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51. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice

Author

Cloonan, Suzanne M., Glass, Kimberly, Laucho-Contreras, Maria E., Bhashyam, Abhiram R., Cervo, Morgan, Pabon, Maria A., Konrad, Csaba, Polverino, Francesca, Siempos, Ilias I., Perez, Elizabeth, Mizumura, Kenji, Ghosh, Manik C., Parameswaran, Harikrishnan, Williams, Niamh C., Rooney, Kristen T., Chen, Zhi-Hua, Goldklang, Monica P., Yuan, Guo-Cheng, Moore, Stephen C., Demeo, Dawn L., Rouault, Tracey A., D'Armiento, Jeanine M., Schon, Eric A., Manfredi, Giovanni, Quackenbush, John, Mahmood, Ashfaq, Silverman, Edwin K., Owen, Caroline A., and Choi, &.Augustine M.K.

Subjects
Emphysema, Pulmonary -- Genetic aspects -- Care and treatment, Bronchitis -- Analysis -- Genetic aspects -- Care and treatment, Cigarette smoke -- Health aspects, Chelation therapy -- Methods -- Patient outcomes, Molecular targeted therapy -- Methods -- Patient outcomes, Biological sciences, Health
Abstract

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeuticition for the mitochondrial-iron axis in COPD., COPD presents as a complex, debilitating lung disease that encompasses a variety of clinical and pathologic phenotypes ranging from airway inflammation (chronic bronchitis) to destruction of lung tissue (emphysema) and [...]

Published
2016
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52. Differences in Clinical Features and Comorbid Burden between HLA-C∗06:02 Carrier Groups in >9,000 People with Psoriasis

Author

Douroudis, Konstantinos, primary, Ramessur, Ravi, additional, Barbosa, Ines A., additional, Baudry, David, additional, Duckworth, Michael, additional, Angit, Caroline, additional, Capon, Francesca, additional, Chung, Raymond, additional, Curtis, Charles J., additional, Di Meglio, Paola, additional, Goulding, Jonathan M.R., additional, Griffiths, Christopher E.M., additional, Lee, Sang Hyuck, additional, Mahil, Satveer K., additional, Parslew, Richard, additional, Reynolds, Nick J., additional, Shipman, Alexa R., additional, Warren, Richard B., additional, Yiu, Zenas Z.N., additional, Simpson, Michael A., additional, Barker, Jonathan N., additional, Dand, Nick, additional, Smith, Catherine H., additional, Evans, Ian, additional, Murphy, Ruth, additional, McPherson, Tess, additional, Kleyn, Elise, additional, Laws, Philip, additional, Becher, Gabrielle, additional, Bewley, Anthony, additional, Rashid, Amir, additional, Alabas, Oras, additional, Morrison, Simon, additional, Ahmed, Shehnaz, additional, Pearson, Eleanor, additional, Richards, Josh, additional, Mackenzie, Teena, additional, Kirby, Brian, additional, Burden, David, additional, Lawson, Linda, additional, McElhone, Kathleen, additional, Ormerod, Anthony, additional, Owen, Caroline, additional, Aldoori, Nadia, additional, Ali, Mahmud, additional, Anstey, Alex, additional, Antony, Fiona, additional, Archer, Charles, additional, August, Suzanna, additional, Balasubramaniam, Periasamy, additional, Baxter, Kay, additional, Bonsall, Alexandra, additional, Brown, Victoria, additional, Burova, Katya, additional, Butt, Aamir, additional, Caswell, Mel, additional, Cliff, Sandeep, additional, Costache, Mihaela, additional, Darne, Sharmela, additional, Davies, Emily, additional, DeGiovanni, Claudia, additional, Desai, Trupti, additional, DeSilva, Bernadette, additional, Diba, Victoria, additional, Domanne, Eva, additional, Dymond, Harvey, additional, Fahy, Caoimhe, additional, Ferguson, Leila, additional, Gkini, Maria-Angeliki, additional, Godwin, Alison, additional, Hammonds, Fiona, additional, Johnson, Sarah, additional, Joseph, Teresa, additional, Kalavala, Manju, additional, Khorshid, Mohsen, additional, Labinoti, Liberta, additional, Lawson, Nicole, additional, Layton, Alison, additional, Lees, Tara, additional, Levell, Nick, additional, Lewis, Helen, additional, Lyon, Calum, additional, McBride, Sandy, additional, McCormack, Sally, additional, McKenna, Kevin, additional, Mellor, Serap, additional, Norris, Paul, additional, Popli, Urvi, additional, Perera, Gay, additional, Ponnambath, Nabil, additional, Ramsay, Helen, additional, Ranasinghe, Aruni, additional, Reeken, Saskia, additional, Rose, Rebecca, additional, Rotarescu, Rada, additional, Salvary, Ingrid, additional, Sands, Kathy, additional, Sinha, Tapati, additional, Stefanescu, Simina, additional, Sundararaj, Kavitha, additional, Taghipour, Kathy, additional, Taylor, Michelle, additional, Thomson, Michelle, additional, Topliffe, Joanne, additional, Verdolini, Roberto, additional, Wachsmuth, Rachel, additional, Wade, Martin, additional, Wahie, Shyamal, additional, Walsh, Sarah, additional, Walton, Shernaz, additional, Wilcox, Louise, additional, and Wright, Andrew, additional

