An update on nonhuman primate usage for drug and vaccine evaluation against filoviruses.

INTRODUCTION: Due to their faithful recapitulation of human disease, nonhumanprimates (NHPs) are considered the gold standard for evaluating drugs against Ebolavirus and other filoviruses. The long-term goal is to reduce the reliance on NHPswith more ethical alternatives. In silico simulations and organoidmodels have the potential to revolutionize drug testing by providing accurate,human-based systems that mimic disease processes and drug responses without theethical concerns associated with animal testing. However, as these emergingtechnologies are still in their developmental infancy, NHP models are presentlyneeded for late-stage evaluation of filovirus vaccines and drugs, as theyprovide critical insights into the efficacy and safety of new medicalcountermeasures. AREAS COVERED: In this review, the authors introduce available NHP models andexamine the existing literature on drug discovery for all medically significantfiloviruses in corresponding models. EXPERT OPINION: A deliberate shift towards animal-free models is desired to alignwith the 3Rs of animal research. In the short term, the use of NHP models canbe refined and reduced by enhancing replicability and publishingnegative data. Replacement involves a gradual transition, beginning withthe selection and optimization of better small animal models; advancingorganoid systems, and using in silico models to accurately predictimmunological outcomes.

[The current situation of occupational health in the Internet industry and countermeasures].

As an important force in promoting the transformation and upgrading of the national economy, the occupational health of the Internet industry's employees has received widespread attention. This paper examines the current situation of occupational health risks and management in the Internet industry at home and abroad, and on this basis reveals the physical and mental health problems of Internet industry employees. Combining the existing regulations, policies and standard documents at home and abroad, countermeasures are proposed to improve the relevant laws and regulations and their guidelines, implement relevant job design requirements, build a healthy working environment, optimise the work management system and carry out workplace health promotion, in order to provide ideas to accelerate the improvement of occupational health issues in the Internet industry.

Repurposing FDA-approved drugs to treat chemical weapon toxicities: Interactive case studies for trainees.

The risk of a terrorist attack in the United States has created challenges on how to effectively treat toxicities that result from exposure to chemical weapons. To address this concern, the United States has organized a trans-agency initiative across academia, government, and industry to identify drugs to treat tissue injury resulting from exposure to chemical threat agents. We sought to develop and evaluate an interactive educational session that provides hands-on instruction on how to repurpose FDA-approved drugs as therapeutics to treat toxicity from exposure to chemical weapons. As part of the Rutgers Summer Undergraduate Research Fellowship program, 23 undergraduate students participated in a 2-h session that included: (1) an overview of chemical weapon toxicities, (2) a primer on pharmacology principles, and (3) an interactive session where groups of students were provided lists of FDA-approved drugs to evaluate potential mechanisms of action and suitability as countermeasures for four chemical weapon case scenarios. The interactive session culminated in a competition for the best grant "sales pitch." From this interactive training, students improved their understanding of (1) the ability of chemical weapons to cause long-term toxicities, (2) impact of route of administration and exposure scenario on drug efficacy, and (3) re-purposing FDA-approved drugs to treat disease from chemical weapon exposure. These findings demonstrated that an interactive training exercise can provide students with new insights into drug development for chemical threat agent toxicities.

Terrorism as Coalitional Predation: Explaining Definitional Ambiguities and Precautionary Responses.

Terrorism continues to be an enigmatic and contested concept, lacking a universally accepted definition despite extensive scholarly debate. Lay intuitions, however, demonstrate a notable convergence in identifying acts as "terrorism" when specific situational features are present, such as indiscriminate violence and out-group perpetration. These features elicit predictable and robust precautionary responses, raising the question: Is there a unified and parsimonious explanation for these phenomena? It is hypothesized that a situational template exists in the human mind, the coalitional predation template (CPT), which evolved not to detect modern-day terrorism, per se, but to identify and respond to situations of predatory coalitional conflict. The paper examines the potential cues and mechanisms that constitute the psychological systems activated by such threats, suggesting that matching the input cues of the CPT triggers well-documented precautionary responses to terrorism. However, this cue-based system may not align neatly with contemporary threats, leading to disproportionate responses to some threats while underestimating others. The model also posits that interpretations of violence can vary due to incomplete cues and the social position of the evaluator, leading to public disagreements and inconsistencies in defining terrorism. Consequently, arriving at an unambiguous and widely accepted definition of terrorism may not be possible. The model presented may account for a range of phenomena, including the inclination towards attributing mental illness to particular violent incidents and the uncanny surface similarities between terrorism and war crimes. The findings have significant implications for both the theoretical understanding of terrorism and practical policy responses.

