Defense Threat Reduction Agency Research Articles

Alterations in Germinal Center (GC) Formation and B Cell Activation during Severe Orientia tsutsugamushiInfection in Mice

Abstract Scrub typhus is a poorly studied, but life-threatening, disease caused by the bacterium Orientia tsutsugamushi (Ot). Humoral immunity in scrub typhus patients wanes as early as one-year post-infection; yet its underlying mechanisms remain unclear. The objective of this study is to delineate mechanisms underlying humoral immune dysregulation and B cell dysfunction during acute Ot infection. Using a lethal scrub typhus C57BL/6 murine model, we evaluated splenic GC responses by immunofluorescent staining. Splenic germinal centers (GL-7 +cells) were formed at D4, but were nearly absent at D8, accompanied by randomly scattered T cells. Both infection days had comparable numbers of GC B cells and T follicular helper (Tfh) cells, indicating that GC loss at D8 was less likely due to cell death, but rather dysregulation in GC formation. To confirm this hypothesis, we performed RNAseq analysis of purified B220 +B cells and revealed a set of differentially expressed genes associated with B cell adhesion (S1PR1, ICAM1, GPR183) and co-stimulation (CD40, ICOS-L, SLAMF1) at D8. Notably, the downregulation of S1PR2 (a GC-specific adhesion gene) was most evident at D8, correlating to disrupted GC formation. Furthermore, transcriptomic data revealed significant downregulation of 71% B cell activation genes on D8, suggesting attenuation of B cell activation. Additional studies with low- and high-virulence Ot strains and comparative flow cytometry revealed significant differences in both B cell subsets (plasmablasts, marginal zone B cells) and T cell subsets (Tfh and Tfr cells). This is the first study showing marked dysregulation of B cell responses during Ot infection, which helps understand the transient immunity associated with scrub typhus. Supported by grants from NIH (R01 AI132674, R21 AI156536, R21 AI153586, R01 EY028773, T32 AI007526), Department of Defense Threat Reduction Agency grant (HDTRA1-19-1-0043), UTMB IHII Data Acquisition (CIRWH&IHII Pilot/ Phase II Research grant) and UTMB Center for Biodefense and Emerging Infectious Diseases (Pilot grant)

Predictive performance of multi-model ensemble forecasts of COVID-19 across European nations.

Background: Short-term forecasts of infectious disease contribute to situational awareness and capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise forecasts’ predictive performance by combining independent models into an ensemble. Here we report the performance of ensemble predictions of COVID-19 cases and deaths across Europe from March 2021 to March 2022. Methods: We created the European COVID-19 Forecast Hub, an online open-access platform where modellers upload weekly forecasts for 32 countries with results publicly visualised and evaluated. We created a weekly ensemble forecast from the equally-weighted average across individual models' predictive quantiles. We measured forecast accuracy using a baseline and relative Weighted Interval Score (rWIS). We retrospectively explored ensemble methods, including weighting by past performance. Results: We collected weekly forecasts from 48 models, of which we evaluated 29 models alongside the ensemble model. The ensemble had a consistently strong performance across countries over time, performing better on rWIS than 91% of forecasts for deaths (N=763 predictions from 20 models), and 83% forecasts for cases (N=886 predictions from 23 models). Performance remained stable over a 4-week horizon for death forecasts but declined with longer horizons for cases. Among ensemble methods, the most influential choice came from using a median average instead of the mean, regardless of weighting component models. Conclusions: Our results support combining independent models into an ensemble forecast to improve epidemiological predictions, and suggest that median averages yield better performance than methods based on means. We highlight that forecast consumers should place more weight on incident death forecasts than case forecasts at horizons greater than two weeks. Funding: European Commission, Ministerio de Ciencia, Innovación y Universidades, FEDER; Agència de Qualitat i Avaluació Sanitàries de Catalunya; Netzwerk Universitätsmedizin; Health Protection Research Unit; Wellcome Trust; European Centre for Disease Prevention and Control; Ministry of Science and Higher Education of Poland; Federal Ministry of Education and Research; Los Alamos National Laboratory; German Free State of Saxony; NCBiR; FISR 2020 Covid-19 I Fase; Spanish Ministry of Health / REACT-UE (FEDER); National Institutes of General Medical Sciences; Ministerio de Sanidad/ISCIII; PERISCOPE European H2020; PERISCOPE European H2021; InPresa; National Institutes of Health, NSF, US Centers for Disease Control and Prevention, Google, University of Virginia, Defense Threat Reduction Agency.

Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial

An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40-125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081. The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n=92), icatibant (bradykinin antagonist; n=96), apremilast (PDE4 inhibitor; n=67), celecoxib/famotidine (COX2/histamine blockade; n=30), IC14 (anti-CD14; n=67), dornase alfa (inhaled DNase; n=39) and razuprotafib (Tie2 agonist; n=22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28-0.90; median posterior HR for death 1.67, 95% CrI 0.79-3.58). None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic. Quantum Leap Healthcare Collaborative is the trial sponsor. Funding for this trial has come from: the COVID R&D Consortium, Allergan, Amgen Inc., Takeda Pharmaceutical Company, Implicit Bioscience, Johnson & Johnson, Pfizer Inc., Roche/Genentech, Apotex Inc., FAST Grant from Emergent Venture George Mason University, The DoD Defense Threat Reduction Agency (DTRA), The Department of Health and Human ServicesBiomedical Advanced Research and Development Authority (BARDA), and The Grove Foundation. Effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government.

(Invited) Spin and Optical Properties of the Silicon Vacancy in 4H-SiC for Quantum Science and Technology

Silicon vacancies in SiC are of significant interest for quantum information and sensing due to their unusual combination of long spin coherence time, optical addressability, and room-temperature operation in an industrially-relevant semiconductor. We characterize the spin and optical properties of the V2 silicon vacancy in 4H-SiC for both single defects and ensembles. We also show that they can be deterministically placed with sub-micron precision using focused Li ion implantation. Low-temperature photoluminescence excitation spectroscopy of the spin-dependent optical transitions of single silicon vacancies reveals two sharp lines with linewidths near the radiative lifetime limit. These lines correspond to the ms=±1/2 and ms=±3/2 states of an S=3/2 spin system that can be optically initialized, coherently manipulated with RF pulses, and read out via spin-dependent photoluminescence. We measure the different properties of spins in the two bases, and compare them to theoretical models. To suppress the limiting effects of the nuclear spin bath, we grow isotopically purified SiC with a very low abundance of 29Si and 13C. Our room temperature spin coherence measurements show orders-of-magnitude improvement of the coherence times in these materials. In particular, the inhomogeneous dephasing time T2 * in the ms=±1/2 basis shows a ~100x improvement, reaching 20 μs. We consider the prospects of this system for quantum sensing and as an efficient spin-photon interface for use in quantum networks.This work was supported by the U.S. Office of Naval Research, the OSD Quantum Sciences and Engineering Program, the Defense Threat Reduction Agency, and the Center for Integrated Nanotechnologies, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science. Sandia National Laboratories is a multi-mission laboratory managed and operated by National Technology and Engineering Solutions of Sandia, LLC., a wholly owned subsidiary of Honeywell International, Inc., for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-NA-0003525.

