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Brian Crucian,1 Adriana Babiak-Vazquez,2 Smith Johnston,1 Duane L Pierson,1 C Mark Ott,1 Clarence Sams1 1Biomedical Research and Environmental Sciences Division, NASA-Johnson Space Center, 2Epidemiology/Lifetime Surveillance of Astronaut Health, KBR-Wyle, Houston, TX, USA Background: The environment of spaceflight may elevate an astronaut’s clinical risk for specific diseases. The purpose of this study was to derive, as accurately as currently possible, an assessment of in-flight clinical “incidence” data, based on observed clinical symptoms in astronauts on board the International Space Station (ISS).Methods: Electronic medical records were examined from 46 long-duration ISS crew members, each serving approximately a 6-month mission on board the ISS, constituting 20.57 total flight years. Incidence for immunological-related adverse health events or relevant clinical symptoms was tabulated in a non-identifiable fashion. Event categories included infectious diseases, allergies, and rashes/hypersensitivities. A subsequent re-evaluation of more notable events, either of prolonged duration or unresponsive to treatment, was performed.Results: For the disease/symptom categories used in this evaluation, the ISS incidence rate was 3.40 events per flight year. Skin rashes were the most reported event (1.12/flight year) followed by upper respiratory symptoms (0.97/flight year) and various other (non-respiratory) infectious processes. During flight, 46% of crew members reported an event deemed “notable”. Among the notable events, 40% were classified as rashes/hypersensitivities. Characterization of on-orbit rashes manifested as redness with irritation, and could present on a variety of body locations.Conclusion: Based on reported symptoms, astronauts experience adverse medical events of varying severity during long-duration spaceflights. The data suggests caution, from both a vehicle design and biomedical countermeasures perspective, as space agencies plan for prolonged deep space exploration missions. Keywords: spaceflight, immunity, clinical incidence, astronauts, gravity, clinical risk, disease

Abstract Background Dysregulation of the immune system has been shown to occur during spaceflight, although the detailed nature of the phenomenon and the clinical risks for exploration class missions have yet to be established. Also, the growing clinical significance of immune system evaluation combined with epidemic infectious disease rates in third world countries provides a strong rationale for the development of field-compatible clinical immunology techniques and equipment. In July 2002 NASA performed a comprehensive immune assessment on field team members participating in the Haughton-Mars Project (HMP) on Devon Island in the high Canadian Arctic. The purpose of the study was to evaluate the effect of mission-associated stressors on the human immune system. To perform the study, the development of techniques for processing immune samples in remote field locations was required. Ten HMP-2002 participants volunteered for the study. A field protocol was developed at NASA-JSC for performing sample collection, blood staining/processing for immunophenotype analysis, whole-blood mitogenic culture for functional assessments and cell-sample preservation on-location at Devon Island. Specific assays included peripheral leukocyte distribution; constitutively activated T cells, intracellular cytokine profiles, plasma cortisol and EBV viral antibody levels. Study timepoints were 30 days prior to mission start, mid-mission and 60 days after mission completion. Results The protocol developed for immune sample processing in remote field locations functioned properly. Samples were processed on Devon Island, and stabilized for subsequent analysis at the Johnson Space Center in Houston. The data indicated that some phenotype, immune function and stress hormone changes occurred in the HMP field participants that were largely distinct from pre-mission baseline and post-mission recovery data. These immune changes appear similar to those observed in astronauts following spaceflight. Conclusion The immune system changes described during the HMP field deployment validate the use of the HMP as a ground-based spaceflight/planetary exploration analog for some aspects of human physiology. The sample processing protocol developed for this study may have applications for immune studies in remote terrestrial field locations. Elements of this protocol could possibly be adapted for future in-flight immunology studies conducted during space missions.

