Mild Hypoxia Reduces the Precision of Vestibular Perception

Background: The respiratory muscles require ~15% of the total oxygen uptake ([Formula: see text]O2) during vigorous exercise. A high oxygen cost of breathing (O2cost) may be a component of exercise intolerance because of increased demand for blood flow and oxygen to respiratory muscles at the expense of other active skeletal muscles (e.g., quadriceps during cycling). Limited evidence in adults with obesity shows higher O2cost related to higher body mass index (BMI). However, the relation between comprehensive body composition metrics with O2cost is less clear. Purpose: Our purpose was to determine the association between body fat percentage and related metrics with O2cost. We tested the hypothesis that a higher body fat percentage in younger adults free of overt disease would be associated with higher O2cost. Methods: We enrolled adults (20-39 years old) with a BMI <40 kg/m2 and no cardiometabolic or pulmonary diseases, uncontrolled hypertension, or recent nicotine use. We determined the O2cost by calculating the slope of [Formula: see text]O2, measured via indirect calorimetry, during a 5-minute resting baseline and the final 4 minutes of 8-minute eucapnic voluntary hyperpnea stages performed at 40 and 60 L/min. Respiratory rate was maintained at 20 breaths per minute with a 1:1 duty cycle. We measured anthropometrics and assessed body composition via dual X-ray absorptiometry (DXA). We employed Spearman's rank partial correlations (ρ) and present data as median [IQR]. Results: The participant (n=26) characteristics were: 24[6] years old; 42% female; 8% Asian, 15% Black, 77% White; 31% Latinx; 4.10[1.06] L forced vital capacity (FVC). All calculated O2cost slopes between stages had R2>0.99. The O2cost (6.28[1.78] mL O2/L) was not correlated with BMI (28.4[9.5] kg/m2; ρ<0.01, P=0.98). The O2cost was also not correlated with DXA body fat percentage (25.9[21.1]%; ρ=-0.06, P=0.79) or visceral adipose tissue mass (433[571] g; ρ=-0.10, P=0.67). Additionally, the O2cost was not correlated with waist circumference (88.0[24.6] cm; ρ=0.02, P=0.94) or waist-to-hip ratio (0.83[0.06]; ρ=0.19, P=0.34). Moreover, no meaningful correlations existed between O2cost and any body composition metric after statistically adjusting for age, sex, race, and ethnicity (ρ≤|0.22|, P≥0.27). Interestingly, when FVC was added to this model, we found a moderate positive correlation between the O2cost and waist-to-hip ratio (ρ=0.48, P=0.03), but no significant correlations were observed with other metrics (ρ≤|0.24|, P≥0.30). Conclusion: These preliminary data suggest that the oxygen cost of breathing is moderately associated with waist-to-hip ratio when FVC is included alongside other traditional covariates (e.g., sex, race, and ethnicity) in young adults with and without obesity, who are free from overt disease. Future studies with larger cohorts are needed to determine the potential role of FVC in mediating the association between waist-to-hip and O2cost among young adults. Florida State University Graduate School Legacy Fellowship (CD), National Institutes of Health K01HL160772 (JCW), and American Heart Association 23CDA1037938 (JCW). 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.

Vestibular roll tilt thresholds partially mediate age-related effects on balance.

Experimental investigation and evaluation of influence of oxygen concentration on characteristic parameters of coal spontaneous combustion

Objectives Whether a higher or lower partial pressure of oxygen (PaO2) could impact outcomes in patients with coronavirus disease 2019 (COVID-19) remains a matter of debate. So, we planned this retrospective analysis to determine if a higher or lower partial pressure of oxygen in blood had any effect on outcomes in COVID-19 patients. Material and method The records of COVID-19 patients from the beginning of 2020 to the end of 2022 were scanned. Patients were sub-grouped into two groups based on the partial pressure of oxygen (PaO2) values on arterial blood gas (ABG), i.e., high PaO2group,PaO2 value of 80-100 mm Hg, and low PaO2group,PaO2 value of 60-80 mm Hg for the first 48 hours after the initiation of oxygenation and/or mechanical ventilation. The two groups were compared in terms of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen (FiO2) concentration (P/F ratio), Sequential Organ Failure Assessment (SOFA) score at presentation and after 48 hours, and clinical outcomes, including mortality, time of mortality, extubation, acute kidney injury (AKI), and change in Glasgow Coma Scale (GCS). Results SOFA score was significantly higher in the low PaO2 group as compared to the high PaO2 group both at baseline (4.59 {1.79} versus 5.51 {1.15}; p-value: 0.005) and at 48 hours (3.06 {1.39} versus 5.11 {2.13}; p-value: 0.007). However, the change in SOFA score over 48 hours did not achieve statistical significance (-1.000 {0.97} versus 0.53 {2.34}; p-value: 0.257). Out of a total of 37 patients, 21 patients died in the high PaO2 group, while 18 patients died in the low PaO2 group. Conclusion Our study highlights that targeting either low or high arterial oxygen content while considering oxygen therapy for COVID-19 patients did not significantly alter the outcomes.

