Public health and medical preparedness for mass casualties from the deliberate release of synthetic opioids.

The large amounts of opioids and the emergence of increasingly potent illicitly manufactured synthetic opioids circulating in the unregulated drug supply in North America and Europe are fueling not only the ongoing public health crisis of overdose deaths but also raise the risk of another type of disaster: deliberate opioid release with the intention to cause mass harm. Synthetic opioids are highly potent, rapidly acting, can cause fatal ventilatory depression, are widely available, and have the potential to be disseminated for mass exposure, for example, if effectively formulated, via inhalation or ingestion. As in many other chemical incidents, the health consequences of a deliberate release of synthetic opioid would manifest quickly, within minutes. Such an incident is unlikely, but the consequences could be grave. Awareness of the risk of this type of incident and preparedness to respond are required to save lives and reduce illness. Coordinated planning across the entire local community emergency response system is also critical. The ability to rapidly recognize the opioid toxidrome, education on personal protective actions, and training in medical management of individuals experiencing an opioid overdose are key components of preparedness for an opioid mass casualty incident.

A systems approach for resources management during the COVID-19 pandemic: Multi-agency perspectives from New England.

The emergence of COVID-19 in the United States has overwhelmed local hospitals, produced shortages in critical protective supplies for medical staff, and created backlogs in burials and cremations. Because systemic disruptions occur most acutely at a local scale, facilitating resource coordination across a broad region can assist local responses to COVID-19 surges. This article describes a structured systems approach for coordinating COVID-19 resource distribution across the six New England states of the United States. The framework combines modeling tools to anticipate resource shortages in medical supplies, personnel needs, and fatality management for individual states. The approach allows decision makers to understand the magnitude of local outbreaks and equitably allocate resources within a region based on the present and future needs. This model contributed to determining material distribution in New England as the 2020 COVID-19 surges unfolded in the spring and fall seasons. Using a systems analysis, the model demonstrates the translation of anticipated COVID-19 cases into resource demands to enable regional coordination of scarce resources.

Can Comorbidity Data Explain Cross-State and Cross-National Difference in COVID-19 Death Rates?

Many efforts to predict the impact of COVID-19 on hospitalization, intensive care unit (ICU) utilization, and mortality rely on age and comorbidities. These predictions are foundational to learning, policymaking, and planning for the pandemic, and therefore understanding the relationship between age, comorbidities, and health outcomes is critical to assessing and managing public health risks. From a US government database of 1.4 million patient records collected in May 2020, we extracted the relationships between age and number of comorbidities at the individual level to predict the likelihood of hospitalization, admission to intensive care, and death. We then applied the relationships to each US state and a selection of different countries in order to see whether they predicted observed outcome rates. We found that age and comorbidity data within these geographical regions do not explain much of the international or within-country variation in hospitalization, ICU admission, or death. Identifying alternative explanations for the limited predictive power of comorbidities and age at the population level should be considered for future research.

An Analytical Perspective on Pandemic Recovery.

After implementing restrictions to curb the spread of coronavirus, governments in the United States and around the world are trying to identify the path to social and economic recovery. The White House and the Centers for Disease Control and Prevention have published guidelines to assist US states, counties, and territories in planning these efforts. As the impact of the coronavirus pandemic has not been uniform, these central guidelines need to be translated into practice in ways that recognize variation among jurisdictions. We present a core methodology to assist governments in this task, presenting a case for appropriate actions at each stage of recovery based on scientific data and analysis. Specifically, 3 types of data are needed: data on the spread of disease should be analyzed alongside data on the overall health of the population and data on infrastructure-for example, the capacity of health systems. Local circumstances will produce different needs and present different setbacks, and governments may need to reinstate as well as relax restrictions. Transparent, defensible analysis can assist in making these decisions and communicating them to the public. In the absence of a widely administered vaccine, analysis remains one of our most important tools in addressing the coronavirus pandemic.

Mass Casualty Decontamination in a Chemical or Radiological/Nuclear Incident with External Contamination: Guiding Principles and Research Needs.