Infrasound propagation with realistic terrain and atmospheres using a finite-difference time-domain method

Numerous infrasound observations and complementary numerical simulations have shown that infrasound propagation is strongly influenced by terrain within approximately 10 km from the source. Recent computational efforts using ray theory have shown that terrain influence extends over hundreds of km and is especially strong for waves ducted in the troposphere. Wind and temperature gradients also have a strong influence on propagation at these distances, which suggests that both terrain and atmospheric structure need to be accounted for in waveform modeling at a wide range of distances. Here we show preliminary results from numerical simulations of linear acoustic propagationthrough a moving, inhomogeneous atmosphere using a finite-difference time domain propagation code. We compare our synthetic waveforms in two and three dimensions with existing community infrasound propagation codes and discuss future developments, including open source licensing. Finally, we present preliminary comparisons between modeling and observations from a large-scale explosion at the Utah Testing and Training Range. This scenario highlights the importance of using full-wave modeling compared to ray methods to explain the observed waveforms. [Work funded by the Defense Threat Reduction Agency. Cleared for release.]

Preclinical immunogenicity and efficacy of a candidate COVID-19 vaccine based on a vesicular stomatitis virus-SARS-CoV-2 chimera

SummaryBackgroundTo investigate a vaccine technology with potential to protect against coronavirus disease 2019 (COVID-19) and reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a single vaccine dose, we developed a SARS-CoV-2 candidate vaccine using the live vesicular stomatitis virus (VSV) chimeric virus approach previously used to develop a licensed Ebola virus vaccine.MethodsWe generated a replication-competent chimeric VSV-SARS-CoV-2 vaccine candidate by replacing the VSV glycoprotein (G) gene with coding sequence for the SARS-CoV-2 Spike glycoprotein (S). Immunogenicity of the lead vaccine candidate (VSV∆G-SARS-CoV-2) was evaluated in cotton rats and golden Syrian hamsters, and protection from SARS-CoV-2 infection also was assessed in hamsters.FindingsVSV∆G-SARS-CoV-2 delivered with a single intramuscular (IM) injection was immunogenic in cotton rats and hamsters and protected hamsters from weight loss following SARS-CoV-2 challenge. When mucosal vaccination was evaluated, cotton rats did not respond to the vaccine, whereas mucosal administration of VSV∆G-SARS-CoV-2 was found to be more immunogenic than IM injection in hamsters and induced immunity that significantly reduced SARS-CoV-2 challenge virus loads in both lung and nasal tissues.InterpretationVSV∆G-SARS-CoV-2 delivered by IM injection or mucosal administration was immunogenic in golden Syrian hamsters, and both vaccination methods effectively protected the lung from SARS-CoV-2 infection. Hamsters vaccinated by mucosal application of VSV∆G-SARS-CoV-2 also developed immunity that controlled SARS-CoV-2 replication in nasal tissue.FundingThe study was funded by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and The International AIDS Vaccine Initiative, Inc. (IAVI), New York, USA. Parts of this research was supported by the Biomedical Advanced Research and Development Authority (BARDA) and the Defense Threat Reduction Agency (DTRA) of the US Department of Defense.

Early human judgment forecasts of human monkeypox, May 2022

Early human judgment forecasts of human monkeypox, May 2022

Changes in the structure of lipid A in glycosylated outer membrane vesicles (glycOMVs) suppress the activation of glycan-specific B1 cells in vivo

Abstract B1 cells differ from B2 cells in their developmental origin, phenotype, and function. They are anatomically located in various tissues of the immune system, and contribute to around 90% of the circulating antibodies in blood. B1 cells are often activated in a T-cell independent manner promoted by either antigens that contain a B-cell mitogen such as LPS, or by molecules that have highly repetitive structures such as bacterial capsular polysaccharides, with both pathways having the potential to undergo class-switch recombination and somatic hypermutation. Previously, we have shown that immunization with bacterial outer membrane vesicles engineered to display defined glycan structures on their surface (glycOMVs) promotes a strong glycan-specific IgG response for a wide range of bacterial and mammalian glycans. Here, we show that the structure of lipid A in these (glycOMVs) displaying the oncofetal antigen polysialic acid (polySia), influences the activation and class-switching of polySia-specific B1 cells from the spleen and peritoneal cavity in mice. We found that structural remodeling of lipid A from its normal hexa-acylated structure to a penta-acylated variant prevents the activation of polySia-specific B1 cells in the spleen and enhances the activation of polySia-specific B2 cells from the peritoneal cavity. Interestingly, we observed no changes in the glycan-specific IgG titers following immunization of wildtype B6 mice with either construct, even though there was no B cell activation in the spleen of mice receiving penta-acylated glycOMVs. However, these same glycOMVs failed to promote a glycan-specific IgG response in T-deficient mice, suggesting that this response was entirely T-cell dependent. This work was supported by Bill and Melinda Gates Foundation grant OPP1217652 (to MPD), NSF grants CBET-1159581, CBET-1264701 and CBET-1936823 (to MPD), the Defense Threat Reduction Agency (DTRA) grants HDTRA1-15-10052 and HDTRA1-20-10004 (to MPD), NIH grants 1R01GM137314 and 1R01GM127578 (to MPD) and the Fleming Scholars Fellowship (to NLB).