Published
2022
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56. Communication that matters: empowering staff to partner with patients and carers through changes in patient communication.

Author

Owen, Caroline, Mouritz, Fiona, Chiswell, Meg, Martin, Peter, and Dimech, Andrew

Subjects
SELF-efficacy, MEDICAL care, EVALUATION of human services programs, CONFERENCES & conventions, CAREGIVERS, PATIENT-professional relations, COMMUNICATION, PATIENTS' attitudes
Abstract

Introduction In an era of evolving digital approaches, maintaining a person-centred approach is critical to cancer care, including considering how patients, carers and family experience information and communication, and how they participate in shared decision making. Peter MacCallum Cancer Centre implemented the organisation-wide Your Thoughts Matter (YTM) communication program to drive innovative changes to the experiences of patients, families and carers. By ensuring core communication skills are consistently delivered at every patient encounter by every staff member, patients are empowered to share their thoughts on "what matters to them", shifting the focus from "what is the matter with them". Aim To achieve measurable improvement in the patients' experience of healthcare by strengthening communication between health professionals and patients. Description YTM is an evidence-based program designed to build capacity and embed core communication skills within health services. Peter Mac implemented the program in three phases: developing a faculty of staff and consumers to deliver training; delivering multidisciplinary interactive face-to-face communication workshops for staff, focussing on clinical care and clinical administration teams; and implementing of a question prompt sheet to help patients communicate with staff. Outcomes Despite implementation commencing during COVID-19 restrictions, more than 1500 staff completed training. Staff completed pre- and post-training selfefficacy surveys and evaluated the workshop training experience. 469 patients and carers completed a real-time feedback communication survey, reporting a generally positive experience while highlighting areas for improvement. Evaluation data report improvements in patient interactions with staff, with a decrease in complaints and an increase in compliments. Staff report feeling more equipped to deliver person-centred care and better prepared to support patients, carers and families. Conclusion The YTM program is achieving significant improvements in person-centred care and communication, supporting staff and ensuring patients and carers have answers to the questions that matter to them most throughout each stage of their care. [ABSTRACT FROM AUTHOR]

Published
2024

57. Proteinases

Author

Owen, Caroline A., Campbell, Edward J., Evans, Timothy W., editor, and Haslett, Christopher, editor

Published
1996
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59. A Novel Protective Role for Matrix Metalloproteinase-8 in the Pulmonary Vasculature

