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Juthaporn Cowan,1,2 Sunita Mulpuru,1,2 Sara J Abdallah,2 Anchal Chopra,3 Andrew Purssell,1 Michaeline McGuinty,1 Gonzalo G Alvarez,1,2 Antonio Giulivi,2,4 Vicente Corrales-Medina,1,2 Derek MacFadden,1,2 Loree Boyle,1 Delvina Hasimja,1 Kednapa Thavorn,2,5,6 Ranjeeta Mallick,2 Shawn D Aaron,1,2 D William Cameron1,2 1Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 2Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 3Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada; 4Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada; 5School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada; 6Institute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaCorrespondence: Juthaporn Cowan Email jcowan@toh.caBackground: Observational studies suggest that immunoglobulin treatment may reduce the frequency of acute exacerbations of COPD (AECOPD).Objective: To inform the design of a future randomised control trial (RCT) of intravenous immunoglobulin (IVIG) treatment efficacy for AECOPD prevention.Methods: A pilot RCT was conducted. We recruited patients with COPD hospitalized for AECOPD, or from ambulatory clinics with one severe, or two moderate AECOPD in the previous year regardless of their serum IgG level. Patients were allocated in a 1:1 ratio with balanced randomisation to monthly IVIG or normal saline for 1 year. The primary outcome was feasibility defined as pre-specified accrual, adherence, and follow-up rates. Secondary outcomes included safety, tolerance, AECOPD rates, time to first AECOPD, quality of life, and healthcare costs.Results: Seventy patients were randomized (37 female; mean age 67.7; mean FEV1 35.1%). Recruitment averaged 4.5± 0.9 patients per month (range 0– 8), 34 (49%) adhered to at least 80% of planned treatments, and four (5.7%) were lost to follow-up. There were 35 serious adverse events including seven deaths and one thromboembolism. None was related to IVIG. There were 56 and 48 moderate and severe AECOPD in the IVIG vs control groups. In patients with at least 80% treatment adherence, median time to first moderate or severe AECOPD was 275 vs 114 days, favoring the IVIG group (HR 0.76, 95% CI 0.3– 1.92).Conclusion: The study met feasibility criteria for recruitment and retention, but adherence was low. A trend toward more robust treatment efficacy in adherent patients supports further study, but future trials must address treatment adherence.Trial registration number: NCT0290038, registered 24 February 2016, https://clinicaltrials.gov/ct2/show/NCT02690038 and NCT03018652, registered January 12, 2017, https://clinicaltrials.gov/ct2/show/NCT03018652.Keywords: recurrent AECOPD, pilot RCT, immunoglobulin treatment, IVIG

Dana Unninayar,1 Sara J Abdallah,2 D William Cameron,2– 4 Juthaporn Cowan2– 4 1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 2Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 3Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 4Centre of Infection, Immunity and Inflammation, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, CanadaCorrespondence: Juthaporn CowanThe Ottawa Hospital, General Campus, 501 Smyth Road, Box 223, Ottawa, Ontario, K1H 8L6, CanadaTel +1 613-737-8899 X 79617Fax +1 613-737-8352Email jcowan@toh.caAbstract: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and episodes of worsening respiratory symptoms and pulmonary function, termed acute exacerbations of COPD (AECOPD). AECOPD episodes are associated with heightened airway inflammation and are often triggered by infection. A subset of COPD patients develops frequent exacerbations despite maximal existing standard medical therapy. It is therefore clear that a targeted and more effective prevention strategy is needed. Immunoglobulins are glycoprotein molecules that are secreted by B lymphocytes and plasma cells and play a critical role in the adaptive immune response against many pathogens. Altered serum immunoglobulin levels have been observed in patients with immunodeficiencies and inflammatory diseases. Serum immunoglobulin has also been identified as potential biomarkers of AECOPD frequency. Since plasma-derived polyvalent immunoglobulin treatment is effective in preventing recurrent infections in immunodeficient patients and in suppressing inflammation in many inflammatory diseases, it may be conceivable that immunoglobulin treatment may be effective in preventing recurrent AECOPD. In this article, we provide a review of the current knowledge on immunoglobulin treatment in patients with COPD and discuss plausible mechanisms as to how immunoglobulin treatment may work to reduce AECOPD frequency.Keywords: chronic obstructive pulmonary disease, immunoglobulin treatment, exacerbation

