Physiological determinants of decreased peak leg oxygen uptake in chronic disease: a systematic review and meta-analysis.

This systematic review and meta-analysis examined the physiological mechanisms responsible for lower peak exercise leg oxygen uptake (V̇o2) in patients with chronic disease. Studies measuring peak leg V̇o2 (primary outcome) and its physiological determinants during large (cycle) or small muscle mass exercise (single-leg knee extension, SLKE) in patients with chronic disease were included in this meta-analysis. Pooled estimates for each outcome were reported as a weighted mean difference (WMD) between chronic disease and controls. We included 10 studies that measured peak leg V̇o2 in patients with chronic disease (n = 109, mean age: 45 yr; encompassing chronic obstructive pulmonary disease, COPD, heart failure with reduced ejection fraction, HFrEF, or chronic renal failure, RF) and age-matched controls (n = 88). In pooled analysis, peak leg V̇o2 (WMD; -0.23 L/min, 95% CI: -0.32 to -0.13), leg oxygen (O2) delivery (WMD: -0.27 L/min, 95% CI: -0.37 to -0.17), and muscle O2 diffusive conductance (WMD: -5.2 mL/min/mmHg, 95% CI: -7.1 to -3.2) were all significantly lower during cycle and SLKE exercise in chronic disease versus controls. These results highlight that during large and small muscle mass exercise in patients with COPD, HFrEF, or RF, there is no single factor causing peak V̇o2 limitations. Specifically, the lower peak V̇o2 in these pathologies is due to not only the expected impairments in convective O2 delivery but also impairments in muscle oxygen diffusive transport from capillary to mitochondria. Whether impaired muscle O2 transport is caused solely by inactivity or additional muscle pathology remains in question.NEW & NOTEWORTHY Peripheral (skeletal muscle and vasculature) factors contribute significantly to reduced exercise capacity during both large and small muscle mass exercise in chronic diseases such as COPD, HFrEF, or RF and should be important targets of therapy in addition to the primary organs (lungs, heart, and kidneys) affected by disease.

Endurance exercise training changes the limitation on muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ in normoxia from the capacity to utilize O2 to the capacity to transport O2.

Maximal oxygen (O2 ) uptake ( V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ ) is an important parameter with utility in health and disease. However, the relative importance of O2 transport and utilization capacities in limiting muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ before and after endurance exercise training is not well understood. Therefore, the present study aimed to identify the mechanisms determining muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ pre- and post-endurance exercise training in initially sedentary participants. In five initially sedentary young males, radial arterial and femoral venous P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ (blood samples), leg blood flow (thermodilution), and myoglobin (Mb) desaturation (1 H nuclear magnetic resonance spectroscopy) were measured during maximal single-leg knee-extensor exercise (KE) breathing either 12%, 21% or 100% O2 both pre and post 8 weeks of KE training (1 h, 3 times per week). Mb desaturation was converted to intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ using an O2  half-saturation pressure of 3.2 mmHg. Pre-training muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ was not significantly different across inspired O2 conditions (12%: 0.47 ± 0.10; 21%: 0.52 ± 0.13; 100%: 0.54 ± 0.01 L min-1 , all q > 0.174), despite significantly greater muscle mean capillary-intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ gradients in normoxia (34 ± 3 mmHg) and hyperoxia (40 ± 7 mmHg) than hypoxia (29 ± 5 mmHg, both q < 0.024). Post-training muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ was significantly different across all inspired O2 conditions (12%: 0.59 ± 0.11; 21%: 0.68 ± 0.11; 100%: 0.76 ± 0.09 mmHg, all q < 0.035), as were the muscle mean capillary-intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ gradients (12%: 32 ± 2; 21%: 37 ± 2; 100%: 45 ± 7 mmHg, all q < 0.029). In these initially sedentary participants, endurance exercise training changed the basis of limitation on muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ in normoxia from the mitochondrial capacity to utilize O2 to the capacity to transport O2 to the mitochondria. KEY POINTS: Maximal O2 uptake is an important parameter with utility in health and disease. The relative importance of O2 transport and utilization capacities in limiting muscle maximal O2 uptake before and after endurance exercise training is not well understood. We combined the direct measurement of active muscle maximal O2 uptake with the measurement of muscle intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ before and after 8 weeks of endurance exercise training. We show that increasing O2 availability did not increase muscle maximal O2 uptake before training, whereas increasing O2 availability did increase muscle maximal O2 uptake after training. The results suggest that, in these initially sedentary participants, endurance exercise training changed the basis of limitation on muscle maximal O2 uptake in normoxia from the mitochondrial capacity to utilize O2 to the capacity to transport O2 to the mitochondria.

