United States Army Medical Research Research Articles

The Power of We.

"The Power of We" is a personal tribute to the individuals and organizations that collaborated in the discovery and advancement of knowledge of the hantaviruses following the original isolation of Hantaan virus by Ho Wang Lee. It focuses on the work done primarily at the United States Army Medical Research Institute of Infectious Diseases during the decade of the 1980s under the leadership of Joel Dalrymple, who worked in close partnership with Ho Wang Lee. These early studies helped define the global distribution of Seoul virus and provided seminal information on its maintenance and transmission among urban rats. Other collaborations involved partners in Europe, Asia, and Latin America and resulted in the isolation of novel hantaviruses, a better understanding of their global distribution, and validation of diagnostics and therapeutic interventions for treatment of human diseases. By working in partnership, scientists from around the world made critical discoveries that led to a better understanding of the hantaviruses. "The Power of We" demonstrates that we all benefit when we work together with a shared vision, a common commitment to excellence, and mutual respect.

A bibliometric study on Marburg virus research with prevention and control strategies

Marburg virus (MARV) is a pathogenic zoonotic RNA virus etiologic for Marburg virus disease (MVD), a severe hemorrhagic fever. This is a rare disease, with a high fatality rate, that spreads via infected blood or body fluids or indirectly via fomites (contaminated objects and substances such as clothed, beds, personal protective equipment, or medical equipments). A few vaccines to protect against MARV are undergoing clinical trials, but there is not yet an approved vaccine against this disease. Eventually, prevention and control guidelines should be adhered to rigorously to alleviate this infection. This bibliometric analysis aimed to harness narrative evaluation, emphasizing the significance of quantitative approaches and delineating the most thought-provoking concerns for researchers using VOSviewer software (Centre for Science and Technology Studies, Leiden University, the Netherlands). “Marburg Virus” OR “MARV” AND “Diseases” search criteria were used for the analysis of articles published between 1962 and 2022. Co-occurrence analysis was carried out, which characterized different thematic clusters. From this analysis, we found that 1688 published articles, and the number of publications increased across that period annually, with a growth rate of 8.78%. It is also conspicuous that the number of publications in the United States reached its acme during this period (i.e., 714 publications, accounting for 42.29% of the total), and the United States Army Medical Research Institute of Infectious Diseases published the most literature (i.e., 146 papers). Our study found that the three pre-eminent authors of Marburg virus papers were “FELDMANN, HEINZ“ of the National Institute of Allergy and Infectious Diseases, United States, “BECKER, STEPHAN” of the Philipps University of Marburg, Germany, and “GEISBERT, THOMAS W” of the University of Texas Medical Branch, United States. In this study we found that “JOURNAL OF VIROLOGY” has published the most pertinent literature, totaling 88 articles, followed by “The journal of Infectious Diseases”, which published 76 relevant papers, and “VIRUSES”, which published 52 corresponding papers. The most cited paper on the Marburg virus was published in Nature Medicine, with 522 total citations and 29 citations/year. Studies of the changing epidemiology and evolving nature of the virus and its ecological niche are required; breakthrough and implementation of the efficacious vaccine candidate(s), prophylaxis and therapeutic alternatives and supervision strategies, unveiling awareness-raising programs, and developing apposite and timely preparedness, prevention, and proactive control strategies are of utmost importance.

Independent Effects Of Hypoxia And Altitude On Human Physiology

PURPOSE: Decreased fraction of inspired oxygen (FiO2) is often used to simulate the atmospheric partial pressure of oxygen decreases experienced during high altitude sojourns. Therefore, we aimed to independently investigate hypoxia and altitude by isolating oxygen concentration and barometric pressure. METHODS: 18 subjects completed 3 trials (sea level, hypoxia, altitude). 90-minute duration and intensity matched hypoxic stimuli were induced via decreased FiO2 or 4,200 m ascent. Relative tissue oxygenation change and cardiovascular variables were measured during rest and a 3-minute step-test. RESULTS: Muscle oxygenated hemoglobin (O2Hb) and muscle deoxygenated hemoglobin (HHb) were not different across environments during rest or exercise (p > 0.339) with alterations noted during rest to exercise transitions (p < 0.001). Resting brain O2Hb at hypoxia and altitude were lower than sea level (p < 0.012), but not different than each other (p = 0.278). Exercising brain O2Hb was lower at altitude than sea level (p = 0.007) similarly trending compared to hypoxia (p = 0.066). Exercising brain O2Hb was not different between hypoxia and sea level (p = 0.158). Brain HHb at hypoxia and altitude were higher than sea level (p < 0.001), but not different than each other (p = 0.158). Exercise HR at hypoxia (141 ± 4 beats·min-1) and altitude (141 ± 3 beats·min-1) were lower than sea level (127 ± 44 beats·min-1, p < 0.002), but not different than each other (p > 0.208). Exercise stroke volume at altitude (109.6 ± 4.1 mL) was higher than hypoxia (97.8 ± 3.3 mL) and sea level (99.8 ± 3.9 mL, p < 0.010) with no differences between hypoxia and sea level (p = 0.481). Exercise cardiac output at hypoxia (13.8 ± 0.6 L) and altitude (15.5 ± 0.7 L) were greater than sea level (12.6 ± 0.5 L, p < 0.006) with altitude greater than hypoxia (p = 0.001). CONCLUSIONS: During acute hypoxic stimuli, skeletal muscle maintains oxygenation while the brain does not. Tissue oxygenation may be mediated by environmentally driven cardiovascular compensation. FiO2 decreases may not satisfactorily simulate all physiological outcomes experienced during altitude induced barometric pressure decreases. Funding: Department of Defense United States Army Medical Research and Materiel Command (DOD USAMRMC: W81XWH-15-2-0075).

