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Exertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics - as those in the initial stages of the disease - the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO 2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients' out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in "minor/trivial" COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV 1 .

In this paper we investigate the application of phase-shifting digital holography for the real-time characterization of electromagnetic sources in the THz frequency range. We use an off-the-shelf terahertz detector array composed of 64 × 64 power-sensitive pixels, over an area of 96 mm × 96 mm , to record intensity interferograms cast between the coherent radiation emitted from a reference source and an unknown antenna under test. This approach parallelizes the acquisition process with respect to conventional near-field point scanning methods, reducing the measurement time by orders of magnitude. In our system, the measurement time is limited only by the refresh rate of the detector array and the speed of a delay line stage that is used to phase-shift the reference wave. As a proof-of-principle demonstration, we map the 2D near-field distribution and estimate the far-field radiation pattern emitted by a plano-convex PTFE spherical lens antenna illuminated by a diagonal horn at 290 GHz frequency with ∼ 1 Hz refresh rate., (© 2024. The Author(s).)

Optical tweezers enable noncontact trapping of microscale objects using light. It is not known how tightly it is possible to three-dimensionally (3D) trap microparticles with a given photon budget. Reaching this elusive limit would enable maximally stiff particle trapping for precision measurements on the nanoscale and photon-efficient tweezing of light-sensitive objects. Here, we customize the shape of light fields to suit specific particles, with the aim of optimizing trapping stiffness in 3D. We show, theoretically, that the confinement volume of microspheres held in sculpted optical traps can be reduced by one to two orders of magnitude. Experimentally, we use a wavefront shaping-inspired strategy to passively suppress the Brownian fluctuations of microspheres in every direction concurrently, demonstrating order-of-magnitude reductions in their confinement volumes. Our work paves the way toward the fundamental limits of optical control over the mesoscopic realm.

Rationale: It is increasingly recognized that adults with preserved ratio impaired spirometry (PRISm) are prone to increased morbidity. However, the underlying pathophysiological mechanisms are unknown. Objectives: Evaluate the mechanisms of increased dyspnea and reduced exercise capacity in PRISm. Methods: We completed a cross-sectional analysis of the CanCOLD (Canadian Cohort Obstructive Lung Disease) population-based study. We compared physiological responses in 59 participants meeting PRISm spirometric criteria (post-bronchodilator FEV 1  < 80% predicted and FEV 1 /FVC ⩾ 0.7), 264 control participants, and 170 ever-smokers with chronic obstructive pulmonary disease (COPD), at rest and during cardiopulmonary exercise testing. Measurements and Main Results: Individuals with PRISm had lower total lung, vital, and inspiratory capacities than healthy controls (all P  < 0.05) and minimal small airway, pulmonary gas exchange, and radiographic parenchymal lung abnormalities. Compared with healthy controls, individuals with PRISm had higher dyspnea/[Formula: see text]o 2 ratio at peak exercise (4.0 ± 2.2 vs. 2.9 ± 1.9 Borg units/L/min; P  < 0.001) and lower [Formula: see text]o 2peak (74 ± 22% predicted vs. 96 ± 25% predicted; P  < 0.001). At standardized submaximal work rates, individuals with PRISm had greater Vt/inspiratory capacity (Vt%IC; P  < 0.001), reflecting inspiratory mechanical constraint. In contrast to participants with PRISm, those with COPD had characteristic small airways dysfunction, dynamic hyperinflation, and pulmonary gas exchange abnormalities. Despite these physiological differences among the three groups, the relationship between increasing dyspnea and Vt%IC during cardiopulmonary exercise testing was similar. Resting IC significantly correlated with [Formula: see text]o 2peak ( r  = 0.65; P  < 0.001) in the entire sample, even after adjusting for airflow limitation, gas trapping, and diffusing capacity. Conclusions: In individuals with PRISm, lower exercise capacity and higher exertional dyspnea than healthy controls were mainly explained by lower resting lung volumes and earlier onset of dynamic inspiratory mechanical constraints at relatively low work rates. Clinical trial registered with www.clinicaltrials.gov (NCT00920348).

Millimeter and terahertz wave imaging has emerged as a powerful tool for applications such as security screening, biomedical imaging, and material analysis. However, intensity images alone are often insufficient for detecting variations in the dielectric constant of a sample, and extraction of material properties without additional phase information requires extensive prior knowledge of the sample. Digital holography provides a means for intensity-only detectors to reconstruct both amplitude and phase images. Here we utilize a commercially available source and detector array, both operating at room temperature, to perform digital holography in real-time for the first time in the mm-wave band (at 290 GHz). We compare the off-axis and phase-shifting approaches to digital holography and discuss their trade-offs and practical challenges in this regime. Owing to the low pixel count, we find phase-shifting holography to be the most practical and high fidelity approach for such commercial mm-wave cameras even under real-time operational requirements.

Introduction: Individuals with asthma breathe at higher operating lung volumes during exercise compared with healthy individuals, which contributes to increased exertional dyspnoea. In health, females are more likely to develop exertional dyspnoea than males at a given workload or ventilation, and therefore, it is possible that females with asthma may develop disproportional dyspnoea on exertion. The purpose of this study was to compare operating lung volume and dyspnoea responses during exercise in females with and without asthma., Methods: Sixteen female controls and 16 females with asthma were recruited for the study along with 16 male controls and 16 males with asthma as a comparison group. Asthma was confirmed using American Thoracic Society criteria. Participants completed a cycle ergometry cardiopulmonary exercise test to volitional exhaustion. Inspiratory capacity manoeuvres were performed to estimate inspiratory reserve volume (IRV) and dyspnoea was evaluated using the Modified Borg Scale., Results: Females with asthma exhibited elevated dyspnoea during submaximal exercise compared with female controls (p<0.05). Females with asthma obtained a similar IRV and dyspnoea at peak exercise compared with healthy females despite lower ventilatory demand, suggesting mechanical constraint to tidal volume (V T ) expansion. V T -inflection point was observed at significantly lower ventilation and V̇ O 2 in females with asthma compared with female controls. Forced expired volume in 1 s was significantly associated with V T -inflection point in females with asthma (R 2 =0.401; p<0.01) but not female controls (R 2 =0.002; p=0.88)., Conclusion: These results suggest that females with asthma are more prone to experience exertional dyspnoea, secondary to dynamic mechanical constraints during submaximal exercise when compared with females without asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Reduced lung diffusing capacity for carbon monoxide (DL CO ) at rest and increased ventilation ( ⩒ E )-carbon dioxide output ( ⩒ CO 2 ) during exercise are frequent findings in dyspneic smokers with largely preserved FEV 1 . It remains unclear whether low DL CO and high ⩒ E - ⩒ CO 2 are mere reflections of alveolar destruction (i.e. emphysema) or impaired pulmonary perfusion in non-emphysematous tissue contributes to these functional abnormalities. Sixty-four smokers (41 males, FEV 1 = 84 ± 13%predicted) underwent pulmonary function tests, an incremental exercise test, and quantitative chest computed tomography. Total pulmonary vascular volume (TPVV) was calculated for the entire segmented vascular tree (VIDA Vision™). Using the median % low attenuation area (-950 HU), participants were dichotomized into "Trace" or "Mild" emphysema (E), each group classified into preserved versus reduced DL CO . Within each emphysema subgroup, participants with abnormally low DL CO showed lower TPVV, higher ⩒ E - ⩒ CO 2 , and exertional dyspnea than those with preserved DL CO ( p  < 0.05). TPVV ( r  = 0.34; p  = 0.01), but not emphysema ( r = -0.05; p  = 0.67), correlated with lower DL CO after adjusting for age and height. Despite lower emphysema burden, Trace-E participants with reduced DL CO had lower TPVV, higher dyspnea, and lower peak work rate than the Mild-E with preserved DL CO ( p  < 0.05). Interestingly, TPVV (but not emphysema) correlated inversely with both dyspnea-work rate ( r = -0.36, p  = 0.004) and dyspnea- ⩒ E slopes ( r = -0.40, p  = 0.001). Reduced pulmonary vascular volume adjusted by emphysema extent is associated with low DL CO and heightened exertional ventilation in dyspneic smokers with minor emphysema. Impaired perfusion of non-emphysematous regions of the lungs has greater functional and clinical consequences than hitherto assumed in these subjects.

