, Montellà, N, Muñoz, L, Toran, P, Simonet, P, Jané, C, Martín-Cantera, C, Borrell, E, PROactive Consortium members, Ivanoff, N, Corriol-Rohou, S, Jarrod, I, Erzen, D, Brindicci, C, Higenbottam, T, Scuri, M, McBride, P, Kamel, N, Tabberer, M, Dobbels, F, De Boer, P, Kulich, K, Glendenning, A, Rudell, K, Wilson, FJ, Nikai, E, Van der Molen, T, MacNee, B, Frei, A, Groningen Research Institute for Asthma and COPD (GRIAC), and EU/IMI Joint Undertaking

Subjects
Male, PROactive Consortium members, Respiratory System, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Medicine and Health Sciences, Pooled data, Determinants, COPD, biology, Patrones de progresión, General Medicine, Lama, Análisis de conglomerados, Respiratory Function Tests, MPOC, Female, EPOC, Determinantes, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Patrons de progressió, Physical activity, 616.2, 03 medical and health sciences, FEV1/FVC ratio, Cluster analysis, Multinomial logistic regression model, Internal medicine, Urban Training Study Group, medicine, Humans, Anàlisi de clústers, In patient, Exercise, Patterns of progression, business.industry, 1103 Clinical Sciences, medicine.disease, biology.organism_classification, C600, Urban Training Study Group and PROactive Consortium members, B900, Dyspnea, 030228 respiratory system, Usual care, Actividad física, Sedentary Behavior, Activitat física, business
Abstract

Introduction: Although mean physical activity in COPD patients declines by 400–500 steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to identify distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants. Methods: We pooled data from two cohorts (usual care arm of Urban Training [NCT01897298] and PROactive initial validation [NCT01388218] studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns. Results: In 291 COPD patients (mean ± SD 68 ± 8 years, 81% male, FEV1 59 ± 19%pred) we identified three distinct physical activity progression patterns: Inactive (n = 173 [59%], baseline: 4621 ± 1757 steps/day, 12-month change (Δ): −487 ± 1201 steps/day), Active Improvers (n = 49 [17%], baseline: 7727 ± 3275 steps/day, Δ: + 3378 ± 2203 steps/day) and Active Decliners (n = 69 [24%], baseline: 11 267 ± 3009 steps/day, Δ: −2217 ± 2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR [95% CI] 0.94 [0.90–0.98] per 10 m, P = .001) and a higher mMRC dyspnea score (1.71 [1.12–2.60] per 1 point, P = .012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver. Conclusions: The natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline. Introducción: Aunque la actividad física en pacientes con EPOC declina una media anual de 400-500 pasos/día, se desconoce si esta progresión es igual en todos los pacientes. Este estudio pretendió identificar los patrones de progresión de la actividad física mediante métodos libres de hipótesis y evaluar sus determinantes. Métodos: Se estudiaron 291 pacientes con EPOC estable (media ± DE: 68 ± 8 años, 81% hombres, VEMS 59 ± 19%pred) de dos cohortes europeas con actividad física basal y a 12 meses (acelerómetro Dynaport MoveMonitor). Se identificaron conglomerados (patrones) de progresión de actividad física basados en los niveles y cambios de pasos/día usando k-means, y se compararon entre patrones las características sociodemográficas, interpersonales, ambientales, clínicas y psicosociales basales. Resultados: Se identificaron tres patrones: inactivo (n = 173 [59%], basal: 4.621 ± 1.757 pasos/día, cambio en 12 meses (Δ): −487 ± 1.201 pasos/día), activo que aumenta (n = 49 [17%], basal: 7.727 ± 3.275 pasos/día, Δ: +3.378 ± 2.203 pasos/día) y activo que reduce (n = 69 [24%], basal: 11.267 ± 3.009 pasos/día, Δ: −2.217 ± 2.085 pasos/día). La distancia en la prueba de la marcha de 6 minutos (6MWD) y la disnea se asociaron independientemente con ser inactivo: RRR [IC 95%] 0,94 [0,90-0,98] por cada 10 m de 6MWD (p = 0,001) y 1,71 [1,12-2,60] por cada punto en la escala mMRC (p = 0,012), respectivamente, en comparación con el patrón activo que reduce. No se encontraron variables basales independientemente asociadas con ser activo que aumenta. Conclusiones: La progresión natural de la actividad física en pacientes con EPOC es heterogénea. Mientras que el patrón de pacientes inactivo se relaciona con peores características clínicas de EPOC, no se pudo predecir la evolución de los activos a aumentar o reducir. info:eu-repo/semantics/acceptedVersion

Published
2021

7. Patient-reported outcomes in adults with type 1 diabetes in global real-world clinical practice: the SAGE study

Author

Wilmot E, Close K, Jurisic-Erzen D, Bruttomesso D, Ampudia-Blasco F, Bosnyak Z, de Climens A, Bigot G, Peters A, Renard E, Berard L, Calliari L, and Seufert J

Abstract

AIMS: This secondary analysis of the SAGE study aimed to evaluate the association between glycaemic control and patient-reported outcomes (PROs), in adults with type 1 diabetes (T1DM) across different age groups and regions. MATERIALS AND METHODS: SAGE was a multinational, cross-sectional, observational study in adults with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64, and =65years), and reported across different regions. PRO questionnaires were applied to assess hypoglycaemia fear (Hypoglycemia Fear Survey-II [HFS-II]), diabetes-related distress (Problem Areas In Diabetes [PAID]), insulin treatment satisfaction (Insulin Treatment Satisfaction Questionnaire [ITSQ]), and diabetes-specific quality of life (Audit of Diabetes Dependent Quality of Life [ADDQoL]). Multivariable analysis was performed to evaluate the relationship between HbA1c target achievement (

Published
2021

8. Patterns of Physical Activity Progression in Patients With COPD [Patrones de progresión de la actividad física en pacientes con EPOC]

Author

Koreny, M. Demeyer, H. Benet, M. Arbillaga-Etxarri, A. Balcells, E. Barberan-Garcia, A. Gimeno-Santos, E. Hopkinson, N.S. De Jong, C. Karlsson, N. Louvaris, Z. Polkey, M.I. Puhan, M.A. Rabinovich, R.A. Rodríguez-Roisin, R. Vall-Casas, P. Vogiatzis, I. Troosters, T. Garcia-Aymerich, J. Delgado, A. Torrent-Pallicer, J. Vilaró, J. Rodriguez-Roisín, R. Chiaradía, D.A.R. Marín, A. Ortega, P. Celorrio, N. Monteagudo, M. Montellà, N. Muñoz, L. Toran, P. Simonet, P. Jané, C. Martín-Cantera, C. Borrell, E. Ivanoff, N. Corriol-Rohou, S. Jarrod, I. Erzen, D. Brindicci, C. Higenbottam, T. Scuri, M. McBride, P. Kamel, N. Tabberer, M. Dobbels, F. de Boer, P. Kulich, K. Glendenning, A. Rudell, K. Wilson, F.J. Hopkinson, N.S. Nikai, E. van der Molen, T. MacNee, B. Frei, A. The Urban Training Study Group PROactive Consortium members The Urban Training Study Group The PROactive Consortium members

Abstract

Introduction: Although mean physical activity in COPD patients declines by 400–500 steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to identify distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants. Methods: We pooled data from two cohorts (usual care arm of Urban Training [NCT01897298] and PROactive initial validation [NCT01388218] studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns. Results: In 291 COPD patients (mean ± SD 68 ± 8 years, 81% male, FEV1 59 ± 19%pred) we identified three distinct physical activity progression patterns: Inactive (n = 173 [59%], baseline: 4621 ± 1757 steps/day, 12-month change (Δ): −487 ± 1201 steps/day), Active Improvers (n = 49 [17%], baseline: 7727 ± 3275 steps/day, Δ: + 3378 ± 2203 steps/day) and Active Decliners (n = 69 [24%], baseline: 11 267 ± 3009 steps/day, Δ: −2217 ± 2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR [95% CI] 0.94 [0.90–0.98] per 10 m, P =.001) and a higher mMRC dyspnea score (1.71 [1.12–2.60] per 1 point, P =.012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver. Conclusions: The natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline. © 2020 SEPAR

Published
2021

9. Validity and responsiveness of the Daily-and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments

Author

Garcia-Aymerich, J. Puhan, M.A. Corriol-Rohou, S. De Jong, C. Demeyer, H. Dobbels, F. Erzen, D. Frei, A. Gimeno-Santos, E. Hopkinson, N.S. Ivanoff, N. Karlsson, N. Louvaris, Z. Polkey, M.I. Rabinovich, R.A. Scuri, M. Tabberer, M. Vogiatzis, I. Troosters, T.

Abstract

Background The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation. Objective To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries. Methods We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID. Results We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score. Conclusions The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables. © Author(s) (or their employer(s)) 2021.

Published
2021

12. Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status

Author

Cruz, Alvaro A., primary, Riley, John H., additional, Bansal, Aruna T., additional, Ponte, Eduardo V., additional, Souza-Machado, Adelmir, additional, Almeida, Paula C.A., additional, Biao-Lima, Valmar, additional, Davis, Maggie, additional, Bates, Stewart, additional, Adcock, Ian M., additional, Sterk, Peter J., additional, Chung, Kian Fan, additional, Alcantara-Neves, N., additional, Almeida, P.C.A., additional, Amorim, L., additional, Araujo, M.I., additional, Barnes, K.C., additional, Barreto, M.L., additional, Belitardo, E., additional, Bião-Lima, V., additional, Cardoso, L., additional, Camargos, P.A., additional, Chatkin, J.M., additional, Costa, R.S., additional, Coelho, A.C.C., additional, Cooper, P.J., additional, Cruz, A.A., additional, Cruz, C.S., additional, Cunha, J., additional, de Jesus, J.V., additional, Fernandes, J., additional, Franco, R.A., additional, Gomes-Filho, I., additional, Lima-Matos, A., additional, Figueiredo, C.A., additional, Lessa, M.A., additional, Lins, L., additional, Mello, L.M., additional, Moura-Santos, P., additional, Muniz, I.S., additional, Paixao-Araujo, I., additional, Pinheiro, G.P., additional, Ponte, E.V., additional, Rodrigues, L.C., additional, Santana, C.V.N., additional, Santos-Lima, G., additional, Souza, T.M.O., additional, Souza-Machado, A., additional, Souza-Machado, C., additional, Stelmach, R., additional, Vasquez, V.S., additional, Adcock, I.M., additional, Ahmed, H., additional, Auffray, C., additional, Bakke, P., additional, Baribaud, F., additional, Bel, E.H., additional, Bigler, J., additional, Bisgaard, H., additional, Boedigheimer, M.J., additional, Bønnelykke, K., additional, Brandsma, J., additional, Brinkman, P., additional, Bucchioni, E., additional, Burg, D., additional, Bush, A., additional, Caruso, M., additional, Chaiboonchoe, A., additional, Chanez, P., additional, Compton, C.H., additional, Corfield, J., additional, D'Amico, A., additional, Dahlén, B., additional, Dahlén, S.E., additional, De Meulder, B., additional, Djukanovic, R., additional, Erpenbeck, V.J., additional, Erzen, D., additional, Fichtner, K., additional, Fitch, N., additional, Fleming, L.J., additional, Formaggio, E., additional, Fowler, S.J., additional, Frey, U., additional, Gahlemann, M., additional, Geiser, T., additional, Goss, V., additional, Guo, Y.-K., additional, Hashimoto, S., additional, Haughney, J., additional, Hedlin, G., additional, Hekking, P.W., additional, Higenbottam, T., additional, Hohlfeld, J.M., additional, Holweg, C., additional, Horváth, I., additional, Howarth, P., additional, James, A.J., additional, Knowles, R.G., additional, Knox, A.J., additional, Krug, N., additional, Lefaudeux, D., additional, Loza, M.J., additional, Lutter, R., additional, Manta, A., additional, Masefield, S., additional, Matthews, J.G., additional, Mazein, A., additional, Meiser, A., additional, Middelveld, R.J.M., additional, Miralpeix, M., additional, Montuschi, P., additional, Mores, N., additional, Murray, C.S., additional, Musial, J., additional, Myles, D., additional, Pahus, L., additional, Pandis, I., additional, Pavlidis, S., additional, Postle, A., additional, Powel, P., additional, Praticò, G., additional, Puig Valls, M., additional, Rao, N., additional, Roberts, A., additional, Roberts, G., additional, Rowe, A., additional, Sandström, T., additional, Schofield, J.P.R., additional, Seibold, W., additional, Selby, A., additional, Shaw, D.E., additional, Sigmund, R., additional, Singer, F., additional, Skipp, P.J., additional, Sousa, A.R., additional, Sterk, P.J., additional, Sun, K., additional, Thornton, B., additional, van Aalderen, W.M., additional, van Geest, M., additional, Vestbo, J., additional, Vissing, N.H., additional, Wagener, A.H., additional, Wagers, S.S., additional, Weiszhart, Z., additional, Wheelock, C.E., additional, and Wilson, S.J., additional

Published
2020
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14. Stratification of asthma phenotypes by airway proteomic signatures

Author

Schofield, James P.R., Burg, Dominic, Nicholas, Ben, Strazzeri, Fabio, Brandsma, Joost, Staykova, Doroteya, Folisi, Caterina, Bansal, Aruna T., Xian, Yang, Guo, Yike, Rowe, Anthony, Corfield, Julie, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven Erik, Fowler, Stephen J., Howarth, Peter, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sun, Kai, Pandis, Ioannis, Riley, John, Auffray, Charles, De Meulder, Bertrand, Lefaudeux, Diane, Sousa, Ana R., Adcock, Ian M., Chung, Kian Fan, Sterk, Peter J., Skipp, Paul J., Djukanovi?, Ratko, Ahmed, H., Allen, D., Badorrek, P., Ballereau, S., Baribaud, F., Bedding, A., Behndig, A. F., Berglind, A., Berton, A., Bigler, J., Boedigheimer, M. J., Brinkman, P., Bush, A., Campagna, D., Casaulta, C., Chaiboonchoe, A., Davison, T., De Meulder, B., Delin, I., Dennison, P., Dodson, P., El Hadjam, L., Erzen, D., Faulenbach, C., Fichtner, K., Fitch, N., Formaggio, E., Gahlemann, M., Galffy, G., Garissi, D., Garret, T., Gent, J., Guillmant-Farry, E., Henriksson, E., Hoda, U., Hohlfeld, J. M., Hu, X., James, A., Johnson, K., Jullian, N., Kerry, G., Knowles, R., Konradsen, J. R., Kretsos, K., Krueger, L., Lantz, A. S., Larminie, C., Latzin, P., Lefaudeux, D., Lemonnier, N., Lowe, L. A., Lutter, R., Manta, A., Mazein, A., McEvoy, L., Menzies-Gow, A., Mores, N., Murray, C. S., and Nething, K.

Abstract

© 2019 Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.

