Ramsook, Andrew H

Abstract On average, females have smaller airways than males. The largest discrepancy in airway size occurs during puberty, when endogenous sex hormone concentrations diverge between males and females. Transgender individuals often use gender‐affirming hormone therapy (GAHT) to align physical characteristics with gender identity. It is unknown whether GAHT influences airway size (luminal area and length). We evaluated the large conducting airways before starting GAHT and while undergoing years of GAHT. This retrospective within‐subject study included 12 adult transgender individuals who underwent CT scanning before starting GAHT and again after ≥1 year of GAHT. For each transgender individual, we identified two matched cisgender controls (one male and one female) who also underwent two CT scans over a comparable time interval for longitudinal comparison. We used a three‐dimensional reconstruction of CT imaging to measure luminal areas. Within‐subject changes in airway size between scans were assessed using Student's paired t ‐tests in transgender individuals undergoing feminizing hormone therapy. Variance between scans was assessed using Levene's test. Pre‐scans occurred an average of 2.0 ± 3.1 years before beginning GAHT. Transgender persons were on GAHT for an average of 3.3 ± 1.7 years (range, 1.0 – 6.7 years) at their second scan. We found no significant differences in airway luminal cross‐sectional areas for transgender persons on feminizing hormone therapy. The variance in airway size change between scans was not statistically different between transgender individuals and control subjects. Our findings suggest that the size of large conducting airways might remain unchanged after a period (>1 year) on GAHT.

Background: Hypoxia challenges the regulation of arterial oxygenation (SaO 2 ), eliciting a compensatory increase in ventilation ([Formula: see text]E) to preserve blood-gas homeostasis. However, the ability to maintain blood-gas homeostasis during hypoxic exercise may differ between sexes due to differences in chemoreflex drive and the mechanical capacity to augment ventilation. The purpose of this study was to evaluate sex differences in ventilatory and blood-gas responses to progressive hypoxia during moderate walking exercise. Specifically, we asked whether females would be more susceptible to hypoxemia. We hypothesized that females would exhibit a smaller ventilatory response and a less steep ventilatory CO 2 -response (Δ[Formula: see text]E/ΔPaCO 2 ) compared with males, resulting in a greater reduction in SaO 2 during progressive hypoxia. Methods: Twenty-six physically active adults (15M: age 35.3±9.4; [Formula: see text]O 2 max 54.3±15.5 mL/kg/min, 11F: age 36.2±9.0; [Formula: see text]O 2 max 44.6±5.2 mL/kg/min) were studies during two visits. Visit 1: we determined the participants’ maximal oxygen uptake ([Formula: see text]O 2 max) during an incremental treadmill test. Visit 2: participants walked at ~50% of their [Formula: see text]O 2 max while we reduced the fraction of inspired oxygen (FiO 2 ) progressively every 5 minutes (0.21, 0.19, 0.17, 0.15, 0.13, 0.12, 0.11). Arterial blood samples were collected from a brachial artery catheter during the final 30 seconds of each stage; cardiometabolic and ventilatory data were averaged over the final minute of each stage. The test ended when peripheral oxygen saturation (SpO 2 ) fell below 70%. Because 0.13 FiO 2 was the lowest stage completed by all participants, Δ responses were calculated from 0.21 to 0.13 FiO 2 . Independent t-tests compared Δ responses between sexes; data are mean±SD, significance was set at p < 0.05. Results: There was no significant difference in ΔSaO 2 between sexes across hypoxia (M: −22.0±3.7%; F: −22.8±5.5%; p = 0.89). Males had higher arterial oxygen content (CaO 2 ) than females across all stages (M: 20.6±1.2 to 16.0±1.4 mL O 2 ·dL -1 ; F: 18.5±1.1 to 13.8±2.0 mL O 2 ·dL -1 ), but the ΔCaO 2 during hypoxia was not significantly different between sexes (M: −4.6±0.7; F: −4.7±1.4 mL O 2 ·dL -1 ; p = 0.86). Similarly, there was no significant difference in the change in arterial CO 2 (ΔPaCO 2 ) between