To investigate the influence of biological sex, independent of differences in aerobic fitness and body fatness, on the change in gastro-intestinal temperature (∆Tgi) and whole-body sweat rate (WBSR) of children exercising under uncompensable heat stress. Seventeen boys (mean±SD; 13.7±1.3 years) and 18 girls (13.7±1.4) years) walked for 45 min at a fixed rate of metabolic heat production per kg body mass (8 W·kg-1) in 40°C and 30% relative humidity. Sex and V̇O2peak were entered into a Bayesian hierarchical general additive model (HGAM) for Tgi. Sex, V̇O2peak and the evaporative requirement for heat balance (Ereq) were entered into a Bayesian hierarchical linear regression for WBSR. For 26 (12 M, 14 F) of the 35 children with measured body composition, body fat percentage was entered in a separate HGAM and hierarchical linear regression for Tgi and WBSR respectively. Conditional on sex-specific mean V̇O2peak, ∆Tgi was 1.00°C [90% credible intervals: 0.84, 1.16] for boys and 1.17°C [1.01, 1.33] for girls, with a difference of 0.17°C [-0.39, 0.06]. When sex differences in V̇O2peak were accounted for, the difference in ∆Tgi between boys and girls was 0.01°C [-0.25, 0.22]. The difference in WBSR between boys and girls was 0.03 L·h-1 [-0.02, 0.07], when isolated from differences in Ereq. The difference in ∆Tgi between boys and girls was -0.10°C [-0.38, 0.17] when sex differences in body fat (%) were accounted for. Biological sex did not independently influence the ∆Tgi and WBSR of children exercising under uncompensable heat stress.

Excessive dynamic airway collapse (EDAC) is a recognized cause of exertional dyspnea arising due to invagination of the trachea and/ or main bronchi. EDAC is typically assessed by evaluating large airway movement with forced expiratory maneuvers. This differs from the respiratory response to exercise hyperpnea. We aimed to evaluate large airway movement during physical activity, with continuous bronchoscopy during exercise (CBE), in healthy subjects and compare findings with resting bronchoscopic maneuvers and imaging techniques. Twenty-eight individuals were recruited to complete two visits including treadmill-based CBE, to voluntary exhaustion and cine magnetic resonance imaging (MRI) with forced expiratory maneuvers at rest. 25 subjects (aged 29 (26 - 33) years, 52% female) completed the study (n=2 withdrew before bronchoscopy, and one was unable to tolerate insertion of bronchoscope). The majority (76%) achieved a peak heart rate of >90% predicted during CBE. The procedure was prematurely terminated in five subjects (n=3; elevated blood pressure and n=2; minor oxygen desaturation). The CBE assessment enabled adequate tracheal visualization in all cases. Excessive dynamic airway collapse (tracheal collapse ≥50%) was identified in 16 subjects (64%) on MRI, and in 6 (24%) individuals during resting bronchoscopy, but in no cases with CBE. No serious adverse events were reported, but minor adverse events were evident. The CBE procedure permits visualization of large airway movement during physical activity. In healthy subjects, there was no evidence of EDAC during strenuous exercise, despite evidence during forced maneuvers on imaging, thus challenging conventional approaches to diagnosis.

Breathing effort is important to quantify to understand mechanisms underlying central and obstructive sleep apnea, respiratory-related arousals, and the timing and effectiveness of invasive or non-invasive mechanically assisted ventilation. Current quantitative methods to evaluate breathing effort rely on inspiratory esophageal or epiglottic pressure swings or changes in diaphragm electromyographic (EMG) activity, where units are problematic to interpret and compare between individuals and to measured ventilation. This paper derives a novel method to quantify breathing effort in units directly comparable to measured ventilation by applying respiratory mechanics first principles to convert continuous transpulmonary pressure measurements into "attempted" airflow expected to have arisen without upper airway obstruction. The method was evaluated using data from eleven subjects undergoing overnight polysomnography, including 6 obese patients with severe obstructive sleep apnea (OSA), including one who also had frequent central events, and 5 healthy-weight controls. Classic respiratory mechanics showed excellent fits of airflow and volume to transpulmonary pressures during wake periods of stable unobstructed breathing (mean ± SD r² = 0.94 ± 0.03), with significantly higher respiratory system resistance in patients compared to healthy controls (11.2 ± 3.3 vs 7.1 ± 1.9 cmH2O·l-1·sec, P=0.032). Subsequent estimates of attempted airflow from transpulmonary pressure changes clearly highlighted periods of acute and prolonged upper airway obstruction, including within the first few breaths following sleep onset in patients. This novel technique provides unique quantitative insights into the complex and dynamically changing inter-relationships between breathing effort and achieved airflow during periods of obstructed breathing in sleep.

Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship.NEW & NOTEWORTHY This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms.

