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1. Estimating the Prevalence of AATD Patients in the UK to Identify Underdiagnosis and Determine the Eligibility for Potential Augmentation Therapy

Author

Newnham M, Quinn M, and Turner AM

Subjects
alpha 1 antitrypsin deficiency, chronic obstructive pulmonary disease, epidemiology, Diseases of the respiratory system, RC705-779
Abstract

Michael Newnham,1,2 Mark Quinn,1 Alice M Turner1,2 1Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 2University Hospitals Birmingham, Birmingham, UKCorrespondence: Alice M Turner, Institute of Applied Health Research, University of Birmingham, Birmingham, UK, Email a.m.turner@bham.ac.ukPurpose: Alpha 1 antitrypsin deficiency (AATD) is a genetic risk factor for chronic obstructive pulmonary disease (COPD). Whilst testing for the condition is relatively simple, there is a disconnect in published literature between genetic epidemiology and numbers of patients known to specialists. This makes planning services for patients difficult. We aimed to estimate the number of patients likely to have lung disease eligible for specific AATD therapy within the UK.Patients and Methods: The THIN database was used to determine the prevalence of AATD and symptomatic COPD. This, and published rates of AATD were used to extrapolate THIN data to the population size of the UK to give an indicative population size for symptomatic AATD patients who have lung disease. The Birmingham AATD registry was used to describe age at diagnosis, rate of lung disease and symptomatic lung disease for patients with PiZZ (or equivalent) AATD, together with the time from symptom onset to diagnosis, in order to aid interpretation of the THIN data and improve modeling.Results: THIN data showed COPD prevalence of 3%, and AATD prevalence of 0.005– 0.2%, depending on how stringently AATD diagnostic codes were applied. The majority of Birmingham AATD patients were diagnosed between the ages 46– 55, whilst patients recorded in THIN tended to be older. The rate of COPD was similar in the THIN and Birmingham patients diagnosed with AATD. Modelling to the size of the UK demonstrated a likely symptomatic AATD population of between 3016 and 9866 people.Conclusion: AATD is likely to be under-diagnosed in the UK. Based on projected patient numbers an expansion to specialist services is desirable, in particular if specific therapy for AATD such as augmentation were to be introduced to the healthcare system.Keywords: alpha 1 antitrypsin deficiency, chronic obstructive pulmonary disease, epidemiology

Published
2023

6. Genome-wide association study in chronic thromboembolic pulmonary hypertension reveals new insights into aetiology: S108

Author

Newnham, M, Toshner, M, Bleda, M, Auger, W R, Barberà, J A, Bogaard, H J, Cannon, J, Coghlan, G, Corris, P A, Delcroix, M, Dunning, J, Elding, H, Gibbs, S, Hadinnapola, C, Jenkins, D, Kiely, D, Lang, I, Maher, E, Ng, C, Peacock, A, Screaton, N, Sheares, K, Simpson, M, Soranzo, N, Taboada, D, Trembath, R, Tsui, S, Wilkins, M R, Wort, S J, Gräf, S, Pepke-Zaba, J, and Morrell, N W

Published
2017
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9. Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension

Author

Harbaum, Lars, primary, Rhodes, Christopher J., additional, Wharton, John, additional, Lawrie, Allan, additional, Karnes, Jason H., additional, Desai, Ankit A., additional, Nichols, William C., additional, Humbert, Marc, additional, Montani, David, additional, Girerd, Barbara, additional, Sitbon, Olivier, additional, Boehm, Mario, additional, Novoyatleva, Tatyana, additional, Schermuly, Ralph T., additional, Ghofrani, H. Ardeschir, additional, Toshner, Mark, additional, Kiely, David G., additional, Howard, Luke S., additional, Swietlik, Emilia M., additional, Gräf, Stefan, additional, Pietzner, Maik, additional, Morrell, Nicholas W., additional, Wilkins, Martin R., additional, Southgate, L, additional, Machado, RD, additional, Martin, J, additional, Ouwehand, WH, additional, Pauciulo, MW, additional, Arora, A, additional, Lutz, K, additional, Ahmad, F, additional, Archer, SL, additional, Argula, R, additional, Austin, ED, additional, Badesch, D, additional, Bakshi, S, additional, Barnett, C, additional, Benza, R, additional, Bhatt, N, additional, Burger, CD, additional, Chakinala, M, additional, Elwing, J, additional, Fortin, T, additional, Frantz, RP, additional, Frost, A, additional, Garcia, JGN, additional, Harley, J, additional, He, H, additional, Hill, NS, additional, Hirsch, R, additional, Ivy, D, additional, Klinger, J, additional, Lahm, T, additional, Marsolo, K, additional, Martin, LJ, additional, Nathan, SD, additional, Oudiz, RJ, additional, Rehman, Z, additional, Robbins, I, additional, Roden, DM, additional, Rosenzweig, EB, additional, Saydain, G, additional, Schilz, R, additional, Simms, RW, additional, Simon, M, additional, Tang, H, additional, Tchourbanov, AY, additional, Thenappan, T, additional, Torres, F, additional, Walsworth, AK, additional, Walter, RE, additional, White, RJ, additional, Wilt, J, additional, Yung, D, additional, Kittles, R, additional, Aman, J, additional, Knight, J, additional, Hanscombe, KB, additional, Gall, H, additional, Ulrich, A, additional, Bogaard, HJ, additional, Church, C, additional, Coghlan, JG, additional, Condliffe, R, additional, Corris, PA, additional, Danesino, C, additional, Elliott, CG, additional, Franke, A, additional, Ghio, S, additional, Gibbs, JSR, additional, Houweling, AC, additional, Kovacs, G, additional, Laudes, M, additional, MacKenzie Ross, RV, additional, Moledina, S, additional, Newnham, M, additional, Olschewski, A, additional, Olschewski, H, additional, Peacock, AJ, additional, Pepke-Zaba, J, additional, Scelsi, L, additional, Seeger, W, additional, Shaffer, CM, additional, Sitbon, O, additional, Suntharalingam, J, additional, Treacy, C, additional, Vonk Noordegraaf, A, additional, Waisfisz, Q, additional, Wort, SJ, additional, Trembath, RC, additional, Germain, M, additional, Cebola, I, additional, Ferrer, J, additional, Amouyel, P, additional, Debette, S, additional, Eyries, M, additional, Soubrier, F, additional, and Trégouët, DA, additional

Published
2022
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11. Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Author

