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Background: Patients with asthma use short-acting β-agonists (SABA) to relieve symptoms but SABA alone does not treat underlying inflammation. Thus, over-reliance on SABA may result in poor asthma control and negative health outcomes., Objective: To describe use of SABA and characterise the relationship with severe exacerbations in the Canadian provinces of Nova Scotia (NS) and Alberta (AB)., Methods: In this longitudinal Canadian SABA In Asthma (SABINA) study, patients with an asthma diagnosis were identified between 2016 and 2020 within two provincial administrative datasets (Health Data Nova Scotia and Alberta Health Services). All patients were followed for ≥24 months, with the first 12 months used to measure baseline asthma severity. Medication use and the relationship of SABA overuse (three or more canisters per year) with severe asthma exacerbations were characterised descriptively and via regression analysis., Results: A total of 115 478 patients were identified (NS: n=8034; AB: n=107 444). SABA overuse was substantial across both provinces (NS: 39.4%; AB: 28.0%) and across all baseline disease severity categories. Patients in NS with SABA overuse had a mean±sd annual rate of 0.46±1.11 exacerbations, compared to 0.30±1.36 for those using fewer than three canisters of SABA. Patients in AB had mean±sd exacerbation rates of 0.31±0.86 and 0.17±0.62, respectively. The adjusted risk of severe exacerbation was associated with SABA overuse (NS: incidence ratio rate 1.36, 95% CI 1.18-1.56; AB: incidence ratio rate 1.32, 95% CI 1.27-1.38)., Conclusion: This study supports recent updates to Canadian Thoracic Society and Global Initiative for Asthma guidelines for asthma care. SABA overuse is associated with increased risk of severe exacerbations and can be used to identify patients at a higher risk for severe exacerbations., Competing Interests: Conflict of Interest: S.G. Noorduyn, M. Soliman and M. Talukdar are employees of AstraZeneca Canada Inc. C. Qian and K. Johnston are employees of Broadstreet HEOR, which received funds from AstraZeneca Canada Inc. for this work. B.L. Walker has received advisory board and speaker's honoraria from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim and Sanofi, unrelated to this work. P. Hernandez received funding from AstraZeneca to his institution and company for data acquisition and covered costs to conduct the study at the local site. He has received grants paid to his institution from Canadian Institute of Health Research, Boehringer Ingelheim, Cyclomedica, Grifols and Vertex, and received speaker honoraria from AstraZeneca, Boehringer Ingelheim and Janssen. He received honoraria from and participated in advisory boards for Acceleron, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novartis, Sanofi, Takeda, Teva and Valeo. He volunteered at Canadian Thoracic Society as an executive committee and Board member unrelated to this work. E. Penz has received research funds paid to her institution from AstraZeneca and Saskatchewan Cancer Agency, Canadian Institutes of Health Research, Saskatchewan Health Research Foundation and Respiratory Research Centre unrelated to this work. She has received consulting fees from GlaxoSmithKline, AstraZeneca and Sanofi Genzyme unrelated to this work. She received honoraria for participation on advisory boards, lecture series and educational events from AstraZeneca, GlaxoSmithKline, Sanofi, Boehringer Ingelheim and the International Centre for Evidence-Based Medicine, unrelated to this work. She is a Co-Chair of the COPD Assembly of Canadian Thoracic Society, Medical Lead at the Lung Cancer Screening Prevention Program, Saskatchewan Cancer Agency and a member of the Institute for Cancer Research Advisory Board, Canadian Institute for Health Research., (Copyright ©The authors 2022.)