sexes (M: −5.8±1.5 mmHg; F: −6.5±3.6 mmHg, p = 0.51). In contrast, males exhibited a significantly greater increase in ventilation (Δ[Formula: see text]E: +13.9±4.2 L·min -1 ) than females (+8.6±2.7 L·min -1 ; p = 0.003). Consequently, the ventilatory CO 2 -response (Δ[Formula: see text]E/ΔPaCO 2 ) was steeper in males (−2.46±0.66 L·min -1 ·mmHg -1 ) compared with females (−1.57±0.68 L·min -1 ·mmHg -1 ; p = 0.004). However, when Δ[Formula: see text]E was expressed relative to maximal ventilatory capacity (%[Formula: see text]Emax), there was no sex difference (M: 8.8±2.6% vs F: 8.3±2.8%; p = 0.68). Conclusion: Females were not more susceptible to hypoxemia than males; both sexes showed comparable reductions in SaO 2 during moderate exercise in progressive hypoxia. Reductions in PaCO 2 were also similar, indicating comparable ventilatory drive. Although males exhibited a larger absolute increase in [Formula: see text]E and a steeper ventilatory CO 2 -response, this difference disappeared when Δ[Formula: see text]E was expressed relative to %[Formula: see text]Emax. These findings indicate that apparent sex differences in ventilation during hypoxia largely reflect differences in ventilatory capacity rather than true differences in oxygenation or ventilatory drive. Taken together, these findings challenge the assumption that females are inherently more susceptible to hypoxemia or have a lower ventilatory drive than males during moderate hypoxic exercise. Funding: NIH T32 DK007352, UL1 TR002377 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: During hypoxic exercise, oxygen transport becomes increasingly challenged as oxygen availability decreases. As the inspired oxygen fraction (FiO 2 ) decreases, peripheral oxygen saturation (SpO 2 ) gradually declines, then drops rapidly upon reaching the steepest point of the sigmoidal shaped, oxyhemoglobin dissociation curve. This reduction in FiO 2 creates a distinct SpO 2 “breakpoint,” which likely represents the threshold at which compensatory mechanisms, such as increases in ventilation and cardiac output, can no longer maintain arterial oxygenation. Several physiological factors may modulate this breakpoint, including hemoglobin concentration, blood volume, and ventilatory capacity. This study aimed to determine the SpO 2 breakpoint during steady-state, submaximal, hypoxic exercise and examine whether factors like sex, age, and fitness level influence the SpO 2 breakpoint. We hypothesized that SpO 2 breakpoints would differ by sex, age, and fitness level, with earlier breakpoints visible in females, older adults, and those with higher aerobic fitness. Methods: Twenty-six physically active adults (15M: age 35±9 yrs, [Formula: see text]O 2 max 54.3±15.5 mL/kg/min, 11F: age 38±10 yrs, [Formula: see text]O 2 max 44.6±5.2 mL/kg/min) participated in a two-day study. Day one: participants performed a treadmill [Formula: see text]O 2 max test. Day two: participants walked at a steady state of ~50% of their [Formula: see text]O 2 max, for 40 minutes, while FiO 2 was progressively reduced every 5 minutes in a stepwise fashion (0.25, 0.21, 0.19, 0.17, 0.15, 0.13, 0.12, 0.11). The test was terminated when SpO 2 dropped below 70%. SpO 2 was measured continuously using a clinical-grade oximeter. Analysis was performed in RStudio by first determining each participant’s individual SpO 2 vs time breakpoint. Male and Female breakpoints were compared to assess sex-based differences. To evaluate whether SpO 2 breakpoint timing differed by age or fitness level, participants were then divided into tertiles for each variable. Age tertiles were derived from the sample distribution of chronological age, and fitness tertiles were defined using [Formula: see text]O 2 max (L/min). Mean breakpoint times were compared between the highest and lowest tertiles for both age and fitness. Mean SpO 2 breakpoints were compared between groups using independent sample t-tests. Significance was set to p< 0.05. Results: The overall mean breakpoint occurred at an SpO 2 of 90.7±2.8% during the 0.17 FiO 2 stage. No significant sex differences were observed in breakpoint SpO 2 and timing (M: SpO 2 = 