During in vitro fertilisation (IVF) procedures, human preimplantation embryos are cultured in the laboratory. While some laboratories culture in an atmospheric oxygen concentration (˜ 20%), others use a lower concentration (˜ 5%) as this is more comparable to the oxygen concentration observed in the oviduct and the uterus. Animal studies have shown that high oxygen concentration could have a negative impact on embryo quality via reactive oxygen species causing oxidative stress. In humans, it is currently unknown which oxygen concentration provides the best success rates of IVF procedures, eventually resulting in the hightest birth rate of healthy newborns. To determine whether embryo culture at low oxygen concentrations improves treatment outcome (better embryo development and more pregnancies and live births) in IVF and intracytoplasmic sperm injection (ICSI) as compared to embryo culture at atmospheric oxygen concentrations. The Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO electronic databases were searched (up to 4th November 2011) for randomised controlled trials on the effect of low oxygen concentrations for human embryo culture. Furthermore, reference lists of all obtained studies were checked and conference abstracts handsearched. Only truly randomised controlled trials comparing embryo culture at low oxygen concentrations (˜ 5%) with embryo culture at atmospheric oxygen concentrations (˜ 20%) were included in this systematic review and meta-analysis. Two review authors selected the trials for inclusion according to the above criteria. After that two authors independently extracted the data for subsequent analysis, and one author functioned as a referee in case of ambiguities. The statistical analysis was performed in accordance with the guidelines developed by The Cochrane Collaboration. Seven studies with a total of 2422 participants were included in this systematic review. Meta-analysis could be performed with the data of four included studies, with a total of 1382 participants. The methodological quality of the included trials was relatively low. Evidence of a beneficial effect of culturing in low oxygen concentration was found for live birth rate (OR 1.39; 95% CI 1.11 to 1.76; P = 0.005; I(2) = 0%); this would mean that a typical clinic could improve a 30% live birth rate using atmospheric oxygen concentration to somewhere between 32% and 43% by using a low oxygen concentration. The results were very similar for ongoing and clinical pregnancy rates. There was no evidence that culturing embryos under low oxygen concentrations resulted in higher numbers of adverse events such as multiple pregnancies, miscarriages or congenital abnormalities. The results of this systematic review and meta-analysis suggest that culturing embryos under conditions with low oxygen concentrations improves the success rates of IVF and ICSI, resulting in the birth of more healthy newborns.

The present study was conducted to clarify the effects of oxygen concentration under various leaf temperatures on the growth of wheat and rice plants (C3-plants). Seedlings of both species were growth for 7 days in specially devised growth chamber equiped with water culture facilities, under 2.5% O2, 0.03% CO2 and 21% O2, 0.03% CO2, and at light intensity 45 Klx (at 20. 25 and 30°C leaf temperature) or 25 Klx (at 5 and 10°C) under a regime of 12hr light and 12hr darkness. The growth paramenters of the plants were investigated at the start and the end of each experiment. The results obtained are summarized as follows: 1. The dry matter production (ΔWT and RGR) was enhanced in both species under overall leaf temperatures, and plant height and leaf emergence were somewhat inhibited except at 30°C in wheat and 20°C in rice plant with low oxygen ooncentration. 2. NAR of both species enlarged extremely at low oxygen concentration under overall leaf temperatures. According to these results, it can be deduced that acceleration of the apparent photosynthetic rate at low oxygen concentration, due to suppression of the photorespiration et al., persists for a long time. 3. NAR and RGR were enhanced under low leaf temperature (5 and 10°C) at low oxygen concentration, therefore these results suggest that the function of photorespiratory mechanism still may continue under low leaf temperature. 4. It has been shown that the apparent photosynthetic rate increases at low oxygen concentration with leaf temperature increases, and it reaches maximum rate at 30∼35°C. However, RGR of both species at low oxygen concentration in this experiment was greatest at 20°C and it decreased with falling or rising temperature. It is considered that at low oxygen concentration the optimum temperature for the apparent photosynthetic rate as momentary value does not fit the maximum growth of plants. On the other hand, difference between RGR at low oxygen concentration and RGR at normal air was greater under higher temperature, hence it can be explained that the effect of suppression of the photrespiration et al., on the dry matter production is greater under higher temperature. 5. RLGR was reduced under low oxygen concentration, and subsequently decreasing of LAR came out. In spite of decrease of LAR, RGR was increased through greater increase of NAR under low oxygen concentration. 6. The surplus dry matter in plants under low oxygen concentration (ΔW at 2.5%O2-ΔW at 21% O2) was allotted to leaf blades and roots in wheat, and leaf sheaths+stems and roots in rice plant, respectively. It may be considered that above difference was based on the characteristics of species.