Development of fire model source terms and effects in the Hazard Prediction and Assessment Capability (HPAC) atmospheric transport and dispersion code

This paper describes a model which has been developed to represent the input of the products of combustion of large fires into the atmosphere, for subsequent calculation of the transport and dispersion by atmospheric processes. The objective was to have a model suitable for rapid implementation to support the needs of emergency responders. Consequently, the model characterizes the sources by a small number of parameters, which then define the rest of the model in terms of quantity and rate of release of products of combustion. There are two fundamental situations modeled – a hydrocarbon pool fire, and a building fire. The hydrocarbon pool fire is characterized by the area and mass, while the various forms of building fires are reduced to two: wooden buildings and steel-framed buildings, with further discrimination being made by area and duration of the fire. The building fires are assumed to be driven primarily by cellulosic materials, with the amount of such material being normalized to the floor area with parameters taken from the literature. A certain number of toxic contaminants, with levels as suggested by the firefighting literature, are provided in these models. The analyst can amend these levels, or ignore them, as desired. The models developed have been incorporated into the Defense Threat Reduction Agency (DTRA) Hazard Prediction and Capability (HPAC) code. This code breaks down the hazard prediction process into three components: 1) Generation of a source term describing the introduction of the contaminant to the atmosphere; 2) Transport, dispersion, and deposition of the contaminants by atmospheric processes, and; 3) Computation of the effects of the contaminant, usually at the surface. Source term generation modules includes such things as biological and nuclear warfare, and toxic industrial chemicals (TIC). The present work adds a fire module to the mix. • Fires are parameterized to minimize required inputs. • The model is sufficiently flexible that almost any contaminant can be added. • The building fire model is oriented to combustion of the whole building, rather than the contents of the building. • Atmospheric structural variability effects on transport are accounted for. • Doppler weather radar data from a real-world fire is consistent with this model.

Understanding One Health through biological and behavioral risk surveillance in Liberia: a cross-sectional study