90.7±2.7%, time = 18.6 min; F: SpO 2 = 90.7±3.0%, time = 17.7 min; p = 0.961). Age did not significantly influence breakpoint (younger tertile [21-30 yrs] SpO 2 = 91.0±2.4%, time = 18.4 min; older tertile [41-60 yrs] SpO 2 = 91.1±2.4%, time = 17.2 min, p = 0.953). Additionally, fitness level showed no significant difference on breakpoint (low fitness [1.91-3.01 L/min]: SpO 2 = 90.3±3.1%, time = 17.8 min; high fitness [4.38-5.25 L/min]: SpO 2 = 90.4±2.9%, time = 19.2 min; p = 0.992). Conclusion: During a hypoxic, steady state walking exercise, at ~50% [Formula: see text]O 2 max, we observed no difference in the peripheral oxygen saturation breakpoint, across sex, age, and fitness level. This may suggest that moderate exercise in hypoxia does not sufficiently challenge the cardiopulmonary system for individual variations in oxygen transport to influence the breakpoint. These findings imply that the SpO 2 breakpoint, during hypoxic exercise, may represent a physiological marker of the upper limit for maintaining oxygen saturation in healthy adults. Applying this protocol to identify SpO 2 breakpoints may offer insights for improving pharmacological interventions and our understanding of clinical populations with impaired oxygen transport. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

AbstractInterstitial lung disease (ILD) encompasses pulmonary disorders characterized by chronic inflammation and fibrosis that disrupt pulmonary gas exchange. While ILD‐related changes in the lung parenchyma are well‐documented, less is known about how ILD affects luminal area within the large conducting airways. This retrospective, case–control study tested the hypothesis that patients with ILD would have greater large conducting airway luminal areas than healthy matched controls. Three‐dimensional reconstructions of computed tomography images were used to quantify airway luminal areas in patients with ILD (n = 82; 54% female) and healthy controls matched for age, sex, and height. Patients with ILD had 16%–22% greater airway luminal areas across all seven measured large conducting airways compared to controls (all p < 0.001). Among patients with ILD, males had 17%–34% greater height‐normalized airway luminal areas than females (all p < 0.05). These data provide evidence that ILD is associated with greater large conducting airway luminal area, even when matched for key demographic factors. Consistent with observations in health, males with ILD exhibited greater height‐normalized airway size than females. These findings offer new insight into airway remodeling in ILD and highlight potential sex differences in airway luminal area.

AbstractFatiguing inspiratory work has been shown to evoke a sympathetically mediated reflex that has systemic cardiovascular consequences, including increases in heart rate and blood pressure and a decrease in resting limb vascular conductance. Moreover, the response to this reflex appears to be attenuated in females compared with males. It remains to be seen whether this respiratory muscle metaboreflex also exerts an effect on cerebral blood flow. Cerebral blood flow is tightly regulated to maintain homeostasis and critical function. Therefore, it stands to reason that cerebrovascular haemodynamics would not be compromised through this respiratory muscle metaboreflex. We hypothesized that fatiguing inspiratory work would reduce resting limb conductance, but cerebral blood flow would be minimally impaired. Females (34 ± 10 years old, n = 12) and males (31 ± 8 years old, n = 12) performed a 5 min, high‐intensity bout of inspiratory pressure threshold loading (IPTL) designed to evoke the respiratory muscle metaboreflex. In response to IPTL, mean arterial pressure increased in both males and females (p < 0.001), and limb vascular conductance decreased to a greater degree in males than in females (p = 0.005). The cerebrovascular conductance index was higher in females (p = 0.007) but not affected by IPTL (p = 0.417). Our findings suggest that cerebral blood flow is spared from the redistribution of blood flow in response to fatiguing inspiratory work and that this protection is true in both males and females.