0229 Concerns about the future linked with poor sleep quality in U.S. Army Soldiers withdrawing from Afghanistan

Abstract Introduction A special operations unit of U.S. Soldiers rotated through Afghanistan from October, 2001 to the U.S. drawdown in 2020-2021. For these Soldiers, the drawdown has led to uncertainties about the future of the unit and their careers. Psychological stress resulting from these uncertainties could lead to sleep disturbances. This study assessed the relationship between attitudes about the Afghanistan drawdown and sleep. Methods A survey was broadly distributed in July-August 2021. To assess attitudes about the drawdown, participants were asked whether they felt changes in their personal readiness had occurred since the drawdown began. They were asked how they believed the unit should support Afghanistan in the future (remain in Afghanistan, support only through airstrikes, or no further support). Lastly, Soldiers were asked whether the drawdown made them more likely to switch to another unit, get out of the Army, or no change. Subjective sleep quality and duration from the month prior was assessed. Due to the abrupt fall of Kabul, the survey was discontinued earlier than planned, resulting in 35 participants. Results Soldiers were 32.80±5.99 years old. They had been in the unit for 8.89±5.71 years and had deployed to Afghanistan 5.14±3.14 times. The average sleep duration was 6.66±0.79 hours, and the average sleep quality was 63.39%±21.63%. There were no relationships between attitudes and sleep duration. However, regression analyses showed those who reported increased stress (B=18.16, p=.01), decreased morale (B=2.97, p=.006), and decreased motivation (B=2.69, p=.01) since the drawdown began had poorer sleep quality. ANOVA tests showed Soldiers who believed the unit should remain in Afghanistan had poorer sleep quality than those endorsing only air support or no involvement (F(2,29)=6.39, p=.005). Further, those who endorsed being more likely to make a career change had poorer sleep quality than those with no changes in career plans (F(2,29)=3.53, p=.04). Conclusion These results indicate that psychological distress resulting from the drawdown may be impacting sleep quality in this unit. Continuous monitoring of sleep quality may prove to be a sensitive indicator of elevated stress at the unit level. Support (If Any) Support for this study came from the Military Operational Medicine Research Program (MOMRP) of the United States Army Medical Research and Development Command (USAMRDC). Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25. The authors have no conflicts of interest to disclose.

0014 Insufficient sleep is related to poor infantry battle drill performance in special operations Soldiers

Abstract Introduction Although multiple studies have documented the impact of insufficient sleep on Soldier performance, most studies have done so using artificial measures of performance (e.g., tablet or simulator tests). The current study sought to test the relationship between sleep and Soldier performance during infantry battle drill training, a more naturalistic measure of performance. Methods Fifteen junior special operations infantry Soldiers participated in the study. Soldiers wore Phillips Actiwatch Spectrum and reported their subjective sleep duration and quality during the week prior to Close Quarters Battle (CQB) drills. CQB training emphasizes close quarter combat tactics and requires a diverse range of cognitive skills (e.g., memory, decision-making, scanning). Each team of Soldiers performed six iterations of CQB – three using Ultimate Training Munitions (UTM; non-lethal rounds of munition) and three with live ammunition. Experienced leaders monitored each iteration and recorded errors on scorecards that are regularly used by the unit during CQB trainings. Results Participating Soldiers were all male and were 24.3 ± 3.82 years old. Soldiers slept an average of 6.6 hours per night leading up to the exercise and had an average sleep efficiency of 82/100%. The average number of errors committed during the UTM trials was 2.5 ± 1.9, and the average number of errors during the live ammunition trials was 1.1 ± 1.1. The number of errors committed during the live ammunition iterations was negatively correlated with subjective number of hours slept (r = -.67, p = .006) and subjective sleep efficiency/quality (r = -.55, p = .03). A t-test showed those with subjective sleep duration ≥ 7 hours had a significantly lower number of errors than Soldiers with subjective sleep duration &amp;lt; 7 hours (t(14) = 2.26, p = .04). Conclusion Enhancing infantry battle drill performance during training may directly translate to greater success in combat scenarios. These data preliminarily suggest that sleep quality and duration may influence subsequent performance on infantry battle drill training, particularly for Soldiers with limited experience in battle drill conduction who have not yet perfected battle drill techniques. Future studies should enact sleep augmentation to determine the causal influence of sleep on performance in this setting. Support (If Any) Support for this study came from the Military Operational Medicine Research Program (MOMRP) of the United States Army Medical Research and Development Command (USAMRDC). Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25. The authors have no conflicts of interest to disclose.

