Human Immune Cell Epigenomic Signatures in Response to Infectious Diseases and Chemical Exposures.

Variations in DNA methylation patterns in human tissues have been linked to various environmental exposures and infections. Here, we identified the DNA methylation signatures associated with multiple exposures in nine major immune cell types derived from peripheral blood mononuclear cells (PBMCs) at single-cell resolution. We performed methylome sequencing on 111,180 immune cells obtained from 112 individuals who were exposed to different viruses, bacteria, or chemicals. Our analysis revealed 790,662 differentially methylated regions (DMRs) associated with these exposures, which are mostly individual CpG sites. Additionally, we integrated methylation and ATAC-seq data from same samples and found strong correlations between the two modalities. However, the epigenomic remodeling in these two modalities are complementary. Finally, we identified the minimum set of DMRs that can predict exposures. Overall, our study provides the first comprehensive dataset of single immune cell methylation profiles, along with unique methylation biomarkers for various biological and chemical exposures.

Dynamic transcriptomic responses to divergent acute exercise stimuli in young adults.

Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of health, resilience, and performance adaptations. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to confer similar benefits. Mechanisms of action of these distinct stimuli are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n = 21, 12 M/9 F, 22 ± 3 yr) or HITT (n = 19, 11 M/8 F, 22 ± 2 yr). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR ≤ 0.05) immediately (h0, EVs only), h3, and h24 postexercise within and between exercise protocols. In aaddition, all apparently responsive transcripts (FDR < 0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and interregulatory relationships. LVs were compared across time and exercise protocol. TRAD, a longer but less intense stimulus, generally elicited a stronger transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to the exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles following exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress.NEW & NOTEWORTHY We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

Human Health during Space Travel: State-of-the-Art Review.

The field of human space travel is in the midst of a dramatic revolution. Upcoming missions are looking to push the boundaries of space travel, with plans to travel for longer distances and durations than ever before. Both the National Aeronautics and Space Administration (NASA) and several commercial space companies (e.g., Blue Origin, SpaceX, Virgin Galactic) have already started the process of preparing for long-distance, long-duration space exploration and currently plan to explore inner solar planets (e.g., Mars) by the 2030s. With the emergence of space tourism, space travel has materialized as a potential new, exciting frontier of business, hospitality, medicine, and technology in the coming years. However, current evidence regarding human health in space is very limited, particularly pertaining to short-term and long-term space travel. This review synthesizes developments across the continuum of space health including prior studies and unpublished data from NASA related to each individual organ system, and medical screening prior to space travel. We categorized the extraterrestrial environment into exogenous (e.g., space radiation and microgravity) and endogenous processes (e.g., alteration of humans' natural circadian rhythm and mental health due to confinement, isolation, immobilization, and lack of social interaction) and their various effects on human health. The aim of this review is to explore the potential health challenges associated with space travel and how they may be overcome in order to enable new paradigms for space health, as well as the use of emerging Artificial Intelligence based (AI) technology to propel future space health research.

Resting-state heart rate variability after stressful events as a measure of stress tolerance among elite performers.

Introduction: A common trait of elite performers is their ability to perform well when stressed by strong emotions such as fear. Developing objective measures of stress response that reliably predict performance under stress could have far-reaching implications in selection and training of elite individuals and teams. Prior data suggests that (i) Heart rate and heart rate variability (HR/HRV) are associated with stress reaction, (ii) Higher basal sympathetic tone prior to stressful events is associated with higher performance, and (iii) Elite performers tend to exhibit greater increase in parasympathetic tone after a stressful event. Methods: The current study assesses the predictive utility of post-stressful event HR/HRV measures, an under-studied time point in HR/HRV research, in the context of military personnel selection. Specifically, we examined the relationship between a comprehensive set of HR/HRV measures and established questionnaires related to stress tolerance, experimental evaluation of executive function during stress induction, and ecologically valid selection assessment data from a week-long Special Operations Forces selection course (N = 30). Results: We found that post-stressful event HR/HRV measures generally had strong correlations with the neuroticism facet of the NEO personality inventory as well as the general and distress facets of the defensive reactivity questionnaire. HR/HRV measures correlated reliably with a change in executive function measured as a decrease in verbal fluency with exposure to a well-validated stressor. Finally, we observed a divergent pattern of correlation among elite and non-elite SOF candidates. Specifically, among elite candidates, parasympathetic nervous system (PNS) measures correlated positively and sympathetic nervous system (SNS) measures correlated negatively with evaluation of stress tolerance by experts and peers. This pattern was not present in non-elite candidates. Discussion: Our findings demonstrate that post-stressful event HR/HRV data provide an objective non-invasive method to measure the recovery and arousal state in direct reaction to the stressful event and can be used as metrics of stress tolerance that could enhance selection of elite individuals and teams.