The maximal expiratory flow-volume (MEFV) curve is a valuable tool for assessing pulmonary function and diagnosing respiratory disease. Quantifying the shape of the MEFV curve may provide additional insight into pulmonary dysfunction compared to spirometry alone. We questioned if the shape of the MEFV curve could detect signs of abnormal lung emptying dynamics in asymptomatic ex-smokers when compared to never smokers free of cardiopulmonary disease. A retrospective analysis of routine spirometry from 22 asymptomatic ex-smokers (50% female) without a formal diagnosis of chronic obstructive pulmonary disease or other chronic respiratory disease was compared against 48 healthy never smokers (65% female). The shape of the MEFV curve was quantified via the slope-ratio method which generates a unitless value corresponding to the ratio between a line of tangency at a specific lung volume and a chord line intersecting the point of interest and residual volume. A SR of 1 would indicate a linear decrease in flow with decreasing lung volume, whereas a SR >1 or <1 would indicate a convex ( i.e., scooped) or concave ( i.e., bump) shape to the MEFV curve; respectively. Slope-ratio was assessed between 80-20% vital capacity in 2% vital capacity increments. A single average slope-ratio was taken as the mean of all slope-ratio values between 80-20% vital capacity per individual. Data are presented as mean ± SD. Patient demographics, including age, height and weight were not different between ex-smokers and never smokers (all p >0.05). No differences in pulmonary function between ex-smokers and never smokers were observed (FEV 1 : 89±22 vs. 95±20%predicted; FVC: 94±21 vs. 98±19%predicted; FEV 1 /FVC: 94±8 vs. 96±9%predicted, all p >0.05). The average slope-ratio was greater in ex-smokers compared to never smokers (1.74±0.29 vs. 1.45±0.41, p <0.0001). This difference was driven by a greater slope-ratio between 70-50% vital capacity (all, p <0.05). These preliminary data suggest slope-ratio analyses reveal a dysfunctional pattern of lung emptying in asymptomatic ex-smokers with no formal diagnosis of pulmonary disease compared to never smokers n that is not observed through spirometry alone. NSERC (PDF-577750-2023; AHR), NIH (HL139854; MJJ) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Introduction: Regulation of cerebral blood flow (CBF) is vital for ensuring blood supply to cerebral tissue, and studies have shown that CBF increases to match the demands of whole-body exercise. Additionally, studies have shown that an inspiratory muscle metaboreflex induced by fatiguing inspiratory work causes a decrease in blood flow to limbs and splanchnic organs, presumably redirecting blood flow to the activated inspiratory muscles. However, it is unknown if the metaboreflex response is greater when targeting the diaphragm during inspiration as opposed to using all inspiratory muscles. We aimed to determine if middle cerebral artery velocity (MCAv), a surrogate for global CBF, was affected by inspiratory muscle metaboreflex, and if so, if MCAv is affected differently when targeting diaphragmatic pressure (PTL-diaphragm; PTL di ) vs targeting mouth pressure (PTL-mouth; PTL mo ). We hypothesized that MCAv will be preserved with fatiguing inspiratory work, in both PTL di and PTL mo breathing patterns. Methods: We studied 11 (5 females) participants without any cardiorespiratory, metabolic, or musculoskeletal diseases (36±9 yrs, FEV 1 /FVC: 100±8%predicted). Each participant had gastric and esophageal balloon catheters placed to measure respiratory pressures. Blood pressure was continuously recorded via finger photoplethysmography. Transcranial doppler ultrasound continuously recorded MCAv. Participants performed breathing trials through a custom-built inspiratory pressure loading (IPTL) device, designed to open when negative pressure was generated. Each trial was comprised of 15 breaths/minute, with each breath consisting of 70% inspiration and 30% expiration. Trial 1 involved 5 minutes of PTL mo targeting 60% of their maximal inspiratory pressure, and trial 2 consisted of 5 