Purpose: To assess longitudinal changes in official competitive performance in elite runners with androgen-sensitive 46,XY differences of sex development (DSD) during prolonged testosterone suppression. Methods: This retrospective longitudinal study analyzed nine elite 46,XY DSD runners with type II 5α-reductase deficiency who maintained serum testosterone below 2.5 nmol/L after gonadectomy, gonadotropin-releasing hormone agonist treatment, or combined oral contraceptive use. Outdoor performances in sprint, middle-distance, and long-distance events were evaluated. Semester-best performances were compared with pre-suppression personal bests and expressed as percentage change and World Athletics World Ranking points. Results: Before treatment, mean serum testosterone was 22.5 ± 6.5 nmol/L. Follow-up included 16 performance profiles and 44 semester-best observations over 0-1258 days of suppression. Competitive performance declined after testosterone suppression, with mean decrements of 6.0%, 7.1%, 6.5%, 7.2%, 6.6%, and 4.4% across successive semesters. Across the full observation period, the mean performance decrement was 6.5 ± 3.6%, and after two years it remained approximately 6.0 ± 4.5%. No significant difference in percentage decrement was observed between sprint and middle-/long-distance groups, although substantial interindividual variability was present. Conclusion: Sustained testosterone suppression in elite androgen-sensitive 46,XY DSD runners was associated with a clear but heterogeneous reduction in competitive performance. In several athletes, the decrement remained smaller than the expected elite male-female performance gap, suggesting that prior male-range androgen exposure may confer advantages not uniformly abolished by current testosterone suppression.
Neurological and neuropsychological deficits remain common following cardiovascular surgery in infants, yet the mechanisms underlying neuronal injury during deep hypothermic circulatory arrest (DHCA) are not fully understood. Our previous study demonstrated that inhaled nitric oxide (NO) attenuates DHCA induced microglial activation and neurodegeneration. In this study, we investigated whether targeted inhibition of NO synthase (NOS) could reduce brain damage following DHCA. Based on previously published data, we used 2-iminobiotin, a selective inhibitor of both neuronal NOS (nNOS) and inducible NOS (iNOS). Juvenile piglets (~7 weeks old) underwent DHCA (cooled to 18C) for 30 minutes, followed by rewarming either with or without NOS inhibitor. Neuroinflammation and neuronal injury were assessed histologically in the hippocampus. TUNEL staining revealed that NOS inhibitor (TUNEL positive cells; median 1.3%) significantly alleviated neuronal damage compared with non-treatment group (median 6.7%). NOS reduced the microglia activities related to cerebral neuroinflammatory reaction after DHCA. NOS inhibition reduces neuronal degeneration and microglial activation in the hippocampus following DHCA. These findings suggest that the NOS inhibitor reduces neuronal degeneration by ameliorating inflammation.
The purpose of this study is to determine in humans whether lactate inhibits exercise-stimulated lipolysis, fat oxidation, and plasma glucose turnover. Eight healthy active individuals (3 women) completed 4 trials in a semi-randomized order. In two trials, subjects exercised for 60 min at 65±11% (mean±SD) of VO 2 MAX while receiving isovolumetric infusions of either sodium lactate (MOD+LACT trial) or saline (MOD trial). In another trial, exercise intensity was increased to 82±11% of VO 2 MAX (INT trial) to match lactate concentrations to those in the MOD+LACT trial. A trial without exercise was included. Stable isotopes of glycerol and glucose were infused to assess whole-body lipolysis (Ra Glycerol) and glucose turnover rates (Ra Glucose). Fat and carbohydrate oxidation were measured using indirect calorimetry. Basal metabolic rate and plasma concentrations of lactate, glucose, insulin, FFA, and glycerol were similar across trials. Plasma lactate was clamped at 4.31±1.68 mM during the MOD+LACT trial, which tripled MOD concentrations (1.42±0.93 mM; p=0.001) and matched INT concentrations (4.39±1.25 mM; p=0.819). MOD+LACT blunted the exercise-induced elevation in Ra Glycerol of MOD (average during exercise, 7.9±2.0 vs 10.5±2.2 µmol·kg -1 ·min -1 ; p=0.014). However, fat oxidation rates were similar in MOD+LACT and MOD (7.70 ±2.02 vs 7.38±1.47 µmol·kg -1 ·min -1 ; p=0.612) but reduced during INT (5.30±2.93 µmol·kg -1 ·min -1 ; p=0.045). Ra Glucose, plasma glucose, and insulin were elevated during INT but not affected by lactate infusion. Raising circulating lactate concentrations to levels observed during high-intensity exercise blunts exercise-stimulated whole-body lipolysis. However, in these metabolically healthy individuals, that reduction was not sufficient to compromise fat oxidation during moderate intensity exercise.