Background: The precise mechanisms driving poor exercise tolerance in patients with fibrotic interstitial lung diseases (fibrotic ILDs) showing a severe impairment in single-breath lung diffusing capacity for carbon monoxide (D LCO < 40% predicted) are not fully understood. Rather than only reflecting impaired O 2 transfer, a severely impaired D LCO may signal deranged integrative physiologic adjustments to exercise that jointly increase the burden of exertional symptoms in fibrotic ILD., Methods: Sixty-seven subjects (46 with idiopathic pulmonary fibrosis, 24 showing D LCO < 40%) and 22 controls underwent pulmonary function tests and an incremental cardiopulmonary exercise test with serial measurements of operating lung volumes and 0-10 Borg dyspnea and leg discomfort scores., Results: Subjects from the D LCO < 40% group showed lower spirometric values, more severe restriction, and lower alveolar volume and transfer coefficient compared to controls and participants with less impaired D LCO ( P < .05). Peak work rate was ∼45% (vs controls) and ∼20% (vs D LCO > 40%) lower in the former group, being associated with lower (and flatter) O 2 pulse, an earlier lactate (anaerobic) threshold, heightened submaximal ventilation, and lower S pO 2 . Moreover, critically high inspiratory constrains were reached at lower exercise intensities in the D LCO < 40% group ( P < .05). In association with the greatest leg discomfort scores, they reported the highest dyspnea scores at a given work rate. Between-group differences lessened or disappeared when dyspnea intensity was related to indexes of increased demand-capacity imbalance, that is, decreasing submaximal, dynamic ventilatory reserve, and inspiratory reserve volume/total lung capacity ( P > .05)., Conclusions: A severely reduced D LCO in fibrotic ILD signals multiple interconnected derangements (cardiovascular impairment, an early shift to anaerobic metabolism, excess ventilation, inspiratory constraints, and hypoxemia) that ultimately lead to limiting respiratory (dyspnea) and peripheral (leg discomfort) symptoms. D LCO < 40%, therefore, might help in clinical decision-making to indicate the patient with fibrotic ILD who might derive particular benefit from pharmacologic and non-pharmacologic interventions aimed at lessening these systemic abnormalities., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Rationale: Ventilatory demand-capacity imbalance, as inferred based on a low ventilatory reserve, is currently assessed only at peak cardiopulmonary exercise testing (CPET). Peak ventilatory reserve, however, is poorly sensitive to the submaximal, dynamic mechanical ventilatory abnormalities that are key to dyspnea genesis and exercise intolerance. Objectives: After establishing sex- and age-corrected norms for dynamic ventilatory reserve at progressively higher work rates, we compared peak and dynamic ventilatory reserve for their ability to expose increased exertional dyspnea and poor exercise tolerance in mild to very severe chronic obstructive pulmonary disease (COPD). Methods: We analyzed resting functional and incremental CPET data from 275 controls (130 men, aged 19-85 yr) and 359 Global Initiative for Chronic Obstructive Lung Disease patients with stage 1-4 obstruction (203 men) who were prospectively recruited for previous ethically approved studies in three research centers. In addition to peak and dynamic ventilatory reserve (1 - [ventilation / estimated maximal voluntary ventilation] × 100), operating lung volumes and dyspnea scores (0-10 on the Borg scale) were obtained. Results: Dynamic ventilatory reserve was asymmetrically distributed in controls; thus, we calculated its centile distribution at every 20 W. The lower limit of normal (lower than the fifth centile) was consistently lower in women and older subjects. Peak and dynamic ventilatory reserve disagreed significantly in indicating an abnormally low test result in patients: whereas approximately 50% of those with a normal peak ventilatory reserve showed a reduced dynamic ventilatory reserve, the opposite was found in approximately 15% ( P  < 0.001). Irrespective of peak ventilatory reserve and COPD severity, patients who had a dynamic ventilatory reserve below the lower limit of normal at an isowork rate of 40 W had greater ventilatory requirements, prompting earlier attainment of critically low inspiratory reserve. Consequently, they reported higher dyspnea scores, showing poorer exercise tolerance compared with those with preserved dynamic ventilatory reserve. Conversely, patients with preserved dynamic ventilatory reserve but reduced peak ventilatory reserve reported the lowest dyspnea scores, showing the best exercise tolerance. Conclusions: Reduced submaximal dynamic ventilatory reserve, even in the setting of preserved peak ventilatory reserve, is a powerful predictor of exertional dyspnea and exercise intolerance in COPD. This new parameter of ventilatory demand-capacity mismatch may enhance the yield of clinical CPET in the investigation of activity-related breathlessness in individual patients with COPD and other prevalent cardiopulmonary diseases.

The functional disturbances driving "out-of-proportion" dyspnoea in patients with fibrosing interstitial lung disease (f-ILD) showing only mild restrictive abnormalities remain poorly understood. Eighteen patients (10 with idiopathic pulmonary fibrosis) showing preserved spirometry and mildly reduced total lung capacity (≥70% predicted) and 18 controls underwent an incremental cardiopulmonary exercise test with measurements of operating lung volumes and Borg dyspnoea scores. Patients' lower exercise tolerance was associated with higher ventilation (V̇ E )/carbon dioxide (V̇CO 2 ) compared with controls (V̇ E /V̇CO 2 nadir=35 ± 3 versus 29 ± 2; p < 0.001). Patients showed higher tidal volume/inspiratory capacity and lower inspiratory reserve volume at a given exercise intensity, reporting higher dyspnoea scores as a function of both work rate and V̇ E . Steeper dyspnoea-work rate slopes were associated with lower lung diffusing capacity, higher V̇ E /V̇CO 2 , and lower peak O 2 uptake (p < 0.05). Heightened ventilatory demands in the setting of progressively lower capacity for tidal volume expansion on exertion largely explain higher-than-expected dyspnoea in f-ILD patients with largely preserved dynamic and "static" lung volumes at rest., (Copyright © 2023. Published by Elsevier B.V.)

Following pulmonary embolism (PE), a third of patients develop persistent dyspnea, which is commonly termed the post-PE syndrome. The neurophysiological underpinnings of exertional dyspnea in patients with post-PE syndrome without pulmonary hypertension (PH) are unclear. Thus, the current study determined if abnormally high inspiratory neural drive (IND) due, in part, to residual pulmonary gas-exchange abnormalities, was linked to heightened exertional dyspnea and exercise limitation, in such patients. Fourteen participants with post-PE syndrome (without resting PH) and 14 age-, sex-, and body mass index-matched healthy controls undertook pulmonary function testing and a symptom-limited cycle cardiopulmonary exercise test with measurements of IND (diaphragmatic electromyography), ventilatory requirements for CO 2 (V̇e/V̇co 2 ), and perceived dyspnea intensity (modified Borg 0-10 scale). Post-PE (vs. control) had a reduced resting transfer coefficient for carbon monoxide ( K CO : 84 ± 15 vs. 104 ± 14%pred, P < 0.001) and peak oxygen uptake (V̇o 2peak ) (76 ± 14 vs. 124 ± 28%pred, P < 0.001). IND and V̇e/V̇co 2 were higher in post-PE than controls at standardized submaximal work rates ( P < 0.05). Dyspnea increased similarly in both groups as a function of increasing IND but was higher in post-PE at standardized submaximal work rates ( P < 0.05). High IND was associated with low K CO ( r = -0.484, P < 0.001), high V̇e/V̇co 2 nadir ( r = 0.453, P < 0.001), and low V̇o 2peak ( r = -0.523, P < 0.001). In patients with post-PE syndrome, exercise IND was higher than controls and was associated with greater dyspnea intensity. The heightened IND and dyspnea in post-PE, in turn, were strongly associated with low resting K CO and high exercise V̇e/V̇co 2 , which suggest important pulmonary gas-exchange abnormalities in this patient population. NEW & NOTEWORTHY This study is the first to show that increased exertional dyspnea in patients with post-pulmonary embolism (PE) syndrome, without overt pulmonary hypertension, was strongly associated with elevated inspiratory neural drive (IND) to the diaphragm during exercise, compared with healthy controls. The greater IND was associated with impairments in pulmonary gas exchange and significant deconditioning. Our results help to explain why many patients with post-PE syndrome report significant dyspnea at relatively low levels of physical activity.

Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low V˙A/Q˙c, or wasted ventilation related to high V˙A/Q˙c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on V˙A (bronchodilators, antiinflammatory medications) or Q˙c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with V˙A/Q˙c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Low resting inspiratory capacity (IC) and low maximal inspiratory pressure (MIP) have previously been linked to exertional dyspnea, exercise limitation, and poor survival in chronic obstructive pulmonary disease (COPD). The interaction and relative contributions of these two related variables to important clinical outcomes are unknown. The objective of the current study was to examine the interaction between resting IC and MIP (both % predicted), exertional dyspnea, exercise capacity, and long-term survival in patients with COPD. Two hundred and eighty-five patients with mild to advanced COPD completed standard lung function testing and a cycle cardiopulmonary exercise test. Multiple regression determined predictors of the exertional dyspnea-ventilation slope and peak oxygen uptake (V̇o 2peak ). Cox regression determined predictors of 10-year mortality. IC was associated with the dyspnea-ventilation slope (standardized β = -0.42, P < 0.001), whereas MIP was excluded from the regression model ( P = 0.918). IC and MIP were included in the final model to predict V̇o 2peak . However, the standardized β was greater for IC (0.43) than MIP (0.22). After adjusting for age, sex, body mass index, cardiovascular risk, airflow obstruction, and diffusing capacity, resting IC was independently associated with 10-year all-cause mortality (hazard ratio = 1.25, confidence interval 5%-95% = 1.16-1.34, P < 0.001), whereas MIP was excluded from the final model (all P = 0.829). Low resting IC was consistently linked to heightened dyspnea intensity, low V̇o 2peak , and worse survival in COPD even after accounting for airway obstruction, inspiratory muscle strength, and diffusing capacity. These results support the use of resting IC as an important physiological biomarker closely linked to key clinical outcomes in COPD. NEW & NOTEWORTHY To our knowledge, this study is the first to show an independent association between low resting inspiratory capacity (IC) and, severe exertional dyspnea, exercise limitation, and increased mortality risk, after accounting for the severity of airway obstruction, inspiratory muscle strength, and diffusing capacity. These results support the use of resting IC as an important independent physiological biomarker closely linked to key clinical outcomes in COPD.

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO 2 [[Formula: see text]e/[Formula: see text]co 2 ]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD). Objectives: To determine 1 ) the association between high [Formula: see text]e/[Formula: see text]co 2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2 ) its prevalence in a large population-based cohort. Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing, and chest computed tomography. Impaired exercise ventilatory efficiency was defined by a nadir [Formula: see text]e/[Formula: see text]co 2 above the upper limit of normal (ULN), using population-based normative values. Measurements and Main Results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 COPD, and 200 with GOLD 2-4 COPD. Participants with [Formula: see text]e/[Formula: see text]co 2 above the ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale ⩾ 2; odds ratio [5-95% confidence intervals], 1.77 [1.31 to 2.39]) and abnormally low peak [Formula: see text]o 2 ([Formula: see text]o 2peak below the lower limit of normal; odds ratio, 4.58 [3.06 to 6.86]). The Kco had a stronger correlation with nadir [Formula: see text]e/[Formula: see text]co 2 ( r  = -0.38; P  < 0.001) than other relevant lung function and computed tomography metrics. The prevalence of [Formula: see text]e/[Formula: see text]co 2 above the ULN was 24% in COPD (similar in GOLD 1 and 2 through 4), which was greater than in never-smokers (13%) and ever-smokers (12%). Conclusions: [Formula: see text]e/[Formula: see text]co 2 above the ULN was associated with greater dyspnea and low [Formula: see text]o 2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD.

Purpose: To assess whether night-time increases in mechanical loading negatively impact respiratory muscle function in COPD and whether compensatory increases in inspiratory neural drive (IND) are adequate to stabilize ventilatory output and arterial oxygen saturation, especially during sleep when wakefulness drive is withdrawn., Methods: 21 patients with moderate-to-severe COPD and 20 age-/sex-matched healthy controls (CTRL) participated in a prospective, cross-sectional, one-night study to assess the impact of COPD on serial awake, supine inspiratory capacity (IC) measurements and continuous dynamic respiratory muscle function (esophageal manometry) and IND (diaphragm electromyography, EMGdi) in supine sleep., Results: Supine inspiratory effort and EMGdi were consistently twice as high in COPD versus CTRL (p < 0.05). Despite overnight increases in awake total airways resistance and dynamic lung hyperinflation in COPD (p < 0.05; not in CTRL), elevated awake EMGdi and respiratory effort were unaltered in COPD overnight. At sleep onset (non-rapid eye movement sleep, N2), EMGdi was decreased versus wakefulness in COPD (- 43 ± 36%; p < 0.05) while unaffected in CTRL (p = 0.11); however, respiratory effort and arterial oxygen saturation (SpO 2 ) were unchanged. Similarly, in rapid eye movement (stage R), sleep EMGdi was decreased (- 38 ± 32%, p < 0.05) versus wakefulness in COPD, with preserved respiratory effort and minor (2%) reduction in SpO 2 ., Conclusions: Despite progressive mechanical loading overnight and marked decreases in wakefulness drive, inspiratory effort and SpO 2 were well maintained during sleep in COPD. Preserved high inspiratory effort during sleep, despite reduced EMGdi, suggests continued (or increased) efferent activation of extra-diaphragmatic muscles, even in stage R sleep., Clinical Trial Information: The COPD data reported herein were secondary data (Placebo arm only) obtained through the following Clinical Trial: "Effect of Aclidinium/Formoterol on Nighttime Lung Function and Morning Symptoms in Chronic Obstructive Pulmonary Disease" ( https://clinicaltrials.gov/ct2/show/NCT02429765 ; NCT02429765)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ([Formula: see text]O 2max ). Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in healthy individuals, which could translate into greater cardiac output and improved [Formula: see text]O 2max , particularly in untrained individuals. The purpose of the study was to examine whether iNO improved [Formula: see text]O 2max in endurance trained and untrained individuals., Methods: Sixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO., Results: Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). [Formula: see text]O 2max was greater in the endurance trained group (Untrained: 3.1 ± 0.7 vs. Endurance: 4.3 ± 0.9 L min -1 ; p < 0.01), however, there was no effect of condition (p = 0.79) and no group by condition interaction (p = 0.68). Peak cardiac output was also unchanged by iNO in either group., Conclusion: Despite a reduction in right ventricular systolic pressure, the lack of change in [Formula: see text]O 2max with iNO suggests that the pulmonary vasculature does not limit [Formula: see text]O 2max in young healthy individuals, regardless of fitness level., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In health, the near-eucapnic, highly efficient hyperpnea during mild-to-moderate intensity exercise is driven by three obligatory contributions, namely, feedforward central command from supra-medullary locomotor centers, feedback from limb muscle afferents, and respiratory CO 2 exchange (V̇CO 2 ). Inhibiting each of these stimuli during exercise elicits a reduction in hyperpnea even in the continuing presence of the other major stimuli. However, the relative contribution of each stimulus to the hyperpnea remains unknown as does the means by which V̇CO2 is sensed. Mediation of the hyperventilatory response to exercise in health is attributed to the multiple feedback and feedforward stimuli resulting from muscle fatigue. In patients with COPD, diaphragm EMG amplitude and its relation to ventilatory output are used to decipher mechanisms underlying the patients' abnormal ventilatory responses, dynamic lung hyperinflation and dyspnea during exercise. Key contributions to these exercise-limiting responses across the spectrum of COPD severity include high dead space ventilation, an excessive neural drive to breathe and highly fatigable limb muscles, together with mechanical constraints on ventilation. Major controversies concerning control of exercise hyperpnea are discussed along with the need for innovative research to uncover the link of metabolism to breathing in health and disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Time-of-flight three-dimensional (3D) imaging has applications that range from industrial inspection to motion tracking. Depth is recovered by measuring the round-trip flight time of laser pulses, typically using collection optics of several centimeters in diameter. We demonstrate near–video-rate 3D imaging through multimode fibers with a total aperture of several hundred micrometers. We implement aberration correction using wavefront shaping synchronized with a pulsed source and scan the scene at ~23,000 points per second. We image moving objects several meters beyond the end of an ~40-centimeters-long fiber of 50-micrometer core diameter at frame rates of ~5 hertz. Our work grants far-field depth-resolving capabilities to ultrathin microendoscopes, which we expect to have applications to clinical and remote inspection scenarios.