Hazardous chemical, radiological, and nuclear materials threaten public health in scenarios of accidental or intentional release which can lead to external contamination of people.  Without intervention, the contamination could cause severe adverse health effects, through systemic absorption by the contaminated casualties as well as spread of contamination to other people, medical equipment, and facilities.  Timely decontamination can prevent or interrupt absorption into the body and minimize opportunities for spread of the contamination, thereby mitigating the health impact of the incident.  Although the specific physicochemical characteristics of the hazardous material(s) will determine the nature of an incident and its risks, some decontamination and medical challenges and recommended response strategies are common among chemical and radioactive material incidents.  Furthermore, the identity of the hazardous material released may not be known early in an incident.  Therefore, it may be beneficial to compare the evidence and harmonize approaches between chemical and radioactive contamination incidents.  Experts from the Global Health Security Initiative's Chemical and Radiological/Nuclear Working Groups present here a succinct summary of guiding principles for planning and response based on current best practices, as well as research needs, to address the challenges of managing contaminated casualties in a chemical or radiological/nuclear incident.

Evidence-based patient decontamination: an integral component of mass exposure chemical incident planning and response.

Decontaminating patients who have been exposed to hazardous chemicals can directly benefit the patients' health by saving lives and reducing the severity of toxicity. While the importance of decontaminating patients to prevent the spread of contamination has long been recognized, its role in improving patient health outcomes has not been as widely appreciated. Acute chemical toxicity may manifest rapidly-often minutes to hours after exposure. Patient decontamination and emergency medical treatment must be initiated as early as possible to terminate further exposure and treat the effects of the dose already absorbed. In a mass exposure chemical incident, responders and receivers are faced with the challenges of determining the type of care that each patient needs (including medical treatment, decontamination, and behavioral health support), providing that care within the effective window of time, and protecting themselves from harm. The US Department of Health and Human Services and Department of Homeland Security have led the development of national planning guidance for mass patient decontamination in a chemical incident to help local communities meet these multiple, time-sensitive health demands. This report summarizes the science on which the guidance is based and the principles that form the core of the updated approach.

A screening tool to prioritize public health risk associated with accidental or deliberate release of chemicals into the atmosphere.

The Chemical Events Working Group of the Global Health Security Initiative has developed a flexible screening tool for chemicals that present a risk when accidentally or deliberately released into the atmosphere. The tool is generic, semi-quantitative, independent of site, situation and scenario, encompasses all chemical hazards (toxicity, flammability and reactivity), and can be easily and quickly implemented by non-subject matter experts using freely available, authoritative information. Public health practitioners and planners can use the screening tool to assist them in directing their activities in each of the five stages of the disaster management cycle.

Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart.

Despite recent advances in delineating the mechanisms involved in cardiogenesis, cellular lineage specification remains incompletely understood. To explore the relationship between developmental fate and potential, we isolated a cardiac-specific Nkx2.5(+) cell population from the developing mouse embryo. The majority of these cells differentiated into cardiomyocytes and conduction system cells. Some, surprisingly, adopted a smooth muscle fate. To address the clonal origin of these lineages, we isolated Nkx2.5(+) cells from in vitro differentiated murine embryonic stem cells and found approximately 28% of these cells expressed c-kit. These c-kit(+) cells possessed the capacity for long-term in vitro expansion and differentiation into both cardiomyocytes and smooth muscle cells from a single cell. We confirmed these findings by isolating c-kit(+)Nkx2.5(+) cells from mouse embryos and demonstrated their capacity for bipotential differentiation in vivo. Taken together, these results support the existence of a common precursor for cardiovascular lineages in the mammalian heart.

The TRPM7 ion channel functions in cholinergic synaptic vesicles and affects transmitter release.

A longstanding hypothesis is that ion channels are present in the membranes of synaptic vesicles and might affect neurotransmitter release. Here we demonstrate that TRPM7, a member of the transient receptor potential (TRP) ion channel family, resides in the membrane of synaptic vesicles of sympathetic neurons, forms molecular complexes with the synaptic vesicle proteins synapsin I and synaptotagmin I, and directly interacts with synaptic vesicular snapin. In sympathetic neurons, changes in TRPM7 levels and channel activity alter acetylcholine release, as measured by EPSP amplitudes and decay times in postsynaptic neurons. TRPM7 affects EPSP quantal size, an intrinsic property of synaptic vesicle release. Targeted peptide interference of TRPM7's interaction with snapin affects the amplitudes and kinetics of postsynaptic EPSPs. Thus, vesicular TRPM7 channel activity is critical to neurotransmitter release in sympathetic neurons.

MONaKA, a novel modulator of the plasma membrane Na,K-ATPase.