Objectives: Dyspnoea is a common persistent symptom post-coronavirus disease 2019 (COVID-19) illness. However, the mechanisms underlying dyspnoea in the post-COVID-19 syndrome remain unclear. The aim of our study was to examine dyspnoea quality and intensity, burden of mental health symptoms, and differences in exercise responses in people with and without persistent dyspnoea following COVID-19., Methods: 49 participants with mild-to-critical COVID-19 were included in this cross-sectional study 4 months after acute illness. Between-group comparisons were made in those with and without persistent dyspnoea (defined as modified Medical Research Council dyspnoea score ≥1). Participants completed standardised dyspnoea and mental health symptom questionnaires, pulmonary function tests, and incremental cardiopulmonary exercise testing., Results: Exertional dyspnoea intensity and unpleasantness were increased in the dyspnoea group. The dyspnoea group described dyspnoea qualities of suffocating and tightness at peak exercise (p<0.05). Ventilatory equivalent for carbon dioxide ( V ' E / V ' CO 2 ) nadir was higher (32±5 versus 28±3, p<0.001) and anaerobic threshold was lower (41±12 versus 49±11% predicted maximum oxygen uptake, p=0.04) in the dyspnoea group, indicating ventilatory inefficiency and deconditioning in this group. The dyspnoea group experienced greater symptoms of anxiety, depression and post-traumatic stress (all p<0.05). A subset of participants demonstrated gas-exchange and breathing pattern abnormalities suggestive of dysfunctional breathing., Conclusions: People with persistent dyspnoea following COVID-19 experience a specific dyspnoea quality phenotype. Dyspnoea post-COVID-19 is related to abnormal pulmonary gas exchange and deconditioning and is linked to increased symptoms of anxiety, depression and post-traumatic stress., Competing Interests: Conflict of interest: K.L. Lavoie reports consulting fees from AbbVie, Takeda, Astellas, Boehringer Ingelheim, AstraZeneca, Janssen, Novartis, GSK, Bausch and Sojecci Inc., outside the submitted work; payment or honoraria from AbbVie, Boehringer Ingelheim, Takeda, Pfizer, Merck, GSK, Astra-Zeneca, Novartis, Janssen, Bayer, Mundi Pharma, Bayer, Air Liquide, Astellas and Xfacto, outside the submitted work; and participation on a Data Safety Monitoring Board or Advisory Board for Astra-Zeneca, GSK and Bausch, outside the submitted work. Conflict of interest: J. Cowan reports support for the present manuscript from The Ottawa Hospital Foundation; grants or contracts from Octapharma and Takeda, outside the submitted work; payment or honoraria from GSK, Sanofi, EMD Serono, Alexion and Takeda, outside the submitted work; and support for attending meetings and/or travel from Octapharma, outside the submitted work. Conflict of interest: J.A. Chirinos reports grants or contracts from University of Pennsylvania research grants from National Institutes of Health, Fukuda-Denshi, Bristol-Myers Squibb, Microsoft and Abbott, outside the submitted work; consulting fees from Bayer, Sanifit, Fukuda-Denshi, Bristol-Myers Squibb, JNJ, Edwards Life Sciences, Merck, NGM Biopharmaceuticals and the Galway-Mayo Institute of Technology, outside the submitted work; patents planned, issued or pending: inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of Heart Failure and Preserved Ejection Fraction and for the use of biomarkers in heart failure with preserved ejection fraction, outside the submitted work; participant on advisory board for BMS, outside the submitted work; Vice President of North American Artery Society, outside the submitted work; received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft and MicroVision Medical, outside the submitted work; received payments for editorial roles from the American Heart Association, the American College of Cardiology and Wiley, outside the submitted work. Conflict of interest: J.A. Guenette is an associate editor of this journal. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Canadians seeking medical cannabis (MC) may encounter difficulties in finding a healthcare provider (HCP) who authorizes their access to it. Barriers that HCPs face in authorizing MC are unclear. The objectives of this study were to evaluate HCP opinions, knowledge, comfort, and practice in MC prescribing and counseling on recreational cannabis use, and whether the COVID-19 pandemic affected MC prescribing practices., Methods: Eligible participants included HCPs (e.g., attending physicians, nurses, pharmacists) in Canada. A questionnaire evaluating their knowledge, comfort, and practice in medical and recreational cannabis was designed based on instruments developed in previous studies. Between April 13 th -December 13 th 2021, ninety-one healthcare associations were asked to distribute the survey to their members, and an advertisement was placed in the online Canadian Medical Association Journal. Descriptive statistics were used to analyze the results., Results: Twenty-four organizations agreed to disseminate the survey and 70 individuals completed it. Of respondents, 71% were attending physicians or medical residents, while the remainder were nurses, pharmacists or other HCPs. Almost none (6%) received training in MC in professional school but 60% did receive other training (e.g., workshops, conferences). Over half (57%) received more questions regarding MC since recreational cannabis was legalized, and 82% reported having patients who use MC. However, 56% felt