Ghofrani, H.-A. Gomez Sanchez, M.-A. Humbert, M. Pittrow, D. Simonneau, G. Gall, H. Grünig, E. Klose, H. Halank, M. Langleben, D. Snijder, R.J. Escribano Subias, P. Mielniczuk, L.M. Lange, T.J. Vachiéry, J.-L. Wirtz, H. Helmersen, D.S. Tsangaris, I. Barberá, J.A. Pepke-Zaba, J. Boonstra, A. Rosenkranz, S. Ulrich, S. Steringer-Mascherbauer, R. Delcroix, M. Jansa, P. Šimková, I. Giannakoulas, G. Klotsche, J. Williams, E. Meier, C. Hoeper, M.M. Caneva, J. Tuhay, G. Diez, M. Talavera, M.L. Acosta, A. Vulcano, N. Bosio, M. Maldonado, L. Deleo, S. Melatini, L. Keogh, A. Kotlyar, E. Feenstra, J. Dwyer, N. Adams, H. Stevens, W. Steele, P. Proudman, S. Minson, R. Reeves, G. Lavender, M. Ng, B. Mackenzie, M. Barry, L. Gruenberger, M. Huber, C. Lang, I. Tilea, I. Sadushi-Kolici, R. Löffler-Ragg, J. Feistmantl, L.-T. Evrard, P. Louis, R. Guiot, J. Naldi, M. De Pauw, M. Mehta, S. Camacho, R.C. Tovar, P.P. Londoño, A. Campo, F. Garcia, P. Lema, C. Orozco-Levi, M. Martinez, W. Gomez, J.E. Nielsen-Kudsk, J.E. Mellemkjaer, S. Anton, L. Altraja, A. Vihinen, T. Vasankari, T. Sitbon, O. Cottin, V. Têtu, L. Noël-Savina, E. Shearman, N. Tayler, S. Olzik, I. Kulka, C. Grimminger, J. Simon, M. Nolde, A. Oqueka, T. Harbaum, L. Egenlauf, B. Ewert, R. Schulz, C. Regotta, S. Kramer, T. Knoop-Busch, S. Gerhardt, F. Konstantinides, S. Pitsiou, G. Stanopoulos, I. Sourla, E. Mouratoglou, S. Karvounis, H. Pappas, A. Georgopoulos, D. Fanaridis, M. Mitrouska, I. Michalis, L. Pappas, K. Kotsia, A. Gaine, S. Vizza, C.D. Manzi, G. Poscia, R. Badagliacca, R. Agostoni, P. Bruno, N. Farina, S. D'Alto, M. Argiento, P. Correra, A. Di Marco, G.M. Cresci, C. Vannucchi, V. Torricelli, E. Garcea, A. Pesci, A. Sardella, L. Paciocco, G. Pane, F. D'Armini, A.M. Pin, M. Grazioli, V. Massola, G. Sciortino, A. Prediletto, R. Bauleo, C. Airò, E. Ndreu, R. Pavlickova, I. Lunardi, C. Mulè, M. Farruggio, S. Costa, S. Galgano, G. Petruzzi, M. De Luca, A. Lombardi, F. Roncon, L. Conte, L. Picariello, C. Wirtz, G. Alexandre, M. Vonk-Noordegraaf, A. Boogaard, H. Mager, J. Reesink, H. van den Toorn, L.M. Boomars, K. Andreassen, A.K. Castro, G. Tania, G. Baptista, R. Marinho, A. Shiang, T. Oliveira, A. Coutinho, D. Sousa, J. Loureiro, M.J. Repolho, D. Martins Jesus, S.M. Capinha, M. Agostinho, J. Cardoso, T. Rocha, A. Espinha, M. Ivanov, K.I. Alexeeva, D.E. Batalina, M.V. Hegya, D.V. Zvereva, T.N. Avdeev, S.N. Tsareva, N.A. Galyavich, A.S. Nikolaevich, B.A. Filippov, E.V. Yakovleva, O.E. Pavlova, O.B. Skripkina, E.S. Martynyuk, T.V. Bukatova, I.F. Tregubova, A.V. Platonov, D.Y. Kolomeytseva, T.M. Al Dalaan, A. Abdelsayed, A.A. Weheba, I. Saleemi, S. Sakkijha, H. Bohacekova, M. Valkovicova, T. Farkasova, I. Quezada, C.A. Piccari, L. Blanco, I. Sebastian, L. Roman, A. Lopez, M. Otero, R. Elias, T. Jara, L. Asencio, I. Arjona, J.J. Almagro, R.M. Cárdenas, S.L. García, S.A. Rodríguez, P.V. Lopez, R. Garcia, A. Avilés, F.F. De La Pava, S. Yotti, R. Peñate, G.P. Marrero, F.L. Cifrián Martínez, J.M. Martinez-Meñaca, A. Alonso, L.P. Rozas, S.F. Fernandez, D.I. Cuesta, V.M. Söderberg, S. Bartfay, S.-E. Rundqvist, B. Alfetlawi, M. Wodlin, P. Schwarz, E.I. Speich, R. Lador, F. Rochat, T. Gasche-Soccal, P. Hsu, C.-H. Lin, T.-H. Su, H.-M. Lai, W.-T. Chu, C.Y. Hsu, P.-C. Voon, W.-C. Yen, H.-W. Yih-Jer Wu, J. Wu, S.-H. Huang, W.-P. Fong, M.-C. Huang, C.-L. Kuo, P.-H. Lin, Y.-H. Lin, J.-L. Hung, C.-S. Wu, C.-K. Sung, S.-H. Huang, W.-C. Cheng, C.-C. Kuo, S.-H. Wang, W.-H. Ho, W.-J. Hsu, T.-S. Mutlu, B. Atas, H. Ongen, G. Un, Z. Okumus, G. Hanta, I. Corris, P. Peacock, A. Church, C. Toshner, M. Newnham, M. NEW COLLABORATORS LIST