Increased intrapulmonary shunt and alveolar dead space post-COVID-19.

Increased intrapulmonary shunt (QS/Qt) and alveolar dead space (VD/VT) are present in early recovery from 2019 Novel Coronavirus (COVID-19). We hypothesized patients recovering from severe critical acute illness (NIH category 3-5) would have greater and longer lasting increased QS/Qt and VD/VT than patients with mild-moderate acute illness (NIH 1-2). Fifty-nine unvaccinated patients (33 males, aged 52 [38-61] yr, body mass index [BMI] 28.8 [25.3-33.6] kg/m2; median [IQR], 44 previous mild-moderate COVID-19, and 15 severe-critical disease) were studied 15-403 days postacute severe acute respiratory syndrome coronavirus infection. Breathing ambient air, steady-state mean alveolar Pco2, and Po2 were recorded simultaneously with arterial Po2/Pco2 yielding aAPco2, AaPo2, and from these, QS/Qt%, VD/VT%, and relative alveolar ventilation (40 mmHg/[Formula: see text], VArel) were calculated. Median [Formula: see text] was 39.4 [35.6-41.1] mmHg, [Formula: see text] 92.3 [87.1-98.2] mmHg; [Formula: see text] 32.8 [28.6-35.3] mmHg, [Formula: see text] 112.9 [109.4-117.0] mmHg, AaPo2 18.8 [12.6-26.8] mmHg, aAPco2 5.9 [4.3-8.0] mmHg, QS/Qt 4.3 [2.1-5.9] %, and VD/VT16.6 [12.6-24.4]%. Only 14% of patients had normal QS/Qt and VD/VT; 1% increased QS/Qt but normal VD/VT; 49% normal QS/Qt and elevated VD/VT; 36% both abnormal QS/Qt and VD/VT. Previous severe critical COVID-19 predicted increased QS/Qt (2.69 [0.82-4.57]% per category severity [95% CI], P < 0.01), but not VD/VT. Increasing age weakly predicted increased VD/VT (1.6 [0.1-3.2]% per decade, P < 0.04). Time since infection, BMI, and comorbidities were not predictors (all P > 0.11). VArel was increased in most patients. In our population, recovery from COVID-19 was associated with increased QS/Qt in 37% of patients, increased VD/VT in 86%, and increased alveolar ventilation up to ∼13 mo postinfection. NIH severity predicted QS/Qt but not elevated VD/VT. Increased VD/VT suggests pulmonary microvascular pathology persists post-COVID-19 in most patients.NEW & NOTEWORTHY Using novel methodology quantifying intrapulmonary shunt and alveolar dead space in COVID-19 patients up to 403 days after acute illness, 37% had increased intrapulmonary shunt and 86% had elevated alveolar dead space likely due to independent pathology. Elevated shunt was partially related to severe acute illness, and increased alveolar dead space was weakly related to increasing age. Ventilation was increased in the majority of patients regardless of previous disease severity. These results demonstrate persisting gas exchange abnormalities after recovery.

Blood Gas Transport: Carriage of Oxygen and Carbon Dioxide in Blood.

The ways in which oxygen (O2) and carbon dioxide (CO2) are carried in the blood are well known and well understood, with a plethora of textbooks, both general and lung specific, all presenting the topic in a very similar manner. This first of two companion chapters similarly summarizes this information. First, carriage of gases by physical solution is described, followed by discussion of O2, carbon monoxide, and CO2 transport in that order. However, what available texts have not emphasized is why knowing how gases are carried in blood matters, and the second, companion, chapter specifically addresses that critical aspect of gas exchange physiology. In fact, each of the chapters in this volume describes physiological behavior that depends more or less directly on the dissociation curves of O2 and CO2.

