High aboveground carbon stock of African tropical montane forests.

Tropical forests store 40-50 per cent of terrestrial vegetation carbon1. However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests2. Owing to climatic and soil changes with increasing elevation3, AGC stocks are lower in tropical montane forests compared with lowland forests2. Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4 megagrams of carbon per hectare (95% confidence interval 137.1-164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network4 and about 70 per cent and 32 per cent higher than averages from plot networks in montane2,5,6 and lowland7 forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa8. We find that the low stem density and high abundance of large trees of African lowland forests4 is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to help to guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse9,10 and carbon-rich ecosystems.

A Research Agenda to Improve Outcomes in Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease. An Official American Thoracic Society Research Statement.

BACKGROUND: Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes. OBJECTIVES: To prioritize a list of research topics related to diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease and atrial fibrillation) by summarizing existing evidence and using consensus-based methods. METHODS: A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real-time based on their potential for advancing the field. RESULTS: Gaps spanned the translational science spectrum from basic science to implementation: 1) disease mechanisms, 2) epidemiology, 3) subphenotyping, 4) diagnosis and management, 5) clinical trials, 6) care delivery, 7) medication access, adherence and side effects, 8) risk factor mitigation, 9) cardiac and pulmonary rehabilitation, and 10) health equity. Seventeen experts participated and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after 2 rounds of voting. Range of summative Likert score was -15 to 25. Highest priority was "Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements." Health equity was identified as an important topic that should be embedded within all research. CONCLUSIONS: We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

The detailed clinical objectives approach to designing clinical trials and choosing estimands.

Objective setting is a necessary early step in the development of a clinical trial. ICH E9(R1) notes that the clinical objectives of a trial lead directly to the choice of estimands but barely discusses objectives themselves. Indeed, there is very little guidance anywhere in literature about objectives in clinical trials. This article identifies the substantial overlap between description of estimands and high quality definitions of objectives. It consequently shows that the estimand is decided by the precise choice of trial objective, and that therefore estimand decisions should be made at the objective level. The Detailed Clinical Objectives approach is proposed to support this. It emphasises clarity, specificity and a clinical focus when choosing and documenting objectives. Template text and examples are included to provide guidance on how it can be used in real trials. Finally, we describe objective-driven trial design, emphasising how strong objective setting establishes an important foundation for rigorous trial design discussions, logistical and operational decision-making during trial preparations, and clear communication of results and conclusions at the end of the trial. Highlighting the distinctions between objectives and estimands, we note how an objective-based framework can build on the ICH E9(R1) estimand framework to address many of its unanswered questions.

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have a positive, neutral, or negative effect on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether discontinuation compared with continuation of ACEIs or ARBs changed the number of days alive and out of the hospital through 30 days. Design, Setting, and Participants: A randomized clinical trial of 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization (enrolled: April 9-June 26, 2020; final follow-up: July 26, 2020). Interventions: Discontinuation (n = 334) or continuation (n = 325) of ACEIs or ARBs. Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression. Results: Among 659 patients, the median age was 55.1 years (interquartile range [IQR], 46.1-65.0 years), 14.7% were aged 70 years or older, 40.4% were women, and 100% completed the trial. The median time from symptom onset to hospital admission was 6 days (IQR, 4-9 days) and 27.2% of patients had an oxygen saturation of less than 94% of room air at baseline. In terms of clinical severity, 57.1% of patients were considered mild at hospital admission and 42.9% were considered moderate. There was no significant difference in the number of days alive and out of the hospital in patients in the discontinuation group (mean, 21.9 days [SD, 8 days]) vs patients in the continuation group (mean, 22.9 days [SD, 7.1 days]) and the mean ratio was 0.95 (95% CI, 0.90-1.01). There also was no statistically significant difference in death (2.7% for the discontinuation group vs 2.8% for the continuation group; odds ratio [OR], 0.97 [95% CI, 0.38-2.52]), cardiovascular death (0.6% vs 0.3%, respectively; OR, 1.95 [95% CI, 0.19-42.12]), or COVID-19 progression (38.3% vs 32.3%; OR, 1.30 [95% CI, 0.95-1.80]). The most common adverse events were respiratory failure requiring invasive mechanical ventilation (9.6% in the discontinuation group vs 7.7% in the continuation group), shock requiring vasopressors (8.4% vs 7.1%, respectively), acute myocardial infarction (7.5% vs 4.6%), new or worsening heart failure (4.2% vs 4.9%), and acute kidney failure requiring hemodialysis (3.3% vs 2.8%). Conclusions and Relevance: Among patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19 if there is an indication for treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04364893.

