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David C Poole,1,2 Howard H Erickson1 1Department of Anatomy and Physiology, 2Department of Kinesiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA Abstract: As the Thoroughbreds race for the final stretch, 44 hooves flash and thunder creating a cacophony of tortured air and turf. Orchestrated by selective breeding for physiology and biomechanics, expressed as speed, the millennia-old symphony of man and beast reaches its climax. At nearly 73 kilometers per hour (45 mph) over half a ton of flesh and bone dwarfs its limpet-like jockey as, eyes wild and nostrils flaring, their necks stretch for glory. Beneath each resplendent livery-adorned, latherin-splattered coat hides a monstrous heart trilling at 4 beats per second, and each minute, driving over 400 L (105 gallons) of oxygen-rich blood from lungs to muscles. Matching breath to stride frequency, those lungs will inhale 16 L (4 gallons) of air each stride moving >1,000 L/min in and out of each nostril – and yet failing. Engorged with blood and stretched to breaking point, those lungs can no longer redden the arterial blood but leave it dusky and cyanotic. Their exquisitely thin blood–gas barrier, a mere 10.5 μm thick (1/50,000 of an inch), ruptures, and red cells invade the lungs. After the race is won and lost, long after the frenetic crowd has quieted and gone, that blood will clog and inflame the airways. For a few horses, those who bleed extensively, it will overflow their lungs and spray from their nostrils incarnadining the walls of their stall: a horrifically poignant canvas that strikes at horse racing’s very core. That exercise-induced pulmonary hemorrhage (EIPH) occurs is a medical and physiological reality. That every reasonable exigency is not taken to reduce/prevent it would be a travesty. This review is not intended to provide an exhaustive coverage of EIPH for which the reader is referred to recent reviews, rather, after a brief reminder of its physiologic and pathologic bases, focus is brought on the latest developments in EIPH discovery as this informs state-of-the-art knowledge, the implementation of that knowledge and recommendations for future research and treatment. Keywords: epistaxis, Thoroughbred racehorse, pulmonary capillary rupture, vascular pressure, alveolar pressure, nasal airway collapse

The purpose of this paper is to provide an introduction to the study of oxygen uptake (VO(2)) dynamics or kinetics. Following the onset of exercise, both muscle and pulmonary VO(2) rise in a near-exponential fashion towards the anticipated 'steady-state' VO(2) demand. However, it can take 2-4 min, or even longer at higher work rates, before this steady state is attained. Slow VO(2) kinetics increase the so-called O(2) deficit and obligate a greater contribution from anaerobic mechanisms of ATP production (involving the breakdown of muscle high energy phosphates and lactate production from glycogen) to meet the ATP requirement of the exercise task. A primary goal in this area of research is therefore to elucidate the physiological mechanisms which control and/or limit the rate at which muscle VO(2) increases following the onset of exercise. At higher intensities of exercise, a continued increase in both muscle and pulmonary VO(2) is observed with time despite the external work rate remaining constant. This continued rise in VO(2), beyond the anticipated steady-state requirement for the work rate, has been termed the VO(2) 'slow component,' and establishing the mechanistic basis for this phenomenon is another important goal of research in this field. This paper provides an overview of some of the factors which might contribute to both the fundamental and slow phases of the VO(2) kinetics and, in so doing, provides general background material for the more specific papers that follow. [ABSTRACT FROM AUTHOR]

Exercise-induced pulmonary haemorrhage (EIPH) is a serious condition that affects the health and possibly the performance of all racehorses. However, only two treatments, furosemide and the Flair™ equine nasal strip, both of which reduce capillary transmural pressure, have been successful in reducing EIPH. Alternatively, transient impairment of platelet function and coagulation during exercise has been considered an additional contributor to EIPH. Consequently, herbal formulations designed to enhance platelet function, and hence coagulation, are hypothesized to reduce EIPH. To investigate the validity of this hypothesis, five Thoroughbred horses completed three maximal incremental exercise tests on a 10% inclined treadmill in a randomized cross-over design experiment. Treatments included twice daily oral administration (for 3 days) of a placebo (PL; cornstarch) and two herbal formulas, Yunnan Paiyao (YP) or Single Immortal (SI). Blood samples for coagulation profiles, complete blood counts and biochemistry profiles were collected before each exercise test. During each test, pulmonary arterial pressure, oxygen uptake, arterial blood gases, plasma lactate and time-to-fatigue were measured. Severity of EIPH was quantified via bronchoalveolar lavage (BAL) at 30–60 min post-exercise. The herbal formulations were not effective in decreasing EIPH (×106 red blood cells ml−1 BAL fluid: PL, 27.1±11.6; YP, 33.2±23.4; SI, 35.3±15.4, P>0.05) or in changing any of the other variables measured with the exception of time-to-fatigue, which was slightly but significantly prolonged by Single Immortal compared with placebo and Yunnan Paiyao (PL, 670±9.6 s; YP, 665±5.5 s; SI, 685±7.9 s, P<0.05). Thus, these results do not support the use of these herbal formulations in the prevention of EIPH. [ABSTRACT FROM PUBLISHER]