Abstract

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors

Published
2021

12. Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Author

Ghofrani, H.A., Gomez Sanchez, M.-A. (Miguel-Angel), Humbert, M., Pittrow, D. (David), Simonneau, G. (Gérald), Gall, H. (Henning), Grünig, E. (Ekkehard), Klose, H. (Hans), Halank, M. (Michael), Langleben, D. (David), Snijder, R., Escribano Subías, P. (Pilar), Mielniczuk, L.M. (Lisa M.), Lange, T.J. (Tobias J.), Vachiéry, J.-L. (Jean-Luc), Wirtz, H. (Hubert), Helmersen, D.S. (Douglas S.), Tsangaris, I. (Iraklis), Barberá, J.A. (Joan A.), Pepke-Zaba, J. (Joanna), Boonstra, A. (Anco), Rosenkranz, S. (Stephan), Ulrich, S. (Silvia), Steringer-Mascherbauer, R. (Regina), Delcroix, M. (Marion), Jansa, P. (Pavel), Šimková, I. (Iveta), Giannakoulas, G. (George), Klotsche, J. (Jens), Williams, E. (Evgenia), Meier, C. (Christian), Hoeper, M.M. (Marius M.), Caneva, J. (Jorge), Tuhay, G. (Graciela), Diez, M. (Mirta), Talavera, M.L. (Maria Lujan), Acosta, A. (Adriana), Vulcano, N. (Norberto), Bosio, M. (Martin), Maldonado, L. (Lorena), Deleo, S. (Sabino), Melatini, L. (Luciano), Keogh, A. (Anne), Kotlyar, E. (Eugene), Feenstra, J. (John), Dwyer, N. (Nathan), Adams, H. (Heath), Stevens, W. (Wendy), Steele, P. (Peter), Proudman, S. (Susanna), Minson, R. (Robert), Reeves, G. (Glenn), Lavender, M. (Melanie), Ng, B. (Benjamin), Mackenzie, M. (Michele), Barry, L. (Lisa), Gruenberger, M. (Margarethe), Huber, C. (Charlotte), Lang, I. (Irene), Tilea, I. (Ioana), Sadushi-Kolici, R. (Roela), Löffler-Ragg, J. (Judith), Feistmantl, L.-T. (Lisa-Theresa), Evrard, P. (Patrick), Louis, R. (Renaud), Guiot, J. (Julien), Naldi, M. (Marco), De Pauw, M. (Michel), Mehta, S. (Sanjay), Camacho, R.C. (Rafael Conde), Tovar, P.P. (Patricia Parada), Londoño, A. (Alejandro), Campo, F. (Felipe), Garcia, P. (Paula), Lema, C. (Camila), Orozco-Levi, M. (Mauricio), Martinez, W. (William), Gomez, J.E. (Juan Esteban), Nielsen-Kudsk, J.E. (Jens Erik), Mellemkjaer, S. (Soren), Anton, L. (Ly), Altraja, A. (Alan), Vihinen, T. (Tapani), Vasankari, T. (Tuija), Sitbon, O. (Olivier), Cottin, V. (Vincent), Têtu, L. (Laurent), Noël-Savina, E. (Elise), Shearman, N. (Nicole), Tayler, S. (Susanne), Olzik, I. (Ilona), Kulka, C. (Christine), Grimminger, J. (Jan), Simon, M. (Marcel), Nolde, A. (Anna), Oqueka, T. (Tim), Harbaum, L. (Lars), Egenlauf, B. (Benjamin), Ewert, R. (Ralf), Schulz, C. (Christian), Regotta, S. (Sabine), Kramer, T. (Tilmann), Knoop-Busch, S. (Susanne), Gerhardt, F. (Felix), Konstantinides, S. (Stavros), Pitsiou, G. (Georgia), Stanopoulos, I. (Ioannis), Sourla, E. (Evdokia), Mouratoglou, S. (Sofia), Karvounis, H.I., Pappas, A. (Athanasios), Georgopoulos, D. (Dimitrios), Fanaridis, M. (Michail), Mitrouska, I. (Ioanna), Michalis, L.K. (Lampros), Pappas, K. (Konstantinos), Kotsia, A. (Anna), Gaine, S. (Sean), Vizza, C.D. (Carmine Dario), Manzi, G. (Giovanna), Poscia, R. (Roberto), Badagliacca, R. (Roberto), Agostoni, P. (Piergiuseppe), Bruno, N. (Noemi), Farina, S. (Stefania), D'Alto, M. (Michele), Argiento, P. (Paola), Correra, A. (Anna), Di Marco, G.M. (Giovanni Maria), Cresci, C. (Chiara), Vannucchi, V. (Vieri), Torricelli, E. (Elena), Garcea, A. (Alessio), Pesci, A. (Alberto), Sardella, L. (Luca), Paciocco, G. (Giuseppe), Pane, F. (Federico), D'Armini, A.M. (Andrea Maria), Pin, M. (Maurizio), Grazioli, V. (Valentina), Massola, G. (Giulia), Sciortino, A. (Antonio), Prediletto, R. (Renato), Bauleo, C. (Carolina), Airò, E. (Edoardo), Ndreu, R. (Rudina), Pavlickova, I. (Ivana), Lunardi, C. (Claudio), Mulè, M. (Massimiliano), Farruggio, S. (Silvia), Costa, S. (Serena), Galgano, G. (Giuseppe), Petruzzi, M. (Mario), De Luca, A. (Anna), Lombardi, F. (Francesco), Roncon, L. (Loris), Conte, L. (Luca), Picariello, C. (Claudio), Wirtz, G. (Gil), Alexandre, M. (Myriam), Vonk Noordegraaf, A. (Anton), Boogaard, H. (H.), Mager, J. (J.), Reesink, H.J. (Herre), Toorn, L.M. (Leon) van den, Boomars, K.A.T. (Karin), Andreassen, A.K. (Arne K.), Castro, G. (Graça), Tania, G. (Gonçalves), Baptista, R. (Rui), Marinho, A. (António), Shiang, T. (Teresa), Oliveira, A. (Ana), Coutinho, D. (Daniel), Sousa, J. (Joana), Loureiro, M.J. (Maria José), Repolho, D. (Débora), Martins Jesus, S.M. (Susana Maria), Capinha, M. (Marta), Agostinho, J. (João), Cardoso, T. (Tania), Rocha, A. (Andreia), Espinha, M. (Mafalda), Ivanov, K.I. (Kyundyul Ivanovich), Alexeeva, D.E. (Dalyana Eduardovna), Batalina, M.V. (Marina Vadimovna), Hegya, D.V. (Daria Viktorovna), Zvereva, T.N. (Tatyana Nikolaevna), Avdeev, S.N. (Sergey Nikolaevich), Tsareva, N.A. (Natalia Anatolievna), Galyavich, A.S. (Albert Sarvatovich), Nikolaevich, B.A. (Bykov Aleksander), Filippov, E.V. (Evgeny Vladimirovich), Yakovleva, O.E. (Olga Eduardovna), Pavlova, O.B. (Olga Borisovna), Skripkina, E.S. (Elena Sergeevna), Martynyuk, T.V. (Tamila Vitalievna), Bukatova, I.F. (Irina Fedorovna), Tregubova, A.V. (Anna Viktorovna), Platonov, D.Y. (Dmitry Yurievich), Kolomeytseva, T.M. (Tatyana Mikhaylovna), Al Dalaan, A. (Abdullah), Abdelsayed, A.A. (Abeer Abeer), Weheba, I. (Ihab), Saleemi, S. (Sarferaz), Sakkijha, H. (Hussam), Bohacekova, M. (Marcela), Valkovicova, T. (Tatiana), Farkasova, I. (Iveta), Quezada, C.A. (Carlos Andres), Piccari, L. (Lucilla), Blanco, I. (Isabel), Sebastian, L. (Laura), Roman, A. (Antonio), Lopez, M. (Manuel), Otero, R. (Remedios), Elias, T. (Teresa), Jara, L. (Luis), Asencio, I. (Isabel), Arjona, J.J. (Josefa Jiménez), Almagro, R.M. (Raúl Menor), Cárdenas, S.L. (Salvador López), García, S.A. (Salvador Alcaraz), Rodríguez, P.V. (Patricia Villanueva), Lopez, R. (Raquel), Garcia, A. (Alberto), Avilés, F.F. (Francisco Fernandez), De La Pava, S. (Sebastian), Yotti, R. (Raquel), Peñate, G.P. (Gregorio Pérez), Marrero, F.L. (Fernando León), Cifrián Martínez, J.M. (José Manuel), Martinez-Meñaca, A. (Amaya), Alonso, L.P. (Lecue Pilar), Rozas, S.F. (Sonia Fernandez), Fernandez, D.I. (David Iturbe), Cuesta, V.M. (Victor Mora), Söderberg, S. (Stefan), Bartfay, S.-E. (Sven-Erik), Rundqvist, B. (Bengt), Alfetlawi, M. (Monthir), Wodlin, P. (Peter), Schwarz, E.I. (Esther Irene), Speich, R. (Rudolf), Lador, F. (Frédéric), Rochat, T. (Thierry), Gasche-Soccal, P. (Paola), Hsu, C.-H. (Chih-Hsin), Lin, T.-H. (Tsung-Hsien), Su, H.-M. (Ho-Ming), Lai, W.-T. (Wen-Ter), Chu, C.Y. (Chun Yuan), Hsu, P.-C. (Po-Chao), Voon, W.-C. (Wen-Chol), Yen, H.-W. (Hsueh-Wei), Yih-Jer Wu, J. (Jacob), Wu, S.-H. (Shu-Hao), Huang, W.-P. (Wen-Pin), Fong, M.-C. (Man-Cai), Huang, C.-L. (Chien-Lung), Kuo, P.-H. (Ping-Hung), Lin, Y.-H. (Yen-Hung), Lin, J.-L. (Jiunn-Lee), Hung, C.-S. (Chi-Sheng), Wu, C.-K. (Cho-Kai), Sung, S.-H. (Shih-Hsien), Huang, W.-C. (Wei-Chun), Cheng, C.-C. (Chin-Chang), Kuo, S.-H. (Shu-Hung), Wang, W.-H. (Wen-Hwa), Ho, W.-J. (Wan-Jing), Hsu, T.-S. (Tsu-Shiu), Mutlu, B. (Bülent), Atas, H. (Halil), Ongen, G. (Gul), Un, Z. (Zeynep), Okumus, G. (Gulfer), Hanta, I. (Ismail), Corris, P. (Paul), Peacock, A. (Andrew), Church, C. (Colin), Toshner, M. (Mark), Newnham, M. (Michael), Ghofrani, H.A., Gomez Sanchez, M.