Computational modelling of cardiovascular pathophysiology to risk stratify commercial spaceflight.

For more than 60 years, humans have travelled into space. Until now, the majority of astronauts have been professional, government agency astronauts selected, in part, for their superlative physical fitness and the absence of disease. Commercial spaceflight is now becoming accessible to members of the public, many of whom would previously have been excluded owing to unsatisfactory fitness or the presence of cardiorespiratory diseases. While data exist on the effects of gravitational and acceleration (G) forces on human physiology, data on the effects of the aerospace environment in unselected members of the public, and particularly in those with clinically significant pathology, are limited. Although short in duration, these high acceleration forces can potentially either impair the experience or, more seriously, pose a risk to health in some individuals. Rather than expose individuals with existing pathology to G forces to collect data, computational modelling might be useful to predict the nature and severity of cardiovascular diseases that are of sufficient risk to restrict access, require modification, or suggest further investigation or training before flight. In this Review, we explore state-of-the-art, zero-dimensional, compartmentalized models of human cardiovascular pathophysiology that can be used to simulate the effects of acceleration forces, homeostatic regulation and ventilation-perfusion matching, using data generated by long-arm centrifuge facilities of the US National Aeronautics and Space Administration and the European Space Agency to risk stratify individuals and help to improve safety in commercial suborbital spaceflight.

Handheld Sonographic Cardiovascular Imaging Under Hypergravity Conditions.

INTRODUCTION: Real-time cardiovascular imaging during hypergravity exposure has been historically limited by technological and physical challenges. Previous efforts at sonographic hypergravity imaging have used fixed ultrasound probes; the use of hand-held ultrasound, particularly performed by minimally trained laypersons, has been less explored. Here we will discuss handheld sonography to self-visualize carotid vascular and cardiac changes during hypergravity.METHODS: Three subjects with variable ultrasound experience ranging from no familiarity to extensive clinical experience used handheld ultrasound at rest and under stepwise +Gz hypergravity exposures (maximum +3.5 Gz) to visualize carotid vascular changes. Subxiphoid cardiac ultrasound was obtained by the most experienced subject. Subjects had variable prior hypergravity experience; all were trained in anti-G straining techniques. Sonographically inexperienced subjects underwent a brief (< 5 min) familiarization with the ultrasound probe, user interface, and desirable viewing window immediately prior to centrifugation; real-time coaching was provided. Ultrasound images were correlated to self-reported symptoms and hemodynamic data.RESULTS: Handheld ultrasound performed as desired; all subjects were successful at obtaining ultrasound images with adequate capture of windows of interest. Subxiphoid imaging efforts were limited by probe overheating and associated with variable quality of imaging due to probe displacement from straining techniques; the subject noted transient, mild discomfort and ecchymosis after imaging in the subxiphoid region.DISCUSSION: Even individuals with minimal or no ultrasound experience successfully obtained usable images under centrifuge conditions. While there were some limitations, this technical demonstration provides initial validation of handheld sonography as an available tool for real-time cardiovascular imaging in a hypergravity environment.Blue RS, Ong KM. Handheld sonographic cardiovascular imaging under hypergravity conditions. Aerosp Med Hum Perform. 2024; 95(3):158-164.

Layperson Physiological Tolerance and Operational Performance in Centrifuge-Simulated Spaceflight.

INTRODUCTION: Prior study has indicated that individuals of varied age, medical history, and limited-to-no experience tolerate spaceflight conditions. We sought to expand upon the understanding of layperson response to hypergravity conditions expected in commercial spaceflight by exposing subjects, following minimal training, to centrifuge-simulated, high-fidelity commercial spaceflight profiles. We further explored how these individuals perform in simulated operational activities during and following hypergravity.METHODS: Volunteer subjects participated in up to five centrifuge runs (maximum +4.0 Gz, +4.5 Gx, 6.1 G resultant; onset rate <0.5 Gz · s-1, ≤1 Gx · s-1). Profiles included two winged spacecraft simulations with sequential and combined +Gx/+Gz and two capsule simulations representing nominal +Gx launch and reentry. The final profile simulated a capsule launch abort, with a more dynamic cycling of +Gx exposures and oscillatory multi-axis exposures simulating parachutes and water motion. Touchscreen tablets were used to administer pattern-replication tasks during and after profiles.RESULTS: A total of 46 subjects participated, including 4 diabetics and 9 with cardiac disease. There was increased frequency of motion sickness, subjectively associated with capsule-type profiles, and increased termination of participation compared to prior studies. There was no association between medical history, age, sex, or motion sickness history and tolerance or noncompletion. Tablet test errors were common; accuracy and time to completion were associated with age. There was no association between any time metric or accuracy and sex.DISCUSSION: This study improves understanding of layperson tolerance in commercial spaceflight analog conditions, and the capsular profiles broaden the applicability of the findings. The frequency of task errors highlights the potential for mistakes in operational activities when performed by laypersons.Blue RS, Ong KM, Ray K, Menon A, Mateus J, Auñón-Chancellor S, Shah R, Powers W. Layperson physiological tolerance and operational performance in centrifuge-simulated spaceflight. Aerosp Med Hum Perform. 2023; 94(8):584-595.

Blood Glucose Alterations and Continuous Glucose Monitoring in Centrifuge-Simulated Spaceflight.