Furosemide (FUR) and the equine nasal strip (NS) decrease exercise-induced pulmonary haemorrhage (EIPH) compared with control (CON) conditions in the Thoroughbred horse during near-maximal running trials. As FUR and NS have potential performance-enhancing properties, we studied Thoroughbreds running to fatigue to test the hypothesis that time-to-fatigue (TTF) would be increased, yet EIPH reduced, in FUR and NS compared with CON. Thoroughbred geldings (n=6) were run to volitional fatigue on a level treadmill (1 m s−1 increment per minute from an initial trot) every two weeks (order randomized) under CON, NS, FUR (1 mg kg−1; 4 h prior) and FUR+NS conditions. Pulmonary arterial pressure (Ppa) and pulmonary gas exchange were measured throughout exercise, while arterial blood gases were sampled at the end of each 1-min stage. EIPH severity was quantified via bronchoalveolar lavage (BAL) at 30 min post-exercise. TTF was increased for all experimental conditions (i.e. an additional 20±13, 28±8 and 40±6 s for NS, FUR and FUR+NS, respectively; P<0.05) compared with CON. Peak mean Ppa was significantly reduced (P<0.05) for FUR (93.6±6.3 mmHg) and FUR+ NS (95.4±5.1 mmHg), yet unchanged with NS (98.0±5.8 mmHg; P>0.05) compared with CON (100.5±4.9 mmHg). All three experimental conditions exhibited a significant reduction in EIPH compared with CON (64.1±36.8× 6 red blood cells (RBCs) ml−1); however, no significant difference was noted between these conditions (×106 RBCs ml−1: 29.1±16.8, 20.9±13.1 and 26.7±19.8 for NS, FUR and FUR+NS, respectively). Furthermore, no differences for either end-exercise cardiorespiratory (i.e. V˙O2 or V˙CO2) or blood-borne metabolic (i.e. blood gases, lactate or pH) variables were observed. These findings demonstrate that both FUR and NS enhance TTF and reduce EIPH to a similar degree during high-speed treadmill running to fatigue. [ABSTRACT FROM PUBLISHER]

From a physiological perspective, the delineation between steady-state and non-steady-state exercise, also referred to as the maximal metabolic steady state, holds paramount importance for evaluating athletic performance and designing and monitoring training programs. The critical power and the maximal lactate steady state are two widely used indices to estimate this threshold, yet previous studies consistently reported significant discrepancies between their associated power outputs. These findings have fueled the debate regarding the interchangeability of critical power and the maximal lactate steady state in practice. This paper reviews the methodological intricacies intrinsic to the determination of these thresholds, and elucidates how inappropriate determination methods and methodological inconsistencies between studies have contributed to the documented differences in the literature. Through a critical examination of relevant literature and by integration of our laboratory data, we demonstrate that differences between critical power and the maximal lactate steady state may be reconciled to only a few Watts when applying appropriate and strict determination criteria, so that both indices may be used to estimate the maximal metabolic steady-state threshold in practice. To this end, we have defined a set of good practice guidelines to assist scientists and coaches in obtaining the most valid critical power and maximal lactate steady state estimates., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This investigation evaluated the microvascular permeability and ultrastructure of skeletal muscle capillaries in the skeletal muscle of diabetic (DIA) rats using two-photon laser scanning microscopy (TPLSM) and transmission electron microscopy (TEM). Microvascular permeability was assessed in the tibialis anterior muscle of control (CON) and DIA (streptozocin) male Wistar rats ( n = 20, 10-14 wk) by in vivo imaging using TPLSM after fluorescent dye intravenous infusion. Fluorescent dye leakage was quantified to determine microvascular permeability. The ultrastructure was imaged by TEM ex vivo to calculate the size and number of intercellular clefts between capillary endothelial cells and also intracellular vesicles. Compared with control, the volumetrically determined interstitial fluorescent dye leakage, the endothelial cell thickness, and the number of intercellular clefts per capillary perimeter were significantly higher, and the cleft width was significantly narrower in tibialis anterior (TA) of DIA (interstitial fluorescent dye leakage, 2.88 ± 1.40 vs. 10.95 ± 1.41 µm 3 × min × 10 6 ; endothelial thickness, 0.28 ± 0.02 vs. 0.45 ± 0.03 µm; number of intercellular clefts per capillary perimeter, 6.3 ± 0.80 vs. 13.6 ± 1.7/100 µm; cleft width, 11.92 ± 0.95 vs. 8.40 ± 1.03 nm, CON vs. DIA, respectively, all P < 0.05). The size of intracellular vesicles in the vascular endothelium showed an increased proportion of large vesicles in the DIA group compared with the CON group ( P < 0.05). Diabetes mellitus enhances the microvascular permeability of skeletal muscle microvessels due, in part, to a higher density and narrowing of the endothelial intercellular clefts, and larger intracellular vesicles. NEW & NOTEWORTHY Microvascular permeability in diabetic muscle was investigated using our original two-photon scanning laser microscopy method. Compared with controls, the leakage volume was increased in diabetic muscle, which was atrophic with smaller capillary diameter, endothelial cell thickening, and the appearance of more endothelial intercellular gaps or clefts, and large vesicles. Hyperpermeability was closely related to ultrafine structural changes of the capillary endothelial cell junctions.

