Comprehensive assessment of physiological responses in women during the ESA dry immersion VIVALDI microgravity simulation.

Astronauts in microgravity experience multi-system deconditioning, impacting their inflight efficiency and inducing dysfunctions upon return to Earth gravity. To fill the sex gap of knowledge in the health impact of spaceflights, we simulate microgravity with a 5-day dry immersion in 18 healthy women (ClinicalTrials.gov Identifier: NCT05043974). Here we show that dry immersion rapidly induces a sedentarily-like metabolism shift mimicking the beginning of a metabolic syndrome with a drop in glucose tolerance, an increase in the atherogenic index of plasma, and an impaired lipid profile. Bone remodeling markers suggest a decreased bone formation coupled with an increased bone resorption. Fluid shifts and muscular unloading participate to a marked cardiovascular and sensorimotor deconditioning with decreased orthostatic tolerance, aerobic capacity, and postural balance. Collected datasets provide a comprehensive multi-systemic assessment of dry immersion effects in women and pave the way for future sex-based evaluations of countermeasures.

Corrigendum: Editorial: Rising stars in environmental, aviation and space physiology: 2022.

[This corrects the article DOI: 10.3389/fphys.2023.1230752.].

Running vs. resistance exercise to counteract deconditioning induced by 90-day head-down bedrest.

Spaceflight is associated with enhanced inactivity, resulting in muscular and cardiovascular deconditioning. Although physical exercise is commonly used as a countermeasure, separate applications of running and resistive exercise modalities have never been directly compared during long-term bedrest. This study aimed to compare the effectiveness of two exercise countermeasure programs, running and resistance training, applied separately, for counteracting cardiovascular deconditioning induced by 90-day head-down bedrest (HDBR). Maximal oxygen uptake ( V ˙ O2max), orthostatic tolerance, continuous ECG and blood pressure (BP), body composition, and leg circumferences were measured in the control group (CON: n = 8), running exercise group (RUN: n = 7), and resistive exercise group (RES: n = 7). After HDBR, the decrease in V ˙ O2max was prevented by RUN countermeasure and limited by RES countermeasure (-26% in CON p < 0.05, -15% in RES p < 0.05, and -4% in RUN ns). Subjects demonstrated surprisingly modest orthostatic tolerance decrease for different groups, including controls. Lean mass loss was limited by RES and RUN protocols (-10% in CON vs. -5% to 6% in RES and RUN). Both countermeasures prevented the loss in thigh circumference (-7% in CON p < 0.05, -2% in RES ns, and -0.6% in RUN ns) and limited loss in calf circumference (-10% in CON vs. -7% in RES vs. -5% in RUN). Day-night variations in systolic BP were preserved during HDBR. Decrease in V ˙ O2max positively correlated with decrease in thigh (r = 0.54 and p = 0.009) and calf (r = 0.52 and p = 0.012) circumferences. During this 90-day strict HDBR, running exercise successfully preserved V ˙ O2max, and resistance exercise limited its decline. Both countermeasures limited loss in global lean mass and leg circumferences. The V ˙ O2max reduction seems to be conditioned more by muscular than by cardiovascular parameters.

Spinal changes after 5-day dry immersion as shown by magnetic resonance imaging (DI-5-CUFFS).

Astronauts frequently report microgravity-induced back pain, which is generally more pronounced in the beginning of a spaceflight. The dry immersion (DI) model reproduces the early effects of microgravity in terms of global support unloading and fluid shift, both of which are involved in back pain pathogenesis. Here, we assessed spinal changes induced by exposure to 5 days of strict DI in 18 healthy men (25-43-yr old) with (n = 9) or without (n = 9) thigh cuffs countermeasure. Intervertebral disk (IVD) height, spinal cord position, and apparent diffusion coefficient (ADC; reflecting global water motion) were measured using magnetic resonance imaging before and after DI. After DI, IVD height increased in thoracic (+3.3 ± 0.8 mm; C7-T12) and lumbar (+4.5 ± 0.4 mm; T12-L5) regions but not in the cervical region (C2-C7) of the spine. An increase in ADC after DI was observed at the L1 (∼6% increase, from 3.2 to 3.4 × 10-3 mm2/s; P < 0.001) and L2 (∼3% increase, from 3.4 to 3.5 × 10-3 mm2/s; P = 0.005) levels. There was no effect of thigh cuffs on spinal parameters. This change in IVD after DI follows the same "gradient" pattern of height increase from the cervical to the lumbar region as observed after bed rest and spaceflight. The increase in ADC at L1 level positively correlated with reported back pain. These findings emphasize the utility of the DI model for studying early spinal changes observed in microgravity.