BackgroundThe 2014 Ebola crisis in West Africa mainly affected Guinea, Liberia, and Sierra Leone, claiming the lives of over 11 000 people, including health-care workers. Following this crisis, the Ebola Host Project worked to identify the wildlife reservoir for the virus that started the epidemic, to detect other related filoviruses, and to better understand ecological and human behavioral dynamics that could inform future risk reduction and prevention strategies. Here, we report key ecological and behavioral results for Liberia. MethodsIn Liberia, this cross-sectional study was conducted in 13 sites throughout eight counties. The project used a One Health biological-behavioral surveillance approach that included catch-and-release wildlife sampling and behavioral risk surveys. These sites were chosen from counties with forested areas inhabited by bats and rodents and included counties that were both severely and minimally impacted by the Ebola crisis. The analysis included 5000 bat and rodent biological samples, and the behavioural risk survey included 585 enrolled human participants from eight counties. Participants were selected from villages within a 5 km range of the 18 sampling sites, and they provided writteninformed consent. In addition to US based approvals, the Liberian National Ethical and Review Board, the Liberian Forest Development Authority and local government authorities approved the study and community work. FindingsThis sampling effort led to the first-time discovery of an Ebolavirus in a west African bat (Miniopterus inflatus) in January 2019. Across five of the eight counties, including Nimba County where the infected Miniopterus inflatus was sampled, mosquitos and tsetse flies were also identified as present vectors. Respondents reported the ways in which they interfaced with taxa of interest such as rodents. These interactions included wildlife consumption and proximity to human dwellings—interactions that present the risk of zoonotic infections that may go misdiagnosed as fevers of unknown origin. Respondents additionally described gaps in knowledge around topics such as the aetiology of Ebola in Liberia, as well as changes in the level of concern towards Ebola risk, which rose during the crisis but later returned to pre-crisis levels. InterpretationOur results highlight how, against the backdrop of human-wildlife interactions in these Liberian communities that present spillover risk, there exist opportunities to bridge knowledge gaps and create cues to encourage continued vigilance against transmission. FundingThis project was funded by USAID, and analysis with regard to the risk of acute febrile illnesses continues with funding from the US Defense Threat Reduction Agency.

Operational Considerations in Global Health Modeling.

Epidemiological modeling and simulation can contribute cooperatively across multifaceted areas of biosurveillance systems. These efforts can be used to support real-time decision-making during public health emergencies and response operations. Robust epidemiological modeling and simulation tools are crucial to informing risk assessment, risk management, and other biosurveillance processes. The Defense Threat Reduction Agency (DTRA) has sponsored the development of numerous modeling and decision support tools to address questions of operational relevance in response to emerging epidemics and pandemics. These tools were used during the ongoing COVID-19 pandemic and the Ebola outbreaks in West Africa and the Democratic Republic of the Congo. This perspective discusses examples of the considerations DTRA has made when employing epidemiological modeling to inform on public health crises and highlights some of the key lessons learned. Future considerations for researchers developing epidemiological modeling tools to support biosurveillance and public health operations are recommended.

(Invited) Total Dose Effects and Single Event Upsets During Radiation Damage of GaN and SiC

In critical defense applications and autonomous vehicles, there is an increasing transition from high-voltage Si power devices, which are limited in current ratings and power efficiency, to commercial wide bandgap (WBG) power devices. SiC and GaN power devices are now used in the automotive, wireless, and industrial power markets, but their adoption into space and avionic applications is hindered by their susceptibility to permanent degradation and catastrophic failure from heavy-ion exposure. Efforts to space qualify WBG power devices have revealed they are susceptible to damage from the high-energy, heavy-ion space radiation environment (galactic cosmic rays) that cannot be shielded. Higher voltage devices are more susceptible to these effects; as a result, to date, there are space-qualified GaN transistors now available, but limited to 300 V. Recent radiation testing of 600-V and higher GaN transistors has shown failure susceptibility at about 50% of the rated voltage, or less. Similarly, SiC power devices have undergone several generations of advances commercially, improving their overall reliability, but catastrophically fail at less than 50% of their rated voltage. SiC components have demonstrated susceptibility to radiation damage under heavy-ion single-event effects testing, reducing their utility in the space galactic cosmic ray (GCR) environment. In SiC-based Schottky diodes, catastrophic single-event burnout (SEB) and other single-event effects (SEE) have been observed at ~40% of the rated operating voltage, as well as an unacceptable degradation in leakage current at ~20% of the rated operating voltage. SEE caused by terrestrial cosmic radiation (neutrons) have also been identified by industry as a limiting factor for the use of SiC-based electronics in aircraft. Currently, small satellite applications require a Total Ionizing Dose (TID) resilience of 30 krad (Si) and Single Event Latch-up (SEL) hardened up to 80 MeV-cm2/mg linear energy transfer. Radiation hardening comes with a cost. As with Si power MOSFETs, electrical performance will suffer from hardening techniques. The two primary failure radiation damage concerns in current generations of electronics for space applications are (i) Single event upset, in which incident ionizing radiation results in the flipping of a bit from 0 to 1 or vice versa. While this may be a problem for data loss or operation, it does not lead to permanent damage of the device and (ii) Total dose failure, in which irradiation leads to the creation of a sufficient density of defects. These then lead to degradation of the electrical properties to the point of permanent failure. In this talk we will review radiation damage results for GaN and SiC and compare these to initial data for Ga2O3.Work performed as part of Interaction of Ionizing Radiation with Matter University Research Alliance (IIRM-URA ) , sponsored by the Department of the Defense, Defense Threat Reduction Agency under award HDTRA1-20-2-0002. The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. *Current address: Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI 53706