Published
2019

15. Treatable traits in the European U-BIOPRED adult asthma cohorts

Author

Simpson, Andrew J., Hekking, Pieter-Paul, Shaw, Dominick E., Fleming, L. J., Roberts, Graham, Riley, John H., Bates, Stewart, Sousa, A. R., Bansal, A. T., Pandis, Ioannis, Sun, K., Bakke, Per S., Caruso, Massimo, Dahlen, Barbro, Dahlen, Sven-Erik, Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sandstrom, Thomas, Singer, Florian, Adcock, I. M., Wagers, Scott S., Djukanovic, R., Chung, Kian Fan, Sterk, P. J., Fowler, S. J., Ahmed, H., Auffray, C., Bakke, P., Baribaud, F., Bates, S., Bel, E. H., Bigler, J., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Caruso, M., Chaiboonchoe, A., Chanez, P., Chung, F. K., Compton, C. H., Corfield, J., D'Amico, A., Dahlen, B., Dahlen, S. E., De Meulder, B., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Formaggio, E., Frey, U., Gahlemann, M., Geiser, T., Goss, V., Guo, Y., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C., Horvath, I., Howarth, P., James, A. J., Knowles, R., Knox, A. J., Krug, N., Lefaudeux, D., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Middelveld, R. J. M., Miralpeix, M., Montuschi, P., Mores, N., Murray, C. S., Musial, J., Myles, D., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Pratico, G., Puig Valls, M., Rao, N., Riley, J., Roberts, A., Roberts, G., Rowe, A., Sandstrom, T., Schofield, J. P. R., Seibold, W., Selby, A., Shaw, D. E., Sigmund, R., Singer, F., Skipp, P. J., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, C. E., and Wilson, S. J.

Abstract

mprovements in asthma outcomes have stalled over the past decade, which may be attributed to treating patients on the basis of a generic diagnostic label. The taxonomy “Treatable Traits” was proposed by Agusti et al (2016) as a precision medicine approach for the diagnosis and management of chronic airway diseases that is based on the identification of genetic, phenotypic and psychosocial characteristics for which therapeutic interventions are known to improve respiratory health ...

Published
2019

16. Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux

Author

Perotin, Jeanne-Marie, Schofield, James PR, Wilson, Susan J, Ward, Jonathan, Brandsma, Joost, Strazzeri, Fabio, Bansal, Aruna, Yang, Xian, Rowe, Anthony, Corfield, Julie, Lutter, Rene, Shaw, Dominick E, Bakke, Per S, Caruso, Massimo, Dahlen, Barbro, Fowler, Stephen J, Horvath, Ildiko, Howarth, Peter, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandstrom, Thomas, Sun, Kai, Pandis, Ioannis, Auffray, Charles, De Meulder, Bertrand, Lefaudeux, Diane, Riley, John H, Sousa, Ana R, Dahlen, Sven-Erik, Adcock, Ian M, Chung, Kian Fan, Sterk, Peter J, Skipp, Paul J, Collins, Jane E, Davies, Donna E, Djukanovic, Ratko, Adcock, IM, Ahmed, H, Auffray, C, Bakke, P, Banssal, AT, Baribaud, F, Bates, S, Bel, EH, Bigler, J, Bisgaard, H, Boedigheimer, MJ, Bonnelykke, K, Brandsma, J, Brinkman, P, Bucchioni, E, Burg, D, Bush, A, Caruso, M, Chaiboonchoe, A, Chanez, P, Chung, KF, Compton, CH, Corfield, J, D'Amico, A, Dahlen, SE, De Meulder, B, Djukanovic, R, Erpenbeck, VJ, Erzen, D, Fichtner, K, Fitch, N, Fleming, LJ, Formaggio, E, Fowler, SJ, Frey, U, Gahlemann, M, Geiser, T, Guo, Y, Hashimoto, S, Haughney, J, Hedlin, G, Hekking, PW, Higenbottam, T, Hohlfeld, JM, Holweg, C, Horvath, I, Howarth, P, James, AJ, Knowles, R, Knox, AJ, Krug, N, Lefaudeux, D, Loza, MJ, Lutter, R, Manta, A, Masefield, S, Matthews, JG, Mazein, A, Meiser, A, Middelveld, RJM, Miralpeix, M, Montuschi, P, Mores, N, Murray, CS, Musial, J, Myles, D, Pahus, L, Pandis, I, Pavlidis, S, Powell, P, Pratico, G, Puig Valls, M, Rao, N, Riley, J, Roberts, A, Roberts, G., Rowe, A, Sandstrom, T, Seibold, W, Selby, A, Shaw, DE, Sigmund, R, Singer, F, Skipp, PJ, Sousa, AR, Sterk, PJ, Sun, K, Thornton, B, van Aalderen, WM, van Geest, M, Vestbo, J, Vissing, NH, Wagener, AH, Wagers, SS, Weiszhart, Z, Wheelock, CE, Wilson, SJ, Aliprantis, Antonios, Allen, David, Alving, Kjell, Badorrek, P, Balgoma, David, Ballereau, S, Barber, Clair, Batuwitage, Manohara Kanangana, Bautmans, An, Bedding, A, Behndig, AF, Beleta, Jorge, Berglind, A, Berton, A, Bochenek, G, Braun, A, Campagna, D, Carayannopoulos, L, Casaulta, C, Chaleckis, Romanas, Dahlen, B, Davison, T, De Alba, J, De Lepeleire, I, Dekker, T, Delin, I, Dennison, P, Dijkhuis, A, Dodson, P, Dyson, K, Edwards, J, El Hadjam, L, Emma, R, Ericsson, M, Faulenbach, C, Flood, Breda, Galffy, G, Gallart, H, Garissi, D, Gent, J., Gerhardsson de Verdier, M, Gibeon, D, Gomez, Cristina, Gove, K, Guillmant-Farry, E, Henriksson, E, Hewitt, L, Hoda, U, Hu, Richard, Hu, S, Hu, X, Jeyasingham, E, Johnson, K, Jullian, N, Kamphuis, J, Kennington, EJ, Kerry, D, Kerry, G, Klueglich, M, Knobel, H, Kolmert, Johan, Konradsen, JR, Kots, M, Kretsos, Kosmas, Krueger, L, Kuo, S, Kupczyk, M, Lambrecht, Bart, Lantz, A-S, Larminie, Christopher, Larsson, LX, Latzin, P, Lazarinis, N, Lemonnier, N, Lone-Latif, S, Lowe, LA, Marouzet, L, Martin, J, Mathon, C, McEvoy, L, Meah, S, Menzies-Gow, A, Metcalf, L, Mikus, M, Monk, P, Naz, S, Nething, K, Nicholas, B, Nihlen, U, Nilsson, Peter, Niven, R, Nordlund, B, Nsubuga, S, Ostling, J, Pacino, A, Palkonen, S, Pellet, J, Pennazza, G, Petren, A, Pink, S, Pison, C, Postle, A, Rahman-Amin, M, Ravanetti, L, Ray, E, Reinke, S, Reynolds, L, Riemann, K, Robberechts, Martine, Rocha, JP, Rossios, C, Russell, K, Rutgers, M, Santini, G, Santoninco, M, Saqi, M, Schoelch, C, Schofield, JPR, Scott, S, Sehgal, N, Sjodin, M, Smids, B, Smith, Caroline, Smith, J, Smith, KM, Soderman, P, Sogbessan, A, Spycher, F, Staykova, D, Stephan, S, Stokholm, J, Strandberg, K, Sunther, M, Szentkereszty, M, Tamasi, L, Tariq, K, Thorngren, J-O, Thorsen, Jonathan, Valente, S, van de Pol, Marianne, van Drunen, CM, Van Eyll, J, Versnel, J, Vink, A, von Garnier, C, Vyas, A, Wald, F, Walker, S, Ward, J, Wetzel, K, Wiegman, C, Williams, S, Yang, X, Yeyasingham, E, Yu, W, Zetterquist, W, Zolkipli, Z, Zwinderman, AH, Prins, J-B, Visintin, L, Evans, H, Puhl, M, Buzermaniene, L, Hudson, V, Bond, L, de Boer, P, Widdershoven, G, Supple, D, Hamerlijnck, D, Negus, J, Sergison, L, Onstein, S, MacNee, W, Bernardini, R, Bont, Louis, Wecksell, P-A, Draper, Aleksandra, Gozzard, Neil, Commission of the European Communities, Publica, Pulmonology, AII - Inflammatory diseases, Ear, Nose and Throat, Epidemiology and Data Science, APH - Methodology, and NIHR Southampton Biomedical Research Centre

Subjects
severe asthma, Pulmonary and Respiratory Medicine, endotyping, Gastrointestinal, phenotyping, Settore BIO/14 - FARMACOLOGIA, [SDV]Life Sciences [q-bio], Respiratory System, ROWE, Gene Expression, Article, Endoscopy, Gastrointestinal, Epithelium, CCN Intercellular Signaling Proteins, Patent application, 03 medical and health sciences, 0302 clinical medicine, Shareholder, gatroesophageal reflux, Nothing, Proto-Oncogene Proteins, Medicine and Health Sciences, Humans, Medicine, Obesity, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, U-BIOPRED Study Group, Science & Technology, business.industry, U-BIOPRED, digestive, oral, and skin physiology, Airway inflammation, Conflict of interest, Biology and Life Sciences, Endoscopy, Asthma, digestive system diseases, 3. Good health, 030228 respiratory system, Spin out, Case-Control Studies, Law, Honorarium, Gastroesophageal Reflux, business, Life Sciences & Biomedicine
Abstract

Gastro-oesophageal reflux disease (GORD) and obesity are associated with frequent exacerbations and poor quality of life in asthmatics. Multiple mechanisms have been proposed for the effect of obesity, including modification of inflammation affecting epithelial cell proliferation and wound repair, while the role of GORD is poorly understood and proton pump inhibitor (PPI) are of variable efficacy. GORD might exert a deleterious effect by inducing vagal reflex, neuroinflammation and directly ( via microaspiration) triggering airway inflammation. Studies of reflux in animal models and human bronchial epithelial cell culture show varying impact on inflammation and airway remodelling. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr PEROTIN has nothing to disclose. Conflict of interest: Dr Schofield has nothing to disclose. Conflict of interest: Dr Wilson has nothing to disclose. Conflict of interest: Dr Ward has nothing to disclose. Conflict of interest: Dr Brandsma has nothing to disclose. Conflict of interest: Dr Strazzeri has nothing to disclose. Conflict of interest: Dr Bansal has nothing to disclose. Conflict of interest: Dr Yang has nothing to disclose. Conflict of interest: Dr Rowe reports and a full time employee and shareholder of Janssen Pharmaceutical Companies of Johnson and Johnson. Conflict of interest: Miss Corfield has nothing to disclose. Conflict of interest: Dr Lutter has nothing to disclose. Conflict of interest: Prof. Shaw reports personal fees and non-financial support from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Teva, personal fees from Circassia, and a grant from GSK, outside the submitted work. Conflict of interest: Dr Bakke reports personal fees from GSK, AZ, Novartis andTeva, outside the submitted work. Conflict of interest: MC have no conflict of interest to disclose. Conflict of interest: Dr Dahlen has nothing to disclose. Conflict of interest: Dr Fowler reports personal fees and non-financial support from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Teva, outside the submitted work. Conflict of interest: Dr Horvath reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novartis, CSL, Chiesi, Roche, GSK, Berlin-Chemie and Sandoz, outside the submitted work. Conflict of interest: Dr Howarth reports personal fees from GSK, outside the submitted work. Conflict of interest: Dr Krug has nothing to disclose. Conflict of interest: Dr Montuschi has nothing to disclose. Conflict of interest: Dr Sanak has nothing to disclose. Conflict of interest: Dr Sandstrom reports other monetary support from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr Sun has nothing to disclose. Conflict of interest: Dr Pandis has nothing to disclose. Conflict of interest: Dr Auffray reports grants from Innovative Medicine Initiative, during the conduct of the study. Conflict of interest: Dr De Meulder reports grants from Innovative Medicine Initiative, during the conduct of the study. Conflict of interest: Ms. Lefaudeux reports grants from Innovative Medicine Initiative, grants from Innovative Medicine Initiative, during the conduct of the study. Conflict of interest: Dr Riley reports and I have shares in and I am employed by GSK. Conflict of interest: Dr Sousa has nothing to disclose. Conflict of interest: Dr Dahlen has nothing to disclose. Conflict of interest: Dr Adcock reports grants from EU-IMI, during the conduct of the study. Conflict of interest: KFC has received honoraria for participating in Advisory Board meetings of GSK, AZ, BI, Teva, Novartis and Merck regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. Conflict of interest: Dr Sterk reports grants from Innovative Medicines Initiative, during the conduct of the study. Conflict of interest: Dr Skipp has nothing to disclose. Conflict of interest: Dr Collins reports a patent application for use of a genetically modified Drosophila line carrying one or more mammalian genes associated with a chronic respiratory disease and uses to screen the impact of such genes. Conflict of interest: Dr Davies has nothing to disclose. Conflict of interest: Dr Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline. He is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company.

Published
2019
Full Text
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17. Stratification of asthma phenotypes by airway proteomic signatures