Associations between gait speed and brain structure in amnestic mild cognitive impairment: a quantitative neuroimaging study.

BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) present gait disturbances including slower speed and higher variability when compared to cognitively healthy individuals (CHI). Brain neuroimaging could explore higher levels of motor control. Our purpose was to look for an association between morphometrics and gait parameters in each group. We hypothesized that the relation between morphological cerebral alteration and gait speed are different following the group. METHODS: Fifty-three participants (30 with aMCI and 23 CHI) were recruited in this French cross-sectional study (mean 72 ± 5 years, 38% female). Gait speed and gait variability (coefficients of variation of stride time (STV) and stride length (SLV)) were measured using GAITrite® system. CAT12 software was used to analyse volume and surface morphometry like gray matter volume (GMV) and cortical thickness (CT). Age, gender and education level were used as potential cofounders. RESULTS: aMCI had slower gait speed and higher STV when compared to CHI. In aMCI the full adjusted linear regression model showed that lower gait speed was associated with decreased GMV and lower CT in bilateral superior temporal gyri (p < 0.36). In CHI, no association was found between gait speed and brain structure. Higher SLV was correlated with reduced GMV in spread regions (p < 0.05) and thinner cortex in the middle right frontal gyrus (p = 0.001) in aMCI. In CHI, higher SLV was associated with reduced GMV in 1 cluster: the left lingual (p = 0.041). CONCLUSIONS: These findings indicate that lower gait speed is associated with specific brain structural changes as reduced GMV and CT during aMCI.

Specific age-correlated activation of top hierarchical motor control areas during gait-like plantar stimulation: An fMRI study.

A better understanding of gait disorders that are associated with aging is crucial to prevent adverse outcomes. The functional study of gait remains a thorny issue due to technical constraints inherent to neuroimaging procedures, as most of them require to stay supine and motionless. Using an MRI-compatible system of boots reproducing gait-like plantar stimulation, we investigated the correlation between age and brain fMRI activation during simulated gait in healthy adults. Sixty-seven right-handed healthy volunteers aged between 20 and 77 years old (49.2 ± 18.0 years; 35 women) were recruited. Two paradigms were assessed consecutively: (a) gait-like plantar stimulation and (b) chaotic and not gait-related plantar stimulation. Resulting statistical parametric maps were analyzed with a multiple-factor regression that included age and a threshold determined by Monte-Carlo simulation to fulfill a family-wise error rate correction of p < .05. In the first paradigm, there was an age-correlated activation of the right pallidum, thalamus and putamen. The second paradigm showed an age-correlated deactivation of both primary visual areas (V1). The subtraction between results of the first and second paradigms showed age-correlated activation of the right presupplementary motor area (Brodmann Area [BA] 6) and right mid-dorsolateral prefrontal cortex (BA9-10). Our results show age-correlated activity in areas that have been associated with the control of gait, highlighting the relevance of this simulation model for functional gait study. The specific progressive activation of top hierarchical control areas in simulated gait and advancing age corroborate a progressive loss of automation in healthy older adults.

A dry immersion model of microgravity modulates platelet phenotype, miRNA signature, and circulating plasma protein biomarker profile.

Ground based research modalities of microgravity have been proposed as innovative methods to investigate the aetiology of chronic age-related conditions such as cardiovascular disease. Dry Immersion (DI), has been effectively used to interrogate the sequelae of physical inactivity (PI) and microgravity on multiple physiological systems. Herein we look at the causa et effectus of 3-day DI on platelet phenotype, and correlate with both miRomic and circulating biomarker expression. The miRomic profile of platelets is reflective of phenotype, which itself is sensitive and malleable to the exposome, undergoing responsive transitions in order to fulfil platelets role in thrombosis and haemostasis. Heterogeneous platelet subpopulations circulate at any given time, with varying degrees of sensitivity to activation. Employing a DI model, we investigate the effect of acute PI on platelet function in 12 healthy males. 3-day DI resulted in a significant increase in platelet count, plateletcrit, platelet adhesion, aggregation, and a modest elevation of platelet reactivity index (PRI). We identified 15 protein biomarkers and 22 miRNA whose expression levels were altered after DI. A 3-day DI model of microgravity/physical inactivity induced a prothrombotic platelet phenotype with an unique platelet miRNA signature, increased platelet count and plateletcrit. This correlated with a unique circulating protein biomarker signature. Taken together, these findings highlight platelets as sensitive adaptive sentinels and functional biomarkers of epigenetic drift within the cardiovascular compartment.

Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial.

OBJECTIVES: To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. METHODS: We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. RESULTS: The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58-86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45-2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points. CONCLUSION: In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04325893 (https://clinicaltrials.gov/ct2/show/NCT04325893).

Vascular and Microvascular Dysfunction Induced by Microgravity and Its Analogs in Humans: Mechanisms and Countermeasures.

Weightlessness and physical inactivity have deleterious cardiovascular effects. The space environment and its ground-based models offer conditions to study the cardiovascular effects of physical inactivity in the absence of other vascular risk factors, particularly at the macro- and microcirculatory levels. However, the mechanisms involved in vascular dysfunction and remodeling are not sufficiently studied in the context of weightlessness and its analogs including models of physical inactivity. Here, we summarize vascular and microvascular changes induced by space flight and observed in models of microgravity and physical inactivity and review the effects of prophylactic strategies (i.e., countermeasures) on vascular and microvascular function. We discuss physical (e.g., exercise, vibration, lower body negative pressure, and artificial gravity) and nutritional/pharmacological (e.g., caloric restriction, resveratrol, and other vegetal extracts) countermeasures. Currently, exercise countermeasure appears to be the most effective to protect vascular function. Although pharmacological countermeasures are not currently considered to fight vascular changes due to microgravity, nutritional countermeasures are very promising. Dietary supplements/natural health products, especially plant extracts, should be extensively studied. The best prophylactic strategy is likely a combination of countermeasures that are effective not only at the cardiovascular level but also for the organism as a whole, but this strategy remains to be determined.

MNX (Medium Duration Nutrition and Resistance-Vibration Exercise) Bed-Rest: Effect of Resistance Vibration Exercise Alone or Combined With Whey Protein Supplementation on Cardiovascular System in 21-Day Head-Down Bed Rest.

Current inflight countermeasures do not completely prevent bone and cardiovascular changes induced by microgravity. High load Resistance Exercise combined with whole body Vibration (RVE) demonstrated benefits on bone and cardiovascular system during previous Head-Down Bed Rest (HDBR) studies. We examined the effectiveness of RVE alone or combined with a nutritional supplementation of Whey protein (NeX) on cardiovascular deconditioning. Eight male subjects (age 34 ± 8 years) in a crossover design completed three 21-day HDBR campaigns (Control-CON, RVE, and NeX). Pre and post HDBR Orthostatic Tolerance (OT) was evaluated by a 15-min head-up tilt test followed by increasing levels of Lower Body Negative Pressure (LBNP). Heart rate (HR), blood pressure (BP), and Sympathetic Index (ΣI) through spectral analysis were measured during OT test. Plasma Volume (PV), and Maximal Oxygen Uptake (VO2max) were measured before and after each campaign. Left ventricular mass, left ventricular end diastolic (LVEDV), end systolic (LVESV), stroke (SV) volumes, and circumferential deformation at rest and during an orthostatic stress simulated by a 30 mmHg LBNP were measured by cardiac MRI. RVE failed to prevent any change in these variables and NeX did not have any additional effect over exercise alone. In the 3 groups, (1) OT time dropped similarly (bed rest p < 0.001), (2) HR and ΣI were increased at rest at the end of HDBR and HR increased markedly during LBNP-tilt test, with inability to increase further the ΣI, (3) PV dropped (bed rest p < 0.001), along with LVEDV, LVESV and SV (p = 0.08, p < 0.001, and p = 0.045, respectively), (4) Left ventricle mass did not change significantly, (5) Deformation of the heart assessed by global circumferential strain was preserved and early diastolic circumferential strain rate was increased during orthostatic stress at the end of HDBR, illustrating preserved systolic and diastolic function respectively, without any difference between groups. Despite the drop in PV and LV volumes, RVE and NeX tended to alleviate the decrease in VO2max. In conclusion, RVE and NeX failed to prevent the cardiovascular deconditioning induced by a 21 day-HDBR.

The Effect of Five-Day Dry Immersion on the Nervous and Metabolic Mechanisms of the Circulatory System.

