Assessment of Sex-Dependent Medical Outcomes During Spaceflight.

Background: In this study sex-differences in medical outcomes during spaceflight are reviewed and probabilistic risk assessment (PRA) is used to assess the impact on spaceflight missions of varying lengths. Materials and Methods: We use PRA to simulate missions of 42 days, 6 months, and 2.5 years. We model medical outcomes using three crews: two men and two women, four women, or four men. Total medical events (TME), crew health index (CHI), probability (0-1) of medical evacuation (pEVAC), probability of loss of crew life (pLOCL), and influential medical conditions were determined. Results: No differences were seen in any metric for the 42-day mission. There were no differences seen for any mission length, in any crew, for TME, CHI, pLOCL, or environmental causes of pEVAC. Sex-dependent differences are seen for rates of nonemergent pEVAC during the 6 month and 2.5-year missions, where women have a higher pEVAC in the 182-day (0.0388 vs. 0.0354) and 2.5-year missions (0.350 vs. 0.228). These differences were driven by higher incidence of partially treated urinary tract infection (UTI). In the 2.5 year mission, with resupply of medical resources, the influence of UTI in women on pEVAC decreases (0.35-0.11). Conclusion: Although resupply is unlikely for deep space missions, modeled results suggest that sex-specific medical needs can be readily managed through preventive measures and inclusion of appropriate medical capabilities. Within its many limitations, PRA is a useful tool to estimate medical risks in unique environments where only expert opinion was previously available.

Probabilistic Risk Assessment of Prophylactic Surgery Before Extended-Duration Spaceflight.

Introduction. Prophylactic surgery before spaceflight may eliminate the risk of appendicitis and cholecystitis in astronauts on deep space missions. However, even minimally invasive surgery increases the risk of small bowel obstruction (SBO). Probabilistic risk assessment (PRA) is a method that can be used to estimate the benefits and risks of prophylactic surgery. Methods. Risks of appendicitis and cholecystitis during a 2.5-year Mars mission are compared to the risk of SBO after laparoscopic removal of the appendix, gallbladder, or both. A PRA model using Monte Carlo methodology was used to forecast the risks. Results. Prophylactic appendectomy and cholecystectomy combined, conferred an increased probability of medical evacuation (pEVAC) due to SBO as compared to the no surgery group. A slightly higher probability for the loss of crew life (pLOCL) was found in the no surgery group when compared to the cases in which either prophylactic appendectomy alone, or appendectomy plus cholecystectomy are performed. Discussion. The need for medical evacuation can be viewed as a potential risk for death in the context of a space mission where evacuation is not possible. Because of the higher pEVAC due to SBO and relatively small benefit in the reduction of pLOCL in the prophylactic surgery groups, this analysis does not support the prophylactic removal of appendix and/or gallbladder for spaceflight. Future advances in surgical or medical technique or mission medical capabilities may change these results. This work demonstrates the utility of PRA in providing quantitative answers to "what if" questions where limited information is available.

Quantification of Medical Risk on the International Space Station Using the Integrated Medical Model.

INTRODUCTION: The Integrated Medical Model (IMM) is a quantified, evidence-based decision support tool developed by National Aeronautics and Space Administration (NASA) to assist in the assessment of the medical risk of human spaceflight missions. The IMM utilizes a probabilistic risk assessment (PRA) approach to simulate potential in-flight medical events and resultant health and mission outcomes.METHODS: The IMM has been utilized to estimate the medical risk associated with International Space Station (ISS) missions. The IMM outputs that have been most informative to the ISS program are the probabilities of evacuation (pEVAC) and loss of crew life (pLOCL). These outputs are incorporated into a continuously maintained ISS PRA model so that its quantification of total ISS mission risk includes the medical risk.RESULTS: Results of this analysis revealed that the forecasted risk values of pEVAC and pLOCL due to medical events were improved by using the IMM with the ISS PRA model instead of using data from prior sources in which these values were underestimated.DISCUSSION: The IMM provides an evidence-based PRA approach to directly communicate and integrate medical risk with other ISS risks. A comparison of IMM outputs of pEVAC and pLOCL to empirical spaceflight data and analog population data revealed that IMM outputs were comparable with actual experience. With appropriate outcome context, these findings increase subject matter expert confidence in the accuracy of IMM risk estimates. IMM outputs provide quantifiable objective estimates of medical risk that can be used to inform mission risk assessments and to optimize crew health.Walton ME, Kerstman EL. Quantification of medical risk on the International Space Station using the Integrated Medical Model. Aerosp Med Hum Perform. 2020; 91(4):332-342.

Demonstration of reverse fatty acid transport from rat cardiomyocytes.

