Systematic review of the effectiveness of standalone passive countermeasures on microgravity-induced physiologic deconditioning.

A systematic review of literature was conducted to evaluate the effectiveness of passive countermeasures in ameliorating the cardiopulmonary and musculoskeletal effects of gravitational unloading on humans during spaceflight. This systematic review is the third of a series being conducted by the European Space Agency to evaluate the effectiveness of countermeasures to physiologic deconditioning during spaceflight. With future long-duration space missions on the horizon, it is critical to understand the effectiveness of existing countermeasures to promote astronaut health and improve the probability of future mission success. An updated search for studies examining passive countermeasures was conducted in 2021 to supplement results from a broader search conducted in 2017 for all countermeasures. Ground-based analogue and spaceflight studies were included in the search. A total of 647 articles were screened following removal of duplicates, of which 16 were included in this review. Data extraction and analysis, quality assessment of studies, and transferability of reviewed studies to actual spaceflight based on their bed-rest protocol were conducted using dedicated tools created by the Aerospace Medicine Systematic Review Group. Of the 180 examined outcomes across the reviewed studies, only 20 were shown to have a significant positive effect in favour of the intervention group. Lower body negative pressure was seen to significantly maintain orthostatic tolerance (OT) closer to baseline as comparted to control groups. It also was seen to have mixed efficacy with regards to maintaining resting heart rate close to pre-bed rest values. Whole body vibration significantly maintained many balance-related outcome measures close to pre-bed rest values as compared to control. Skin surface cooling and centrifugation both showed efficacy in maintaining OT. Centrifugation also was seen to have mixed efficacy with regards to maintaining VO2max close to pre-bed rest values. Overall, standalone passive countermeasures showed no significant effect in maintaining 159 unique outcome measures close to their pre-bed rest values as compared to control groups. Risk of bias was rated high or unclear in all studies due to poorly detailed methodologies, poor control of confounding variables, and other sources of bias (i.e. inequitable recruitment of participants leading to a higher male:female ratios). The bed-rest transferability (BR) score varied from 2-7, with a median score of 5. Generally, most studies had good BR transferability but underreported on factors such as control of sunlight or radiation exposure, diet, level of exercise and sleep-cycles. We conclude that: (1) Lack of standardisation of outcome measurement and methodologies has led to large heterogeneity amongst studies; (2) Scarcity of literature and high risk of bias amongst existing studies limits the statistical power of results; and (3) Passive countermeasures have little or no efficacy as standalone measures against cardiopulmonary and musculoskeletal deconditioning induced by spaceflight related to physiologic deterioration due to gravity un-loading.

Leveraging Space-Flown Technologies to Deliver Healthcare with Holographic Physical Examinations.

INTRODUCTION: Musculoskeletal injuries are one of the more common injuries in spaceflight. Physical assessment of an injury is essential for diagnosis and treatment. Unfortunately, when musculoskeletal injuries occur in space, the flight surgeon is limited to two-dimensional videoconferencing and, potentially, observations made by the crew medical officer. To address these limitations, we investigated the feasibility of performing physical examinations on a three-dimensional augmented reality projection using a mixed-reality headset, specifically evaluating a standard shoulder examination.METHODS: A simulated patient interaction was set up between Western University in London, Ontario, Canada, and Huntsville, AL, United States. The exam was performed by a medical student, and a healthy adult man volunteered to enable the physical exam.RESULTS: All parts of the standard shoulder physical examination according to the Bates Guide to the Physical Exam were performed with holoportation. Adaptation was required for the palpation and some special tests.DISCUSSION: All parts of the physical exam were able to be completed. The true to anatomical size of the holograms permitted improved inspection of the anatomy compared to traditional videoconferencing. Palpation was completed by instructing the patient to palpate themselves and comment on relevant findings asked by the examiner. Range of motion and special tests for specific pathologies were also able to be completed with some modifications due to the examiner not being present to provide resistance. Future work should aim to improve the graphics, physician communication, and haptic feedback during holoportation.Levschuk A, Whittal J, Trejos AL, Sirek A. Leveraging space-flown technologies to deliver healthcare with holographic physical examinations. Aerosp Med Hum Perform. 2024; 95(4):214-218.