Military Injuries-Understanding Posttraumatic Epilepsy, Health, and Quality-of-Life Effects of Caregiving: Protocol for a Longitudinal Mixed Methods Observational Study.

BackgroundVeterans with posttraumatic epilepsy (PTE), particularly those with comorbidities associated with epilepsy or traumatic brain injury (TBI), have poorer health status and higher symptom burden than their peers without PTE. One area that has been particularly poorly studied is that of the role of caregivers in the health of veterans with PTE and the impact caring for someone with PTE has on the caregivers themselves.ObjectiveIn this study, we aim to address the following: describe and compare the health and quality of life of veterans and caregivers of veterans with and without PTE; evaluate the change in available supports and unmet needs for services among caregivers of post-9/11 veterans with PTE over a 2-year period and to compare support and unmet needs with those without PTE; and identify veteran and caregiver characteristics associated with the 2-year health trajectories of caregivers and veterans with PTE compared with veterans without PTE.MethodsWe conducted a prospective cohort study of the health and quality of life among 4 groups of veterans and their caregivers: veterans with PTE, nontraumatic epilepsy, TBI only, and neither epilepsy nor TBI. We will recruit participants from previous related studies and collect information about both the veterans and their primary informal caregivers on health, quality of life, unmet needs for care, PTE and TBI symptoms and treatment, relationship, and caregiver experience. Data sources will include existing data supplemented with primary data, such as survey data collected at baseline, intermittent brief reporting using ecological momentary assessment, and qualitative interviews. We will make both cross-sectional and longitudinal comparisons, using veteran-caregiver dyads, along with qualitative findings to better understand risk and promotive factors for quality of life and health among veterans and caregivers, as well as the bidirectional impact of caregivers and care recipients on one another.ResultsThis study was approved by the institutional review boards of the University of Utah and Salt Lake City Veterans Affairs and is under review by the Human Research Protection Office of the United States Army Medical Research and Development Command. The Service Member, Veteran, and Caregiver Community Stakeholders Group has been formed and the study questionnaire will be finalized once the panel reviews it. We anticipate the start of recruitment and primary data collection by January 2022.ConclusionsNew national initiatives aim to incorporate the caregiver into the veteran’s treatment plan; however, we know little about the impact of caregiving—both positive and negative—on the caregivers themselves and on the veterans for whom they provide care. We will identify specific needs in this understudied population, which will inform clinicians, patients, families, and policy makers about the specific impact and needs to equip caregivers in caring for veterans at home.International Registered Report Identifier (IRRID)PRR1-10.2196/30975

305 Subjective sleep predicts Cadet performance during U.S. Army Reserve Officer Training Corps Advanced Camp

Abstract Introduction U.S. Army Reserve Officer Training Corps (ROTC) Advanced Camp (AC) is a 29-day training that assesses military skills and leadership potential in college students training to become Commissioned Officers (i.e. Cadets). Military trainings are widely known to disrupt normative sleep. Additionally, operational sleep disruption is linked to performance decrements. This study examined the ability for objective and subjective sleep during ROTC AC to predict Cadet performance. Methods One hundred and fifty-nine ROTC Cadets (age 22.06±2.49 years; 76.1% male) wore an actiwatch device continuously for 29 days during AC. Paper surveys administered at the end of AC captured subjective sleep metrics during the training. ROTC instructors evaluated Cadet performance and provided scores of overall class rank and summary performance. Multiple and ordinal linear regressions assessed the predicative utility of subjective (sleep duration [SD]; Global score [Global] from the Pittsburgh Sleep Quality Index) and objective (Total Sleep Time [TST]; Sleep Efficiency [SE]; Sleep Latency Onset [SOL]; Wake After Sleep Onset [WASO] from actigraphy) sleep on performance. Results The interaction of SD and Global, when controlling for age and gender, significantly predicted increased Cadet rank, F(4,153) = 3.09, p = 0.018. Models testing the prediction of SD and Global on summary performance score were non-significant. Further, regressing of both Cadet rank and summary performance individually on objective sleep metrics, when controlling for age and gender, resulted in non-significant findings. Conclusion Subjective and objective sleep showed no significant individual predictive utility on performance. However, the combined subjective model significantly predicted that Cadets who slept worse (lower SD; higher Global) during AC received a lower rank at the end of the training. These findings suggest there may be a unique combined predictive utility of subjective sleep on performance when compared to the predictive power of individual variables. Therefore, subjective sleep may be better for predicting operational performance than objective sleep. Future analyses will refine these models and examine how performance on individual AC events may be influenced by sleep. Support for this study came from the Military Operational Medicine Research Program (MOMRP) of the United States Army Medical Research and Development Command (USAMRDC). Support (if any):

293 Predictive utility of a brief scale to identify U.S. Army Soldiers who are genetically vulnerable and resilient to sleep loss

