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.

Unique functional diversity during early Cenozoic mammal radiation of North America.

Mammals influence nearly all aspects of energy flow and habitat structure in modern terrestrial ecosystems. However, anthropogenic effects have probably altered mammalian community structure, raising the question of how past perturbations have done so. We used functional diversity (FD) to describe how the structure of North American mammal palaeocommunities changed over the past 66 Ma, an interval spanning the radiation following the K/Pg and several subsequent environmental disruptions including the Palaeocene-Eocene Thermal Maximum (PETM), the expansion of grassland, and the onset of Pleistocene glaciation. For 264 fossil communities, we examined three aspects of ecological function: functional evenness, functional richness and functional divergence. We found that shifts in FD were associated with major ecological and environmental transitions. All three measures of FD increased immediately following the extinction of the non-avian dinosaurs, suggesting that high degrees of ecological disturbance can lead to synchronous responses both locally and continentally. Otherwise, the components of FD were decoupled and responded differently to environmental changes over the last ~56 Myr.

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.

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.

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.

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.

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.

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.

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).

Exercise training in COPD: muscle O2 transport plasticity.

Both convective oxygen (O2) transport to, and diffusive transport within, skeletal muscle are markedly diminished in patients with COPD. However, it is unknown how these determinants of peak muscle O2 uptake (V'mO2peak) respond to exercise training in patients with COPD. Therefore, the purpose of this study was to assess the plasticity of skeletal muscle O2 transport determinants of V'mO2peak in patients with COPD.Adaptations to 8 weeks of single-leg knee-extensor exercise training were measured in eight patients with severe COPD (mean±sem forced expiratory volume in 1 s (FEV1) 0.9±0.1 L) and eight healthy, well-matched controls. Femoral arterial and venous blood samples, and thermodilution-assessed leg blood flow were used to determine muscle O2 transport and utilisation at maximal exercise pre- and post-training.Training increased V'mO2peak in both COPD (by ∼26% from 271±29 to 342±35 mL·min-1) and controls (by ∼32% from 418±37 to 553±41 mL·min-1), restoring V'mO2peak in COPD to only ∼80% of pre-training control V'mO2peak Muscle diffusive O2 transport increased similarly in both COPD (by ∼38% from 6.6±0.9 to 9.1±0.9 mL·min-1·mmHg-1) and controls (by ∼36% from 10.4±0.7 to 14.1±0.8 mL·min-1·mmHg-1), with the patients reaching ∼90% of pre-training control values. In contrast, muscle convective O2 transport increased significantly only in controls (by ∼26% from 688±57 to 865±69 mL·min-1), leaving patients with COPD (438±45 versus 491±51 mL·min-1) at ∼70% of pre-training control values.While muscle diffusive O2 transport in COPD was largely restored by exercise training, V'mO2peak remained constrained by limited plasticity in muscle convective O2 transport.

An early burst in brachiopod evolution corresponding with significant climatic shifts during the Great Ordovician Biodiversification Event.

We employ modified tip-dating methods to date divergence times within the Strophomenoidea, one of the most abundant and species-rich brachiopod clades to radiate during the Great Ordovician Biodiversification Event (GOBE), to determine if significant environmental changes at this time correlate with the diversification of the clade. Models using origination, extinction and sampling rates to estimate prior probabilities of divergence times strongly support both high rates of anatomical change per million years and rapid divergences shortly before the clade first appears in the fossil record. These divergence times indicate much higher rates of cladogenesis than are typical of brachiopods during this interval. The correspondence of high speciation rates and high anatomical disparity suggests punctuated (speciational) change drove the high frequencies of early anatomical change, which in turn suggests increased ecological opportunities rather than shifting developmental constraints account for high rates of anatomical change. The pulse of rapid evolution began coincident with cooling temperatures, the start of major oscillations in sea level and increased levels of atmospheric oxygen. Our results suggest that these factors permitted major geographical and ecological expansion of strophomenoids with intervals of geographical isolation, resulting in elevated speciation rates and corresponding elevated frequencies of punctuated change.

Use of External Comparators for Health Technology Assessment Submissions Based on Single-Arm Trials.