Lower body negative pressure as a research tool and countermeasure for the physiological effects of spaceflight: A comprehensive review.

Lower Body Negative Pressure (LBNP) redistributes blood from the upper body to the lower body. LBNP may prove to be a countermeasure for the multifaceted physiological changes endured by astronauts during spaceflight related to cephalad fluid shift. Over more than five decades, beginning with the era of Skylab, advancements in LBNP technology have expanded our understanding of neurological, ophthalmological, cardiovascular, and musculoskeletal adaptations in space, with particular emphasis on mitigating issues such as bone loss. To date however, no comprehensive review has been conducted that chronicles the evolution of this technology or elucidates the broad-spectrum potential of LBNP in managing the diverse physiological challenges encountered in the microgravity environment. Our study takes a chronological perspective, systematically reviewing the historical development and application of LBNP technology in relation to the various pathophysiological impacts of spaceflight. The primary objective is to illustrate how this technology, as it has evolved, offers an increasingly sophisticated lens through which to interpret the systemic effects of space travel on human physiology. We contend that the insights gained from LBNP studies can significantly aid in formulating targeted and effective countermeasures to ensure the health and safety of astronauts. Ultimately, this paper aspires to promote a more cohesive understanding of the broad applicability of LBNP as a countermeasure against multiple bodily effects of space travel, thereby contributing to a safer and more scientifically informed approach to human space exploration.

Developing improved crash prevention approaches through in-depth investigation of motorcycle crash causation patterns.

Despite advancements in road safety, Powered Two-Wheelers (PTWs) remain a vulnerable group with disproportionately high crash rates. This paper presents an in-depth analysis of PTW crashes in six European countries, with a case study of Loss of Control in Curves (LoCC), to address the gap between crash causation and prevention. By examining crash causation factors and their linkage to prevention strategies, the study illustrates various approaches for connecting causes and countermeasures. These approaches, which are applicable to different crash scenarios, include looking forward in the crash causation chains, looking backward, looking at only the last cause (critical events), or the first cause, or following a systemic approach. The research introduces a set of guidelines following the safe system approach, aiming to enhance the understanding of crash prevention among policymakers. The systemic approach to countermeasures, bridges the shortcomings of traditional crash causation studies that may exhibit bias or a narrow focus on "root causes". The proposed approach emphasizes the need for a comprehensive view of crash scenarios (i.e., considering the entire crash causation chain or multiple causation chains) and ensuring that preventive measures address the full spectrum of the system. It also takes in to account external factors such as cost, benefits, and politics, leading to improved road safety outcomes. The study findings are significant for researchers, since it is a step forward in in-depth crash causation studies, as well as road practitioners and policymakers, in providing a strategic framework for more effective and efficient road safety interventions.

How Global Collaboration Can Improve the Medical Countermeasure Life Cycle for Infectious Disease Outbreaks.

Infectious disease outbreaks have become increasingly common and require global partnership for adequate preparedness and response. During outbreaks, medical countermeasures (MCMs)-vaccines, therapeutics, and diagnostics-need to reach patients quickly. Recent outbreaks exemplify that products with regulatory approval can expand access and reach patients quicker than investigational products. Unfortunately, insufficient funding globally and differences in funders' prioritization puts gains and future efforts at risk. Of primary concern is (1) lack of a feasible regulatory path and clinical capability to achieve regulatory approval for new MCMs for many diseases; and (2) the need for partners with the mandate, funding, and capabilities to support long-term sustainment of manufacturing capability and stockpiling of licensed products. Without collaboration, the global community runs the risk of losing the capabilities built through years of investment and being underprepared to combat future threats. Synergies between funders are critical to create long-term sustainment of products to ensure access.

Multi-level decisions for addressing trade-off in the cross-regional water-environment-agriculture interactive system under constraint of water ecological carrying capacity.