Author

Schofield, James P. R., Burg, Dominic, Nicholas, Ben, Strazzeri, Fabio, Brandsma, Joost, Staykova, Doroteya, Folisi, Caterina, Bansal, Aruna T., Xian, Yang, Guo, Yike, Rowe, Anthony, Corfield, Julie, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven-Erik, Fowler, Stephen J., Horvath, Ildiko, Howarth, Peter, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandstrom, Thomas, Sun, Kai, Pandis, Ioannis, Riley, John, Auffray, Charles, De Meulder, Bertrand, Lefaudeux, Diane, Sousa, Ana R., Adcock, Ian M., Chung, Kian Fan, Sterk, Peter J., Skipp, Paul J., Djukanovic, Ratko, Ahmed, H., Allen, D., Badorrek, P., Ballereau, S., Baribaud, F., Batuwitage, M. K., Bedding, A., Behndig, A. F., Berglind, A., Berton, A., Bigler, J., Boedigheimer, M. J., Bonnelykke, K., Brinkman, P., Bush, A., Campagna, D., Casaulta, C., Chaiboonchoe, A., Davison, T., De Meulder, B., Delin, I., Dennison, P., Dodson, P., El Hadjam, L., Erzen, D., Faulenbach, C., Fichtner, K., Fitch, N., Formaggio, E., Gahlemann, M., Galffy, G., Garissi, D., Garret, T., Gent, J., Guillmant-Farry, E., Henriksson, E., Hoda, U., Hohlfeld, J. M., Hu, X., James, A., Johnson, K., Jullian, N., Kerry, G., Klueglich, M., Knowles, R., Konradsen, J. R., Kretsos, K., Krueger, L., Lantz, A. -S, Larminie, C., Latzin, P., Lefaudeux, D., Lemonnier, N., Lowe, L. A., Lutter, R., Manta, A., Mazein, A., McEvoy, L., Menzies-Gow, A., Mores, N., Murray, C. S., Nething, K., Nihlen, U., Niven, R., Nordlund, B., Nsubuga, S., Pellet, J., Pison, C., Pratico, G., Puig Valls, M., Riemann, K., Rocha, J. P., Rossios, C., Santini, G., Saqi, M., Scott, S., Sehgal, N., Selby, A., Soderman, P., Sogbesan, A., Spycher, F., Stephan, S., Stokholm, J., Sunther, M., Szentkereszty, M., Tamasi, L., Tariq, K., Valente, S., van Aalderen, W. M., van Drunen, C. M., Van Eyll, J., Vyas, A., Yu, W., Zetterquist, W., Zolkipli, Z., Zwinderman, A. H., Adriaens, Nora, Aliprantis, Antonios, Alving, Kjell, Bakke, Per, Balgoma, David, Barber, Clair, Baribaud, Frederic, Bates, Stewart, Bautmans, An, Beleta, Jorge, Bochenek, Grazyna, Braun, Armin, Carayannopoulos, Leon, Rocha, Joao Pedro Carvalho da Purificacao, Chaleckis, Romanas, D'Amico, Arnaldo, De Alba, Jorge, De Lepeleire, Inge, Dekker, Tamara, Dijkhuis, Annemiek, Draper, Aleksandra, Edwards, Jessica, Emma, Rosalia, Ericsson, Magnus, Flood, Breda, Gallart, Hector, Gomez, Cristina, Gove, Kerry, Gozzard, Neil, Haughney, John, Hewitt, Lorraine, Hohlfeld, Jens, Holweg, Cecile, Hu, Richard, Hu, Sile, Kamphuis, Juliette, Kennington, Erika J., Kerry, Dyson, Knobel, Hugo, Kolmert, Johan, Kots, Maxim, Kuo, Scott, Kupczyk, Maciej, Lambrecht, Bart, Lone-Latif, Saeeda, Loza, Matthew J., Marouzet, Lisa, Martin, Jane, Masefield, Sarah, Mathon, Caroline, Meah, Sally, Meiser, Andrea, Metcalf, Leanne, Mikus, Maria, Miralpeix, Montse, Monk, Philip, Naz, Shama, Nilsson, Peter, Ostling, Jorgen, Pacino, Antonio, Palkonen, Susanna, Pavlidis, Stelios, Pennazza, Giorgio, Petren, Anne, Pink, Sandy, Postle, Anthony, Powell, Pippa, Rahman-Amin, Malayka, Rao, Navin, Ravanetti, Lara, Ray, Emma, Reinke, Stacey, Reynolds, Leanne, Robberechts, Martine, Roberts, Amanda, Russell, Kirsty, Rutgers, Michael, Santoninco, Marco, Schoelch, Corinna, Sjodin, Marcus, Smids, Barbara, Smith, Caroline, Smith, Jessica, Smith, Katherine M., Thorngren, John-Olof, Thornton, Bob, Thorsen, Jonathan, van de Pol, Marianne, van Geest, Marleen, Versnel, Jenny, Vink, Anton, Wald, Frans, Walker, Samantha, Weiszhart, Zsoka, Wetzel, Kristiane, Wheelock, Craig E., Wiegman, Coen, Williams, Sian, Wilson, Susan J., Woodcock, Ashley, Yang, Xian, Yeyasingham, Elizabeth, Prins, Jan-Bas, Gahlemann, Martina, Visintin, Luigi, Evans, Hazel, Puhl, Martine, Buzermaniene, Lina, Hudson, Val, Bond, Laura, de Boer, Pim, Widdershoven, Guy, Sigmund, Ralf, Supple, David, Hamerlijnck, Dominique, Negus, Jenny, Kamphuis, Julitte, Sergison, Lehanne, Onstein, Susanne, MacNee, William, Bernardini, Renato, Bont, Louis, Wecksell, Per-Ake, Schofield, James P. R., Burg, Dominic, Nicholas, Ben, Strazzeri, Fabio, Brandsma, Joost, Staykova, Doroteya, Folisi, Caterina, Bansal, Aruna T., Xian, Yang, Guo, Yike, Rowe, Anthony, Corfield, Julie, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven-Erik, Fowler, Stephen J., Horvath, Ildiko, Howarth, Peter, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandstrom, Thomas, Sun, Kai, Pandis, Ioannis, Riley, John, Auffray, Charles, De Meulder, Bertrand, Lefaudeux, Diane, Sousa, Ana R., Adcock, Ian M., Chung, Kian Fan, Sterk, Peter J., Skipp, Paul J., Djukanovic, Ratko, Ahmed, H., Allen, D., Badorrek, P., Ballereau, S., Baribaud, F., Batuwitage, M. K., Bedding, A., Behndig, A. F., Berglind, A., Berton, A., Bigler, J., Boedigheimer, M. J., Bonnelykke, K., Brinkman, P., Bush, A., Campagna, D., Casaulta, C., Chaiboonchoe, A., Davison, T., De Meulder, B., Delin, I., Dennison, P., Dodson, P., El Hadjam, L., Erzen, D., Faulenbach, C., Fichtner, K., Fitch, N., Formaggio, E., Gahlemann, M., Galffy, G., Garissi, D., Garret, T., Gent, J., Guillmant-Farry, E., Henriksson, E., Hoda, U., Hohlfeld, J. M., Hu, X., James, A., Johnson, K., Jullian, N., Kerry, G., Klueglich, M., Knowles, R., Konradsen, J. R., Kretsos, K., Krueger, L., Lantz, A. -S, Larminie, C., Latzin, P., Lefaudeux, D., Lemonnier, N., Lowe, L. A., Lutter, R., Manta, A., Mazein, A., McEvoy, L., Menzies-Gow, A., Mores, N., Murray, C. S., Nething, K., Nihlen, U., Niven, R., Nordlund, B., Nsubuga, S., Pellet, J., Pison, C., Pratico, G., Puig Valls, M., Riemann, K., Rocha, J. P., Rossios, C., Santini, G., Saqi, M., Scott, S., Sehgal, N., Selby, A., Soderman, P., Sogbesan, A., Spycher, F., Stephan, S., Stokholm, J., Sunther, M., Szentkereszty, M., Tamasi, L., Tariq, K., Valente, S., van Aalderen, W. M., van Drunen, C. M., Van Eyll, J., Vyas, A., Yu, W., Zetterquist, W., Zolkipli, Z., Zwinderman, A. H., Adriaens, Nora, Aliprantis, Antonios, Alving, Kjell, Bakke, Per, Balgoma, David, Barber, Clair, Baribaud, Frederic, Bates, Stewart, Bautmans, An, Beleta, Jorge, Bochenek, Grazyna, Braun, Armin, Carayannopoulos, Leon, Rocha, Joao Pedro Carvalho da Purificacao, Chaleckis, Romanas, D'Amico, Arnaldo, De Alba, Jorge, De Lepeleire, Inge, Dekker, Tamara, Dijkhuis, Annemiek, Draper, Aleksandra, Edwards, Jessica, Emma, Rosalia, Ericsson, Magnus, Flood, Breda, Gallart, Hector, Gomez, Cristina, Gove, Kerry, Gozzard, Neil, Haughney, John, Hewitt, Lorraine, Hohlfeld, Jens, Holweg, Cecile, Hu, Richard, Hu, Sile, Kamphuis, Juliette, Kennington, Erika J., Kerry, Dyson, Knobel, Hugo, Kolmert, Johan, Kots, Maxim, Kuo, Scott, Kupczyk, Maciej, Lambrecht, Bart, Lone-Latif, Saeeda, Loza, Matthew J., Marouzet, Lisa, Martin, Jane, Masefield, Sarah, Mathon, Caroline, Meah, Sally, Meiser, Andrea, Metcalf, Leanne, Mikus, Maria, Miralpeix, Montse, Monk, Philip, Naz, Shama, Nilsson, Peter, Ostling, Jorgen, Pacino, Antonio, Palkonen, Susanna, Pavlidis, Stelios, Pennazza, Giorgio, Petren, Anne, Pink, Sandy, Postle, Anthony, Powell, Pippa, Rahman-Amin, Malayka, Rao, Navin, Ravanetti, Lara, Ray, Emma, Reinke, Stacey, Reynolds, Leanne, Robberechts, Martine, Roberts, Amanda, Russell, Kirsty, Rutgers, Michael, Santoninco, Marco, Schoelch, Corinna, Sjodin, Marcus, Smids, Barbara, Smith, Caroline, Smith, Jessica, Smith, Katherine M., Thorngren, John-Olof, Thornton, Bob, Thorsen, Jonathan, van de Pol, Marianne, van Geest, Marleen, Versnel, Jenny, Vink, Anton, Wald, Frans, Walker, Samantha, Weiszhart, Zsoka, Wetzel, Kristiane, Wheelock, Craig E., Wiegman, Coen, Williams, Sian, Wilson, Susan J., Woodcock, Ashley, Yang, Xian, Yeyasingham, Elizabeth, Prins, Jan-Bas, Gahlemann, Martina, Visintin, Luigi, Evans, Hazel, Puhl, Martine, Buzermaniene, Lina, Hudson, Val, Bond, Laura, de Boer, Pim, Widdershoven, Guy, Sigmund, Ralf, Supple, David, Hamerlijnck, Dominique, Negus, Jenny, Kamphuis, Julitte, Sergison, Lehanne, Onstein, Susanne, MacNee, William, Bernardini, Renato, Bont, Louis, and Wecksell, Per-Ake

Abstract

Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.

Published
2019
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18. IL-17-high asthma with features of a psoriasis immunophenotype

Author

Östling, Jörgen, van Geest, Marleen, Schofield, James P. R., Jevnikar, Zala, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven-Erik, Fowler, Stephen J., Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandström, Thomas, Sun, Kai, Pandis, Ioannis, Auffray, Charles, Sousa, Ana R., Guo, Yike, Adcock, Ian M., Howarth, Peter, Chung, Kian Fan, Bigler, Jeanette, Sterk, Peter J., Skipp, Paul J., Djukanovic, Ratko, Vaarala, Outi, Ahmed, H., Auffray, C., Bakke, P., Bansal, A. T., Baribaud, F., Bates, S., Bel, E. H., Bigler, J., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Caruso, M., Chaiboonchoe, A., Chanez, P., Chung, K. F., Compton, C. H., Corfield, J., D'Amico, A., Dahlen, S. E., De Meulder, B., Djukanovic, R., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L. J., Formaggio, E., Fowler, S. J., Frey, U., Gahlemann, M., Geiser, T., Guo, Y., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C., Horvath, I., Howarth, P., James, A. J., Knowles, R., Knox, A. J., Krug, N., Lefaudeux, D., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Middelveld, R. J. M., Miralpeix, M., Montuschi, P., Mores, N., Murray, C. S., Musial, J., Myles, D., Pahus, L., Pandis, I., Pavlidis, S., Powell, P., Pratico, G., Valls, M. Puig, Rao, N., Riley, J., Roberts, A., Roberts, G., Rowe, A., Sandström, T., Seibold, W., Selby, A., Shaw, D. E., Sigmund, R., Singer, F., Skipp, P. J., Sousa, A. R., Sterk, P. J., Sun, K., Thornton, B., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, C. E., Wilson, S. J., Östling, Jörgen, van Geest, Marleen, Schofield, James P. R., Jevnikar, Zala, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven-Erik, Fowler, Stephen J., Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandström, Thomas, Sun, Kai, Pandis, Ioannis, Auffray, Charles, Sousa, Ana R., Guo, Yike, Adcock, Ian M., Howarth, Peter, Chung, Kian Fan, Bigler, Jeanette, Sterk, Peter J., Skipp, Paul J., Djukanovic, Ratko, Vaarala, Outi, Ahmed, H., Auffray, C., Bakke, P., Bansal, A. T., Baribaud, F., Bates, S., Bel, E. H., Bigler, J., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Caruso, M., Chaiboonchoe, A., Chanez, P., Chung, K. F., Compton, C. H., Corfield, J., D'Amico, A., Dahlen, S. E., De Meulder, B., Djukanovic, R., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L. J., Formaggio, E., Fowler, S. J., Frey, U., Gahlemann, M., Geiser, T., Guo, Y., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C., Horvath, I., Howarth, P., James, A. J., Knowles, R., Knox, A. J., Krug, N., Lefaudeux, D., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Middelveld, R. J. M., Miralpeix, M., Montuschi, P., Mores, N., Murray, C. S., Musial, J., Myles, D., Pahus, L., Pandis, I., Pavlidis, S., Powell, P., Pratico, G., Valls, M. Puig, Rao, N., Riley, J., Roberts, A., Roberts, G., Rowe, A., Sandström, T., Seibold, W., Selby, A., Shaw, D. E., Sigmund, R., Singer, F., Skipp, P. J., Sousa, A. R., Sterk, P. J., Sun, K., Thornton, B., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, C. E., and Wilson, S. J.

Abstract

Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Published
2019
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19. A computational framework for complex disease stratification from multiple large-scale datasets

Author

De Meulder, B., Lefaudeux, D., Bansal, A. T., Mazein, A., Chaiboonchoe, A., Ahmed, H., Balaur, I., Saqi, M., Pellet, J., Ballereau, S., Lemonnier, N., Sun, K., Pandis, I., Yang, X., Batuwitage, M., Kretsos, K., van Eyll, J., Bedding, A., Davison, T., Dodson, P., Larminie, C., Postle, A., Corfield, J., Djukanovic, R., Chung, K. F., Adcock, I. M., Guo, Y. -K., Sterk, P. J., Manta, A., Rowe, A., Baribaud, F., Auffray, C., Gibeon, D., Hoda, U., Kuo, S., Meah, S., Meiser, A., Fleming, L. J., Hu, S., Pavlidis, S., Rossios, C., Russel, K., Wiegman, C., Nezhad, A. T., Oehmichen, A., O'Malley, D., Guitton, F., Emam, I., Agapow, P., Rice, P., Miles, S., Elyasigomari, V., Bel, E., Brinkman, P., Dekker, T., Dijkhuis, A., Hashimoto, S., Hekking, P. -P., Lone-Latif, S., Lutter, R., Ravanetti, L., Smids, B., van Aalderen, W., van de Pol, M., van Drunen, K., van Drunen, M., Wagener, A., Zwinderman, K., Adriaens, N., Carusi, A. M., Richard, F., Nogueira, M. M., Taibi, N., Brasier, O., Aliprantis, A., Alving, K., Faulenbach, C., Braun, A., Hohlfeld, J., Krug, N., Badorrek, P., Bakke, P., Berglind, A., Chaleckis, R., Dahlen, B., Delin, I., Gallart, H., Gomez, C., Hedlin, G., Henriksson, E., James, A. J., Kolmert, J., Konradsen, J., Kupczyk, M., Lantz, A. -S., Lazarinis, L., Mathon, C., Middelveld, R., Naz, S., Nordlund, B., Petren, A., Reinke, S., Sjodin, M., Soderman, P., Strandberg, K., Wheelock, C. E., Zetterquist, W., Balgoma, D., Brandsma, J., Burg, D., Dennison, P., Nicholas, B., Schofield, J. P. R., Skipp, P. J., Staykova, D., Tariq, K., Ward, J., Wilson, S. J., Barber, C., Loza, M. J., Bautmans, A., Sandstrom, T., Behndig, A. F., De Alba, J., Beleta, J., Berton, A., de Verdier, M. G., Nihlen, U., Ostling, J., Dalentoft, T., Lindgren, E., Boedigheimer, M. J., Hu, R., Hu, X., Yu, W., Bigler, J., Bonnelykke, K., Thorsen, J., Vising, N., Bisgaard, H., Bochenek, G., Caruso, M., Emma, R., Campagna, D., Thornton, B., Carayannopoulos, L., Gent, J., Manzies-Gow, A., Sogbesan, A., da Purificacao Rocha, P. C., Pedro, J., Chanez, P., Edwards, J., Flood, B., Hudson, V., Kennington, E. J., Metcalf, L., Rahman-Amin, M., Reynolds, L., Roberts, A., Smith, J., Supple, D., Versnel, J., Walker, S., Coleman, C., Hasan, S., Compton, C., Myles, D., Riley, J., Sousa, A. R., Yeyasingham, E., Pennazza, G., Santoninco, M., D'Amico, A., Dahlen, S. -E., de Boer, P., Robberechts, M., De Lepeleire, I., Fitch, N., Garret, T., Wagers, S., Draper, A., Thorngren, J. -O., Ericsson, M., Erpenbeck, V., Kluglich, M., Nething, K., Riemann, K., Schoelch, C., Seibold, W., Sigmund, R., Wald, F., Wetzel, K., Fichtner, K., Erzen, D., Galffy, G., Horvath, I., Szentkereszty, M., Tamasi, L., Fowler, S. J., Krueger, L., Singer, F., Frey, U., Gahlemann, M., Geiser, T., Hewitt, L., Howarth, P., Marouzet, L., Martin, J., Pink, S., Ray, E., Roberts, G., Smith, C., Gove, K., Gozzard, N., Williams, S., Haughney, J., Higgenbottam, T., Matthews, J. G., Holweg, C., Rutgers, M., Kamphuis, J., Kerry, D., Vink, A., Knobel, H., Knowles, R., Shaw, D. E., Smith, K. M., Know, A., Kots, M., Lambrecht, B., Masefield, S., Nilsson, P., Mikus, M., Miralpeix, M., Monk, P., Mores, N., Valente, S., Montuschi, P., Murray, C. S., Musial, J., Pacino, A., Pahus, L., Palkonen, S., Powel, P., Rao, N., Santini, G., Vestbo, J., von Garnier, C., Weiszhart, Z., Woodcock, A., Biryukov, M., Schneider, R., Herzinger, S., Satagopam, V., Gu, W., da Silva, A. B., Tielmann, A., Bergeron, J., Gaudette, A., Silberberg, A., Henderson, D., Hayat, S., Elefsinioti, A., Moltzen, E. K., Harbo, I. S., Birgitte, J., Bratfalean, D., Houston, P., Kisler, B., Capdevila, F. B., Verbeeck, D., Marchetti, G., Rahal, G., Schuermann, H. D., Mazuranok, L., Hendlich, M., Painell'S, L., Marren, D., Martasek, J., Rimell, J., Romacker, M., Braxenthaler, M., Sansone, S. -A., Rocca-Serra, P., Commission of the European Communities, Pulmonology, Graduate School, Experimental Immunology, Paediatric Pulmonology, Ear, Nose and Throat, Epidemiology and Data Science, APH - Methodology, ARD - Amsterdam Reproduction and Development, Consortium, U-Biopred Study Group And The Etriks, Rocca-Serra, P, Sansone, S, De Meulder, Bertrand [0000-0002-2108-7657], and Apollo - University of Cambridge Repository