uncomfortable or ambivalent regarding their knowledge of MC, and 27% were unfamiliar with the requirements for obtaining MC in Canada. The most common symptoms for recommending MC were pain and nausea, whereas the most common conditions for recommending it were cancer and intractable pain. The strongest barrier to authorizing MC was uncertainty in safe and effective dosage and routes of administration. The strongest barrier to recommending or authorizing MC was the lack of research evidence demonstrating its safety and efficacy. During the pandemic, many respondents reported that a greater number of their patients used cannabis to relieve anxiety and depression., Conclusions: Our results suggest that HCPs across Canada who responded to our survey are unfamiliar with topics related to MC. The strongest barriers appear to be lack of clinical research, and uncertainty in safe and effective MC administration. Increasing research, training, and knowledge may help HCPs feel more equipped to make informed treatment/prescribing decisions, which may help to improve access to MC., (© 2022. The Author(s).)

Fatigue is a common, debilitating, and poorly understood symptom post-COVID-19. We sought to better characterize differences in those with and without post-COVID-19 fatigue using cardiopulmonary exercise testing. Despite elevated dyspnoea intensity ratings, V̇O 2 peak (ml/kg/min) was the only significant difference in the physiological responses to exercise (19.9 ± 7.1 fatigue vs. 24.4 ± 6.7 ml/kg/min non-fatigue, p = 0.04). Consistent with previous findings, we also observed a higher psychological burden in those with fatigue in the context of similar resting cardiopulmonary function. Our findings suggest that lower cardiorespiratory fitness and/or psychological factors may contribute to post-COVID-19 fatigue symptomology. Further research is needed for rehabilitation and symptom management following SARS-CoV-2 infection., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is a viral infection which can cause a variety of respiratory, gastrointestinal, and vascular symptoms. The acute illness phase generally lasts no more than 2-3 weeks. However, there is increasing evidence that a proportion of COVID-19 patients experience a prolonged convalescence and continue to have symptoms lasting several months after the initial infection. A variety of chronic symptoms have been reported including fatigue, dyspnea, myalgia, exercise intolerance, sleep disturbances, difficulty concentrating, anxiety, fever, headache, malaise, and vertigo. These symptoms are similar to those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic multi-system illness characterized by profound fatigue, sleep disturbances, neurocognitive changes, orthostatic intolerance, and post-exertional malaise. ME/CFS symptoms are exacerbated by exercise or stress and occur in the absence of any significant clinical or laboratory findings. The pathology of ME/CFS is not known: it is thought to be multifactorial, resulting from the dysregulation of multiple systems in response to a particular trigger. Although not exclusively considered a post-infectious entity, ME/CFS has been associated with several infectious agents including Epstein-Barr Virus, Q fever, influenza, and other coronaviruses. There are important similarities between post-acute COVID-19 symptoms and ME/CFS. However, there is currently insufficient evidence to establish COVID-19 as an infectious trigger for ME/CFS. Further research is required to determine the natural history of this condition, as well as to define risk factors, prevalence, and possible interventional strategies., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

The effects of high external ammonia (HEA) exposure on breathing and the potential involvement of ammonia transporting Rh proteins in ammonia sensing were assessed in larval and adult zebrafish. Acute exposure of adults to either 250 or 500 μM (NH 4 ) 2 SO 4 caused increases in ventilation amplitude (A VENT ) without affecting frequency (f VENT ), resembling the ventilatory response to hypercapnia rather than hypoxia, during which f VENT was increased exclusively. The hyperventilatory response to HEA was prevented by hyperoxia, indicating that control of breathing through ammonia sensing is likely secondary to O 2 chemoreception. Neuroepithelial cells (NECs) isolated from gill filaments exhibited a significant increase of intracellular [Ca 2+ ] in response to 1 mM NH 4 Cl but this response was small (roughly 30%) compared to the response to hypercapnia (37.5 mmHg; ~800% increase). Immunohistochemistry (IHC) failed to reveal the presence of Rh proteins (Rhcgb, Rhbg or Rhag) in gill filament NECs. Knockout of rhcgb did not affect the ventilatory response of adults to HEA. Larvae at 4 days post fertilization (dpf) responded to HEA with increases in f VENT (A VENT was not measured). The hyperventilatory response of larvae to HEA was attenuated (60% reduction) after treatment from 0 to 4 dpf with the sympathetic neurotoxin 6-hydroxydopamine. In larvae, Rhcgb, Rhbg and Rhag were undetectable by IHC in cutaneous