Introduction: Evaluation of the intensity and quality of activity-related dyspnea is potentially useful in people with chronic obstructive pulmonary disease (COPD). The present study sought to examine associations between qualitative dyspnea descriptors, dyspnea intensity ratings, dynamic respiratory mechanics, and exercise capacity during cardiopulmonary exercise testing (CPET) in COPD and healthy controls., Methods: In this cross-sectional study, 261 patients with mild-to-very severe COPD (forced expiratory volume in 1 s, 62 ± 25%pred) and 94 age-matched controls (forced expiratory volume in 1 s, 114 ± 14%pred) completed an incremental cycle CPET to determine peak oxygen uptake (V˙O2peak). Throughout exercise, expired gases, operating lung volumes, and dyspnea intensity were assessed. At peak exercise, dyspnea quality was assessed using a modified 15-item questionnaire., Results: Logistic regression analysis revealed that among 15 dyspnea descriptors, only those alluding to the cluster "unsatisfied inspiration" were consistently associated with an increased likelihood for both critical inspiratory mechanical constraint (end-inspiratory lung volume/total lung capacity ratio ≥0.9) during exercise and reduced exercise capacity (V˙O2peak < lower limit of normal) in COPD (odds ratio (95% confidence interval), 3.26 (1.40-7.60) and 3.04 (1.24-7.45), respectively; both, P < 0.05). Thus, patients reporting "unsatisfied inspiration" (n = 177 (68%)) had an increased relative frequency of critical inspiratory mechanical constraint and low exercise capacity compared with those who did not select this descriptor, regardless of COPD severity or peak dyspnea intensity scores., Conclusions: In patients with COPD, regardless of disease severity, reporting descriptors in the unsatisfied inspiration cluster complemented traditional assessments of dyspnea during CPET and helped identify patients with critical mechanical abnormalities germane to exercise intolerance., (Copyright © 2021 by the American College of Sports Medicine.)

Patients with mild chronic obstructive pulmonary disease (COPD) and lower resting diffusing capacity for carbon monoxide (DL CO ) often report troublesome dyspnea during exercise although the mechanisms are not clear. We postulated that in such individuals, exertional dyspnea is linked to relatively high inspiratory neural drive (IND) due, in part, to the effects of reduced ventilatory efficiency. This cross-sectional study included 28 patients with GOLD I COPD stratified into two groups with ( n  = 15) and without ( n  = 13) DL CO less than the lower limit of normal (2 ( V̇ E / V̇ CO 2 ), and respiratory mechanics during incremental cycle exercise in the three groups. Spirometry and resting lung volumes were similar between COPD groups. During exercise, dyspnea, IND and V̇ E / V̇ CO 2 were higher at equivalent work rates (WR) in the DL CO CO CO CO E / V̇ CO 2 at a given work rate. Higher ventilatory requirements in the DL CO

There is well established evidence that the minute ventilation ( V ' E )/carbon dioxide output ( V ' CO 2 ) relationship is relevant to a number of patient-related outcomes in COPD. In most circumstances, an increased V ' E / V ' CO 2 reflects an enlarged physiological dead space ("wasted" ventilation), although alveolar hyperventilation (largely due to increased chemosensitivity) may play an adjunct role, particularly in patients with coexistent cardiovascular disease. The V ' E / V ' CO 2 nadir, in particular, has been found to be an important predictor of dyspnoea and poor exercise tolerance, even in patients with largely preserved forced expiratory volume in 1 s. As the disease progresses, a high nadir might help to unravel the cause of disproportionate breathlessness. When analysed in association with measurements of dynamic inspiratory constraints, a high V ' E / V ' CO 2 is valuable to ascertain a role for the "lungs" in limiting dyspnoeic patients. Regardless of disease severity, cardiocirculatory (heart failure and pulmonary hypertension) and respiratory (lung fibrosis) comorbidities can further increase V ' E / V ' CO 2 A high V ' E / V ' CO 2 is a predictor of poor outcome in lung resection surgery, adding value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of disease severity. Considering its potential usefulness, the V ' E / V ' CO 2 should be valued in the clinical management of patients with COPD., Competing Interests: Conflict of interest: J.A. Neder has nothing to disclose. Conflict of interest: D.C. Berton has nothing to disclose. Conflict of interest: D.B. Philips has nothing to disclose. Conflict of interest: D.E. O'Donnell has nothing to disclose., (Copyright ©ERS 2021.)

Background and Objective: The combination of both reduced resting diffusing capacity of the lung for carbon monoxide (DL CO ) and ventilatory efficiency (increased ventilatory requirement for CO 2 clearance [V˙ E /V˙CO 2 ]) has been linked to exertional dyspnoea and exercise intolerance in chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are poorly understood. The current study examined if low resting DL CO and higher exercise ventilatory requirements were associated with earlier critical dynamic mechanical constraints, dyspnoea and exercise limitation in patients with mild COPD., Methods: In this retrospective analysis, we compared V˙ E /V˙CO 2 , dynamic inspiratory reserve volume (IRV), dyspnoea and exercise capacity in groups of patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 COPD with (1) a resting DL CO at or greater than the lower limit of normal (≥LLN; Global Lung Function Initiative reference equations [n = 44]) or (2) below the E /V˙CO 2 (nadir and slope) was consistently higher in the DL CO  < LLN compared with the other groups (all p < 0.05). The DL CO  < LLN group had lower IRV and greater dyspnoea intensity at standardized submaximal work rates and lower peak work rate and oxygen uptake than the other two groups (all p < 0.05)., Conclusion: Reduced exercise capacity in patients with DL CO  < LLN was related to higher ventilatory requirements, a faster rate of decline in dynamic IRV and greater dyspnoea during exercise. These simple measurements should be considered for the clinical evaluation of unexplained exercise intolerance in individuals with ostensibly mild COPD., (© 2021 Asian Pacific Society of Respirology.)

During submaximal exercise, minute ventilation ( V' E ) increases in proportion to metabolic rate ( i.e. carbon dioxide production ( V' CO 2 )) to maintain arterial blood gas homeostasis. The ratio V' E / V' CO 2 , commonly termed ventilatory efficiency, is a useful tool to evaluate exercise responses in healthy individuals and patients with chronic disease. Emerging research has shown abnormal ventilatory responses to exercise (either elevated or blunted V' E / V' CO 2 ) in some chronic respiratory and cardiovascular conditions. This review will briefly provide an overview of the physiology of ventilatory efficiency, before describing the ventilatory responses to exercise in healthy trained endurance athletes, patients with asthma, and patients with obesity. During submaximal exercise, the V' E / V' CO 2 response is generally normal in endurance-trained individuals, patients with asthma and patients with obesity. However, in endurance-trained individuals, asthmatics who demonstrate exercise induced-bronchoconstriction, and morbidly obese individuals, the V' E / V' CO 2 can be blunted at maximal exercise, likely because of mechanical ventilatory constraint., Competing Interests: Conflict of interest: S.É. Collins has nothing to disclose. Conflict of interest: D.B. Phillips has nothing to disclose. Conflict of interest: A.R. Brotto has nothing to disclose. Conflict of interest: Z.H. Rampuri has nothing to disclose. Conflict of interest: M.S. Stickland has nothing to disclose., (Copyright ©ERS 2021.)