There is a distinct lack of understanding regarding the training patterns of elite athletes during pregnancy. This retrospective case study of training data is the first to our knowledge to examine the training patterns, performance, health, and delivery outcomes of a 35-year-old professional cyclist across the perinatal period. During her pregnancy, she cycled a total of 351.15 hours (approximately four times the current minimum recommendations) with an average of 9.00 5.42 hours per week with no health complications or injuries. She trained regularly (4 2 sessions per week) at moderate to vigorous intensity for the majority (95%) of the training sessions during her pregnancy. The average altitude that the participant cycled at during pregnancy was 564.83 587.52m with a maximum altitude of 2310 m and a maximum solar load of 46C. She delivered via planned cesarean-section at 38 +5 week of gestation and experienced no maternal or fetal complications.
Cardiovascular diseases remain the leading cause of death among women in the United States, and arterial stiffness is a strong predictor of cardiovascular events and mortality. Growing evidence suggests that neighborhood socioeconomic context contributes to cardiovascular risk, yet the physiological pathways linking neighborhood disadvantage to vascular health remain unclear. This study examined whether cardiorespiratory fitness (CRF) mediates the association between neighborhood deprivation (ND) and arterial stiffness in postmenopausal women. Ninety-one Black and White postmenopausal women [47 and 44, respectively, age: 64(8) yr] completed maximal treadmill testing to determine peak oxygen uptake ([Formula: see text]), and arterial stiffness was assessed via carotid-femoral pulse wave velocity (cf-PWV). ND was quantified using the area deprivation index averaged across residential addresses over the previous 25 yr. ND was associated with both lower [Formula: see text] (r = -0.45, P < 0.001) and higher cf-PWV (r = 0.28, P = 0.008). In hierarchical regression models adjusting for age, systolic blood pressure, and race, [Formula: see text] emerged as the strongest predictor of cf-PWV (B = -0.10, P = 0.003). Mediation analysis using bootstrapping revealed a significant indirect effect of ND on cf-PWV through [Formula: see text], whereas the direct effect of ND was not significant, consistent with indirect-only mediation. These findings suggest that lower CRF may partially explain the relationship between ND and vascular aging among postmenopausal women. Thus, efforts should be focused on improving access to physical activity opportunities for women facing high levels of social disadvantage.NEW & NOTEWORTHY Neighborhood disadvantage is associated with increased cardiovascular risk, yet the physiological pathways linking social environments to vascular health remain unclear. In postmenopausal women, we found that cardiorespiratory fitness mediated the relationship between neighborhood deprivation and arterial stiffness. Higher neighborhood deprivation was associated with lower fitness, which in turn was associated with greater arterial stiffness. These findings highlight cardiorespiratory fitness as a potential physiological and modifiable pathway linking adverse social environments to vascular aging.