Author

Dieffenbach, Paul B., primary, Mallarino Haeger, Christina, additional, Rehman, Rakhshinda, additional, Corcoran, Alexis M., additional, Coronata, Anna Maria F., additional, Vellarikkal, Shamsudheen K., additional, Chrobak, Izabela, additional, Waxman, Aaron B., additional, Vitali, Sally H., additional, Sholl, Lynette M., additional, Padera, Robert F., additional, Lagares, David, additional, Polverino, Francesca, additional, Owen, Caroline A., additional, and Fredenburgh, Laura E., additional

Published
2021
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60. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD

Author

Mizumura, Kenji, Cloonan, Suzanne M., Nakahira, Kiichi, Bhashyam, Abhiram R., Cervo, Morgan, Kitada, Tohru, Glass, Kimberly, Owen, Caroline A., Mahmood, Ashfaq, Washko, George R., Hashimoto, Shu, Ryter, Stefan W., and Choi, Augustine M.K.

Subjects
Medical research, Medicine, Experimental, Lung diseases, Obstructive -- Analysis -- Development and progression, Autophagy (Cytology) -- Research, Extracellular signal-regulated kinases -- Physiological aspects, Cigarette smoke -- Health aspects, Necrosis -- Development and progression -- Risk factors, Health care industry
Abstract

The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, [Pink1.sup.-/-] mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD., Introduction Chronic obstructive pulmonary disease (COPD) contributes significantly to the global burden of disease as the fourth leading cause of mortality worldwide (1). This disease includes clinical phenotypes of emphysema [...]

Published
2014
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61. Dysregulation of miR-103a Mediates Cigarette Smoking-induced Lipid-laden Macrophage Formation.

Author

Yin Zhu, Yohan Han, Almuntashiri, Sultan, Dutta, Saugata, Xiaoyun Wang, Owen, Caroline A., and Duo Zhang

Subjects
HOMEOSTASIS, ALVEOLAR macrophages, CHRONIC obstructive pulmonary disease, LIPOPROTEIN receptors, MACROPHAGES, CIGARETTES, LIPIDS
Abstract

Cigarette smoke (CS) is considered a major risk factor for chronic obstructive pulmonary disease (COPD) that is currently the third leading cause of death in the United States. Studies have indicated that patients with COPD have elevated blood low-density lipoprotein levels, which may contribute to the dysregulation of lipid metabolism. Accumulating data show that microRNAs (miRNAs) are involved in various human diseases. However, the role of microRNAs in the pathogenesis of COPD remains poorly defined. In this study, we found that miR-103a expression was significantly reduced in alveolar macrophages from smokers and patients with COPD versus that in alveolar macrophages from nonsmokers. Our data indicated that reactive oxygen species negatively regulate miR-103a in macrophages. Functionally, miR-103a modulates the expressions of genes involved in lipid metabolism and directly targets low-density lipoprotein receptors in macrophages. Furthermore, overexpression of miR-103a suppressed the accumulation of lipid droplets and reduced the reactive oxygen species, both in vitro and in vivo. Taken together, our findings indicate that downregulation of miR-103a contributes to cigarette smoke-induced lipid-laden macrophage formation and plays a critical role in lipid homeostasis in lung macrophages in the pathogenesis of COPD. [ABSTRACT FROM AUTHOR]

Published
2022
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62. Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction

Author

Lam, Hilaire C., Cloonan, Suzanne M., Bhashyam, Abhiram R., Haspel, Jeffery A., Singh, Anju, Sathirapongsasuti, J. Fah, Cervo, Morgan, Yao, Hongwei, Chung, Anna L., Mizumura, Kenji, An, Chang Hyeok, Shan, Bin, Franks, Jonathan M., Haley, Kathleen J., Owen, Caroline A., Tesfaigzi, Yohannes, Washko, George R., Quackenbush, John, Silverman, Edwin K., Rahman, Irfan, Kim, Hong Pyo, Mahmood, Ashfaq, Biswal, Shyam S., Ryter, Stefan W., and Choi, Augustine M.K.