NECs yet the f VENT to HEA following Rhbg knockdown was slightly (22%) attenuated. Thus, the hyperventilatory response to external ammonia in adult zebrafish, while apparently initiated by activation of NECs, does not require Rhcgb, nor is the entry of ammonia into NECs reliant on other Rh proteins. The lack of colocalization of Rh proteins with NECs suggests that the entry of ammonia into NECs in larvae, also is not facilitated by this family of ammonia channels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with pulmonary and extra-pulmonary factors contributing to exercise intolerance. The primary self-reported exercise-limiting symptom may reflect the primary pathophysiological factor contributing to exercise intolerance. We compared physiological and perceptual responses at the symptom-limited peak of incremental cardiopulmonary cycle exercise testing between people with COPD reporting breathlessness (B, n = 34), leg discomfort (LD, n = 16), or a combination of B and LD (BOTH, n = 42) as their main exercise-limiting symptom(s). Despite similarly impaired health status, symptomology and peak exercise capacity, the B group had greater restrictive constraints on tidal volume expansion at end-exercise and was more likely to report unpleasant qualities of exertional breathlessness than LD and BOTH groups. In conclusion, reporting breathlessness as the primary exercise-limiting symptom indicated the presence of distinct lung pathophysiology and symptom perception during exercise in people with COPD., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report for this work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Context: Explanations provided by health professionals may underpin helpful or harmful symptom beliefs and expectations of people living with chronic breathlessness., Objectives: This study sought perspectives from health professionals with clinical/research expertise in chronic breathlessness on priority issues in chronic breathlessness explanations and research., Methods: Authors (n = 74) of publications specific to chronic breathlessness were invited to a three-round Delphi survey. Responses to open-ended questions (Round 1 "What is important to: include/avoid when explaining chronic breathlessness; prioritize in research?") were transformed to Likert scale (1-9) items for rating in subsequent rounds. A priori consensus was defined as ≥70% of respondents rating an item as important (Likert rating 7-9) and interquartile range ≤2., Results: Of the 31 Round 1 respondents (nine countries, five professional disciplines), 24 (77%) completed Rounds 2 and 3. Sixty-three items met consensus (include n = 28; avoid n = 9; research n = 26). Explanations of chronic breathlessness should use patient-centered communication; acknowledge the distress, variability, and importance of this sensation; emphasize current management principles; clarify maladaptive beliefs and expectations; and avoid moral culpability and inappropriate reassurance. Research priorities included the need 1) for a comprehensive understanding of breathlessness science; 2) to optimize, explore, and develop effective interventions, both pharmacological and nonpharmacological; and 3) determine effective models of care including strategies for education and training of health professionals and people caring for, or living with, chronic breathlessness., Conclusion: These consensus-based concepts for chronic breathlessness explanations and research provide a starting point for conversations between patients, carers, clinicians, and researchers within the chronic breathlessness community., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Rates of cannabis consumption range from 40% to 74% among people living with HIV (PLWH). Little is known about the reasons for cannabis use, related modes of administration, effectiveness for symptom relief, or undesirable effects in the modern antiretroviral therapy (ART) era. Our aim was to conduct an exploratory study to identify potential areas for further evaluation and intervention. Materials and Methods: From January to June 2018, health care providers at the Chronic Viral Illness Service in Montreal, Canada, asked their patients about cannabis use during routine visits. Patients reporting cannabis use were invited to complete a 20-min coordinator-administered questionnaire. Questions related to patterns of use, modes of administration, reasons for use, secondary effects, and HIV health-related factors (e.g., adherence to ART). Results: One hundred and four PLWH reporting cannabis use participated. Median age was 54 years (interquartile range [IQR] 46-59), 13% were female, and 42% were HIV-Hepatitis C co-infected. Median CD4 count was 590 cells/mm 3 (IQR 390-821), 95% of participants were on ART, and 88% had suppressed viral loads. Reported cannabis use was more than once daily (32%); daily (25%); weekly (22%); monthly (17%); and rarely (twice to thrice per year; 6%). The majority of participants (97%) smoked dry plant cannabis. Other modes included vaping (12%), capsules (2%), edibles (21%), and oils (12%). Common reasons for