Building Scientific Capability and Reducing Biological Threats: The Effect of Three Cooperative Bio-Research Programs in Kazakhstan.

Cooperative research programs aimed at reducing biological threats have increased scientific capabilities and capacities in Kazakhstan. The German Federal Foreign Office's German Biosecurity Programme, the United Kingdom's International Biological Security Programme and the United States Defense Threat Reduction Agency's Biological Threat Reduction Program provide funding for partner countries, like Kazakhstan. The mutual goals of the programs are to reduce biological threats and enhance global health security. Our investigation examined these cooperative research programs, summarizing major impacts they have made, as well as common successes and challenges. By mapping various projects across the three programs, research networks are highlighted which demonstrate best communication practices to share results and reinforce conclusions. Our team performed a survey to collect results from Kazakhstani partner scientists on their experiences that help gain insights into enhancing day-to-day approaches to conducting cooperative scientific research. This analysis will serve as a basis for a capability maturity model as used in industry, and in addition builds synergy for future collaborations that will be essential for quality and sustainment.

Gaps in toxic industrial chemical model systems: Improvements and changes over past 10 years

AbstractTo assess the hazards of the releases of toxic industrial chemicals (TICs) to the atmosphere, comprehensive model systems are often used, which begin with the scenario definition and end with an estimate of health risk. In 2008 and 2010, the US Department of Homeland Security and Defense Threat Reduction Agency sponsored reports that identified knowledge gaps in TIC modeling. The current paper discusses which of the knowledge gaps were satisfactorily resolved in the past 10 years by new theoretical and experimental research, such as the 2010 and 2015–2016 Jack Rabbit field experiments. For example, the linked source emissions and transport and dispersion (T&amp;D) models have been shown, in comparisons with Jack Rabbit II observations, to not have large mean biases. Consequently, the T&amp;D models are less likely to be the cause of model system overpredictions of casualties observed after large TIC accidental releases, such as the Festus, Macdona, and Graniteville chlorine railcar incidents. It may be that the deposition models and/or the health effects models still need improvement. In addition to comments on the knowledge gaps identified 10 years ago, a few new knowledge gaps are addressed, such as indoor T&amp;D and deposition, and estimating the magnitude of the saturation deposition value for various substrates and chemicals.

Potential for community based surveillance of febrile diseases: Feasibility of self-administered rapid diagnostic tests in Iquitos, Peru and Phnom Penh, Cambodia.