minutes of PTL di targeting 60% transdiaphragmatic pressure. CO 2 was administered during IPTL to avoid hypocapnia. Cerebrovascular conductance index (CVCi) was calculated from MCAv. A paired t-test compared the 2 trials, deltas are calculated from end task to baseline, and data are reported as mean±SD. Results: The transdiaphragmatic pressures (PTP di ) between the two trials were different (PTL mo : 5,051±2,620, PTL di : 7,082±2,200 cmH 2 O·s/min; p=0.009). The change inMAP were not different between trials (PTL mo : 8±4, PTL di : 13±9 ΔmmHg; p=0.10). There was no difference in the change in MCAv (PTL mo : 10.07±21.51, PTL di : 9.66±22.10 Δcm/s; p=0.96) or CVCi (PTL mo : 0.03±0.23, PTL di : -0.01±0.17 Δcm/s/mmHg; p=0.55) between the two trials. Conclusion: These findings suggest that the inspiratory muscle metaboreflex does not impair CBF regulation during IPTL; this is true regardless of inspiratory muscle recruitment. Further work should focus on continuing the breathing exercises until exhaustion. NIH (HL139854); NSERC (PDF-577750-2023) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Fatiguing inspiratory muscle work can trigger the sympathetically-mediated respiratory muscle metaboreflex. Activating this reflex has been shown to increase blood pressure and heart rate while decreasing peripheral blood flow. Studies have shown females have an attenuated mean arterial pressure response (MAP) compared to males despite similar workloads to fatiguing inspiratory muscle work, suggesting females may have an attenuated respiratory muscle metaboreflex. However, the sex difference effects of respiratory muscle metaboreflex effects on resting limb vascular conductance (LVC) remains unknown. The purpose of this study was to investigate whether sex differences exist in LVC responses to fatiguing inspiratory muscle work. We hypothesize that males would exhibit a greater decrease in LVC compared to females. Methods: Eight healthy females (F; 35±11 years) and 8 healthy males (M; 31±6 years) completed the study. Participants completed a 5-minute baseline followed by a 5-minute inspiratory pressure threshold loading (IPTL) trial. The breathing pattern was set to 60% of their maximal inspiratory mouth pressure with a breathing frequency of 15 breaths/minute and an inspired duty cycle of 0.7 to activate the respiratory muscle metaboreflex. CO 2 was introduced into the inspired circuit to prevent hypocapnia. Continuous MAP (finger photoplethysmography) and heart rate (electrocardiogram) were recorded. Continuous blood velocity and diameters of the superficial femoral artery were measured using duplex ultrasonography. Leg blood flow (LBF) was calculated as the product of mean blood velocity and femoral artery cross-sectional area. LVC was calculated as LBF/mean arterial pressure. These data were averaged in 30-second segments and reported from 5-minute mark of IPTL (End-Task % of baseline). Groups were compared using Student’s t -test and analyzed using a two-way repeated-measures ANOVA. Results: Pulmonary function was within predicted ranges for all participants (FEV 1 /FVC: [F vs. M]: 100±8 vs. 100±9%predicted; P=0.919). Heart rate ([Baseline: F vs. M]: 70±13 vs. 73±8 bpm; P=0.571) and MAP (Baseline: [F vs. M]: 90±12 vs. 95±8 mmHg; P=0.378) were not different between females and males at baseline or throughout the IPTL trial (Group Main Effect: p>0.05 for both). Additionally, LBF decreased in response to IPTL but there was no difference between groups (End-Task: [F vs. M]: -31±33 vs. -21±24%baseline; Time Main Effect: P=0.012, Group Main Effect: P=0.352). When accounting for blood pressure, LVC also decreased during IPTL but was not different between females and males (End-Task: [F vs. M]: -37±30 vs. -33±24%baseline; Time Main Effect: p<0.001, Group Main Effect: P=0.655). Conclusion: These preliminary data suggest LVC decreases during a 5-minute period of fatiguing inspiratory work using IPTL; however, IPTL does not elicit variable LVC decreases between females and males. NIH (HL139854); NSERC (PDF-577750-2023) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.