Abstract Introduction Sleep loss that is inherent to military operations can lead to cognitive errors and potential mission failure. Single Nucleotide Polymorphisms (SNPs) allele variations of several genes (COMT, ADORA2A, TNFa, CLOCK, DAT1) have been linked with inter-individual cognitive resilience to sleep loss through various mechanisms. U.S. Army Soldiers with resilience-related alleles may be better-suited to perform cognitively-arduous duties under conditions of sleep loss than those without these alleles. However, military-wide genetic screening is costly, arduous, and infeasible. This study tested whether a brief survey of subjective resilience to sleep loss (1) can demarcate soldiers with and without resilience-related alleles, and, if so, (2) can predict cognitive performance under conditions of sleep loss. Methods Six SNPs from the aforementioned genes were sequenced from 75 male U.S. Army special operations Soldiers (age 25.7±4.1). Psychomotor vigilance, response inhibition, and decision-making were tested after a night of mission-driven total sleep deprivation. The Iowa Resilience to Sleeplessness Test (iREST) Cognitive Subscale, which measures subjective cognitive resilience to sleep loss, was administered after a week of recovery sleep. A receiver operating characteristic (ROC) curve was used to determine whether the iREST Cognitive Subscale can discriminate between gene carriers, and a cutoff score was determined. Cognitive performance after sleep deprivation was compared between those below/above the cutoff score using t-tests or Mann-Whitney U tests. Results The iREST discriminated between allele variations for COMT (ROC=.65,SE=.07,p=.03), with an optimal cutoff score of 3.03 out of 5, with 90% sensitivity and 51.4% specificity. Soldiers below the cutoff score had significantly poorer for psychomotor vigilance reaction time (t=-2.39,p=.02), response inhibition errors of commission (U=155.00,W=246.00,p=.04), and decision-making reaction time (t=2.13,p=.04) than Soldiers above the cutoff score. Conclusion The iREST Cognitive Subscale can discriminate between those with and without specific vulnerability/resilience-related genotypes. If these findings are replicated, the iREST Cognitive Subscale could be used to help military leaders make decisions about proper personnel placement when sleep loss is unavoidable. This would likely result in increased safety and improved performance during military missions. Support (if any) Support for this study came from the Military Operational Medicine Research Program of the United States Army Medical Research and Development Command.

304 The relationship between basic personality, subjective sleep duration, and psychological distress during a military deployment

Abstract Introduction Extended, overseas operations (deployments) increase the likelihood that military personnel will experience psychological distress. Reduced sleep during deployments is a key correlate of psychological distress. Thus, it is imperative to identify mechanisms that adaptively modulate the relationship between insufficient sleep and psychological distress. Research has recently connected basic personality traits (i.e., the Big Five: extraversion, agreeableness, conscientiousness, neuroticism, and openness) to more sleep. The current project aimed to examine the relationship between basic personality traits, subjective sleep duration (SSD), and psychological distress during an operational deployment. Methods 488 soldiers took surveys both prior to and half-way through a nine-month deployment. The pre-deployment survey included the Big Five Index, and three standardized measures of psychological distress commonly used to screen military personnel for anxiety (Generalized Anxiety Disorder; GAD-7), depression (Patient Health Questionnaire; PHQ-8), and post-traumatic stress (Posttraumatic Symptom Disorder Checklist; PCL-4). The mid-deployment survey included an item from the Pittsburgh Sleep Quality Index measuring SSD and the same psychological distress measures from the pre-deployment survey. General linear models were used to test the interaction between SSD and each basic personality trait on each measure of psychological distress at mid-deployment while accounting for psychological distress at pre-deployment. Results Of the Big Five, conscientiousness was the only trait to significantly moderate the relationship between SSD and anxiety, t = 2.11, p = .035, where higher conscientiousness weakened the relationship. Further only agreeableness attenuated the relationship between depression and SSD, t = 2.10, p = .036. Interestingly, the only Big Five trait that moderated the relationship between SSD and PTS was openness, insomuch that openness strengthened the relationship, t = -1.92, p = .055. Conclusion The relationship between SSD and psychological distress was uniquely impacted by different personality traits. These results reinforce the age-old concept that behavior is the product of a complex, nuanced, and puzzling interaction between the individual and the environment. The current research motivates further research into personality as an adaptive mechanism for optimizing military wellbeing. Support (if any) Support for this study came from the Military Operational Medicine Research Program (MOMRP) of the United States Army Medical Research and Development Command (USAMRDC).

307 Sleep and occupational wellbeing in active duty U.S Army Soldiers

Abstract Introduction Insufficient sleep is ubiquitous among active duty service members in operational settings. Although insufficient sleep has been linked to poor cognitive, psychological, and physiological outcomes in military populations, little research has investigated the impact of insufficient sleep on Soldier occupational wellbeing. This study examined the longitudinal association between sleep quality and occupational functioning in a population of active duty U.S. Army Soldiers. Methods Sixty male Soldiers (age 25.41±3.74 years) participated. Sleep quality and occupational outcomes were assessed four weeks apart (before and after an annual training mission). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Occupational outcome measures included the Emotional Exhaustion Scale, Walter Reed Functional Impairment Short Scale, Role Overload Scale, and Perceived Stress Scale. Linear regressions assessed the prediction of PSQI Global Score on occupational outcome scores. Student’s t-tests compared occupational outcomes between “good” and “poor” sleepers (PSQI Global Score &amp;gt; 5 = poor sleeper). Results Poorer sleep quality at baseline broadly predicted poor occupational outcomes post-training. Specifically, higher PSQI Global Scores predicted higher emotional exhaustion (B = 1.6, p &amp;lt; 0.001, R2 = 0.25), functional impairment (B = 0.29, p &amp;lt; 0.03, R2 = 0.14), role overload (B = 28, p &amp;lt; 0.008, R2 = 0.12), and perceived stress (B = 0.34, p &amp;lt; 0.004, R2 = 0.2). Furthermore, occupational outcome scores were significantly higher in poor sleepers than good sleepers: emotional exhaustion: (t(58) = -4.18, p &amp;lt; .001); functional impairment: (t(59) = -3.68, p = .001); role overload (t(58) = -3.20, p = .002); and perceived stress (t(58) = -2.43, p = .02). Conclusion This study identified a longitudinal relationship between sleep quality and occupational outcomes, suggesting that service members with poor sleep may be at risk for experiencing poor workplace wellbeing. Given the association between service member wellbeing and likelihood to re-enlist, insufficient sleep may negatively impact Soldier attrition. Future studies should aim to augment sleep quality and track occupational outcomes in this population. Support (if any) This work was funded by the Military Operational Medicine Research Program of the United States Army Medical Research and Development Command.

690 An Analysis of Objective and Subjective Sleep and Infection Symptoms of Medical Personnel Working through the COVID-19 Pandemic

IntroductionThere is a well-established connection between sleep and the immune system, and in the midst of a global pandemic, it is vital to understand the relationship between COVID-19 symptomatology and sleep. While our communities practice safety protocols, medical personnel working on the COVID-19 response effort are at high risk for exposure and contraction. This creates an urgent need to better understand whether sleep may contribute to COVID-19 symptom onset, severity, and recovery. This study examined the relationship between subjective and objective sleep during infection.MethodsFifty volunteers (age 35.15±9.97) considered high risk for COVID-19 participated in the study. The sample consisted mostly of medical personnel (93.27%) working through the pandemic. Over six months, participants completed monthly surveys and daily logs via Qualtrics. These surveys included questions about sleep, infection symptoms, COVID-19 tests and diagnoses, and mood. Wrist-worn actigraphy was collected continuously throughout the study. Sleep duration, latency, wake after sleep onset, and efficiency were processed using Philips Actiware 6.0. Actigraphy and survey data were analyzed using SPSS v. 25.ResultsSixty-two percent of participants experienced infection symptoms. Those experiencing symptoms were significantly more likely to report having poorer sleep quality t(255.59)=5.78, p=<.001, poorer mood upon waking t(258.03)=6.53, p=<.001, feeling less alert upon waking t(255.61)=4.56, p=<.001, and spending more time awake at night t(2.66.98)=-7.29, p=<.001. Results showed that compared to those asymptomatic, participants with cough t(2164)=2.07, p=.039, diarrhea t(2161)=2.51, p=.012, and headache t(106.18)=7.05, p=<.001 all had significantly less total sleep time, while those with body aches spent significantly more time awake at night t(2164)=2.10, p=.036.ConclusionThis preliminary examination of the data broadly suggests that medical personnel experiencing infection symptoms may have difficulty obtaining adequate sleep. Further, specific infection symptoms may share a stronger relationship with key sleep parameters than others. These findings support further testing of the bi-direction relationship between infection symptoms and sleep. Results from this research will contribute to enhancing prevention, detection, and treatment guidance related to future domestic and globally-experienced infections.Support (if any)Support for this study comes from there Military Operational Medicine Research Program of the United States Army Medical Research and Development Command.

Safety and immunogenicity of an inactivated eastern equine encephalitis virus vaccine

BackgroundEastern equine encephalitis virus (EEEV) is a mosquito borne alphavirus spread primarily in Atlantic and Gulf Coast regions of the United States. EEEV is the causative agent of a devastating meningoencephalitis syndrome, with approximately 30% mortality and significant morbidity. There is no licensed human vaccine against EEEV. An inactivated EEEV vaccine has been offered under investigational new drug (IND) protocols at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. MethodsHealthy at-risk laboratory personnel received inactivated PE-6 strain EEEV (TSI-GSD 104) vaccine under two separate IND protocols. Protocol FY 99–11 (2002–2008) had a primary series consisting of doses on day 0, 7, and 28. Protocol FY 06–31 (2008–2016) utilized a primary series with doses on day 0 and 28, and month 6. Participants with an inadequate immune response, plaque reduction neutralization test with 80% cut-off (PRNT80) titer < 40, received booster vaccination. Volunteers with prior EEEV vaccination were eligible to enroll for booster doses based on annual titer evaluation. ResultsThe FY06-31 dosing schema resulted in significantly greater post-primary series immune response (PRNT80 ≥ 40) rates (84% vs 54%) and geometric mean titers (184.1 vs 39.4). The FY 06–31 dosing schema also resulted in significantly greater cumulative annual immune response rates from 1 to up to 7 years post vaccination (75% vs 59%) and geometric mean of titers (60.1 vs 43.0). The majority of probably or definitely related adverse events were mild and local; there were no probably or definitely related serious adverse events. ConclusionsInactivated PE-6 EEEV vaccine is safe and immunogenic in at-risk laboratory personnel. A prolonged primary series, with month 6 dose, significantly improved vaccine immunogenicity both post-primary series and longitudinally on annual titers. Despite decades of safe use under IND, full licensure is not planned due to manufacturing constraints, and ongoing development of alternatives.

Vaccine-related major cutaneous reaction size correlates with cellular-mediated immune responses after tularaemia immunisation.

Objectives Francisella tularensis, the causative agent of tularaemia, is an exceptionally infectious bacterium, potentially fatal for humans if left untreated and with the potential to be developed as a bioweapon. Both natural infection and live‐attenuated vaccine strain (LVS) confer good protection against tularaemia. LVS vaccination is traditionally administered by scarification, and the formation of a cutaneous reaction or take at the vaccination site is recognised as a clinical correlate of protection. Although previous studies have suggested that high antibody titres following vaccination might serve as a useful surrogate marker, the immunological correlates of protection remain unknown.MethodsWe investigated the host T‐cell‐mediated immune (T‐CMI) responses elicited following immunisation with LVS vaccine formulated by the DynPort Vaccine Company (DVC‐LVS) or the United States Army Medical Research Institute of Infectious Diseases (USAMRIID‐LVS). We compared T‐CMI responses prompted by these vaccines and correlated them with take size.ResultsWe found that both LVS vaccines elicited similar T‐CMI responses. Interestingly, take size associated with the T cells’ ability to proliferate, secrete IFN‐γ and mobilise degranulation, suggesting that these responses play an essential role in tularaemia protection.ConclusionsThese results renew the appreciation for vaccination through the scarification as a prime route of inoculation to target pathogens driving specific T‐CMI responses and provide further evidence that T‐CMI plays a role in protection from tularaemia.

The proteome of human Fallopian tube lavages during the phase of embryo transit reveals candidate proteins for the optimization of preimplantation embryo culture.

Are there phase-specific changes in the early secretory (ES) phase human tubal lavage proteome that can inform and potentially optimize IVF culture media? The human tubal lavage proteome during the ES phase relative to the menstrual phase reveals substantial differential protein abundance in pathways such as glycolysis, redox homeostasis and activation of 14-3-3 zeta-mediated signaling. The Fallopian tube is uniquely suited to the development of the preimplantation embryo as it transits the tube during the ES phase of the menstrual cycle. Euploid cleavage-stage embryo arrest may reflect incomplete recapitulation of in-vivo conditions by current media formulations. Proteome-wide analysis of distal tubal lavage specimens collected from 26 healthy women undergoing open microtubal anastomosis surgery from January 2013 to January 2018 was performed. Specimens were grouped by menstrual cycle phase in order to analyze phase-specific differences in protein abundance. For the murine embryo assay, single-cell embryos (N = 482) were collected from superovulated wild type C57BL/6 female mice and cultured in microdrops over 5 days for the assessment of blastocyst development. Human tubal lavage specimens were processed for label-free mass spectrometry. Reported menstrual cycle day was confirmed by measuring serum hormones. Key protein targets in the ES phase were validated via immunoblot. The ES phase-specific increase in 14-3-3 zeta protein was confirmed via ELISA of conditioned media obtained from primary human Fallopian tube epithelial cell culture. A murine embryo assay was performed to investigate the impact of graduated concentrations of 14-3-3 zeta on the blastocyst development rate. Comparison of the ES and menstrual phase human tubal lavage proteomes revealed 74 differentially expressed proteins with enrichment of pathways and biological processes involved in the regulation of carbohydrate metabolism, oxidative stress and cell survival. The adapter-regulator protein 14-3-3 zeta was among the most significantly increased in the ES phase. Supplementation of embryo culture media with 14-3-3 zeta at concentrations tested did not significantly improve the murine blastocyst development. Although select associations were recapitulated in the conditioned media from sex steroid exposed primary human tubal epithelial cells, cell culture represents an in-vitro approximation. Changes to embryo culture media, such as protein supplementation, must undergo rigorous preclinical safety testing prior to adoption for human use. This study represents the first description of the human Fallopian tube lavage proteome across the menstrual cycle, revealing a unique proteomic signature during the ES phase. Although supplementation of culture media with 14-3-3 zeta at appropriate concentrations showed no significant impact on the murine blastocyst development rate, other biologically plausible candidate proteins for individual or high throughput testing strategies are identified. This work was funded in part by an Army Medical Department Advanced Medical Technology Initiative grant from the United States Army Medical Research and Materiel Command's Telemedicine and Advanced Technology Research Center. There are no competing interests. N/A.

The Western Equine Encephalitis Lyophilized, Inactivated Vaccine: An Update on Safety and Immunogenicity.

BackgroundWestern Equine Encephalitis (WEE) is a naturally acquired infection and potentially devastating bioweapon, with no specific human countermeasures. An experimental inactivated Western Equine Encephalitis Vaccine (WEEV; WEE TSI-GSD 210) has been used under an IND (investigational New Drug) protocol at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976.MethodsOver 24 years from 1987 to 2011, 876 subjects received 3 primary vaccine doses under 3 studies with 1,537 booster doses administered (FY87-8, phase 2, laboratory workers, vaccine lots 1-81-1, 1-81-2, and 2-1-91; FY99-12, phase 2 laboratory workers, lot 2-1-91; and FY09-02, phase 1 healthy volunteer, lot 3-1-92). Post-vaccination safety and immunogenicity [plaque reduction neutralization test 80% (PRNT80) > 1:40] were analyzed.ResultsOverall PRNT80 response to the primary series in FY87-8 was 42% (326/770) but dropped to 16% (14/87) in FY99-12, prompting study FY09-02, which achieved 89% (17/19). The first booster response rate was 68% (814/1194) in FY87-8, 53% (171/324) in FY99-12, and 100% (10/10) in FY09-02. The majority of definitely related adverse reactions (AEs) were mild and local with no definitely related serious AEs. No laboratory acquired WEE infection was documented during this period despite 4 reported exposures in vaccinated subjects.ConclusionThe TSI-GSD 210 WEE vaccine was immunogenic, safe and well tolerated. Use of this vaccine could be considered in an emergency setting. Despite decades of safe and effective use under IND, full licensure is not planned due to manufacturing constraints, and a strategic decision to develop alternatives.Clinical Trial Registration https://clinicaltrials.gov/, identifier NCT01159561.

Ocular Surface - Merging Challenges and Opportunities.

Dichotomies are double-edged: they can simplify and enlighten as well as exaggerate and entangle. Seeing the eye as anterior segment vs. posterior segment simplifies the formidable task of dissecting the function of the eye. Yet this view creates artificial divisions in a coherent whole. Clearly, vision requires the convergence of the light refractive function of the front of the eye with the light sensing function of the back of the eye. The National Eye Institute has long aimed to foster research across the visual pathway. Finding the right balance is a constant work in progress. A recently held scientific meeting which we co-organized with the United States Army Medical Research Institute of Chemical Defense, offered an opportunity to take stock of what the anterior segment in general, and the ocular surface in particular, bring to our understanding of biology and disease of the eye. Multiple dichotomies surfaced: acute vs. chronic disease; epithelial vs. endothelial damage; fibrotic vs. vascular pathology; inflammation vs. resolution response; chemical exposure vs. countermeasure; monotherapy vs. combination therapy; mechanistic vs. exploratory research; human vs. animal model. Merging some of these dichotomies is the goal of this paper.

0189 Sleep Duration and Subjective Resilience to Sleep Loss Predict Functional Impairment in Elite Infantrymen During Military Training

Abstract Introduction Insufficient sleep during military operations is detrimental to cognition, physical performance, and general health outcomes. However, there is evidence of inter-individual differences in resilience to sleep loss. Therefore, some Soldiers may be more resilient to the effects of sleep loss than others. This study examined the relationship between sleep duration, resilience, and Soldier well-being during a deployment-readiness training event. Methods Seventy-six male Soldiers (aged 25.7±4.0y) from the 75th Ranger Regiment participated while undergoing a two-week training exercise. Surveys were administered at the completion of training and queried subjective measures of sleep duration during training, functional impairment (Walter Reed Functional Impairment Scale), and resilience to sleep loss (Iowa Resilience to Sleepiness Test; iREST). The independent relationships between sleep duration, resilience to sleep loss, and functional impairment were assessed using linear regressions. The interaction between sleep duration and resilience to sleep loss was assessed using SPSS Process (Model 1). Results Shorter sleep duration during training predicted higher functional impairment at the end of training (B=-.71, p=.001). Less resilience to sleep loss also predicted higher functional impairment (B=.07,p=.004). An interaction between sleep duration and resilience predicted Soldier impairment (R2 change: .06; F(1,68)=.17,p=.03). Individuals with both shorter sleep duration during training and less resilience had the highest functional impairment. Those with more sleep, and those with high resilience and less sleep, both had lower functional impairment. Conclusion This study suggests the iREST can be used as a quick, subjective screening tool to indicate who may be most vulnerable to the effects of sleep loss. Identifying individual resilience to sleep loss may be useful in the military context for prescribing sleep strategies before and during missions in order to enhance Soldier readiness and performance. Support Support for this study came from the Military Operational Medicine Research Program (MOMRP) of the United States Army Medical Research and Development Command (USAMRDC).