INTRODUCTION: Sympathetic stimulation is known to be associated with transient alterations of blood glucose (BG) concentration; spaceflight acceleration may be similarly associated with alterations of BG, potentially posing a risk to diabetic individuals engaging in future spaceflight activities. Despite prior studies demonstrating diabetic subjects' tolerance to centrifuge-simulated spaceflight, data are lacking regarding blood glucose response to hypergravity. It remains unclear whether hypergravity or associated physiological response may pose a risk to diabetics. Continuous glucose monitors (CGM) offer a means of noninvasive glucose monitoring and may be useful in spaceflight and analog environments. Here, we describe the results of continuous glucose monitoring during centrifuge-simulated spaceflight.METHODS: Subjects participated in 1-5 centrifuge-simulated spaceflight profiles (maximum +4.0 Gz, +6.0 Gx, 6.1 G resultant). Data collection included heart rate, blood pressure, electrocardiogram, continuous glucose via CGM, intermittent fingerstick BG, and postrun questionnaires regarding symptoms related to hypergravity exposure.RESULTS: CGM data were collected from 26 subjects, including 4 diabetics. While diabetic subjects had significantly higher BG compared to nondiabetics, this was not associated with any difference in symptoms or tolerance. Transient hypergravity-associated CGM glucose alterations did not affect tolerance of the centrifuge experience. CGM data were found to be reliable with occasional exceptions, including four instances of false critical low glucose alarms.DISCUSSION: While further study is necessary to better characterize CGM fidelity during hypergravity and other spaceflight-related stressors, CGM may be a feasible option for spaceflight and analog settings. As in prior studies, individuals with well-controlled diabetes appear able to tolerate the accelerations anticipated for commercial spaceflight.Ong KM, Rossitto JJ, Ray K, Dufurrena QA, Blue RS. Blood glucose alterations and continuous glucose monitoring in centrifuge-simulated spaceflight. Aerosp Med Hum Perform. 2022; 93(9):688-695.

A mathematical model and inference method for bacterial colonization in hospital units applied to active surveillance data for carbapenem-resistant enterobacteriaceae.

Widespread use of antibiotics has resulted in an increase in antimicrobial-resistant microorganisms. Although not all bacterial contact results in infection, patients can become asymptomatically colonized, increasing the risk of infection and pathogen transmission. Consequently, many institutions have begun active surveillance, but in non-research settings, the resulting data are often incomplete and may include non-random testing, making conventional epidemiological analysis problematic. We describe a mathematical model and inference method for in-hospital bacterial colonization and transmission of carbapenem-resistant Enterobacteriaceae that is tailored for analysis of active surveillance data with incomplete observations. The model and inference method make use of the full detailed state of the hospital unit, which takes into account the colonization status of each individual in the unit and not only the number of colonized patients at any given time. The inference method computes the exact likelihood of all possible histories consistent with partial observations (despite the exponential increase in possible states that can make likelihood calculation intractable for large hospital units), includes techniques to improve computational efficiency, is tested by computer simulation, and is applied to active surveillance data from a 13-bed rehabilitation unit in New York City. The inference method for exact likelihood calculation is applicable to other Markov models incorporating incomplete observations. The parameters that we identify are the patient-patient transmission rate, pre-existing colonization probability, and prior-to-new-patient transmission probability. Besides identifying the parameters, we predict the effects on the total prevalence (0.07 of the total colonized patient-days) of changing the parameters and estimate the increase in total prevalence attributable to patient-patient transmission (0.02) above the baseline pre-existing colonization (0.05). Simulations with a colonized versus uncolonized long-stay patient had 44% higher total prevalence, suggesting that the long-stay patient may have been a reservoir of transmission. High-priority interventions may include isolation of incoming colonized patients and repeated screening of long-stay patients.

Theory of partial agonist activity of steroid hormones.

The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS), which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

Inferring mechanisms from dose-response curves.

The steady state dose-response curve of ligand-mediated gene induction usually appears to precisely follow a first-order Hill equation (Hill coefficient equal to 1). Additionally, various cofactors/reagents can affect both the potency and the maximum activity of gene induction in a gene-specific manner. Recently, we have developed a general theory for which an unspecified sequence of steps or reactions yields a first-order Hill dose-response curve (FHDC) for plots of the final product versus initial agonist concentration. The theory requires only that individual reactions "dissociate" from the downstream reactions leading to the final product, which implies that intermediate complexes are weakly bound or exist only transiently. We show how the theory can be utilized to make predictions of previously unidentified mechanisms and the site of action of cofactors/reagents. The theory is general and can be applied to any biochemical reaction that has a FHDC.

A theoretical framework for gene induction and experimental comparisons.

Ligand-mediated gene induction by steroid receptors is a multistep process characterized by a dose-response curve for gene product that follows a first-order Hill equation. This behavior has classically been explained by steroid binding to receptor being the rate-limiting step. However, this predicts a constant potency of gene induction (EC(50)) for a given receptor-steroid complex, which is challenged by the findings that various cofactors/reagents can alter this parameter in a gene-specific manner. These properties put strong constraints on the mechanisms of gene induction and raise two questions: How can a first-order Hill dose-response curve (FHDC) arise from a multistep reaction sequence, and how do cofactors modify potency? Here we introduce a theoretical framework in which a sequence of steps yields an FHDC for the final product as a function of the initial agonist concentration. An exact determination of all constants is not required to describe the final FHDC. The theory predicts mechanisms for cofactor/reagent effects on gene-induction potency and maximal activity and it assigns a relative order to cofactors in the sequence of steps. The theory is supported by several observations from glucocorticoid receptor-mediated gene induction. It identifies the mechanism and matches the measured dose-response curves for different concentrations of the combination of cofactor Ubc9 and receptor. It also predicts that an FHDC cannot involve the DNA binding of preformed receptor dimers, which is validated experimentally. The theory is general and can be applied to any biochemical reaction that shows an FHDC.