Bellagio II Report: Terrestrial Applications of Space Medicine Research.

AbstractINTRODUCTION: For over 50 yr, investigators have studied the physiological adaptations of the human system during short- and long-duration spaceflight exposures. Much of the knowledge gained in developing health countermeasures for astronauts onboard the International Space Station demonstrate terrestrial applications. To date, a systematic process for translating these space applications to terrestrial human health has yet to be defined.METHODS: In the summer of 2017, a team of 38 international scientists launched the Bellagio ll Summit Initiative. The goals of the Summit were: 1) To identify space medicine findings and countermeasures with highest probability for future terrestrial applications; and 2) To develop a roadmap for translation of these countermeasures to future terrestrial application. The team reviewed public domain literature, NASA databases, and evidence books within the framework of the five-stage National Institutes of Health (NIH) translation science model, and the NASA two-stage translation model. Teams then analyzed and discussed interdisciplinary findings to determine the most significant evidence-based countermeasures sufficiently developed for terrestrial application.RESULTS: Teams identified published human spaceflight research and applied translational science models to define mature products for terrestrial clinical practice.CONCLUSIONS: The Bellagio ll Summit identified a snapshot of space medicine research and mature science with the highest probability of translation and developed a Roadmap of terrestrial application from space medicine-derived countermeasures. These evidence-based findings can provide guidance regarding the terrestrial applications of best practices, countermeasures, and clinical protocols currently used in spaceflight.Sides MB, Johnston SL III, Sirek A, Lee PH, Blue RS, Antonsen EL, Basner M, Douglas GL, Epstein A, Flynn-Evans EE, Gallagher MB, Hayes J, Lee SMC, Lockley SW, Monseur B, Nelson NG, Sargsyan A, Smith SM, Stenger MB, Stepanek J, Zwart SR; Bellagio II Team. Bellagio II report: terrestrial applications of space medicine research. Aerosp Med Hum Perform. 2021; 92(8):650669.

Space Medicine Training in Canada.

INTRODUCTION: Aerospace medicine training is often difficult to obtain outside of military education streams. Undergraduate medical trainees and residents may undertake training opportunities, but often have trouble locating programs and/or receiving credit for their experiences and learning. In many countries, no formal aerospace medicine training program or pathway exists and trainees must search out opportunities on their own. Canada is used as an example of a country which, until recently, had no defined civilian aerospace medicine training program or credentialing pathway. Recent development of a Diploma in Aerospace Medicine certified by the Royal College of Physicians and Surgeons now outlines a series of competencies for trainees and medical professionals seeking advancement in aerospace medicine. Growth of the aviation and aerospace fields will require more training opportunities and more aerospace medicine professionals to support the increased number of aviators and the spacefaring population. This will be particularly important as commercial space companies develop the potential for civilian spaceflight. While few opportunities exist for training, we highlight the major aerospace medicine training opportunities that have been recently available to Canadians. It is our hope that highlighting previous and current opportunities may aid in the development of a formal training program leading to certification in aerospace medicine for Canadians and act as an example for other nations.Sirek A, Samoil K, Harrison MF. Space medicine training in Canada. Aerosp Med Hum Perform. 2019; 90(8):725-729.

Pak1 mediates the stimulatory effect of insulin and curcumin on hepatic ChREBP expression.