0188 Mood Disorders Moderate the Relationship Between Sleep Quality and Leadership Development for U.S. Army Officer Candidates During ROTC Advanced Camp

Abstract Introduction U.S. Army Reserve Officer Training Corps (ROTC) Cadets are college students training to be Army Officers. During a month-long capstone course (Advanced Camp), Cadets are rated on their leadership ability. Little work has been done to determine predictors of leadership ability at Advanced Camp. This study examined the effect of poor sleep and mood disorders -- two prevalent factors among college students -- on leadership ability. Methods Metrics on leadership, sleep quality, anxiety, and depression, were assessed in 159 ROTC Cadets (22.06±2.49 years; 23.90%female) at Days 1 (Baseline), 14 (Mid), and 29 (Post) of Advanced Camp. Leadership ratings were determined by ROTC Instructors over the course of Advanced Camp (1–5 score; higher score indicates poorer leadership). Predictors were the Pittsburgh Sleep Quality Index, Generalized Anxiety Disorder-7, and Patient Health Questionnaire-9. The relationships between the predictors and leadership scores were tested using linear regression. The interaction between mood disorders and sleep quality on leadership was tested using SPSS Process (Model 1). Results Poorer sleep quality at the Post time point (reflecting the prior 2 weeks of sleep) predicted poorer leadership (B=.05,p=.03), while sleep quality from Baseline (B=.03,p=.14) and Mid (B=.01,p=.67) did not. Higher anxiety and depression scores from all time points predicted poorer leadership (p-values&amp;lt;.03). There was an interaction: higher anxiety and high depression predicted poorer leadership only in the context of poor sleep quality (not good or average sleep quality) [anxiety: R2=.04,F(1,159)=6.04,p=.02; interaction: R2=.03,F(1,155)=5.30,p=.02]. Conclusion The current study identified a relationship between sleep quality and leadership ratings in ROTC cadets. This relationship was moderated by anxiety and depression. ROTC instructors should encourage ROTC Cadets to take advantage of sleep opportunities at Advanced Camp in order to maximize leadership potential. Support Support for this study came from the Military Operational Medicine Research Program (MOMRP) of the United States Army Medical Research and Development Command (USAMRDC). Disclaimer: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army or of the US

The Other 51%: An Updated Characterization of the Female Rat’s Estrous Cycle

The estrous cycle in female rats is analogous to the menstrual cycle in humans, lasting 4–5 days on average, and is composed of 4 main stages (proestrus, estrus, metestrus and diestrus) and 4 transitional stages. Each stage differs in length and is characterized by distinctive cell types with unique morphologies, which helps in the histological identification of each specific stage. Generally due to added expense and/or increased variables, animal research has historically been conducted on male animal models, and those findings are applied across the whole population.The most notable limitation in the utilization of the female animal model is the added unknown variability caused by hormonal fluctuation on the experiment. The main aim of this study was to create estrous synchronization of each experimental cohort, limiting the introduction of these variables. Although group housing has been shown to induce spontaneous synchronization (in mice), the inability to select for a specific stage, as well as limited success in rats, required an alternative method. We used luteinizing hormone‐releasing hormone analog (LHRHa) one week prior to exposure to induce estrous synchronization. Estrous stage was assessed via vaginal lavage and crystal violet staining. Slide comparisons of lavage cells collected prior to and after chemical manipulation showed differences in quantity and/or morphology of cells in each stage. In our study, we targeted a successful synchronization to the diestrus stage at 168 hours post‐injection. In our assessment of over 140 animals, we found that synchronization was successful 49.3% of the time. Overall, the use of LHRHa to induce estrous synchronization maximized experimental time management and limited estrous‐cycle‐dependent physiological and metabolic changes, enabling biochemical data to be collected and interpreted with minimal extraneous variables. These data are extremely beneficial to the drug discovery process, as researchers now look for more gender‐balanced models to assess new therapeutics.DISCLAIMERSThe views expressed in this poster are those of the author(s) and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense, and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011), and the Animal Welfare Act of 1966 (P.L. 89–544), as amended.

The U.S. Government's Apparent Co-Ownership of Patents Protecting Remdesivir

Some preliminary evidence suggests the antiviral drug remdesivir can accelerate recovery from COVID-19, although (as of writing) there is no clear evidence it can actually save the lives of people with COVID-19. Given its promise, remdesivir has been given emergency use authorization by the Food and Drug Administration and is currently being used in hospitals around the world. Remdesivir is manufactured by Gilead Sciences, Inc. (“Gilead”) and is widely perceived as being “owned” by Gilead.However, our analysis indicates that the U.S. government likely has a legal right to claim co-ownership of remdesivir—or at least co-ownership of the core U.S. patents that cover the chemical structure of remdesivir—as well as methods of using the remdesivir to treat various diseases. This is because U.S. government scientists working with United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and the Centers for Disease Control and Prevention (CDC) appear to have contributed in various ways to the “invention” of remdesivir—perhaps to the selection of the compound as a drug candidate, and more clearly to the discovery of remdesivir’s antiviral properties. Based on their intellectual contributions, these government scientists should probably be named as co-inventors on these patents. If these U.S. government scientists are indeed inventors of the patents on remdesivir, then, under U.S. patent law, the patents are presumed co-owned by the U.S. government. If remdesivir proves safe and effective in treating COVID-19, as the world hopes it will, the U.S. government could exercise its patent rights to lower prices and expand access to remdesivir, if need be. This report poses a critical question—if the U.S. government co-invented remdesivir, with substantial investment by the American public in its development, why should Gilead alone profit and control who can manufacture it?