Subjects
Quality Control, 0301 basic medicine, Computer science, Bioinformatics, Systems biology, Big data, Environmental data, Machine Learning, Set (abstract data type), 03 medical and health sciences, Structural Biology, Modelling and Simulation, Cluster Analysis, U-BIOPRED Study Group and the eTRIKS Consortium, Disease, False Positive Reactions, Cluster analysis, Molecular signatures, Molecular Biology, lcsh:QH301-705.5, ‘Omics data, 'Omics data, business.industry, Systems Biology, Applied Mathematics, 1199 Other Medical And Health Sciences, Data science, 3. Good health, Computer Science Applications, Systems medicine, 030104 developmental biology, lcsh:Biology (General), Feature (computer vision), Modeling and Simulation, Stratification, Scale (map), business, Biomarkers, Research Article
Abstract

Background Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-‘omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-‘omics signatures of disease states. Methods The framework is divided into four major steps: dataset subsetting, feature filtering, ‘omics-based clustering and biomarker identification. Results We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-‘omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. Conclusions This framework will help health researchers plan and perform multi-‘omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine. Electronic supplementary material The online version of this article (10.1186/s12918-018-0556-z) contains supplementary material, which is available to authorized users.

Published
2018
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20. Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial

Author

Wanner, Christoph, Heerspink, Hiddo J. L., Zinman, Bernard, Inzucchi, Silvio E., Koitka-Weber, Audrey, Mattheus, Michaela, Hantel, Stefan, Woerle, Hans-Juergen, Broedl, Uli C., von Eynatten, Maximilian, Groop, Per-Henrik, Aizenberg, D., Ulla, M., Waitman, J., De Loredo, L., Farias, J., Fideleff, H., Lagrutta, M., Maldonado, N., Colombo, H., Ferre Pacora, F., Wasserman, A., Maffei, L., Lehman, R., Selvanayagam, J., d'Emden, M., Fasching, P., Paulweber, B., Toplak, H., Luger, A., Drexel, H., Prager, R., Schnack, C., Schernthaner, G., Fliesser-Goerzer, E., Kaser, S., Scheen, A., Van Gaal, Luc, Hollanders, G., Kockaerts, Y., Capiau, L., Chachati, A., Persu, A., Hermans, M., Vantroyen, D., Vercammen, C., Van de Borne, P., Mathieu, C., Benhalima, Katrien, Lienart, F., Mortelmans, J., Strivay, M., Vereecken, G., Keymeulen, B., Lamkanfi, F., Chacra, A., Eliaschewitz, F., Zanella, M., Faludi, A., Bertolami, M., Hayashida, C., Nunes Salles, J., Monte, O., Dinato, M., Manenti, E., Rassi, N., Halpern, A., Lima Filho, M., Ayoub, J., Felicio, J., Borges, J., Gross, J., Sgarbi, J., Betti, R., Tiburcio, A., Purisch, S., Schmid, H., Takahashi, M., Castro, M., Rea, R., Hissa, M., Geloneze Neto, B., Saraiva, J., Henein, S., Lochnan, H., Imran, S. A., Clayton, D., Bayly, K., Berlingieri, J., Boucher, P., Chan, Y., Gupta, M., Chehayeb, R., Ouellett, A., Ur, E., Woo, V., Zinman, B., St Amour, E., Terront Lozano, M., Yupanqui Lozno, H., Urina, M., Lopez Jaramillo, P., Jaramillo, N., Sanchez, G., Perez, G., Tusek, S., Mirosevic, G., Goldoni, V., Jurisic-Erzen, D., Balasko, A., Balic, S., Drvodelic-Sunic, E., Varzic, S. Canecki, Machkova, M., Weiner, P., Lastuvka, J., Olsovsky, J., Krarup, T., Ridderstrale, M., Tarnow, L., Boesgaard, T. Wellov, Lihn, A. Saetre, Christensen, P., Juhl, H., Urhammer, S., Lund, P., Adojaan, B., Jakovlev, U., Lanno, R., Lubi, M., Marandi, T., Gouet, D., Courreges, J., Zaoui, P., Choukroun, G., Petit, C., Formagne, L., Estour, B., Mabire, P., Daugenet, C., Lemarie, B., Clavel, S., Aure, P., Remaud, P., Halimi, J., Hadjadj, S., Couffinhal, T., Glonti, S., Metreveli, D., Lominadze, Z., Giorgadze, E., Burtchuladze, T., Javashvili, L., Kurashvili, G., Kurashvili, R., Virsaladze, D., Nadareishvili, L., Khomasuridze, A., Cahill, T., Green, F., MacRury, S., Waldron, M., Middleton, A., McKnight, J., Pearson, E., Butler, M., Choksi, M., Caldwell, I., Farmer, I., Wyatt, N., Patrick, J., O'Brien, I., Devers, M., Bousboulas, S., Pappas, S., Piaditis, G., Vryonidou, A., Tentolouris, N., Karamitsos, K., Manes, C., Benroubi, M., Avramidis, I., Ozaki, R., Tan, K., Siu, S., Tsang, C., Dudas, M., Nagy, K., Salamon, C., Ip, T., Geroo, L., Patkay, J., Tabak, A., Juhasz, F., Szentpeteri, I., Tamas, G., Ghaisas, N., Bantwal, G., Mohan, V., Gupta, J., Sadhu, N., Kulkarni, A., Garg, N., Reddy, S., Deshpande, N., Gutlapalli, K., Pillai, M., Premchand, R., Badgandi, M., Jain, S., Aravind, S., Shamanna, P., Pandey, A., Gupta, S., Pramono, B., Saksono, H. Dante, Agung, P., Wahono, S. Djoko, Suastika, K., Tanggo, Y., Juwana, Y., Siswanto, B., Adawi, F., Efrati, S., Mazen, E., Bashkin, A., Herskovits, T., Jaffe, A., Schiff, E., Wainstein, J., Taddei, S., Aiello, A., Arca, M., Calabro, P., Cignarelli, M., Fioretto, P., Reggiani, G. Marchesini, Gnasso, A., Marchionni, N., Marsilii, A., Bucci, M., Mezzetti, A., Pozzilli, P., Colivicchi, F., Santini, M., Moro, E., Toscano, V., Fucili, A., Semplicini, A., Monno, S., Furui, K., Higashiue, S., Hiramatsu, N., Kawamitsu, K., Takenaka, T., Takahashi, H., Hojo, F., Onishi, Y., Izumino, K., Okubo, M., Wakida, Y., Kondo, Y., Hieshima, K., Jinnouchi, H., Suzuki, A., Ito, M., Park, S., Kim, Y., Hong, T., Park, H., Gwon, H., Kim, H., Kang, K., Jeong, M., Seung, K., Lim, D., Rha, S., Tahk, S., Yang, J., Yoon, J., Shin, M., Kim, D., Jeong, J., Ahmad, N. Nik, Mustafa, N., Mohamed, W. Wan, Fung, Y., Ghani, R. Abdul, Chandramouli, A., Chee, K., Kadir, K. Abdul, Ling, K., Abu Hassan, M., Foo, S., Lee, S., Garcia Hernandez, P., Aguilar-Salinas, C., Vidrio Velazquez, M., Flores, F., Alpizar Salazar, M., Micher Escalante, D., Garcia Soria, M., Cardona Munoz, E., Storms, G., Schaper, N., Kooy, A., Krekels, M., van Bemmel, T., Verhoeven, R., Mulder, H., Oldenburg-Ligtenberg, P., Gonkel, F., de Jong, A., van Soest, J., Viergever, P., Mevissen, H., Lochorn, G., Zwiers, G., Hoogslag, P., Ronner, E., Nierop, P., Al-Windy, N., Kragten, J., Dekelver, P., Benatar, J., Krebs, J., Scott, R., Heggen, E., Berz, A., Fossum, C., Hurtig, U., Langslet, G., Baranowski, M., Sparby, J., Karlsson, T., Karlsson, Thomas, Delgado Torres, C., Rodriguez Escudero, A., Lisson, R., Allemant Maldonado, A., Gallardo Rojas, W., Gonzales Bravo, L., Lema Osores, J., Farfan, J., Zapata, L., Godoy Junchaya, J., Roldan Concha, Y., Urquiaga Calderon, J., Sy, R., Tan, G., Aquitania, G., De Los Santos, G., Panelo, A., Roderos, O., Rosales, R., Toledo, R., Liwag, A., Ramoncito, H., Skokowska, E., Krzyzagorska, E., Ogorek, M., Wojnowski, L., Spyra, J., Konieczny, M., Piesiewicz, W., Kus, W., Ocicka-Kozakiewicz, A., Orlowska-Kunikowska, E., Zmuda, W., Duarte, S., Leitao, A., Monteiro, P., Rita, H., Salgado, V., Pinto, L., Queiros, J., Teixeira, J., Rogado, C., Duarte, R., Sobral do Rosario, F., Silva, A., Andrade, L., Velez, M., Brazao, M., Istratoaie, O., Lichiardopol, R., Catrinoiu, D., Militaru, C., Zetu, C., Barbonta, D., Cosma, D., Crisan, C., Pop, L., Esip, V., Khetagurova, F., Petrov, A., Arutyunov, G., Boyarkin, M., Agafyina, A., Vorokhobina, N., Petunina, N., Libov, I., Zalevskaya, A., Nikolaev, K., Barbarash, O., Potemkin, V., Bystrova, A., Krasilnikova, E., Barbarich, V., Chumakova, G., Tarasov, N., Meleshkevich, T., Zateyshchikov, D., Lantseva, O., Belenkiy, D., Obrezan, A., Rossolko, L., Fillipova, E., Yakhontova, P., Khokhlov, A., Tan, R., Sum, C., Chang, H., Distiller, L., Pretorius, M., Nortje, H., Mitha, E., Burgess, L., Blignaut, S., Venter, T., Moodley, R., Lombaard, J., Govind, U., Naidoo, V., Mookadam, M., Engelbrecht, J., Omar, M., Jurgens, J., Podgorski, G., Vawda, H., Naidoo, D., Emanuel, S., Roodt, A., Amod, A., Van Zyl, L., Segura, J., Brito, M., Fernandez-Cruz, A., Artola, S., Iglesias, R., Toural, E., Garcia-Ortiz, L., Saban, J., Mesa, J., Vidal, J., Linares, J., del Canizo, F., Rigla, M., Suarez, C., Llorente, I., Moreno, B., Antoli, A., Gomez Peralta, F., Iglesias, M., Pereg, V., de Teresa, L., Camafort, M., Trescoli, C., Satarasinghe, R., Somasundaram, N., Siyambalapitiya, S., Antonypillai, C., Bulugahapitiya, D., Medagama, U., Huang, C., Lu, Y., Hwang, J., Chiang, C., Wen, M., Chen, J., Lai, W., Chang, K., Wang, J., Yeh, H., Kriangsak, P., Deerochanawong, C., Suwanwalaikorn, S., Mangklabruks, A., Kaewsuwanna, P., Piyayotai, D., Iabluchanskyi, M., Samoylov, O., Godlevska, O., Kovalyova, O., Voloshyna, O., Tseluyko, V., Zotov, S., Vykhovanyuk, I., Dulgeroff, A., Mayfield, R., Zaniewski-Singh, M., Ullal, J., Aloi, J., De La Rosa, R., Mosely, J., Wittmer, B., Aronoff, S., Rosenfeld, J., Seidner, M., Warren, M., Fishman, N., Weiss, R., Arif, A., Sandberg, M., Lewis, D., Ball, E., Graf, R., Breton, C., Tamayo, R., Richards, R., Cefalu, W., Uwaifo, G., Zayour, D., Hoffman, J., Fitz-Patrick, D., Khan, B., Blaze, K., Bressler, P., Halpern, S., Chappell, D., Bergenstal, R., Cuddihy, R., Matfin, G., Freedman, Z., Gonzalez-Campoy, J., Lerman, S., Rendell, M., Sitar, S., Reeves, M., Howard, T., Soufer, J., Miranda-Palma, B., Laliotis, A., Shomali, M., Teltser, M., Hurley, D., Morawski, E., Cherlin, R., Houchin, V., Welch, M., Goytia-Leos, D., Syed, M., Kowaloff, E., Weinrauch, L., Peniston, J., Brockmyre, A., First, B., Feld, L., Huffman, D., Nassim, O., Gottschlich, G., Patel, A., Knopke, C., Hernandez, M., Diaz, J., Giugliano, G., Nicasio, J., Eagerton, D., Huntley, R., Reed, J., Magee, M., Hippert, R., Sofley, C., Alzohaili, O., Levins, P., Anspach, R., Shah, S., Brusco, O., Naidu, J., Lindenbaum, J., Jacks, R., Hammond, G., Arena, C., Saxman, K., Mach, M., Kerstein, H., Kereiakes, D., Wahlen, J., Wehmeier, K., Chaykin, L., Rothman, J., Fogelfeld, L., Stroger, John H., Bittar, N., Rosenstock, J., Kayne, D., Navarro, J., Colfer, H., Mokshagundam, S., Shandilya, L., Connery, L., Wysham, C., Dela Llana, A., Jardula, M., MacAdams, M., Flippo, G., Heurich, E., Curtis, C., Sanders, D., Rawls, R., Velazquez, F., Osea, E., Mahood, K., Feldman, G., Eder, F., Riley, E., Fowler, W., Jain, M., Shepard, M., Schear, M., Barker, B., Strout, C., Obiekwe, O., Shanik, M., Green, C., Blakney, E., Roberson, K., Bretton, E., Pish, R., Kaveh, K., Maynard, B., Barager, W., Soldyshev, R., Austin, B., Parmar, P., Simpson, R., Chauhan, A., Kasper, J., Burr, R., Patel, N., Mariano, H., Pluto, T., Bratcher, C., Juarez, M., Levinson, L., Awad, A., Longshaw, K., Hoffman, K., Richwine, R., Molter, D., Boscia, J., Kowalyk, S., Lemis, P., Liss, J., Orr, R., Riser, J., Wood, J., Ubani, A., Paine, W., Hassani, F., Miranda, F., Hansen, V., Hansen, Val R., Farris, N., Bowden, R., Ajani, D., Maw, K., Andersen, J., Bergman, B., Dunmyer, S., Brandon, D., Anderson, M., Bononi, P., Prawer, J., Seidman, B., Cruz, H., Wilks, K., DiSanto, L., Buynak, R., Christensen, T., Denker, P., Koppel, W., Stedman, M., Lewy-Alterbaum, L., Karim, S., Shapiro, J., Gardner, T., Oskin, T., Gabra, N., Malano, J., Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Kidney Center (GKC), Methods in Medicines evaluation & Outcomes research (M2O), and EMPA-REG OUTCOME Investigators