Abstract: Eccentric contractions (ECC) induce excessive intracellular calcium ion (Ca2+) accumulation and muscle structural damage in localized regions of the muscle fibers. In this investigation, we present the novel hypothesis that the ryanodine receptor (RyR) plays a central role in evoking a Ca2+ dynamics profile that is markedly distinguishable from other muscle adaptive responses., Competing Interests: Disclosure of conflicts of interest: The authors have no conflicts of interest directly related to the content of this article., (Copyright © 2024 by the American College of Sports Medicine.)

Hydrogen peroxide (H 2 O 2 ) is one of the key signaling factors regulating skeletal muscle adaptation to muscle contractions. Eccentric (ECC) and concentric (CONC) contractions drive different muscle adaptations with ECC resulting in greater changes. The present investigation tested the hypothesis that ECC produces higher cytosolic and mitochondrial H 2 O 2 concentrations [H 2 O 2 ] and alters gene expression more than CONC. Cytosolic and mitochondrial H 2 O 2 -sensitive fluorescent proteins, HyPer7 and MLS-HyPer7, were expressed in the anterior tibialis muscle of C57BL6J male mice. Before and for 60 min after either CONC or ECC (100 Hz, 50 contractions), [H 2 O 2 ] cyto and [H 2 O 2 ] mito were measured by in vivo fluorescence microscopy. RNA sequencing was performed in control (noncontracted), CONC, and ECC muscles to identify genes impacted by the contractions. [H 2 O 2 ] cyto immediately after ECC was greater than after CONC (CONC: +6%, ECC: +11% vs. rest, P < 0.05) and remained higher for at least 60 min into recovery. In contrast, the elevation of [H 2 O 2 ] mito was independent of the contraction modes (time; P < 0.0042, contraction mode; P = 0.4965). The impact of ECC on [H 2 O 2 ] cyto was abolished by NADPH oxidase 2 (Nox2) inhibition (GSK2795039). Differentially expressed genes were not present after CONC or ECC + GSK but were found after ECC and were enriched for vascular development and apoptosis-related genes, among others. In conclusion, in mouse anterior tibialis, ECC, but not CONC, evokes a pronounced cytosolic H 2 O 2 response, caused by Nox2, that is mechanistically linked to gene expression modifications. NEW & NOTEWORTHY This in vivo model successfully characterized the effects of eccentric (ECC) and concentric (CONC) contractions on cytosolic and mitochondrial [H 2 O 2 ] in mouse skeletal muscle. Compared with CONC, ECC induced higher and more sustained [H 2 O 2 ] cyto -an effect that was abolished by Nox2 inhibition. ECC-induced [H 2 O 2 ] cyto elevations were requisite for altered gene expression.