Blood Gas Transport: Implications for O2 and CO2 Exchange in Lungs and Tissues.

The well-known ways in which O2 and CO2 (and other gases) are carried in the blood were presented in the preceding chapter. However, what the many available texts about O2 and CO2 transport do not emphasize is why knowing how gases are carried in blood matters, and this second, companion, article specifically addresses that critical aspect of gas exchange physiology. During gas exchange, both at the lungs and in the peripheral tissues, it is the shapes and the slopes of the O2 and CO2 binding curves that explain almost all of the behaviors of each gas and the quantitative differences observed between them. This conclusion is derived from first principle considerations of the gas exchange processes. Dissociation curve shape and slope differences explain most of the differences between O2 and CO2 in both diffusive exchange in the lungs and tissues and convective exchange/transport in, and between, the lungs and tissues. In fact, each of the chapters in this volume describes physiological behavior that depends more or less directly on the dissociation curves of O2 and CO2.

Combination of hyperoxia and a right-shifted HbO2 dissociation curve delays V̇o2 kinetics during maximal contractions in isolated muscle.

Acute enhancement of peripheral O2 diffusion may accelerate skeletal muscle O2 uptake (V̇o2) kinetics and lessen fatigue during transitions from rest to maximal contractions. Surgically isolated canine gastrocnemius muscles in situ (n = 6) were studied during transitions from rest to 4 min of electrically stimulated isometric tetanic contractions at V̇o2peak, in two conditions: normoxia (CTRL) and hyperoxia ([Formula: see text] = 1.00) + administration of a drug (RSR-13), which right shifts the Hb-O2 dissociation curve (Hyperoxia + RSR-13). Before and during contractions, muscles were pump-perfused with blood at constant elevated flow ([Formula: see text]) and infused with the vasodilator adenosine. Arterial ([Formula: see text]) and muscle venous ([Formula: see text]) O2 concentrations were determined at rest and at 5- to 7-s intervals during contractions; V̇o2 was calculated as [Formula: see text]·([Formula: see text] - [Formula: see text]). Po2 at 50% of Hb saturation (standard P50) and mean microvascular Po2 ([Formula: see text]) were calculated by the Hill equation and a numerical integration technique. P50 [42 ± 7 (means ± SD) mmHg vs. 33 ± 2 mmHg, P = 0.02] and [Formula: see text] (218 ± 73 mmHg vs. 49 ± 4 mmHg, P = 0.003) were higher in Hyperoxia + RSR-13. Muscle force and fatigue were not different in the two conditions. V̇o2 kinetics (monoexponential fitting) were unexpectedly slower in Hyperoxia + RSR-13, due to a longer time delay (TD) [9.9 ± 1.7 s vs. 4.4 ± 2.2 s (P = 0.001)], whereas the time constant (τ) was not different [13.7 ± 4.3 s vs. 12.3 ± 1.9 s (P = 0.37)]; the mean response time (TD + τ) was longer in Hyperoxia + RSR-13 [23.6 ± 3.5 s vs. 16.7 ± 3.2 s (P = 0.003)]. Increased O2 availability deriving, in Hyperoxia + RSR-13, from higher [Formula: see text] and from presumably greater intramuscular O2 stores did not accelerate the primary component of the V̇o2 kinetics, and delayed the metabolic activation of oxidative phosphorylation.NEW & NOTEWORTHY In isolated perfused skeletal muscle, during transitions from rest to V̇o2peak, hyperoxia and a right-shifted oxyhemoglobin dissociation curve increased O2 availability by increasing microvascular Po2 and by presumably increasing intramuscular O2 stores. The interventions did not accelerate the primary component of the V̇o2 kinetics (as calculated from blood O2 unloading) and delayed the metabolic activation of oxidative phosphorylation. V̇o2 kinetics appear to be mainly controlled by intramuscular factors related to the use of high-energy "buffers."

Metabolic Silencing via Methionine-Based Amino Acid Restriction in Head and Neck Cancer.

In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.