The complex-enhanced hierarchical relationship among multiple stakeholders in the water-environment-agriculture interactive system has been overlooked. This study develops a leader-follower-enhanced framework (named as FCMLP) that integrates variable-weight combination prediction model, multi-level programming, and fuzzy credibility constrained programming, which can effectively address the above problems under uncertainties. Five water ecological carrying capacity (WECC) statuses are treated as a critical constraint into the modeling framework to improve the accuracy of decision-making. An interactive fuzzy satisfaction algorithm is advanced for solving this multi-level problem, in which COD discharge minimization, economic benefits maximization, and grain yield maximization are taken as the upper-, middle-, and lower-level goals, respectively. The framework is applied to plan the cross-regional water-environment-agriculture interactive system in the Beijing-Tianjin-Hebei and Yangtze River Economic Belt. Solutions reveal that increased WECC status and credibility level would decrease 1.40%-1.74%, 0.71%-9.61%, and 1.63%-2.26% of water resources allocation, COD emissions, and economic benefits, respectively. Crop area and grain yield would dramatically decline by 4.13%-4.46% and 4.03%-4.67% when a credibility level increases from 0.8 to 1, respectively. The overall satisfactory degree would range from 0.58 to 0.70, which illustrates interactive decision-making process of multiple stakeholders. Significant differences can be observed in the optimized schemes of water resources allocation and environmental-economic-agricultural performances among various models. The amounts of allocated water resources, pollutant discharge, and economic output from the FCMLP model would be respectively 11.30%-13.45%, 14.90%-15.21%, and 73.12%-73.48% higher than those from the environment- and agriculture-oriented schemes, yet 13.81%, 32.05%, and 15.29% lower than those from the economy-oriented scheme. Some water adaptability countermeasures are given for ensuring the scientific operation of the South-to-North Water Transfer Project and alleviating conflicts between water source and receiving areas. Further exploration of the optimization scheme of water-environment-energy-agriculture system driven by climate change is still required for guaranteeing the dynamic balance of regional resources.

The disaster liaison for pediatric and perinatal medicine: A new system in Japan.

BACKGROUND: Worldwide, children, newborns, and pregnant or postpartum women are vulnerable to disasters and emergency situations, and providing support to this population is of great concern. Japan is located in a disaster-prone area, so disaster response and risk reduction strategies are important priorities. METHODS: We introduce a system called the Disaster Liaison for Pediatric and Perinatal Medicine (DLPPM). This was created with a specific focus on perinatal children and pregnant women in Japan. We report the details of its activities, discuss its challenges, and draw on lessons learned for the further development of perinatal support systems, particularly for children. RESULTS: The lessons learned from the activities of the DLPPM include the following: (1) establish a support system for emergency specialists beyond those with pediatric and perinatal specialties; (2) mitigate the risk of indirect damage caused by primary disasters; and (3) establish a networking function linked to existing pediatric and perinatal medicine facilities. CONCLUSIONS: By establishing similar systems, we believe that it will be feasible to address pediatric and perinatal care needs in disaster response contexts in other countries and regions around the world.

Effects of radiation mitigating amino acid mixture on mice of different sexes.

To date, few FDA-approved medical countermeasures are available for addressing hematopoietic acute radiation syndrome (H-ARS). In this study, we present our latest research findings focusing on the evaluation of a novel radiation mitigator known as the mitigating amino acid mixture (MAAM). MAAM is composed of five amino acids as the recently reported amino acid-based oral rehydration solution for mitigating gastrointestinal (GI)-ARS. CD2F1 male and female mice were exposed to 60Co-γ total body irradiation (TBI) at 9.0 or 9.5 Gy. Following irradiation, mice were orally administered with MAAM or a saline vehicle control once daily for a duration of 14 days, commencing 24 h after TBI. Mouse survival and body weight change were monitored for 30 days after irradiation. Complete blood counts (CBCs), bone marrow (BM) stem and progenitor cell survival (clonogenicity), and a serum cytokine antibody array were analyzed using samples from day 30 surviving mice. Our data revealed that MAAM treatment significantly enhanced survival rates in irradiated male CD2F1 mice, and the survival rate increased from 25% in the vehicle control group to 60% in the MAAM-treated group (p < 0.05) after 9.0 Gy TBI. The number of BM colonies significantly increased from 41.8 ± 6.4 /104 cells (in the vehicle group) to 78.5 ± 17.0 /104 cells (in the MAAM group) following 9.0 Gy TBI. Furthermore, MAAM treatment led to a decrease in the levels of six cytokines/proteins [cluster of differentiation 40 (CD40), interleukin (IL)-17A, C-X-C motif chemokine 10 (CXCL10/CRG-2), cutaneous T cell-attracting chemokine (CTACK), macrophage inflammatory protein (MIP)-3ß, and IL-1ß] and an increase in the levels of five other cytokines/proteins [IL-3Rß, IL-5, leptin, IL-6, and stem cell factor (SCF)] in mouse serum compared to the vehicle group after 9.0 Gy TBI. However, similar alleviating effects of MAAM were not observed in the irradiated CD2F1 female mice. The serum cytokine profile in the irradiated female mice was different compared to the irradiated male mice. In summary, our data suggest that the beneficial effects of the mitigative amino acid combination treatment after radiation exposure may depend on sex.