Rapid diagnostic tests (RDTs) have the potential to identify infectious diseases quickly, minimize disease transmission, and could complement and improve surveillance and control of infectious and vector-borne diseases during outbreaks. The U.S. Defense Threat Reduction Agency’s Joint Science and Technology Office (DTRA-JSTO) program set out to develop novel point-of-need RDTs for infectious diseases and deploy them for home use with no training. The aim of this formative study was to address two questions: 1) could community members in Iquitos, Peru and Phnom Penh, Cambodia competently use RDTs of different levels of complexity at home with visually based instructions provided, and 2) if an RDT were provided at no cost, would it be used at home if family members displayed febrile symptoms? Test kits with written and video (Peru only) instructions were provided to community members (Peru [n = 202]; Cambodia [n = 50]) or community health workers (Cambodia [n = 45]), and trained observers evaluated the competency level for each of the several steps required to successfully operate one of two multiplex RDTs on themselves or other consenting participant (i.e., family member). In Iquitos, >80% of residents were able to perform 11/12 steps and 7/15 steps for the two- and five-pathogen test, respectively. Competency in Phnom Penh never reached 80% for any of the 12 or 15 steps for either test; the percentage of participants able to perform a step ranged from 26–76% and 23–72%, for the two- and five-pathogen tests, respectively. Commercially available NS1 dengue rapid tests were distributed, at no cost, to households with confirmed exposure to dengue or Zika virus; of 14 febrile cases reported, six used the provided RDT. Our findings support the need for further implementation research on the appropriate level of instructions or training needed for diverse devices in different settings, as well as how to best integrate RDTs into existing local public health and disease surveillance programs at a large scale.

Foreword by Guest Editor LTC James H. Schreiner, PhD, PMP, CPEM

FOREWORD&#x0D; This special issue of the Industrial and Systems Engineering Review highlights top papers from the 2020 annual General Donald R. Keith memorial capstone conference held at the United States Military Academy in West Point, NY. The conference was certainly a first of its kind virtual conference including asynchronous delivery of paper presentations followed by synchronous question and answer sessions with evaluation panels. Following a careful review of 63 total submissions, eleven were selected for publication in this journal. Unique to this year’s special edition is the mixed selection of seven project team capstone papers, and four honors research papers. Each paper incorporated features of systems or industrial engineering and presented detailed and reflective analysis on the topic. Although there are many elements which cut across the works, three general bodies of knowledge emerged in the papers including: systems engineering and decision analysis, systems design, modeling and simulation, and system dynamics.&#x0D; Systems Engineering and Decision Analysis topics included three unique contributions. Recognized as ‘best paper’ at the 2020 virtual conference, the work of Robinson et al. designed a multi-year predictive cost engineering model enabled through an MS O365 Power BI decision support interface to support U.S. Army Corps of Engineer (USACE) inland waterway national investment strategies. Schloo and Mittal’s work presents research in testing and evaluation of the Engagement Skills Trainer (EST) 2000 towards improving real-world soldier performance. Gerlica et al. employs a robust and scalable K-means clustering methodology to improve decision making in defensive shift schemes for Air Force Baseball outfield personnel.&#x0D; Systems Design works included three unique contributions. Binney et al. worked to design evaluation criteria for military occupational specialties associated with open-source intelligence (OSINT) analysts for the Army’s OSINT Office. Hales et al. interdisciplinary work aided in the design of search and identification systems to be incorporated on autonomous robotics to enable survivability improvements for the Army’s chemical, biological, radiological, nuclear, and explosives (CBRNE) units. Burke and Connell evaluated and designed a performance measurement-based assessment methodology for U.S. Pacific Command’s Key Leader Engagement process.&#x0D; System modeling and simulation included three unique contributions: Arderi et al. simulated and assessed how the Hyper-Enabled Operator (HEO) project improves situational awareness for U.S. Special Forces using the Infantry Warrior Simulation (IWARS). Blanks et al. employed a VBA module and Xpress software for a scheduling optimization model for enhancement of final exam scheduling at the U.S. Air Force Academy. Kelley and Mittal utilized a Batch Run Analysis and Simulation Studio (BRASS) program to batch multiple iterations of IWARS scenarios to study the integration of autonomous systems alongside military units.&#x0D; Finally, two unique contributions utilizing system dynamics (SD) modeling is presented: Dixon and Krueger developed a Vensim SD model to examine how policy recommendations across Central America could restrict gang activities while positively promoting women’s involvement in society. Cromer et al. utilized systems design approaches and a K-means clustering machine learning techniques to develop SD models in support of the U.S. Africa Command and Defense Threat Reduction Agency to examine the interdependence of threats across the Horn of Africa.&#x0D; Thank you and congratulations to the 2020 undergraduate scholars and all authors who provided meaningful contributions through steadfast intellectual efforts in their fields of study! Well done!&#x0D; &#x0D; LTC James H. Schreiner, PhD, PMP, CPEM&#x0D; Program Director, Systems and Decision Sciences (SDS)&#x0D; Department of Systems Engineering&#x0D; United States Military Academy&#x0D; Mahan Hall, Bldg 752, Room 423&#x0D; West Point, NY 10996, USA&#x0D; james.schreiner@westpoint.edu