Fatty acids flow from adipocytes to nonadipose tissues during fasting and exercise and normally are fully oxidized. To determine if nonadipose tissues can export unoxidized FA when FA influx exceeds oxidation, neonatal cardiomyocytes were cultured in 1 microCi (14)C-palmitate in the presence of etomoxir to block oxidation. The cells took up and stored 25% of the radioactivity as (14)C-triacylglycerol in 12 h, but 4.5% of the label was released in 3 h and comigrated with (14)C-palmitate. Both uptake and release of radioactivity were increased by insulin and reduced by the nonspecific inhibitors of FA transporters phloretin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Perfused hearts from etomoxir-treated lean rats released 221 +/- 59 nmol/10 min of FA. Hearts from high-fat-fed lean rats released 366 +/- 172 nmol/10 min (P < 0.05). Hearts from obese rats released 744 +/- 260 and 1,578 +/- 630 nmol/10 min at 8 and 12 weeks of age, respectively. Perfusion with insulin increased FA release by 32%. In vitro and ex vivo findings suggest that nonadipose tissues such as myocardium can export FA when the unoxidized lipid content is excessive.

Octanoate oxidation measured by 13C-NMR spectroscopy in rat skeletal muscle, heart, and liver.

Contribution of octanoate to the oxidative metabolism of the major sites of fatty acid oxidation (heart, liver, and resting and contracting skeletal muscle) was assessed in the intact rat with 13C-NMR spectroscopy. Under inhalation anesthesia, [2,4,6,8-13C4]octanoate was infused into the jugular vein and the sciatic nerve of one limb was stimulated for 1 h. Octanoate was a principal contributor to the acetyl-CoA pool in all tissues examined, with highest oxidation occurring in heart and soleus muscle followed by predominantly red portion of gastrocnemius muscle (RG), liver, and then white portion of gastrocnemius muscle (WG). Fractional contribution of 13C-labeled octanoate to the acetyl-CoA pool (Fc2) was 0.563 +/- 0.066 for heart and 0.367 +/- 0.054 for liver. Significant differences were observed between each of the muscle types during both rest and contraction. In muscle, Fc2 was highest in soleus (0.565 +/- 0.089 rested, 0.564 +/- 0.096 contracted), followed by RG (0.470 +/- 0.092 rested, 0.438 +/- 0.072 contracted), and lowest in WG (0.340 +/- 0.081 rested, 0.272 +/- 0.065 contracted). Our findings demonstrate that the fractional contribution of octanoate to oxidative metabolism correlates with oxidative capacity of the tissue and that octanoate metabolism increases in contracted muscle in proportion to the overall increase in oxidative rate.

Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy.

Glucose is the dominant oxidative fuel for brain, but studies have indicated that fatty acids are used by brain as well. We postulated that fatty acid oxidation in brain could contribute significantly to overall energy usage and account for non-glucose-derived energy production. [2,4,6,8-13C4]octanoate oxidation in intact rats was determined by nuclear magnetic resonance spectroscopy. We found that oxidation of 13C-octanoate in brain is avid and contributes approximately 20% to total brain oxidative energy production. Labeling patterns of glutamate and glutamine were distinct, and analysis of these metabolites indicated compartmentalized oxidation of octanoate in brain. Examination of liver and blood spectra revealed that label from 13C-octanoate was incorporated into glucose and ketones, which enabled calculation of its overall energy contribution to brain metabolism: glucose (predominantly unlabeled) and 13C-labeled octanoate can account for the entire oxidative metabolism of brain. Additionally, flux through anaplerotic pathways relative to tricarboxylic acid cycle flux (Y) was calculated to be 0.08 +/- 0.039 in brain, indicating that anaplerotic flux is significant and should be considered when assessing brain metabolism. Y was associated with the glutamine synthesis compartment, consistent with the view that anaplerotic flux occurs primarily in astrocytes.

Relative rates of anaplerotic flux in rested and contracted rat skeletal muscle measured by 13C NMR spectroscopy.

Flux through anaplerotic pathways in skeletal muscle has not been evaluated quantitatively during both rest and contraction, nor have fibre type-specific rates of anaplerotic flux been studied. Steady-state analysis using 13C NMR spectroscopy enables calculation of Y (flux rate through anaplerotic pathways relative to tricarboxylic acid (TCA) cycle flux). Under inhalation anaesthesia, [2,4,6,8-13C4]octanoate was infused into the jugular vein of the intact rat (n = 10) and the sciatic nerve of one limb was stimulated at the voltage required to elicit maximal force output at 0.5 Hz. In resting muscle, Y was higher in soleus (0.41 +/- 0.22) versus white gastrocnemius (WG) (0.18 +/- 0.11). Y was 0.29 +/- 0.06 in the predominantly red portion of the gastrocnemius (RG) during rest. During contraction, Y was similar to the resting value in soleus (0.34 +/- 0.14), RG (0.20 +/- 0.04) and WG (0.15 +/- 0.08); Y was higher in soleus versus both RG and WG during contraction. These results demonstrate: (1) relative flux through anaplerotic pathways is 15-41 % of TCA cycle flux at rest and during muscle contraction, (2) higher relative anaplerotic flux in oxidative (soleus) versus glycolytic muscle (WG) during rest and in slow-twitch (soleus) versus fast-twitch (RG and WG) muscle during contraction, and (3) relative flux through anaplerotic pathways is maintained in all muscle fibre types during contraction, which indicates that absolute rates of anaplerotic flux rise in proportion to increased oxidation rates during contraction. These results are consistent with a sustained increase in substrate entry into and exit from the TCA cycle through anaplerotic pathways during contraction.