Oxygen exchange between lungs and systemic tissues is essential for life. However, breathing air with high O2 levels can cause pulmonary O2 toxicity (POT)—a serious health hazard for divers breathing O2-enriched gases at high pressure, and patients undergoing hyperbaric O2 therapy or breathing through a mechanical ventilator. POT occurs because increased rates of O2 uptake ( J O2) across the air-blood barrier lead to high intracellular O2 concentration in alveolar type I cells (ATICs), ATIICs, and in pulmonary capillary endothelial cells (PCECs). In principle, one could reduce POT by reducing J O2. According to Fick’s law of diffusion, one approach for reducing J O2 would be to decrease O2 membrane permeability ( P M, O2). In this work, we focus on the possibility of mitigating POT damage by manipulating P M, O2 across the cell membranes of ATICs (which cover about 90% of the alveolar surface) and PCECs.Research from the past 25 years has shown that membrane proteins (e.g., some aquaporins, AQPs) can conduct gases, thereby increasing P M. Notably, AQP5, which has the highest-known CO2 permeability, is highly expressed in the apical membrane of ATICs, and AQP1, which can conduct both CO2 and O2, is highly expressed in both PCECs membranes.We hypothesize that AQP5 mediates a large fraction of J O2 across the alveolar wall, and AQP1 does the same across PCECs membranes. If true, genetic deletion of AQP5 and/or AQP1 should reduce POT. We test this hypothesis with (1) a normobaric POT mouse model in which male mice (wild type, WT, vs knockout, KO) are continuously exposed to >99% O2 (“↑O2”) vs room Air (“Air”) for ~60-72 hr; (2) KO mice genetically deficient in AQP5, AQP1, or both (double knockouts, dKO); and (3) POT assays, namely H2O/dry-lung weight ratio (marker of lung edema) and, on bronchiolar-alveolar lavage fluid, lactate dehydrogenase (LDH; marker for ATIC leakage) and protein (mainly albumin from blood plasma; marker for blood-gas-barrier leakiness).Consistent with previous work (on WT and AQP5- & AQP1-KOs) by others, “H2O/dry weight” data show no differences between WT and KOs under “↑O2” conditions. This negative result is consistent with the observed 10–15% weight loss (presumably all H2O), which would have reduced net Starling forces for ultrafiltration, making AQP KOs irrelevant. However, preliminary LDH and protein data are consistent with the idea that the KO of AQP5 and/or AQP1 reduces POT. For “↑O2,” the AQP1-KO (vs. WT) shows a weak trend towards lower LDH; AQP5-KO and dKO show trends so strong that mean LDH does not differ from WT/“Air.” Moreover, for “↑O2,” AQP5-KO and dKO have protein levels markedly lower than WT/“↑O2.” Finally, for “↑O2,” we observe a progressive decrease in mouse mortality in the sequence WT > AQP1-KO >> AQP5-KO > dKO. If the observed trends continue for larger N’s, our data would argue that AQP5 and AQP1 are protective for POT and point, for the first time, towards a role of AQP5 in conducting O2. ONR: N00014-20-1-2737 This is the full abstract presented at the American Physiology Summit 2023 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: In the United States over 10% of all neonates are born premature (less than 37 weeks gestational age) and many face complications, such as necrotizing enterocolitis (NEC). NEC is the most deadly gastrointestinal disease in preterm neonates with up to 50% mortality. Survivors face life-long complications. NEC is a multifactorial disease caused by 