-A. (Miguel-Angel), Humbert, M., Pittrow, D. (David), Simonneau, G. (Gérald), Gall, H. (Henning), Grünig, E. (Ekkehard), Klose, H. (Hans), Halank, M. (Michael), Langleben, D. (David), Snijder, R., Escribano Subías, P. (Pilar), Mielniczuk, L.M. (Lisa M.), Lange, T.J. (Tobias J.), Vachiéry, J.-L. (Jean-Luc), Wirtz, H. (Hubert), Helmersen, D.S. (Douglas S.), Tsangaris, I. (Iraklis), Barberá, J.A. (Joan A.), Pepke-Zaba, J. (Joanna), Boonstra, A. (Anco), Rosenkranz, S. (Stephan), Ulrich, S. (Silvia), Steringer-Mascherbauer, R. (Regina), Delcroix, M. (Marion), Jansa, P. (Pavel), Šimková, I. (Iveta), Giannakoulas, G. (George), Klotsche, J. (Jens), Williams, E. (Evgenia), Meier, C. (Christian), Hoeper, M.M. (Marius M.), Caneva, J. (Jorge), Tuhay, G. (Graciela), Diez, M. (Mirta), Talavera, M.L. (Maria Lujan), Acosta, A. (Adriana), Vulcano, N. (Norberto), Bosio, M. (Martin), Maldonado, L. (Lorena), Deleo, S. (Sabino), Melatini, L. (Luciano), Keogh, A. (Anne), Kotlyar, E. (Eugene), Feenstra, J. (John), Dwyer, N. (Nathan), Adams, H. (Heath), Stevens, W. (Wendy), Steele, P. (Peter), Proudman, S. (Susanna), Minson, R. (Robert), Reeves, G. (Glenn), Lavender, M. (Melanie), Ng, B. (Benjamin), Mackenzie, M. (Michele), Barry, L. (Lisa), Gruenberger, M. (Margarethe), Huber, C. (Charlotte), Lang, I. (Irene), Tilea, I. (Ioana), Sadushi-Kolici, R. (Roela), Löffler-Ragg, J. (Judith), Feistmantl, L.-T. (Lisa-Theresa), Evrard, P. (Patrick), Louis, R. (Renaud), Guiot, J. (Julien), Naldi, M. (Marco), De Pauw, M. (Michel), Mehta, S. (Sanjay), Camacho, R.C. (Rafael Conde), Tovar, P.P. (Patricia Parada), Londoño, A. (Alejandro), Campo, F. (Felipe), Garcia, P. (Paula), Lema, C. (Camila), Orozco-Levi, M. (Mauricio), Martinez, W. (William), Gomez, J.E. (Juan Esteban), Nielsen-Kudsk, J.E. (Jens Erik), Mellemkjaer, S. (Soren), Anton, L. (Ly), Altraja, A. (Alan), Vihinen, T. (Tapani), Vasankari, T. (Tuija), Sitbon, O. (Olivier), Cottin, V. (Vincent), Têtu, L. (Laurent), Noël-Savina, E. (Elise), Shearman, N. (Nicole), Tayler, S. (Susanne), Olzik, I. (Ilona), Kulka, C. (Christine), Grimminger, J. (Jan), Simon, M. (Marcel), Nolde, A. (Anna), Oqueka, T. (Tim), Harbaum, L. (Lars), Egenlauf, B. (Benjamin), Ewert, R. (Ralf), Schulz, C. (Christian), Regotta, S. (Sabine), Kramer, T. (Tilmann), Knoop-Busch, S. (Susanne), Gerhardt, F. (Felix), Konstantinides, S. (Stavros), Pitsiou, G. (Georgia), Stanopoulos, I. (Ioannis), Sourla, E. (Evdokia), Mouratoglou, S. (Sofia), Karvounis, H.I., Pappas, A. (Athanasios), Georgopoulos, D. (Dimitrios), Fanaridis, M. (Michail), Mitrouska, I. (Ioanna), Michalis, L.K. (Lampros), Pappas, K. (Konstantinos), Kotsia, A. (Anna), Gaine, S. (Sean), Vizza, C.D. (Carmine Dario), Manzi, G. (Giovanna), Poscia, R. (Roberto), Badagliacca, R. (Roberto), Agostoni, P. (Piergiuseppe), Bruno, N. (Noemi), Farina, S. (Stefania), D'Alto, M. (Michele), Argiento, P. (Paola), Correra, A. (Anna), Di Marco, G.M. (Giovanni Maria), Cresci, C. (Chiara), Vannucchi, V. (Vieri), Torricelli, E. (Elena), Garcea, A. (Alessio), Pesci, A. (Alberto), Sardella, L. (Luca), Paciocco, G. (Giuseppe), Pane, F. (Federico), D'Armini, A.M. (Andrea Maria), Pin, M. (Maurizio), Grazioli, V. (Valentina), Massola, G. (Giulia), Sciortino, A. (Antonio), Prediletto, R. (Renato), Bauleo, C. (Carolina), Airò, E. (Edoardo), Ndreu, R. (Rudina), Pavlickova, I. (Ivana), Lunardi, C. (Claudio), Mulè, M. (Massimiliano), Farruggio, S. (Silvia), Costa, S. (Serena), Galgano, G. (Giuseppe), Petruzzi, M. (Mario), De Luca, A. (Anna), Lombardi, F. (Francesco), Roncon, L. (Loris), Conte, L. (Luca), Picariello, C. (Claudio), Wirtz, G. (Gil), Alexandre, M. (Myriam), Vonk Noordegraaf, A. (Anton), Boogaard, H. (H.), Mager, J. (J.), Reesink, H.J. (Herre), Toorn, L.M. (Leon) van den, Boomars, K.A.T. (Karin), Andreassen, A.K. (Arne K.), Castro, G. (Graça), Tania, G. (Gonçalves), Baptista, R. (Rui), Marinho, A. (António), Shiang, T. (Teresa), Oliveira, A. (Ana), Coutinho, D. (Daniel), Sousa, J. (Joana), Loureiro, M.J. (Maria José), Repolho, D. (Débora), Martins Jesus, S.M. (Susana Maria), Capinha, M. (Marta), Agostinho, J. (João), Cardoso, T. (Tania), Rocha, A. (Andreia), Espinha, M. (Mafalda), Ivanov, K.I. (Kyundyul Ivanovich), Alexeeva, D.E. (Dalyana Eduardovna), Batalina, M.V. (Marina Vadimovna), Hegya, D.V. (Daria Viktorovna), Zvereva, T.N. (Tatyana Nikolaevna), Avdeev, S.N. (Sergey Nikolaevich), Tsareva, N.A. (Natalia Anatolievna), Galyavich, A.S. (Albert Sarvatovich), Nikolaevich, B.A. (Bykov Aleksander), Filippov, E.V. (Evgeny Vladimirovich), Yakovleva, O.E. (Olga Eduardovna), Pavlova, O.B. (Olga Borisovna), Skripkina, E.S. (Elena Sergeevna), Martynyuk, T.V. (Tamila Vitalievna), Bukatova, I.F. (Irina Fedorovna), Tregubova, A.V. (Anna Viktorovna), Platonov, D.Y. (Dmitry Yurievich), Kolomeytseva, T.M. (Tatyana Mikhaylovna), Al Dalaan, A. (Abdullah), Abdelsayed, A.A. (Abeer Abeer), Weheba, I. (Ihab), Saleemi, S. (Sarferaz), Sakkijha, H. (Hussam), Bohacekova, M. (Marcela), Valkovicova, T. (Tatiana), Farkasova, I. (Iveta), Quezada, C.A. (Carlos Andres), Piccari, L. (Lucilla), Blanco, I. (Isabel), Sebastian, L. (Laura), Roman, A. (Antonio), Lopez, M. (Manuel), Otero, R. (Remedios), Elias, T. (Teresa), Jara, L. (Luis), Asencio, I. (Isabel), Arjona, J.J. (Josefa Jiménez), Almagro, R.M. (Raúl Menor), Cárdenas, S.L. (Salvador López), García, S.A. (Salvador Alcaraz), Rodríguez, P.V. (Patricia Villanueva), Lopez, R. (Raquel), Garcia, A. (Alberto), Avilés, F.F. (Francisco Fernandez), De La Pava, S. (Sebastian), Yotti, R. (Raquel), Peñate, G.P. (Gregorio Pérez), Marrero, F.L. (Fernando León), Cifrián Martínez, J.M. (José Manuel), Martinez-Meñaca, A. (Amaya), Alonso, L.P. (Lecue Pilar), Rozas, S.F. (Sonia Fernandez), Fernandez, D.I. (David Iturbe), Cuesta, V.M. (Victor Mora), Söderberg, S. (Stefan), Bartfay, S.-E. (Sven-Erik), Rundqvist, B. (Bengt), Alfetlawi, M. (Monthir), Wodlin, P. (Peter), Schwarz, E.I. (Esther Irene), Speich, R. (Rudolf), Lador, F. (Frédéric), Rochat, T. (Thierry), Gasche-Soccal, P. (Paola), Hsu, C.-H. (Chih-Hsin), Lin, T.-H. (Tsung-Hsien), Su, H.-M. (Ho-Ming), Lai, W.-T. (Wen-Ter), Chu, C.Y. (Chun Yuan), Hsu, P.-C. (Po-Chao), Voon, W.-C. (Wen-Chol), Yen, H.-W. (Hsueh-Wei), Yih-Jer Wu, J. (Jacob), Wu, S.-H. (Shu-Hao), Huang, W.-P. (Wen-Pin), Fong, M.-C. (Man-Cai), Huang, C.-L. (Chien-Lung), Kuo, P.-H. (Ping-Hung), Lin, Y.-H. (Yen-Hung), Lin, J.-L. (Jiunn-Lee), Hung, C.-S. (Chi-Sheng), Wu, C.-K. (Cho-Kai), Sung, S.-H. (Shih-Hsien), Huang, W.-C. (Wei-Chun), Cheng, C.-C. (Chin-Chang), Kuo, S.-H. (Shu-Hung), Wang, W.-H. (Wen-Hwa), Ho, W.-J. (Wan-Jing), Hsu, T.-S. (Tsu-Shiu), Mutlu, B. (Bülent), Atas, H. (Halil), Ongen, G. (Gul), Un, Z. (Zeynep), Okumus, G. (Gulfer), Hanta, I. (Ismail), Corris, P. (Paul), Peacock, A. (Andrew), Church, C. (Colin), Toshner, M. (Mark), and Newnham, M. (Michael)