Subjects
Male, Placebo-controlled study, PROGRESSION, Type 2 diabetes, 030204 cardiovascular system & hematology, PLACEBO-CONTROLLED TRIAL, GLOMERULAR-FILTRATION-RATE, HYPERFILTRATION, law.invention, ESTABLISHED CARDIOVASCULAR-DISEASE, Cohort Studies, MELLITUS, 0302 clinical medicine, Randomized controlled trial, Glucosides, law, Medicine, Diabetic Nephropathies, GFR DECLINE, General Medicine, Middle Aged, Nephrology, diabetes mellitus, randomized controlled trials, Disease Progression, Female, Glomerular Filtration Rate, medicine.medical_specialty, Urology, Renal function, 030209 endocrinology & metabolism, Placebo, 03 medical and health sciences, Double-Blind Method, Clinical Research, Diabetes mellitus, BASE-LINE CHARACTERISTICS, END-POINTS, Empagliflozin, Humans, Benzhydryl Compounds, Sodium-Glucose Transporter 2 Inhibitors, Aged, COTRANSPORTER 2 INHIBITION, Models, Statistical, Dose-Response Relationship, Drug, business.industry, chronic kidney disease, medicine.disease, Confidence interval, Diabetes Mellitus, Type 2, Human medicine, business
Abstract

BACKGROUND: Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes.METHODS: Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up).RESULTS: Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; PCONCLUSIONS: The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.

Published
2018

21. Both moderate and severe exacerbations accelerate physical activity decline in COPD patients

Author

Demeyer, H. Costilla-Frias, M. Louvaris, Z. Gimeno-Santos, E. Tabberer, M. Rabinovich, R.A. De Jong, C. Polkey, M.I. Hopkinson, N.S. Karlsson, N. Serra, I. Vogiatzis, I. Troosters, T. Garcia-Aymerich, J. Ivanoff, N. Karlsson, N. Corriol-Rohou, S. Jarrod, I. Erzen, D. Scuri, M. Montacchini, R. McBride, P. Kamel, N. Tabberer, M. Troosters, T. Janssens, W. Demeyer, H. Dobbels, F. De Boer, P. Kulich, K. Polkey, M.I. Hopkinson, N.S. Vogiatzis, I. Nikai, E. Van Der Molen, T. De Jong, C. Rabinovich, R.A. MacNee, B. Puhan, M.A. Frei, A.

Published
2018

22. Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers

Author

Brandsma, J., Goss, V., Yang, X., Bakke, P. S., Caruso, M., Chanez, P., Dahlen, S. -E., Fowler, S. J., Horvath, I., Krug, N., Montuschi, P., Sanak, M., Sandstrom, T., Shaw, D. E., Chung, K. F., Singer, F., Fleming, L. J., Sousa, A. R., Pandis, I., Bansal, A. T., Sterk, P. J., Djukanovic, R., Postle, A. D., Adcock, I. M., Ahmed, H., Auffray, C., Baribaud, F., Bates, S., Bel, E. H., Bigler, J., Bisgaard, H., Boedigheimer, M. J., Bonnelykke, K., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Chaiboonchoe, A., Chung, F. K., Compton, C. H., Corfield, J., D'Amico, A., Dahlen, B., De Meulder, B., Erpenbeck, V. J., Erzen, D., Fichtner, K., Fitch, N., Formaggio, E., Frey, U., Gahlemann, M., Geiser, T., Guo, Y., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P. W., Higenbottam, T., Hohlfeld, J. M., Holweg, C., Howarth, P., James, A. J., Knowles, R. G., Knox, A. J., Lefaudeux, D., Loza, M. J., Lutter, R., Manta, A., Masefield, S., Matthews, J. G., Mazein, A., Meiser, A., Middelveld, R. J. M., Miralpeix, M., Mores, N., Murray, C. S., Musial, J., Myles, D., Pahus, L., Pavlidis, S., Powel, P., Pratico, G., Puig Valls, M., Rao, N., Riley, J., Roberts, A., Roberts, G., Rowe, A., Schofield, J. P. R., Seibold, W., Selby, A., Sigmund, R., Skipp, P. J., Sun, K., Thornton, B., van Aalderen, W. M., van Geest, M., Vestbo, J., Vissing, N. H., Wagener, A. H., Wagers, S. S., Weiszhart, Z., Wheelock, C. E., Wilson, S. J., Pulmonology, AII - Inflammatory diseases, Commission of the European Communities, and Publica

Subjects
0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Epithelial lining fluid, Biochemistry, DISEASE, Analytical Chemistry, Cohort Studies, 0302 clinical medicine, Fibrosis, FIBROSIS, Induced sputum, Lung, COPD, Biochemistry and Molecular Biology, respiratory system, Middle Aged, Lipids, Healthy Volunteers, Cell biology, medicine.anatomical_structure, Phenotype, OBESITY, Original Article, lipids (amino acids, peptides, and proteins), Female, medicine.symptom, Life Sciences & Biomedicine, 0301 Analytical Chemistry, Bronchoalveolar Lavage Fluid, Sputum/chemistry, EXPRESSION, Adult, Settore BIO/14 - FARMACOLOGIA, DYNAMIC LIPIDOMICS, Adolescent, SPUTUM CELL COUNTS, BIOMARKERS, Biology, chronic obstructive pulmonary disease, Bronchoalveolar Lavage Fluid/chemistry, Endocrinology & Metabolism, 03 medical and health sciences, Young Adult, Lipids/analysis, Lung/cytology, Lipidomics, medicine, Humans, SURFACTANT LIPIDS, Aged, Science & Technology, pulmonary fibrosis, Mass spectrometry, Sputum, 0601 Biochemistry And Cell Biology, 1103 Clinical Sciences, Lipid metabolism, Pulmonary surfactant, medicine.disease, Molecular medicine, respiratory tract diseases, Weight status, 030104 developmental biology, 030228 respiratory system, ASTHMA, Biokemi och molekylärbiologi, Homeostasis
Abstract

Background Lung epithelial lining fluid (ELF)—sampled through sputum induction—is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood. Objectives To characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort. Methods Induced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes. Results The induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender. Conclusions We provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism. Electronic supplementary material The online version of this article (10.1007/s11306-018-1412-2) contains supplementary material, which is available to authorized users.

Published
2018
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23. Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk

Author

Zinman, Bernard, Inzucchi, Silvio E., Lachin, John M., Wanner, Christoph, Fitchett, David, Kohler, Sven, Mattheus, Michaela, Biomath, Dipl, Woerle, Hans J., Broedl, Uli C., Johansen, Odd Erik, Albers, Gregory W., Diener, Hans Christoph, Aizenberg, D., Ulla, M., Waitman, J., De Loredo, L., Farias, J., Fideleff, H., Lagrutta, M., Maldonado, N., Colombo, H., Ferre Pacora, F., Wasserman, A., Maffei, L., Lehman, R., Selvanayagam, J., d'Emden, M., Fasching, P., Paulweber, B., Toplak, H., Luger, A., Drexel, H., Prager, R., Schnack, C., Schernthaner, G., Fliesser-Goerzer, E., Kaser, S., Scheen, A., Van Gaal, L., Hollanders, G., Kockaerts, Y., Capiau, L., Chachati, A., Persu, A., Hermans, M., Vantroyen, D., Vercammen, C., Van de Borne, P., Mathieu, C., Benhalima, K., Lienart, F., Mortelmans, J., Strivay, M., Vereecken, G., Keymeulen, B., Lamkanfi, F., Chacra, A., Eliaschewitz, F., Zanella, M., Faludi, A., Bertolami, M., Hayashida, C., Nunes Salles, J., Monte, O., Dinato, M., Manenti, E., Rassi, N., Halpern, A., Lima Filho, M., Ayoub, J., Felicio, J., Borges, J., Gross, J., Sgarbi, J., Betti, R., Tiburcio, A., Purisch, S., Schmid, H., Takahashi, M., Castro, M., Rea, R., Hissa, M., Geloneze Neto, B., Saraiva, J., Henein, S., Lochnan, H., Imran, S. A., Clayton, D., Bayly, K., Berlingieri, J., Boucher, P., Chan, Y., Gupta, M., Chehayeb, R., Ouellett, A., Ur, E., Woo, V., Zinman, B., St Amour, E., Terront Lozano, M., Yupanqui Lozno, H., Urina, M., Lopez Jaramillo, P., Jaramillo, N., Sanchez, G., Perez, G., Tusek, S., Mirosevic, G., Goldoni, V., Jurisic-Erzen, D., Balasko, A., Balic, S., Drvodelic-Sunic, E., Varzic, S. Canecki, Machkova, M., Weiner, P., Lastuvka, J., Olsovsky, J., Krarup, T., Ridderstrale, M., Tarnow, L., Boesgaard, T. Wellov, Lihn, A. Saetre, Christensen, P., Juhl, H., Urhammer, S., Lund, P., Adojaan, B., Jakovlev, U., Lanno, R., Lubi, M., Marandi, T., Gouet, D., Courreges, J., Zaoui, P., Choukroun, G., Petit, C., Formagne, L., Estour, B., Mabire, P., Daugenet, C., Lemarie, B., Clavel, S., Aure, P., Remaud, P., Halimi, J., Hadjadj, S., Couffinhal, T., Glonti, S., Metreveli, D., Lominadze, Z., Giorgadze, E., Burtchuladze, T., Javashvili, L., Kurashvili, G., Kurashvili, R., Virsaladze, D., Nadareishvili, L., Khomasuridze, A., Cahill, T., Green, F., MacRury, S., Waldron, M., Middleton, A., McKnight, J., Pearson, E., Butler, M., Choksi, M., Caldwell, I., Farmer, I., Wyatt, N., Patrick, J., O'Brien, I., Devers, M., Bousboulas, S., Pappas, S., Piaditis, G., Vryonidou, A., Tentolouris, N., Karamitsos, K., Manes, C., Benroubi, M., Avramidis, I., Ozaki, R., Tan, K., Siu, S., Tsang, C., Dudas, M., Nagy, K., Salamon, C., Ip, T., Geroo, L., Patkay, J., Tabak, A., Juhasz, F., Szentpeteri, I., Tamas, G., Ghaisas, N., Bantwal, G., Mohan, V., Gupta, J., Sadhu, N., Kulkarni, A., Garg, N., Reddy, S., Deshpande, N., Gutlapalli, K., Pillai, M., Premchand, R., Badgandi, M., Jain, S., Aravind, S., Shamanna, P., Pandey, A., Gupta, S., Pramono, B., Saksono, H. Dante, Agung, P., Wahono, S. Djoko, Suastika, K., Tanggo, Y., Juwana, Y., Siswanto, B., Adawi, F., Efrati, S., Mazen, E., Bashkin, A., Herskovits, T., Jaffe, A., Schiff, E., Wainstein, J., Taddei, S., Aiello, A., Arca, M., Calabro, P., Cignarelli, M., Fioretto, P., Reggiani, G. Marchesini, Gnasso, A., Marchionni, N., Marsilii, A., Bucci, M., Mezzetti, A., Pozzilli, P., Colivicchi, F., Santini, M., Moro, E., Toscano, V., Fucili, A., Semplicini, A., Monno, S., Furui, K., Higashiue, S., Hiramatsu, N., Kawamitsu, K., Takenaka, T., Takahashi, H., Hojo, F., Onishi, Y., Izumino, K., Okubo, M., Wakida, Y., Kondo, Y., Hieshima, K., Jinnouchi, H., Suzuki, A., Ito, M., Park, S., Kim, Y., Hong, T., Park, H., Gwon, H., Kim, H., Kang, K., Jeong, M., Seung, K., Lim, D., Rha, S., Tahk, S., Yang, J., Yoon, J., Shin, M., Kim, D., Jeong, J., Ahmad, N. Nik, Mustafa, N., Mohamed, W. Wan, Fung, Y., Ghani, R. Abdul, Chandramouli, A., Chee, K., Kadir, K. Abdul, Ling, K., Abu Hassan, M., Foo, S., Lee, S., Garcia Hernandez, P., Aguilar-Salinas, C., Vidrio Velazquez, M., Flores, F., Alpizar Salazar, M., Micher Escalante, D., Garcia Soria, M., Cardona Munoz, E., Storms, G., Schaper, N., Kooy, A., Krekels, M., van Bemmel, T., Verhoeven, R., Mulder, H., Oldenburg-Ligtenberg, P., Gonkel, F., de Jong, A., van Soest, J., Viergever, P., Mevissen, H., Lochorn, G., Zwiers, G., Hoogslag, P., Ronner, E., Nierop, P., Al-Windy, N., Kragten, J., Dekelver, P., Benatar, J., Krebs, J., Scott, R., Heggen, E., Berz, A., Fossum, C., Hurtig, U., Langslet, G., Baranowski, M., Sparby, J., Karlsson, T., Karlsson, Thomas, Delgado Torres, C., Rodriguez Escudero, A., Lisson, R., Allemant Maldonado, A., Gallardo Rojas, W., Gonzales Bravo, L., Lema Osores, J., Farfan, J., Zapata, L., Godoy Junchaya, J., Roldan Concha, Y., Urquiaga Calderon, J., Sy, R., Tan, G., Aquitania, G., De Los Santos, G., Panelo, A., Roderos, O., Rosales, R., Toledo, R., Liwag, A., Ramoncito, H., Skokowska, E., Krzyzagorska, E., Ogorek, M., Wojnowski, L., Spyra, J., Konieczny, M., Piesiewicz, W., Kus, W., Ocicka-Kozakiewicz, A., Orlowska-Kunikowska, E., Zmuda, W., Duarte, S., Leitao, A., Monteiro, P., Rita, H., Salgado, V., Pinto, L., Queiros, J., Teixeira, J., Rogado, C., Duarte, R., Sobral do Rosario, F., Silva, A., Andrade, L., Velez, M., Brazao, M., Istratoaie, O., Lichiardopol, R., Catrinoiu, D., Militaru, C., Zetu, C., Barbonta, D., Cosma, D., Crisan, C., Pop, L., Esip, V., Khetagurova, F., Petrov, A., Arutyunov, G., Boyarkin, M., Agafyina, A., Vorokhobina, N., Petunina, N., Libov, I., Zalevskaya, A., Nikolaev, K., Barbarash, O., Potemkin, V., Bystrova, A., Krasilnikova, E., Barbarich, V., Chumakova, G., Tarasov, N., Meleshkevich, T., Zateyshchikov, D., Lantseva, O., Belenkiy, D., Obrezan, A., Rossolko, L., Fillipova, E., Yakhontova, P., Khokhlov, A., Tan, R., Sum, C., Chang, H., Distiller, L., Pretorius, M., Nortje, H., Mitha, E., Burgess, L., Blignaut, S., Venter, T., Moodley, R., Lombaard, J., Govind, U., Naidoo, V., Mookadam, M., Engelbrecht, J., Omar, M., Jurgens, J., Podgorski, G., Vawda, H., Naidoo, D., Emanuel, S., Roodt, A., Amod, A., Van Zyl, L., Segura, J., Brito, M., Fernandez-Cruz, A., Artola, S., Iglesias, R., Toural, E., Garcia-Ortiz, L., Saban, J., Mesa, J., Vidal, J., Linares, J., del Canizo, F., Rigla, M., Suarez, C., Llorente, I., Moreno, B., Antoli, A., Gomez Peralta, F., Iglesias, M., Pereg, V., de Teresa, L., Camafort, M., Trescoli, C., Satarasinghe, R., Somasundaram, N., Siyambalapitiya, S., Antonypillai, C., Bulugahapitiya, D., Medagama, U., Huang, C., Lu, Y., Hwang, J., Chiang, C., Wen, M., Chen, J., Lai, W., Chang, K., Wang, J., Yeh, H., Kriangsak, P., Deerochanawong, C., Suwanwalaikorn, S., Mangklabruks, A., Kaewsuwanna, P., Piyayotai, D., Iabluchanskyi, M., Samoylov, O., Godlevska, O., Kovalyova, O., Voloshyna, O., Tseluyko, V., Zotov, S., Vykhovanyuk, I., Dulgeroff, A., Mayfield, R., Zaniewski-Singh, M., Ullal, J., Aloi, J., De La Rosa, R., Mosely, J., Wittmer, B., Aronoff, S., Rosenfeld, J., Seidner, M., Warren, M., Fishman, N., Weiss, R., Arif, A., Sandberg, M., Lewis, D., Ball, E., Graf, R., Breton, C., Tamayo, R., Richards, R., Cefalu, W., Uwaifo, G., Zayour, D., Hoffman, J., Fitz-Patrick, D., Khan, B., Blaze, K., Bressler, P., Halpern, S., Chappell, D., Bergenstal, R., Cuddihy, R., Matfin, G., Freedman, Z., Gonzalez-Campoy, J., Lerman, S., Rendell, M., Sitar, S., Reeves, M., Howard, T., Soufer, J., Miranda-Palma, B., Laliotis, A., Shomali, M., Teltser, M., Hurley, D., Morawski, E., Cherlin, R., Houchin, V., Welch, M., Goytia-Leos, D., Syed, M., Kowaloff, E., Weinrauch, L., Peniston, J., Brockmyre, A., First, B., Feld, L., Huffman, D., Nassim, O., Gottschlich, G., Patel, A., Knopke, C., Hernandez, M., Diaz, J., Giugliano, G., Nicasio, J., Eagerton, D., Huntley, R., Reed, J., III, Magee, M., Hippert, R., Sofley, C., Jr., Alzohaili, O., Levins, P., Anspach, R., Shah, S., Brusco, O., Naidu, J., Lindenbaum, J., Jacks, R., Hammond, G., Arena, C., Saxman, K., Mach, M., Kerstein, H., Kereiakes, D., Wahlen, J., Wehmeier, K., Chaykin, L., Rothman, J., Fogelfeld, L., Stroger, John H., Jr., Bittar, N., Rosenstock, J., Kayne, D., Navarro, J., Colfer, H., Mokshagundam, S., Shandilya, L., Connery, L., Wysham, C., Dela Llana, A., Jardula, M., MacAdams, M., Flippo, G., Heurich, E., Curtis, C., Sanders, D., Rawls, R., Velazquez, F., Osea, E., Mahood, K., Feldman, G., Eder, F., Riley, E., Fowler, W., Jain, M., Shepard, M., Schear, M., Barker, B., Strout, C., Obiekwe, O., Shanik, M., Green, C., Blakney, E., Roberson, K., Bretton, E., Pish, R., Kaveh, K., Maynard, B., Barager, W., Soldyshev, R., Austin, B., Parmar, P., Simpson, R., Chauhan, A., Kasper, J., Burr, R., Patel, N., Mariano, H., Pluto, T., Bratcher, C., Juarez, M., Levinson, L., Awad, A., Longshaw, K., Hoffman, K., Richwine, R., Molter, D., Boscia, J., III, Kowalyk, S., Lemis, P., Liss, J., Orr, R., Riser, J., Wood, J., Ubani, A., Paine, W., Hassani, F., Miranda, F., Hansen, V., Hansen, Val R., Farris, N., Bowden, R., Ajani, D., Maw, K., Andersen, J., Bergman, B., Dunmyer, S., Brandon, D., Anderson, M., Bononi, P., Prawer, J., Seidman, B., Cruz, H., Wilks, K., DiSanto, L., Buynak, R., Christensen, T., Denker, P., Koppel, W., Stedman, M., Lewy-Alterbaum, L., Karim, S., Shapiro, J., Gardner, T., Oskin, T., Gabra, N., Malano, J., and EMPA REG OUTCOME Investigators

