Defense Threat Reduction Agency Research Articles

Medical Surge Capacity in Atlanta-Area Hospitals in Response to Tanker Truck Chemical Releases

We designed and conducted a regional full-scale exercise in 2007 to test the ability of Atlanta-area hospitals and community partners to respond to a terrorist attack involving the coordinated release of 2 dangerous chemicals (toluene diisocyanate and parathion) that were being transported through the area by tanker truck. The exercise was designed to facilitate the activation of hospital emergency response plans and to test applicable triage, decontamination, and communications protocols. Plume modeling was conducted by using the Defense Threat Reduction Agency's (DTRA) Hazard Prediction and Assessment Capability (HPAC) V4 program. The scenario went through multiple iterations as exercise planners sought to reduce total injuries to a manageable, but stressful, level for Atlanta's health care infrastructure. Atlanta-area hospitals rapidly performed multiple casualty triage and were able to take in a surge of victims from the simulated attack. However, health care facilities were reticent to push the perceived manageable numbers of victims, and scenarios were modified significantly to lower the magnitude of the simulated attack. Additional coordination with community response partners and incident command training is recommended. Security at health care facilities and decontamination of arriving victims are two areas that will require continued review. Atlanta-area hospitals participated in an innovative regional exercise that pushed facilities beyond traditional scopes of practice and brought together numerous health care community response partners. Using lessons learned from this exercise coupled with subsequent real-world events and training exercises, participants have significantly enhanced preparedness levels and increased the metropolitan region's medical surge capacity in the case of a multiple casualty disaster.

Implementation of the International Health Regulations (2005) Through Cooperative Bioengagement.

Cooperative bioengagement efforts, as practiced by U.S. government-funded entities, such as the Defense Threat Reduction Agency’s Cooperative Biological Engagement Program, the State Department’s Biosecurity Engagement Program, and parallel programs in other countries, exist at the nexus between public health and security. These programs have an explicit emphasis on developing projects that address the priorities of the partner country as well as the donor. While the objectives of cooperative bioengagement programs focus on reducing the potential for accidental or intentional misuse and/or release of dangerous biological agents, many partner countries are interested in bioengagement as a means to improve basic public health capacities. This article examines the extent to which cooperative bioengagement projects address public health capacity building under the revised International Health Regulations and alignment with the Global Health Security Agenda action packages.

Implementation and evaluation of a training program as part of the Cooperative Biological Engagement Program in Azerbaijan.

A training program for animal and human health professionals has been implemented in Azerbaijan through a joint agreement between the United States Defense Threat Reduction Agency and the Government of Azerbaijan. The training program is administered as part of the Cooperative Biological Engagement Program, and targets key employees in Azerbaijan's disease surveillance system including physicians, veterinarians, epidemiologists, and laboratory personnel. Training is aimed at improving detection, diagnosis, and response to especially dangerous pathogens (EDPs), although the techniques and methodologies can be applied to other pathogens and diseases of concern. Biosafety and biosecurity training is provided to all trainees within the program. Prior to 2014, a variety of international agencies and organizations provided training, which resulted in gaps related to lack of coordination of training materials and content. In 2014 a new training program was implemented in order to address those gaps. This paper provides an overview of the Cooperative Biological Engagement Program training program in Azerbaijan, a description of how the program fits into existing national training infrastructure, and an evaluation of the new program's effectiveness to date. Long-term sustainability of the program is also discussed.

Corrigendum: Twisted Baskets

In their Communication the authors made a mistake in acknowledging the funding agency. The authors apologize for the mistake. The correct Acknowledgement should read as follows: The experimental portion of this work was financially supported with funds obtained from the U.S. National Science Foundation (CHE-1305179). The computational portion was financially supported with funds obtained from the Department of Defense, Defense Threat Reduction Agency (HDTRA1-11-1-0042). Computational support from the Ohio Supercomputer Center is gratefully acknowledged. E.D. is grateful for the predoctoral fellowship received from the Turkish National Science Foundation (TUBITAK).