Abstract

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3

Published
2021
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13. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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14. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Knight, J, Hanscombe, KB, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RV, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, A, Waisfisz, Q, Walsworth, AK, Walter, RE, Wharton, J, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, Consortium, UK NIHR Bioresource Rare Diseases, Consortium, UK PAH Cohort Study, Consortium, US PAH Biobank, McCarthy, M, Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, APH - Quality of Care, and ACS - Microcirculation

Subjects
Male, Pulmonary Arterial Hypertension, Genotyping Techniques, [SDV]Life Sciences [q-bio], Genetic Variation, HLA-DP alpha-Chains, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Survival Analysis, Article, SOXF Transcription Factors, Humans, Female, Genetic Predisposition to Disease, HLA-DP beta-Chains, Genome-Wide Association Study, Signal Transduction
Abstract

Background Raregenetic variantscause pulmonary arterial hypertension, but the contribution of commongenetic variationto disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS usedgenotypesfrom 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals.Cross-validationof loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration ofsurvival.All-cause mortalitywas the primary endpoint in survival analyses. Findings A locus nearSOX17(rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus inHLA-DPA1andHLA-DPB1(collectively referred to asHLA-DPA1/DPB1here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. TheSOX17locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional andepigenomicdata indicate that the risk variants nearSOX17altergene regulationvia anenhanceractive inendothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reducedSOX17expression. TheHLA-DPA1/DPB1rs2856830 genotype was strongly associated with survival. Median survival fromdiagnosisin patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baselinedisease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer nearSOX17and inHLA-DPA1/DPB1is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by raremutationsinSOX17. Further studies are needed to confirm the association betweenHLA typingor rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improvesrisk stratificationin clinical practice or trials.

Published
2019
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15. Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis

Author

Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Walter, RE, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Walsworth, AK, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Knight, J, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, Hanscombe, KB, US PAH Biobank Consortium, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RVM, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, British Heart Foundation, Wellcome Trust, and Medical Research Council (MRC)

Subjects
ALPHA, Science & Technology, US PAH Biobank Consortium, Critical Care Medicine, ENDODERM FORMATION, General & Internal Medicine, UK NIHR BioResource Rare Diseases Consortium, Respiratory System, UK PAH Cohort Study Consortium, SUSCEPTIBILITY, SOX17, Life Sciences & Biomedicine, DISEASE
Abstract

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.