Aging is associated with inspiratory muscle dysfunction; however, the impact of aging on diaphragm blood flow (BF) regulation, and whether sex differences exist, is unknown. We tested the hypotheses in young animals that diaphragm BF and vascular conductance (VC) would be greater in females and that aging would decrease the diaphragm's ability to increase BF with contractions. Young (4-6 mo) and old (22-24 mo) Fischer 344 rats were divided into four groups: young female (YF, n = 7), young male (YM, n = 8), old female (OF, n = 9), and old male (OM, n = 9). Diaphragm BF (mL/min/100 g) and VC (mL/mmHg/min/100 g) were determined, via fluorescent microspheres, at rest and during 1 Hz contractions. In YF versus OF, aging blunted the increase in medial costal diaphragm BF (44 ± 5% vs. 16 ± 12%; P < 0.05) and VC (43 ± 7% vs. 21 ± 12%; P < 0.05). Similarly, in YM versus OM, aging blunted the increase in medial costal diaphragm BF (43 ± 6% vs. 24 ± 12%; P < 0.05) and VC (50 ± 6% vs. 34 ± 10%; P < 0.05). In female rats, age increased dorsal costal diaphragm BF, whereas in male rats, age increased crural diaphragm BF ( P < 0.05). Compared with age-matched females, dorsal costal diaphragm BF was lower in YM and OM ( P < 0.05). In conclusion, aging results in an inability to augment medial costal diaphragm BF and alters regional diaphragm BF distribution in response to muscular contractions. Furthermore, sex differences in regional diaphragm BF are present in young and old animals. NEW & NOTEWORTHY This is the first study, to our knowledge, to demonstrate that old age impairs the hyperemic response and alters blood flow distribution in the diaphragm of both female and male rats. In addition, this investigation provides novel evidence of sex differences in regional diaphragm blood flow distribution with contractions. The data presented herein suggest that aging compromises diaphragm vascular function and provides a potential mechanism for the diaphragm contractile dysfunction associated with old age.

Pulmonary hypertension (PH) is a chronic, progressive condition in which respiratory muscle dysfunction is a primary contributor to exercise intolerance and dyspnea in patients. Contractile function, blood flow distribution, and the hyperemic response are altered in the diaphragm with PH, and we sought to determine whether this may be attributed, in part, to impaired vasoreactivity of the resistance vasculature. We hypothesized that there would be blunted endothelium-dependent vasodilation and impaired myogenic responsiveness in arterioles from the diaphragm of PH rats. Female Sprague-Dawley rats were randomized into healthy control (HC, n = 9) and monocrotaline-induced PH rats (MCT, n = 9). Endothelium-dependent and -independent vasodilation and myogenic responses were assessed in first-order arterioles (1As) from the medial costal diaphragm in vitro. There was a significant reduction in endothelium-dependent (via acetylcholine; HC, 78 ± 15% vs. MCT, 47 ± 17%; P < 0.05) and -independent (via sodium nitroprusside; HC, 89 ± 10% vs. MCT, 66 ± 10%; P < 0.05) vasodilation in 1As from MCT rats. MCT-induced PH also diminished myogenic constriction (P < 0.05) but did not alter passive pressure responses. The diaphragmatic weakness, impaired hyperemia, and blood flow redistribution associated with PH may be due, in part, to diaphragm vascular dysfunction and thus compromised oxygen delivery which occurs through both endothelium-dependent and -independent mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hydrogen peroxide (H 2 O 2 ) and calcium ions (Ca 2+ ) are functional regulators of skeletal muscle contraction and metabolism. Although H 2 O 2 is one of the activators of the type-1 ryanodine receptor (RyR1) in the Ca 2+ release channel, the interdependence between H 2 O 2 and Ca 2+ dynamics remains unclear. This study tested the following hypotheses using an in vivo model of mouse tibialis anterior (TA) skeletal muscle. 1 ) Under resting conditions, elevated cytosolic H 2 O 2 concentration ([H 2 O 2 ] cyto ) leads to a concentration-dependent increase in cytosolic Ca 2+ concentration ([Ca 2+ ] cyto ) through its effect on RyR1; and 2 ) in hypoxia (cardiac arrest) and muscle contractions (electrical stimulation), increased [H 2 O 2 ] cyto induces Ca 2+ accumulation. Cytosolic H 2 O 2 (HyPer7) and Ca 2+ (Fura-2) dynamics were resolved by TA bioimaging in young C57BL/6J male mice under four conditions: 1 ) elevated exogenous H 2 O 2 ; 2 ) cardiac arrest; 3 ) twitch (1 Hz, 60 s) contractions; and 4 ) tetanic (30 s) contractions. Exogenous H 2 O 2 (0.1-100 mM) induced a concentration-dependent increase in [H 2 O 2 ] cyto (+55% at 0.1 mM; +280% at 100 mM) and an increase in [Ca 2+ ] cyto (+3% at 1.0 mM; +8% at 10 mM). This increase in [Ca 2+ ] cyto was inhibited by pharmacological inhibition of RyR1 by dantrolene. Cardiac arrest-induced hypoxia increased [H 2 O 2 ] cyto (+33%) and [Ca 2+ ] cyto (+20%) 50 min postcardiac arrest. Compared with the exogenous 1.0 mM H 2 O 2 condition, [H 2 O 2 ] cyto after tetanic muscle contractions rose less than one-tenth as much, whereas [Ca 2+ ] cyto was 4.7-fold higher. In conclusion, substantial increases in [H 2 O 2 ] cyto levels evoke only modest Ca 2+ accumulation via their effect on the sarcoplasmic reticulum RyR1. On the other hand, contrary to hypoxia secondary to cardiac arrest, increases in [H 2 O 2 ] cyto from muscle contractions are small, indicating that H 2 O 2 generation is unlikely to be a primary factor driving the significant Ca 2+ accumulation after, especially tetanic, muscle contractions. NEW & NOTEWORTHY We developed an in vivo mouse myocyte H 2 O 2 imaging model during exogenous H 2 O 2 loading, ischemic hypoxia induced by cardiac arrest, and muscle contractions. In this study, the interrelationship between cytosolic H 2 O 2 levels and Ca 2+ homeostasis during muscle contraction and hypoxic conditions was revealed. These results contribute to the elucidation of the mechanisms of muscle fatigue and exercise adaptation.