Studies assessing dyspnoea and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD) have focussed on patients in clinical settings, not the general population. The aim of this analysis was to compare the prevalence and severity of dyspnoea and impaired HRQoL in individuals with and without COPD from the general population, focussing on mild-moderate COPD. Analysis of the 3-year Canadian Cohort Obstructive Lung Disease (CanCOLD) study included four subgroups: mild COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1); moderate COPD (GOLD 2); non-COPD smokers; and non-COPD never-smokers. The primary outcome was dyspnoea (Medical Research Council (MRC) scale), and the secondary outcome was HRQoL (COPD Assessment Test (CAT) score; Saint George's Respiratory Questionnaire (SGRQ) score). Subgroups were analysed by sex, physician-diagnosed COPD status and exacerbations. 1443 participants (mild COPD (n=397); moderate COPD (n=262(; smokers (n=449) and never-smokers (n=335)) were studied. People with mild COPD were more likely to report more severe dyspnoea (MRC 2 versus 1) than those without COPD (OR (95% CI) 1.42 (1.05-1.91)), and non-COPD never-smokers (OR (95%CI) 1.64 (1.07-2.52)). Among people with mild COPD, more severe dyspnoea was reported in women versus men (MRC2 versus 1; OR (95% CI) 3.70 (2.23-6.14)); people with, versus without, physician-diagnosed COPD (MRC2 versus 1; OR (95% CI) 3.27 (1.71-6.23)), and people with versus without recent exacerbations (MRC2 versus 1; ≥2 versus 0 exacerbations: OR (95% CI) 3.62 (1.02-12.86); MRC ≥3 versus 1; 1 versus 0 exacerbation: OR (95% CI): 9.24 (2.01-42.42)). Similar between-group differences were obtained for CAT and SGRQ scores. Careful assessment of dyspnoea and HRQoL could help identify individuals for earlier diagnosis and treatment., Competing Interests: Conflict of interest: M. Cherian reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. Conflict of interest: D. Jensen reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. He also reports grants and personal fees from AstraZeneca, and grants from Boehringer Ingelheim, Novartis and Tilray, outside the submitted work. Conflict of interest: W.C. Tan reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. Conflict of interest: S. Mursleen reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. S. Mursleen is an employee of and holds shares/options in GSK. Conflict of interest: E.C. Goodall reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. E.C. Goodall is an employee of GSK. Conflict of interest: G.A. Nadeau reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. G.A. Nadeau was an employee of and held shares/options in GSK at the time of the analysis. Conflict of interest: A.M. Awan reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. A.M. Awan is an employee of GlaxoSmithKline. Conflict of interest: D.D. Marciniuk reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. He also reports consultancy fees and research funding (managed by University of Saskatchewan) from AstraZeneca and Boehringer Ingelheim; consultancy fees from the Canadian Foundation for Healthcare Improvement, and the Chinese Committee of Health and Family Planning; consultancy fees and research funding (managed by University of Saskatchewan) from GSK; consultancy fees from Health Canada; consultancy fees and research funding (managed by University of Saskatchewan) from the Lung Association of Saskatchewan; consultancy fees from Mylan; consultancy fees and research funding (managed by University of Saskatchewan) from Novartis; consultancy fees from the Saskatchewan Ministry of Health, Saskatchewan Health Authority, and Yukon Health and Social Services; research funding (managed by University of Saskatchewan) from Canada Health Infoway, the Canadian Institute of Health Research, the Lung Health Institute of Canada, Sanofi, the Saskatchewan Health Research Foundation and Schering-Plough; and is a spokesperson on behalf of the Canadian Thoracic Society, outside the submitted work. Conflict of interest: B.L. Walker reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. She also reports advisory board and speaker fees from AstraZeneca and GSK, outside the submitted work. Conflict of interest: S.D. Aaron reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd, and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. Conflict of interest: D.E. O'Donnell reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd, and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd was funded by GSK. Conflict of interest: K.R. Chapman reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd, and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd. was funded by GSK. He also reports grants from Bayer, grants and personal fees from CSL Behring, grants from Grifols, grants and personal fees