Sprint running performances have improved with the use of advanced footwear technology, but the mechanisms responsible are unknown. Here, we tested two hypothesized mechanisms: 1) faster maximal speeds resulting from greater ground force application, and 2) associated contact time decreases and step length increases that could enable faster late-race velocities. Ten track and five soccer athletes (n = 15) completed randomized, linear 130-m sprint trials in conventional and prototype footwear. The prototypes were highly compliant and resilient in cushioning and stiff in forefoot bending. Instantaneous velocities were recorded with a radar device; contact and aerial times were acquired from ankle-mounted accelerometers throughout; split and final times (60, 100, and 130 m) were recorded with dual-beam laser timing gates. Contact times were also determined from 960 Hz video acquired from 10-m zones between 45 and 80 m. Performance times for the 130-m trials were 1.7% shorter in the prototype versus the conventional spike. Footwear condition differences in velocity were distance-dependent, increasing from a minimum of 0.1% in the first 10 m to a maximum of 3.9% at the 130-m finish line. Video capture zone contact periods were shorter (-1.9%), and estimated stance-averaged ground forces were greater (+1.6%) in the prototype versus conventional footwear. Progressive gait and velocity effects resulted in relatively large prototype versus conventional condition differences in the final 30-m segment for: contact times (-2.5%), aerial times (+6.0%), step lengths (+2.0%), and velocities (+3.0%). We conclude that the prototype footwear enabled gait mechanics that increased both maximal and late-trial sprinting velocities.NEW & NOTEWORTHY Footwear design advances have improved limb-ground dynamics to increase racing speeds across both shorter and longer track racing distances. The mechanisms of footwear-enabled performance improvements are well-established for endurance, but unknown for sprint racing events. Comparisons of advanced versus standard sprinting footwear in track and soccer athletes indicated that the advanced footwear elevated stance-average ground forces and reduced foot-ground contact times. These prototype-enabled gait mechanics improved sprinting performance by increasing maximal and late-trial sprinting speeds.
We previously demonstrated heterogenous vascular resistance (VR) responses to the cold pressor test (CPT) in females. Since cardiac output (CO) is a key determinant of the pressor response, we prospectively examined cardiac contributions to the CPT, hypothesizing that females would exhibit heterogeneous cardiac and vascular responses to the CPT. Nineteen healthy females (24±3 yrs, body mass index 22.9±1.9 kg/m2) and a comparator group of 9 males (23±3 yr, 24.8±1.6 kg/m2) completed a 3-min CPT including continuous measures of mean arterial pressure (MAP; finger photoplethysmography), CO (stroke volume (SV) [echocardiogram] x heart rate (HR) [3-lead electrocardiogram]), and femoral VR (FVR; MAP/femoral blood flow [duplex ultrasound]). The magnitude of CPT-induced changes (Δ) in MAP (p=0.96), HR (p=0.59), CO (p=0.09), and %FVR (p=0.46) were not different between sexes; ΔSV was smaller in females (1.0±5.0 vs. 5.0±3.0 mL, p=0.03). ΔSV responses were distinctly heterogeneous in female participants; females demonstrating positive ΔSV (SVINC; n=10) and negative ΔSV (SVDEC; n=9) were subdivided for subsequent analyses. SVINC had higher ΔSV (5.0±3.0 vs. -3.0 ±2.0mL; p<0.001; by design) and ΔCO (1.11±0.48 vs. 0.47±0.43 L/min; p=0.01) but lower ΔTPR (median: -2 [IQR: 3] vs. 1 [2] mmHg/L/min; p=0.008). %FVR (p=0.87), ΔHR (p=0.13), or ΔMAP (p=0.85) did not differ between subgroups. Among all females, ΔSV was positively associated with ΔCO and negatively associated with ΔTPR but not ΔFVR, ΔHR, or ΔMAP, indicating that heterogeneous SV responses in females may be offset by systemic vascular resistance responses and do not impact the overall magnitude of the pressor response to the CPT.
Surface electromyography (sEMG) may provide reliable biomarkers of contractile muscle fatigue (CMF) during exercise in chronic obstructive pulmonary disease (COPD). This study aimed to: 1) determine the test-retest reliability of amplitude- and frequency-based sEMG metrics recorded from the quadriceps muscle during a constant-work-rate cycling test (CWRT); 2) assess their criterion validity for detecting CMF against potentiated twitch force (TWp); and 3) explore associations between sEMG metrics and physiological outcomes. Adults with COPD referred for pulmonary rehabilitation performed two CWRTs to the limit of tolerance (Tlim) at 75%-80% of the individual peak workload, with physiological responses recorded. CMF was assessed by: 1) amplitude- (root mean square, RMS) and frequency-based sEMG metrics recorded from the right quadriceps, analyzed per pedal stroke and expressed as Z-score changes at Tlim relative to a fatigue-free baseline; and 2) the postexercise change in TWp of the right quadriceps. Relative and absolute test-retest reliability, and criterion validity of sEMG against TWp were assessed. Twenty-five participants completed the assessments. Among the sEMG metrics, only vastus lateralis RMS showed adequate relative reliability [intraclass correlation coefficient (95% CI) = 0.79 (0.74-0.85)] but a nonnegligible standard error of measurement of 0.58. Moreover, vastus lateralis RMS showed 86% sensitivity and specificity versus TWp in identifying CMF. An increase of ≥0.65 Z-scores identified the threshold for sEMG-based CMF. Changes in vastus lateralis RMS were moderately correlated with physiological responses at Tlim (P < 0.05). In conclusion, vastus lateralis RMS derived from sEMG can be used as a biomarker of CMF during cycling in individuals with COPD.NEW & NOTEWORTHY This study provides novel evidence that exercise-induced changes in the amplitude of the vastus lateralis surface electromyography signal during a standardized constant-work-rate cycling test can represent a reliable and valid biomarker of quadriceps contractile muscle fatigue in individuals with moderate-to-severe COPD.