Insulin can stimulate hepatic expression of carbohydrate-responsive element-binding protein (ChREBP). As recent studies revealed potential metabolic beneficial effects of ChREBP, we asked whether its expression can also be regulated by the dietary polyphenol curcumin. We also aimed to determine mechanisms underlying ChREBP stimulation by insulin and curcumin. The effect of insulin on ChREBP expression was assessed in mouse hepatocytes, while the effect of curcumin was assessed in mouse hepatocytes and with curcumin gavage in mice. Chemical inhibitors for insulin signaling molecules were utilized to identify involved signaling molecules, and the involvement of p21-activated protein kinase 1 (Pak1) was determined with its chemical inhibitor and Pak1-/- hepatocytes. We found that both insulin and curcumin-stimulated ChREBP expression in Akt-independent but MEK/ERK-dependent manner, involving the inactivation of the transcriptional repressor Oct-1. Aged Pak1-/- mice showed reduced body fat volume. Pak1 inhibition or its genetic deletion attenuated the stimulatory effect of insulin or curcumin on ChREBP expression. Our study hence suggests the existence of a novel signaling cascade Pak1/MEK/ERK/Oct-1 for both insulin and curcumin in exerting their glucose-lowering effect via promoting hepatic ChREBP production, supports the recognition of beneficial functions of ChREBP, and brings us a new overview on dietary polyphenols.

Doppler ultrasound of the central retinal artery in microgravity.

BACKGROUND: Ocular changes have been noted during long-duration spaceflight; we studied central retinal artery (CRA) blood flow using Doppler before, during, and after long-term microgravity exposure in astronauts compared with data from a control group of nonastronauts subjected to head-down tilt (HDT). METHODS: Available Doppler spectra of International Space Station (ISS) crewmembers were obtained from the NASA Lifetime Surveillance of Astronaut Health database, along with 2D ultrasound-derived measurements of the optic nerve sheath diameter (ONSD). CRA Doppler spectra and optic nerve sheath images were also obtained from healthy test subjects in an acute HDT experiment at 20 min of exposure (the ground-based analogue). RESULTS: HDT CRA peak systolic velocity in the ground-based analogue group increased by an average of 3 cm -s(-1) (33%) relative to seated values. ONSD at 300 of HDT increased by 0.5 mm relative to supine values. CRA Doppler spectra obtained on orbit were of excellent quality and demonstrated in-flight changes of +5 cm x s(-1) (50%) compared to preflight. ONSD increased in ISS crewmembers during flight relative to before flight, with some reversal postflight. DISCUSSION: A significant ONSD response to acute postural change and to spaceflight was demonstrated in this preliminary study. Increases in Doppler peak flow velocities correlated with increases in ONSD. Further investigations are warranted to corroborate the relationship between ONSD, intracranial pressure, and central retinal blood flow for occupational surveillance and research purposes.

Insulin stimulates the expression of carbohydrate response element binding protein (ChREBP) by attenuating the repressive effect of Pit-1, Oct-1/Oct-2, and Unc-86 homeodomain protein octamer transcription factor-1.

The carbohydrate response element binding protein (ChREBP) has been recognized as a key controller of hepatic lipogenesis. Whereas the function of ChREBP has been extensively investigated, mechanisms underlying its transcription remain largely unknown, although ChREBP production is elevated in a hyperinsulinemic mouse model. We located a conserved Pit-1, Oct-1/Oct-2, and Unc-86 (POU) protein binding site (ATGCTAAT) within the proximal promoter region of human ChREBP. This site interacts with the POU homeodomain protein octamer transcription factor-1 (Oct-1), as detected by gel shift and chromatin immunoprecipitation assays. Oct-1 cotransfection in the human HepG2 cell line repressed ChREBP promoter activity approximately 50-75% (P < 0.01 to P < 0.001), and this repression was dependent on the existence of the POU binding site. Furthermore, overexpression of Oct-1 repressed endogenous ChREBP mRNA and protein expression, whereas knockdown of Oct-1 expression, using a lentivirus-based small hairpin RNA approach, led to increased ChREBP mRNA and protein expression. In contrast, HepG2 cells treated with 10 or 100 nM insulin for 4 or 8 h resulted in an approximately 2-fold increase of ChREBP promoter activity (P < 0.05 to P < 0.01). Insulin (10 nM) also stimulated endogenous ChREBP expression in HepG2 and primary hamster hepatocytes. More importantly, we found that the stimulatory effect of insulin on ChREBP promoter activity was dependent on the presence of the POU binding site, and insulin treatment reduced Oct-1 expression levels. Our observations therefore identify Oct-1 as a transcriptional repressor of ChREBP and suggest that insulin stimulates ChREBP expression via attenuating the repressive effect of Oct-1.