Statin-Associated Liver Dysfunction and Muscle Injury: epidemiology, Mechanisms, and Management Strategies.

Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.

Therapeutics Pipeline.

Children have unique physiologic, developmental, and psychosocial needs and unique vulnerabilities, making them a challenging population for which to develop therapeutics. This is particularly apparent in the urgent and chaotic environment of a pandemic or outbreak. Advances in the development of medical countermeasures (MCMs) for pediatric populations have grown substantially over the last decade, and the coronavirus disease 2019 pandemic forced advancements in how we approach pediatric MCM development. Consequently, a MCMs pipeline targeting the pediatric population is essential. This article addresses the challenges inherent in these differences that must be taken into account.

Evaluation methods of BDS-3 ground-segment defensive capability oriented to satellite navigation countermeasures.

Owing to intentional interference and destructions during satellite navigation countermeasures, the security application of global navigation satellite systems (GNSS) faces immense challenges. To ensure the safe application of the GNSS in complex electromagnetic environment, the system-level defensive capability need be assessed, which can make for maintaining GNSS normal service during countering and further realizing the optimal decision. Therefore, this study used the ground control segment in the GNSS as the evaluation object, the bottom indices related to the criterion layers including service performance and station function as the key evaluation indices, and the technical requirement of each index under a secure situation as the standard, to propose the evaluation system including index system and evaluation methods for the ground-segment defensive capability. As BeiDou navigation satellite system III (BDS-3) is a global navigation satellite system independently built and operated by China, it was taken as a case for method verification. Then, BDS-3 two-way observation data between the satellite and the ground and between stations, which was collected from Beijing flight Control Center, from March 5 to 12 (2022) were selected during tests, and the results were compared with the existing standards contained in BDS open service performance standard to evaluate the system-level defensive capability. Evaluation Results of positioning accuracy and error correction ability for the BDS-3's ground stations determined through seven damage experiments with different interference strength show that: Corresponding horizontal and vertical positioning accuracy of stations under test did not exceed 1 m in the statistical period and their convergence time did not exceed the limit (30 min); thus, the ground segment of the BDS-3 has a good defensive capability. Compared to comprehensive evaluation results of the BDS-3, based on the theoretical threshold (the ground-segment threshold ≤48.40 % and the space-segment threshold ≤51.60 %), we know that its ground-segment defense (14.06 %) was worse than GPS ground-segment defense (14.43 %), whereas the ground-segment defense of the BDS/GPS integrated system (15.29 %) was best and its capability evaluation grade was strong. They indicate system's future improvements should focus more on enhancing the development scale and service efficiency of the BDS-3's ground stations in the Western Hemisphere, and reasonably promote system compatibility and interoperability while considering facility cost and operating efficiency.

Underreporting or Failed Notification? Global Botulism Reporting, 2000-2022.

Botulism is a rare, potentially fatal illness caused by botulinum toxins produced by Clostridium bacteria. There are no coordinated worldwide reporting mechanisms for botulism cases and therefore few reliable case frequency estimates. This study aimed to establish an international benchmark for case frequency to determine estimated global rates of underreporting of botulism cases. To this end, a comprehensive, multilingual search of major global and national databases, including gray data and government sources, was performed. Data from case series were pooled, standardized against United Nations midyear population estimates, and analyzed using Kolmogorov-Smirnov tests to identify normally distributed data series. National incidence rates of normally distributed series were compared with that of the United States, which was considered the gold standard due to its extensive data reported for 2004-2018. A total of 6,932 botulism cases from 59 nations were identified in the literature, with a global case fatality rate of 1.37%. The national mean incidence rate ranged from 0.00 to 8.04 cases per million people, with an international mean incidence rate of 0.62 cases per million people. At the continent level, incidence rates tended toward normal distributions, although few countries outside of North America and Europe exhibited normal distributions. Based on comparisons with the US standard, an estimated 88.71% of botulism cases worldwide were unreported in 2016. Better awareness of botulism among healthcare professionals, coordinated global reporting mechanisms, and research on additional contributing factors to underreporting would enable better understanding of global case frequency, thereby potentially reducing the global incidence of botulism and improving outcomes.