δ13C methane source signatures from tropical wetland and rice field emissions.

The atmospheric methane (CH4) burden is rising sharply, but the causes are still not well understood. One factor of uncertainty is the importance of tropical CH4 emissions into the global mix. Isotopic signatures of major sources remain poorly constrained, despite their usefulness in constraining the global methane budget. Here, a collection of new δ13CCH4 signatures is presented for a range of tropical wetlands and rice fields determined from air samples collected during campaigns from 2016 to 2020. Long-term monitoring of δ13CCH4 in ambient air has been conducted at the Chacaltaya observatory, Bolivia and Southern Botswana. Both long-term records are dominated by biogenic CH4 sources, with isotopic signatures expected from wetland sources. From the longer-term Bolivian record, a seasonal isotopic shift is observed corresponding to wetland extent suggesting that there is input of relatively isotopically light CH4 to the atmosphere during periods of reduced wetland extent. This new data expands the geographical extent and range of measurements of tropical wetland and rice δ13CCH4 sources and hints at significant seasonal variation in tropical wetland δ13CCH4 signatures which may be important to capture in future global and regional models. This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part 2)'.

Mechanisms of exercise as a preventative measure to muscle wasting.

Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly results in rapid muscle wasting. Decline in muscle mass contributes to multimorbidity, reduces function, and exerts a substantial, negative impact on the quality of life. The principal mechanisms controlling muscle mass have been well described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways, and epigenetic regulation. In this review, we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.epigenetics; exercise; muscle wasting; resistance training; skeletal muscle.

Prophylactic surgery prior to extended-duration space flight: is the benefit worth the risk?

This article explores the potential benefits and defined risks associated with prophylactic surgical procedures for astronauts before extended-duration space flight. This includes, but is not limited to, appendectomy and cholecystesctomy. Furthermore, discussion of treatment during space flight, potential impact of an acute illness on a defined mission and the ethical issues surrounding this concept are debated in detail.

Limited value of haptics in virtual reality laparoscopic cholecystectomy training.

BACKGROUND: Haptics is an expensive addition to virtual reality (VR) simulators, and the added value to training has not been proven. This study evaluated the benefit of haptics in VR laparoscopic surgery training for novices. METHODS: The Simbionix LapMentor II haptic VR simulator was used in the study. Randomly, 33 laparoscopic novice students were placed in one of three groups: control, haptics-trained, or nonhaptics-trained group. The control group performed nine basic laparoscopy tasks and four cholecystectomy procedural tasks one time with haptics engaged at the default setting. The haptics group was trained to proficiency in the basic tasks and then performed each of the procedural tasks one time with haptics engaged. The nonhaptics group used the same training protocol except that haptics was disengaged. The proficiency values used were previously published expert values. Each group was assessed in the performance of 10 laparoscopic cholecystectomies (alternating with and without haptics). Performance was measured via automatically collected simulator data. RESULTS: The three groups exhibited no differences in terms of sex, education level, hand dominance, video game experience, surgical experience, and nonsurgical simulator experience. The number of attempts required to reach proficiency did not differ between the haptics- and nonhaptics-training groups. The haptics and nonhaptics groups exhibited no difference in performance. Both training groups outperformed the control group in number of movements as well as path length of the left instrument. In addition, the nonhaptics group outperformed the control group in total time. CONCLUSION: Haptics does not improve the efficiency or effectiveness of LapMentor II VR laparoscopic surgery training. The limited benefit and the significant cost of haptics suggest that haptics should not be included routinely in VR laparoscopic surgery training.

The role of haptic feedback in laparoscopic training using the LapMentor II.

