Chemical Safety Concerns of Sulfur Mustard Analog, 2-Chloroethyl Ethyl Sulfide, in Laboratory Study

: Sulfur mustard (SM), a classic chemical weapon in the vesicant category, can induce severe damage, for which the therapy is still limited even today. Laboratory work is essential in unveiling toxicological effects and developing medical countermeasures. Sulfur mustard analog 2-chloroethyl ethyl sulfide (CEES), is employed in the lab for less toxicity. However, due to its similar characteristics to SM (being oily, hydrophobic, and volatile), the manipulation of CEES still needs special attention to avoid personnel injury and laboratory pollution. Here, to clear the chemical safety concerns in the laboratory study of CEES, the working procedure and experimental data are summarized, which might help educate new researchers to be skilled and professional.

Development of Biomarkers for Radiation Biodosimetry and Medical Countermeasures Research: Current Status, Utility, and Regulatory Pathways

Biomarkers are important indicators of biological processes in health or disease. For this reason, they play a critical role in advanced development of radiation biodosimetry tools and medical countermeasures (MCMs). They can aid in the assessment of radiation exposure level, extent of radiation-induced injury, and/or efficacy of an MCM. This meeting report summarizes the presentations and discussions from the 2020 workshop titled, “Biomarkers in Radiation Biodosimetry and Medical Countermeasures,” sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) at the National Institute of Allergy and Infectious Diseases (NIAID). The main goals of this meeting were to: 1. Provide an overview on biomarkers and to focus on the state of science with regards to biomarkers specific to radiation biodosimetry and MCMs; 2. Understand developmental challenges unique to the role of biomarkers in the fields of radiation biodosimetry and MCM development; and 3. Identify existing gaps and needs for translational application.

Rurality Versus Readiness: The Relationship Between State-Level Connection and Capacity Variables and the Management of Medical Stockpiles for a Public Health Emergency

This study investigates what factors contributed to the score a state received for managing its medical countermeasures stockpile pre-COVID-19. It is particularly interested in the relationship between a state’s level of rural population and its countermeasure management capacity. A fixed-effects regression analysis was run using data from 2016 to 2019 to test for a relationship between the percentage of rural population in a state and the states’ countermeasures management score, while controlling for other relevant social, economic, and political variables such as level of social associations, the segregation index, and the level of income inequality. Rurality and physicians per capita proved to be significant and negative. A subsequent analysis found that states with higher levels of rural populations have lower levels of COVID-19 vaccinations, even accounting for effective countermeasure management. This points to rural states having challenges in regard to medical countermeasures that cannot be completely solved with technocratic solutions.

Radiation Medical Countermeasures and Use of EPR Biodosimetry to Facilitate Effectiveness of Applied Clinical Procedures

The utility for electron paramagentic resonance (EPR or ESR)-based radiation biodosimetry has received increasing recognition concerning its potential to assist in guiding the clinical management of medical countermeasures in individuals unwantedly exposed to injurious levels of ionizing radiation. Similar to any of the standard physical dosimetric methods currently employed for screening clinically significant radiation exposures, the EPR-based in vivo dosimetry approach would serve to complement and extend clinical assessments (e.g., blood analyses, cytogenetics, etc.), specifically to more accurately assign the extent of ionizing radiation exposure that individuals might have received. In the case of EPR biodosimetry of biological samples such as nails, teeth, and bones, the method has the capability of providing information on the physical dose at several specific bodily sites and perhaps additonal information on the homogeneity of the exposure as well as its overall magnitude. This information on radiation dose and distribution would be of significant value in providing medical management to given individuals at health risk due to radiation exposure. As these measurements provide information solely on physical measures of the radiation dose and not on the potential biological impact of a particular dose, they are complementary, albeit supplemental, to the array of currently available biologically based biodosimetry and clinical findings. In aggregate, these physical and biological measures of radiation exposure levels (dose) would most certainly provide additional, useful information for the effective medical management of radiation exposed individuals.

Walking distance for vulnerable populations to public health emergency response points of dispensing in New York City

During certain public health emergencies, points of dispensing (PODs) may be used to rapidly distribute medical countermeasures such as antibiotics to the general public to prevent disease. Jurisdictions across the country have identified sites for PODs in preparation for such an emergency; in New York City (NYC), the sites are identified based largely on population density. Vulnerable populations, defined for this analysis as persons with income below the federal poverty level, persons with less than a high school diploma, foreign-born persons, persons of color, persons aged ≥65 years, physically disabled persons, and unemployed persons, often experience a wide range of health inequities. In NYC, these populations are often concentrated in certain geographic areas and rely heavily on public transportation. Because public transportation will almost certainly be affected during large-scale public health emergencies that would require the rapid mass dispensing of medical countermeasures, we evaluated walking distances to PODs. We used an ordinary least squares (OLS) model and a geographically weighted regression (GWR) model to determine if certain characteristics that increase health inequities in the population are associated with longer distances to the nearest POD relative to the general NYC population. Our OLS model identified shorter walking distances to PODs in neighborhoods with a higher percentage of persons with income below the federal poverty level, higher percentage of foreign-born persons, or higher percentage of persons of color, and identified longer walking distances to PODs in neighborhoods with a higher percentage of persons with less than a high school diploma. Our GWR model confirmed the findings from the OLS model and further illustrated these patterns by certain neighborhoods. Our analysis shows that currently identified locations for PODs in NYC are generally serving vulnerable populations equitably—particularly those defined by race or income status—at least in terms of walking distance.

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development of status epilepticus (SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and > 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and > 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and > 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its’ dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.

Differential pathogenesis of closely related 2018 Nigerian outbreak clade III Lassa virus isolates

Nigeria continues to experience ever increasing annual outbreaks of Lassa fever (LF). The World Health Organization has recently declared Lassa virus (LASV) as a priority pathogen for accelerated research leading to a renewed international effort to develop relevant animal models of disease and effective countermeasures to reduce LF morbidity and mortality in endemic West African countries. A limiting factor in evaluating medical countermeasures against LF is a lack of well characterized animal models outside of those based on infection with LASV strain Josiah originating form Sierra Leone, circa 1976. Here we genetically characterize five recent LASV isolates collected from the 2018 outbreak in Nigeria. Three isolates were further evaluated in vivo and despite being closely related and from the same spatial / geographic region of Nigeria, only one of the three isolates proved lethal in strain 13 guinea pigs and non-human primates (NHP). Additionally, this isolate exhibited atypical pathogenesis characteristics in the NHP model, most notably respiratory failure, not commonly described in hemorrhagic cases of LF. These results suggest that there is considerable phenotypic heterogeneity in LASV infections in Nigeria, which leads to a multitude of pathogenesis characteristics that could account for differences between subclinical and lethal LF infections. Most importantly, the development of disease models using currently circulating LASV strains in West Africa are critical for the evaluation of potential vaccines and medical countermeasures.