1) intestinal immaturity, including a poorly developed physical barrier between luminal contents and the rest of the body; 2) an exaggerated immune response; and 3) intestinal dysbiosis, which together can result in irreparable damage to the intestine. Since there is no cure for NEC, prevention is the best strategy. Enhancing our understanding of intestinal epithelial cell (IEC) barrier regulation during early development will provide novel therapeutic targets to prevent NEC. Published evidence indicates roles for the RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) in intestinal development, barrier function, and intestinal repair. Sequencing data from the inflamed tissue of a NEC patient indicates that IMP1 is down-regulated relative to uninflamed tissue. Notably, roles for IMP1 in NEC are not defined. Emerging evidence suggests that mucus complexity, governed by enzymes such as Qsox1, impacts intestinal barrier function and inflammation susceptibility. This study aimed to define the role of IMP1 in NEC pathogenesis using a model of NEC-like intestinal injury in mice with IEC-specific Imp1 overexpression or Imp1 loss. Hypothesis: IMP1 expression is protective in a mouse model of NEC-like intestinal injury. Methods: All studies are OHSU IACUC-approved. This study used: wild-type (WT, control), Imp1 IEC-knockout ( VillinCre;Imp1 fl/fl ; Imp1 Δ IEC ), and Imp1 IEC-overexpression ( VillinCre;lslFLAG-Imp1 OE ; Imp1 IEC-OE ) mice. At post-natal day 4 mice of both sexes were randomly assigned to control or NEC groups. The control mice remained with the dam. NEC was induced with the well-established experimental NEC-like intestinal injury model. Mice were separated from the dam and maintained for 72 hours in an incubator. Pups were gavage-fed NEC formula (mixture of infant formula, puppy replacer, 1:10 dilution of bacteria derived from a premature infant with NEC, and 2.5 ug/g body weight of lipopolysaccharide) every 3 hours from 7am-10pm. Twice daily the pups were exposed to hypoxia (5% oxygen). After 72 hours, tissue was collected for histology, gene, and protein expression analyses. Survival was assessed with Kaplan-Meier curves. Total RNA sequencing was performed using the NovaSeq S4. The mucus and tissue barrier were evaluated by immunofluorescence staining for mucin 2, mucus lectins, occludin, and E-cadherin. Statistical analyses were performed using 2-way ANOVA with Tukey’s test for multiple comparisons and the Mantel-Cox log-rank test for survival analysis. Results: The NEC model induces pneumatosis, histological damage, and a significant up-regulation of inflammatory cytokine gene expression Lcn2 and Il1 b in all three genotypes, p <0.05, n=5-15. Despite damage, Imp1 IEC-OE mice survive 2-times better than WT or Imp1 Δ IEC mice (survival for WT: 27.8%, n=36; Imp1 Δ IEC : 31.6%, n=19; Imp1 IEC-OE : 60%, n=10 mice, p<0.05). RNA-sequencing data indicates that Imp1 IEC-OE mice significantly up-regulate expression of the disulfide catalyst Qsox1 (In NEC: WT: 1077 ± 94.6, Imp1 Δ IEC : 1017 ± 12.75, Imp1 IEC-OE : 1446 ± 45.73, p=0.003 vs WT and p=0.002 vs Imp1 Δ IEC ). Conclusion: Our data suggest that Imp1 expression enhances survival in a mouse model of NEC and promotes expression of a disulfide catalyst Qsox1, which may promote mucus maturation and protect the neonatal small intestine. NIH K01DK129401, R01HD097367, the Gerber Foundation, the OHSU Knight Cancer Institute 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.