from Takeda, grants from Vertex, grants and personal fees from Mereo Biopharma, and grants and personal fees from Sanofi, during the conduct of the study. Conflict of interest: F. Maltais reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd, and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd. was funded by GSK. He also reports research grants paid to his institution from AstraZeneca, GSK and Sanofi, a research grant and fees for speaker bureaus/consultancy from Novartis, grants and personal fees from Boehringer Ingelheim, and a research grant paid to his institution and fees for speaker bureaus/consultancy from Grifols, outside the submitted work. Conflict of interest: P. Hernandez reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd, and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd. was funded by GSK. He also reports honoraria for a medical advisory board from Actelion; honoraria for a medical advisory board and speaker fees for continuing health education, and funding to his institution for conduct of clinical trials from AstraZeneca and Boehringer Ingelheim; funding to his institution for conduct of clinical trials from Cyclomedica; honoraria for medical advisory boards from GlaxoSmithKline and Novartis; funding to his institution for conduct of clinical trials Respivant and Grifols; honoraria for medical advisory boards from Sanofi and Teva; and funding to his institution for conduct of clinical trials from Vertex, all outside the submitted work. Conflict of interest: D.D. Sin reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis. Previous study funding partners were the Respiratory Health Network of the Fonds de la recherche en santé du Québec, the Foundation of the McGill University Health Centre, Almirall, Merck, Nycomed, Pfizer Canada Ltd, and Theratechnologies. Medical writing support provided by Fishawack Communications Ltd. was funded by GSK. He also reports an honorarium for speaking engagement from AstraZeneca and one for attending an advisory board from Boehringer Ingelheim, outside the submitted work. Conflict of interest: A. Benedetti reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis; grants, and lecture and advisory board fees from AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd and GlaxoSmithKline Canada Ltd; grants from Canadian Institutes of Health Research and the Respiratory Health Network of the Fonds de la recherche en santé du Québec; medical writing support provided by Fishawack Communications Ltd funded by GSK; grants from Novartis; and grants from Almirall, Merck, Nycomed, Pfizer Canada Ltd, Theratechnologies and The Foundation of the McGill University Health Centre, all during the conduct of the study. Conflict of interest: J. Bourbeau reports the study is currently funded by the Canadian Respiratory Research Network, the Canadian Institutes of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd and Novartis; grants, and lecture and advisory board fees from AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd and GlaxoSmithKline Canada Ltd; grants from Canadian Institutes of Health Research and the Respiratory Health Network of the Fonds de la recherche en santé du Québec; medical writing support provided by Fishawack Communications Ltd funded by GSK; grants from Novartis; and grants from Almirall, Merck, Nycomed, Pfizer Canada Ltd, Theratechnologies and The Foundation of the McGill University Health Centre, all during the conduct of the study; and consultancy and lecture fees from the Canadian Thoracic Society and CHEST; grants from the Foundation of the MUHC and Aerocrine; grants, and lecture and advisory board fees from Grifols, Novartis and Trudell, and grants from Canadian Institutes of Health Research, all outside the submitted work., (©The authors 2021.)

Background: Previous studies have associated marijuana exposure with increased respiratory symptoms and chronic bronchitis among long-term cannabis smokers. The long-term effects of smoked marijuana on lung function remain unclear., Methods: We determined the association of marijuana smoking with the risk of spirometrically defined chronic obstructive pulmonary disease (COPD) (post-bronchodilator forced expiratory volume in 1 s (FEV 1 )/forced vital capacity ratio <0.7) in 5291 population-based individuals and the rate of decline in FEV 1 in a subset of 1285 males and females, aged ≥40 years, who self-reported use (or non-use) of marijuana and tobacco cigarettes and performed spirometry before and after inhaled bronchodilator on multiple occasions. Analysis for the decline in FEV 1 was performed using random mixed effects regression models adjusted for age, sex and body mass index. Heavy tobacco smoking and marijunana smoking was defined as >20 pack-years and >20 joint-years, respectively., Results: ∼20% of participants had been