We have cloned and characterized mouse and human variants of MONaKA, a novel protein that interacts with and modulates the plasma membrane Na,K-ATPase. MONaKA was cloned based on its sequence homology to the Drosophila Slowpoke channel-binding protein dSlob, but mouse and human MONaKA do not bind to mammalian Slowpoke channels. At least two splice variants of MONaKA exist; the splicing is conserved perfectly between mouse and human, suggesting that it serves some important function. Both splice variants of MONaKA are expressed widely throughout the CNS and peripheral nervous system, with different splice variant expression ratios in neurons and glia. A yeast two-hybrid screen with MONaKA as bait revealed that it binds tightly to the beta1 and beta3 subunits of the Na,K-ATPase. The association between MONaKA and Na,K-ATPase beta subunits was confirmed further by coimmunoprecipitation from transfected cells, mouse brain, and cultured mouse astrocytes. A glutathione S-transferase-MONaKA fusion protein inhibits Na,K-ATPase activity from whole brain or cultured astrocytes. Furthermore, transfection of MONaKA inhibits 86Rb+ uptake via the Na,K-ATPase in intact cells. These results are consistent with the hypothesis that MONaKA modulates brain Na,K-ATPase and may thereby participate in the regulation of electrical excitability and synaptic transmission.

Syntaxin-1A binds to and modulates the Slo calcium-activated potassium channel via an interaction that excludes syntaxin binding to calcium channels.

From its position in presynaptic nerve terminals, the large conductance Ca(2+)-activated K+ channel, Slo, regulates neurotransmitter release. Several other ion channels known to control neurotransmitter release have been implicated in physical interactions with the neurotransmitter release machinery. For example, the Ca(v)2.2 (N-type) Ca2+ channel binds to and is modulated by syntaxin-1A and SNAP-25. Furthermore, a close juxtaposition of Slo and Ca(v)2.2 is presumed to be necessary for functional coupling between the two channels, which has been shown in neurons. We report that Slo exhibits a strong association with syntaxin-1A. Robust co-immunoprecipitation of Slo and syntaxin-1A occurs from transfected HEK293 cells as well as from brain. However, despite this strong interaction and the known association between syntaxin-1A and the II-III loop of Ca(v)2.2, these three proteins do not co-immunoprecipitate in a trimeric complex from transfected HEK293 cells. The Slo-syntaxin-1A co-immunoprecipitation is not significantly influenced by [Ca2+]. Multiple relatively weak interactions may sum up to a tight physical coupling of full-length Slo with syntaxin-1A: the C-terminal tail and the S0-S1 loop of Slo each co-immunoprecipitate with syntaxin-1A. The presence of syntaxin-1A leads to reduced Slo channel activity due to an increased V(1/2) for activation in 100 nM, 1 muM, and 10 microM Ca2+, reduced voltage-sensitivity in 1 microM Ca2+, and slower rates of activation in 10 microM Ca2+. Potential physiological consequences of the interaction between Slo and syntaxin-1A include enhanced excitability through modulation of Slo channel activity and reduced neurotransmitter release due to disruption of syntaxin-1A binding to the Ca(v)2.2 II-III loop.

Control of ion conduction in L-type Ca2+ channels by the concerted action of S5-6 regions.

Voltage-gated L-type Ca(2+) channels from cardiac (alpha(1C)) and skeletal (alpha(1S)) muscle differ from one another in ion selectivity and permeation properties, including unitary conductance. In 110 mM Ba(2+), unitary conductance of alpha(1S) is approximately half that of alpha(1C). As a step toward understanding the mechanism of rapid ion flux through these highly selective ion channels, we used chimeras constructed between alpha(1C) and alpha(1S) to identify structural features responsible for the difference in conductance. Combined replacement of the four pore-lining P-loops in alpha(1C) with P-loops from alpha(1S) reduced unitary conductance to a value intermediate between those of the two parent channels. Combined replacement of four larger regions that include sequences flanking the P-loops (S5 and S6 segments along with the P-loop-containing linker between these segments (S5-6)) conferred alpha(1S)-like conductance on alpha(1C). Likewise, substitution of the four S5-6 regions of alpha(1C) into alpha(1S) conferred alpha(1C)-like conductance on alpha(1S). These results indicate that, comparing alpha(1C) with alpha(1S), the differences in structure that are responsible for the difference in ion conduction are housed within the S5-6 regions. Moreover, the pattern of unitary conductance values obtained for chimeras in which a single P-loop or single S5-6 region was replaced suggest a concerted action of pore-lining regions in the control of ion conduction.