Glomeruli number and glomerular volume are indicators of kidney health and chronic kidney disease (CKD) progression. Low nephron number is predictive of the development of CKD, and increased glomerular volume is associated with hyperfiltration and hypertension. Accurate estimates of glomeruli number are necessary for relating whole body GFR to single nephron GFR (SNGFR) which is an important parameter for mathematical modeling of transport along the nephron. In addition, previous studies had observed larger volumes and greater SNGFR in juxtamedullary glomeruli compared to cortical glomeruli. To enable routine estimation of cortical glomerular density and the size of cortical and juxtamedullary glomeruli, we optimized a cost- and time-effective method for labeling and imaging glomeruli in mouse models. Mice were injected with Alexa fluor 647 conjugated wheat germ agglutinin (WGA-647; 0.5 mg) intracardially. After 4 minutes circulation time, kidneys were perfusion fixed and harvested. Kidneys were sectioned at the midline at 600 µm up to 999 µm and cleared with ethyl cinnamate. Cross sections were imaged on Leica Sp8 with either 10x or 25x objective and 15 µm z-step size. This method enabled visualization of perfused glomerular capillaries and kidney vasculature. The cortical region was identified based on autofluorescence (488 nm laser). Individual glomeruli were identified and counted by automated 3D segmentation in Python. The diameters of individual glomeruli were measured in higher magnification images using Leica LAS X software. Juxtamedullary glomeruli were identified as those within the inner third of the cortex, nearest the medulla. On average, juxtamedullary glomeruli had larger diameters compared to cortical glomeruli. However, the extent of WGA-647 perfusion within individual glomeruli varied along the interlobular vessels. Including heparin (500 U/L) in the WGA-647 injection resulted in better filling or perfusion of glomeruli, especially in the superficial cortex, and as a result the estimated average glomerular diameter increased. In future, this methodology will be applied to compare cortical glomerular density and average glomerular volume in male and female mice and in genetic kidney disease models. National Institutes of Health T32 DK007052, R01 DK125049, U54 DK137329 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: Skeletal muscle regeneration is an energy-demanding process that relies on mitochondria to generate ATP. While healthy skeletal muscle fibers have organized interfibrillar mitochondrial networks organizing architecture segregated into columns along the Z-line of the myofiber, regenerating fibers exhibits altered mitochondrial networks that span several sarcomeres. Despite links between muscle regeneration and altered mitochondrial dynamics and biogenesis, the role of specific cells in remodeling these networks remains unclear. Because muscle stem cells (MuSCs) play a critical role in muscle regeneration, we explored the relationship between MuSCs and mitochondria in regenerating muscle fibers. Methods: To induce muscle regeneration, we used the hindlimb ischemia mouse model of peripheral artery disease (PAD) and the mdx mouse model of Duchenne’s muscular dystrophy (DMD). Furthermore, transgenic reporter mice such as Pax7-tdTomato, H2B-EGFP, and mitoDendra2 were used to mark MuSCs, track nuclei, and label mitochondria, respectively. Fluorescently labeled MuSCs were also transplanted into BaCl 2 -injured muscle to elucidate their behavior and interactions throughout muscle regeneration. Immunofluorescence, single fiber staining, and biochemical assays from harvested muscles were performed for data analysis. Results: Following injury, a significant increase in the number of endogenous MuSCs was observed 7 days post-injury compared to contralateral control, while a dramatic increase in the fusion of MuSCs into myofibers was noted at days 14 and 28. Interestingly, all fused myofibers at days 14 and 28 displayed central nucleation, a hallmark of regeneration that fusion of the MuSC is critical for myofiber regeneration. Primary MuSCs from H2B-EGFP reporter mice were isolated and transplanted into the injured muscle to determine the origin of the centrally located myonuclei. In myofibers where the transplanted MuSCs had fused, centrally located myonuclei were GFP + , indicating their origin from MuSCs. Surprisingly, regenerating muscle fibers isolated from the mitoDendra2 mouse model exhibited high densities of mitochondrial content near the centrally located myonuclei. To evaluate whether MuSCs contribute to producing these central myonuclei near mitochondria, primary MuSCs isolated from mitoDendra2 reporter mice were transplanted into mdx mice. Fused myofibers indeed exhibited high Dendra2 + mitochondrial density between central nuclei along with a restoration of the mitochondrial network. Finally, we also observed a change in myogenic potential and mitochondrial respiration after transplanting MuSCs that have been preconditioned to enhance mitochondrial biogenesis. SIGNIFICANCE RELEVANCE: Overall, these data indicate that MuSC-derived myonuclei synthesize new mitochondria to generate the bioenergetics for myofiber regeneration after muscle injury. This relationship between MuSCs and myofiber mitochondria provides a basis for MuSC-derived mitochondrial transplantation as a therapeutic approach for muscular diseases associated with mitochondrial dysfunction. Acknowledgements: This work was supported by the NIH R01AR080169, R01AG072309, VA Merit Award I02RX005009 (to YCJ) 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.