cannabis use were for pleasure (68%) and to reduce anxiety (57%), stress (55%), and pain (57%). Many participants found cannabis "quite effective" or "extremely effective" (45%) for symptom relief. Secondary effects included feeling high (74%), increased cough (45%), paranoia (22%), palpitations (20%), and increased anxiety (21%). Over two-thirds of participants indicated that secondary effects were not bothersome at all. Most participants (68%) rarely missed doses of their ART, while 27% missed occasionally (once to twice per month). The most commonly accessed sources of information about cannabis were friends (77%) and the internet (55%). Conclusion: The most common reasons for cannabis use in our population were for pleasure, followed by reduction of stress/anxiety and symptoms associated with a medical condition. Most smoke cannabis and rate cannabis as quite effective for symptom relief. While many participants experience secondary effects, most are not bothered by these symptoms. Amid widespread changes in the regulatory landscape of recreational cannabis, health care providers should be prepared to answer questions about cannabis., Competing Interests: The authors have received free product from Tilray, Inc. for use in a clinical trial (Canadian HIV Trials Network PT028), but no financial support was received for this or other studies., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

Purpose of Review: Chronic breathlessness is a troublesome symptom experienced by people with advanced malignant and nonmalignant disease. Disease-directed therapies are often insufficient in the management of chronic breathlessness. Therefore, pharmacological and nonpharmacological breathlessness-specific interventions should be considered for select patients., Recent Findings: There is some evidence to support the use of low-dose opioids (≤30 mg morphine equivalents per day) for the relief of breathlessness in the short term. However, additional studies are needed to understand the efficacy of opioids for chronic breathlessness in the long term.Nonopioid therapies, including inspiratory muscle training, fan-to-face therapy, L-menthol and inhaled nebulized furosemide show some promise for the relief of breathlessness in advanced disease. There is insufficient evidence to support the use of anxiolytics and benzodiazepines and cannabis for chronic breathlessness., Summary: More research is needed to identify therapies for the management of chronic breathlessness.

We examined the impact of bariatric surgery on cardiometabolic, ventilatory and breathlessness responses to incremental cycle exercise testing in adults with class III obesity (n = 6). O 2 consumption, CO 2 production, minute ventilation (V̇) and breathing frequency were reduced during submaximal exercise after surgery. Inspiratory capacity (IC) and inspiratory reserve volume were lower at rest and any given V̇ E during exercise after surgery. In the transition from rest to peak exercise, dynamic IC decreased by 0.13 L before surgery and increased by 0.21 L after surgery. Breathlessness intensity ratings were lower during exercise at power outputs ≥75-watts after surgery (e.g., by 1.0 and 1.4 Borg 0-10 scale units at 75-watts and the highest equivalent power output of 117-watts, respectively). In contrast, bariatric surgery had no effect on breathlessness-V̇ E relationships during exercise. In conclusion, relief of exertional breathlessness following bariatric surgery could not be explained by improved dynamic breathing mechanics, but reflected the awareness of reduced metabolic and ventilatory requirements of exercise., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We tested the hypothesis that abdominal binding (AB) would reduce breathlessness and improve exercise tolerance by enhancing neuromuscular efficiency of the diaphragm during exercise in adults with chronic obstructive pulmonary disease (COPD). In a randomized, controlled, crossover trial, 20 adults with COPD (mean ± SD FEV 1 , 60 ± 16% predicted) completed a symptom-limited constant-load cycle endurance exercise test at 75% of their peak incremental power output with concomitant measures of the diaphragm electromyogram (EMGdi) and respiratory pressures without (CTRL) vs. with AB sufficient to increase end-expiratory gastric pressure (Pga,ee) by 6.7 ± 0.3 cmH 2 O at rest. Compared to CTRL, AB enhanced diaphragmatic neuromuscular efficiency during exercise ( p < 0.05), as evidenced by a 25% increase in the quotient of EMGdi to tidal transdiaphragmatic pressure swing. By contrast, AB had no demonstrable effect on exertional breathlessness and exercise tolerance; spirometry and plethysmography-derived pulmonary function test parameters at rest; and cardiac, metabolic, breathing pattern, inspiratory reserve volume and EMGdi responses during exercise (all p > 0.05 vs. CTRL). In conclusion, enhanced neuromuscular efficiency of the diaphragm during exercise with AB was not associated with relief of exertional breathlessness and improved exercise tolerance in adults with COPD. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01852006.