Subjects
Lung diseases, Obstructive -- Research, Smoking -- Health aspects, Epithelial cells -- Physiological aspects, Health care industry
Abstract

Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired ([Becn1.sup.+/-] or [Map1lc3B.sup.-/-]) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 ([Hdac6.sup.-/Y]) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired [Becn1.sup.+/-], [Map1lc3B.sup.-/-], and [Hdac6.sup.-/Y] mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD., doi:10.1172/JCI69636. Introduction Chronic obstructive pulmonary disease (COPD) contributes substantially to the global burden of disease as the fourth leading cause of morbidity and mortality worldwide (1). The pathogenesis of COPD [...]

Published
2013

63. Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment

Author

Polverino, Francesca, primary, Wu, Tianshi David, additional, Rojas-Quintero, Joselyn, additional, Wang, Xiaoyun, additional, Mayo, Jonathan, additional, Tomchaney, Michael, additional, Tram, Judy, additional, Packard, Samuel, additional, Zhang, Duo, additional, Cleveland, Kristan H., additional, Cordoba-Lanus, Elizabeth, additional, Owen, Caroline A., additional, Fawzy, Ashraf, additional, Kinney, Greg L., additional, Hersh, Craig P., additional, Hansel, Nadia N., additional, Doubleday, Kevin, additional, Sauler, Maor, additional, Tesfaigzi, Yohannes, additional, Ledford, Julie G., additional, Casanova, Ciro, additional, Zmijewski, Jaroslaw, additional, Konhilas, John, additional, Langlais, Paul R., additional, Schnellmann, Rick, additional, Rahman, Irfan, additional, McCormack, Meredith, additional, and Celli, Bartolome, additional

Published
2021
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66. Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease

Author

Lange, Peter, Celli, Bartolome, Agustí, Alvar, Jensen, Gorm Boje, Divo, Miguel, Faner, Rosa, Guerra, Stefano, Marott, Jacob Louis, Martinez, Fernando D., Martinez-Camblor, Pablo, Meek, Paula, Owen, Caroline A., Petersen, Hans, Pinto-Plata, Victor, Schnohr, Peter, Sood, Akshay, Soriano, Joan B., Tesfaigzi, Yohannes, and Vestbo, Jørgen

Published
2015
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68. Purpuric rash on the lower legs.

Author

Shaw, Daniel, Fozdar, Siddiq, and Owen, Caroline

Subjects
FOOD habits, MYALGIA, SCURVY, ORAL drug administration, BLOOD transfusion, EXANTHEMA, DIFFERENTIAL diagnosis, VITAMIN C, PURPURA (Pathology), LEG, TREATMENT effectiveness, PHYSICAL mobility, WEIGHT loss, EDEMA, DISEASE management
Published
2023
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70. Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Author