Adaptation to intermittent stress promotes maintenance of beta-cell compensation: comparison with food restriction.

Intermittent restraint stress delays hyperglycemia in ZDF rats better than pair feeding. We hypothesized that intermittent stress would preserve beta-cell mass through distinct mechanisms from food restriction. We studied temporal effects of intermittent stress on beta-cell compensation during pre-, early, and late diabetes. Six-week-old obese male ZDF rats were restraint-stressed 1 h/day, 5 days/wk for 0, 3, 6, or 13 wk and compared with age-matched obese ZDF rats that had been food restricted for 13 wk, and 19-wk-old lean ZDF rats. Thirteen weeks of stress and food restriction lowered cumulative food intake 10-15%. Obese islets were fibrotic and disorganized and not improved by stress or food restriction. Obese pancreata had islet hyperplasia and showed evidence of neogenesis, but by 19 wk old beta-cell mass was not increased, and islets had fewer beta-cells that were hypertrophic. Both stress and food restriction partially preserved beta-cell mass at 19 wk old via islet hypertrophy, whereas stress additionally lowered alpha-cell mass. Concomitant with maintenance of insulin responses to glucose, stress delayed the sixfold decline in beta-cell proliferation and reduced beta-cell hypertrophy, translating into 30% more beta-cells per islet after 13 wk. In contrast, food restriction did not improve insulin responses or beta-cell hyperplasia, exacerbated beta-cell hypertrophy, and resulted in fewer beta-cells and greater alpha-cell mass than with stress. Thus, preservation of beta-cell mass with adaptation to intermittent stress is related to beta-cell hyperplasia, maintenance of insulin responses to glucose, and reductions in alpha-cell mass that do not occur with food restriction.

Adaptation to mild, intermittent stress delays development of hyperglycemia in the Zucker diabetic Fatty rat independent of food intake: role of habituation of the hypothalamic-pituitary-adrenal axis.

Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity occurs in type 2 diabetes, and stress is assumed to play a causal role. However, intermittent restraint stress, a model mimicking some mild stressors, delays development of hyperglycemia in Zucker diabetic fatty (ZDF) rats. We examine whether such stress delays hyperglycemia independent of stress-induced reductions in hyperphagia and is due to adaptations in gene expression of HPA-related peptides and receptors that ameliorate corticosteronemia and thus hyperglycemia. ZDF rats were intermittently restraint stressed (1 h/d, 5 d/wk) for 13 wk and compared with obese control, pair fed, and lean ZDF rats. After 13 wk, basal hormones were repeatedly measured over 24 h, and HPA-related gene expression was assessed by in situ hybridization. Although restraint initially induced hyperglycemia, this response habituated over time, and intermittent restraint delayed hyperglycemia. This delay was partly related to 5-15% decreased hyperphagia, which was not accompanied by decreased arcuate nucleus NPY or increased POMC mRNA expression, although expression was altered by obesity. Obese rats demonstrated basal hypercorticosteronemia and greater corticosterone responses to food/water removal. Basal hypercorticosteronemia was further exacerbated after 13 wk of pair feeding during the nadir. Importantly, intermittent restraint further delayed hyperglycemia independent of food intake, because glycemia was 30-40% lower than after 13 wk of pair feeding. This may be mediated by increased hippocampal MR mRNA, reduced anterior pituitary POMC mRNA levels, and lower adrenal sensitivity to ACTH, thus preventing basal and stress-induced hypercorticosteronemia. In contrast, 24-h catecholamines were unaltered. Thus, rather than playing a causal role, intermittent stress delayed deteriorations in glycemia and ameliorated HPA hyperactivity in the ZDF rat.