Rationale: A series of studies conducted approximately 40 years ago demonstrated an acute bronchodilator effect of smoked cannabis in healthy adults and adults with asthma. However, the acute effects of vaporized cannabis on airway function in adults with advanced chronic obstructive pulmonary disease (COPD) remain unknown., Objectives: To test the hypothesis that inhaled vaporized cannabis would alleviate exertional breathlessness and improve exercise endurance by enhancing static and dynamic airway function in COPD., Methods: In a randomized controlled trial of 16 adults with advanced COPD (forced expiratory volume in 1 second [FEV 1 ], mean ± SD: 36 ± 11% predicted), we compared the acute effect of 35 mg of inhaled vaporized cannabis (18.2% Δ 9 -tetrahydrocannabinol, <0.1% cannabidiol) versus 35 mg of a placebo control cannabis (CTRL; 0.33% Δ 9 -tetrahydrocannabinol, <0.99% cannabidiol) on physiological and perceptual responses during cardiopulmonary cycle endurance exercise testing; spirometry and impulse oscillometry at rest; and cognitive function, psychoactivity, and mood., Results: Compared with CTRL, cannabis had no effect on breathlessness intensity ratings during exercise at isotime (cannabis, 2.7 ± 1.2 Borg units vs. CTRL, 2.6 ± 1.3 Borg units); exercise endurance time (cannabis, 3.8 ± 1.9 min vs. CTRL, 4.2 ± 1.9 min); cardiac, metabolic, gas exchange, ventilatory, breathing pattern, and/or operating lung volume parameters at rest and during exercise; spirometry and impulse oscillometry-derived pulmonary function test parameters at rest; and cognitive function, psychoactivity, and mood., Conclusions: Single-dose inhalation of vaporized cannabis had no clinically meaningful positive or negative effect on airway function, exertional breathlessness, and exercise endurance in adults with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT03060993).

The objective of the present study was to evaluate the effect of morphine on exertional breathlessness and exercise endurance in advanced chronic obstructive pulmonary disease (COPD).In a randomised crossover trial, we compared the acute effect of immediate-release oral morphine versus placebo on physiological and perceptual responses during constant-load cardiopulmonary cycle exercise testing (CPET) in 20 adults with advanced COPD and chronic breathlessness syndrome.Compared with placebo, morphine reduced exertional breathlessness at isotime by 1.2±0.4 Borg units and increased exercise endurance time by 2.5±0.9 min (both p≤0.014). During exercise at isotime, morphine decreased ventilation by 1.3±0.5 L·min -1 and breathing frequency by 2.0±0.9 breaths·min -1 (both p≤0.041). Compared with placebo, morphine decreased exertional breathlessness at isotime by ≥1 Borg unit in 11 participants (responders) and by <1 Borg unit in nine participants (non-responders). Baseline participant characteristics, including pulmonary function and cardiorespiratory fitness, were similar between responders and non-responders. A higher percentage of responders versus non-responders stopped incremental CPET due to intolerable breathlessness: 82 versus 33% (p=0.028).Immediate-release oral morphine improved exertional breathlessness and exercise endurance in some, but not all, adults with advanced COPD. The locus of symptom-limitation on laboratory-based CPET may help to identify patients most likely to benefit from morphine., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

We tested the hypothesis that elastic binding of the abdomen (AB) would enhance neuromuscular efficiency of the human diaphragm during exercise. Twelve healthy non-obese men aged 24.8 ± 1.7 years (mean ± SE ) completed a symptom-limited constant-load cycle endurance exercise test at 85% of their peak incremental power output with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements under two randomly assigned conditions: unbound control (CTRL) and AB sufficient to increase end-expiratory gastric pressure (Pga,ee) by 5-8 cmH 2 O at rest. By design, AB increased Pga,ee by 6.6 ± 0.6 cmH 2 O at rest. Compared to CTRL, AB significantly increased the transdiaphragmatic pressure swing-to-EMGdi ratio by 85-95% during exercise, reflecting enhanced neuromuscular efficiency of the diaphragm. By contrast, AB had no effect on spirometric parameters at rest, exercise endurance time or an effect on cardiac, metabolic, ventilatory, breathing pattern, dynamic operating lung volume, and perceptual responses during exercise. In conclusion, AB was associated with isolated and acute improvements in neuromuscular efficiency of the diaphragm during exercise in healthy men. The implications of our results are that AB may be an effective means of enhancing neuromuscular efficiency of the diaphragm in clinical populations with diaphragmatic weakness/dysfunction.