Developing Fuzzy Cognitive Mapping Techniques for Consequence Analysis of Second and Third Order Effects

The Defense Threat Reduction Agency (DTRA) is the Department of Defense’s (DOD) official Combat Support Agency for countering weapons of mass destruction (WMD). DTRA focuses on WMD and mitigating the consequences of a chemical, biological, radiological, nuclear and high yield explosive threat (CBRNE). The initial direct effects of a CBRNE incident are well defined and documented; however, the second and third order effect’s are complex and not thoroughly understood or documented. Consequence analysis is the practice of analyzing the effects of major events such as a CBRNE event and can assist in predicting the second and third order effects. Currently there is no method to predict or analyze the second and third order effects of CBRNE events. This research focused on identifying the entities associated with a CBRNE event initially. The use of experts and surveys developed an exhaustive list of entities and associated realtionships. The follow-on research focused on the type and strength of the entity relationships. Next, Fuzzy Cognitive Mapping (FCM) techniques identify and evaluate the complex relationships of the second and third order effects. Using a mind mapping computer program, FCM techniques produced second and third order effect relationships. The final product provided a solid first attempt at analyzing a CBRNE event and the associated second and third order effects. Subsequent research will require greater effort to employ system dynamics techniques to enhance the product and develop a more thorough model.

Consequence Management Assessment Method Synthesis for Combatant Commands

One of the most important roles that the US fulfills in the global war on terror and their integration with Partner Nations (PNs) is minimizing the threats and effects of weapons of mass destruction (WMD) as well as Chemical, Biological, Radiological, Nuclear and Explosive (CBRNE) attacks by enemy nations, rogue elements, or terrorist groups around the world. The Defense Threat Reduction Agency (DTRA) currently implements an assessment framework for determining a PN’s state of CBRNE readiness, but it is unable to conceptualize that assessment at a regional or Combatant Command (CCMD) level. This research uses the Systems Decision Process (SDP) to create an assessment metric that is capable of synchronizing PN CBRNE readiness across a CCMD into a single assessment. This research is focused on developing an effective and flexible Microsoft Access database, which evaluates all global PNs across a wide array of metrics and then synthesizes them through multi-purpose objectives in order to develop an encompassing assessment framework at the CCMD level.

Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study

The limited data available for long-term Ebola virus disease health outcomes suggest that sequelae persist for longer than 1 year after infection. The magnitude of the present outbreak in west Africa necessitates a more complete understanding of the health effects and future medical needs of these patients. We invited adult survivors of the 2007 Bundibugyo Ebola virus outbreak in Uganda and their contacts to take part in an observational study roughly 29 months after the outbreak. We collected information about health status, functional limitations, and demographics. We collected blood samples for clinical chemistry, haematology, and filovirus antibodies using ELISA. Analyses were restricted to probable and confirmed survivors and their seronegative contacts. We recruited 70 survivors of the 2007 Bundibugyo Ebola virus and 223 contacts. We did analyses for 49 probable and confirmed survivors and 157 seronegative contacts. Survivors of the Bundibugyo Ebola virus were at significantly increased risk of ocular deficits (retro-orbital pain [RR 4·3, 95% CI 1·9-9·6; p<0·0001], blurred vision [1·9, 1·1-3·2; p=0·018]), hearing loss (2·3, 1·2-4·5; p=0·010), difficulty swallowing (2·1, 1·1-3·9; p=0·017), difficulty sleeping (1·9, 1·3-2·8; p=0·001), arthralgias (2·0, 1·1-3·6; p=0·020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio [PR] 2·1, 95% CI 1·2-3·6; p=0·008) and limitations due to memory loss or confusion (PR 5·8, 1·5-22·4; p=0·010) were also reported more frequently by survivors of Bundibugyo Ebola virus. Long-term sequelae persist for more than 2 years after Ebola virus disease. Definition of health consequences related to Ebola virus disease could improve patient care for survivors and contribute to understanding of disease pathogenesis. Chemical Biological Technologies Directorate, Defense Threat Reduction Agency.