BACKGROUND: Single-arm trial (SAT) data is increasingly reviewed for drug approvals by regulators and Health Technology Assessment (HTA) bodies. Supplementary data in the form of external comparators (ECs) can be used to provide clinical context to support these drug evaluations. In this study we characterized HTAs for SAT-based submissions, the use of supplementary EC data and outcomes from HTA review. METHODS: HTA Accelerator database was used to describe SAT-based HTA submissions with decisions (2011-2019). RESULTS: A total of 433 SAT-based HTA submissions were identified between 2011 and 2019 with a 13-fold increase during this period. Around 65%(283/433) were in oncology or hem-oncology. Around 52%(226/433) of submissions contained some type of EC data, including prior clinical trials (24%, 104) and real-world data (RWD) (20%, 87), but 40%(175) contained no EC data. The overall acceptance rate for SAT-based submissions was 48% and with RWD EC data acceptance was 59%. In the latest 5-year period (2015-2019), use of RWD ECs increased 22% as a proportion of submissions per year, whereas, prior trial ECs decreased (-14%) and use of no EC remained stable (-2%). Between 2015 to 2017 and 2018 to 2019, acceptance rate for RWD ECs increased by 20% (41% in 2015-2017 to 61% in 2018-2019) whereas prior trial EC use decreased by 10% and no EC submissions decreased 16%. Of 226 submissions using ECs, only 29%(66) used an adjusted indirect treatment comparison method. CONCLUSIONS: SAT-based submissions to HTA bodies are rapidly evolving in terms of composition and acceptance. Types of EC and methodological approach used are important determinants of positive outcomes.

Determinants of the diminished exercise capacity in patients with chronic obstructive pulmonary disease: looking beyond the lungs.

KEY POINTS: Peak oxygen uptake, a primary determinant of prognosis, mortality and quality of life, is diminished in patients with chronic obstructive pulmonary disease (COPD), with mounting evidence supporting an important role for peripheral dysfunction, particularly within skeletal muscle. In patients with severe COPD and activity-matched controls, muscle oxygen transport and utilization were assessed at peak effort during single-leg knee-extensor exercise (KE), where ventilation is assumed to be submaximal. This strategy removes ventilation as the major constraint to exercise capacity in COPD, allowing maximal muscle function to be attained and evaluated. During maximal KE, both convective arterial oxygen delivery to the skeletal muscle microvasculature and subsequent diffusive oxygen delivery to the mitochondria were diminished in patients with COPD compared to control subjects. These findings emphasize the importance of factors, beyond the lungs, that influence exercise capacity in this patient population and may, ultimately, influence the prognosis, mortality and quality of life for patients with COPD. ABSTRACT: Peak oxygen uptake ( V̇O2peak ), a primary determinant of prognosis, mortality and quality of life, is diminished in patients with chronic obstructive pulmonary disease (COPD). Mounting evidence supports an important role of the periphery, particularly skeletal muscle, in the diminished V̇O2peak with COPD. However, the peripheral determinants of V̇O2peak have not been comprehensively assessed in this cohort. Thus, the hypothesis was tested that both muscle convective and diffusive oxygen (O2 ) transport, and therefore skeletal muscle peak O2 uptake ( V̇MO2peak ), are diminished in patients with COPD compared to matched healthy controls, even when ventilatory limitations (i.e. attainment of maximal ventilation) are minimized by using small muscle mass exercise. Muscle O2 transport and utilization were assessed at peak exercise from femoral arterial and venous blood samples and leg blood flow (by thermodilution) in eight patients with severe COPD (forced expiratory volume in 1s (FEV1 ) ± SEM = 0.9 ± 0.1 l, 30% of predicted) and eight controls during single-leg knee-extensor exercise. Both muscle convective O2 delivery (0.44 ± 0.06 vs. 0.69 ± 0.07 l min-1 , P < 0.05) and muscle diffusive O2 conductance (6.6 ± 0.8 vs. 10.4 ± 0.9 ml min-1  mmHg-1 , P < 0.05) were ∼1/3 lower in patients with COPD than controls, resulting in an attenuated V̇MO2peak in the patients (0.27 ± 0.04 vs. 0.42 ± 0.05 l min-1 , P < 0.05). When cardiopulmonary limitations to exercise are minimized, the convective and diffusive determinants of V̇MO2peak , at the level of the skeletal muscle, are greatly attenuated in patients with COPD. These findings emphasize the importance of factors, beyond the lungs, that may ultimately influence this population's prognosis, mortality and quality of life.

Greater exercise tolerance in COPD during acute interval, compared to equivalent constant-load, cycle exercise: physiological mechanisms.