Natural experiments are a form of passive experiments that analyze populations exposed to environmental or behavioral stimuli. Here, we review natural experiments using marathon running as an example of an unusual physiological stressor to illustrate how such approaches can generate new hypotheses or test competing ones using large datasets of training and performance data. Natural experiments have been able to demonstrate that marathons are completed close to, but below, critical speed and that faster athletes complete marathons at a higher fraction of critical speed compared with slower runners. Environmental conditions, such as heat and altitude, as well as training and racing behaviors, including the characteristics of training programs and pacing strategies, have also been demonstrated to impact marathon performance. Findings from the natural experiments discussed herein often align with results from smaller, laboratory-controlled studies. However, the scale of these datasets has allowed for the detection of subtle trends and interactions that otherwise would remain undetected in smaller cohorts. In conclusion, natural experiments have helped advance our understanding of marathon physiology and can effectively complement traditional laboratory-based interventions. Future research may explore hybrid approaches in which researchers conducting well-controlled laboratory experiments collaborate with running platforms to design integrated research studies that combine large sample sizes with laboratory-controlled interventions.
Sleep fragmentation is reported to impair resting vascular function. The aim of this study was to test the hypothesis that acute sleep fragmentation would impair muscle blood flow during exercise. Twenty adults (10 females and 10 males) participated in a randomized crossover study that included one night of habitual sleep and one night of fragmented sleep. Sleep was assessed at home using wrist actigraphy. Arousals from sleep were increased by an audio alarm sounding every 30 min. The morning following each sleep condition, participants performed single handgrip contractions and rhythmic handgrip exercise at 15%, 30%, and 45% MVC. Forearm blood flow (FBF) was measured using Doppler ultrasound. Nightly awakenings and wake after sleep onset significantly increased by 18% and 43%, respectively, after fragmented sleep, leading to lower sleep duration (P < 0.001). Peak FBF and total hyperemic responses following single contractions were similar between sleep conditions (all P > 0.05). During rhythmic handgrip exercise, brachial artery dilation was reduced after fragmented sleep (main effect: 5.5 ± 4.8 vs. 3.3 ± 3.7%; P = 0.01), leading to a lower FBF response to rhythmic exercise (main effect: 122 ± 58 vs. 110 ± 56 mL/min; P = 0.04). Endothelial sensitivity to shear rate was similar between sleep conditions (habitual vs. fragmented: 0.039 ± 0.024 vs. 0.042 ± 0.031%/s-1; P = 0.77). In summary, acute sleep fragmentation decreases skeletal muscle blood flow during exercise. This finding suggests that blunted oxygen delivery may be a contributing factor for exercise performance deficits after disturbed sleep.NEW & NOTEWORTHY We demonstrate that one night of fragmented sleep decreases steady-state blood flow and vascular conductance during low- to moderate-intensity handgrip exercise. This impairment was not due to an impaired rapid vasodilation to single contractions nor altered endothelial sensitivity to shear rate as these variables were unchanged after acute sleep fragmentation. These results reveal a negative impact of disrupted sleep on the steady-state muscle vasodilatory response to rhythmic contractions.