Inhibition of Human Acetylcholinesterase by Enantiomers of V‐Type Chemical Warfare Nerve Agents and Analogs

Chemical warfare nerve agents are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Analytical scale methods using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer were developed for the separation and detection of individual stereoisomers of VX, VR, and VS, and the analogs V1 thru V4. Separation was evaluated with respect to the chromatography parameter resolution (Rs) with a value of 蠅1.7 indicating complete separation. The ChiralCel OD‐H column yielded Rs values &gt;1.7 for each V‐type compound with mobile phase modifier concentrations 蠄2%. Methods that provided the highest Rs values were scaled up to the semi‐preparative level, allowing for isolation and analysis of individual stereoisomers at &gt;99% purity. Ellipticity (Θ) values of each enantiomer were determined by circular dichroism (CD) spectroscopy. VX, V1, V2, and V3 all had a ΘMAX at 221nm, while VR, VS, and V4 had a ΘMAX at 226nm. For all agents, the first eluting isomer had a negative value at ΘMAX [(‐)Θ221‐226], while the second eluting isomers all had positive values at ΘMAX [(+)Θ221‐226]. Individual enantiomers and racemic mixtures of each agent were then incubated with recombinant human acetylcholinesterase to determine their inhibition rate constants (ki). The (+)Θ221‐226 enantiomer was found to be an average of 2‐3 orders of magnitude more inhibitory than the opposite enantiomer of the same agent.The 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.This research was supported by the Defense Threat Reduction Agency – Joint Science and Technology Office, Medical S&amp;T Division.

Use of V‐Agent Analogs to Probe the Active Site of Atypical Butyrylcholinesterase from Oryzias latipes

The atypical butyrylcholinesterase (aBuChE) from Oryzias latipes shares approximately 65% sequence similarity to both acetylcholinesterase and butyrylcholinesterase and was studied for its capacity to spontaneously reactivate following inhibition by organophosphorus nerve agents. The full-length aBuChE protein was expressed and purified from cabbage loopers (Trichoplusia ni larvae) infected with an orally active form of baculovirus. Like other cholinesterases, aBuChE was inhibited by all G- and V-type nerve agents. Interestingly, aBuChE was able to undergo spontaneous reactivation after inhibition with VR. Mass spectrometry of aBuChE after inhibition with VR confirmed the presence of a covalently bound adduct of the size expected for non-aged VR on the peptide containing the active site serine. To understand the effect of substrate volume on rates of reactivation, the capacity of aBuChE to bind and spontaneously reactivate after inhibition with five analogs of VX and VR and the nerve agent VS was examined. The data suggest that the ability of aBuChE to spontaneously reactivate after inhibition by V-agent analogs and the rates of reactivation are related to the structure of the retained group. These results may provide structural information to inform the design of improved oximes to reactivate nerve agent-inhibited acetylcholinesterase or butyrylcholinesterase, and further suggest that re-engineering the active site of a cholinesterase could result in enzymes with clinically relevant rates of nerve agent hydrolysis. This research was supported by the Defense Threat Reduction Agency – Joint Science Technology Office, Medical S&T Division.

A non‐human primate model for Yersinia pestis infection: metabolomic analysis pilot study