When light propagates through opaque material, the spatial information it holds becomes scrambled, but not necessarily lost. Two classes of techniques have emerged to recover this information: methods relying on optical memory effects, and transmission matrix (TM) approaches. Here we develop a general framework describing the nature of memory effects in structures of arbitrary geometry. We show how this framework, when combined with wavefront shaping driven by feedback from a guide-star, enables estimation of the TM of any such system. This highlights that guide-star assisted imaging is possible regardless of the type of memory effect a scatterer exhibits. We apply this concept to multimode fibres (MMFs) and identify a 'quasi-radial' memory effect. This allows the TM of an MMF to be approximated from only one end - an important step for micro-endoscopy. Our work broadens the applications of memory effects to a range of novel imaging and optical communication scenarios.

Purpose: Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure., Methods: Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiO 2  = 0.21) and hyperoxia (FiO 2  = 1.0) to decrease MSNA burst frequency. MSNA burst sequences (i.e. singlets, doublets, triplets and quadruplets) were identified and coupled to changes in diastolic pressure over 15 cardiac cycles as an index of sNVT. sNVT slope for each individual was calculated from the slope of the relationship between peak responses in outcome plotted against normalized burst amplitude., Results: sNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.] -1 vs. hyperoxia 0.0029 ± 0.00098 Δ mmHg total activity [a.u.] -1 ; p = 0.14). sNVT slope was inversely associated with burst frequency during hyperoxia (r = -0.58; p = 0.04), but not normoxia (r = -0.11; p = 0.71). sNVT slope was inversely associated with the apnea-hypopnea index (AHI) (r = -0.62; p = 0.030), but not after age was considered., Conclusions: We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

The measurement of the optical transmission matrix (TM) of an opaque material is an advanced form of space-variant aberration correction. Beyond imaging, TM-based methods are emerging in a range of fields, including optical communications, micro-manipulation, and computing. In many cases, the TM is very sensitive to perturbations in the configuration of the scattering medium it represents. Therefore, applications often require an up-to-the-minute characterisation of the fragile TM, typically entailing hundreds to thousands of probe measurements. Here, we explore how these measurement requirements can be relaxed using the framework of compressive sensing, in which the incorporation of prior information enables accurate estimation from fewer measurements than the dimensionality of the TM we aim to reconstruct. Examples of such priors include knowledge of a memory effect linking the input and output fields, an approximate model of the optical system, or a recent but degraded TM measurement. We demonstrate this concept by reconstructing the full-size TM of a multimode fibre supporting 754 modes at compression ratios down to ∼5% with good fidelity. We show that in this case, imaging is still possible using TMs reconstructed at compression ratios down to ∼1% (eight probe measurements). This compressive TM sampling strategy is quite general and may be applied to a variety of other scattering samples, including diffusers, thin layers of tissue, fibre optics of any refractive profile, and reflections from opaque walls. These approaches offer a route towards the measurement of high-dimensional TMs either quickly or with access to limited numbers of measurements.

Several shortcomings on cardiopulmonary exercise testing (CPET) interpretation have shed a negative light on the test as a clinically useful tool. For instance, the reader should recognize patterns of dysfunction based on clusters of variables rather than relying on rigid interpretative algorithms. Correct display of key graphical data is of foremost relevance: prolixity and redundancy should be avoided. Submaximal dyspnea ratings should be plotted as a function of work rate (WR) and ventilatory demand. Increased work of breathing and/or obesity may normalize peak oxygen uptake (V̇O 2 ) despite a low peak WR. Among the determinants of V̇O 2 , only heart rate is measured during non-invasive CPET. It follows that in the absence of findings suggestive of severe impairment in O 2 delivery, the boundaries between inactivity and early cardiovascular disease are blurred in individual subjects. A preserved breathing reserve should not be viewed as evidence that "the lungs" are not limiting the subject. In this context, measurements of dynamic inspiratory capacity are key to uncover abnormalities germane to exertional dyspnea. A low end-tidal partial pressure for carbon dioxide may indicate either increased "wasted" ventilation or alveolar hyperventilation; thus, direct measurements of arterial (or arterialized) PO 2 might be warranted. Differentiating a chaotic breathing pattern from the normal breath-by-breath noise might be complex if the plotted data are not adequately smoothed. A sober recognition of these limitations, associated with an interpretation report free from technicalities and convoluted terminology, is crucial to enhance the credibility of CPET in the eyes of the practicing physician., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neder, Phillips, Marillier, Bernard, Berton and O’Donnell.)

Key Points: Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO 2 production ( V ̇ E / V ̇ C O 2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD. The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V ̇ E / V ̇ C O 2 , dyspnoea and exercise capacity in patients with mild COPD. Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V ̇ E / V ̇ C O 2 and dyspnoea. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD., Abstract: Patients with mild chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to dyspnoea and exercise intolerance. Previous research in mild COPD has demonstrated an elevated ventilatory equivalent to CO 2 production ( V ̇ E / V ̇ C O 2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. The present study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower V ̇ E / V ̇ C O 2 and dyspnoea, and improve exercise capacity in patients with mild COPD. In this multigroup randomized-control cross-over study, 15 patients with mild COPD (FEV 1  =   89 ± 11% predicted) and 15 healthy controls completed symptom-limited cardiopulmonary exercise tests while breathing normoxic gas or 40 ppm iNO. Compared with placebo, iNO significantly increased peak oxygen uptake (1.80 ± 0.14 vs. 1.53 ± 0.10 L·min -1 , P < 0.001) in COPD, whereas no effect was observed in controls. At an equivalent work rate of 60 W, iNO reduced V ̇ E / V ̇ C O 2 by 3.8 ± 4.2 units (P = 0.002) and dyspnoea by 1.1 ± 1.2 Borg units (P < 0.001) in COPD, whereas no effect was observed in controls. Operating lung volumes and oxygen saturation were unaffected by iNO in both groups. iNO increased peak oxygen uptake in COPD, secondary to reduced V ̇ E / V ̇ C O 2 and dyspnoea. These data suggest that mild COPD patients demonstrate pulmonary microvascular dysfunction that contributes to increased V ̇ E / V ̇ C O 2 , dyspnoea and exercise intolerance. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Background: The purpose of this study was to determine if altered central chemoreceptor characteristics contributed to the elevated ventilation relative to carbon dioxide production (V̇ E /V̇CO 2 ) response during exercise in mild chronic obstructive pulmonary disease (COPD)., Methods: Twenty-nine mild COPD and 19 healthy age-matched control participants undertook lung function testing followed by symptom-limited incremental cardiopulmonary exercise testing . On a separate day, basal (non-chemoreflex) ventilation (V̇ EB ), the central chemoreflex ventilatory recruitment threshold for CO 2 (VRTCO 2 ), and central chemoreflex sensitivity (V̇ ES ) were assessed using the modified Duffin's CO 2 rebreathing method. Resting arterialized blood gas data were also obtained., Results: At standardized exercise intensities, absolute V̇ E and V̇ E /V̇CO 2 were consistently elevated and the end-tidal partial pressure of CO 2 was relatively decreased in mild COPD versus controls (all p < 0.05). There were no between-group differences in resting arterialized blood gas parameters, basal V̇ E , VRTCO 2 , or V̇ ES (all p > 0.05)., Conclusion: These data have established that excessive exercise ventilation in mild COPD is not explained by altered central chemosensitivity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: COPD is associated with nighttime respiratory symptoms, poor sleep quality, and increased risk of nocturnal death. Overnight deterioration of inspiratory capacity (IC) and FEV 1 have been documented previously. However, the precise nature of this deterioration and mechanisms by which evening bronchodilation may mitigate this occurrence have not been studied., Research Question: What is the effect of evening dosing of dual, long-acting bronchodilation on detailed nocturnal respiratory mechanics and inspiratory neural drive (IND)?, Study Design and Methods: A double-blind, randomized, placebo-controlled crossover study assessed the effects of evening long-acting bronchodilation (aclidinium bromide/formoterol fumarate dihydrate: 400/12 μg) or placebo on morning trough IC (12 h after the dose; primary outcome) and serial overnight measurements of spirometry, dynamic respiratory mechanics, and IND (secondary outcomes). Twenty participants with COPD (moderate/severe airway obstruction and lung hyperinflation) underwent serial measurements of IC, spirometry, breathing pattern, esophageal and transdiaphragmatic pressures, and diaphragm electromyography (diaphragmatic electromyography as a percentage of maximum; IND) at 6 time points from 0 to 12 h after the dose and compared with sleeping IND., Results: Compared with placebo, evening bronchodilation was not associated with increased morning trough IC 12 h after the dose (P = .48); however, nadir IC (lowest IC, independent of time), peak IC, area under the curve for 12 h after the dose, and IC for 10 h after the dose were improved (P < .05). During placebo, total airways resistance, lung hyperinflation, IND, and tidal esophageal and transdiaphragmatic pressure swings all increased significantly overnight compared with baseline evening values; however, each of these parameters improved with bronchodilator treatment (P < .05) with no change in ventilation or breathing pattern., Interpretation: Respiratory mechanics significantly deteriorated at night during placebo. Although the morning trough IC was unchanged, evening bronchodilator treatment was associated consistently with sustained overnight improvements in dynamic respiratory mechanics and inspiratory neural drive compared with placebo CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02429765., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The spatial information carried by light is scrambled when it propagates through a scattering medium, such as frosted glass, biological tissue, turbulent air, or multimode optical fibres. Digital optical phase conjugation (DOPC) is a technique that 'pre-aberrates' an illuminating wavefront to compensate for scatterer induced distortion. DOPC systems act as phase-conjugate mirrors: they require a camera to holographically record a distorted wavefront emanating from the scatterer and a spatial light modulator (SLM) to synthesize a phase conjugate of the measured wavefront, which is sent back through the scatterer thus creating a time-reversed copy of the original optical field. High-fidelity DOPC can be technically challenging to achieve as it typically requires pixel-perfect alignment between the camera and SLM. Here we describe a DOPC system in which the normally stringent alignment criteria are relaxed. In our system the SLM and camera are placed in-line in the same optical path from the sample, and the SLM is used in an off-axis configuration. This means high-precision alignment can be achieved by measurement of the transmission matrix (TM) mapping optical fields from the SLM to the camera and vice-versa, irrespective of their relative position. The TM also absorbs and removes other aberrations in the optical system, such as the curvature of the SLM and camera chips. Using our system we demonstrate high-fidelity focussing of light through two ground glass diffusers with a peak-intensity to mean-background ratio of ∼700. We provide a step-by-step guide detailing how to align this system and discuss the trade-offs with alternative configurations. We also describe how our setup can be used as a 'single-pixel camera' based DOPC system, offering potential for DOPC at wavelengths in which cameras are not available or are prohibitively expensive.

Background: Exertional dyspnea in interstitial lung disease (ILD) remains difficult to manage despite advances in disease-targeted therapies. Pulmonary opioid receptors present a potential therapeutic target for nebulized fentanyl to provide dyspnea relief., Methods: ILD patients were characterized with reference to healthy volunteers. A randomized, double-blind, placebo-controlled crossover comparison of 100 mcg nebulized fentanyl vs placebo on dyspnea intensity and inspiratory neural drive (IND) during constant work rate (CWR) cycle exercise was performed in 21 ILD patients., Results: Dyspnea intensity in ILD increased in association with an increase in IND (diaphragm activation) from a high resting value of 16.66 ± 6.52 %-60.04 ± 12.52 % of maximum (r = 0.798, p < 0.001). At isotime during CWR exercise, Borg dyspnea intensity ratings with fentanyl vs placebo were 4.1 ± 1.2 vs 3.8 ± 1.2, respectively (p = 0.174), and IND responses were also similar., Conclusion: IND rose sharply during constant work rate exercise in association with dyspnea intensity in mild to moderate ILD but was not different after nebulized fentanyl compared with placebo., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The thin and flexible nature of optical fibres often makes them the ideal technology to view biological processes in-vivo, but current microendoscopic approaches are limited in spatial resolution. Here, we demonstrate a route to high resolution microendoscopy using a multicore fibre (MCF) with an adiabatic multimode-to-single-mode "photonic lantern" transition formed at the distal end by tapering. We show that distinct multimode patterns of light can be projected from the output of the lantern by individually exciting the single-mode MCF cores, and that these patterns are highly stable to fibre movement. This capability is then exploited to demonstrate a form of single-pixel imaging, where a single pixel detector is used to detect the fraction of light transmitted through the object for each multimode pattern. A custom computational imaging algorithm we call SARA-COIL is used to reconstruct the object using only the pre-measured multimode patterns themselves and the detector signals.

Introduction: We evaluated the safety and feasibility of high-intensity interval training via a novel telemedicine ergometer (MedBIKE™) in children with Fontan physiology., Methods: The MedBIKE™ is a custom telemedicine ergometer, incorporating a video game platform and live feed of patient video/audio, electrocardiography, pulse oximetry, and power output, for remote medical supervision and modulation of work. There were three study phases: (I) exercise workload comparison between the MedBIKE™ and a standard cardiopulmonary exercise ergometer in 10 healthy adults. (II) In-hospital safety, feasibility, and user experience (via questionnaire) assessment of a MedBIKE™ high-intensity interval training protocol in children with Fontan physiology. (III) Eight-week home-based high-intensity interval trial programme in two participants with Fontan physiology., Results: There was good agreement in oxygen consumption during graded exercise at matched work rates between the cardiopulmonary exercise ergometer and MedBIKE™ (1.1 ± 0.5 L/minute versus 1.1 ± 0.5 L/minute, p = 0.44). Ten youth with Fontan physiology (11.5 ± 1.8 years old) completed a MedBIKE™ high-intensity interval training session with no adverse events. The participants found the MedBIKE™ to be enjoyable and easy to navigate. In two participants, the 8-week home-based protocol was tolerated well with completion of 23/24 (96%) and 24/24 (100%) of sessions, respectively, and no adverse events across the 47 sessions in total., Conclusion: The MedBIKE™ resulted in similar physiological responses as compared to a cardiopulmonary exercise test ergometer and the high-intensity interval training protocol was safe, feasible, and enjoyable in youth with Fontan physiology. A randomised-controlled trial of a home-based high-intensity interval training exercise intervention using the MedBIKE™ will next be undertaken.

Assessment of the ventilatory response to exercise is important in evaluating mechanisms of dyspnea and exercise intolerance in chronic cardiopulmonary diseases. The characteristic mechanical derangements that occur during exercise in chronic respiratory conditions have previously been determined in seminal studies using esophageal catheter pressure-derived measurements. In this brief review, we examine the emerging role and clinical utility of conventional assessment of dynamic respiratory mechanics during exercise testing. Thus, we provide a physiologic rationale for measuring operating lung volumes, breathing pattern, and flow-volume loops during exercise. We consider standardization of inspiratory capacity-derived measurements and their practical implementation in clinical laboratories. We examine the evidence that this iterative approach allows greater refinement in evaluation of ventilatory limitation during exercise than traditional assessments of breathing reserve. We appraise the available data on the reproducibility and responsiveness of this methodology. In particular, we review inspiratory capacity measurement and derived operating lung volumes during exercise. We demonstrate, using recent published data, how systematic evaluation of dynamic mechanical constraints, together with breathing pattern analysis, can provide valuable insights into the nature and extent of physiological impairment contributing to exercise intolerance in individuals with common chronic obstructive and restrictive respiratory disorders., (Copyright © 2020 Milne, Domnik, Phillips, James, Vincent, Neder and O'Donnell.)

The majority of smokers with chronic obstructive pulmonary disease (COPD) have mild airflow limitation as determined by simple spirometry. Although small airway dysfunction is the hallmark of COPD, many studies attest to complex heterogeneous physiological impairments beyond increased airway resistance. These impairments are related to inflammation of lung parenchyma and its microvasculature, which is obscured by simple spirometry. Recent studies using advanced radiological imaging have highlighted significant structural abnormalities in smokers with relatively preserved spirometry. These important studies have generated considerable interest and have reinforced the pressing need to better understand the physiological consequences of various morphological abnormalities, and their impact on the clinical outcomes and natural history of COPD. The overarching objective of this review is to provide a concise overview of the importance and utility of cardiopulmonary exercise testing (CPET) in clinical and research settings. CPET uniquely allows evaluation of integrated abnormalities of the respiratory, cardio-circulatory, metabolic, peripheral muscle and neurosensory systems during increases in physiologic stress. This brief review examines the results of recent studies in mild COPD that have uncovered consistent derangements in pulmonary gas exchange and development of "restrictive" dynamic mechanics that together contribute to exercise intolerance. We examine the evidence that compensatory increases in inspiratory neural drive from respiratory control centers are required during exercise in mild COPD to maintain ventilation commensurate with increasing metabolic demand. The ultimate clinical consequences of this high inspiratory neural drive are earlier onset of critical respiratory mechanical constraints and increased perceived respiratory discomfort at relatively low exercise intensities., (Copyright © 2020 James, Milne, Phillips, Neder and O'Donnell.)

Cardiopulmonary exercise testing (CPET) is a method for evaluating pulmonary and cardiocirculatory abnormalities, dyspnea, and exercise tolerance in healthy individuals and patients with chronic conditions. During exercise, ventilation ( V˙ E ) increases in proportion to metabolic demand [i.e., carbon dioxide production ( V˙ CO 2 )] to maintain arterial blood gas and acid-base balance. The response of V˙ E relative to V˙ CO 2 ( V˙ E / V˙ CO 2 ) is commonly termed ventilatory efficiency and is becoming a common physiological tool, in conjunction with other key variables such as operating lung volumes, to evaluate exercise responses in patients with chronic conditions. A growing body of research has shown that the V˙ E / V˙ CO 2 response to exercise is elevated in conditions such as chronic heart failure (CHF), pulmonary hypertension (PH), interstitial lung disease (ILD), and chronic obstructive pulmonary disease (COPD). Importantly, this potentiated V˙ E / V˙ CO 2 response contributes to dyspnea and exercise intolerance. The clinical significance of ventilatory inefficiency is demonstrated by findings showing that the elevated V˙ E / V˙ CO 2 response to exercise is an independent predictor of mortality in patients with CHF, PH, and COPD. In this article, the underlying physiology, measurement, and interpretation of exercise ventilatory efficiency during CPET are reviewed. Additionally, exercise ventilatory efficiency in varying disease states is briefly discussed., (Copyright © 2020 Phillips, Collins and Stickland.)

Patients with mild chronic obstructive pulmonary disease (COPD) demonstrate resting pulmonary vascular dysfunction as well as a blunted pulmonary diffusing capacity (DLCO) and pulmonary capillary blood volume (V C ) response to exercise. The transition from the upright to supine position increases central blood volume and perfusion pressure, which may overcome microvascular dysfunction in an otherwise intact alveolar-capillary interface. The present study examined whether the supine position normalized DLCO and V C responses to exercise in mild COPD. Sixteen mild COPD participants and 13 age-, gender-, and height-matched controls completed DLCO maneuvers at rest and during exercise in the upright and supine position. The multiple FI O 2 -DLCO method was used to determine DLCO, V C , and membrane diffusion capacity (D M ). All three variables were adjusted for alveolar volume (DLCOAdj, V C Adj, and D M Adj). The supine position reduced alveolar volume similarly in both groups, but oxygen consumption and cardiac output were unaffected. DLCOAdj, D M Adj, and V C Adj were all lower in COPD. These same variables all increased with upright and supine exercise in both groups. DLCOAdj was unaffected by the supine position. V C Adj increased in the supine position similarly in both groups. D M Adj was reduced in the supine position in both groups. While the supine position increased exercise V C Adj in COPD, the increase was of similar magnitude to healthy controls; therefore, exercise V C remained blunted in COPD. The persistent reduction in exercise DLCO and V C when supine suggests that pulmonary vascular destruction is a contributing factor to the blunted DLCO and V C response to exercise in mild COPD. NEW & NOTEWORTHY Patients with mild chronic obstructive pulmonary disease demonstrate a combination of reversible pulmonary microvascular dysfunction and irreversible pulmonary microvascular destruction.

Purpose: Chronic heart failure (CHF) is characterized by heightened sympathetic nervous activity, carotid chemoreceptor (CC) sensitivity, marked exercise intolerance and an exaggerated ventilatory response to exercise. The purpose of this study was to determine the effect of CC inhibition on exercise cardiovascular and ventilatory function, and exercise tolerance in health and CHF., Methods: Twelve clinically stable, optimally treated patients with CHF (mean ejection fraction: 43 ± 2.5%) and 12 age- and sex-matched healthy controls were recruited. Participants completed two time-to-symptom-limitation (TLIM) constant load cycling exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 μg⋅kg -1 ⋅min -1 ; order randomized). Ventilation was measured using expired gas data and operating lung volume data were determined during exercise by inspiratory capacity maneuvers. Cardiac output was estimated using impedance cardiography, and vascular conductance was calculated as cardiac output/mean arterial pressure., Results: There was no change in TLIM in either group with dopamine (CHF: saline 13.1 ± 2.4 vs. dopamine 13.5 ± 1.6 min, p = 0.78; Control: saline 10.3 ± 1.2 vs. dopamine 11.5 ± 1.3 min, p = 0.16). In CHF patients, dopamine increased cardiac output ( p = 0.03), vascular conductance ( p = 0.01) and oxygen delivery ( p = 0.04) at TLIM, while ventilatory parameters were unaffected ( p = 0.76). In controls, dopamine improved vascular conductance at TLIM ( p = 0.03), but no other effects were observed., Conclusion: Our findings suggest that the CC contributes to cardiovascular regulation during full-body exercise in patients with CHF, however, CC inhibition does not improve exercise tolerance., (Copyright © 2020 Collins, Phillips, McMurtry, Bryan, Paterson, Wong, Ezekowitz, Forhan and Stickland.)

Background: Patients with chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to exertional dyspnea and exercise intolerance. We recently demonstrated enhanced activity and sensitivity of the carotid chemoreceptor (CC) in COPD which may alter ventilatory and cardiovascular regulation and negatively affect exercise tolerance. We sought to determine whether CC inhibition improves ventilatory and cardiovascular regulation, dyspnea and exercise tolerance in COPD., Methods: Twelve mild-moderate COPD patients (FEV 1 83 ± 15 %predicted) and twelve age- and sex-matched healthy controls completed two time-to-symptom limitation (T LIM ) constant load exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 μg·kg -1 ·min -1 , order randomized) to inhibit the CC. Ventilatory responses were evaluated using expired gas data and dyspnea was evaluated using a modified Borg scale. Inspiratory capacity maneuvers were performed to determine operating lung volumes. Cardiac output was estimated using impedance cardiography and vascular conductance was calculated as cardiac output/mean arterial pressure (MAP)., Results: At a standardized exercise time of 4-min and at T LIM ; ventilation, operating volumes and dyspnea were unaffected by dopamine in COPD patients and controls. In COPD, dopamine decreased MAP and increased vascular conductance at all time points. In controls, dopamine increased vascular conductance at T LIM , while MAP was unaffected., Conclusion: There was no change in time to exhaustion in either group with dopamine. These data suggest that the CC plays a role in cardiovascular regulation during exercise in COPD; however, ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in COPD patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Single-pixel cameras reconstruct images from a stream of spatial projection measurements recorded with a single-element detector, which itself has no spatial resolution. This enables the creation of imaging systems that can take advantage of the ultra-fast response times of single-element detectors. Here we present a single-pixel camera with a temporal resolution of 200 ps in the visible and short-wave infrared wavelengths, used here to study the transit time of distinct spatial modes transmitted through few-mode and orbital angular momentum mode conserving optical fiber. Our technique represents a way to study the spatial and temporal characteristics of light propagation in multimode optical fibers, which may find use in optical fiber design and communications.