Neutron Radiobiology and Dosimetry.

As the U.S. prepares for the possibility of a radiological or nuclear incident, or anticipated lunar and Mars missions, the exposure of individuals to neutron radiation must be considered. More information is needed on how to determine the neutron dose to better estimate the true biological effects of neutrons and mixed-field (i.e., neutron and photon) radiation exposures. While exposure to gamma-ray radiation will cause significant health issues, the addition of neutrons will likely exacerbate the biological effects already anticipated after radiation exposure. To begin to understand the issues and knowledge gaps in these areas, the National Institute of Allergy and Infectious Diseases (NIAID), Radiation Nuclear Countermeasures Program (RNCP), Department of Defense (DoD), Defense Threat Reduction Agency (DTRA), and National Aeronautics and Space Administration (NASA) formed an inter-agency working group to host a Neutron Radiobiology and Dosimetry Workshop on March 7, 2019 in Rockville, MD. Stakeholder interests were clearly positioned, given the differences in the missions of each agency. An overview of neutron dosimetry and neutron radiobiology was included, as well as a historical overview of neutron exposure research. In addition, current research in the fields of biodosimetry and diagnostics, medical countermeasures (MCMs) and treatment, long-term health effects, and computational studies were presented and discussed.

Human Consequences of Multiple Nuclear Detonations in New Delhi (India): Interdisciplinary Requirements in Triage Management.

The human casualties from simulated nuclear detonation scenarios in New Delhi, India are analyzed, with a focus on the distribution of casualties in urban environments and the theoretical application of a nuclear-specific triage system with significant innovation in interdisciplinary disaster management applicable generally to urban nuclear detonation medical response. Model estimates of nuclear war casualties employed ESRI’s ArcGIS 9.3, blast and prompt radiation were calculated using the Defense Nuclear Agency’s WE program, and fallout radiation was calculated using the Defense Threat Reduction Agency’s (DTRA’s) Hazard Prediction and Assessment Capability (HPAC) V404SP4, as well as custom GIS and database software applications. ESRI ArcGISTM programs were used to calculate affected populations from the Oak Ridge National Laboratory’s LandScanTM 2007 Global Population Dataset for areas affected by thermal, blast and radiation data. Trauma, thermal burn, and radiation casualties were thus estimated on a geographic basis for New Delhi, India for single and multiple (six) 25 kt detonations and a single 1 mt (1000 kt) detonation. Major issues related to the emergency management of a nuclear incident are discussed with specific recommendations for improvement. The consequences for health management of thermal burn and radiation patients is the worst, as burn patients require enormous resources to treat, and there will be little to no familiarity with the treatment of radiation victims. Of particular importance is the interdisciplinary cooperation necessary for such a large-scale emergency response event, which would be exemplified by efforts such as the application of a Nuclear Global Health Workforce.

Shedding of Marburg Virus in Naturally Infected Egyptian Rousette Bats, South Africa, 2017.

We detected Marburg virus RNA in rectal swab samples from Egyptian rousette bats in South Africa in 2017. This finding signifies that fecal contamination of natural bat habitats is a potential source of infection for humans. Identified genetic sequences are closely related to Ravn virus, implying wider distribution of Marburg virus in Africa.

Countermeasures for Preventing and Treating Opioid Overdose.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic "nanosponge" decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder.