In this essay I review and summarize four older “thought” papers about how science is communicated and practiced. These papers were written by the Nobel Prize winner Peter Medawar, the eminent physiologist Julious Comroe, Eugene Robin a renowned clinical investigator, and David Horrobin an innovative scientist and early player in biotechnology. These papers all question how we frame what we do and tell stories about what we find. Several caution against excessive objectivity, hype, groupthink, and what we now call fear of missing out. They argue for imagination, creativity and critical thinking. While there are many threats to biomedical research beyond the control of individual scientists, I believe these papers offer insight about things we can do from the inside out to improve the practice and culture of science. I am also hopeful that insights from these papers, if broadly acted on, could help improve public confidence in and support for biomedical research.

Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer's 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting, in which metabolic constraints reshape functional dynamics across brain networks.

INTRODUCTION:Acute hypoxia can impair cognitive performance, yet the underlying systemic and cerebral physiological mechanisms remain unclear. The objective of this study was to elucidate the systemic and cerebral physiological responses associated with changes in cognitive performance during acute hypoxia. METHODS:There were 11 healthy subjects (5 females) who completed a cognitive test during baseline normoxia (21% fraction of inspired oxygen, FIO2) followed by 2 randomized hypoxia trials: 11.8% FIO2 (moderate hypoxia) and 7.7% FIO2 (severe hypoxia). Subjects were instrumented with an arterial catheter, transcranial doppler ultrasound, and near-infrared spectroscopy to measure systemic (arterial O2 saturation) and cerebral oxygenation (cerebrovascular conductance and cerebral tissue saturation). RESULTS:Moderate hypoxia reduced arterial O2 saturation and cerebral tissue saturation, with no change in cerebrovascular conductance. Severe hypoxia decreased arterial O2 saturation, cerebrovascular conductance, and cerebral tissue saturation. Cognitive performance did not differ from baseline during either hypoxia condition (omission rate, errors/min: baseline 0 ± 1 vs. moderate hypoxia 1 ± 1; baseline 1 ± 1 vs. severe hypoxia 1 ± 1). No associations were observed between physiological changes and cognitive performance during moderate hypoxia. During severe hypoxia, smaller declines in arterial O2 saturation (r = 0.643) and greater declines in cerebrovascular conductance (r = -0.651) were associated with increased omission rates. DISCUSSION:Cognitive performance during acute severe hypoxia correlated with cerebral oxygenation and blood flow. Associations differed between moderate and severe hypoxia, suggesting that both duration and severity of hypoxia influence the relationship between physiological responses and cognitive performance.

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. Although 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 nonmodifiable (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.

Spirometry is central to measuring pulmonary function and diagnosing respiratory disease. From spirometry, a flow-volume curve is generated and evaluating the shape of this curve may provide additional insight into pulmonary dysfunction compared to spirometry alone. We sought to determine if the shape of the flow-volume curve could detect signs of abnormal lung emptying in asymptomatic ex-smokers compared to never-smokers. A retrospective analysis of the shape of the flow-volume curves generated from routine spirometry from 61 ex-smokers (46% female) with normal spirometry and no diagnosis of respiratory disease and 42 never-smokers (58% female) was performed. The shape of the flow-volume curve was quantified via the slope ratio method. A slope ratio of 1 would indicate a linear decrease in flow with decreasing lung volume, whereas a slope ratio > 1 indicates a scooped pattern to the flow-volume curve, as seen in obstructive lung disease. Both ex-smokers and never-smokers had normal pulmonary function (Forced Expiratory Volume in 1 s (FEV1): 97 ± 20 vs. 97 ± 18%predicted; forced vital capacity (FVC): 99 ± 21 vs. 98 ± 18%predicted; and FEV1/FVC ratio: 97 ± 05 vs. 99 ± 6%predicted, all p > 0.05). The average slope ratio was higher in ex-smokers compared to never-smokers (1.90 ± 0.93 vs. 1.50 ± 0.78, p < 0.001). These findings suggest that slope ratio analyses may supplement pulmonary function testing to identify subclinical patterns of abnormal lung emptying dynamics in ostensibly healthy ex-smokers. This pattern is distinct from normal healthy ageing and support the inclusion of slope ratio as a tool to supplement evaluation of pulmonary function.

Endurance performance is predicted by maximal oxygen uptake, its fractional utilisation at lactate threshold (FULT) and exercise economy. These variables are used to estimate speed or power at lactate threshold (LT) and lactate turnpoint (LTP), which serve as performance proxies. This study examined the relationships between these variables in a large cohort of runners and cyclists and quantified their relative contributions to performance prediction. 495 runners (105 females) and 393 cyclists (42 females) completed incremental exercise tests to determine maximal oxygen uptake (running [R]: 56 mL/kg/min, 3.94 L/min; cycling [C]: 52 mL/kg/min, 3.99 L/min), economy (R: 220 mL/kg/km; C: 14.7 mL/min/W), FULT (R: 78

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.

The human brain, one of the most energy-demanding organs, continuously adapts to internal and external challenges. Hypoxia, a reduction in oxygen availability, poses a substantial threat to brain function. Despite its importance, the nature of the brain's adaptive response to hypoxia remains poorly understood. In this study, we investigated dynamic functional connectivity (FC) under acute hypoxic conditions (FiO2 = 7.7 % and 11.8 %) in healthy adults using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and concurrent advanced physiological monitoring, including partial pressures of end-tidal oxygen (PetO2) and carbon dioxide (PetCO2) and peripheral oxygen saturation (SpO2), and a Go/No-Go cognitive task to assess behavioral performance. Principal component analysis identified a hypoxia-responsive component in dynamic FCs across 400 cerebral parcels. This component captured hypoxia-specific FC changes that coincided with a critical drop in PetO2 (∼53 mmHg), preceding subsequent changes in SpO2, bulk BOLD signals, and behavioral performance. These FC changes were network-specific, with a marked increase primarily centered on the default mode network (DMN), which selectively synchronized with other high-level cognitive networks. In contrast, hypoxia-responsive connectivity showed limited involvement of visual networks, including connectivity with the DMN. These findings suggest that the brain engages in proactive and structured FC adaptations in anticipation of oxygen decline, rather than in response to it. FC-based metrics offer new insights into the temporal dynamics of brain resilience and may hold translational value for the early detection of vulnerability in neurological or neurodegenerative disorders.

Alcohol consumption acutely disrupts physiology and behavior. Yet, the modifying effects of age, biological sex, and health behaviors are not well understood. In this retrospective cohort study, we analyzed 5,109,185 person-days from 20,968 participants and fit generalized additive models to estimate within-person associations between alcohol intake and nocturnal resting heart rate (RHR), heart rate variability (HRV), sleep duration, and next-day physical activity. Models were stratified by age and sex, and adjusted for drinking frequency, body mass index, weekday/weekend, and season, and accounted for between-person differences via person-mean centering. We also assessed whether drinking earlier in the day, longer post-drinking sleep, and reducing physical activity attenuated disruptions. Acute alcohol consumption was associated with dose-dependent increases in nocturnal RHR and reductions in HRV, alongside decreases in sleep duration and next-day physical activity. These changes were more pronounced in females than males and in younger than older adults: consuming one drink more than personal average, compared with one less, was associated with an increase in RHR by 2.8 bpm (99.9% CI: 2.7, 2.9) in females and 2.4 bpm (99.9% CI: 2.3, 2.4) in males, while HRV declined by 3.8 ms (99.9% CI: -4.1, -3.5) in females and 3.3 ms (99.9% CI: -3.5, -3.1) in males. Drinking earlier in the day, obtaining longer post-drinking sleep, and reducing activity each reduced these effects. Alcohol consumption acutely disrupts cardiovascular regulation, sleep duration, and next-day physical activity, with stronger disruptions in females and younger adults. Behavioral modifications may mitigate these disruptions.

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.

Hemorrhagic shock is a leading cause of preventable death among military and civilian trauma patients. Although caused by severe hypovolemia, the threshold of blood volume reduction that triggers recruitment of compensatory mechanisms varies markedly. Individuals have been classified as having low tolerance (LT) or high tolerance (HT) to hypovolemia; however, molecular features contributing to tolerance remain unclear. Here we investigate multiomics correlates of hypovolemia tolerance and molecular responses underlying physiological compensating mechanisms of blood loss. Healthy adult human subjects (n = 133) recruited from two sites underwent lower body negative pressure (LBNP) to simulate progressive hemorrhage. The primary outcome variable was hemodynamic instability accompanied by onset of decompensated shock defined by systolic blood pressure <80 mmHg. Participants were classified into HT (n = 90) and LT (n = 43) subjects using a cumulative stress index quantifying maximal LBNP tolerance. Genome-wide messenger ribonucleic acid (mRNA), microRNA, whole exome sequencing, and select protein abundances were assayed using blood samples collected immediately before and after LBNP procedure. LBNP produced extensive transcriptomic response at post- compared with pre-LBNP, including natural killer cell-mediated immunity activation and gas transport processes inhibition. Differentially expressed microRNAs (miRNAs) also regulated these enriched processes. Tolerance group-specific signals include alpha-beta T cell activation and major histocompatibility complex (MHC) class II protein complex assembly inhibition in HT group. Integrated analysis of multiple molecular layers demonstrated a role of cytokines and epigenetic regulators in molecular mechanisms of compensating for progressive hemorrhage. Overall, our results indicate that individual tolerances to central hypovolemia are associated with specific genomic mechanisms underlying the capacity to compensate for severe blood loss.NEW & NOTEWORTHY This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals' tolerance levels for progressive blood loss.

Field-based sport research involves studies that collect data from athletes and/or teams during competition and/or their daily training environments. Over the last decade, sport-specific field-based research projects have significantly increased in number and complexity, partially owing to the further development of more portable measurement equipment (e.g., indirect calorimetry, desktop blood/gas analyzers, portable laboratories, etc.) and/or wearable or consumable technologies (e.g., smart watches, sensors, core temp pills, etc.). However, given these rapid advances and novelty, challenges remain in the validity and applicability of these devices. Unfortunately, there are no global ethical or best-practice standards for the use of portable devices and/or wearables in sport; however, this review will outline various opportunities and challenges. Many decision trade-offs are required when designing field-based research studies to balance gold-standard scientific rigor and strict research control with highly applied, but less-controlled, "real-world" conditions. To our knowledge, there are no narrative reviews that take a wholistic view of the logistical and methodological considerations of field-based research in athletes. Accordingly, this review takes a multi-disciplinary methodological approach (physiological, nutritional/energetic, biomechanical, musculoskeletal, cognitive, and psychosocial factors), along with the logistical considerations involved in project planning, research design, and ethics of field-based research with elite athletes and/or teams. We also provide practical guidance for characterizing the extreme demands of elite training and competition to support research that ultimately catalyzes improved understanding of the limits of human capacity. We hope this review can serve as a practical guide for researchers undertaking elite athlete field-based research.

This study tested the hypothesis that neural and vascular α2-adrenergic mechanisms contribute to sympathetic baroreflex regulation of human blood pressure. Muscle sympathetic nerve activity (MSNA; peroneal microneurography) was measured, and sympathetic action potentials (APs) were extracted from the filtered MSNA neurogram (continuous wavelet transform) in eight participants (5 females; 28 ± 7 yr) during a baseline (BSL) condition and a dexmedetomidine infusion (DEX; α2-adrenergic receptor agonist; 10-min loading dose at 0.225 µg/kg; maintenance dose: 0.1-0.5 µg/kg/h). Sympathetic AP baroreflex threshold and sensitivity gains were measured (spontaneous method). We quantified the transduction of integrated MSNA to diastolic blood pressure (DBP; signal averaging) and calculated an index of transduction gain as the slope of the relationship between maximum DBP and the number of cardiac cycles to maximum DBP. DEX reset the baroreflex operating point for medium APs to lower firing probabilities (AP cluster 4; BSL: 20 ± 6 to DEX: 6 ± 5%, P < 0.0004), lower DBP (72 ± 9 to 65 ± 10 mmHg, P < 0.0001), and reduced gain (AP cluster 4: -6.5 ± 2.0 to -2.0 ± 0.7%/mmHg, P < 0.0001). DEX reset the AP baroreflex sensitivity operating point to fewer AP clusters/burst (3.4 ± 0.7 to 2.9 ± 0.8 clusters/burst, P = 0.0156) but did not change gain. DEX reduced DBP transduction (cardiac cycle 6: 4.3 ± 3.2 to 3.3 ± 2.0 mmHg, P = 0.0032), increased the time to peak DBP (6 ± 1 to 11 ± 3 cardiac cycles, P = 0.0054), and reduced the DBP transduction gain (0.81 ± 0.72 to 0.36 ± 0.37 mmHg/cardiac cycle, P = 0.0012). These data suggest that neural and vascular α2-adrenergic mechanisms contribute to integrative sympathetic baroreflex regulation of blood pressure in humans.NEW & NOTEWORTHY Intravenous dexmedetomidine infusion (selective α2-adrenergic receptor agonist) 1) reduced the firing probability and strength of baroreflex control over medium-sized sympathetic action potentials in muscle sympathetic nerve activity (MSNA) and 2) attenuated the transduction of MSNA bursts to changes in blood pressure (BP) by reducing the magnitude of BP responses and increasing the time to peak BP. These data suggest that neural and vascular α2-adrenergic mechanisms contribute to sympathetic baroreflex regulation of human BP.

Objective:To evaluate if cardiac troponin values predict poor outcomes in COVID-19 patients across the range of patients of different sex and age. Methods:We examined high-sensitivity cardiac troponin T (hs-cTnT) levels in 1,050 severely ill hospitalized COVID-19 patients who had hs-cTnT data available and participated in the Expanded Access Program for convalescent plasma study during the first wave (April-August 2020) of the COVID-19 pandemic. Results:We observed a continuous relationship between hs-cTnT levels and mortality in hospitalized males and females with COVID-19. This finding was present regardless of sex or age. Conclusion:These data indicate the prognostic ability of hs-cTnT to predict mortality in hospitalized COVID-19 patients across all relevant patient groups. Clinical Trials registration number:NCT04338360.

Acute exposure to severe hypoxia impairs cognitive performance, yet the integrated brain mechanisms underlying this temporary decline remain unclear. This study examined regional variations in cerebral oxygen metabolism during acute hypoxia and their relationship to cognitive impairment. Eleven young, healthy participants (26.5 ± 4.5 years old) performed the Go/No-Go task during two sessions, each of which includes three minutes of hypoxia (FiO2 = 7.7 %). Cerebral blood flow (CBF) was assessed using pCASL MRI in one session, while blood-oxygen-level-dependent (BOLD) signals were acquired in another. Fractional changes in CBF (δCBF) and BOLD (δBOLD) were combined using a modified Davis model, adjusted for physiological differences between normoxia and acute and severe hypoxia, to calculate the fractional change in cerebral metabolic rate of oxygen (δCMRO2). Group-level z-normalized δCMRO2 maps revealed significant regional heterogeneity, with most pronounced reductions in areas associated with the dorsal and ventral attention networks and executive frontoparietal networks. These regions exhibited δCMRO2 reductions exceeding the hemispheric average (-9.6 ± 7.9 %) and were associated with increased commission errors during the Go/No-Go task, reflecting impaired inhibitory control and sustained attention. This study highlights the brain's adaptive prioritization of certain networks under oxygen deprivation, providing insights into the physiological mechanisms underlying hypoxia-induced cognitive impairments. These findings enhance our understanding of how acute hypoxia affects brain function, emphasizing the importance of network-specific adaptations in maintaining cognitive performance during oxygen deprivation.

This study leverages an experiment of nature framework to examine sex-based differences in ultraendurance swimming using English Channel performance data. Males were faster than females, with the greatest differences observed among older swimmers and top performers. Performance was optimal in moderately cool water temperatures (17–18°C). These findings highlight how naturally occurring endurance events provide unique opportunities to study physiological limits and the combined influences of sex, age, and environment on human performance.