Optical tweezers are a highly versatile tool for exploration of the mesoscopic world, permitting non-contact manipulation of nanoscale objects. However, direct illumination with intense lasers restricts their use with live biological specimens, and limits the types of materials that can be trapped. Here we demonstrate an indirect optical trapping platform which circumvents these limitations by using hydrodynamic forces to exert nanoscale-precision control over aqueous particles, without directly illuminating them. Our concept is based on optically actuated micro-robotics: closed-loop control enables highly localised flow-fields to be sculpted by precisely piloting the motion of optically-trapped micro-rotors. We demonstrate 2D trapping of absorbing particles which cannot be directly optically trapped, stabilise the position and orientation of yeast cells, and demonstrate independent control over multiple objects simultaneously. Our work expands the capabilities of optical tweezers platforms, and represents a new paradigm for manipulation of aqueous mesoscopic systems.

Purpose and Methods: To compare the effects of thoracic load carriage on the ventilatory and perceptual responses to graded exercise, 14 pairs of height-matched, physically active males and females completed randomly ordered modified Balke treadmill exercise tests with and without a correctly sized and fitted 20.4 kg backpack and work clothing. Subjects walked at 1.56 m.s - 1 while grade was increased by 2% every 2 min until exhaustion. Ventilatory responses were measured with open circuit spirometry and perceptual responses were evaluated using the modified Borg scale. Inspiratory capacity maneuvers were performed to calculate operating lung volumes., Results: Despite height matching, males had significantly greater lung volumes and peak oxygen uptake ([Formula: see text]O 2peak ). Peak [Formula: see text]O 2 and ventilation ([Formula: see text] E ) were lower (p < 0.05) for all subjects under load. Throughout exercise, the ventilatory equivalents for [Formula: see text]O 2 and carbon dioxide production were significantly higher in females, independent of condition. At similar relative submaximal intensities (%[Formula: see text]O 2peak ), there was no difference in [Formula: see text] E between conditions in either group, however, all subjects adopted a rapid and shallow breathing pattern under load with decreased tidal volume secondary to lower end-inspiratory lung volume. The relative changes in breathing pattern and operating lung volume between unloaded and loaded conditions were similar between males and females. Females reported significantly higher dyspnea ratings for a given [Formula: see text] E compared to males; however, the relationship between dyspnea and [Formula: see text] E was unaffected by load carriage., Conclusion: The relative response patterns for ventilatory and perceptual responses to graded exercise with thoracic loading were similar in males and females.

Background: Previous work suggests that mild chronic obstructive pulmonary disease (COPD) patients have greater lung dysfunction than previously appreciated from spirometry alone. There is evidence of pulmonary microvascular dysfunction in mild COPD, which may reduce diffusing capacity (DLCO) and increase ventilatory inefficiency during exercise. The purpose of this study was to determine if DLCO, pulmonary capillary blood volume (Vc), and membrane diffusing capacity (Dm) are diminished during exercise in mild COPD, and whether this is related to ventilatory inefficiency and dyspnea., Methods: Seventeen mild COPD patients (FEV 1 /FVC: 64 ± 4%, FEV 1  = 94 ± 11% pred ) and 17 age- and sex-matched controls were recruited. Ten moderate COPD patients were also tested for comparison (FEV 1  = 66 ± 7% pred ). DLCO, Vc, and Dm were determined using the multiple-fraction of inspired oxygen (F I O 2 ) DLCO method at baseline and during steady-state cycle exercise at 40W, 50%, and 80% of V˙O 2peak . Using expired gas data, ventilatory inefficiency was assessed by V˙ E /V˙CO 2 ., Results: Compared to controls, mild COPD had lower DLCO at baseline and during exercise secondary to diminished Vc (P < 0.05). No difference in Dm was observed between controls and mild COPD at rest or during exercise. Patients with high V˙ E /V˙CO 2 (i.e. ≥34) had lower Vc and greater dyspnea ratings compared to control at 40W. Moderate COPD patients were unable to increase Vc with increasing exercise intensity, suggesting further pulmonary vascular impairment with increased obstruction severity., Conclusion: Despite relatively minor airflow obstruction, mild COPD patients exhibit a diminished DLCO and capillary blood volume response to exercise, which appears to contribute to ventilatory inefficiency and greater dyspnea., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Dyspnea has been reported to be a main contributor to exercise avoidance in asthma. While traditional markers of ventilation do not explain the heightened dyspnea during exercise in patients with asthma, this study proposed that exertional dyspnea in asthma was due to high-operating lung volumes, which may be improved with a short-acting β2-agonist. On two separate days, 16 patients with asthma and 16 controls completed a lung function test and incremental exercise tests to exhaustion. On one of the days (order randomized), 400 µg salbutamol was administered before exercise. Inspiratory capacity (IC), inspiratory reserve volume (IRV), and dyspnea (modified Borg scale) were evaluated throughout exercise. Compared with controls, patients with asthma reported greater dyspnea at the same absolute submaximal workloads. Furthermore, patients with asthma demonstrated altered breathing responses to exercise, characterized by reduced IC and IRV throughout exercise compared with controls. The reduced IRV was associated with increased dyspnea in patients with asthma. Salbutamol did not affect dyspnea or operating lung volumes in either group. The increased perception of dyspnea during incremental exercise in patients with asthma appears to be secondary to a reduction in IRV, which is unaffected by an inhaled β2-agonist. NEW & NOTEWORTHY Increased exertional dyspnea in asthma appears to be due to high operating lung volumes and is not affected by salbutamol.

Key Points: The reason(s) for the increased central arterial stiffness in chronic obstructive pulmonary disease (COPD) are not well understood. In this study, we inhibited the carotid chemoreceptor with both low-dose dopamine and hyperoxia, and observed a decrease in central arterial stiffness and muscle sympathetic nervous activity in COPD patients, while no change was observed in age- and risk-matched controls. Carotid chemoreceptor inhibition increased vascular conductance, secondary to reduced arterial blood pressure in COPD patients. Findings from the current study suggest that elevated carotid chemoreceptor activity may contribute to the increased arterial stiffness typically observed in COPD patients., Abstract: Chronic obstructive pulmonary disease (COPD) patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (forced expired volume in 1 s (FEV 1 ) predicted ± SD: 83 ± 18%) and 13 age- and risk-matched controls completed resting CV function measurements with either i.v. saline or i.v. dopamine (2 μg kg -1  min -1 ) while breathing normoxic or hyperoxic air (100% O 2 ). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxic or hyperoxic air. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P < 0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (P < 0.05) in COPD, while no change was observed in controls. CC inhibition decreased PWV and MSNA, and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in COPD., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

The linear Doppler shift is familiar as the rise and fall in pitch of a siren as it passes by. Less well known is the rotational Doppler shift, proportional to the rotation rate between source and receiver, multiplied by the angular momentum carried by the beam. In extreme cases the Doppler shift can be larger than the rest-frame frequency and for a red shift, the observed frequency then becomes "negative." In the linear case, this effect is associated with the time reversal of the received signal, but it can be observed only with supersonic relative motion between the source and receiver. However, the rotational case is different; if the radius of rotation is smaller than the wavelength, then the velocities required to observe negative frequencies are subsonic. Using an acoustic source at [Formula: see text]100 Hz we create a rotational Doppler shift larger than the laboratory-frame frequency. We observe that once the red-shifted wave passes into the "negative frequency" regime, the angular momentum associated with the sound is reversed in sign compared with that of the laboratory frame. These low-velocity laboratory realizations of extreme Doppler shifts have relevance to superoscillatory fields and offer unique opportunities to probe interactions with rotating bodies and aspects of pseudorelativistic frame translation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)