or were current marijuana smokers with most having smoked tobacco cigarettes in addition (83%). Among heavy marijuana users, the risk of COPD was significantly increased (adjusted OR 2.45, 95% CI 1.55-3.88). Compared to never-smokers of marijuana and tobacco, heavy marijuana smokers and heavy tobacco smokers experienced a faster decline in FEV 1 by 29.5 mL·year -1 (p=0.0007) and 21.1 mL·year -1 (p<0.0001), respectively. Those who smoked both substances experienced a decline of 32.31 mL·year -1 (p<0.0001)., Interpretation: Heavy marijuana smoking increases the risk of COPD and accelerates FEV 1 decline in concomitant tobacco smokers beyond that observed with tobacco alone., Competing Interests: Conflict of interest: W.C. Tan reports grants from Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants-93326) with industry partners AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc., Pfizer Canada Ltd, during the conduct of the study. Conflict of interest: J. Bourbeau reports grants from Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants-93326) with industry partners AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc., Pfizer Canada Ltd, during the conduct of the study. Conflict of interest: S.D. Aaron has nothing to disclose. Conflict of interest: J.C. Hogg has nothing to disclose. Conflict of interest: F. Maltais has nothing to disclose. Conflict of interest: P. Hernandez reports grants from Canadian Institute Health Research, during the conduct of the study; grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Takeda, personal fees from Merck, Grifols, Pfizer and Almirall, grants from CSL Behring, outside the submitted work. Conflict of interest: D.D. Marciniuk has nothing to disclose. Conflict of interest: K.R. Chapman reports grants from Novartis, Almirall, Boehringer Ingelheim, Forest, GSK, AstraZeneca, Amgen, Roche, CSL Behring, Grifols, Genentech and Kamada, during the conduct of the study; UHN administered personal support from CIHR (GSK Research Chair in Respiratory Health Care Delivery), outside the submitted work. Conflict of interest: T. To has nothing to disclose. Conflict of interest: J.M. FitzGerald has nothing to disclose. Conflict of interest: B.L. Walker reports grants from Canadian Institute of Health Research, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada, GlaxoSmithKline Canada and Novartis, during the conduct of the study; grants from Respiratory Health Strategic Clinical Network Alberta, personal fees from AstraZeneca, GlaxoSmithKline and Novartis, outside the submitted work. Conflict of interest: J. Road has nothing to disclose. Conflict of interest: L. Zheng has nothing to disclose. Conflict of interest: G. Zhou has nothing to disclose. Conflict of interest: T. Yau has nothing to disclose. Conflict of interest: A. Benedetti has nothing to disclose. Conflict of interest: D. O'Donnell has nothing to disclose. Conflict of interest: D.D. Sin reports grants from Merck, personal fees for advisory board work from Sanofi-Aventis and Regeneron, grants and personal fees from Boehringer Ingelheim, grants and personal fees for lectures and advisory board work from AstraZeneca, personal fees for lectures and advisory board work from Novartis, outside the submitted work., (Copyright ©ERS 2019.)

Patients with chronic obstructive pulmonary disease (COPD) have decreased ventilatory and cerebrovascular responses to hypercapnia. Antioxidants increase the ventilatory response to hypercapnia in healthy humans. Cerebral blood flow is an important determinant of carbon dioxide/hydrogen ion concentration at the central chemoreceptors and may be affected by antioxidants. It is unknown whether antioxidants can improve the ventilatory and cerebral blood flow response in individuals in whom these are diminished. Thus, we aimed to determine the effect of vitamin C administration on the ventilatory and cerebrovascular responses to hypercapnia during healthy ageing and in COPD. Using transcranial Doppler ultrasound, we measured the ventilatory and cerebral blood flow responses to hyperoxic hypercapnia before and after an intravenous vitamin C infusion in healthy young ( Younger ) and older ( Older ) subjects and in moderate COPD. Vitamin C increased the ventilatory response in COPD patients (mean (95% CI) 1.1 (0.9-1.1) versus 1.5 (1.1-2.0) L·min -1 ·mmHg -1 , p<0.05) but not in Younger (2.5 (1.9-3.1) versus 2.4 (1.9-2.9) L·min -1 ·mmHg -1 , p>0.05) or Older (1.3 (1.0-1.7) versus 1.3 (1.0-1.7) L·min -1 ·mmHg -1 , p>0.05) healthy subjects. Vitamin C did not affect the cerebral blood flow response in the young or older healthy subjects or COPD subjects (p>0.05). Vitamin C increases the ventilatory but not cerebrovascular response to hyperoxic hypercapnia in patients with moderate COPD., Competing Interests: Conflicts of Interest: None declared.