Blood flow regulation within the microvasculature reflects a complex interaction of regulatory mechanisms and varies spatially and temporally according to conditions such as metabolism, growth, injury, and disease. Understanding the role of microvascular flow distributions across conditions is of interest to investigators spanning multiple disciplines; however, data collection within networks can be labor-intensive and challenging due to limited resolution. To overcome these experimental challenges, computational network models that can accurately simulate vascular behavior are highly beneficial. Constrained constructive optimization (CCO) is a commonly used algorithm for vascular simulation, particularly well known for its adaptability toward vascular modeling across tissues. The present work demonstrates an implementation of CCO aimed to simulate a branching arteriolar microvasculature in healthy skeletal muscle, validated against literature including comprehensive rat gluteus maximus vasculature datasets, and reviews a list of user-specified adjustable model parameters to understand how their variability affects the simulated networks. Network geometric properties, including mean element diameters, lengths, and numbers of bifurcations per order, Horton's law ratios, and fractal dimension, demonstrate good validation once model parameters are adjusted to experimental data. This model successfully demonstrates hemodynamic properties such as Murray's law and the network Fahraeus effect. Application of centrifugal and Strahler ordering schemes results in divergent descriptions of identical simulated networks. This work introduces a novel CCO-based model focused on generating branching skeletal muscle microvascular arteriolar networks based on adjustable model parameters, thus making it a valuable tool for investigations into skeletal muscle microvascular structure and tissue perfusion.NEW & NOTEWORTHY The present work introduces a CCO-based algorithm for generating branching arteriolar networks, with adjustable model parameters to enable modeling in varying skeletal muscle tissues. The geometric and hemodynamic parameters of the generated networks have been comprehensively validated using experimental data collected previously in-house and from literature. This is one of few validated CCO-based models to specialize in skeletal muscle microvasculature and acts as a beneficial tool for investigating the microvasculature for hypothesis testing and validation.

Despite the prognostic effect of physical activity, acute bouts of high-volume endurance exercise can induce cardiac stress and postexercise hypercoagulation associated with increased thrombotic risk. The aim of this study was to explore the effect of high-volume endurance exercise on coagulation and thrombotic activity in recreational cyclists. Thirty-four recreational cyclists completed 4.8 ± 0.3 h of cycling at 45 ± 5% of maximal power output on a bicycle ergometer. Intravenous blood samples were collected preexercise, immediately postexercise, 24 and 48 h postexercise, and analyzed for brain natriuretic peptide (BNP), cardiac troponin (cTn), C-reactive protein (CRP), D-dimer, thrombin-antithrombin (TAT) complex, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and TF-to-TFPI ratio (TF:TFPI). An increase in cTn was observed postexercise (P < 0.001). CRP concentrations were increased at 24 and 48 h postexercise compared with preexercise concentrations (P ≤ 0.001). TF was elevated at 24 h postexercise (P < 0.031) and TFPI was higher immediately postexercise (P < 0.044) compared with all other time points. TF:TFPI was increased at 24 and 48 h postexercise compared with preexercise (P < 0.025). TAT complex was reduced at 48 h postexercise compared with preexercise (P = 0.015), D-dimer was higher immediately postexercise compared with all other time points (P ≤ 0.013). No significant differences were observed in BNP (P > 0.05). High-volume endurance cycling induced markers of cardiac stress among recreational cyclists. However, plasma coagulation and fibrinolytic activity suggest no increase in thrombotic risk after high-volume endurance exercise.NEW & NOTEWORTHY In this study, a high-volume endurance exercise protocol induced markers of cardiac stress and altered plasma coagulation and fibrinolytic activity for up to 48 h in recreationally active cyclists. However, analysis of coagulation biomarkers indicates no increase in thrombotic risk when appropriate hydration and rest protocols are implemented.