INTRODUCTION: Laparoscopic surgery has become the standard of care for many surgical diseases. Haptic (tactile) feedback (HFB) is considered an important component of laparoscopic surgery. Virtual reality simulation (VRS) is an alternative method to teach surgical skills to surgeons in training. Newer VRS trainers such as the Simbionix Lap Mentor II provide significantly improved tactile feedback. However, VRSs are expensive and adding HFB software adds an estimated cost of $30,000 to the commercial price. The HFB provided by the Lap Mentor II has not been validated by an independent party. We used the Simbionix Lap Mentor II in this study to demonstrate the effect of adding an HFB mechanism in the VRS trainer. MATERIALS AND METHODS: The study was approved by the University of Cincinnati Institutional Review Board. Twenty laparoscopically novice medical students were enrolled. Each student was asked to perform three different tasks on the Lap Mentor II and repeat each one five times. The chosen tasks demanded significant amount of traction and counter traction. The first task was to pull leaking tubes enough and clip them. The second task was stretching a jelly plate enough to see its attachments to the floor and cut these attachments. In the third task, the trainee had to separate the gallbladder from its bed on the liver. The students were randomized into two groups to perform the tasks with and without HFB. We used accuracy, speed, and economy of movement as scales to compare the performance between the two groups. The participants also completed a simple questionnaire that highlighted age, sex, and experiences in videogame usage. RESULTS: The two groups were comparable in age, sex, and videogame playing. No differences in the accuracy, the economy, and the speed of hand movement were noticed. In fact, adding HFB to the Lap Mentor II simulator did not contribute to any improvement in the performance of the trainees. Interestingly, we found that videogame expert players tend to have faster and more economic motion in their dominant hands. However, the performance accuracy was not significantly affected. CONCLUSION: The presence of HFB has less effect than it thought to be on the performance of the novice trainees. This may suggest that better HFB is still needed. However, there may be visual compensation for the lack of haptics. Playing videogames has a positive impact on economy, and the speed of the dominant had motion without affecting its accuracy. Further research is needed to clarify the value of haptics to the expert surgeon and compare it to the new trainees.

Intraperitoneal gas insufflation will be required for laparoscopic visualization in space: a comparison of laparoscopic techniques in weightlessness.

BACKGROUND: Laparoscopic surgery (LS) is contemplated during long duration space flight, but it typically necessitates intraabdominal hypertension (IAH) from insufflation to create a surgical domain. Because there are spontaneous changes in abdominal wall behavior in weightlessness (0g) that have been previously suggested to increase LS visualization, we studied the comparative laparoscopic visualization between gasless (noGAS), abdominal wall retraction (AWR), and standard 15 mmHg gas insufflation (GAS) during weightlessness. STUDY DESIGN: In-flight LS was performed on four anesthetized pigs during weightlessness obtained through parabolic flight in a research aircraft. GAS was studied during 27 parabolas and compared with 20 parabolas using AWR-LS and 12 with noGAS. Pelvic visualization was scored in real time during flight by 2 or 3 surgeons per parabola and postflight through review of compiled digital video disk (DVD) images by 29 independent reviewers. Physical measurements of the sagittal (anterior-posterior) and transverse dimensions of anesthetized pigs were recorded during 39 parabolas. RESULTS: Despite consistent increases in the sagittal abdominal dimension in weightlessness (GAS and noGAS), on-board scored visualization in 0g was unchanged for noGAS (p=0.78) and decreased during AWR (p=0.09), compared with 1g. Although AWR was considered feasible in 1g, spontaneous visceral movements reduced the surgical domain in 0g. Neither AWR nor noGAS was believed safe. But visualization during GAS in 0g was increased over that in 1g (p < 0.001). CONCLUSIONS: Both noGAS and AWR are impractical in weightlessness. Gas insufflation will be required. With insufflation, visualization and perceived ability to perform LS was improved by weightlessness.

Evaluation of teleoperated surgical robots in an enclosed undersea environment.

The ability to support surgical care in an extreme environment is a significant issue for both military medicine and space medicine. Telemanipulation systems, those that can be remotely operated from a distant site, have been used extensively by the National Aeronautics and Space Administration (NASA) for a number of years. These systems, often called telerobots, have successfully been applied to surgical interventions. A further extension is to operate these robotic systems over data communication networks where robotic slave and master are separated by a great distance. NASA utilizes the National Oceanographic and Atmospheric Administration (NOAA) Aquarius underwater habitat as an analog environment for research and technology evaluation missions, known as NASA Extreme Environment Mission Operations (NEEMO). Three NEEMO missions have provided an opportunity to evaluate teleoperated surgical robotics by astronauts and surgeons. Three robotic systems were deployed to the habitat for evaluation during NEEMO 7, 9, and 12. These systems were linked via a telecommunications link to various sites for remote manipulation. Researchers in the habitat conducted a variety of tests to evaluate performance and applicability in extreme environments. Over three different NEEMO missions, components of the Automated Endoscopic System for Optimal Positioning (AESOP), the M7 Surgical System, and the RAVEN were deployed and evaluated. A number of factors were evaluated, including communication latency and semiautonomous functions. The M7 was modified to permit a remote surgeon the ability to insert a needle into simulated tissue with ultrasound guidance, resulting in the world's first semi-autonomous supervisory-controlled medical task. The deployment and operation of teleoperated surgical systems and semi-autonomous, supervisory-controlled tasks were successfully conducted.

Severe traumatic injury during long duration spaceflight: Light years beyond ATLS.