objective: WDR77, a component of 20S PRMT5 containing a methyltransferase complex, can modify certain arginines in several splicosome Sm proteins and histones to dimethylarginine, which may play a role in transcriptional regulation. Studies have shown that the expression level of WDR77 plays a role in many systemic cancers such as non-small cell lung cancer, prostate cancer and ovarian cancer, and is positively correlated with poor prognosis of most cancers. However, WDR77 has not been studied in detail in glioma, and its biological significance in glioma has not been fully clarified. This study focused on glioma and explored the characterization and prognostic value of WDR77 in glioma, aiming to explore the role of WDR77 in glioma and its feasibility as a potential prognostic factor, so as to guide the clinical treatment of glioma in order to improve the prognosis of patients. Methods: In this study, the role of WDR77 in glioma and its feasibility as a potential prognostic factor were studied by bioinformatics analysis. In this study, transcriptome gene expression profiles and clinical data of 1018 glioma patients were collected from the Chinese glioma Genome Atlas Database (CGGA). The target gene WDR77 was selected from the candidate genes after four-layer analysis filtering (including survival analysis filtering, independent prognostic analysis filtering, ROC curve filtering and clinical correlation analysis filtering). Differential expression analysis, survival analysis, independent prognosis analysis, ROC curve analysis and clinical correlation analysis of the target gene WDR77 were performed to explore the feasibility of WDR77 as a potential prognostic factor for glioma. Then, immunoinfiltration analysis, co-expression analysis and GSEA analysis of the target gene WDR77 were performed to explore the role and mechanism of WDR77 in glioma. Results: WDR77 is significantly overexpressed in gliomas, which is associated with poor prognosis in gliomas (including GBM and LGG), and leads to shorter overall survival in LGG patients (HR =2.8, P =8.9 e-08). WDR77 was an independent prognostic factor for glioma (HR=2.110; 95%CI=1.700 – 2.618; P <0.001), WDR77 had good prognostic accuracy (AUC values for 1-year, 3-year, and 5-year overall survival were 0.710, 0.761, and 0.799, respectively). WDR77 was positively correlated with regulatory pathways such as regulatory T cell differentiation and macrophage differentiation, and with immune cell infiltration such as CD4 + T cells (r=0.523, P =8.78e-35) and macrophages (r=0.509, P =1.36e-32). Conclusion: WDR77 is a novel molecular marker that can be used as an independent prognostic factor for human glioma, and the high expression of WDR77 suggests a poor prognosis for glioma. WDR77 may be a potential immunotherapeutic target for human glioma, and WDR77 affects the occurrence and development of glioma through multiple molecular pathways. National Clinical Key Specialty Project Foundation ; Shanxi Scholarship Council of China;Lvliang City high-level scientific and technological talents development project 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.

The Special Master’s Program at Georgetown University Medical Center (GUMC SMP) is a one year academic enhancement MS program that prepares students for future success in medical school. Its curriculum covers about half of the material in the first year basic science curriculum of Georgetown’s School of Medicine, supplemented with complementary graduate courses. GUMC SMP students attend the relevant basic science lectures with first year medical students (M1), are assessed by completing the same multiple choice questions used for their M1 counterparts and are graded against the M1 average to determine grades for corresponding SMP medical courses. In 2015, a second campus, the Georgetown Downtown SMP (GTDT), was opened that follows the same curriculum, but with all material delivered in a fully “flipped” manner. The GTDT students' average undergraduate GPA and MCAT scores are not different from the GUMC SMP students, whereas the average GPAs of SMP students are significantly lower than GPAs of their M1 peers (3.2 vs 3.7 in M1 class). The GTDT students review the lecture capture (LC) recordings of medical (or graduate) lectures on their own time and attend 2-4 hrs of class time four days per week during which the GTDT instructor provides active learning sessions to reinforce the material. The current research expands on our earlier findings, by evaluating the GTDT cohort performance in six medical physiology exams and three medical gross anatomy (GA) exams over the past five years compared to GUMC SMP peers and M1 students. Using the Student’s t test with the Bonferroni correction for multiple comparisons, significance level was designated at p<0.05. Our results indicate that the GTDT students continued to outperform their GUMC SMP counterparts in all exams, reaching statistical significance in three out of six medical physiology exams and three out of three medical GA exams. The GTDT students also had higher average scores than their peer M1 students on five out of six medical physiology exams, reaching significance in three out of the six M1 exams. GTDT averages were higher than M1 students on GA exams, but differences did not reach statistical significance. The higher GTDT performance is most likely attributable to the students being actively engaged in flipped learning in all classroom sessions. Additionally, GTDT students’ responses to anonymous polling showed that they felt the active learning exercises were beneficial to their overall learning and their long-term retention of the material. Overall, our results continue to validate the successful use of the active learning environment in medical education, confirm its successful use in the GTDT program, and suggest that the flipped learning modality results in overall better learning outcomes in a rigorous medical curriculum. Georgetown University 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.