The metabolic cost of walking (MCOW), or oxygen uptake normalized to distance, provides information on the energy expended during movement. There are conflicting reports as to whether sex differences in MCOW exist, with scarce evidence investigating factors that explain potential sex differences. This study 1) tested the hypothesis that females exhibit a higher MCOW than males, 2) determined whether normalizing to stepping cadence ameliorates the hypothesized sex difference, and 3) explored whether more habitual step counts and time in intensity-related physical activity, and less sedentary time were associated with a decreased MCOW. Seventy-six participants (42 females, 24 ± 5 yr) completed a five-stage, graded treadmill protocol with speeds increasing from 0.89 to 1.79 m/s (6-min walking stage followed by 4-min passive rest). Steady-state oxygen uptake (via indirect calorimetry) and stepping cadence (via manual counts) were determined. Gross and net MCOW, normalized to distance traveled (km) and step-cadence (1,000 steps) were calculated for each stage. Thirty-nine participants (23 females) wore an activPAL on their thigh for 6.9 ± 0.4 days. Normalized to distance, females had greater gross MCOW (J/kg/km) at all speeds (P < 0.014). Normalized to stepping frequency, females exhibited greater gross and net MCOW at 1.12 and 1.79 m/s (J/kg/1,000 steps; P < 0.01) but not at any other speeds (P < 0.075). Stature was negatively associated with free-living cadence (r = -0.347, P = 0.030). Females expend more energy/kilometer traveled than males, but normalizing to stepping cadence attenuated these differences. Such observations provide an explanation for prior work documenting higher MCOW among females and highlight the importance of stepping cadence when assessing the MCOW.NEW & NOTEWORTHY Whether there are sex differences in the metabolic cost of walking (MCOW) and the factors that may contribute to these are unclear. We demonstrate that females exhibit a larger net MCOW than males. These differences were largely attenuated when normalized to stepping cadence. Free-living activity was not associated with MCOW. We demonstrate that stepping cadence, but not free-living activity, partially explains the higher MCOW in females than males.

During aging, muscles undergo atrophy, which is partly accounted for by a loss of sarcomeres in series. Serial sarcomere number (SSN) is associated with aspects of muscle mechanical function including the force-length and force-velocity-power relationships; hence, the age-related loss of SSN contributes to declining performance. Training emphasizing eccentric contractions increases SSN in young healthy rodents; however, the ability for eccentric training to increase SSN in old age is unknown. Ten young (8 mo) and 11 old (32 mo) male Fisher344/BN rats completed 4 wk of unilateral eccentric plantar flexion training. Pre- and posttraining, the plantar flexors were assessed for the torque-frequency, passive torque-angle, and torque-velocity-power relationships. The soleus, lateral gastrocnemius (LG), and medial gastrocnemius (MG) were harvested for SSN assessment via laser diffraction, with the untrained leg used as a control. In the untrained leg/pretraining, old rats had lower SSN in the soleus, LG, and MG, lower maximum torque, power, and shortening velocity, and greater passive torque than young. Young showed increased soleus and MG SSN following training. In contrast, old had no change in soleus SSN and experienced SSN loss in the LG. Pre- to posttraining, young experienced an increase in maximum isometric torque, whereas old had reductions in maximum torque, shortening velocity, and power, and increased passive torque. Our results show that although young muscle has the ability to add sarcomeres in response to maximal eccentric training, this stimulus could be not only ineffective, but also detrimental to aged muscle leading to dysfunctional remodeling.NEW & NOTEWORTHY The loss of sarcomeres in series with age contributes to declining muscle performance. The present study investigated whether eccentric training could improve performance via serial sarcomere addition in old muscle, like in young muscle. Four weeks of maximal eccentric training induced serial sarcomere addition in the young rat plantar flexors and improved in vivo performance, however, led to dysfunctional remodeling accompanied by further impaired performance in old rats.

Sarcolemmal membrane excitability is often evaluated by considering the peak-to-peak amplitude of the compound muscle action potential (M wave). However, the first and second M-wave phases represent distinct properties of the muscle action potential, which are differentially affected by sarcolemma properties and other factors such as muscle architecture. Contrasting with previous studies in which voluntary contractions have been used to induce muscle fatigue, we used repeated electrically induced tetanic contractions of the adductor pollicis muscle and assessed the kinetics of M-wave properties during the course of the contractions. Eighteen participants (24 ± 6 yr; means ± SD) underwent 30 electrically evoked tetanic contractions delivered at 30 Hz, each lasting 3 s with 1 s intervals. We recorded the amplitudes of the first and second M-wave phases for each stimulation. During the initial stimulation train, the first and second M-wave phases exhibited distinct kinetics. The first phase amplitude showed a rapid decrease to reach ∼59% of its initial value (P < 0.001), whereas the second phase amplitude displayed an initial transient increase of ∼19% (P = 0.007). Within subsequent trains, both the first and second phase amplitudes consistently decreased as fatigue developed with a reduction during the last train reaching ∼47% of its initial value (P < 0.001). Analyzing the first M wave of each stimulation train unveiled different kinetics for the first and second phases during the initial trains, but these distinctions disappeared as fatigue progressed. These findings underscore the interplay of factors affecting the M wave and emphasize the significance of separately scrutinizing its first and second phases when assessing membrane excitability adjustments during muscle contractions.NEW & NOTEWORTHY Our understanding of how the first and second phases of the compound muscle action potential (M wave) behave during fatigue remains incomplete. Using electrically evoked repeated tetanic contractions of the adductor pollicis, we showed that the first and second phases of the M wave followed distinct kinetics only during the early stages of fatigue development. This suggests that the factors affecting the M-wave first and second phases may change as fatigue develops.