Joyner, Michael J.

ABSTRACT Anti‐Spike monoclonal antibodies (mAbs) progressively lost efficacy during the COVID‐19 pandemic due to the emergence and predominance of resistant SARS‐CoV‐2 variants. By contrast, high‐titre COVID‐19 convalescent plasma (CCP) collected from vaccinated donors recently recovered from infection provides a polyclonal source of antibodies that remains effective in clearing SARS‐CoV‐2 in immunosuppressed patients, unable to mount an adequate immune response against the virus. We conducted a systematic review and individual participant data meta‐analysis to examine the effect of CCP in immunocompromised patients persistently positive for SARS‐CoV‐2 viraemia following mAb therapy, and to evaluate possible biological factors associated with a favourable outcome. Electronic databases were searched for studies published from January 2020 to January 2026. All studies including eligible cases were considered in the systematic review. Unpublished cases were also collected from investigators of the selected studies. The protocol was registered at PROSPERO (CRD420251142891). Forty‐seven cases (30 cases from 12 published studies and 17 unpublished cases) were included. In 33 out of 47 patients (70.2%) with a mAb‐resistant infection, SARS‐CoV‐2 clearance occurred following CCP transfusion, with a mean of 2.7 CCP units administered. In logistic regression, total CCP volume transfused was positively associated with SARS‐CoV‐2 clearance. In conclusion, CCP transfusion was associated with SARS‐CoV‐2 clearance in persistently positive immunocompromised patients following failure of anti‐Spike mAb therapy.

Heart rate variability (HRV) is a widely utilized approach for investigating cardiovascular health and human performance. Methodological approaches, analyses, and interpretations of HRV can vary extensively, and scientific debates on HRV reliability and utility remain. These debates have been amplified in recent years by the rapid growth and ubiquity of wearable devices, and their incorporation into scientific research studies. The present guidelines paper takes an evidence-based approach to propose more consistent and rigorous measurement and interpretation of HRV within human cardiovascular research and application. First, HRV has some utility as a cardiovascular risk stratification tool, but is not appropriate to employ as a specific marker of cardiac sympathetic outflow or sympathovagal balance. While time-domain and spectral analysis can more accurately reflect respiratory modulation of cardiac vagal (parasympathetic) activity, caution is necessary to avoid overinterpretation, particularly with respect to the concept of “vagal tone”. Numerous experimental, demographic, and environmental factors influence HRV assessment, interpretation, and reliability. Specifically, it is critical to account for non-modifiable (age, sex, race/ethnicity, etc.) and modifiable (i.e., exercise, physical fitness, etc.) factors within participant samples. Furthermore, technical approaches such as the HRV input signal (e.g., electrocardiography vs. photoplethysmography), length of recording, location of recordings (i.e., laboratory vs. field), respiratory rate and depth, and analytical approaches (i.e., time vs. frequency domain) can all impact rigor, reliability, and study interpretations. Finally, with respect to the rapid advancements of HRV assessment using wearable technology, investigators should interpret and contextualize findings within the limitations outlined in this guideline review.

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.