Joyner, Michael J.

This study investigated the impact of integrated muscle sympathetic nerve activity (MSNA) discharge patterns on human neurocirculatory regulation. In 13 healthy females (42 ± 15 years), the transduction of integrated MSNA (peroneal microneurography) into mean arterial pressure (MAP; arterial catheter) was studied during an intravenous infusion of a nicotinic ganglionic antagonist (trimethaphan camsylate, 1-7 mg/min). Neurovascular transduction (signal averaging) was studied based on the overall response, burst sequence (singlet, doublet, and triplet+), and burst amplitude (binned into tertials: small, medium, and large bursts). Data (mean ± SD) are reported for a 10-minute baseline (BSL), the one-minute period at the midpoint of the trimethaphan infusion with integrated MSNA bursts (TM-Mid), and the last minute of trimethaphan infusion with integrated MSNA bursts (TM-Last). During BSL, the MAP transduction responses were greatest for triplets+ (singlets: 0.9 ± 0.2 mmHg, doublets: 2.0 ± 0.6 mmHg, triplet+: 2.6 ± 0.9 mmHg; P < 0.01) and large bursts (small: 1.0 ± 0.3 mmHg, medium: 1.7 ± 0.5 mmHg, large: 2.2 ± 0.7 mmHg; P < 0.01). Trimethaphan infusion reduced integrated MSNA burst frequency resulting in a greater proportion of singlets (BSL: 45 ± 18 %, TM-Mid: 75 ± 23 %, TM-Last: 94 ± 20 %; P < 0.01), a lower proportion of doublets, and a lower proportion of triplets+ (BSL: 23 ± 19 %, TM-Mid: 9 ± 18 %, TM-Last: 0 ± 0 %; P < 0.01). Trimethaphan infusion reduced integrated MSNA burst amplitude resulting in a greater proportion of small bursts (BSL: 33 ± 0.2 %, TM-Mid: 60 ± 26 %, TM-Last: 78 ± 37 %; P < 0.01), a lower proportion of medium bursts, and a lower proportion of large bursts (BSL: 34 ± 1 %, TM-Mid: 17 ± 26 %, TM-Last: 1 ± 5 %; P < 0.01). Trimethaphan-mediated changes in MSNA burst frequency and amplitude were associated with reduced overall MAP transduction responses (BSL: 1.6 ± 0.5 mmHg, TM-Mid: 0.5 ± 0.2 mmHg, TM-Last: 0.3 ± 0.3 mmHg; P < 0.01). Linear regression analyses demonstrated that the trimethaphan-mediated reduction in the proportion of large bursts ( β = 0.02 ± 0.008 mmHg/%, R2 = 0.13, P = 0.03) more strongly affected sympathetic neurovascular transduction responses than reductions in the proportion of triplet+ burst sequences (P = 0.91). These findings suggest that time varying MSNA discharge patterns, particularly variations in burst amplitude, support human neurocirculatory regulation. This work was supported by the National Institutes of Health and the Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Cystic fibrosis (CF) is a genetic disorder in which patients have dysfunctional cystic fibrosis transmembrane regulatory (CFTR) proteins in the lungs that disrupt ion regulation resulting in a thick, viscous mucus layer on the airway epithelium. Consequential poor mucociliary clearance leads to repeated infections and chronic inflammation contributing to bronchiectasis which is associated with increased airway luminal area. CFTR modulator therapy can improve and even restore the function and expression of a mutated CFTR gene which has been shown to improve sweat chloride levels and pulmonary symptoms rapidly. However, the effect of CFTR modulator therapy on large conducting airway luminal area is unclear. We compared large conducting airway luminal area in patients with CF before and after initiating CFTR modulator therapy. We hypothesized that airway luminal area would normalize (decrease) after initiating CFTR modulator therapy. Methods: Twenty-three patients with CF (32±15 years, 11 female) with computed tomography (CT) imaging of their lungs before and after initiating CFTR modulator therapy were included in analyses. In each patient we measured seven large conducting airways (trachea, left and right main bronchus, bronchus intermediate, left and right upper lobe, and left lower lobe) before and after CFTR modulator therapy initiation. To control the potential effect of height, airway luminal area (mm2) was divided by patient height (cm). Paired t-tests compared differences between luminal area before after initiating CFTR modulator therapy. Results: Patients were taking CFTR modulator therapy for a median of 1.1 years (range: 22–2111 days) at the time of their CT imaging after initiating CFTR modulator therapy. Large conducting airway luminal area was not different before and after initiating CFTR modulator therapy in all seven airways: trachea (1.50±0.35 vs. 1.56±0.34 mm2/cm, p=0.14), right main bronchus (1.05±0.21 vs. 1.09±0.19 mm2/cm, p=0.11), bronchus intermediate (0.68±0.16 vs. 0.68±0.16 mm2/cm, p=0.54), right upper lobe (0.42±0.10 vs. 0.45±0.09 mm2/cm, p=0.27), left main bronchus (0.81±0.19 vs. 0.83±0.18 mm2/cm, p=0.21), left upper lobe (0.51±0.13 vs. 0.52±0.13 mm2/cm, p=0.45), and left lower lobe (0.44±0.11 vs. 0.46±0.10 mm2/cm, p=0.42). Conclusion: There was no change in large conducting airway luminal area after initiating CFTR modulator therapy suggesting CFTR modulator therapy may not reverse CF-associated airway luminal area changes. However, longitudinal analysis and investigation into the small airways are necessary for a comprehensive understanding of the effect of CFTR modulator therapy on airway luminal area changes. Funding: NIH (HL139854 to MJJ, HL131151 to SEB) and NSERC (PDF-577750-2023 to AHR). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Purpose: While it is well-known that elite males are faster than elite females in all Olympic-length swimming events, less is known about the age of the divergence in swimming performance between the sexes. Thus, this observational study compared swimming performance of elite male and female youths. Methods: We collected the all-time best 100 U.S. freestyle swimming performance times of boys and girls aged 5 to 18 years for six freestyle swimming events from 50m to 1500m. We compared data using univariate ANOVAs and Chi-squared tests. Results: Swimming performance improved with increasing age for both boys and girls (p<0.001) until a plateau— which began at a younger age for girls (15 years) than boys (17 years; sex × age; p<0.001). Before age 8, there was no sex difference in swimming performance (p>0.05). Beginning at age 9 however, boys swimming performance was faster than girls (1.0% to 1.3% depending on distance), and this sex difference in performance increased in magnitude until 18 years (p<0.001; 6.6% to 11.0% depending on distance). While boys represent 50% of the top 100 age-group performances at ages 5 and 6, boys represent an increasingly larger proportion of top performances across years of age including nearly 100% of all top 100 age-group performances beginning at age 15—except for one notable female swimmer in the 1500m Conclusion: Among elite youth swimmers, boys have increasingly faster performances than girls beginning at age 9 years, with minimal sex differences in swimming performance before 9 years. Additionally, boys represent an increasingly larger proportion of the top 100 age-group performances of all-time. No funding. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: The compensatory reserve metric (CRM) provides a novel marker of hemodynamic status in prediction of sudden cardiovascular decompensation during central hypovolemia. The CRM has previously been calculated using arterial waveforms obtained from a photoplethysmographic volume-clamp technique. However, the in-field use of pulse oximetry is becoming more prominent in research and medicine. To improve in-field applicability of the CRM, this project aimed to validate pulse-oximetry derived CRM values relative to physiologic data during simulated hemorrhage through application of lower body negative pressure (LBNP). Methods: Forty-nine healthy adults (25 females) underwent a graded LBNP protocol with the following 5-minute stages: -0, -15, -30, -45, -60, -70, -80, -90, and 100 mmHg, or until the onset of pre-syncopal symptoms (tolerance) was reached. Arterial waveforms were sampled using pulse oximetry (Massimo Radical 7). The CRM was calculated using a validated one-dimensional convolutional neural network. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. SpO2 was measured using pulse oximetry. Cardiac output and stroke volume were estimated using the photoplethysmographic volume-clamp. Data were binned for the last thirty seconds of each completed stage, and at tolerance. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. A priori significance was set at P<0.05. Results: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 50±12% ( P<0.001) mean reduction in stroke volume, 65±27% ( P<0.001) increase in heart rate, 18±8% ( P<0.001) reduction in mean arterial pressure, 21±7% ( P<0.001) systolic blood pressure, 8±9% ( P<0.001) diastolic blood pressure, and 39±12% ( P<0.001) pulse pressure. The CRM obtained using pulse oximetry was significantly associated with a reduction in stroke volume ( P<0.001), increase in heart rate ( P<0.001), and reductions in systolic ( P=0.033), diastolic ( P=0.036), and pulse pressure ( P=0.002). There was no statistically significant association between CRM and cardiac output ( P=0.421), SpO2 ( P=0.408), or mean arterial pressure ( P=0.214). Conclusion: The CRM obtained using pulse oximetry may be a valid, reliable marker of hemodynamic status with promising in-field applications. Future studies warrant investigation of feasibility and applicability within various contexts ranging from the operating room to the battlefield. The presented work was funded in part by the Congressionally Directed Medical Research Program (Award No. DM180240) and Offce of Naval Research (Awards No. N00014-18-D-7001 and N00014-19-C-2017). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

AbstractInfluenzavirus is among the most relevant candidates for a next pandemic. We review here the phylogeny of former influenza pandemics, and discuss candidate lineages. After briefly reviewing the other existing antiviral options, we discuss in detail the evidences supporting the efficacy of passive immunotherapies against influenzavirus, with a focus on convalescent plasma.

ABSTRACT Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% ( P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization. IMPORTANCE As SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.