Published
2018

17. P117 Machine learning tool provides new insights into risk assessment in pulmonary endarterectomy

Author

Bunclark, K, primary, Liley, J, additional, Newnham, M, additional, Ruggiero, A, additional, Cannon, JE, additional, Coghlan, G, additional, Lordan, J, additional, Howard, L, additional, Jenkins, D, additional, Johnson, M, additional, Kiely, DG, additional, Ng, C, additional, Screaton, N, additional, Sheares, K, additional, Taboada, D, additional, Tsui, S, additional, Wort, SJ, additional, Pepke-Zaba, J, additional, and Toshner, M, additional

Published
2019
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19. A Multicentre Study of Anticoagulation in Operable Chronic Thromboembolic Pulmonary Hypertension

Author

Bunclark, K., primary, Newnham, M., additional, Chiu, Y.-D., additional, Ruggiero, A., additional, Villar, S., additional, Cannon, J., additional, Coghlan, G., additional, Corris, P.A., additional, Howard, L., additional, Jenkins, D., additional, Johnson, M., additional, Kiely, D., additional, Ng, C., additional, Screaton, N., additional, Sheares, K., additional, Taboada, D., additional, Tsui, S., additional, Wort, J., additional, Pepke-Zaba, J., additional, and Toshner, M., additional

Published
2019
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20. Traumatic Cardiac Tamponade in the Golden Hour

Author

French, S, additional, Gardner, Y, additional, Cousins, K, additional, Desulme, B, additional, Lewis, R, additional, Newnham, M, additional, Reid, G, additional, Williams-Johnson, J, additional, Soltau, P, additional, Stephension, S, additional, and Dasgupta, S, additional

Published
2018
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21. S51 Patient pathway mapping of uk referrals to the national pulmonary endarterectomy mdt (june 2015 – may 2016)

Author

Bunclark, K, primary, Abraham, N, additional, Almeida, L Amaral, additional, Cannon, J, additional, Clare, S, additional, Doughty, N, additional, Dunning, J, additional, Ng, C, additional, Newnham, M, additional, Ponnaberanam, A, additional, Ruggiero, A, additional, Screaton, N, additional, Sheares, K, additional, Speed, N, additional, Taboada, D, additional, Toshner, M, additional, Tsui, S, additional, Jenkins, D, additional, and Pepke-Zaba, J, additional

Published
2017
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23. S108 Genome-wide association study in chronic thromboembolic pulmonary hypertension reveals new insights into aetiology

Author

Newnham, M, primary, Toshner, M, additional, Bleda, M, additional, Auger, WR, additional, Barberà, JA, additional, Bogaard, HJ, additional, Cannon, J, additional, Coghlan, G, additional, Corris, PA, additional, Delcroix, M, additional, Dunning, J, additional, Elding, H, additional, Gibbs, S, additional, Hadinnapola, C, additional, Jenkins, D, additional, Kiely, D, additional, Lang, I, additional, Maher, E, additional, Ng, C, additional, Peacock, A, additional, Screaton, N, additional, Sheares, K, additional, Simpson, M, additional, Soranzo, N, additional, Taboada, D, additional, Trembath, R, additional, Tsui, S, additional, Wilkins, MR, additional, Wort, SJ, additional, Gräf, S, additional, Pepke-Zaba, J, additional, and Morrell, NW, additional

Published
2017
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24. S50 Camphor score: sustained improvement in patient reported outcomes following pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension

Author

Newnham, M, primary, Bunclark, K, additional, Abraham, N, additional, Almeida, L Amaral, additional, Cannon, J, additional, Clare, S, additional, Doughty, N, additional, Dunning, J, additional, Ng, C, additional, Ponnaberanam, A, additional, Scholtes, S, additional, Sheares, K, additional, Speed, N, additional, Taboada, D, additional, Toshner, M, additional, Tsui, S, additional, Jenkins, D, additional, and Pepke-Zaba, J, additional

Published
2017
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25. S109 Adamts13 protein levels are decreased in chronic thromboembolic pulmonary hypertension and implicated in its pathobiology

Author

Newnham, M, primary, South, K, additional, Bleda, M, additional, Cannon, J, additional, Gräf, S, additional, Hadinnapola, C, additional, Sheares, K, additional, Taboada, D, additional, Wilkins, MR, additional, Wharton, J, additional, Pepke-Zaba, J, additional, Laffan, M, additional, Lane, DA, additional, Toshner, M, additional, and Morrell, NW, additional

Published
2017
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26. Tea: An Alternative Adsorbent for the Preservation of Cellulose Triacetate Film

Author

Nel, P, Bell, J, Newnham, M, Nel, P, Bell, J, and Newnham, M

Abstract

Cellulose triacetate (CTA) film, the main film base of the Twentieth Century, is inherently unstable, affected by autocatalytic deterioration through hydrolysis. The release of, and subsequent exposure to, acetic acid known as ‘vinegar syndrome’ accelerates deterioration, placing all cellulose acetate materials at risk or actively deteriorating. Preservation techniques rely on cold storage to slow deterioration or microenvironments with adsorbent materials to remove corrosives and/or pollutants. However, commercially available adsorbents can be expensive and difficult to access. This research investigated the potential for tea and tea waste to act as an alternative, low cost, accessible adsorbent for the preservation of CTA film. Adsorption capabilities of various tea varieties and treatments were compared with activated charcoal, silica gel and molecular sieves. Testing established tea as an effective adsorbent of water and acetic acid vapour, with an aversion to adsorption of the plasticiser dibutyl-phthalate. Use of tea waste also involves additional cost, sustainability and accessibility benefits along with lessened corrosive potential. These findings support tea as a potentially viable alternative adsorbent for the preservation of CTA film, requiring further research into optimum application systems.

Published
2017

28. Guidelines on Management of the Patient with Diabetic Foot Infection.

Author

East, J., Ferguson, T., Newnham, M. S., Titus, I., Vickers, I., and Brown, H.

Abstract

Objective: This guideline provides recommendations for the management of diabetic foot infections (DFI) and is meant to standardize in-hospital and post-discharge care with the aim of reducing post-infection disability, particularly from high amputation rates prevalent in Jamaica. It is targeted at General Surgeons leading multidisciplinary treatment teams in the local, Jamaican context, but may be relevant in other middle-income countries with similar healthcare and socio-economic demographics. Methods: The format of the guideline borrows generic elements from others identified in the literature. Synthesis involved crafting a discussion paper outlining all components of management of DFI, detailed systematic examination of the literature, particularly research emanating from Jamaica and the Caribbean, and preparation of referenced draft recommendations. Several iterations later, the final guideline was approved by the full committee. Recommendations: Recommended public health interventions to prevent DFI precede the guideline. The guideline recommends hospitalization for established DFI and management by multidisciplinary teams led by General Surgeons. Hyperglycaemia is managed preferably with basal-bolus insulin. The affected limb should be clinically assessed for severe or critical limb ischaemia (CLI) and ankle-brachial index (ABI) measured, non-invasive angiography (duplex or computed tomography) performed if ABI ≤ 0.5 and the result discussed with a vascular surgeon. If CLI is diagnosed and revascularization is not feasible, amputation no lower than below knee level should be contemplated. Wounds should be assessed for extent of infection (including osteomyelitis) and debrided, tissue sent for culture, and empirical bactericidal broad spectrum intravenous antibiotic therapy initiated. Methicillin-resistant Staphylococcus aureus coverage should be considered for severe or rapidly spreading DFI, pending culture reports. Wounds should be inspected, debrided and dressed daily. After-discharge care includes provision of diabetic foot care education, outpatient wound care, discontinuation of antibiotics when appropriate, early off-loading for slowly healing plantar wounds originating from or evolving into neuropathic ulcers, and referral for orthoses and prostheses. [ABSTRACT FROM AUTHOR]

Published
2019
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35. Management of Breast Abscesses in Jamaican Women Is There Need for a Paradigm Shift?