Circulating monocytes contribute to atherogenesis and vascular dysfunction. Although clinical cardiovascular disease presents in adulthood, its biological origins often begin in youth and differ substantially between females and males. Twelve males and nine females (13-17 yr) completed an acute exercise protocol consisting of 10, 2-min cycling bouts at 70% of maximal work rate interspersed with 1-min rest intervals, performed before and after an 8-wk supervised endurance training intervention with brief supplementary strength work (60 min/session, 3 sessions/wk). Blood was collected before and immediately after each exercise challenge. Peripheral blood monocytes were isolated, and whole transcriptome RNA sequencing (RNA-seq) was performed. Before training, acute exercise induced a markedly greater monocyte transcriptomic response in females compared with males [5,135 vs. 567 differentially expressed transcripts, false discovery rate (FDR) < 0.1]. Pathway analyses identified vascular function-related pathways in males, whereas females showed enrichment of pathways related to adipose tissue cross talk and oxidative metabolism. Following training, the acute transcriptomic response was markedly attenuated in both sexes (165 transcripts in males and 94 in females, FDR < 0.1), representing an ∼98% reduction in females and a ∼70% reduction in males relative to pre-training responses. These findings reveal sex-specific monocyte responses to acute exercise in youth and suggest that endurance exercise alters immune transcriptional responsiveness in pathways relevant to vascular and cardiovascular health.NEW & NOTEWORTHY Acute exercise induced a markedly greater monocyte transcriptomic response in female adolescents than in males. Females showed activation of pathways related to adipose tissue signaling and oxidative metabolism, whereas males exhibited vascular-function pathways. Following exercise training, the monocyte transcriptomic response to acute exercise was substantially attenuated in both sexes. These findings identify sex-specific immune transcriptional responses to exercise during adolescence with potential implications for cardiovascular health.
This study investigated cerebral hemodynamics, intracranial pressure (ICP), and cognitive function in 18 older men (median 72 yr, interquartile range 68-75, 94% with ≥1 comorbidity) during a 15-min, 30° head-down tilt (HDT). Participants were monitored with continuous noninvasive hemodynamic measurements, transcranial and carotid Doppler ultrasound, and optic nerve sheath diameter. Cognitive testing was performed before and after HDT. Hemodynamic changes were compared with data from anesthetized, positive-pressure-ventilated patients undergoing surgery with pneumoperitoneum during steep HDT. During HDT, mean arterial pressure at ear level increased [6.0 mmHg (95% confidence interval 4.25, 7.8)], whereas systolic arterial blood pressure at heart level (SBPheart) decreased [-10.2 mmHg (-12.4, -8.0)]. Heart rate, stroke volume, and cardiac index (CI) were unchanged. Despite increased estimated ICP, internal carotid artery and middle cerebral artery blood velocities and flow remained unchanged throughout HDT, suggesting preserved cerebral autoregulation. CI was the strongest predictor of internal carotid blood flow (β = 0.3), with a 1 L·min-1·m-2 increase predicting an 84 mL·min-1 increase in cerebral blood flow. Cognitive testing was mainly unaffected by HDT. Comparison with anesthetized patients revealed different hemodynamic responses to HDT. Mean arterial blood pressure at heart level increased in anesthetized patients [14.1 mmHg (8.9, 19.3); P < 0.0001] but decreased in awake participants [-6.2 mmHg (-11.8, -0.6); P < 0.0001]. CI declined after HDT in anesthetized patients [-0.39 L·min-1·m-2 (-0.59, -0.18); P < 0.001] but was unchanged in awake participants. Cerebral blood flow remained unaltered in both groups, suggesting effective autoregulation. These findings suggest that short-duration steep HDT in older individuals does not compromise cerebral blood flow or cognitive function.NEW & NOTEWORTHY In awake older men, self-reporting as healthy but with prevalent well-controlled comorbidities, 15 min of 30° head-down tilt did not affect cerebral blood flow or induce cognitive decline despite significantly increasing noninvasively measured intracranial pressure. Mean arterial pressure at heart level decreased during tilt, ensuring only a marginal increase in mean arterial pressure at ear level. These hemodynamic effects differed considerably from those in anesthetized laparoscopy patients.