Flume, Patrick A, primary, Biner, Reta Fischer, additional, Downey, Damian G, additional, Brown, Cynthia, additional, Jain, Manu, additional, Fischer, Rainald, additional, De Boeck, Kris, additional, Sawicki, Gregory S, additional, Chang, Philip, additional, Paz-Diaz, Hildegarde, additional, Rubin, Jaime L, additional, Yang, Yoojung, additional, Hu, Xingdi, additional, Pasta, David J, additional, Millar, Stefanie J, additional, Campbell, Daniel, additional, Wang, Xin, additional, Ahluwalia, Neil, additional, Owen, Caroline A, additional, Wainwright, Claire E, additional, Gibson, Ronald L., additional, Rowe, Steven M., additional, Lechtzin, Noah, additional, Ahrens, Richard C., additional, McCoy, Karen S., additional, Aitken, Moira, additional, Donaldson, Scott H., additional, McBennett, Kimberly Ann, additional, Pilewski, Joseph M., additional, Billings, Joanne, additional, Milla, Carlos, additional, Rubenstein, Ronald, additional, Rosenbluth, Daniel Brian, additional, Linnemann, Rachel, additional, Powers, Michael R., additional, Fortner, Christopher, additional, Frederick, Carla Anne, additional, Liou, Theodore G., additional, Black, Philip, additional, Wang, Janice, additional, Colombo, John L., additional, Berdella, Maria, additional, Indihar, Maria Veronica, additional, Brown, Cynthia D., additional, Anstead, Michael, additional, Bilodeau, Lara, additional, Sicilian, Leonard, additional, Tolle, James Jerome, additional, Moffett, Kathryn, additional, Nasr, Samya, additional, Taylor-Cousar, Jennifer, additional, Barto, Tara Lynn, additional, Antos, Nicholas, additional, Rogers, John S., additional, Quick, Bryon, additional, Thompson, Henry R., additional, Sawicki, Gregory, additional, Barnett, Bruce, additional, Zanni, Robert L., additional, Smith, Thomas C., additional, Schultz, Karen D., additional, Keating, Claire, additional, Flume, Patrick, additional, Omlor, Gregory J., additional, Ashare, Alix, additional, Voter, Karen, additional, Mehdi, Nighat, additional, Ortiz, Maria Gabriela Tupayachi, additional, Gardner, Tonia E., additional, Boas, Steven R., additional, Messore, Barbara, additional, Zemanick, Edith, additional, Jain, Raksha, additional, McCarthy, Michael, additional, Kissner, Dana G., additional, Patel, Kapilkumar, additional, McNamara, John, additional, Philley, Julie, additional, Berlinski, Ariel, additional, Calimano, Francisco J., additional, Chin, Terry, additional, Conrad, Douglas, additional, Daines, Cori, additional, Raissy, Hengameh H., additional, Keens, Thomas G., additional, Lascano, Jorge E., additional, McWilliams, Bennie, additional, Morrissey, Brian, additional, Reyes, Santiago, additional, Chittivelu, Subramanyam, additional, Hussain, Sabiha, additional, Stone, Arvey, additional, Wallace, James, additional, Klingsberg, Ross, additional, Biller, Julie A., additional, Bui, Stephanie, additional, Sommerburg, Olaf, additional, Bignamini, Elisabetta, additional, Collura, Mirella, additional, Moller, Alexander, additional, Salvatore, Donatello, additional, Belleguic, Chantal, additional, Bentur, Lea, additional, Efrati, Ori, additional, Kerem, Eitan, additional, Prais, Dario, additional, Gallego, Esther Quintana, additional, Barry, Peter, additional, Livnat-Levanon, Galit, additional, Asensi, Jose Ramon Villa, additional, Armstrong, David Stuart, additional, de la Cruz, Oscar Asensio, additional, Gilchrist, Francis, additional, Tullis, Diana Elizabeth, additional, Quon, Bradley, additional, Lands, Larry C., additional, Morrison, Nancy, additional, Lavoie, Annick, additional, Linnane, Barry, additional, Elidemir, Okan, additional, Ringshausen, Felix, additional, Kappler, Matthias, additional, Hebestreit, Helge, additional, Mainz, Jochen, additional, Kiefer, Alexander, additional, Koerner-Rettberg, Cordula, additional, Staab, Doris, additional, Gleiber, Wolfgang, additional, Pressler, Tacjana, additional, Stehling, Florian, additional, Hector, Andreas, additional, Sutharsan, Sivagurunathan, additional, Naehrlich, Lutz, additional, Downey, Damian, additional, Davies, Jane Carolyn, additional, Ketchell, Robert Ian, additional, Carroll, Mary Patricia, additional, Doe, Simon, additional, MacGregor, Gordon, additional, Nash, Edward Fairbairn, additional, Withers, Nicholas, additional, Peckham, Daniel Gavin, additional, Ledson, Martin James, additional, Kansra, Sonal, additional, Lee, Timothy William Rayner, additional, Delaisi, Bertrand, additional, Rault, Gilles, additional, Le Bihan, Jean, additional, Hubert, Dominique, additional, Fajac, Isabelle, additional, Sermet-Gaudelus, Isabelle, additional, Bakker, Marleen, additional, Arets, Bert, additional, De Boeck, Christiane, additional, Chiron, Raphael, additional, Reix, Philippe, additional, Mainguy, Catherine, additional, van Braeckel, Eva, additional, Malfroot, Anne, additional, Durieu, Isabelle, additional, Dufeu, Nadine Desmazes, additional, Prevotat, Anne, additional, van der Meer, Renske, additional, Merkus, Petrus, additional, Weersink, E.J.M., additional, Gomez-Aguero, Isabel Barrio, additional, Gartner, Silvia, additional, Jover, Amparo Sole, additional, Fernandez, Antonio Alvarez, additional, Cox, Desmond William, additional, McKone, Edward F., additional, Plant, Barry James, additional, Selvadurai, Hiranjan, additional, Bowler, Simon David, additional, Wainwright, Claire Elizabeth, additional, Smith, Daniel, additional, Middleton, Peter Gordon, additional, Wilson, John William, additional, Volpi, Sonia, additional, Colombo, Carla, additional, Fabrizzi, Benedetta, additional, Lucidi, Vincenzina, additional, Cresta, Federico, additional, Cucchiara, Salvatore, additional, Eber, Ernst, additional, Ellemunter, Helmut, additional, Huttegger, Isidor, additional, Hjelte, Lena, additional, Krantz, Christina, additional, and Gilljam, Marita, additional

Published
2021
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77. Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study

Author

Rungapiromnan, W., Mason, K.J., Lunt, M., McElhone, K., Burden, A. D., Rutter, M.K., Warren, R.B., Griffiths, C.E.M., Ashcroft, D.M., Barker, Jonathan, Benham, Marilyn, Browne, Fiona, Evans, Ian, Hussain, Sagair, Kirby, Brian, Lawson, Linda, McPherson, Tess, Murphy, Ruth, Owen, Caroline, Ormerod, Anthony, Pearson, Eleanor, Reynolds, Nick, Richards, Josh, Smith, Catherine, and BADBIR Study Group, .

Subjects
musculoskeletal diseases, skin and connective tissue diseases
Abstract

Background:\ud The cardiovascular safety profile of biologic therapies used for psoriasis is unclear.\ud \ud Objectives:\ud To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort.\ud \ud Methods:\ud Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis‐α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups.\ud \ud Results:\ud We included 5468 biologic‐naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25–p75) follow‐up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16–3.21), 1.93 (1.05–3.34), 1.94 (1.09–3.32), 1.92 (0.93–3.45) and 1.43 (0.84–2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41–2.22); ustekinumab vs. adalimumab: 0.81 (0.30–2.17); etanercept vs. adalimumab: 0.81 (0.28–2.30)] and methotrexate against adalimumab [1.05 (0.34–3.28)].\ud \ud Conclusions:\ud In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow‐up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs.

Published
2020

78. Using real‐world data to guide ustekinumab dosing strategies for psoriasis: a prospective pharmacokinetic‐pharmacodynamic study

Author

Pan, Shan, Tsakok, Teresa, Dand, Nick, Lonsdale, Dagan O., Loeff, Floris C., Bloem, Karien, de Vries, Annick, Baudry, David, Duckworth, Michael, Mahil, Satveer, Pushpa‐Rajah, Angela, Russell, Alice, Alsharqi, Ali, Becher, Gabrielle, Murphy, Ruth, Wahie, Shyamal, Wright, Andrew, Griffiths, Christopher E.M., Reynolds, Nick J., Barker, Jonathan, Warren, Richard B., Burden, A. David, Rispens, Theo, Standing, Joseph F., Smith, Catherine H., Benham, Marilyn, Evans, Ian, Hussain, Sagair, Kirby, Brian, Lawson, Linda, Mason, Kayleigh, McElhone, Kathleen, Ormerod, Anthony, Owen, Caroline, Barnes, Michael R., Di Meglio, Paola, Emsley, Richard, Evans, Andrea, and Payne, Katherine

Abstract

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real‐world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first‐line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti‐drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one‐compartment model. A maximum effect (Emax) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half‐maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring “dashboard” to individualize dosing and improve treatment outcomes.

Published
2020

79. Additional file 1 of ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction

Author

Xiaoyun Wang, Zhang, Duo, Higham, Andrew, Wolosianka, Sophie, Xiaoyan Gai, Zhou, Lu, Petersen, Hans, Pinto-Plata, Victor, Divo, Miguel, Silverman, Edwin K., Bartolome Celli, Singh, Dave, Yongchang Sun, and Owen, Caroline A.

Subjects
Data_FILES
Abstract

Additional file 1.

Published
2020
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82. Development of a continuous respiration olfactometer for odorant delivery synchronous with natural respiration during recordings of brain electrical activity

Author

Owen, Caroline M., Patterson, John, and Simpson, David G.

Subjects
Olfactometry -- Equipment and supplies, Brain -- Electric properties, Respiration -- Measurement, Medical geography -- Methods, Biological sciences, Business, Computers, Health care industry
Abstract

The continuous respiration olfactometer (CRO) was designed as a respiration-synchronous method for derivering odorants during recordings of brain electrical activity, providing control and monitoring of the timing of the delivery as well as the quantities of odorant involved. The CRO incorporates a purpose-built electronic system designed with very specific temporal and quantitative chracteristics, and is composed of four main parts: the respiratory monitoring apparatus, the odorant/air delivery system, the serial interface device and the respiratory monitoring software. Tests were undertaken to determine the performance of the system with reference to the accuracy and precision of timing and control of odorant delivery. Tests were also undertaken to determine the effects of variations in natural respiration between subjects on the capability of the respiratory monitoring system, using a group Of 50 Subjects, to test the success of a variable gain control to optimize the range of the digitized respiratory output. The delivery system wits able to provide information concerning quantities of air or odorant delivered, and the stimulus timing information required for integration with neurophysiological recording techniques. Index Terms--Brain topography, delivery apparatus, olfactometry, olfactory, respiratory monitoring.

Published
2002

85. Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

Author

Lam, Hilaire C., primary, Cloonan, Suzanne M., additional, Bhashyam, Abhiram R., additional, Haspel, Jeffery A., additional, Singh, Anju, additional, Sathirapongsasuti, J. Fah, additional, Cervo, Morgan, additional, Yao, Hongwei, additional, Chung, Anna L., additional, Mizumura, Kenji, additional, An, Chang Hyeok, additional, Shan, Bin, additional, Franks, Jonathan M., additional, Haley, Kathleen J., additional, Owen, Caroline A., additional, Tesfaigzi, Yohannes, additional, Washko, George R., additional, Quackenbush, John, additional, Silverman, Edwin K., additional, Rahman, Irfan, additional, Kim, Hong Pyo, additional, Mahmood, Ashfaq, additional, Biswal, Shyam S., additional, Ryter, Stefan W., additional, and Choi, Augustine M.K., additional

Published
2020
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86. Clinical Impact of Antibodies against Ustekinumab in Psoriasis: An Observational, Cross-Sectional, Multicenter Study

Author

Loeff, Floris C., primary, Tsakok, Teresa, additional, Dijk, Lisanne, additional, Hart, Margreet H., additional, Duckworth, Michael, additional, Baudry, David, additional, Russell, Alice, additional, Dand, Nick, additional, van Leeuwen, Astrid, additional, Griffiths, Christopher E.M., additional, Reynolds, Nick J., additional, Barker, Jonathan, additional, Burden, A. David, additional, Warren, Richard B., additional, de Vries, Annick, additional, Bloem, Karien, additional, Wolbink, Gerrit Jan, additional, Smith, Catherine H., additional, Rispens, Theo, additional, Benham, Marilyn, additional, Burden, David, additional, Evans, Ian, additional, Griffiths, Christopher, additional, Hussain, Sagair, additional, Kirby, Brian, additional, Lawson, Linda, additional, Mason, Kayleigh, additional, McElhone, Kathleen, additional, Murphy, Ruth, additional, Ormerod, Anthony, additional, Owen, Caroline, additional, Reynolds, Nick, additional, Smith, Catherine, additional, Warren, Richard, additional, Barker, Jonathan N.W.N., additional, Barnes, Michael R., additional, DiMeglio, Paola, additional, Emsley, Richard, additional, Evans, Andrea, additional, Payne, Katherine, additional, and Stocken, Deborah, additional

Published
2020
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89. Poikilodermatous plaque-like hemangioma: Case series of a newly defined entity

Author

Semkova, Kristina, primary, Carr, Richard, additional, Grainger, Mark, additional, Green, Ruth, additional, Hafejee, Abdul, additional, Makrygeorgou, Areti, additional, Melly, Lucy, additional, Motta, Luisa, additional, Newsham, John, additional, Owen, Caroline, additional, Sillars, Joanne, additional, Taibjee, Saleem, additional, and Calonje, Eduardo, additional

Published
2019
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97. Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy

Author

Yiu, Z. Z. N., Sorbe, C., Lunt, M., Rustenbach, S. J., Kuehl, L., Augustin, M., Mason, K. J., Ashcroft, D. M., Griffiths, C. E. M., Warren, R. B., Ormerod, Anthony D., Barker, Jonathan N. W. N., Evans, Lan, McElhone, Kathleen, Smith, Catherine H., Reynolds, Nick J., Murphy, Ruth, Benham, Marilyn, Burden, A. David, Hussain, Sagair, Kirby, Brims, Lawson, Linda, and Owen, Caroline M.

Abstract

BackgroundPatients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments.ObjectivesTo develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies.MethodsThe risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C‐statistic, the calibration slope and the calibration in the large.ResultsOverall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism‐corrected C‐statistic of 0·64 [95% confidence interval (CI) 0·60–0·69], calibration in the large of 0·02 (95% CI −0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70–1·07), while external validation performance was poor, with C‐statistic 0·52 (95% CI 0·42–0·62), calibration in the large 0·06 (95% CI −0·25 to 0·37) and calibration slope 0·36 (95% CI −0·24 to 0·97).ConclusionsWe present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.

Published
2019

98. Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the UK and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Author

Yiu, Z. Z. N., Ashcroft, D. M., Evans, I, McElhone, K., Lunt, M., Smith, C. H., Walton, S., Murphy, R., Reynolds, N. J., Ormerod, A. D., Griffiths, C. E. M., Warren, R. B., Irshad, Shamila, Wilde, Victoria, Tahir, Saliha, Ali, Hassan, Mason, Kayleigh, Hussain, Sagair, Granger, Emily, Chalmers, Robert, Flohr, Carsten, Watson, Karen, Prieto-Merino, David, Barker, Jonathan, Benham, Marilyn, Burden, David, Griffiths, Christopher, Kirby, Brian, Lawson, Linda, Ormerod, Anthony, Owen, Caroline, Reynolds, Nick, and Warren, Richard

Abstract

BackgroundPatients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections.ObjectivesTo compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies.MethodsA prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen‐ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs).ResultsIn total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person‐years) [95% confidence interval (CI) 35·7–64·0], compared with 14·2 per 1000 person‐years (95% CI 11·5–17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01–3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58–5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14–10·70).ConclusionsInfliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland.

Published
2019

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