KEY POINTS: Exercise intolerance is common in chronic obstructive pulmonary disease (COPD) patients. In patients with COPD, we compared an interval exercise (IE) protocol (alternating 30 s at 100% peak work rate (WRpeak ) with 30 s at 50% WRpeak ) with moderate-intensity constant-load exercise (CLE) at 75% WRpeak , which yielded the same work rate. Exercise endurance time and total work output were almost twice as high for IE than CLE. At exercise isotime (when work completed was the same between IE and CLE), IE was associated with less dynamic hyperinflation, lower blood lactate concentration, and greater respiratory and locomotor muscle oxygenation, but there were no differences in ventilation or cardiac output. However, at the limit of tolerance for each modality, dynamic hyperinflation was not different between IE and CLE, while blood lactate remained lower and muscle oxygenation higher with IE. Taken together, these findings suggest that dynamic hyperinflation and not muscle-based factors dictate the limits of tolerance in these COPD patients. ABSTRACT: The relative importance of ventilatory, circulatory and peripheral muscle factors in determining tolerance to exercise in patients with chronic obstructive pulmonary disease (COPD) is not known. In 12 COPD patients (forced expiratory volume in one second: 58 ± 17%pred.) we measured ventilation, cardiac output, dynamic hyperinflation, local muscle oxygenation, blood lactate and time to exhaustion during (a) interval exercise (IE) consisting of 30 s at 100% peak work rate alternating with 30 s at 50%, and (b) constant-load exercise (CLE) at 75% peak work rate, designed to produce the same average work rate. Exercise time was substantially longer during IE than CLE (19.5 ± 4.8 versus 11.4 ± 2.1 min, p = 0.0001). Total work output was therefore greater during IE than CLE (81.3 ± 27.7 versus 48.9 ± 23.8 kJ, p = 0.0001). Dynamic hyperinflation (assessed by changes from baseline in inspiratory capacity, ΔIC) was less during IE than CLE at CLE exhaustion time (isotime, p = 0.009), but was similar at exhaustion (ΔICCLE : -0.38 ± 0.10 versus ΔICIE : -0.33 ± 0.12 l, p = 0.102). In contrast, at isotime, minute ventilation, cardiac output and systemic oxygen delivery did not differ between protocols (P > 0.05). At exhaustion in both protocols, the vastus lateralis and intercostal muscle oxygen saturation were higher in IE than CLE (p = 0.014 and p = 0.0002, respectively) and blood lactate concentrations were lower (4.9 ± 2.4 mmol l-1 versus 6.4 ± 2.2 mmol l-1 , p = 0.039). These results suggest that (1) exercise tolerance with COPD is limited by dynamic hyperinflation; and (2) cyclically lower (50%) effort intervals in IE help to preserve muscle oxygenation and reduce metabolic acidosis compared with CLE at the same average work rate; but these factors do not appear to determine time to exhaustion.

Respiratory and locomotor muscle blood flow during exercise in health and chronic obstructive pulmonary disease.

NEW FINDINGS: What is the topic of this review? The work presented here focuses mostly on testing the theory of blood flow redistribution from the locomotor to the respiratory muscles during heavy exercise in healthy participants and in patients with COPD. What advances does it highlight? Studies presented and the direct experimental approach to measure muscle blood flow by indocyanine green dye detected by near infrared spectroscopy, show that exercise interferes with respiratory muscle blood flow especially in COPD, but even in healthy. ABSTRACT: We have developed an indicator-dilution method to measure muscle blood flow at rest and during exercise using the light absorbing tracer indocyanine green dye (ICG) injected as an intravenous bolus, with surface optodes placed over muscles of interest to record the ICG signal by near-infrared spectroscopy. Here we review findings for both quadriceps and intercostal muscle blood flow (measured simultaneously) in trained cyclists and in patients with chronic obstructive pulmonary disease (COPD). During resting hyperpnoea in both athletes and patients, intercostal muscle blood flow increased with ventilation, correlating closely and linearly with the work of breathing, with no change in quadriceps flow. During graded exercise in athletes, intercostal flow at first increased, but then began to fall approaching peak effort. Unexpectedly, in COPD, intercostal muscle blood flow during exercise fell progressively from resting values, contrasting sharply with the response to resting hyperpnoea. During exercise at peak intensity, we found no quadriceps blood flow reduction in favour of the respiratory muscles in either athletes or patients. In COPD at peak exercise, when patients breathed 21% oxygen in helium or 100% oxygen, there was no redistribution of blood flow observed between legs and respiratory muscles in either direction. Evidence of decrease in leg blood flow and increase in respiratory muscle flow was found only when imposing expiratory flow limitation (EFL) during exercise in healthy individuals. However, because EFL caused substantial physiological derangement, lowering arterial oxygen saturation and raising end-tidal PCO2 and heart rate, these results cannot be projected onto normal exercise.