Author

Newnham, M. S., Brown, H., Martin, A. C., Plummer, J. M., Mitchell, D. I. G., and Cawich, S. O.

Abstract

Copyright of West Indian Medical Journal is the property of West Indian Medical Journal (WIMJ) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2012
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36. Open Abdominal Aortic Aneurysm Repair in the Era of Endovascular Repair.

Author

Leake, P.-A., Hamilton-Johnson, T. N., Harry, M., Gordon-Strachan, G. M., Plummer, J. M., and Newnham, M. S.

Abstract

Copyright of West Indian Medical Journal is the property of West Indian Medical Journal (WIMJ) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2011

37. Population mobility, globalization, and antimicrobial drug resistance.

Author

MacPherson DW, Gushulak BD, Baine WB, Bala S, Gubbins PO, Holtom P, Segarra-Newnham M, MacPherson, Douglas W, Gushulak, Brian D, Baine, William B, Bala, Shukal, Gubbins, Paul O, Holtom, Paul, and Segarra-Newnham, Marisel

Abstract

Population mobility is a main factor in globalization of public health threats and risks, specifically distribution of antimicrobial drug-resistant organisms. Drug resistance is a major risk in healthcare settings and is emerging as a problem in community-acquired infections. Traditional health policy approaches have focused on diseases of global public health significance such as tuberculosis, yellow fever, and cholera; however, new diseases and resistant organisms challenge existing approaches. Clinical implications and health policy challenges associated with movement of persons across barriers permeable to products, pathogens, and toxins (e.g., geopolitical borders, patient care environments) are complex. Outcomes are complicated by high numbers of persons who move across disparate and diverse settings of disease threat and risk. Existing policies and processes lack design and capacity to prevent or mitigate adverse health outcomes. We propose an approach to global public health risk management that integrates population factors with effective and timely application of policies and processes. [ABSTRACT FROM AUTHOR]

Published
2009

38. Management of Obstetric Anal Sphincter Injuries at the University Hospital of the West Indies.

Author

Cawich, S. O., Mitchell, D. I. G., Martin, A., Brown, H., daCosta, V. E., Lewis, T., Newnham, M., and Christie, L.

Abstract

Copyright of West Indian Medical Journal is the property of West Indian Medical Journal (WIMJ) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2008

40. Effect of ritonavir-containing regimens on lipids compared to other protease inhibitors.

Author

Segarra-Newnham M and Haselkorn SM

Abstract

Protease inhibitor (PI) therapy may cause increases in lipids. Data are limited on how different PIs compare with each other within the same patient. Our objective was to evaluate the effect of ritonavir-containing regimens on triglycerides (TG) and total cholesterol (TC) after treatment with other PIs in the same patient. Eighteen patients were evaluated. A significant increase in both TC and TG was seen in patients receiving ritonavir-containing regimens compared to other PIs (TC 229 vs. 204 and TG 313 vs. 231, p < 0.05). Three patients were receiving lipid-lowering therapy prior to ritonavir. One patient needed a dose adjustment; two patients were started on lipid-lowering therapy and one on diet after ritonavir therapy was initiated. Patients starting ritonavir therapy need to be closely monitored for changes in lipids. Changes or addition of lipid-lowering therapy may be needed even if other PIs did not cause a change in lipid values. [ABSTRACT FROM AUTHOR]

Published
2003

42. Terminal Ileum Duplication An Unusual Case of Small Bowel Obstruction.

Author

Newnham, M. S., Coard, K. C., Brown, B. R., and Martin, A. C.

Abstract

Copyright of West Indian Medical Journal is the property of West Indian Medical Journal (WIMJ) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2013

43. Guidelines in Surgery: Implications for Quality of Care at the University Hospital of the West Indies and Jamaica.

Author

Plummer, J. M. and Newnham, M. S.

Abstract

The article offers information on the guidelines in surgery and several implications for quality of care at the University Hospital of the West Indies and Jamaica. Topics discussed include information on the increased quality of care in surgery; discussions on the effort to improve quality in clinical care; and the information on the initiative to develop evidence-based guidelines for improving quality in clinical care.

Published
2019
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45. Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension

Author

Hadinnapola, CMB, Bleda, M, Haimel, M, Screaton, N, Swift, A, Dorfmuller, P, Preston, SD, Southwood, M, Hernandez Sanchez, J, Martin, J, Treacy, C, Yates, K, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Gibbs, S, Girerd, B, Holden, S, Humbert, M, Kiely, DG, Lawrie, A, Machado, R, Mackenzie Ross, R, Moledina, S, Montani, S, Newnham, M, Peacock, A, Pepke Zaba, J, Rayner-Matthews, P, Shamardina, O, Soubrier, F, Southgate, L, Suntharalingam, J, Toshner, MR, Trembath, R, Vonk Noordegraaf, A, Wilkins, MR, Wort, SJ, Wharton, J, Graf, S, and Morrell, NW

Subjects
EIF2AK4, pulmonary venoocclusive disease, pulmonary hypertension, genetics, human, prognosis, 3. Good health
Abstract

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR BioResource - Rare Diseases Study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of < 1:10,000 in control data sets and predicted to be deleterious (by CADD, PolyPhen-2 and SIFT predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of PVOD/PCH. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO: 33 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as idiopathic and heritable PAH. These patients cannot be identified reliably by CT, but a low KCO and a young age of diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation., The National Institute of Health Research (NIHR) BioResource for Rare Diseases provided funding for sequencing and analysis. The study was supported by a British Heart Foundation Special Project Grant and a Medical Research Council (UK) Experimental Challenge Award.

47. S50 Camphor score: sustained improvement in patient reported outcomes following pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension

Author

Newnham, M, Bunclark, K, Abraham, N, Almeida, L Amaral, Cannon, J, Clare, S, Doughty, N, Dunning, J, Ng, C, Ponnaberanam, A, Scholtes, S, Sheares, K, Speed, N, Taboada, D, Toshner, M, Tsui, S, Jenkins, D, and Pepke-Zaba, J

Abstract

IntroductionThe CAMPHOR (Cambridge Pulmonary Hypertension Outcome Review) score is an internationally validated patient reported outcome (PRO) measure for pulmonary hypertension, including chronic thromboembolic pulmonary hypertension (CTEPH). It assesses 3 areas: activity (score 0–30), symptoms (0–25) and quality of life (QoL) (0–25); with a higher score indicating a worse PRO. CTEPH frequently causes debilitating symptoms and functional impairment, which can be improved in selected patients with pulmonary endarterectomy (PEA). However, a subset will have residual pulmonary hypertension. We aim to assess PROs in patients with CTEPH undergoing PEA.MethodsConsecutive CTEPH patients undergoing PEA from June 2006 to August 2016 at the UK National PEA centre, were included in this retrospective analysis. Patients are reviewed after PEA every 6–12 months for at least 5 years. CAMPHOR scores were recorded prospectively when patients attended hospital assessment and at each follow-up, ensuring high capture.Results1151 patients underwent PEA during the study period. Of those, 937 (81%) had a CAMPHOR score recorded at baseline (pre-PEA) and 816 (77% of 1059 alive) at follow-up within a year of PEA (post-PEA). We confirmed significant improvements in 6 min walk distance and haemodynamics post-PEA (pre/post-PEA median ±IQR: 6 mwd 300±199 Metres/360±165; mPAP 45±15/25±13 mmHg; PVR 669±478/246±214 dynes.s.cm-5; CI 2.2±0.8/2.3±0.7 L/min/m2). The difference in median CAMPHOR scores pre- and post-PEA improved by 6,7 and 9 points for activity, QoL and symptoms respectively. The median difference for individuals having consecutive paired pre- and post-PEA scores also improved (median ±IQR: activity 4±7; QoL 4±8; symptoms 7±8). Patients were dichotomised into those with significant residual pulmonary hypertension (previously reported risk threshold of ≥30 mmHg , n=302) and those without (n=569). The improvement in CAMPHOR score was greater and more sustained in those without residual pulmonary hypertension (fsigure 1).ConclusionPROs relating to activity, QoL and symptoms improve after PEA in CTEPH when evaluated by CAMPHOR score. The improvement is sustained up to 5 years in those without residual pulmonary hypertension. Ongoing work will examine the utility of PROs in addition to traditional clinical outcome measures.AcknowledgementsNational Pulmonary Hypertension Centres UK and Ireland for referring patients considered for PEA.[Figure]

Published
2017
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48. S51 Patient pathway mapping of uk referrals to the national pulmonary endarterectomy mdt (june 2015 – may 2016)

Author

Bunclark, K, Abraham, N, Almeida, L Amaral, Cannon, J, Clare, S, Doughty, N, Dunning, J, Ng, C, Newnham, M, Ponnaberanam, A, Ruggiero, A, Screaton, N, Sheares, K, Speed, N, Taboada, D, Toshner, M, Tsui, S, Jenkins, D, and Pepke-Zaba, J

Abstract

IntroductionPulmonary endarterectomy (PEA) is the treatment of choice for Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and can be offered to selected patients with Chronic Thromboembolic Disease without pulmonary hypertension (CTED). Our aim was to map the pathway of UK patients referred to the National PEA MDT and their onwards management.MethodsAll consecutive individuals referred to the National PEA MDT at Papworth Hospital between June 2015 and May 2016 were included. Patients were divided into CTEPH/CTED groups and their pathways followed until July 2017.ResultsOf the 316 referrals to the PEA MDT there were 246 cases of CTEPH, 46 of CTED and 24 with alternate diagnoses. Age range of referrals was 22–88 years (mean 59 years). 51% were male. The majority of CTEPH cases had technically operable disease (n=200, 81%) with 130 proceeding to PEA (65%). 53% of all CTEPH cases were operated on (figure 1). Median time from first MDT discussion to PEA was 230 days with a median surgical waiting list time of 115 days. 11 patients required ongoing targeted therapy post-operatively. Of the 70 individuals with an operable disease distribution who did not proceed to PEA, 34 patients chose to decline surgery and 36 were rejected by the surgical team due to co-morbid conditions (n=28) or limited symptoms (n=8). Two patients with distal CTEPH underwent Balloon Pulmonary Angioplasty (BPA). Remaining patients were medically managed with targeted therapy. Of CTED cases, 28 (61%) had an operable disease distribution with 8 (29%) proceeding to PEA. 17% of total CTED referrals were operated on.ConclusionThis patient pathway mapping is the first undertaken for any national CTEPH/CTED cohort. The majority of UK CTEPH cases suitable for PEA are operated on (65%). The duration of time between MDT referral and PEA is reflective of disease complexity and decision-making process. We observe a group of highly selected individuals with Chronic Thromboembolic Disease (CTED) without pulmonary hypertension who undergo PEA after careful consideration of their symptoms and operative risk.[Figure]

Published
2017
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49. P184 Age should not be a barrier to pulmonary endarterectomy in carefully selected patients

Author

Newnham, M, Hernandez-Sanchez, J, Dunning, J, Ng, C, Tsui, S, Bunclark, K, Sheares, K, Taboada, D, Toshner, M, Pepke-Zaba, J, Jenkins, D, and Cannon, J

Abstract

IntroductionWe previously reported that hospital survival in patients over 70 years undergoing pulmonary endarterectomy (PEA) was comparable to those under 70, albeit with longer hospital and intensive care unit (ICU) stays.1Octogenarians have acceptable morbidity and mortality outcomes following cardiac surgery. We aimed to assess if this also applies to PEA surgery.MethodsConsecutive patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH) from June 2006 to August 2016 at the National referral centre for PEA were included in a retrospective analysis. The cohort was dichotomized into over and under 80 years according to age at surgery. Pre-operative baseline and post-operative 3–6 month follow-up data were recorded, with follow-up data included until November 2016.Results1152 individuals underwent PEA (1115 under 80 years, 37 over 80) during the study period. Baseline and 3–6 month follow up variables and outcomes are summarised in Table 1. Survival is lower in the over 80 group (Log-rank test, p=0.002), but is no different from an age and sex matched UK reference population (p=0.5) (Office of National Statistics). The hospital length of stay was longer in those over 80 (median: 19 vs. 14 days; p=0.001), however, there was no difference in NYHA class, haemodynamics, type of surgical disease, CAMPHOR score or ICU length of stay between the two age groups. There were more concomitant cardiac surgical procedures in the over 80 group (26% vs 11%, p=0.006), although this was not statistically significant when accounting for multiple testing.ConclusionsWe found similar outcomes in patients under and over 80 years old undergoing PEA, except for a prolonged hospital length of stay in those over 80. Whilst survival is reduced in the over 80 group compared to the under 80, it is no different to the age-sex matched population. Age alone should not be a contraindication for PEA and individuals with suspected CTEPH should be referred for specialist evaluation.ReferenceBerman M, Hardman G, Sharples L, Pepke-Zaba J, Sheares K, Tsui S, et al. Pulmonary endarterectomy: Outcomes in patients aged ≥70. Eur J Cardiothorac Surg2012;41(6):154–60.[Figure]

Published
2017
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50. Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD

Author

Ellis P, Bailey E, Choate R, Holm KE, Sandhaus RA, Turner AM, and Newnham M

Subjects
chronic obstructive pulmonary disease, copd, alpha-1 antitrypsin deficiency, aatd, cardiovascular disease, Diseases of the respiratory system, RC705-779
Abstract

Paul Ellis,1,2 Emily Bailey,2 Radmila Choate,3 Kristen E Holm,4,5 Robert A Sandhaus,5,6 Alice M Turner,1,2 Michael Newnham1,2 1Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 2University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 3University of Kentucky College of Public Health, Lexington, KY, USA; 4Division of Neurology and Behavioural Health, National Jewish Health, Denver, CO, USA; 5AlphaNet, Kissimmee, FL, USA; 6Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USACorrespondence: Paul Ellis, Email p.ellis@bham.ac.ukAim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD.Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE.Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001).Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.Keywords: chronic obstructive pulmonary disease, COPD, alpha-1 antitrypsin deficiency, AATD, cardiovascular disease

Published
2024

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