Skeletal muscle generates heat via contraction-dependent (shivering) and independent (nonshivering) mechanisms. While this thermogenic capacity of skeletal muscle undoubtedly contributes to the body temperature homeostasis of animals and impacts various cellular functions, the intracellular temperature and its dynamics in skeletal muscle in vivo remain elusive. We aimed to determine the intracellular temperature and its changes within skeletal muscle in vivo during contraction and following relaxation. In addition, we tested the hypothesis that sarcoplasmic reticulum Ca 2+ ATPase (SERCA) generates heat and increases the myocyte temperature during a transitory Ca 2+ -induced contraction-relaxation cycle. The intact spinotrapezius muscle of anesthetized adult male Wistar rats (n = 18) was exteriorized and loaded with the fluorescent probe Cellular Thermoprobe for Fluorescence Ratio (49.3 μM) by microinjection over 1 s. The fluorescence ratio (i.e., 580 nm/515 nm) was measured in vivo during 1) temperature increases induced by means of an external heater, and 2) Ca 2+ injection (3.9 nL, 2.0 mM). The fluorescence ratio increased as a linear function of muscle surface temperature from 25 °C to 40 °C (r 2  = 0.97, P < 0.01). Ca 2+ injection (3.9 nL, 2.0 mM) significantly increased myocyte intracellular temperature: An effect that was suppressed by SERCA inhibition with cyclopiazonic acid (CPA, Ca 2+ : 38.3 ± 1.4 °C vs Ca 2+ +CPA: 28.3 ± 2.8 °C, P < 0.01 at 1 min following injection). While muscle shortening occurred immediately after the Ca 2+ injection, the increased muscle temperature was maintained during the relaxation phase. In this investigation, we demonstrated a novel model for measuring the intracellular temperature of skeletal muscle in vivo and further that heat generation occurs concomitant principally with SERCA functioning and muscle relaxation., Competing Interests: Declaration of competing interest The author declares that there are no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, respiratory muscle and cardiac impairments, and exercise intolerance. Specifically, impaired gas exchange increases work of the diaphragm; however, compromised contractile function precludes the diaphragm from meeting the increased metabolic demand of chronic hyperventilation in PH. Given that muscle contractile function is in part, dependent upon adequate blood flow ( Q ˙ ), diaphragmatic dysfunction may be predicated by an inability to match oxygen delivery with oxygen demand. We hypothesized that PH rats would demonstrate a decreased hyperemic response to contractions compared to healthy controls. Methods: Sprague-Dawley rats were randomized into healthy (HC, n = 7) or PH (n = 7) groups. PH rats were administered monocrotaline (MCT) while HC rats received vehicle. Disease progression was monitored via echocardiography. Regional and total diaphragm blood flow and vascular conductance at baseline and during 3 min of electrically-stimulated contractions were determined using fluorescent microspheres. Results: PH rats displayed morphometric and echocardiographic criteria for disease (i.e., acceleration time/ejection time, right ventricular hypertrophy). In all rats, total costal diaphragm Q ˙ increased during contractions and did not differ between groups. In HC rats, there was a greater increase in medial costal Q ˙ compared to PH rats (55% ± 3% vs. 44% ± 4%, p < 0.05), who demonstrated a redistribution of Q ˙ to the ventral costal region. Conclusion: These findings support a redistribution of regional diaphragm perfusion and an impaired medial costal hyperemic response in PH, suggesting that PH alters diaphragm vascular function and oxygen delivery, providing a potential mechanism for PH-induced diaphragm contractile dysfunction., 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 © 2023 Schulze, Horn, Weber, Behnke, Poole and Musch.)