Tracheomalacia (TM), the most common abnormality of the pediatric trachea, results in dynamic expiratory airway collapse due to weakened cartilage and reduced smooth muscle tone. Although bronchodilators such as albuterol are widely used in children with wheezing, their impact on TM remains unclear because prior studies have not simultaneously evaluated tracheal and lung mechanics in vivo. This study aimed to separately quantify the effects of albuterol on both tracheal distensibility and compliance, as well as lung compliance, using a controlled porcine model. Ten spontaneously breathing swine underwent high-resolution computed tomography (CT) imaging at multiple controlled tracheal lumen pressures (PLUM) ranging from +10 to -10 cmH2O, both before and after administration of 5 mg nebulized albuterol. Tracheal and pleural pressures were simultaneously recorded. Three-dimensional airways and lungs were segmented from CT images to calculate cross-sectional areas and volumes. Tracheal distensibility and compliance, as well as lung compliance, were determined by the slope of area or volume versus transmural pressure. Albuterol significantly increased tracheal distensibility (4.30 ± 1.0 to 4.78 ± 1.3 mm2/mmHg, P = 0.010) and tracheal compliance (327 ± 102 to 367 ± 117 mm³/mmHg, P = 0.018). Lung compliance also increased significantly in 9 evaluable swine [(2.9 ± 1) × 104 to (3.8 ± 1.1) × 104 mm³/mmHg, P = 0.010]. Albuterol increases both tracheal and lung compliance, supporting clinical concerns that bronchodilators may exacerbate airway collapse in TM. These findings demonstrate the complex and competing mechanical effects of bronchodilators in TM and stress the importance of accounting for both tracheal and lung responses in managing dynamic airway collapse.NEW & NOTEWORTHY This study introduces an in vivo swine model to simultaneously assess how albuterol alters tracheal and lung compliance. Albuterol increased compliance in both regions, potentially exacerbating airway collapse in tracheomalacia. These findings clarify the paradoxical effects of bronchodilators and emphasize the importance of individualized respiratory management for pediatric patients with airway abnormalities often mistaken for asthma.
Ventilatory "inefficiency" during exercise in obstructive lung disease-such as that resulting from increased dead space or ventilation-perfusion mismatch-is commonly interpreted as a perturbation that requires an additional increase in minute ventilation and thus in Ve/Vco(2) to preserve PaCO2 homeostasis. This observation raises a fundamental question: how could an increase in Ve/Vco(2) during exercise be actively directed toward defending Pa-CO2 stability if no known neural signal, governing respiration, directly encodes ventilatory "inefficiency"? We retrospectively analyzed the lung-function and anthropometric data, as well as ventilatory and gas-exchange responses obtained at rest, lactate threshold (LaT), and peak exercise, of 443 patients with obstructive lung disease who underwent cardiopulmonary exercise testing and spanning a wide range of Ve/Vco(2) . Relationships between PETCO2 and Ve/Vco(2) , estimated Va/Vco(2) , and Vd/Vco(2) were examined using power-law regression. Patients were then stratified by peak Ve/Vco(2) , and group differences were assessed using Welch ANOVA, with effect sizes expressed as eta(2) and Cohen's d. Across rest, LaT, and peak exercise, PETCO2 exhibited a continuous approximate to 1/x relationship with Ve/Vco(2) that closely paralleled PETCO2-Va/Vco(2) . Stratification by Ve/Vco(2) consistently identified very large effect sizes for PETCO2. This PETCO2-Ve/Vco(2) "phenotype" was also present in the normocapnic range. Hypercapnia was observed only in patients with low Ve/Vco(2) . Arterial P-CO2 obtained just at the exercise cessation retained a similar pattern, remaining inversely related to peak Ve/Vco(2) . The present study supports the view that Pa-CO2 is emergent, and not defended, in this cohort of patients with chronic obstructive pulmonary disease (COPD). Implications for control of breathing during exercise are discussed.NEW & NOTEWORTHY Despite very different levels of obstructive lung disease and ventilatory insufficiency, PETCO2 and PaCO2 display an inverse relationship with Ve/Vco(2) across exercise levels. Stratification by Ve/Vco(2) demonstrates that interindividual differences in Ve/Vco(2) were driven by changes in effective alveolar ventilation. These results support the view that Pa-CO2 stability is apparent during exercise. Pa-CO2 passively emerges from the interactions between a constrained respiratory plant at any ventilatory drive.