Subjects
riesgo, compuestos de bencidrilo, type 2 diabetes mellitus, Original Contributions, humanos, Medizin, 030204 cardiovascular system & hematology, blood pressure, cardiovascular diseases, hematocrit, stroke, 0302 clinical medicine, Glucosides, glucósidos, 030212 general & internal medicine, Myocardial infarction, Stroke, mediana edad, anciano, OUTCOMES, Hazard ratio, Middle Aged, ISCHEMIC-STROKE, Anesthesia, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cardiology, TRIAL, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Risk, medicine.medical_specialty, Clinical Sciences, enfermedades cardiovasculares, Clinical Neurology, Placebo, 03 medical and health sciences, Outcome Assessment (Health Care), Internal medicine, medicine, Empagliflozin, Diabetes Mellitus, Humans, Hypoglycemic Agents, accidente cerebrovascular, Benzhydryl Compounds, METAANALYSIS, Aged, Advanced and Specialized Nursing, Science & Technology, business.industry, MORTALITY, Type 2 Diabetes Mellitus, medicine.disease, Confidence interval, Blood pressure, hipoglicemiantes, Peripheral Vascular Disease, evaluación de resultados (asistencia sanitaria), Cardiovascular System & Cardiology, Neurology (clinical), Neurosciences & Neurology, business, FOLLOW-UP
Abstract

Supplemental Digital Content is available in the text., Background and Purpose— In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89–1.56; P=0.26). We further investigated cerebrovascular events. Methods— Patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years. Results— The numeric difference in stroke between empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81–1.45; P=0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke. Conclusions— In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with empagliflozin versus placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Published
2017

24. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME (R) trial

Author

Fitchett, David, Zinman, Bernard, Wanner, Christoph, Lachin, John M., Hantel, Stefan, Salsali, Afshin, Johansen, Odd Erik, Woerle, Hans J., Broedl, Uli C., Inzucchi, Silvio E., Aizenberg, D., Ulla, M., Waitman, J., De Loredo, L., Farias, J., Fideleff, H., Lagrutta, M., Maldonado, N., Colombo, H., Ferre Pacora, F., Wasserman, A., Maffei, L., Lehman, R., Selvanayagam, J., d'Emden, M., Fasching, P., Paulweber, B., Toplak, H., Luger, A., Drexel, H., Prager, R., Schnack, C., Schernthaner, G., Fliesser-Goerzer, E., Kaser, S., Scheen, A., Van Gaal, L., Hollanders, G., Kockaerts, Y., Capiau, L., Chachati, A., Persu, A., Hermans, M., Vantroyen, D., Vercammen, C., Van de Borne, P., Mathieu, C., Benhalima, K., Lienart, F., Mortelmans, J., Strivay, M., Vereecken, G., Keymeulen, B., Lamkanfi, F., Chacra, A., Eliaschewitz, F., Zanella, M., Faludi, A., Bertolami, M., Hayashida, C., Nunes Salles, J., Monte, O., Dinato, M., Manenti, E., Rassi, N., Halpern, A., Lima Filho, M., Ayoub, J., Felicio, J., Borges, J., Gross, J., Sgarbi, J., Betti, R., Tiburcio, A., Purisch, S., Schmid, H., Takahashi, M., Castro, M., Rea, R., Hissa, M., Geloneze Neto, B., Saraiva, J., Henein, S., Lochnan, H., Imran, S. A., Clayton, D., Bayly, K., Berlingieri, J., Boucher, P., Chan, Y., Gupta, M., Chehayeb, R., Ouellett, A., Ur, E., Woo, V., Zinman, B., St Amour, E., Terront Lozano, M., Yupanqui Lozno, H., Urina, M., Lopez Jaramillo, P., Jaramillo, N., Sanchez, G., Perez, G., Tusek, S., Mirosevic, G., Goldoni, V., Jurisic-Erzen, D., Balasko, A., Balic, S., Drvodelic-Sunic, E., Varzic, S. Canecki, Machkova, M., Weiner, P., Lastuvka, J., Olsovsky, J., Krarup, T., Ridderstrale, M., Tarnow, L., Boesgaard, T. Wellov, Lihn, A. Saetre, Christensen, P., Juhl, H., Urhammer, S., Lund, P., Adojaan, B., Jakovlev, U., Lanno, R., Lubi, M., Marandi, T., Gouet, D., Courreges, J., Zaoui, P., Choukroun, G., Petit, C., Formagne, L., Estour, B., Mabire, P., Daugenet, C., Lemarie, B., Clavel, S., Aure, P., Remaud, P., Halimi, J., Hadjadj, S., Couffinhal, T., Glonti, S., Metreveli, D., Lominadze, Z., Giorgadze, E., Burtchuladze, T., Javashvili, L., Kurashvili, G., Kurashvili, R., Virsaladze, D., Nadareishvili, L., Khomasuridze, A., Cahill, T., Green, F., MacRury, S., Waldron, M., Middleton, A., McKnight, J., Pearson, E., Butler, M., Choksi, M., Caldwell, I., Farmer, I., Wyatt, N., Patrick, J., O'Brien, I., Devers, M., Bousboulas, S., Pappas, S., Piaditis, G., Vryonidou, A., Tentolouris, N., Karamitsos, K., Manes, C., Benroubi, M., Avramidis, I., Ozaki, R., Tan, K., Siu, S., Tsang, C., Dudas, M., Nagy, K., Salamon, C., Ip, T., Geroo, L., Patkay, J., Tabak, A., Juhasz, F., Szentpeteri, I., Tamas, G., Ghaisas, N., Bantwal, G., Mohan, V., Gupta, J., Sadhu, N., Kulkarni, A., Garg, N., Reddy, S., Deshpande, N., Gutlapalli, K., Pillai, M., Premchand, R., Badgandi, M., Jain, S., Aravind, S., Shamanna, P., Pandey, A., Gupta, S., Pramono, B., Saksono, H. Dante, Agung, P., Wahono, S. Djoko, Suastika, K., Tanggo, Y., Juwana, Y., Siswanto, B., Adawi, F., Efrati, S., Mazen, E., Bashkin, A., Herskovits, T., Jaffe, A., Schiff, E., Wainstein, J., Taddei, S., Aiello, A., Arca, M., Calabro, P., Cignarelli, M., Fioretto, P., Reggiani, G. Marchesini, Gnasso, A., Marchionni, N., Marsilii, A., Bucci, M., Mezzetti, A., Pozzilli, P., Colivicchi, F., Santini, M., Moro, E., Toscano, V., Fucili, A., Semplicini, A., Monno, S., Furui, K., Higashiue, S., Hiramatsu, N., Kawamitsu, K., Takenaka, T., Takahashi, H., Hojo, F., Onishi, Y., Izumino, K., Okubo, M., Wakida, Y., Kondo, Y., Hieshima, K., Jinnouchi, H., Suzuki, A., Ito, M., Park, S., Kim, Y., Hong, T., Park, H., Gwon, H., Kim, H., Kang, K., Jeong, M., Seung, K., Lim, D., Rha, S., Tahk, S., Yang, J., Yoon, J., Shin, M., Kim, D., Jeong, J., Ahmad, N. Nik, Mustafa, N., Mohamed, W. Wan, Fung, Y., Ghani, R. Abdul, Chandramouli, A., Chee, K., Kadir, K. Abdul, Ling, K., Abu Hassan, M., Foo, S., Lee, S., Garcia Hernandez, P., Aguilar-Salinas, C., Vidrio Velazquez, M., Flores, F., Alpizar Salazar, M., Micher Escalante, D., Garcia Soria, M., Cardona Munoz, E., Storms, G., Schaper, N., Kooy, A., Krekels, M., van Bemmel, T., Verhoeven, R., Mulder, H., Oldenburg-Ligtenberg, P., Gonkel, F., de Jong, A., van Soest, J., Viergever, P., Mevissen, H., Lochorn, G., Zwiers, G., Hoogslag, P., Ronner, E., Nierop, P., Al-Windy, N., Kragten, J., Dekelver, P., Benatar, J., Krebs, J., Scott, R., Heggen, E., Berz, A., Fossum, C., Hurtig, U., Langslet, G., Baranowski, M., Sparby, J., Karlsson, T., Karlsson, Thomas, Delgado Torres, C., Rodriguez Escudero, A., Lisson, R., Allemant Maldonado, A., Gallardo Rojas, W., Gonzales Bravo, L., Lema Osores, J., Farfan, J., Zapata, L., Godoy Junchaya, J., Roldan Concha, Y., Urquiaga Calderon, J., Sy, R., Tan, G., Aquitania, G., De Los Santos, G., Panelo, A., Roderos, O., Rosales, R., Toledo, R., Liwag, A., Ramoncito, H., Skokowska, E., Krzyzagorska, E., Ogorek, M., Wojnowski, L., Spyra, J., Konieczny, M., Piesiewicz, W., Kus, W., Ocicka-Kozakiewicz, A., Orlowska-Kunikowska, E., Zmuda, W., Duarte, S., Leitao, A., Monteiro, P., Rita, H., Salgado, V., Pinto, L., Queiros, J., Teixeira, J., Rogado, C., Duarte, R., Sobral do Rosario, F., Silva, A., Andrade, L., Velez, M., Brazao, M., Istratoaie, O., Lichiardopol, R., Catrinoiu, D., Militaru, C., Zetu, C., Barbonta, D., Cosma, D., Crisan, C., Pop, L., Esip, V., Khetagurova, F., Petrov, A., Arutyunov, G., Boyarkin, M., Agafyina, A., Vorokhobina, N., Petunina, N., Libov, I., Zalevskaya, A., Nikolaev, K., Barbarash, O., Potemkin, V., Bystrova, A., Krasilnikova, E., Barbarich, V., Chumakova, G., Tarasov, N., Meleshkevich, T., Zateyshchikov, D., Lantseva, O., Belenkiy, D., Obrezan, A., Rossolko, L., Fillipova, E., Yakhontova, P., Khokhlov, A., Tan, R., Sum, C., Chang, H., Distiller, L., Pretorius, M., Nortje, H., Mitha, E., Burgess, L., Blignaut, S., Venter, T., Moodley, R., Lombaard, J., Govind, U., Naidoo, V., Mookadam, M., Engelbrecht, J., Omar, M., Jurgens, J., Podgorski, G., Vawda, H., Naidoo, D., Emanuel, S., Roodt, A., Amod, A., Van Zyl, L., Segura, J., Brito, M., Fernandez-Cruz, A., Artola, S., Iglesias, R., Toural, E., Garcia-Ortiz, L., Saban, J., Mesa, J., Vidal, J., Linares, J., del Canizo, F., Rigla, M., Suarez, C., Llorente, I., Moreno, B., Antoli, A., Gomez Peralta, F., Iglesias, M., Pereg, V., de Teresa, L., Camafort, M., Trescoli, C., Satarasinghe, R., Somasundaram, N., Siyambalapitiya, S., Antonypillai, C., Bulugahapitiya, D., Medagama, U., Huang, C., Lu, Y., Hwang, J., Chiang, C., Wen, M., Chen, J., Lai, W., Chang, K., Wang, J., Yeh, H., Kriangsak, P., Deerochanawong, C., Suwanwalaikorn, S., Mangklabruks, A., Kaewsuwanna, P., Piyayotai, D., Iabluchanskyi, M., Samoylov, O., Godlevska, O., Kovalyova, O., Voloshyna, O., Tseluyko, V., Zotov, S., Vykhovanyuk, I., Dulgeroff, A., Mayfield, R., Zaniewski-Singh, M., Ullal, J., Aloi, J., De La Rosa, R., Mosely, J., Wittmer, B., Aronoff, S., Rosenfeld, J., Seidner, M., Warren, M., Fishman, N., Weiss, R., Arif, A., Sandberg, M., Lewis, D., Ball, E., Graf, R., Breton, C., Tamayo, R., Richards, R., Cefalu, W., Uwaifo, G., Zayour, D., Hoffman, J., Fitz-Patrick, D., Khan, B., Blaze, K., Bressler, P., Halpern, S., Chappell, D., Bergenstal, R., Cuddihy, R., Matfin, G., Freedman, Z., Gonzalez-Campoy, J., Lerman, S., Rendell, M., Sitar, S., Reeves, M., Howard, T., Soufer, J., Miranda-Palma, B., Laliotis, A., Shomali, M., Teltser, M., Hurley, D., Morawski, E., Cherlin, R., Houchin, V., Welch, M., Goytia-Leos, D., Syed, M., Kowaloff, E., Weinrauch, L., Peniston, J., Brockmyre, A., First, B., Feld, L., Huffman, D., Nassim, O., Gottschlich, G., Patel, A., Knopke, C., Hernandez, M., Diaz, J., Giugliano, G., Nicasio, J., Eagerton, D., Huntley, R., Reed, J., III, Magee, M., Hippert, R., Sofley, C., Jr., Alzohaili, O., Levins, P., Anspach, R., Shah, S., Brusco, O., Naidu, J., Lindenbaum, J., Jacks, R., Hammond, G., Arena, C., Saxman, K., Mach, M., Kerstein, H., Kereiakes, D., Wahlen, J., Wehmeier, K., Chaykin, L., Rothman, J., Fogelfeld, L., Stroger, John H., Jr., Bittar, N., Rosenstock, J., Kayne, D., Navarro, J., Colfer, H., Mokshagundam, S., Shandilya, L., Connery, L., Wysham, C., Dela Llana, A., Jardula, M., MacAdams, M., Flippo, G., Heurich, E., Curtis, C., Sanders, D., Rawls, R., Velazquez, F., Osea, E., Mahood, K., Feldman, G., Eder, F., Riley, E., Fowler, W., Jain, M., Shepard, M., Schear, M., Barker, B., Strout, C., Obiekwe, O., Shanik, M., Green, C., Blakney, E., Roberson, K., Bretton, E., Pish, R., Kaveh, K., Maynard, B., Barager, W., Soldyshev, R., Austin, B., Parmar, P., Simpson, R., Chauhan, A., Kasper, J., Burr, R., Patel, N., Mariano, H., Pluto, T., Bratcher, C., Juarez, M., Levinson, L., Awad, A., Longshaw, K., Hoffman, K., Richwine, R., Molter, D., Boscia, J., III, Kowalyk, S., Lemis, P., Liss, J., Orr, R., Riser, J., Wood, J., Ubani, A., Paine, W., Hassani, F., Miranda, F., Hansen, V., Hansen, Val R., Farris, N., Bowden, R., Ajani, D., Maw, K., Andersen, J., Bergman, B., Dunmyer, S., Brandon, D., Anderson, M., Bononi, P., Prawer, J., Seidman, B., Cruz, H., Wilks, K., DiSanto, L., Buynak, R., Christensen, T., Denker, P., Koppel, W., Stedman, M., Lewy-Alterbaum, L., Karim, S., Shapiro, J., Gardner, T., Oskin, T., Gabra, N., Malano, J., EMPA-REG OUTCOME Trial, and EMPA-REG OUTCOME(R) trial investigators

Subjects
medicine.medical_specialty, Cardiac & Cardiovascular Systems, Aha Fasttrack, BLOOD-PRESSURE, 030209 endocrinology & metabolism, Cardiovascular disease, Hospitalization, Mortality, Type 2 diabetes, 030204 cardiovascular system & hematology, COLLABORATION, GUIDELINES, DOUBLE-BLIND, MELLITUS, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Empagliflozin, Medicine, ddc:610, Adverse effect, Science & Technology, COTRANSPORTER 2 INHIBITION, business.industry, MORTALITY, Hazard ratio, Heart Failure/Cardiomyopathy, medicine.disease, INSULIN, Editor's Choice, Endocrinology, Blood pressure, DISEASES, SAFETY, Heart failure, Cardiovascular System & Cardiology, Number needed to treat, Cardiology, Fast Track, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine
Abstract

Aims We previously reported that in the EMPA-REG OUTCOME(R) trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure. Methods and results Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin [265/4687 patients (5.7%)] than with placebo [198/2333 patients (8.5%)] [hazard ratio, HR: 0.66 (95% confidence interval: 0.55-0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47-0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization [36.8 vs. 39.6%; HR: 0.89 (0.82-0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo. Conclusion In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure., This work was supported by Boehringer Ingelheim and Eli Lilly and Company. Boehringer Ingelheim was involved in the design and conduct of the study; collection, analysis, and interpretation of data; and preparation of this manuscript. Eli Lilly's involvement was limited to co-funding of the study. Funding to pay the Open Access publication charges for this article was provided by Boehringer Ingelheim.

Published
2016

25. Validity of physical activity monitors during daily life in patients with COPD

Author

Rabinovich, R.A. Louvaris, Z. Raste, Y. Langer, D. Van Remoortel, H. Giavedoni, S. Burtin, C. Regueiro, E.M.G. Vogiatzis, I. Hopkinson, N.S. Polkey, M.I. Wilson, F.J. MacNee, W. Westerterp, K.R. Troosters, T. Brindicci, C. Higenbottam, T. Dobbels, F. Tabberer, M.X. Garcia-Aymerich, J. Puhan, M. Frei, A. van der Molen, T. De Jong, C. de Boer, P. Jarrod, I. McBride, P. Kamel, N. Rudell, K. Ivanoff, N. Kulich, K. Glendenning, A. Karlsson, N.X. Corriol-Rohou, S. Nikai, E. Erzen, D.

Abstract

Symptoms during physical activity and physical inactivity are hallmarks of chronic obstructive pulmonary disease (COPD). Our aim was to evaluate the validity and usability of six activity monitors in patients with COPD against the doubly labelled water (DLW) indirect calorimetry method. 80 COPD patients (mean±SD age 68±6 years and forced expiratory volume in 1 s 57±19% predicted) recruited in four centres each wore simultaneously three or four out of six commercially available monitors validated in chronic conditions for 14 consecutive days. A priori validity criteria were defined. These included the ability to explain total energy expenditure (TEE) variance through multiple regression analysis, using TEE as the dependent variable with total body water (TBW) plus several physical activity monitor outputs as independent variables; and correlation with activity energy expenditure (AEE) measured by DLW. The Actigraph GT3X (Actigraph LLC, Pensacola, FL, USA), and DynaPort MoveMonitor (McRoberts BV, The Hague, the Netherlands) best explained the majority of the TEE variance not explained by TBW (53% and 70%, respectively) and showed the most significant correlations with AEE (r=0.71, p

Published
2013

26. PREGNANCY WITH TYPE I DIABETES TREATED WITH AN INSULIN PUMP. RISKS FOR LARGE FOR GESTATIONAL AGE INFANTS AND ALTERNATING BASAL-BOLUS INSULIN RATIO

Author

Leksic, G., Maja Baretić, Ivanisevic, M., and Jurisic-Erzen, D.

Subjects
type 1 diabetes mellitus, insulin pump, pregnancy, large for gestational age
Abstract

BACKGROUND AND AIMS: The aim of this study was to identify parameters that contribute the most to the development of large for gestational age (LGA) infants in a cohort of patients with type 1 diabetes mellitus (T1DM) treated with an insulin pump during pregnancy. Furthemore, basal and bolus insulin changes during pregnancy were also evaluated. METHODS: The data of patients was retrospectively analyzed. Inclusion criteria were HbA1c ≤7.0% (53mmol/mol) and BMI

27. Expression of neuronal nitric oxide synthase in fast rat skeletal muscle

Author

Tamara Šoić-Vranić, Bobinac, D., Jurišić-Erzen, D., Muhvić, D., Sandri, M., and Jerković, R.

Subjects
Male, Gene Expression Regulation, musculoskeletal, neural, and ocular physiology, NOS, sarkolema, mišićna vlakna, Muscle Fibers, Fast-Twitch, Animals, Nitric Oxide Synthase, Rats, Wistar, musculoskeletal system, Muscle, Skeletal, tissues, Immunohistochemistry, Rats
Abstract

The neuronal isoform of nitric oxide synthase (nNOS), the enzyme that catalyzes the formation of nitric oxide (NO), is expressed in normal rat skeletal muscle where it is localized at the sarcolemma, reflecting the molecular assocoation between nNOS and subsarcolemmal dystrophin complex. The expression of nNOS in fast twitch skeletal muscles such as m. extensor digitorum longus (EDL) and m. tibialis anterior (TA) is much greather than in slow-twitch muscles such as m. soleus (SOL). Muscle fibers which predominate in fast-twitch skeletal muscles are fast muscle fibers (type IIA, IIX and IIB) while slow-twitch muscles are mainly composed of slow type of fibers (type I). The aim of present study was to explore if all fast fiber types express nNOS. By immunohistochemical analysis of muscle cryosections of EDL and TA rat skeletal muscles we have demonstrated that the staining for nNOS expression was similar in type IIA and IIX, at the lower level in type I, while it was absent in IIB muscle fibers.

29. Glycemic Variability in Type 1 Diabetes Mellitus Pregnancies-Novel Parameters in Predicting Large-for-Gestational-Age Neonates: A Prospective Cohort Study.

Author

Leksic G, Baretić M, Gudelj L, Radic M, Milicic I, Ivanišević M, and Jurisic-Erzen D

Abstract

Pregnancies with type 1 diabetes mellitus (T1DM) have a high incidence of large-for-gestational-age neonates (LGA) despite optimal glycemic control. In recent years, glycemic variability (GV) has emerged as a possible risk factor for LGA, but the results of the conducted studies are unclear. This study analyzed the association between GV and LGA development in pregnancies with T1DM. This was a prospective cohort study of patients with T1DM who used continuous glucose monitoring (CGM) during pregnancy. Patients were followed from the first trimester to birth. GV parameters were calculated for every trimester using the EasyGV calculator. The main outcomes were LGA or no-LGA. Logistic regression analysis was used to assess the association between GV parameters and LGA. In total, 66 patients were included. The incidence of LGA was 36%. The analysis extracted several GV parameters that were significantly associated with the risk of LGA. The J-index was the only significant parameter in every trimester of pregnancy (odds ratios with confidence intervals were 1.33 (1.02, 1.73), 3.18 (1.12, 9.07), and 1.37 (1.03, 1.82), respectively. Increased GV is a risk factor for development of LGA. The J-index is a possible novel GV parameter that may be assessed in all three trimesters of pregnancy together with glycated hemoglobin and time-in-range.

Published
2022
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30. Mechanisms associated with increased physical activity in patients undergoing self-management behaviour modification in the randomised PHYSACTO trial.

Author

Bourbeau J, Sedeno M, Li PZ, Troosters T, Hamilton A, De Sousa D, Maltais F, Erzen D, and Lavoie KL

Abstract

Introduction: In this analysis of the PHYSACTO® study, we assessed the efficacy of a self-management behaviour modification (SMBM) programme to improve physical activity (PA) levels, and the extent to which effects were mediated by readiness to change, motivation and confidence., Methods: PHYSACTO® was a randomised, partially double-blind, parallel-group, 12-week trial to evaluate the effects of treatment on exercise capacity and PA. COPD patients received placebo, tiotropium 5 µg or tiotropium/olodaterol 5/5 µg, with or without exercise training, all with an SMBM intervention (the Living Well with COPD programme). Changes were assessed in readiness to change (stage of change visual analogue scale [VAS]), motivation (Treatment Self-Regulation Questionnaire [TSRQ]) and confidence (Perceived Competence Scale [PCS]) to engage in PA., Results: PA was increased in all patients with complete PA data at Week 12 (n=262; +6038 steps·week -1 , p<0.001). Significant increases were observed in patients' readiness to change (VAS 0.7 [0.6-0.8]), autonomous regulation (TRSQ 0.2 [0.1-0.3]) and confidence (PCS 0.5 [0.3-0.6]) (all p<0.01). Of note, 23% of the total effect of SMBM on steps·week -1 was found to be mediated by increases in readiness to change, 5% by TSRQ autonomous regulation and 12% by PCS., Conclusion: Our study demonstrated that an SMBM programme delivered to COPD patients increased PA, mediated by an improvement of three key hypothesised mechanisms of change: readiness to change, autonomous motivation and confidence. For the first time, this study shows that an SMBM programme can be successful in altering the mechanisms of change targeted by the intervention., Competing Interests: Conflict of interest: J. Bourbeau reports grants from McGill University, the Research Institute of the McGill University Health Centre, Aerocrine, the Canadian Respiratory Research Network/Canadian Institute of Health Research, Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis outside the submitted work. Conflict of interest: M. Sedeno is an employee of RESPIPLUS and, in this salaried position, works with a variety of companies and receives no payment or honoraria directly from them for services rendered. Conflict of interest: P.Z. Li has nothing to disclose. Conflict of interest: T. Troosters reports his institute has received speaker fees and consultancy fees for activities related to physical activity and exercise in COPD from Boehringer Ingelheim; his institute received speaker and consultancy fees for activities around physical activity and exercise from AstraZeneca; and he was principal investigator of the IMI-JU PROactive project, all during the conduct of the study; and grants from Research Foundation Flanders outside the submitted work. Conflict of interest: A. Hamilton is an employee of Boehringer Ingelheim (Canada) Ltd. Conflict of interest: D. De Sousa is an employee of Boehringer Ingelheim. Conflict of interest: F. Maltais reports personal fees and non-financial support from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Novartis and Grifols, outside the submitted work. Conflict of interest: D. Erzen has nothing to disclose. Conflict of interest: K.L. Lavoie reports investigator-initiated research support and speaking fees from Abbvie, consulting fees and speaking fees from Boehringer Ingelheim, consulting fees from Janssen and AstraZeneca, consulting and speaking fees from Astellas, speaking fees from Bayer, consulting and speaking fees from Novartis, and speaking fees from Mundipharma, outside the submitted work., (©ERS 2021.)

Published
2021
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31. Effect of Bronchodilation, Exercise Training, and Behavior Modification on Symptoms and Physical Activity in Chronic Obstructive Pulmonary Disease.

Author

Troosters T, Maltais F, Leidy N, Lavoie KL, Sedeno M, Janssens W, Garcia-Aymerich J, Erzen D, De Sousa D, Korducki L, Hamilton A, and Bourbeau J

Subjects
Accelerometry, Adult, Aged, Combined Modality Therapy, Double-Blind Method, Drug Combinations, Female, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive drug therapy, Pulmonary Disease, Chronic Obstructive physiopathology, Treatment Outcome, Behavior Therapy methods, Benzoxazines therapeutic use, Bronchodilator Agents therapeutic use, Exercise, Pulmonary Disease, Chronic Obstructive therapy, Tiotropium Bromide therapeutic use
Abstract

Rationale: Bronchodilation and exercise training (ExT) improve exercise tolerance in patients with chronic obstructive pulmonary disease (COPD); however, behavior modification is required to impact daily physical activity (PA)., Objectives: To assess whether tiotropium/olodaterol, with or without ExT, would improve exercise endurance time (EET) and PA compared with placebo in patients participating in a self-management behavior-modification (SMBM) program., Methods: This was a 12-week, randomized, partially double-blind, placebo-controlled, parallel-group trial in patients with COPD (PHYSACTO; NCT02085161). All patients were enrolled into SMBM and randomized 1:1:1:1 to once-daily placebo, tiotropium 5 μg, tiotropium/olodaterol 5/5 μg, or tiotropium/olodaterol 5/5 μg plus 8 weeks ExT. EET, measured by endurance shuttle walk test after 8 weeks, was the primary endpoint. Additional endpoints assessed downstream effects on PA (measured via accelerometry), and activity-related dyspnea and difficulty (using validated patient-reported questionnaires)., Measurements and Main Results: SMBM plus tiotropium/olodaterol, with or without ExT, significantly improved EET at Week 8 versus SMBM plus placebo (treatment ratio vs. placebo: with ExT, 1.46; 95% confidence interval, 1.20-1.78; P = 0.0002; without ExT, 1.29; 95% confidence interval, 1.06-1.57; P = 0.0109). No significant increases in steps per day from baseline were observed over SMBM plus placebo at Week 12 (increase of 1,098) when other therapies were added. Adding tiotropium/olodaterol, with or without ExT, to SMBM reduced activity-related dyspnea versus placebo, whereas adding tiotropium/olodaterol plus ExT reduced activity-related difficulty., Conclusions: Tiotropium/olodaterol, with or without ExT, improved EET in patients with COPD taking part in an SMBM program. Combination bronchodilation, with or without ExT, did not provide additional increases in objective PA compared with SMBM alone but did reduce PA-related dyspnea and difficulty. Clinical trial registered with www.clinicaltrials.gov (NCT02085161).

Published
2018
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32. Leiomyosarcoma of the renal vein: analysis of outcome and prognostic factors in the world case series of 67 patients.

Author

Novak M, Perhavec A, Maturen KE, Pavlovic Djokic S, Jereb S, and Erzen D

Abstract

Background: Leiomyosarcoma is a rare malignant mesenchymal tumour. Some cases of leiomyosarcoma of the renal vein (LRV) have been reported in the literature, but no analysis of data and search for prognostic factors have been done so far. The aim of this review was to describe the LRV, to analyse overall survival (OS), local recurrence free survival (LRFS) and distant metastases free survival (DMFS) in LRV world case series and to identify significant predictors of OS, LRFS and DMFS., Methods: Cases from the literature based on PubMed search and a case from our institution were included., Results: Sixty-seven patients with a mean age of 56.6 years were identified; 76.1% were women. Mean tumour size was 8.9 cm; in 68.7% located on the left side. Tumour thrombus extended into the inferior vena cava lumen in 13.4%. All patients but one underwent surgery (98.5%). After a median follow up of 24 months, the OS was 79.5%. LRFS was 83.5% after a median follow up of 21.5 months and DMFS was 76.1% after a median follow up of 22 months. Factors predictive of OS in univariate analysis were surgical margins, while factors predictive of LRFS were inferior vena cava luminal extension and grade. No factors predictive of DMFS were identified. In multivariate analysis none of the factors were predictive of OS, LRFS and DMFS., Conclusions: Based on the literature review and presented case some conclusions can be made. LRV is usually located in the hilum of the kidney. It should be considered in differential diagnosis of renal and retroperitoneal masses, particularly in women over the age 40, on the left side and in the absence of haematuria. Core needle biopsy should be performed. Patients should be managed by sarcoma multidisciplinary team. LRV should be surgically removed, with negative margins.

Published
2016
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33. Enhancing exercise tolerance and physical activity in COPD with combined pharmacological and non-pharmacological interventions: PHYSACTO randomised, placebo-controlled study design.

Author

Troosters T, Bourbeau J, Maltais F, Leidy N, Erzen D, De Sousa D, Korducki L, and Hamilton A

Subjects
Adult, Aged, Australia, Canada, Combined Modality Therapy, Double-Blind Method, Europe, Exercise Test, Female, Humans, Male, Middle Aged, Multivariate Analysis, New Zealand, Quality of Life, Regression Analysis, Self Care, Treatment Outcome, United States, Walking, Bronchodilator Agents therapeutic use, Exercise Therapy methods, Exercise Tolerance drug effects, Pulmonary Disease, Chronic Obstructive therapy, Research Design
Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with exercise limitation and physical inactivity, which are believed to have significant long-term negative health consequences for patients. While a number of COPD treatments and exercise training programmes increase exercise capacity, there is limited evidence for their effects on physical activity levels, with no clear association between exercise capacity and physical activity in clinical trials. Physical activity depends on a number of behaviour, environmental and physiological factors. We describe the design of the PHYSACTO trial, which is investigating the effects of bronchodilators, either alone or with exercise training, in combination with a standardised behaviour-change self-management programme, on exercise capacity and physical activity in patients with COPD. It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training., Methods and Analysis: Patients are being recruited from 34 sites in Australia, New Zealand, the USA, Canada and Europe. Patients receiving a multicomponent intervention designed to support behaviour change related to physical activity are randomised to four treatment arms: placebo, tiotropium, tiotropium+olodaterol, and tiotropium+olodaterol+exercise training. The primary outcome is improvement in exercise capacity after 8 weeks, measured by endurance time during a shuttle walk test. The secondary outcome is improvement in physical activity, including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory-Short Form and the novel hybrid PROactive instrument. Additionally, the influence of moderating variables (ie, factors influencing a patient's choice to be physically active) on increases in physical activity is also explored., Ethics and Dissemination: The study has been approved by the relevant Institutional Review Boards, Independent Ethics Committee and Competent Authority according to national and international regulations. The findings of the trial will be disseminated through relevant peer-reviewed journals and international conference presentations., Trial Registration Number: NCT02085161., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Published
2016
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34. Behaviour-change intervention in a multicentre, randomised, placebo-controlled COPD study: methodological considerations and implementation.

Author

Bourbeau J, Lavoie KL, Sedeno M, De Sousa D, Erzen D, Hamilton A, Maltais F, Troosters T, and Leidy N

Subjects
Adult, Aged, Australia, Canada, Combined Modality Therapy, Double-Blind Method, Europe, Exercise Test, Female, Humans, Male, Middle Aged, New Zealand, Quality of Life, Self Care, Treatment Outcome, United States, Walking, Benzoxazines administration & dosage, Bronchodilator Agents administration & dosage, Exercise Therapy methods, Pulmonary Disease, Chronic Obstructive therapy, Research Design, Tiotropium Bromide administration & dosage
Abstract

Introduction: Chronic obstructive pulmonary disease is generally progressive and associated with reduced physical activity. Both pharmacological therapy and exercise training can improve exercise capacity; however, these are often not sufficient to change the amount of daily physical activity a patient undertakes. Behaviour-change self-management programmes are designed to address this, including setting motivational goals and providing social support. We present and discuss the necessary methodological considerations when integrating behaviour-change interventions into a multicentre study., Methods and Analysis: PHYSACTO is a 12-week phase IIIb study assessing the effects on exercise capacity and physical activity of once-daily tiotropium+olodaterol 5/5 µg with exercise training, tiotropium+olodaterol 5/5 µg without exercise training, tiotropium 5 µg or placebo, with all pharmacological interventions administered via the Respimat inhaler. Patients in all intervention arms receive a behaviour-change self-management programme to provide an optimal environment for translating improvements in exercise capacity into increases in daily physical activity. To maximise the likelihood of success, special attention is given in the programme to: (1) the Site Case Manager, with careful monitoring of programme delivery; (2) the patient, incorporating patient-evaluation/programme-evaluation measures to guide the Site Case Manager in the self-management intervention; and (3) quality assurance, to help identify and correct any problems or shortcomings in programme delivery and ensure the effectiveness of any corrective steps. This paper documents the comprehensive methods used to optimise and standardise the behaviour-change self-management programme used in the study to facilitate dialogue on the inclusion of this type of programme in multicentre studies., Ethics and Dissemination: The study has been approved by the relevant Institutional Review Boards, Independent Ethics Committee and Competent Authority according to national and international regulations. The results of this study will be disseminated through relevant, peer-reviewed journals and international conference presentations., Trial Registration Number: NCT02085161., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Published
2016
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35. Inverse Levels of Adiponectin in Type 1 and Type 2 Diabetes Are in Accordance with the State of Albuminuria.

Author

Ljubic S, Jazbec A, Tomic M, Piljac A, Jurisic Erzen D, Novak B, Kastelan S, Lovrencic MV, and Brkljacic N

Abstract

Aims. To investigate the behaviour of adiponectin (ApN) in patients with type 1 and type 2 diabetic nephropathy. Methods. ApN and inflammatory and other markers of the metabolic syndrome were compared across diabetes types, albumin excretion rate (AER), and creatinine clearance (CrCl) categories in 219 type 1 and type 2 diabetic patients. Results. Significant differences among ApN levels according to AER were found in both types of diabetes (F = 8.45, df = 2, P < 0.001). With the progression of albuminuria, ApN increased in type 1 and decreased in type 2 diabetes. Patients with decreased CrCl had higher ApN levels than those with normal CrCl in either type of diabetes (F = 12.7, df = 1, P < 0.001). The best model for ApN (R (2) = 0.9002) obtained from stepwise regression in type 1 diabetes included CrCl, BMI, WBC, CRP, and age, while in type 2 diabetes (R (2) = 0.2882) it included ppPG, LDL, and UA. Conclusion. ApN behaved differently in relation to albuminuria, increasing with its progression in type 1 diabetes and decreasing in type 2 diabetes. It was however increased in the subgroups with decreased CrCl in both types of diabetes. Albuminuria seems to be more important than renal insufficiency in the definition of ApN levels in type 1 and type 2 diabetes.

Published
2015
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36. Single oral inoculation with Escherichia coli (ATCC 25922) stimulates generalised production of nitric oxide in mice.

Author

Nemec A, Pavlica Z, Crossley DA, Zdovc I, Erzen D, Sentjurc M, Nemec M, and Petelin M

Subjects
Animals, Female, Male, Mice, Mice, Inbred BALB C, Nitric Oxide Synthase metabolism, Random Allocation, Escherichia coli physiology, Escherichia coli Infections metabolism, Nitric Oxide biosynthesis
Abstract

Nitric oxide (NO) production was investigated in the lungs, thoracic aorta, heart, liver, spleen, kidneys and brain of mice inoculated orally with Escherichia coli ATCC 25922. Detection of NO was performed by electron paramagnetic resonance (EPR) using diethyldithiocarbamate (DETC) spin trap. Nitric oxide synthase (NOS) inhibitors [nonselective: L-NAME and inducible NOS (iNOS) selective: 1400W] were used to determine the source of NO. Spin-trap only and untreated mice were included as controls. Within 2.5 hours (h) of a single oral inoculation with E. coli half of the animals had increased NO levels in all investigated organs. Thereafter the signals dropped before increasing again to reach maximal median values by 25 h in all organs of all inoculated mice. The most intense response occurred in livers, followed by aorta and lungs. Early (2.5 h) inhibition of the signal was achieved using both NOS inhibitors. L-NAME was also effective at 25 h, while 1400W-treated mice had increased NO levels beyond 7 h. The generalised increase in NO production in the short and longer term indicates a host response to E. coli administered by the oral route of infection.

Published
2009
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37. Measurement of total antioxidant capacity in gingival crevicular fluid and serum in dogs with periodontal disease.

Author

Pavlica Z, Petelin M, Nemec A, Erzen D, and Skaleric U

Subjects
Age Factors, Alveolar Bone Loss veterinary, Analysis of Variance, Animals, Dental Plaque pathology, Dental Plaque veterinary, Dogs, Periodontal Diseases blood, Periodontal Diseases metabolism, Periodontium diagnostic imaging, Periodontium pathology, Radiography, Regression Analysis, Antioxidants metabolism, Dog Diseases blood, Dog Diseases metabolism, Gingival Crevicular Fluid metabolism, Periodontal Diseases veterinary
Abstract

Objective: To determine whether gingival crevicular fluid (GCF) and serum total antioxidant capacities (TACs) correlate with the degree of severity of periodontal disease in dogs., Animals: 41 Toy and Miniature Poodles., Procedures: After assessment of the degree of severity of naturally occurring periodontitis, GCF samples from both maxillary fourth premolars and a blood sample were collected from each dog. The condition of the periodontium of the entire dentition and at each site of GCF collection was recorded. Clinical parameters assessed included plaque index, gingival index, and probing depth. Radiographic analysis of alveolar bone level was also performed. Total antioxidant capacity was measured in GCF and serum samples by use of a commercial kit., Results: Dogs with gingivitis and minimal periodontitis had significantly higher TAC in GCF than dogs with advanced periodontitis. Bivariate regression analysis revealed significant negative correlations between TAC in GCF and clinical parameters and age. The TAC in serum was significantly negatively correlated with the degree of gingival inflammation but was not significantly correlated with age., Conclusions and Clinical Relevance: TAC in GCF is related to the degree of severity of periodontal disease in dogs. This is likely the result of release of reactive oxygen species by activated phagocytes and fibroblasts in the inflamed periodontal tissues. The results of our study suggest that the local delivery of antioxidants may be a useful adjunctive treatment for periodontitis in dogs.

Published
2004
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