Synergistic effect of vascular endothelial growth factor gene inactivation in endothelial cells and skeletal myofibres on muscle enzyme activity, capillary supply and endurance exercise in mice.

NEW FINDINGS: What is the central question of this study? Does vascular endothelial growth factor (VEGF) expressed by both endothelial cells and skeletal myofibres maintain the number of skeletal muscle capillaries and regulate endurance exercise? What is the main finding and its importance? VEGF expressed by both endothelial cells and skeletal myofibres is not essential for maintaining capillary number but does contribute to exercise performance. ABSTRACT: Many chronic diseases lead to exercise intolerance, with loss of skeletal muscle capillaries. While many muscle cell types (myofibres, satellite cells, endothelial cells, macrophages and fibroblasts) express vascular endothelial growth factor (VEGF), most muscle VEGF is stored in myofibre vesicles which can release VEGF to signal VEGF receptor-expressing cells. VEGF gene ablation in myofibres or endothelial cells alone does not cause capillary regression. We hypothesized that simultaneously deleting the endothelial cell (EC) and skeletal myofibre (Skm) VEGF gene would cause capillary regression and impair exercise performance. This was tested in adult mice by simultaneous conditional deletion of the VEGF gene (Skm/EC-VEGF-/- mice) through the use of VEGFLoxP, HSA-Cre-ERT2 and PDGFb-iCre-ERT2 transgenes. These double-deletion mice were compared to three control groups - WT, EC VEGF gene deletion alone and myofibre VEGF gene deletion alone. Three weeks after initiating gene deletion, Skm/EC-VEGF-/- mice, but not SkmVEGF-/- or EC-VEGF-/- mice, reached exhaustion 40 min sooner than WT mice in treadmill tests (P = 0.002). WT, SkmVEGF-/- and EC-VEGF-/- , but not Skm/EC-VEGF-/- , mice gained weight over the 3 weeks. Capillary density, fibre area and capillary: fibre ratio in soleus, plantaris, gastrocnemius and cardiac papillary muscle were similar across the groups. Phosphofructokinase and pyruvate dehydrogenase activities increased only in Skm/EC-VEGF-/- mice. These data suggest that deletion of the VEGF gene simultaneously in endothelial cells and myofibres, while reducing treadmill endurance and despite compensatory augmentation of glycolysis, is not required for muscle capillary maintenance. Reduced endurance remains unexplained, but may possibly be related to a role for VEGF in controlling perfusion of contracting muscle.

Spatiotemporal cluster and incidence analysis of cattle mortality caused by bovine babesiosis in Styria, Austria, between 1998 and 2016.

Reported fatal cases of bovine babesiosis (syn.: piroplasmosis, red water fever) in cattle were analyzed to identify spatial and temporal clusters of their incidence in the Austrian province of Styria. Data were collected within a governmental babesiosis compensation program. Diagnosis was performed using a standardized necropsy protocol. Between 1998 and 2016, a total of 1257 cases of fatal babesiosis were registered and compensated. Within the study interval, annual numbers of fatal babesiosis differed significantly among municipalities. Spatiotemporal analysis covering the entire study period revealed one high-risk cluster in the western and central northern region of Styria and a low-risk cluster in the southeastern part of Styria. Annual temporal analysis demonstrated that cases accumulated in June. Annual spatial analysis revealed consistently that cases mainly occurred in the western and central northern regions, whereas they occurred rarely in the southeastern regions. These results should increase awareness and facilitate protective actions against ticks during certain time periods and geographic areas.

A Novel Approach for Mixed Manual/Connected Automated Freeway Traffic Management.

Freeway traffic management and control often rely on input from fixed-point sensors. A sufficiently high sensor density is required to ensure data reliability and accuracy, which results in high installation and maintenance costs. Moreover, fixed-point sensors encounter difficulties to provide spatiotemporally and wide-ranging information due to the limited observable area. This research exploits the utilization of connected automated vehicles (CAVs) as an alternative data source for freeway traffic management. To handle inherent uncertainty associated with CAV data, we develop an interval type 2 fuzzy logic-based variable speed limit (VSL) system for mixed traffic. The simulation results demonstrate that when more 10% CAVs are deployed, the performance of the proposed CAV-based system can approach that of the detector-based system. It is demonstrated in addition that the introduction of CAVs may make VSL obsolete at very high CAV-equipment rates.