Yersinia pestis, the etiological agent of the plague, is a potential biothreat agent. Upon inhalation, the Gram‐negative bacterium causes pneumonic plague, a rapidly progressing, severe lung infection that is usually fatal. Only limited work using metabolite profiles to study the progression of the disease has been done, and exact mechanisms that facilitate disease are not well‐characterized. In this study, African Green monkeys were exposed to aerosolized highly virulent Y. pestis CO92 and metabolomic profiling of plasma samples was conducted. Comparison of control counterparts to the disease states at earlier time points (6 hours to 18 hours) versus at later time points (24 hours onwards) showed mainly two‐fold higher increases in the levels of certain polyunsaturated fatty acids, long chain fatty acids and metabolites from fatty acid metabolism pathway. Significant alterations in metabolites related to early inflammation and oxidative stress, increased energy demands to the host, and potential renal dysfunction were revealed. The metabolomics of plasma have the potential to provide a more thorough understanding of the Y. pestis pathogenesis, which may assist future treatment of this disease.The grant # TMTI0029_09_WR_T from Department of Defense Chemical and Biological Defense program through the Defense Threat Reduction Agency is acknowledged.DISCLAIMER“Research was conducted in compliance with the Animal Welfare Act and all other Federal requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.”

The Disaster Preparedness Program: a new model for sustainable capacity building through civil-military collaboration

Abstract Background The Disaster Preparedness Program (DPP) is a partnership between The Center for Disaster and Humanitarian Assistance Medicine (CDHAM)—a part of the Uniformed Services University of the Health Sciences—and the United States Africa Command (USAFRICOM). The DPP aims to assist African partner nations to enhance their disaster preparedness and response capabilities. The programme takes a whole-of-government approach to disaster preparedness and response, with an emphasis on plan development and, in some cases, creation of an autonomous national disaster management agency. Methods The DPP worked with the Embassy and other US government stakeholders to identify key ministries involved in disaster preparedness. With DPP assistance, a technical team from the partner nation undertook a comprehensive assessment of their current disaster response capabilities. This information was used to construct a disaster management strategic work plan that identified specific gaps in disaster preparedness. A disaster simulation exercise was conducted with representatives from agencies and ministries involved in disaster response. They applied their existing structure, plans and resources to a scenario designed for their country by CDHAM in order to identify any additional shortfalls in the plan. The finalised work plan could then be used by the partner nation to prioritise and address immediate needs. Findings Since 2009, CDHAM has worked with 16 partner nations. Ten countries have developed national pandemic influenza preparedness and response plans. By December, 2014, one country had used this plan to prevent the spread of Ebola, one country adapted this plan to a whole-of-government Ebola response, and six others are currently in the process of adopting this approach. Eight African armies have drafted military support to civil authorities disaster contingency plans, and one army has used this approach with Ebola. Ten countries have developed disaster management strategic work plans and are currently conducting activities in partnership with the US State Partnership Program, USAFRICOM, the Defense Threat Reduction Agency and the World Bank to fill gaps in their national disaster preparedness. Interpretation Although the work with the DPP is expected to enhance partner nations' preparedness and response to disasters, measuring the outcomes of these projects may take several years. The next phase of the DPP will focus on sustained support to local programmes while working with them to assess improvements in their response capabilities. As a result of these successful partnerships, CDHAM is now also playing a major role in assisting west African partner nations with Ebola preparedness activities. Funding Initially provided through USAID, but funding is now provided through the Defense Security Cooperation Agency's Overseas Humanitarian, Disaster, and Civic Aid.

Spatiotemporal spread of the 2014 outbreak of Ebola virus disease in Liberia and the effectiveness of non-pharmaceutical interventions: a computational modelling analysis