Traumatic injury strikes unexpectedly among the healthiest members of the human population, and has been an inevitable companion of exploration throughout history. In space flight beyond the Earth's orbit, NASA considers trauma to be the highest level of concern regarding the probable incidence versus impact on mission and health. Because of limited resources, medical care will have to focus on the conditions most likely to occur, as well as those with the most significant impact on the crew and mission. Although the relative risk of disabling injuries is significantly higher than traumatic deaths on earth, either issue would have catastrophic implications during space flight. As a result this review focuses on serious life-threatening injuries during space flight as determined by a NASA consensus conference attended by experts in all aspects of injury and space flight.In addition to discussing the impact of various mission profiles on the risk of injury, this manuscript outlines all issues relevant to trauma during space flight. These include the epidemiology of trauma, the pathophysiology of injury during weightlessness, pre-hospital issues, novel technologies, the concept of a space surgeon, appropriate training for a space physician, resuscitation of injured astronauts, hemorrhage control (cavitary and external), surgery in space (open and minimally invasive), postoperative care, vascular access, interventional radiology and pharmacology.Given the risks and isolation inherent in long duration space flight, a well trained surgeon and/or surgical capability will be required onboard any exploration vessel. More specifically, a broadly-trained surgically capable emergency/critical care specialist with innate capabilities to problem-solve and improvise would be desirable. It will be the ultimate remote setting, and hopefully one in which the most advanced of our societies' technologies can be pre-positioned to safeguard precious astronaut lives. Like so many previous space-related technologies, these developments will also greatly improve terrestrial care on earth.

Intra-abdominal pressure effects on porcine thoracic compliance in weightlessness: implications for physiologic tolerance of laparoscopic surgery in space.

OBJECTIVE: Laparoscopic surgery (LS) is envisioned as an option for spaceflight, but requires intra-abdominal hypertension (IAH) to create the surgical domain. Prolonged weightlessness induces physiologic deconditioning that questions the ability of ill or injured astronauts to tolerate IAH. On earth, IAH results in marked ventilatory embarrassment. As there has been no previous study of physiologic changes related to LS in weightlessness, we studied anesthetized pigs in parabolic flight. DESIGN: Parabolic flight research laboratory. SUBJECTS: Five anesthetized Yorkshire pigs. INTERVENTIONS: Subjects were transported from an animal care facility and secured aboard an aircraft capable of generating hypergravity and weightlessness. Mechanical ventilation was performed using pressure control and positive end-expiratory pressure at 15 and 2 cm H2O, respectively; rate 12 breaths/min. Three abdominal conditions were used during LS: insufflation to produce IAH, abdominal wall retraction (AWR), and no abdominal wall manipulation (baseline). During each parabola breath by breath-tidal volumes (Vt) were recorded by a transport ventilator (HT-50 Newport Medical). MEASUREMENTS AND MAIN RESULTS: Least square means (LS-means) of weight corrected Vt (milliliter per kilogram) by gravity (g) and abdominal condition were determined using a mixed effects model for repeated measures analysis. Increasing gravity (g) consistently reduced Vt (p = 0.0011) as did insufflation (p < 0.0001). In 1g, Vt (LS-mean 13.7, 95% confidence interval [CI]: 12.4-15.0) was relatively unaffected by AWR (LS-mean 12.8, 95% CI: 11.5-14.00), but markedly decreased by IAH (LS-mean 10.00, 95% CI: 8.9-11.1), an effect accentuated in hypergravity (LS-mean 8.1, 95% CI: 6.4-9.8). In weightlessness, Vt reduction during insufflation was near obviated (LS-mean 12.3, 95% CI: 10.6-14.1), and AWR regularly but inconsistently increased the Vt above 1g baseline (LS-mean 13.7, 95% CI: 11.7-15.8). CONCLUSIONS: Weightlessness protects against thoracic compliance changes that are inherent in IAH during induced pneumoperitoneum in gravity. The technique-related physiologic cost of performing LS in space deconditioned astronauts should be incorporated into design concepts for space surgery systems.

Manual suturing quality at acceleration levels equivalent to spaceflight and a lunar base.

INTRODUCTION: Cutaneous wounds, either from injuries or as a result of surgical incisions, are a likely possibility that future space medicine specialists will need to address. While there has been some prior study of manual suturing in microgravity (0 G), there has been no study of manual suturing in reduced gravity consistent with that of the Moon. METHODS: Six separate operators with varying degrees of surgical experience (four trained surgeons, and two non-surgeons) attempted to manually suture wound phantoms during the reduced gravity phases of parabolic flight simulating either 0 G or lunar gravity (0.16 G). Each operator subjectively evaluated the difficulty and relative speed in performing the same task in different environments, serving as their own internal control. There were 20-s periods of 1 G that were carefully timed for each surgeon to compare to the approximately 20 s available for each parabola of either 0 G or 0.16 G. RESULTS: Six periods of 1 G were used as controls to perform manual suturing of the phantoms. There were 51 parabolas of 0 G and 67 parabolas of 0.16 G performed by the six operators. As judged subjectively by the operators themselves and by group inspection of the sutured phantoms, there was no qualitative difference in the adequacy of wound closure as judged by suture placement accuracy and wound coaptation. There was consensus, though, that suturing in microgravity was significantly slower, as has been noted in more complex surgical studies. DISCUSSION: The technical aspects of wound management during exploration-class missions in prolonged microgravity or lunar missions with reduced gravity (0.16 G) will likely not present challenges beyond those faced in addressing the tremendous logistical and training obstacles to providing experienced and equipped surgeons on-board such a mission.

Evaluation of unmanned airborne vehicles and mobile robotic telesurgery in an extreme environment.

As unmanned extraction vehicles become a reality in the military theater, opportunities to augment medical operations with telesurgical robotics become more plausible. This project demonstrated an experimental surgical robot using an unmanned airborne vehicle (UAV) as a network topology. Because battlefield operations are dynamic and geographically challenging, the installation of wireless networks is not a feasible option at this point. However, to utilize telesurgical robotics to assist in the urgent medical care of wounded soldiers, a robust, high bandwidth, low latency network is requisite. For the first time, a mobile surgical robotic system was deployed to an austere environment and surgeons were able to remotely operate the systems wirelessly using a UAV. Two University of Cincinnati surgeons were able to remotely drive the University of Washington's RAVEN robot's end effectors. The network topology demonstrated a highly portable, quickly deployable, bandwidth-sufficient and low latency wireless network required for battlefield use.

Transcontinental telesurgical nephrectomy using the da Vinci robot in a porcine model.

OBJECTIVES: Robotic telesurgery has been demonstrated over long distances and offers theoretical benefits to urologic training and the care of patients in remote regions. The multiple arms and three-dimensional vision of the da Vinci robotic system provide a platform conducive to long-distance telementoring and telesurgery. Whereas prior telesurgical efforts have used dedicated lines for information transmission, the public Internet offers a less expensive alternative. It was the intent of this study to test the validity of using the da Vinci system in urologic telesurgery, and to conduct telerobotic nephrectomies using the public Internet. METHODS: We performed four right nephrectomies in porcine models using the da Vinci robotic system. Telementoring and telesurgical approaches were used, with resident surgeons operating a console adjacent to the swine, while attending surgeons simultaneously operated a second console at distances of 1300 and 2400 miles from the operating room. RESULTS: All four procedures and both telementoring and telesurgical models were successful. Round-trip delays from 450 to 900 ms were demonstrated. Blood loss was minimal, and there were no intraoperative complications. CONCLUSIONS: This study represents the first use of the da Vinci Surgical System in urologic telesurgery and the first successful telesurgical nephrectomy in an animal model.

Virtual reality laparoscopic skill assessment in microgravity.

BACKGROUND: The objective of the study was to assess if performance of basic laparoscopic skills on a virtual reality (VR) simulator is impaired in microgravity relative to normal gravitational influences. MATERIALS AND METHODS: Fourteen subjects with various educational backgrounds underwent basic laparoscopy skill training for five consecutive days on the ground before flying aboard NASA's KC-135 zero-gravity laboratory. The participants performed basic laparoscopic exercises (clip applying, grasping, cutting, and suturing) on a VR laparoscopy simulator, both on the ground and during 25-s microgravity windows in parabolic flight. Skill levels after ground training were compared with skill levels in performing the same tasks in microgravity. Blinded reviewers measured the number of tasks successfully completed, tissue damage number, left and right hand path lengths during task execution, and percentage of task attempts that resulted in successful completion. RESULTS: A significant increase in tissue injury (t test, P < 0.05) and task erosion were seen in clip applying, cutting, and grasping in microgravity (45%, 20% and 57% decrease in task attempts that resulted in a successful completion, respectively). However, there was no significant difference in the left and right hand path lengths, and the total number of tasks successfully completed on the ground versus in microgravity, for any of the four laparoscopic exercises (t test, P > 0.05). CONCLUSION: This study demonstrates decreased efficiency and increased injury to the simulated tissues in performing laparoscopic skills during microgravity as compared to performing these skills in standard gravitational influence. Additional experiments are indicated to further develop and validate VR microgravity surgical simulation.