Nitric oxide (NO) is a gaseous neurotransmitter, which, in adult mammals, modulates the acute hypoxic ventilatory response; its role in the control of breathing in fish during development is unknown. We addressed the interactive effects of developmental age and NO in the control of piscine breathing by measuring the ventilatory response of zebrafish (Danio rerio) adults and larvae to NO donors and by inhibiting endogenous production of NO. In adults, sodium nitroprusside (SNP), a NO donor, inhibited ventilation; the extent of the ventilatory inhibition was related to the pre-existing ventilatory drive, with the greatest inhibition exhibited during exposure to hypoxia (PO2=5.6 kPa). Inhibition of endogenous NO production using L-NAME suppressed the hypoventilatory response to hyperoxia, supporting an inhibitory role of NO in adult zebrafish. Neuroepithelial cells (NECs), the putative oxygen chemoreceptors of fish, contain neuronal nitric oxide synthase (nNOS). In zebrafish larvae at 4 days post-fertilization, SNP increased ventilation in a concentration-dependent manner. Inhibition of NOS activity with L-NAME or knockdown of nNOS inhibited the hypoxic (PO2=3.5 kPa) ventilatory response. Immunohistochemistry revealed the presence of nNOS in the NECs of larvae. Taken together, these data suggest that NO plays an inhibitory role in the control of ventilation in adult zebrafish, but an excitatory role in larvae., (© 2015. Published by The Company of Biologists Ltd.)

This randomized, double-blind, crossover study examined the effects of a clothing ensemble made of a synthetic fabric promoted as having superior cooling properties (COOL) on exercise performance and its physiological and perceptual determinants during cycle exercise in ambient laboratory conditions that mimic environmental conditions of indoor training/sporting facilities. Twenty athletes (15 men:5 women) aged 25.8 ± 1.2 years (mean ± SEM) with a maximal rate of O2 consumption of 63.7 ± 1.5 mL·kg(-1)·min(-1) completed cycle exercise testing at 85% of their maximal incremental power output to exhaustion while wearing an ensemble consisting of a fitted long-sleeved shirt and full trousers made of either COOL or a synthetic control fabric (CTRL). Exercise endurance time was not different under COOL versus CTRL conditions: 12.38 ± 0.98 versus 11.75 ± 1.10 min, respectively (P > 0.05). Similarly, COOL had no effect on detailed thermoregulatory (skin and esophageal temperatures), cardiometabolic, ventilatory, and perceptual responses to exercise (all P > 0.05). In conclusion, clothing made of a synthetic fabric with purported "cooling" properties did not improve high-intensity cycle exercise endurance in trained athletes under ambient laboratory conditions that mimic the environmental conditions of indoor training/sporting facilities., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Severe hypoxia elicits aquatic surface respiration (ASR) behaviour in many species of fish, where ventilation of the gills at the air-water interface improves O2 uptake and survival. ASR is an important adaptation that may have given rise to air breathing in vertebrates. The neural substrate of this behaviour, however, is not defined. We characterized ASR in developing and adult zebrafish (Danio rerio) to ascertain a potential role for peripheral chemoreceptors in initiation or modulation of this response. Adult zebrafish exposed to acute, progressive hypoxia (PO2 from 158 to 15 mmHg) performed ASR with a threshold of 30 mmHg, and spent more time at the surface as PO2 decreased. Acclimation to hypoxia attenuated ASR responses. In larvae, ASR behaviour was observed between 5 and 21 days postfertilization with a threshold of 16 mmHg. Zebrafish decreased swimming behaviour (i.e. distance, velocity and acceleration) as PO2 was decreased, with a secondary increase in behaviour near or below threshold PO2 . In adults that underwent a 10-day intraperitoneal injection regime of 10 μg g(-1) serotonin (5-HT) or 20 μg g(-1) acetylcholine (ACh), an acute bout of hypoxia (15 mmHg) increased the time engaged in ASR by 5.5 and 4.9 times, respectively, compared with controls. Larvae previously immersed in 10 μmol l(-1) 5-HT or ACh also displayed an increased ASR response. Our results support the notion that ASR is a behavioural response that is reliant upon input from peripheral O2 chemoreceptors. We discuss implications for the role of chemoreceptors in the evolution of air breathing., (© 2015. Published by The Company of Biologists Ltd.)