Dual bronchodilation with tiotropium/olodaterol further reduces activity-related breathlessness versus tiotropium alone in COPD.

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference -0.357, 95% CI -0.661- -0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation.

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

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

Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD.

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001). Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies. Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.

The effect of prior knowledge of test endpoint on non-local muscle fatigue.

INTRODUCTION: If the work duration or volume is known, it is common for individuals to anticipate this challenge by pursuing a strategy that may decrease the initial force output and maintain a force level that ensures a force reserve towards the end of the task. However, it is unknown whether this is a global strategy that is transferred to a non-exercised muscle following fatigue of a contralateral homologous muscle. METHODS: To clarify if prior knowledge of task endpoint has an effect on non-local muscle fatigue (NLMF), 15 male participants (22.4 ± 3.8 years) completed four conditions: (1) KNtest > fatigue (known endpoint after fatigue), (2) UNKtest > fatigue (unknown endpoint after fatigue), (3) KNtest > control (known endpoint without fatigue), (4) UNKtest > control (unknown endpoint without fatigue). For fatigue conditions, a maximal intensity, unilateral knee extension protocol was completed (two sets of 100 s maximal voluntary isometric contractions (MVIC) with 60 s rest between), whereas the control condition involved rest (260 s). The participants were either informed (known (KN) conditions) or not informed (unknown (UNK) conditions) of the duration of a post-intervention strength-endurance test (contralateral knee extension MVIC, ≥30 s). RESULTS: During the strength-endurance test, the UNKtest > fatigue displayed meaningful decreases in force (UNKtest > fatigue 10-12% over first 30 s), which was largest at the 25-30-s period (UNKtest > fatigue 7.4-41.1% from 25 to 1930s) compared to KNtest > fatigue and KNtest > control conditions, respectively. CONCLUSION: Prior knowledge of task endpoint can modify NLMF and affect pacing strategies.

Evaluation of the effects of olodaterol on exercise endurance in patients with chronic obstructive pulmonary disease: results from two 6-week crossover studies.

BACKGROUND: Two replicate, double-blind, placebo-controlled, 6-week crossover studies assessed the effect of the once-daily long-acting ß2-agonist olodaterol 5 µg and 10 µg on constant work-rate cycle endurance in patients with moderate to very severe chronic obstructive pulmonary disease. METHODS: Patients received placebo, olodaterol 5 µg once daily (QD) and olodaterol 10 µg QD in a randomised order for 6 weeks each, with a 2-week washout period in between. The primary end point was change in endurance time during constant work-rate cycle ergometry to symptom limitation at 75 % maximal work capacity after 6 weeks of treatment (2 h post-dose), based on log10-transformed data. Key secondary end points were inspiratory capacity at isotime and intensity of breathing discomfort at isotime. RESULTS: 151 and 157 patients were randomised and treated in Studies 1222.37 and 1222.38, respectively, with 147 and 154 being included in the full analysis sets. Mean endurance time at week 6 was increased compared to placebo by 14.0 % (Study 1222.37; p < 0.001) and 11.8 % (Study 1222.38; p < 0.01) with olodaterol 5 µg, and by 13.8 % (Study 1222.37; p < 0.001) and 10.5 % (Study 1222.38; p < 0.01) with olodaterol 10 µg. Inspiratory capacity at isotime increased with olodaterol 5 µg (Study 1222.37, 0.182 L, p < 0.0001; Study 1222.38, 0.084 L, p < 0.05) and 10 µg (Study 1222.37, 0.174 L; Study 1222.38, 0.166 L; both studies, p < 0.0001), and breathing discomfort was significantly reduced in Study 1222.37 (olodaterol 5 µg, 0.77 Borg units, p < 0.001; olodaterol 10 µg, 0.63 Borg units, p < 0.01) but not Study 1222.38. CONCLUSIONS: These studies provide further characterisation of the efficacy of olodaterol, showing that improvements in airflow (forced expiratory volume in 1 s) are associated with increases in inspiratory capacity and improvements in exercise endurance time. TRIAL REGISTRATIONS: NCT01040130 (1222.37) and NCT01040793 (1222.38).

Detection of Intravascular Injection During Lumbar Medial Branch Blocks: A Comparison of Aspiration, Live Fluoroscopy, and Digital Subtraction Technology.

BACKGROUND CONTEXT: Medial branch blocks may have unrecognized vascular uptake potentially resulting in false- negative results. PURPOSE: To determine the rate of unintended vascular injection of contrast medium during medial branch blocks (MBB) with digital subtraction (DS) technology in the context of negative vascular uptake as determined by live fluoroscopy. STUDY DESIGN/SETTING: Prospective Study in an academic medical center. PATIENT SAMPLE: 344 consecutive MBBs in 80 subjects. OUTCOME MEASURES: The presence of vascular flow as determined by live fluoroscopy and DS technology. METHODS: Unintended vascular injection of contrast medium was determined on 344 consecutive MBBs in 84 subjects, first using live fluoroscopy followed by DS. If live fluoroscopy initially detected vascular uptake, the needle was repositioned until no vascular flow was detected. Once no vascular uptake was confirmed by live fluoroscopy, a contrast medium was then injected while being visualized with DS to again assess the presence or absence of vascular flow undetected by live fluoroscopy. RESULTS: Live fluoroscopy revealed inadvertent vascular uptake in 38 of the 344 blocks [11% (95% CI 8.0-15%)]. DS uncovered an additional 27 of the 344 blocks [7.8% (95% CI 5.3-11.4%)] with evidence of vascular uptake that were not detected with conventional live fluoroscopy. CONCLUSION: DS enhances the ability to detect inadvertent vascular flow during medial branch blocks. This study demonstrates that standard live fluoroscopy can miss a small percentage of cases with unintentional vascular uptake during MBB when compared with DS and may contribute to occasional false-negative responses.

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4).

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 µg or 5/5 µg, tiotropium 2.5 µg or 5 µg, or olodaterol 5 µg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 µg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease.

BACKGROUND: This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting ß2-agonist olodaterol in patients with chronic obstructive pulmonary disease. METHODS: This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol FDC 2.5/5 µg and tiotropium + olodaterol FDC 5/5 µg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events. RESULTS: A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 µg and 2.5/5 µg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 µg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 µg were 0.115 L versus olodaterol 5 µg, 0.127 L versus tiotropium 2.5 µg and 0.110 L versus tiotropium 5 µg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified. CONCLUSIONS: Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.

Increasing carbon storage in intact African tropical forests.

The response of terrestrial vegetation to a globally changing environment is central to predictions of future levels of atmospheric carbon dioxide. The role of tropical forests is critical because they are carbon-dense and highly productive. Inventory plots across Amazonia show that old-growth forests have increased in carbon storage over recent decades, but the response of one-third of the world's tropical forests in Africa is largely unknown owing to an absence of spatially extensive observation networks. Here we report data from a ten-country network of long-term monitoring plots in African tropical forests. We find that across 79 plots (163 ha) above-ground carbon storage in live trees increased by 0.63 Mg C ha(-1) yr(-1) between 1968 and 2007 (95% confidence interval (CI), 0.22-0.94; mean interval, 1987-96). Extrapolation to unmeasured forest components (live roots, small trees, necromass) and scaling to the continent implies a total increase in carbon storage in African tropical forest trees of 0.34 Pg C yr(-1) (CI, 0.15-0.43). These reported changes in carbon storage are similar to those reported for Amazonian forests per unit area, providing evidence that increasing carbon storage in old-growth forests is a pan-tropical phenomenon. Indeed, combining all standardized inventory data from this study and from tropical America and Asia together yields a comparable figure of 0.49 Mg C ha(-1) yr(-1) (n = 156; 562 ha; CI, 0.29-0.66; mean interval, 1987-97). This indicates a carbon sink of 1.3 Pg C yr(-1) (CI, 0.8-1.6) across all tropical forests during recent decades. Taxon-specific analyses of African inventory and other data suggest that widespread changes in resource availability, such as increasing atmospheric carbon dioxide concentrations, may be the cause of the increase in carbon stocks, as some theory and models predict.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis.

The novel long-acting ß2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 µg) QD via Respimat®, formoterol 12 µg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 µg, 883 received olodaterol 10 µg, 885 received placebos, and 460 received formoterol 12 µg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 µg (marketed and registered dose) and 10 µg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.

Breathing Techniques Affect Female but Not Male Hip Flexion Range of Motion.

Two protocols were undertaken to help clarify the effects of breathing techniques on hamstrings (hip flexion) range of motion (ROM). The protocols examined effects of breathing conditions on ROM and trunk muscle activity. Protocol 1: Thirty recreationally active participants (15 male, 15 female, 20-25 years) were monitored for changes in single-leg raise (SLR) ROM with 7 breathing conditions before or during a passive supine SLR stretch. Breathing conditions included prestretch inhale, prestretch exhale, inhale-during stretch, exhale-during stretch, neutral, hyperventilation, and hypoventilation before stretch. Protocol 2: Eighteen recreationally active participants (9 male, 9 female, 20-25 years) were monitored for electromyographic (EMG) activity of the rectus abdominus, external obliques, lower abdominal stabilizers, and lower erector spinae while performing the 7 breathing conditions before or during a passive SLR stretch. Control exhibited less ROM (p = 0.008) than the prestretch inhale (7.7%), inhale-during stretch (10.9%), and hypoventilation (11.2%) conditions with females. Protocol 3: Greater overall muscle activity in the prestretch exhale condition was found compared with inhale-during stretch (43.1%↓; p = 0.029) and hypoventilation (51.2%↓; p = 0.049) conditions. As the inhale-during stretch and hypoventilation conditions produced the lowest levels of muscle activity for both sexes and the highest ROM for the females, it can be assumed that both mechanical and neural factors affect female SLR ROM. Lesser male ROM might be attributed to anatomical differences such as greater joint stiffness. The breathing techniques may have affected intra-abdominal pressure, trunk muscle cocontractions, and sympathetic neural activity to enhance female ROM.

The responsiveness of different exercise tests in Chronic Obstructive Pulmonary Disease: a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by reduced exercise tolerance and improving physical performance is an important therapeutic goal. A variety of exercise tests are commonly used to assess exercise tolerance, including laboratory and field-based tests. The responsiveness of these tests to common COPD interventions is yet to be compared, but may inform test selection in clinical and research settings. RESEARCH QUESTION: What exercise test possesses the greatest sensitivity to change pre- to post-intervention in patients with COPD? STUDY DESIGN AND METHODS: 154 patients with symptomatic COPD were recruited and randomised (2:1:1) to six weeks of long-acting muscarinic antagonist (LAMA), pulmonary rehabilitation (PR), or usual care (UC). Pre- and post-intervention, participants performed a ramp-incremental and constant work rate cycle ergometer exercise test (ICET and CWRCT), incremental and endurance shuttle walk test (ISWT and ESWT), six-minute walk test (6MWT), and a four metre gait speed test (4MGS). RESULTS: 103 participants (67 ± 8 y; 75 [73%] males; FEV1: 50.6 ± 16.8 % predicted) completed the study. Significant improvements in the ICET, CWRCT, ISWT, ESWT, and 6MWT were observed following PR (p<0.05), with the greatest improvements seen in the constant work rate protocols (% change: CWRCT: 42%; ESWT: 41%). INTERPRETATION: The ESWT and CWRCT appeared to be the most responsive exercise test protocols to LAMA and PR. The magnitude of change was much greater after a programme of rehabilitation compared to bronchodilator therapy.

Validation of Constant Work Rate Cycling Endurance Time for Use in Chronic Obstructive Pulmonary Disease Clinical Trials.

Rationale: A COPD Foundation working group sought to identify measures of exercise endurance, a meaningful aspect of physical functioning in everyday life among patients with chronic obstructive pulmonary disease (COPD) that is not fully accepted in regulatory decision making, hampering drug development. Objectives: To demonstrate, as we previously asserted (Casaburi COPD 2022;9:252), that constant work rate cycling endurance time is an appropriate exercise endurance measure in patients with COPD. Methods: To validate this assertion, we assembled an integrated database of endurance time responses, including 8 bronchodilator (2,166 subjects) and 15 exercise training (3,488 subjects) studies (Casaburi COPD 2022;9:520). Results: Construct validity was demonstrated: 1) peak physiologic and perceptual responses were similar for constant work rate and incremental cycling; 2) after bronchodilator therapy, there were greater increases in endurance time in patients with more severe airflow limitation; 3) after exercise training, endurance time increases were similar across airflow limitation severities; and 4) there were correlations between changes in endurance time and changes in mechanistically related physiologic and perceptual variables. Test-retest reliability was demonstrated, with consistency of changes in endurance time at two time points after the intervention. Responsiveness was confirmed, with significant increases in endurance time after active (but not placebo) bronchodilator therapy, with greater increases seen with more severe airflow limitation and after exercise training. On the basis of regression analysis using multiple anchor variables, the minimum important difference for endurance time increase is estimated to be approximately 1 minute. Conclusions: Constant work rate cycling endurance time is a valid exercise endurance measure in COPD, suitable for contributing to the evaluation of treatment benefit supporting regulatory decision making and evidence-based therapeutic recommendations.

Detecting improvements in dyspnea in COPD using a three-minute constant rate shuttle walking protocol.

RATIONALE: We examined the responsiveness of a 3-minute constant rate shuttle walking protocol to detect improvements in exertional dyspnea following acute bronchodilation in COPD. Our hypothesis was that the 3-minute constant rate shuttle walking protocol would be able to adequately put forth improvements in exertional dyspnea following acute bronchodilation in this population. METHODS: Using a placebo controlled, double-blind cross-over design, 39 patients with moderate to severe COPD performed a 3-min constant rate shuttle walking test during which they were asked to walk on a flat corridor at a speed that was externally imposed by an audio signal. During the test, dyspnea was graded using the 10-point modified Borg scale. The test was performed twice, following the administration of saline placebo or of 500 µg nebulized ipratropium bromide. RESULTS: Improvements of respiratory pattern (respiratory rate and tidal volume) and statistically and clinically significant reductions in Borg dyspnea scores (∆ dyspnea score = 1.0 ± 0.2, p < 0.01) were seen during the 3-min shuttle walking protocol with ipratropium bromide compared to placebo. CONCLUSION: This 3-minute shuttle walking protocol adequately detected dyspnea and breathing pattern improvements following acute bronchodilation in COPD.

A Conceptual Framework for Use of Increased Endurance Time During Constant Work Rate Cycle Ergometry as a Patient-Focused Meaningful Outcome in COPD Clinical Trials.

The Chronic Lung Disease Biomarker and Clinical Outcome Assessment Qualification Consortium (CBQC) evaluates the potential of biomarkers and outcome measures as drug development tools. Exercise endurance is an objective indicator of treatment benefit, closely related to daily physical function. Therefore, it is an ideal candidate for an outcome for drug development trials. Unfortunately, no exercise endurance measure is qualified by regulatory authorities for use in trials of chronic obstructive pulmonary disease (COPD) and no approved COPD therapies have claims of improving exercise endurance. Consequently, it has been challenging for developers to consider this outcome when designing clinical trials for new therapies. Endurance time during constant work rate cycle ergometry (CWRCE), performed on an electronically braked stationary cycle ergometer, provides an exercise endurance measure under standardized conditions. Baseline individualized work rate for each participant is set using an incremental test. During CWRCE the patient is encouraged to continue exercising for as long as possible. Although not required, physiological and sensory responses (e.g., pulmonary ventilation, heart rate, dyspnea ratings) are frequently collected to support interpretation of endurance time changes. Exercise tolerance limit is reached when the individual is limited by symptoms, unable to maintain pedaling cadence or unable to continue safely. At exercise cessation, exercise duration is recorded. An CWRCE endurance time increase from the pre-treatment baseline is proposed as a key efficacy endpoint in clinical trials. In COPD, improved exercise endurance has a direct relationship to the experience of physical functioning in daily life, which is a patient-centered, meaningful benefit.

Endurance Time During Constant Work Rate Cycle Ergometry in COPD: Development of an Integrated Database From Interventional Studies.

Introduction: The COPD Biomarkers Qualification Consortium (CBQC) was formed under COPD Foundation management, with the goal of qualifying biomarkers and clinical outcome assessments through established regulatory processes for chronic obstructive pulmonary disease (COPD). Within CBQC, a working group evaluated opportunities for qualification of an exercise endurance measure. In a recent publication (Chronic Obstr Pulm Dis. 2022; 9[2]:252-265), we described a conceptual framework establishing exercise endurance's direct relationship to an individual with COPD's experience of physical functioning in daily life, and that increase in exercise endurance is a patient-centered, meaningful treatment benefit. We further proposed endurance time during constant work rate cycle ergometery (CWRCE) as a useful efficacy endpoint in clinical therapeutic intervention trials. In this current publication, we describe the process of assembling an integrated database of endurance time responses to interventions in COPD. Methods: We sought participant-level data from published studies incorporating CWRCE as an outcome measure. A literature search screened 2993 publications and identified 553 studies for assessment. Two interventions had sufficient data across studies to warrant data extraction: bronchodilators and rehabilitative exercise training. Investigators were contacted and requested to provide participant-by-participant data from their published studies. Results: The final dataset included data from 8 bronchodilator studies (2166) participants and 15 exercise training studies (3488 participants). The database includes 71 variables per participant, comprising demographic, pulmonary function, and detailed physiologic response data. This paper provides a detailed description of the analysis population, while analysis supporting the validation/qualification process and addressing other scientific questions will be described in subsequent publications.