Parasympathetic reactivation is the underlying mechanism for the rapid fall in heart rate (HR) post-exercise. A delayed decrease in the HR during the first minute after graded exercise is a powerful predictor of overall mortality and is linked to unfavorable clinical outcomes. Chronic kidney disease (CKD) is characterized by an altered autonomic function with heightened sympathetic and weakened parasympathetic activity. Given that exercise training has been shown to improve autonomic function and parasympathetic reactivation after exercise, the purpose of the present study was to test two hypotheses: 1) patients with CKD experience delayed HR recovery (HRR) compared to controls at the cessation of exercise due to attenuated cardiac vagal reactivation; 2) 12 weeks of aerobic exercise training would improve cardiac vagal reactivation in patients with CKD. Twenty-seven patients with CKD stages III and IV [eGFR between 15-59 mL/min/1.73m2] and eighteen age-matched controls were enrolled. All participants underwent cardiopulmonary exercise testing (CPET) in accordance with the modified Balke protocol. Participants were instrumented with a 12-lead ECG for HR assessment, and ventilation and pulmonary gas exchange were recorded breath-by-breath throughout the exercise tests using a metabolic analyzer. Post-exercise cardiac vagal reactivation was indexed via HRR [absolute HR decay (HRR60s)] and HR variability (HRV) metrics [root mean square of successive differences (RMSSD)] during 60 seconds of recovery following the test. To assess HRR kinetics over the entire recovery period, individual data were modeled with a monoexponential fit and the time constant (τ, time to reach ~63.2% of the total HRR, in seconds) was calculated. Comparisons between patients with CKD and controls were made based on the percentage of predicted HRmax obtained during the CPET using the following equation: HRmax= 208−0.7xage. Patients with CKD were then randomly assigned to exercise (n=17) or non-aerobic stretching (n=11) interventions consisting of three sessions per week for 12 weeks. Training sessions began at 20 minutes and increased by five minutes weekly to a maximum of 45 minutes. Intensity started at 50% of heart rate reserve and rose 5% each week to a target of 75%. CPET was repeated at the end of the 12 weeks. The percentage of predicted HRmax obtained at CPET was similar between patients and controls (CKD: 87±9 vs. CON: 86±5 %HRmax; P =0.448). The HRR60s was blunted in patients with CKD compared to controls (∆HRR60s; CKD: -11±4 vs. CON: -17±5 bpm; P =0.001), and τ was significantly longer in patients with CKD (τ; CKD: 144±31 vs. CON: 116±21 s; P = 0.002). Additionally, RMSSD increased at the cessation of exercise in both groups, but to a lesser extent in CKD patients compared to controls (ΔRMSSD; CKD: 0.5±4 vs. CON: 1.3±3 ms; P = 0.032). There was no significant difference in the maximum HR obtained during the CPET before and after 12 weeks of exercise training (pre: 142±10 vs. post: 136±20 bpm, P =0.178) or stretching (pre: 148±20 vs. post: 142±20 bpm, P =0.107). Twelve weeks of exercise training did not improve HRR60s (ΔHRR60s; pre: -11±4 vs. post: -11±8 bpm, P =0.692) nor vagal activity as measured by HRV. These findings support the hypothesis that patients with CKD exhibit impaired vagal reactivation, which may contribute to the increased cardiovascular risk associated with CKD. However, contrary to our hypothesis, 12 weeks of cycling exercise training may not be sufficient to enhance cardiac vagal reactivation. Future studies should explore different exercise modalities and manipulate training variables such as intensity, volume, and frequency to assess their potential impact on cardiac vagal reactivation in patients with CKD. This project was funded by the National Institutes of Health (NIH R01HL135183; NIH R61AT10457; NIH R33AT010457-03). 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.