The 2014 epidemic of Ebola virus disease in parts of west Africa defines an unprecedented health threat. We developed a model of Ebola virus transmission that integrates detailed geographical and demographic data from Liberia to overcome the limitations of non-spatial approaches in projecting the disease dynamics and assessing non-pharmaceutical control interventions. We modelled the movements of individuals, including patients not infected with Ebola virus, seeking assistance in health-care facilities, the movements of individuals taking care of patients infected with Ebola virus not admitted to hospital, and the attendance of funerals. Individuals were grouped into randomly assigned households (size based on Demographic Health Survey data) that were geographically placed to match population density estimates on a grid of 3157 cells covering the country. The spatial agent-based model was calibrated with a Markov chain Monte Carlo approach. The model was used to estimate Ebola virus transmission parameters and investigate the effectiveness of interventions such as availability of Ebola treatment units, safe burials procedures, and household protection kits. Up to Aug 16, 2014, we estimated that 38·3% of infections (95% CI 17·4-76·4) were acquired in hospitals, 30·7% (14·1-46·4) in households, and 8·6% (3·2-11·8) while participating in funerals. We noted that the movement and mixing, in hospitals at the early stage of the epidemic, of patients infected with Ebola virus and those not infected was a sufficient driver of the reported pattern of spatial spread. The subsequent decrease of incidence at country and county level is attributable to the increasing availability of Ebola treatment units (which in turn contributed to drastically decreased hospital transmission), safe burials, and distribution of household protection kits. The model allows assessment of intervention options and the understanding of their role in the decrease in incidence reported since Sept 7, 2014. High-quality data (eg, to estimate household secondary attack rate, contact patterns within hospitals, and effects of ongoing interventions) are needed to reduce uncertainty in model estimates. US Defense Threat Reduction Agency, US National Institutes of Health.

R&amp;D ekes out an increase in FY 2015 budget request

With spending caps in place, President Obama proposes an off-budget fund to support additional R&D. NASA would ground a flying observatory, and DOE would sharply curtail its nonproliferation programs.

Pupillary light response in guinea pigs and swine exposed to organophosphate agents (1143.5)

Here we report a study to more precisely define and quantify the relationship between organophosphate agent exposure, including pesticides and nerve agents, with cholinesterase inhibition and the ocular biomarkers that are induced. A thorough investigation of these relationships was conducted to subsequently refine pupillary algorithms for the automated detection of organophosphate exposures with greater specificity regarding level of exposure, the extent of cholinesterase inhibition, and the temporal presentation and persistence of the ocular biomarkers. A guinea pig model was exposed to varying concentrations of parathion (pesticide), soman and VX (nerve agents) to methodically detail both the temporal and quantitative occurrence of pupillary deficits (anticholinesterase biomarkers) to determine the most sensitive, accurate diagnostic algorithms in these animal models. Dose‐response curves and temporal‐response curves for both pupillary deficits and generalized symptoms were developed for each agent used. Based upon previous studies dose ranges were conducted from the LD50 to 3000‐fold below the LD50 to incorporate lethal and sub‐lethal exposures without decreasing the potential sensitivity of the ocular biomarkers. In addition, cholinesterase assays were performed at various time points post‐exposure. The key finding of this study was that after exposure to organophosphates changes in pupillary response were detected prior to changes in acetylcholine esterase levels in guinea pigs. This opens the possibility of early detection to organophosphate exposure in a non‐invasive manner that does not require the use of enzyme markers. We are in the process of duplicating these studies in swine and swine data will be presented.Grant Funding Source: Supported by Defense Threat Reduction Agency

Optimization of the nucleocapsid protein sequences of human measles virus and canine distemper virus to human and canine codon usage bias increases sequence identity and protein expression (145.3)

Amino acids are coded for by two to six different RNA codons and frequency of codon use, known as codon usage bias (CUB), varies between species. Since viruses do not have tRNAs, the translation of viral proteins depends upon utilization of host tRNA, and is impacted by the host’s CUB. We are investigating the importance of codon usage in morbilliviral host adaptation and pathogenicity. Previously we determined that human CUB had significantly higher relative adaptiveness for 6 of 7 CDV proteins than canine CUB. For this study we constructed nucleic acid sequences for HMV and CDV N proteins that were optimized to human and canine CUB. For both viral N proteins, the human and canine codon optimized sequences had increased nucleic acid and codon identity compared to wild type. In addition, codon optimization of the CDV N protein to either the human or canine CUB increased its nucleic acid identity to the wild type (WT) HMV N protein from 66.3% (HMV WT vs CDV WT) to 71.8% (Human CUB vs WT) and 72.2% (Canine CUB vs WT). Finally, protein expression from human and canine CUB optimized HMV and CDV N protein nucleic acid sequences transfected into human (293 HEK) cells was increased over that of the WT constructs. These results indicate that further adaptation of HMV and CDV to the mammalian CUB could potentially enhance viral expression.Grant Funding Source: Supported by Department of Defense Threat Reduction Agency