The purpose of the study was to investigate the regulatory and metabolic changes in the circulatory system when simulating microgravity conditions in a five-day dry immersion. These changes reflect the adaptation processes characteristic for the initial stages of a space flight or a short-duration space flight. Studies were conducted with 13 healthy male volunteers aged 21 to 29 years. The assessment of regulatory and metabolic processes in the circulatory system was based on the heart rate variability (HRV) and urine proteomic profile analysis. It was found that the restructuring of hemodynamics during 5 days hypogravity begins with the inclusion of the nervous circuit of regulation, and for manifestations at the body fluids protein composition level and activation of the metabolic regulation, these periods are apparently insufficient. Perhaps this is due to the fact that the metabolic regulation, being evolutionarily ancient and genetically determined, is more stable and requires more time for its pronounced activation when stimulated by extreme life conditions.

Cardiovascular System Under Simulated Weightlessness: Head-Down Bed Rest vs. Dry Immersion.

BACKGROUND: The most applicable human models of weightlessness are -6° head-down bed rest (HDBR) and head-out dry immersion (DI). A detailed experimental comparison of cardiovascular responses in both models has not yet been carried out, in spite of numerous studies having been performed in each of the models separately. OBJECTIVES: We compared changes in central hemodynamics, autonomic regulation, plasma volume, and water balance induced by -6° HDBR and DI. METHODS: Eleven subjects participated in a 21-day HDBR and 12 subjects in a 3-day DI. During exposure, measurements of the water balance, blood pressure, and heart rate were performed daily. Plasma volume evolution was assessed by the Dill-Costill method. In order to assess orthostatic tolerance time (OTT), central hemodynamic responses to orthostatic stimuli, and autonomous regulation, the 80° lower body negative pressure-tilt test was conducted before and right after both exposures. RESULTS: For most of the studied parameters, the changes were co-directional, although they differed in their extent. The changes in systolic blood pressure and total peripheral resistance after HDBR were more pronounced than those after DI. The OTT was decreased in both groups: to 14.2 ± 3.1 min (vs. 27.9 ± 2.5 min before exposure) in the group of 21-day HDBR and to 8.7 ± 2.1 min (vs. 27.7 ± 1.2 min before exposure) in the group of 3-day DI. CONCLUSIONS: In general, cardiovascular changes during the 21-day HDBR and 3-day DI were co-directional. In some cases, changes in the parameters after 3-day DI exceeded changes after the 21-day HDBR, while in other cases the opposite was true. Significantly stronger effects of DI on cardiovascular function may be due to hypovolemia and support unloading (supportlessness).

Development of dynamic cell and organotypic skin models, for the investigation of a novel visco-elastic burns treatment using molecular and cellular approaches.

BACKGROUND: Burn injuries are a major cause of morbidity and mortality worldwide. Despite advances in therapeutic strategies for the management of patients with severe burns, the sequelae are pathophysiologically profound, up to the systemic and metabolic levels. Management of patients with a severe burn injury is a long-term, complex process, with treatment dependent on the degree and location of the burn and total body surface area (TBSA) affected. In adverse conditions with limited resources, efficient triage, stabilisation, and rapid transfer to a specialised intensive care burn centre is necessary to provide optimal outcomes. This initial lag time and the form of primary treatment initiated, from injury to specialist care, is crucial for the burn patient. This study aims to investigate the efficacy of a novel visco-elastic burn dressing with a proprietary bio-stimulatory marine mineral complex (MXC) as a primary care treatment to initiate a healthy healing process prior to specialist care. METHODS: A new versatile emergency burn dressing saturated in a >90% translucent water-based, sterile, oil-free gel and carrying a unique bio-stimulatory marine mineral complex (MXC) was developed. This dressing was tested using LabSkin as a burn model platform. LabSkin a novel cellular 3D-dermal organotypic full thickness human skin equivalent, incorporating fully-differentiated dermal and epidermal components that functionally models skin. Cell and molecular analysis was carried out by in vitro Real-Time Cellular Analysis (RTCA), thermal analysis, and focused transcriptomic array profiling for quantitative gene expression analysis, interrogating both wound healing and fibrosis/scarring molecular pathways. In vivo analysis was also performed to assess the bio-mechanical and physiological effects of this novel dressing on human skin. RESULTS: This hybrid emergency burn dressing (EBD) with MXC was hypoallergenic, and improved the barrier function of skin resulting in increased hydration up to 24 h. It was demonstrated to effectively initiate cooling upon application, limiting the continuous burn effect and preventing local tissue from damage and necrosis. xCELLigence RTCA® on primary human dermal cells (keratinocyte, fibroblast and micro-vascular endothelial) demonstrated improved cellular function with respect to tensegrity, migration, proliferation and cell-cell contact (barrier formation) [1]. Quantitative gene profiling supported the physiological and cellular function finding. A beneficial quid pro quo regulation of genes involved in wound healing and fibrosis formation was observed at 24 and 48 h time points. CONCLUSION: Utilisation of this EBD + MXC as a primary treatment is an effective and easily applicable treatment in cases of burn injury, proving both a cooling and hydrating environment for the wound. It regulates inflammation and promotes healing in preparation for specialised secondary burn wound management. Moreover, it promotes a healthy remodelling phenotype that may potentially mitigate scarring. Based on our findings, this EBD + MXC is ideal for use in all pre-hospital, pre-surgical and resource limited settings.