Neuroepithelial cells (NECs) of the fish gill are respiratory chemoreceptors that detect changes in O2 and CO2/H(+) and are homologous to type I cells of the mammalian carotid body. In zebrafish (Danio rerio), stimulation of NECs by hypoxia or hypercapnia initiates inhibition of K(+) channels and subsequent membrane depolarisation. The goal of the present study was to further elucidate, in zebrafish NECs, the signalling pathways that underlie CO2/H(+) sensing and generate intracellular Ca(2+) ([Ca(2+)]i) signals. Breathing frequency was elevated maximally in fish exposed to 5 % CO2 (~37.5 mmHg). Measurement of [Ca(2+)]i in isolated NECs using Fura-2 imaging indicated that [Ca(2+)]i increased in response to acidic hypercapnia (5 % CO2, pH 6.6) and isocapnic acidosis (normocapnia, pH 6.6), but not to isohydric hypercapnia (5 % CO2, pH 7.6). Measurement of intracellular pH (pHi) using BCECF demonstrated a rapid decrease in pHi in response to acidic and isohydric hypercapnia, while isocapnic acidosis produced a smaller change in pHi. Intracellular acidification was reduced by the carbonic anhydrase inhibitor, acetazolamide, without affecting [Ca(2+)]i responses. Moreover, intracellular acidification using acetate (at constant extracellular pH) was without effect on [Ca(2+)]i. The acid-induced increase in [Ca(2+)]i persisted in the absence of extracellular Ca(2+) and was unaffected by Ca(2+) channel blockers (Cd(2+), Ni(2+) or nifedipine). The results of this study demonstrate that, unlike type I cells, extracellular H(+) is critical to the hypercapnia-induced increase in [Ca(2+)]i in NECs. The increase in [Ca(2+)]i occurs independently of pHi and appears to originate primarily from Ca(2+) derived from intracellular stores.

The current study investigated the role of hydrogen sulphide (H2S) in oxygen sensing, intracellular signalling and promotion of ventilatory responses to hypoxia in adult and larval zebrafish (Danio rerio). Both larval and adult zebrafish exhibited a dose-dependent increase in ventilation to sodium sulphide (Na2S), an H2S donor. In vertebrates, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are enzymes that catalyse the endogenous production of H2S. In adult zebrafish, inhibition of both CBS and CSE with aminooxyacetate (AOA) and propargyl glycine (PPG) blunted or abolished the hypoxic hyperventilation, and the addition of Na2S to the water partially rescued the effects of inhibiting endogenous H2S production. In zebrafish larvae (4 days post-fertilization), gene knockdown of either CBS or CSE using morpholinos attenuated the hypoxic ventilatory response. Furthermore, the intracellular calcium concentration of isolated neuroepithelial cells (NECs), which are putative oxygen chemoreceptors, increased significantly when these cells were exposed to 50 μm Na2S, supporting a role for H2S in Ca(2+)-evoked neurotransmitter release in these cells. Finally, immunohistochemical labelling showed that NECs dissociated from adult gill contained CBS and CSE, whereas cutaneous NECs in larval zebrafish expressed only CSE. Taken together, these data show that H2S can be produced in the putative oxygen-sensing cells of zebrafish, the NECs, in which it appears to play a pivotal role in promoting the hypoxic ventilatory response., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Adult zebrafish, Danio rerio, exhibit hyperventilatory responses to absolute environmental CO2 levels as low as 1.0 mmHg. The ability of zebrafish to detect and respond to low ambient CO2 appears to be mediated by chemosensory neuroepithelial cells (NECs) of the gill filaments. Recent electrophysiological characterization of this response revealed that the partial pressure-dependent depolarization of NECs in response to a hypercapnic stimulus is dependent on the rate of acidification associated with the hydration of CO2 and the inhibition of background K(+) channels. In order to further elucidate the signaling pathway underlying CO2 chemotransduction in NECs, we used microfluorimetric techniques to study intracellular changes in pH (pHi) and calcium ([Ca(2+)]i). Using the ratiometric indicators BCECF-AM and fura-2-AM, we found that a hypercapnic stimulus evoked a decrease in pHi and an increase in [Ca(2+)]i.