Simulation-based Testbed for Bio-Surveillance Systems

The U.S. Defense Threat Reduction Agency (DTRA) is funding multiple development efforts directed at enhanced platforms to support bio-surveillance analysts under their Bio-surveillance Ecosystem (BSVE) program. These efforts include well-integrated user interface systems and advanced algorithmic concepts to facilitate analysis of diverse, pertinent data sources including traditional bio-surveillance data sources as well as social media inputs. A central challenge in this development effort is a practical, effective, method to test these prototype systems. This presentation discusses a simulation-based testbed to allow quantitative evaluation of analytical methods through controlled injection of simulated outbreak-related information into test data streams.

Correction: Inhibition of IGF-1R Prevents Ionizing Radiation-Induced Primary Endothelial Cell Senescence

A funding organization and multiple grants to the second author (RMD) were incorrectly omitted from the Funding Statement. The Funding Statement should read: This study was supported by a USUHS Intramural Grant, and a USUHS predoctoral grant. The work was additionally funded by Defense Threat Reduction Agency grant H.1006_09_US_R and Defense Medical Research and Development Program grant D10_I_AR_J7_119 from the US Department of Defense to RMD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

In the NEWS: A ROUNDUP OF NEWS AND INFORMATION FROM OUR COMMUNITY

In <i>the</i> NEWS: A ROUNDUP OF NEWS AND INFORMATION FROM OUR COMMUNITY

Limiting the worldwide flow of weapons and their components through established maritime transport

The world maritime industry contains a plethora of participants ranging from importers and exporters to carriers and intermediaries involved in one or more of the supply chain flows of physical, information, and financial. Many nations see global trade as a regulated activity whereby for security reasons certain goods may be excluded from specific nations or parties. The manner for prohibiting this trade is inconsistent, hence multinational agreements and voluntary arrangements have been implemented, especially with regard to limiting the proliferation of weapons. This article, based on research funded by the U.S. Defense Threat Reduction Agency (DTRA), maps the global maritime industry, identifies gaps that could potentially foster proliferation activities among those nations not participating in international agreements to thwart such practices, and recommends changes to multinational agreements, improvements to industry employed processes, and encourages the development of public-private partnerships.

Nuclear war between Israel and Iran: lethality beyond the pale

BackgroundThe proliferation of nuclear technology in the politically volatile Middle East greatly increases the likelihood of a catastrophic nuclear war. It is widely accepted, while not openly declared, that Israel has nuclear weapons, and that Iran has enriched enough nuclear material to build them. The medical consequences of a nuclear exchange between Iran and Israel in the near future are envisioned, with a focus on the distribution of casualties in urban environments.MethodsModel 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. Further development for thermal burn casualties was based on Brode, as modified by Binninger, to calculate thermal fluence. 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.ResultsTrauma, thermal burn, and radiation casualties were thus estimated on a geographic basis for three Israeli and eighteen Iranian cities. Nuclear weapon detonations in the densely populated cities of Iran and Israel will result in an unprecedented millions of numbers of dead, with millions of injured suffering without adequate medical care, a broad base of lingering mental health issues, a devastating loss of municipal infrastructure, long-term disruption of economic, educational, and other essential social activity, and a breakdown in law and order.ConclusionsThis will cause a very limited medical response initially for survivors in Iran and Israel. Strategic use of surviving medical response and collaboration with international relief could be expedited by the predicted casualty distributions and locations. 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. Any rational analysis of a nuclear war between Iran and Israel reveals the utterly unacceptable outcomes for either nation.