DI-5-CUFFS: Venoconstrictive Thigh Cuffs Limit Body Fluid Changes but Not Orthostatic Intolerance Induced by a 5-Day Dry Immersion.

Venoconstrictive thigh cuffs are used by cosmonauts to ameliorate symptoms associated with cephalad fluid shift. A ground simulation of microgravity, using the dry immersion (DI) model, was performed to assess the effects of thigh cuffs on body fluid changes and dynamics, as well as on cardiovascular deconditioning. Eighteen healthy men (25-43 years), randomly divided into two groups, (1) control group or (2) group with thigh cuffs worn 10 h/day, underwent 5-day DI. Cardiovascular responses to orthostatic challenge were evaluated using the lower body negative pressure (LBNP) test; body fluid changes were assessed by bio-impedance and hormonal assay; plasma volume evolution was estimated using hemoglobin-hematocrit; subjective tolerance was assessed by questionnaires. DI induced a decrease in plasma volume of 15-20%. Reduction in total body water of 3-6% stabilized toward the third day of DI. This reduction was derived mostly from the extracellular compartment. During the acute phase of DI, thigh cuffs limited the decrease in renin and the increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), the loss in total body water, and tended to limit the loss in calf volume, extracellular volume and plasma volume. At the later stable phase of DI, a moderate protective effect of thigh cuffs remained evident on the body fluids. Orthostatic tolerance time dropped after DI without significant difference between groups. Thigh cuff countermeasure slowed down and limited the loss of body water and tended to limit plasma loss induced by DI. These observed physiological responses persisted during periods when thigh cuffs were removed. However, thigh cuffs did not counteract decreased tolerance to orthostatic challenge.

DI-5-Cuffs: Lumbar Intervertebral Disc Proteoglycan and Water Content Changes in Humans after Five Days of Dry Immersion to Simulate Microgravity.

Most astronauts experience back pain after spaceflight, primarily located in the lumbar region. Intervertebral disc herniations have been observed after real and simulated microgravity. Spinal deconditioning after exposure to microgravity has been described, but the underlying mechanisms are not well understood. The dry immersion (DI) model of microgravity was used with eighteen male volunteers. Half of the participants wore thigh cuffs as a potential countermeasure. The spinal changes and intervertebral disc (IVD) content changes were investigated using magnetic resonance imaging (MRI) analyses with T1-T2 mapping sequences. IVD water content was estimated by the apparent diffusion coefficient (ADC), with proteoglycan content measured using MRI T1-mapping sequences centered in the nucleus pulposus. The use of thigh cuffs had no effect on any of the spinal variables measured. There was significant spinal lengthening for all of the subjects. The ADC and IVD proteoglycan content both increased significantly with DI (7.34 ± 2.23% and 10.09 ± 1.39%, respectively; mean ± standard deviation), p < 0.05). The ADC changes suggest dynamic and rapid water diffusion inside IVDs, linked to gravitational unloading. Further investigation is needed to determine whether similar changes occur in the cervical IVDs. A better understanding of the mechanisms involved in spinal deconditioning with spaceflight would assist in the development of alternative countermeasures to prevent IVD herniation.

Vitamin D concentration and focal brain atrophy in older adults: a voxel-based morphometric study.

Vitamin D is involved in brain health and function. Our objective was to determine whether lower 25-hydroxyvitamin D (25OHD) concentration was associated with focal brain volume reduction in older adults. Serum 25OHD concentration was measured among 53 older adults (72 ± 5 years; 38% female; mean 25OHD = 67.3 ± 20.8 nmol/L). Gray matter volume (GMV) was automatically segmented using voxel-based morphometry with CAT12 software. Covariables were age, gender, education, total intracranial volume, and season. Serum 25OHD was positively associated with GMV in left calcarine sulcus (P < 0.05, TFCE, FWE-corrected). We found atrophy of the calcarine sulcus with lower 25OHD concentrations in older adults.