Objective Quantification and Topographic Dioptric Demand of Near-Work.

Purpose: The assessment of myopigenic environmental risk factors such as near-work relies on subjective data. Although diaries and questionnaires on near-work show correlation to some degree, it remains unknown how they may correspond to ground truth. This is an important consideration because valid estimates of near-work have great utility for understanding the mechanisms by which dioptric demand drives excessive eye-growth, which is not yet entirely understood. To this end, we assessed a novel eye-tracking system to quantify near-work. Method: We compared subjective entries from diaries to objective data on accommodative demand acquired with a three-dimensional eye-tracker in 20 participants. Each test involved approximately one-hour exposure to ecological near-work environments. Furthermore, topographical dioptric demand maps were computed in retinal coordinates. Results: Our study suggests a frequent mismatch between objectively and subjectively labeled data of near-work tasks (concordance 74.6%). Objective and subjective estimates of dioptric demand showed a moderate correlation and were not significantly different (R2 = 0.59, P = .35). Instead, accommodative demand with an agreement between objective and subjective near-work labels showed a high correlation and were significantly different (R2 = 0.79, P = .016). The accumulated topographical dioptric demand of ecological near-work environments did not present myopigenic defocus stimuli to the retina periphery. Thus extreme close-up near-work presented peripheral defocus stimuli that have been proposed to curb excessive eye growth. Conclusions: The proposed objective measurement method may provide improvements over subjective methods for estimating near-work parameters. Translational Relevance: The topographic dioptric demand maps highlight a possible conflict of causal mechanisms of the two myopia models: "excessive near-work" and "peripheral optical defocus."

Improving population-level refractive error monitoring via mixture distributions.

INTRODUCTION: Sampling and describing the distribution of refractive error in populations is critical to understanding eye care needs, refractive differences between groups and factors affecting refractive development. We investigated the ability of mixture models to describe refractive error distributions. METHODS: We used key informants to identify raw refractive error datasets and a systematic search strategy to identify published binned datasets of community-representative refractive error. Mixture models combine various component distributions via weighting to describe an observed distribution. We modelled raw refractive error data with a single-Gaussian (normal) distribution, mixtures of two to six Gaussian distributions and an additive model of an exponential and Gaussian (ex-Gaussian) distribution. We tested the relative fitting accuracy of each method via Bayesian Information Criterion (BIC) and then compared the ability of selected models to predict the observed prevalence of refractive error across a range of cut-points for both the raw and binned refractive data. RESULTS: We obtained large raw refractive error datasets from the United States and Korea. The ability of our models to fit the data improved significantly from a single-Gaussian to a two-Gaussian-component additive model and then remained stable with ≥3-Gaussian-component mixture models. Means and standard deviations for BIC relative to 1 for the single-Gaussian model, where lower is better, were 0.89 ± 0.05, 0.88 ± 0.06, 0.89 ± 0.06, 0.89 ± 0.06 and 0.90 ± 0.06 for two-, three-, four-, five- and six-Gaussian-component models, respectively, tested across US and Korean raw data grouped by age decade. Means and standard deviations for the difference between observed and model-based estimates of refractive error prevalence across a range of cut-points for the raw data were -3.0% ± 6.3, 0.5% ± 1.9, 0.6% ± 1.5 and -1.8% ± 4.0 for one-, two- and three-Gaussian-component and ex-Gaussian models, respectively. CONCLUSIONS: Mixture models appear able to describe the population distribution of refractive error accurately, offering significant advantages over commonly quoted simple summary statistics such as mean, standard deviation and prevalence.

Preserved peak exercise capacity in Andean highlanders with excessive erythrocytosis both before and after isovolumic hemodilution.