Spaceflight poses a myriad of environmental stressors to astronauts´ physiology including microgravity and radiation. The individual impacts of microgravity and radiation on the immune system have been extensively investigated, though a comprehensive review on their combined effects on immune system outcomes is missing. Therefore, this review aims at understanding the synergistic, additive, and antagonistic interactions between microgravity and radiation and their impact on immune function as observed during spaceflight-analog studies such as rodent hindlimb unloading and cell culture rotating wall vessel models. These mimic some, but not all, of the physiological changes observed in astronauts during spaceflight and provide valuable information that should be considered when planning future missions. We provide guidelines for the design of further spaceflight-analog studies, incorporating influential factors such as age and sex for rodent models and standardizing the longitudinal evaluation of specific immunological alterations for both rodent and cellular models of spaceflight exposure., (© 2024. The Author(s).)

Astronauts are known to exhibit a variety of immunological alterations during spaceflight including changes in leukocyte distribution and plasma cytokine concentrations, a reduction in T-cell function, and subclinical reactivation of latent herpesviruses. These alterations are most likely due to mission-associated stressors including circadian misalignment, microgravity, isolation, altered nutrition, and increased exposure to cosmic radiation. Some of these stressors may also occur in terrestrial situations. This study sought to determine if crewmembers performing winterover deployment at Palmer Station, Antarctica, displayed similar immune alterations. The larger goal was to validate a ground analog suitable for the evaluation of countermeasures designed to protect astronauts during future deep space missions. For this pilot study, plasma, saliva, hair, and health surveys were collected from Palmer Station, Antarctica, winterover participants at baseline, and at five winterover timepoints. Twenty-six subjects consented to participate over the course of two seasons. Initial sample processing was performed at Palmer, and eventually stabilized samples were returned to the Johnson Space Center for analysis. A white blood cell differential was performed (real time) using a fingerstick blood sample to determine alterations in basic leukocyte subsets throughout the winterover. Plasma and saliva samples were analyzed for 30 and 13 cytokines, respectively. Saliva was analyzed for cortisol concentration and three latent herpesviruses (DNA by qPCR), EBV, HSV1, and VZV. Voluntary surveys related to general health and adverse clinical events were distributed to participants. It is noteworthy that due to logistical constraints caused by COVID-19, the baseline samples for each season were collected in Punta Arenas, Chile, after long international travel and during isolation. Therefore, the Palmer pre-mission samples may not reflect a true normal 'baseline'. Minimal alterations were observed in leukocyte distribution during winterover. The mean percentage of monocyte concentration elevated at one timepoint. Plasma G-CSF, IL1RA, MCP-1, MIP-1β, TNFα, and VEGF were decreased during at least one winterover timepoint, whereas RANTES was significantly increased. No statistically significant changes were observed in mean saliva cytokine concentrations. Salivary cortisol was substantially elevated throughout the entire winterover compared to baseline. Compared to shedding levels observed in healthy controls (23%), the percentage of participants who shed EBV was higher throughout all winterover timepoints (52-60%). Five subjects shed HSV1 during at least one timepoint throughout the season compared to no subjects shedding during pre-deployment. Finally, VZV reactivation, common in astronauts but exceptionally rare in ground-based stress analogs, was observed in one subject during pre-deployment and a different subject at WO2 and WO3. These pilot data, somewhat influenced by the COVID-19 pandemic, do suggest that participants at Palmer Station undergo immunological alterations similar to, but likely in reduced magnitude, as those observed in astronauts. We suggest that winterover at Palmer Station may be a suitable test analog for spaceflight biomedical countermeasures designed to mitigate clinical risks for deep space missions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Long-term space missions trigger a prolonged neuroendocrine stress response leading to immune system dysregulation evidenced by susceptibility to infections, viral reactivation, and skin irritations. However, due to existing technical constraints, real-time functional immune assessments are not currently available to crew inflight. The in vitro cytokine release assay (CRA) has been effectively employed to study the stimulated cytokine response of immune cells in whole blood albeit limited to pre- and post-flight sessions. A novel two-valve reaction tube (RT) has been developed to enable the execution of the CRA on the International Space Station (ISS). Methods: In a comprehensive test campaign, we assessed the suitability of three materials (silicone, C-Flex, and PVC) for the RT design in terms of biochemical compatibility, chemical stability, and final data quality analysis. Furthermore, we thoroughly examined additional quality criteria such as safety, handling, and the frozen storage of antigens within the RTs. The validation of the proposed crew procedure was conducted during a parabolic flight campaign. Results: The selected material and procedure proved to be both feasible and secure yielding consistent and dependable data outcomes. This new hardware allows for the stimulation of blood samples on board the ISS, with subsequent analysis still conducted on the ground. Discussion: The resultant data promises to offer a more accurate understanding of the stress-induced neuroendocrine modulation of immunity during space travel providing valuable insights for the scientific community. Furthermore, the versatile nature of the RT suggests its potential utility as a testing platform for various other assays or sample types., Competing Interests: MB is employed and MaV was employed by Kayser Italia S.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Buchheim, Feuerecker, Balsamo, Vukich, Van Walleghem, Tabury, Quintens, Vermeesen, Baselet, Baatout, Rattenbacher, Antunes, Ngo-Anh, Crucian and Choukér.)

The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals. This postulate was tested concurrently with the studies to elucidate the toxicity of lunar dust (LD), which is believed to contain psROS due to high-speed micrometeoroid bombardment that fractured and pulverized lunar surface regolith. Results from studies of rats intratracheally instilled (ITI) with three LDs (prepared from an Apollo-14 lunar regolith), which differed 14-fold in levels of psROS, and two toxicity reference dusts (TiO 2 and quartz) indicated that psROS had no significant contribution to the dusts' toxicity in the lung. Reported here are results of further investigations by the LD toxicity study team on the toxicological role of oxidants in alveolar neutrophils that were harvested from rats in the 5-dust ITI study and from rats that were exposed to airborne LD for 4 weeks. The oxidants per neutrophils and all neutrophils increased with dose, exposure time and dust's cytotoxicity. The results suggest that alveolar neutrophils play a critical role in particle-induced injury and toxicity in the lung of dust-exposed animals. Based on these results, we propose an adverse outcome pathway (AOP) for particle-associated lung disease that centers on the crucial role of alveolar neutrophil-derived oxidant species. A critical review of the toxicology literature on particle exposure and lung disease further supports a neutrophil-centric mechanism in the pathogenesis of lung disease and may explain previously reported animal species differences in responses to poorly soluble particles. Key findings from the toxicology literature indicate that (1) after exposures to the same dust at the same amount, rats have more alveolar neutrophils than hamsters; hamsters clear more particles from their lungs, consequently contributing to fewer neutrophils and less severe lung lesions; (2) rats exposed to nano-sized TiO 2 have more neutrophils and more severe lesions in their lungs than rats exposed to the same mass-concentration of micron-sized TiO 2 ; nano-sized dust has a greater number of particles and a larger total particle-cell contact surface area than the same mass of micron-sized dust, which triggers more alveolar epithelial cells (AECs) to synthesize and release more cytokines that recruit a greater number of neutrophils leading to more severe lesions. Thus, we postulate that, during chronic dust exposure, particle-inflicted AECs persistently release cytokines, which recruit neutrophils and activate them to produce oxidants resulting in a prolonged continuous source of endogenous oxidative stress that leads to lung toxicity. This neutrophil-driven lung pathogenesis explains why dust exposure induces more severe lesions in rats than hamsters; why, on a mass-dose basis, nano-sized dusts are more toxic than the micron-sized dusts; why lung lesions progress with time; and why dose-response curves of particle toxicity exhibit a hockey stick like shape with a threshold. The neutrophil centric AOP for particle-induced lung disease has implications for risk assessment of human exposures to dust particles and environmental particulate matter.