Intracellular Ca 2+ concentration ([Ca 2+ ] i ) is considered important in the regulation of skeletal muscle mass. This study tested the hypothesis that chronic repeated cooling and/or caffeine ingestion would acutely increase [Ca 2+ ] i and hypertrophy muscles potentially in a fiber-type-dependent manner. Control rats and those fed caffeine were subjected to repeated bidiurnal treatments of percutaneous icing, under anesthesia, to reduce the muscle temperature below ∼5°C. The predominantly fast-twitch tibialis anterior (TA) and slow-twitch soleus (SOL) muscles were evaluated after 28 days of intervention. The [Ca 2+ ] i elevating response to icing was enhanced by caffeine loading only in the SOL muscle, with the response present across a significantly higher temperature range than in the TA muscle under caffeine-loading conditions. In both the TA and SOL muscles, myofiber cross-sectional area (CSA) was decreased by chronic caffeine treatment (mean reductions of 10.5% and 20.4%, respectively). However, in the TA, but not the SOL, CSA was restored by icing (+15.4 ± 4.3% vs. noniced, P < 0.01). In the SOL, but not TA, icing + caffeine increased myofiber number (20.5 ± 6.7%, P < 0.05) and satellite cell density (2.5 ± 0.3-fold) in cross sections. These contrasting muscle responses to cooling and caffeine may reflect fiber-type-specific [Ca 2+ ] i responses and/or differential responses to elevated [Ca 2+ ] i .

Background: To what extent sex-related differences in cardiorespiratory fitness (CRF) impact postoperative patient mortality and corresponding implications for surgical risk stratification remains to be established., Methods: To examine this, we recruited 640 patients (366 males vs. 274 females) who underwent cardiopulmonary exercise testing prior to elective colorectal surgery. Patients were defined high risk if peak oxygen uptake was <14.3 mL kg -1  min -1 and ventilatory equivalent for carbon dioxide at 'anaerobic threshold' >34. Between-sex CRF and mortality was assessed, and sex-specific CRF thresholds predictive of mortality was calculated., Results: Seventeen percent of deaths were attributed to sub-threshold CRF, which was higher than established risk factors for cardiovascular disease (CVD). The group (independent of sex) exhibited a 5-fold higher mortality (high vs. low risk patients hazard ratio = 4.80, 95% confidence interval 2.73-8.45, p < 0.001). Females exhibited 39% lower CRF (p < 0.001) with more classified high risk than males (36 vs. 23%, p = 0.001), yet mortality was not different (p = 0.544). Upon reformulation of sex-specific CRF thresholds, lower cut-offs for mortality were observed in females, and consequently, fewer (20%) were stratified with sub-threshold CRF compared to the original 36% (p < 0.001)., Conclusions: Low CRF accounted for more deaths than traditional CVD risk factors, and when CRF was considered relative to sex, the disproportionate number of females stratified unfit was corrected. These findings support clinical consideration of 'sex-specific' CRF thresholds to better inform postoperative mortality and improve surgical risk stratification., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

In rats with type II diabetes mellitus (T2DM) compared with nondiabetic healthy controls, muscle blood flow (Q̇m) to primarily glycolytic hindlimb muscles and the diaphragm muscle are elevated during submaximal treadmill running consequent to lower skeletal muscle mass, a finding that held even when muscle mass was normalized to body mass. In rats with heart failure with reduced ejection fraction (HF-rEF) compared with healthy controls, hindlimb Q̇m was lower, whereas diaphragm Q̇m is elevated during submaximal treadmill running. Importantly, T2DM is the most common comorbidity present in patients with HF-rEF, but the effect of concurrent T2DM and HF-rEF on limb and respiratory Q̇m during exercise is unknown. We hypothesized that during treadmill running (20 m·min -1 ; 10% incline), hindlimb and diaphragm Q̇m would be higher in T2DM Goto-Kakizaki rats with HF-rEF (i.e., HF-rEF + T2DM) compared with nondiabetic Wistar rats with HF-rEF. Ejection fractions were not different between groups (HF-rEF: 30 ± 5; HF-rEF + T2DM: 28 ± 8%; P = 0.617), whereas blood glucose was higher in HF-rEF + T2DM (209 ± 150 mg/dL) compared with HF-rEF rats (113 ± 28 mg/dL; P = 0.040). Hindlimb muscle mass normalized to body mass was lower in rats with HF-rEF + T2DM (36.3 ± 1.6 mg/g) than in nondiabetic HF-rEF counterparts (40.3 ± 2.7 mg/g; P < 0.001). During exercise, Q̇m was elevated in rats with HF-rEF + T2DM compared with nondiabetic counterparts to the hindlimb (HF-rEF: 100 ± 28; HF-rEF + T2DM: 139 ± 23 mL·min -1 ·100 g -1 ; P < 0.001) and diaphragm (HF-rEF: 177 ± 66; HF-rEF + T2DM: 215 ± 93 mL·min -1 ·100g -1 ; P = 0.035). These data suggest that the pathophysiological consequences of T2DM on hindlimb and diaphragm Q̇m during treadmill running in the GK rat persist even in the presence of HF-rEF. NEW & NOTEWORTHY Herein, we demonstrate that rats comorbid with heart failure with reduced ejection fraction (HF-rEF) and type II diabetes mellitus (T2DM) have a higher hindlimb and respiratory muscle blood flow during submaximal treadmill running (20 m·min -1 ; 10% incline) compared with nondiabetic HF-rEF counterparts. These data may carry important clinical implications for roughly half of all patients with HF-rEF who present with T2DM.

When exercising humans increase their oxygen uptake (V̇O 2 ) 20-fold above rest the numbers are staggering: Each minute the O 2 transport system - lungs, cardiovascular, active muscles - transports and utilizes 161 sextillion (10 21 ) O 2 molecules. Leg extension exercise increases the quadriceps muscles' blood flow 100-times; transporting 17 sextillion O 2 molecules per kilogram per minute from microcirculation (capillaries) to mitochondria powering their cellular energetics. Within these muscles, the capillary network constitutes a prodigious blood-tissue interface essential to exchange O 2 and carbon dioxide requisite for muscle function. In disease, microcirculatory dysfunction underlies the pathophysiology of heart failure, diabetes, hypertension, pulmonary disease, sepsis, stroke and senile dementia. Effective therapeutic countermeasure design demands knowledge of microvascular/capillary function in health to recognize and combat pathological dysfunction. Dated concepts of skeletal muscle capillary (from the Latin capillus meaning 'hair') function prevail despite rigorous data-supported contemporary models; hindering progress in the field for future and current students, researchers and clinicians. Following closely the 100th anniversary of August Krogh's 1920 Nobel Prize for capillary function this Evidence Review presents an anatomical and physiological development of this dynamic field: Constructing a scientifically defensible platform for our current understanding of microcirculatory physiological function in supporting blood-mitochondrial O 2 transport. New developments include: 1. Putative roles of red blood cell aquaporin and rhesus channels in determining tissue O 2 diffusion. 2. Recent discoveries regarding intramyocyte O 2 transport. 3. Developing a comprehensive capillary functional model for muscle O 2 delivery-to-V̇O 2 matching. 4. Use of kinetics analysis to discriminate control mechanisms from collateral or pathological phenomena., Competing Interests: DCP is a Function Editorial Board Member and is blinded from reviewing or making decisions for this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

Academic dishonesty is prevalent in universities in the form of cheating on examinations, with the problem being much greater in classes that have a large number of students that require close seating arrangements for in-class exams. The scenario described below was experienced during an in-class exam that included the possibility of an Honor Code violation between two students that was observed independently by three different faculty proctors. Herein we detail an objective, statistical approach taken to maintain exam and academic integrity that is compelling and transparent to students and the University Honor Council. Using the established error-similarity analysis for multiple-choice exams, it was determined that the number of identical incorrect answers found on the exams of the two individuals in question was sufficiently greater than the number expected by chance (probability of P < 0.00001). The number of total identical incorrect answers found on the remaining exams (across 65 students, n = 89 comparisons) was plotted as function of the number of total incorrect answers found on these exams (incorrect answers ranged from 1 to 22) and clearly supported that there was an Honor Code violation between the two students in question. The techniques used herein established, beyond a reasonable doubt, that a form of cheating had occurred between these students. However, caution must be taken as further investigation is requisite to establish whether the Honor Code violation was unidirectional (one student copying off the other) or bidirectional (collusion between the two students) in nature. NEW & NOTEWORTHY Academic dishonesty is prevalent in universities, especially on examinations with a large number of students in close seating arrangements. Cheating on a multiple-choice exam was suspected by observations from proctors of the examination. Application of error-similarity analysis associated with identical incorrect answers demonstrated that the probability of cheating was confirmed ( P < 0.00001) between two examinees. Further comparisons with the remaining exams provided graphic evidence that a violation of the University's Honor Code had occurred.

Objective: To compare the rate of energy expenditure of low efficiency walking with high efficiency walking., Design: Laboratory based experimental study., Setting: United States., Participants: 13 healthy adults (six women, seven men) with no known gait disorder, mean (±standard deviation) age 34.2±16.1 years, height 174.2±12.6 cm, weight 78.2±22.5 kg, and body mass index 25.6±6.0., Intervention: Participants performed three, five minute walking trials around an indoor 30 m course. The first trial consisted of walking at a freely chosen walking speed in the participant's usual style. The next two trials consisted of low efficiency walks in which participants were asked to duplicate the walks of Mr Teabag and Mr Putey (acted by John Cleese and Michael Palin, respectively) in the legendary Monty Python Ministry of Silly Walks (MoSW) skit that first aired in 1970. Distance covered during the five minute walks was used to calculate average speed. Ventilation and gas exchange were collected throughout to determine oxygen uptake (V̇O 2 ; mL O 2 /kg/min) and energy expenditure (EE; kcal/kg/min; 1 kcal=4.18 kJ), reported as mean±standard deviation., Main Outcome Measures: V̇O 2 and EE., Results: V̇O 2 and EE were about 2.5 times higher (P<0.001) during the Teabag walk compared with participants' usual walk (27.9±4.8 v 11.3±1.9 mL O 2 /kg/min; 0.14±0.03 v 0.06±0.01 kcal/kg/min), but were not different during the Putey walk (12.3±1.8 mL/kg/min; 0.06±0.01 kcal/kg/min). Each minute of Teabag walking increased EE over participants' usual walking by an average of 8.0 kcal (range 5.5-12.0) in men and by 5.2 kcal (range 3.9-6.2) in women, and qualified as vigorous intensity physical activity (>6 resting metabolic equivalents)., Conclusions: For adults with no known gait disorder who average approximately 5000 steps/day, exchanging about 22%-34% of their daily steps with higher energy, low efficiency walking in Teabag style-requiring around 12-19 min-could increase daily EE by 100 kcal. Adults could achieve 75 minutes of vigorous intensity physical activity per week by walking inefficiently for about 11 min/day. Had an initiative to promote inefficient movement been adopted in the early 1970s, we might now be living among a healthier society. Efforts to promote higher energy-and perhaps more joyful-walking should ensure inclusivity and inefficiency for all., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

An inaugural workshop supported by "The Leo and Anne Albert Charitable Trust," was held October 4-7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimer's and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain., Competing Interests: None to declare., (© 2022 – The authors. Published by IOS Press.)

New Findings: What is the topic of this review? The relationships and physiological mechanisms underlying the clinical benefits of cardiorespiratory fitness (CRF) in patients undergoing major intra-abdominal surgery. What advances does it highlight? Elevated CRF reduces postoperative morbidity/mortality, thus highlighting the importance of CRF as an independent risk factor. The vascular protection afforded by exercise prehabilitation can further improve surgical risk stratification and postoperative outcomes., Abstract: Surgery accounts for 7.7% of all deaths globally and the number of procedures is increasing annually. A patient's 'fitness for surgery' describes the ability to tolerate a physiological insult, fundamental to risk assessment and care planning. We have evolved as obligate aerobes that rely on oxygen (O 2 ). Systemic O 2 consumption can be measured via cardiopulmonary exercise testing (CPET) providing objective metrics of cardiorespiratory fitness (CRF). Impaired CRF is an independent risk factor for mortality and morbidity. The perioperative period is associated with increased O 2 demand, which if not met leads to O 2 deficit, the magnitude and duration of which dictates organ failure and ultimately death. CRF is by far the greatest modifiable risk factor, and optimal exercise interventions are currently under investigation in patient prehabilitation programmes. However, current practice demonstrates potential for up to 60% of patients, who undergo preoperative CPET, to have their fitness incorrectly stratified. To optimise this work we must improve the detection of CRF and reduce potential for interpretive error that may misinform risk classification and subsequent patient care, better quantify risk by expressing the power of CRF to predict mortality and morbidity compared to traditional cardiovascular risk factors, and improve patient interventions with the capacity to further enhance vascular adaptation. Thus, a better understanding of CRF, used to determine fitness for surgery, will enable both clinicians and exercise physiologists to further refine patient care and management to improve survival., (© 2022 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)