In chronic mountain sickness (CMS), increased blood oxygen (O2)-carrying capacity due to excessive erythrocytosis (EE, [Hb] ≥ 21 g/dL) could be offset, especially during exercise by both impaired cardiac output (Q̇t) and O2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak V̇o2 despite increased blood O2-carrying capacity, and that isovolumic hemodilution (IVHD) improves exercise capacity. In 14 male residents of Cerro de Pasco, Peru (4,340 m), six with and eight without EE, we measured peak cycle-exercise capacity, V̇o2, Q̇t, arterial blood gas parameters, and (resting) blood volume. This was repeated for participants with EE after IVHD, reducing hematocrit by 20% (from 67% to 53%). From these data, we quantified the major O2 transport pathway components (ventilation, pulmonary alveolar-capillary diffusion, Q̇t, and blood-muscle mitochondria diffusion). Participants with EE had similar peak V̇o2, systemic O2 delivery, and O2 extraction as non-EE controls, however, with lower Q̇t and higher arterial [O2]. After IVHD, peak V̇o2 was preserved (but not enhanced), with lower O2 delivery (despite higher Q̇t) balanced by greater O2 extraction. The considerable variance in exercise capacity across the 14 individuals was explained essentially completely by differences in both pulmonary and muscle O2 diffusional conductances and not by any differences in ventilation, [Hb], nor Q̇t. In conclusion, EE does not result in lower peak V̇o2 in Andean males, and IVHD maintains, but does not enhance, exercise capacity.NEW & NOTEWORTHY Male Andean highlanders with and without excessive erythrocytosis (EE) have similar peak V̇o2 at 4,340 m, with higher arterial [O2] in EE and lower cardiac output (Q̇t), thus maintaining similar O2 delivery. Peak V̇o2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O2 delivery balanced by slightly increased Q̇t and greater O2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak V̇o2.

Towards the Reduction of Pt Loading in High Temperature Proton Exchange Membrane Fuel Cells - Effect of Fe-N-C in Pt-Alloy Cathodes.

Pt poisoning by phosphate in high temperature proton exchange membrane fuel cells (HT-PEMFC) leads to loadings up to 1 mgPt cm-2 per electrode of costly materials. While cheaper Fe-N-C catalysts are unaffected by phosphate deactivation and contribute to the catalysis of the oxygen reduction reaction, their volumetric activity is substantially lower. In this study, the effect of Pt-loading reduced hybrid cathodes for HT-PEMFC is investigated using commercial Celtec®-P-based assembling. A promising effect of Fe-N-C incorporation in terms of acid attraction and activity retention is found. A longer activation (230 h, 0.3 A cm-2 ) for the hybrid membrane electrode assembly (MEA) is necessary, due to the slower acid distribution within Fe-N-Cs. This study shows the potential of Pt-content reduction by up to 25 % compared to standard MEA using hybrid electrodes. Moreover, important insights for future strategies of cell activation are revealed for these hybrid MEAs.

Determinants of maximal oxygen consumption.

This article lays out the determinants of maximal O2 consumption (VO2max) achieved during high intensity endurance exercise. It is not a traditional topical review but rather an educational essay that intertwines chance observations made during an unrelated research project with a subsequent program of stepwise thought, analysis and experimentation to reveal how O2 is delivered to and used by the mitochondria. The centerpiece is the recognition that O2 is delivered by an inter-dependent system of transport components functioning as a "bucket brigade", made up of the lungs, heart, blood and circulation, and the muscles themselves, each of which affects O2 transport by similar amounts as they change. There is thus no single "limiting factor" to VO2max. Moreover, each component is shown to quantitatively affect the performance of the others. Mitochondrial respiration is integrated into the O2 transport system analysis to reveal its separate contribution to VO2max, and to show that mitochondrial PO2 at VO2max must be extremely low. Clinical application of the O2 transport systems analysis is described to separate central cardiopulmonary from peripheral tissue contributions to exercise limitation, illustrated by a study of patients with COPD. Finally, a short discussion of why muscles operating maximally must endure an almost anoxic state is offered. The hope is that in sum, both the increased understanding of O2 transport and the scientific approach to achieving that understanding described in the review can serve as a model for solving other complex problems going forward.

Blinking and normal ocular surface in school-aged children and the effects of age and screen time.

PURPOSE: Baseline ocular surface characteristics in children require investigation. This study characterised blinking and relationships with ocular symptoms, tear film and digital device use. METHODS: 45 children aged 6-15 years (56% female) participated in a cross-sectional study. Ocular surface symptoms (Instant Ocular Symptoms Survey, Dry Eye Questionnaire 5, Symptoms Assessment in Dry Eye, Ocular Surface Disease Index, Ocular Comfort Index and Numerical Rating Scale) and clinical indices (lipid layer thickness, tear secretion and stability, meibomian gland) were assessed. Blink rate and interblink interval were measured in situ using a wearable eye-tracking headset (Pupil Labs GmbH, Germany). Associations between blinking, ocular surface, age, and digital device use (bivariate and partial correlations) and between automated and manually counted blink rate (Bland & Altman) were examined. RESULTS: Mean blink rate and interblink interval were 20.5±10.5 blinks/min and 2.9±1.9 s during conversation. There was no difference between automated and manual blink rate (p=0.78) and no relationship between blinking and digital device use, age or sex. Mean group symptoms were within normal range and not associated with clinical measurements including blinking. Greater tear volume was associated with a faster blink rate (r=0.46, p=0.001) and shorter interblink interval (r=-0.36, p=0.02). Older age was associated with improved tear volume (r=0.37, p=0.01) and stability (r=0.38, p=0.01). CONCLUSIONS: Blinking characterised in situ was not impacted by age or habitual digital device use. A faster blink rate was associated with greater tear volume but not symptoms. Improved tear function was found with age suggesting that the ocular surface continues to develop through childhood.

Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery.

BACKGROUND: Pathological evidence suggests that coronavirus disease 2019 (COVID-19) pulmonary infection involves both alveolar damage (causing shunt) and diffuse microvascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar dead space in moderate COVID-19 during acute illness and recovery. METHODS: We studied 30 patients (22 males; mean±sd age 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled oxygen and carbon dioxide concentrations were measured, yielding alveolar-arterial differences for each gas (P A-aO2 and P a-ACO2 , respectively) from which shunt and alveolar dead space were computed. RESULTS: For acute COVID-19 patients, group mean (range) for P A-aO2 was 41.4 (-3.5-69.3) mmHg and for P a-ACO2 was 6.0 (-2.3-13.4) mmHg. Both shunt (% cardiac output) at 10.4% (0-22.0%) and alveolar dead space (% tidal volume) at 14.9% (0-32.3%) were elevated (normal: <5% and <10%, respectively), but not correlated (p=0.27). At recovery, shunt was 2.4% (0-6.1%) and alveolar dead space was 8.5% (0-22.4%) (both p<0.05 versus acute). Shunt was marginally elevated for two patients; however, five patients (30%) had elevated alveolar dead space. CONCLUSIONS: We speculate impaired pulmonary gas exchange in early COVID-19 pneumonitis arises from two concurrent, independent and variable processes (alveolar filling and pulmonary vascular obstruction). For most patients these resolve within weeks; however, high alveolar dead space in ∼30% of recovered patients suggests persistent pulmonary vascular pathology.

Estimating 3D spatiotemporal point of regard: a device evaluation.

This paper presents and evaluates a system and method that record spatiotemporal scene information and location of the center of visual attention, i.e., spatiotemporal point of regard (PoR) in ecological environments. A primary research application of the proposed system and method is for enhancing current 2D visual attention models. Current eye-tracking approaches collapse a scene's depth structures to a 2D image, omitting visual cues that trigger important functions of the human visual system (e.g., accommodation and vergence). We combined head-mounted eye-tracking with a miniature time-of-flight camera to produce a system that could be used to estimate the spatiotemporal location of the PoR-the point of highest visual attention-within 3D scene layouts. Maintaining calibration accuracy is a primary challenge for gaze mapping; hence, we measured accuracy repeatedly by matching the PoR to fixated targets arranged within a range of working distances in depth. Accuracy was estimated as the deviation from estimated PoR relative to known locations of scene targets. We found that estimates of 3D PoR had an overall accuracy of approximately 2° omnidirectional mean average error (OMAE) with variation over a 1 h recording maintained within 3.6° OMAE. This method can be used to determine accommodation and vergence cues of the human visual system continuously within habitual environments, including everyday applications (e.g., use of hand-held devices).

Atomic-Scale Rectification and Inelastic Electron Tunneling Spectromicroscopy.

The phenomenon of rectification describes the emergence of a DC current from the application of an oscillating voltage. Although the origin of this effect has been associated with the nonlinearity in the current-voltage I(V) relation, a rigorous understanding of the microscopic mechanisms for this phenomenon remains challenging. Here, we show the close connection between rectification and inelastic electron tunneling spectroscopy and microscopy for single molecules with a scanning tunneling microscope. While both techniques are based on nonlinear features in the I(V) curve, comprehensive line shape analyses reveal notable differences that highlight the two complementary techniques of nonlinear conductivity spectromicroscopy for probing nanoscale systems.

Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity.

STUDY OBJECTIVES: Chronic mountain sickness (CMS) is commonly observed among Andean and other highland populations. Sleep-disordered breathing (SDB) is highly prevalent at high altitude, and SDB and nocturnal hypoxemia have been observed in CMS. Phlebotomy is commonly performed to treat CMS, but it is unknown whether reducing hematocrit improves SDB. We hypothesized that isovolemic hemodilution (IVHD) in CMS would reduce SBD severity and improve sleep efficiency. METHODS: Six participants with CMS and 8 without CMS, all residents of Cerro de Pasco, Peru (altitude 4340 m), completed baseline nocturnal sleep studies. CMS participants then underwent IVHD, and nocturnal sleep studies were repeated 24-48 hours after IVHD. We analyzed sleep apnea severity, nocturnal oxygenation, and sleep quality in those with CMS relative to those without CMS, and the effects of IVHD in CMS participants. RESULTS: Participants with CMS did not have altered sleep architecture, sleep apnea severity, or nocturnal oxygenation relative to non-CMS participants. However, IVHD in CMS increased apnea-hypopnea index (40.9 ± 6.9 events/h to 61.5 ± 7.7 events/h, P = .009). IVHD increased oxyhemoglobin desaturation index (P = .008) and the percentage of sleep time spent with oxyhemoglobin saturation at or below 80% (P = .012). There was no effect of IVHD on sleep efficiency, arousal index, or sleep staging. CONCLUSIONS: In this cohort, CMS was not associated with worsened SDB or changes in sleep architecture. IVHD, a putative therapeutic option for participants with CMS, appears to worsen nocturnal oxygenation and SDB within 48 hours post-IVHD. CITATION: Sanchez-Azofra A, Villafuerte FC, DeYoung PN, et al. Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity. J Clin Sleep Med. 2022;18(10):2423-2432.

Ergogenic value of oxygen supplementation in chronic obstructive pulmonary disease.

Patients with COPD exhibit limited exercise endurance time compared to healthy age-matched individuals. Oxygen supplementation is often applied to improve endurance time during pulmonary rehabilitation in patients with COPD and thus a comprehensive understanding of the mechanisms leading to improved endurance is desirable. This review analyses data from two studies by our research group investigating the effect of oxygen supplementation on cerebrovascular, systemic, respiratory and locomotor muscle oxygen availability on the same cohort of individuals with advanced COPD, and the mechanisms associated with improved endurance time in hyperoxia, which was essentially doubled (at the same power output). In hyperoxia at isotime (the time at which patients became exhausted in normoxia) exercise was associated with greater respiratory and locomotor muscle (but not frontal cortex) oxygen delivery (despite lower cardiac output), lower lactate concentration and less tachypnoea. Frontal cortex oxygen saturation was higher, and respiratory drive lower. Hence, improved endurance in hyperoxia appears to be facilitated by several factors: increased oxygen availability to the respiratory and locomotor muscles, less metabolic acidosis, and lower respiratory drive. At exhaustion in both normoxia and hyperoxia, only cardiac output and breathing pattern were not different between conditions. However, minute ventilation in hyperoxia exceeded the critical level of ventilatory constraints (VE/MVV > 75-80%). Lactate remained lower and respiratory and locomotor muscle oxygen delivery greater in hyperoxia, suggesting greater muscle oxygen availability improving muscle function. Taken together, these findings suggest that central haemodynamic and ventilatory limitations and not contracting muscle conditions dictate endurance time in COPD during exercise in hyperoxia.