Urine, humidity condensate, and other sources of non-potable water are processed onboard the International Space Station (ISS) by the Water Recovery System (WRS) yielding potable water. While some means of microbial control are in place, including a phosphoric acid/hexavalent chromium urine pretreatment solution, many areas within the WRS are not available for routine microbial monitoring. Due to refurbishment needs, two flex lines from the Urine Processor Assembly (UPA) within the WRS were removed and returned to Earth. The water from within these lines, as well as flush water, was microbially evaluated. Culture and culture-independent analysis revealed the presence of Burkholderia , Paraburkholderia , and Leifsonia . Fungal culture also identified Fusarium and Lecythophora . Hybrid de novo genome analysis of the five distinct Burkholderia isolates identified them as B. contaminans, while the two Paraburkholderia isolates were identified as P. fungorum . Chromate-resistance gene clusters were identified through pangenomic analysis that differentiated these genomes from previously studied isolates recovered from the point-of-use potable water dispenser and/or current NCBI references, indicating that unique populations exist within distinct niches in the WRS. Beyond genomic analysis, fixed samples directly from the lines were imaged by environmental scanning electron microscopy, which detailed networks of fungal-bacterial biofilms. This is the first evidence of biofilm formation within flex lines from the UPA onboard the ISS. For all bacteria isolated, biofilm potential was further characterized, with the B. contaminans isolates demonstrating the most considerable biofilm formation. Moreover, the genomes of the B. contaminans revealed secondary metabolite gene clusters associated with quorum sensing, biofilm formation, antifungal compounds, and hemolysins. The potential production of these gene cluster metabolites was phenotypically evaluated through biofilm, bacterial-fungal interaction, and hemolytic assays. Collectively, these data identify the UPA flex lines as a unique ecological niche and novel area of biofilm growth within the WRS. Further investigation of these organisms and their resistance profiles will enable engineering controls directed toward biofilm prevention in future space station water systems., Competing Interests: The authors declare that there are no known competing finical interests or personal relationships that could influence the data or conclusions reported here. All authors have confirmed and verified., (© 2023 Published by Elsevier B.V.)

Purpose: Initial military training (IMT) is a transitionary period wherein immune function may be suppressed and infection risk heightened due to physical and psychological stress, communal living, and sleep deprivation. This study characterized changes in biomarkers of innate and adaptive immune function, and potential modulators of those changes, in military recruits during IMT., Methods: Peripheral leukocyte distribution and mitogen-stimulated cytokine profiles were measured in fasted blood samples, Epstein-Barr (EBV), varicella zoster (VZV), and herpes simplex 1 (HSV1) DNA was measured in saliva by quantitative polymerase chain reaction as an indicator of latent herpesvirus reactivation, and diet quality was determined using the healthy eating index measured by food frequency questionnaire in 61 US Army recruits (97% male) at the beginning (PRE) and end (POST) of 22-wk IMT., Results: Lymphocytes and terminally differentiated cluster of differentiation (CD)4+ and CD8+ T cells increased PRE to POST, whereas granulocytes, monocytes, effector memory CD4+ and CD8+ T cells, and central memory CD8+ T cells decreased ( P ≤ 0.02). Cytokine responses to anti-CD3/CD28 stimulation were higher POST compared with PRE, whereas cytokine responses to lipopolysaccharide stimulation were generally blunted ( P < 0.05). Prevalence of EBV reactivation was higher at POST ( P = 0.04), but neither VZV nor HSV1 reactivation was observed. Diet quality improvements were correlated with CD8+ cell maturation and blunted proinflammatory cytokine responses to anti-CD3/CD28 stimulation., Conclusions: Lymphocytosis, maturation of T-cell subsets, and increased T-cell reactivity were evident POST compared with PRE IMT. Although EBV reactivation was more prevalent at POST, no evidence of VZV or HSV1 reactivation, which are more common during severe stress, was observed. Findings suggest increases in the incidence of EBV reactivation were likely appropriately controlled by recruits and immune-competence was not compromised at the end of IMT., (Copyright © 2023 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "œwork of the United States Government"œ for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Isolation is stressful and negatively affects sleep and mood and might also affect the structure and function of the brain. Physical exercise improves brain function. We investigated the influence of physical exercise during isolation on sleep, affect, and neurobehavioral function. N = 16 were isolated for 30 days with daily exercise routines (ISO 100 ) and n = 16 isolated for 45 days with every second day exercise (ISO 50 ). N = 27 were non-isolated controls who either exercised on a daily basis (CTRL Ex ) or refused exercise (CTRL NonEx ) for 30 days. At the beginning and the end of each intervention, intravenous morning cortisol, melatonin, brain-derived neurotrophic factor and IGF-1, positive and negative affect scales, electroencephalography, cognitive function, and sleep patterns (actigraphy) were assessed. High levels of cortisol were observed for the isolated groups ( p < .05) without negative effects on the brain, cognitive function, sleep, and mood after 4 to 6 weeks of isolation, where physical exercise was performed regularly. An increase in cortisol and impairments of sleep quality, mood, cognitive function, and neurotrophic factors ( p < .05) were observed after 4 weeks of absence of physical exercise in the CTRL NonEx group. These findings raise the assumption that regular physical exercise routines are a key component during isolation to maintain brain health and function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AM declared a shared affiliation with the author SK to the handling editor at the time of review., (Copyright © 2023 Klein, Braunsmann, Koschate, Hoffmann, Foitschik, Krieger, Crucian, Schneider and Abeln.)

Long-duration spaceflight impacts human physiology, including well documented immune system dysregulation. The space food system has the potential to serve as a countermeasure to maladaptive physiological changes during spaceflight. However, the relationship between dietary requirements, the food system, and spaceflight adaptation requires further investigation to adequately define countermeasures and prioritize resources on future spaceflight missions. We evaluated the impact of an enhanced spaceflight diet, with increased quantity and variety of fruits, vegetables, fish, and other foods rich in flavonoids and omega-3 fatty acids, compared to a standard spaceflight diet on multiple health and performance outcomes in 16 subjects over four 45-day closed chamber missions in the NASA Human Exploration Research Analog (HERA). Subjects consuming the enhanced spaceflight diet had lower cholesterol levels, lower stress (i.e. cortisol levels), better cognitive speed, accuracy, and attention, and a more stable microbiome and metatranscriptome than subjects consuming the standard diet. Although no substantial changes were observed in the immune response, there were also no immune challenges, such as illness or infection, so the full benefits of the diet may not have been apparent in these analog missions. These results indicate that a spaceflight diet rich in fruits, vegetables, and omega-3 fatty acids produces significant health and performance benefits even over short durations. Further investigation is required to fully develop dietary countermeasures to physiological decrements observed during spaceflight. These results will have implications for food resource prioritization on spaceflight missions., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

(1) Background: After spending a year wintering in Antarctica, individual expedition members have reported increased or even new allergic reactions to environmental allergens after their return. (2) Methods: Blood samples from five overwintering crews were analyzed using the chip based multiplex ALEX Allergy Explorer (MacroArray Diagnostics GmbH, Austria). (3) Results: About one third of the 39 participants displayed specific IgEs against pollen. In most individuals, kinetics showed a reduction in the specific IgE at the time about nine months after deployment to Antarctica. Five participants had the highest specific IgE levels after returning to the "normal" world. The examination of the specific IgE relative to house dust mites and storage mites showed different kinetics. Six out of 10 had the highest specific IgE concentrations at the inner Antarctic measurement time point. These data corresponded well to the general situation in the stations. At the stations themselves, there were almost no pollen particle load, especially at Concordia. (4) Conclusions: Antarctic long-term confinement can induce an altered immune function, which is in some individuals pronounced after return to the familiar allergen environment. Future prospective studies in larger cohorts are needed to further specify these first results.

During long duration orbital space missions, astronauts experience immune system dysregulation, the persistent reactivation of latent herpesviruses, and some degree of clinical incidence. During planned NASA 'Artemis' deep space missions the stressors that cause this phenomenon will increase, while clinical care capability will likely be reduced. There is currently minimal clinical laboratory capability aboard the International Space Station (ISS). The ability to monitor the white blood cell count (WBC) and differential during spaceflight has been an unmet NASA medical requirement, primarily due to a lack of capable hardware. We performed ground and flight validation of a device designed to monitor WBC and differential within minutes from a fingerstick blood sample. This device is miniaturized, robust, and generally compatible with microgravity operations. Ground testing for spaceflight consisted of vibration tolerance, power/battery and interface requirements, electromagnetic interference (EMI), and basic evaluation of sample preparation and operations in the context of spaceflight constraints. The in-flight validation performed aboard the ISS by two astronauts included assessment of three levels of control solution (blood) samples as well as a real time analysis of a fingerstick blood sample by one of the crewmembers. Flight and ground testing of the same lot of control solutions yielded similar total WBC values. There was some select discrepancy between flight and ground data for the differential analysis. However, the data suggest that this issue is due to compromise of the control solutions as a result of storage length before flight operations, and not due to a microgravity-associated issue with instrument performance. This evaluation also yielded lessons learned regarding crewmember training for technique-sensitive small-volume biosample collection and handling in microgravity. The fingerstick analysis was successful and was the first real-time hematology assessment performed during spaceflight. This device may provide an in-mission monitoring capability for astronauts thereby assisting Flight Surgeons and the crew medical officer during both orbital and deep space missions., (Published by Elsevier B.V.)

Long-duration spaceflight is known to cause immune dysregulation in astronauts. Biomarkers of immune system function are needed to determine both the need for and effectiveness of potential immune countermeasures for astronauts. Whereas plasma cytokine concentrations are a well-established biomarker of immune status, salivary cytokine concentrations are emerging as a sensitive indicator of stress and inflammation. For this study, to aid in characterizing immune dysregulation during spaceflight, plasma and saliva cytokines were monitored in astronauts before, during and after long-duration spaceflight onboard the International Space Station. Blood was collected from 13 astronauts at 3 timepoints before, 5 timepoints during and 3 timepoints after spaceflight. Saliva was collected from 6 astronauts at 2 timepoints before spaceflight, 2 timepoints during and 3 timepoints following spaceflight. Samples were analyzed using multiplex array technology. Significant increases in the plasma concentration of IL-3, IL-15, IL-12p40, IFN-α2, and IL-7 were observed during spaceflight compared to before flight baseline. Significant decreases in saliva GM-CSF, IL-12p70, IL-10 and IL-13 were also observed during spaceflight as compared to compared to before flight baseline concentrations. Additionally, plasma TGFβ1 and TGFβ2 concentrations tended to be consistently higher during spaceflight, although these did not reach statistical significance. Overall, the findings confirm an in-vivo hormonal dysregulation of immunity, appearing pro-inflammatory and Th1 in nature, persists during long-duration orbital spaceflight. These biomarkers may therefore have utility for monitoring the effectiveness of biomedical countermeasures for astronauts, with potential application in terrestrial research and medicine., Competing Interests: SSK was employed by KBR. SM was employed by JES Tech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Krieger, Zwart, Mehta, Wu, Simpson, Smith and Crucian.)

Beyond all doubts, the exploration of outer space is a strategically important and priority sector of the national economy, scientific and technological development of every and particular country, and of all human civilization in general. A number of stress factors, including a prolonged confinement in a limited hermetically sealed space, influence the human body in space on board the spaceship and during the orbital flight. All these factors predominantly negatively affect various functional systems of the organism, in particular, the astronaut's immunity. These ground-based experiments allow to elucidate the effect of confinement in a limited space on both the activation of the immunity and the changes of the immune status in dynamics. Also, due to simulation of one or another emergency situation, such an approach allows the estimation of the influence of an additional psychological stress on the immunity, particularly, in the context of the reserve capacity of the immune system. A sealed chamber seems a convenient site for working out the additional techniques for crew members selection, as well as the countermeasures for negative changes in the astronauts' immune status. In this review we attempted to collect information describing changes in human immunity during isolation experiments with different conditions including short- and long-term experiments in hermetically closed chambers with artificial environment and during Antarctic winter-over., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ponomarev, Kalinin, Sadova, Rykova, Orlova and Crucian.)

Space radiation consists of energetic protons and other heavier ions. During the International Space Station program, chromosome aberrations in lymphocytes of astronauts have been analyzed to estimate received biological doses of space radiation. More specifically, pre-flight blood samples were exposed ex vivo to varying doses of gamma rays, while post-flight blood samples were collected shortly and several months after landing. Here, in a study of 43 crew-missions, we investigated whether individual radiosensitivity, as determined by the ex vivo dose-response of the pre-flight chromosome aberration rate (CAR), contributes to the prediction of the post-flight CAR incurred from the radiation exposure during missions. Random-effects Poisson regression was used to estimate subject-specific radiosensitivities from the preflight dose-response data, which were in turn used to predict post-flight CAR and subject-specific relative biological effectiveness (RBEs) between space radiation and gamma radiation. Covariates age, gender were also considered. Results indicate that there is predictive value in background CAR as well as radiosensitivity determined preflight for explaining individual differences in post-flight CAR over and above that which could be explained by BFO dose alone. The in vivo RBE for space radiation was estimated to be approximately 3 relative to the ex vivo dose response to gamma irradiation. In addition, pre-flight radiosensitivity tended to be higher for individuals having a higher background CAR, suggesting that individuals with greater radiosensitivity can be more sensitive to other environmental stressors encountered in daily life. We also noted that both background CAR and radiosensitivity tend to increase with age, although both are highly variable. Finally, we observed no significant difference between the observed CAR shortly after mission and at > 6 months post-mission.

The National Aeronautics and Space Administration (NASA) Twins Study created an integrative molecular profile of an astronaut during NASA's first 1-year mission on the International Space Station (ISS) and included comparisons to an identical Earth-bound twin. The unique biochemical profiles observed when landing on Earth after such a long mission (e.g., spikes in interleukin-1 [IL-1]/6/10, c-reactive protein [CRP], C-C motif chemokine ligand 2 [CCL2], IL-1 receptor antagonist [IL-1ra], and tumor necrosis factor alpha [TNF-α]) opened new questions about the human body's response to gravity and how to plan for future astronauts, particularly around initiation or resolution of inflammation. Here, single-cell, multi-omic (100-plex epitope profile and gene expression) profiling of peripheral blood mononuclear cells (PBMCs) showed changes to blood cell composition and gene expression post-flight, specifically for monocytes and dendritic cell precursors. These were consistent with flight-induced cytokine and immune system stress, followed by skeletal muscle regeneration in response to gravity. Finally, we examined these profiles relative to 6-month missions in 28 other astronauts and detail potential pharmacological interventions for returning to gravity in future missions., Competing Interests: Declaration of Interests Although not relevant to this study, for full disclosure, C.E.M. is a cofounder and board member for Biotia and Onegevity Health as well as an advisor or grantee for Abbvie, ArcBio, Daiichi Sankyo, DNA Genotek, Tempus Labs, and Whole Biome., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exposure to stressful environments weakens immunity evidenced by a detectable reactivation of dormant viruses. The mechanism behind this observation remains unclear. We performed next generation sequencing from RNA extracted from blood samples of 8 male subjects collected before, during and after a 12-month stay at the Antarctic station Concordia. RNA-seq data analysis was done using QIAGEN Ingenuity Pathway Analysis (IPA) software. Data revealed the inactivation of key immune functions such as chemotaxis and leukocyte recruitment which persisted after return. Next to the activation of the stress response eIF2 pathway, interferon signaling was predicted inactivated due to a downregulation of 14 downstream genes involved in antiviral immunity. Among them, the interferon stimulated genes (ISGs) IFITM2 and 3 as well as IFIT3 exhibited the strongest fold changes and IFIT3 remained downregulated even after return. Impairment of antiviral immunity in winter-over crew can be explained by the downregulation of a battery of ISGs., Competing Interests: None., (© 2020 Published by Elsevier Inc.)

Background: Spaceflight impacts astronauts in many ways but little is known on how spaceflight affects the salivary microbiome and the consequences of these changes on astronaut health, such as viral reactivation. In order to understand this, the salivary microbiome was analyzed with 16S rRNA gene amplicon sequencing, and saliva viral titers were analyzed with quantitative polymerase chain reaction (qPCR) with primers specific for Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV) from 10 astronauts pre-flight, in-flight, and post-flight., Results: Streptococcus was the most abundant organism in the saliva, making up 8% of the total organisms detected, and their diversity decreased during spaceflight. Other organisms that had statistically significant changes were Proteobacteria and Fusobacteria which increased during flight and Actinobacteria which decreased during flight. At the genus level, Catonella, Megasphera, and Actinobacillus were absent in more than half of saliva samples collected pre-flight but were then detected during flight. In those subjects that already had these genera pre-flight, their relative abundances increased during flight. Correlation analyses between the microbiome and viral titers revealed a positive correlation with Gracilibacteria, Absconditabacteria, and Abiotrophia and a negative correlation between Oribacterium, Veillonella, and Haemophilus. There was also a significant positive correlation between microbiome richness and EBV viral titers., Conclusions: This is the first study to look at how the salivary microbiome changes as a result of spaceflight and the search for bacterial biomarkers for viral reactivation. Further studies examining the role of specific organisms that were shown to be correlative and predictive in viral reactivation, a serious problem in astronauts during spaceflight, could lead to mitigation strategies to help prevent disease during both short and long duration space missions. Video abstract.

Purpose: We examined in a longitudinal study the role of sodium selenite in sepsis patients in strengthening the immune performance in whole blood samples using immune functional assays., Materials and Methods: This was a sub-study from a randomized, double blinded multicenter clinical trial (SISPCT) registered with www.clinicaltrials.gov (NCT00832039) and with data collected at our center. Full blood samples were incubated with various recall antigens and the supernatants were measured for their cytokine concentrations as markers for immune response. Data from days 0, 4, 7, 14, and 21 (from sepsis onset) were analyzed using a generalized least squares model in R to appropriately take the longitudinal structure and the missing values into account., Results: From the 76 patients enrolled in the study at our center, 40 were randomized to selenium therapy and 36 to placebo. The analyses of immune response assay data showed no statistical difference between the selenium and placebo groups at each of the time points. There was however an overall dampening of cytokine release, which tended to recover over time in both groups., Conclusion: Selenium has long been an adjuvant therapy in treating sepsis. Recently, it was proven to not have beneficial effects on the mortality outcome. Using data from our center in this sub-cohort study, we identified no relative improvement in cytokine release of stimulated blood immune cells ex vivo from patients with selenium therapy over a three-week period. This offers a potential explanation for the lack of beneficial effects of selenium in sepsis patients., (Copyright © 2019. Published by Elsevier Inc.)

The increasing demand of space flights requires a profound knowledge of the chronologic reactions of the human body to extreme conditions. Prior studies already have shown the adverse effects of long-term isolation on psycho-physiological well-being. The chronology of the effects and whether short-term isolation periods already lead to similar effects has not been investigated. Therefore, the aim of the current study was to investigate the effects of short-term isolation (30 days) on mood, cognition, cortisol, neurotrophic factors, and brain activity. 16 participants were isolated in the Human Exploration Research Analog at NASA for 30 days. 17 non-isolated control participants were tested simultaneously. On mission days - 5, 7, 14, 28, and + 5, multiple tests including the Positive and Negative Affect Schedule-X and cognitive tests were conducted, and a 5-min resting electroencephalography was recorded. A fasted morning blood drawing was also done. Increased stress was observed via augmented cortisol levels during the isolation period. Activity within the parietal cortex was reduced over time, probably representing a neural adaptation to less external stimuli. Cognitive performance was not affected, but rather enhanced in both groups. No further significant changes in neurotrophic factors BDNF/IGF-1 and mood could be detected. These results suggest that 30 days of isolation do not have a significant impact on brain activity, neurotrophic factors, cognition, or mood, even though stress levels were significantly increased during isolation. Further studies need to address the question as to what extent increased levels of stress do not affect mental functions during isolation periods.