Women with a history of preeclampsia (hxPE) are at a higher risk of developing cardiovascular disease and related mortality later in life. This association between preeclampsia and chronic cardiovascular risk may be mediated by persistent endothelial dysfunction following preeclampsia. Low-dose aspirin (LDA; 75-150mg/day) is commonly recommended during high-risk pregnancy to reduce preeclampsia incidence and severity and may also help stabilize endothelial function. We hypothesized that LDA use during pregnancy preserves macrovascular and microvascular endothelial function in postpartum women with hxPE. We included three groups: women with hxPE treated with prenatal LDA (hxPE+LDA; n=6; 34±3 years), women with hxPE not treated with prenatal LDA (hxPE-LDA; n=10; 34±2 years), and women with a history of uncomplicated pregnancy (HC; n=10; 35±2 years). Conduit artery endothelial function was assessed via brachial artery flow-mediated dilation (FMD). Microvascular endothelial function was assessed via cutaneous vascular conductance (CVC, %max) response to graded infusions of acetylcholine (10 -10 -10 -1 M) via microdialysis. Relative and absolute FMD in hxPE-LDA were lower compared to HC (relative: 6.0±0.5% vs. 7.7±0.4%, P =0.04; absolute: 0.19±0.01mm vs. 0.24±0.01mm, P =0.01), while hxPE+LDA did not show a difference from HC (relative: 6.3±0.5% vs. 7.7±0.4%, P =0.16; absolute: 0.21±0.01mm vs. 0.24±0.01mm; P =0.27). hxPE-LDA exhibited reduced microvascular endothelium-dependent dilation compared to HC at acetylcholine doses ≥10 -3 M ( P <0.03). hxPE+LDA also showed reduced endothelium-dependent dilation compared to HC, but only at 10 -3 M ( P <0.01). Peak CVC response to acetylcholine in hxPE-LDA was lower than HC (79±5%max vs. 94±4%max, P =0.04), but no significant difference was observed between hxPE+LDA and HC (93±4%max vs. 94±4%max, P =0.99). These findings suggest that prenatal LDA therapy may reduce persistent vascular endothelial dysfunction after pregnancy in women with hxPE. American Heart Association CDA 937990 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: The determinants of aortic pulse pressure (aPP) are assessed via 1) Wave separation analysis to quantify forward (Pf) and backward pressure (Pb) and 2) Reservoir-wave analysis to quantify excess (XSP) and reservoir pressure (RP). Patients with heart failure with preserved ejection fraction (HFpEF) have high arterial stiffness and present with central and peripheral arterial hypertension and a variable stroke volume (SV) response to exercise. The aim of our analysis was to acutely lower ventricular afterload (aPP and its components [RP, Pb]) during exercise with sublingual nitroglycerin (NTG) to determine whether high exercise afterload contributes to the low SV reserve during exercise in adults with HFpEF. Methods: In 34 adults with HFpEF (75% female, age: 69±6 years; BMI: 39±7 kg/m 2 ), we acquired continuous pulmonary (right-heart catheter) and arterial pressures (radial catheter) and simultaneously derived ascending aortic pressure waveforms (via SphygmoCor generalized inverse transfer function) at rest and during 6-minutes of submaximal cycling exercise (20 Watts). Participants were studied in the seated upright position during either a NTG (q15 mins, 400 μg) or placebo (PL) spray condition. We calculated stroke volume (SV) from heart rate (HR; EKG) and cardiac output ([Formula: see text]c; Direct Fick). Data were compared using two-way (condition*stage) ANOVA. Results: Aortic systolic pressure (PL: 135±23 vs NTG: 123±23 mmHg) and aPP (PL: 60±18 vs NTG: 50±18, mmHg) were lower with NTG during exercise (Condition: both, P <0.011), but the changes from rest to exercise were not different (both, Condition*Stage: P >0.290). Pf (PL: 18±6 vs NTG: 14±6 mmHg, condition: P =0.019), Pb (PL: 6±3 vs NTG: 4±2 mmHg, P <0.001) and RP (PL: 50±17 vs NTG: 39±18 mmHg, P =0.003) were lower with NTG at rest and during exercise; whereas, XSP was not different with NTG (PL: 21±7 vs NTG: 22±7 mmHg, P =0.298). The change in pulmonary artery wedge pressure (PAWP) with exercise was lower with NTG (PL: ∆13±7 vs NTG: ∆9±6 mmHg, condition*stage: P =0.024), with lower PAWP at 20 Watts only (PL: 20±9 vs NTG: 15±8 mmHg P =0.004), but the changes in HR, SV, and [Formula: see text]c were not different (all, condition*stage: P >0.566). Conclusion: NTG lowered left ventricular afterload (Pf, Pb, and RP) at rest and during exercise but there was no effect on exercise cardiac reserve in adults with HFpEF. However, the effects of NTG were not limited to changes in afterload as preload was also lower which potentially negated effects on cardiac reserve. NIH - 1P01HL137630 (BDL); AHA - 23POST1022536 (DJW). 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.