Pandemic preparedness and response: a new mechanism for expanding access to essential countermeasures.

As the world comes together through the WHO design and consultation process on a new medical counter-measures platform, we propose an enhanced APT-A (Access to Pandemic Tools Accelerator) that builds on the previous architecture but includes two new pillars - one for economic assistance and another to combat structural inequalities for future pandemic preparedness and response. As part of the APT-A, and in light of the Independent Panel on Pandemic Preparation & Response's call for an enhanced end-to-end platform for access to essential health technologies, we propose a new mechanism that we call the Pandemic Open Technology Access Accelerator (POTAX) that can be implemented through the medical countermeasures platform and the pandemic accord currently under negotiation through the World Health Assembly and supported by the High-Level Meeting review on Pandemic Prevention, Preparedness, and Response at the United Nations. This mechanism will provide (1) conditional financing for new vaccines and other essential health technologies requiring companies to vest licenses in POTAX and pool intellectual property and other data necessary to allow equitable access to the resulting technologies. It will also (2) support collective procurement as well as measures to ensure equitable distribution and uptake of these technologies.

Effects of dynamic visual feedback system on seasickness.

Motion sickness (MS) poses challenges for individuals affected, hindering their activities and travel. This study investigates the effect of a visual dynamic device, forming an artificial horizon plane, on symptoms and physiological changes induced by MS. This device consists of vertical light-emitting diodes whose illumination varies according to the boat's movements. Fifteen subjects with moderate-to-severe MS susceptibility were exposed to a seasickness simulator with and without the device. Symptoms were assessed immediately after exposure. Time spent in the simulator, heart rate, and temperature were also recorded. Symptom intensity at the end of the experience did not differ, but the time spent in the simulator was significantly longer with the device (+46%). Variations in heart rate were also observed. The device delays symptom onset and can be used as a tool against MS. Further research is needed to evaluate its effects, for example, during more prolonged exposure to MS-inducing stimuli.

Oxidative Stress: An Intersection Between Radiation and Sulfur Mustard Lung Injury.

Nuclear and chemical weapons of mass destruction share both a tragic and beneficial legacy in mankind's history and health. The horrific health effects of ionizing radiation and mustard gas exposures unleashed during disasters, wars, and conflicts have been harnessed to treat human health maladies. Both agents of destruction have been transformed into therapies to treat a wide range of cancers. The discovery of therapeutic uses of radiation and sulfur mustard was largely due to observations by clinicians treating victims of radiation and sulfur mustard gas exposures. Clinicians identified vulnerability of leukocytes to these agents and repurposed their use in the treatment of leukemias and lymphomas. Given the overlap in therapeutic modalities, it goes to reason that there may be common mechanisms to target as protective strategies against their damaging effects. This commentary will highlight oxidative stress as a common mechanism shared by both radiation and sulfur mustard gas exposures and discuss potential therapies targeting oxidative stress as medical countermeasures against the devastating lung diseases wrought by these agents.

Risk-based public health impact assessment for drinking water contamination emergencies.

Chemical spills in surface waters pose a significant threat to public health and the environment. This study investigates the public health impacts associated with organic chemical spill emergencies and explores timely countermeasures deployable by drinking water facilities. Using a dynamic model of a typical multi-sourced New England drinking water treatment facility and its distribution network, this study assesses the impacts of various countermeasure deployment scenarios, including source switching, enhanced coagulation via poly­aluminum chloride (PACl), addition of powdered activated carbon (PAC), and temporary system shutdown. This study reveals that the deployment of multiple countermeasures yields the most significant reduction in total public health impacts, regardless of the demand and supply availability. With the combination PAC deployed first with other countermeasures proving to be the most effective strategies, followed by the combination of facility shutdowns. By understanding the potential public health impacts and evaluating the effectiveness of countermeasures, authorities can develop proactive plans, secure additional funding, and enhance their capacity to mitigate the consequences of such events. These insights contribute to safeguarding public health and improving the resilience of drinking water systems in the face of the ever-growing threat of chemical spills.

Pediatric Medical Countermeasures: Antidotes and Cytokines for Radiological and Nuclear Incidents and Terrorism.

The war in Ukraine raises concerns for potential hazards of radiological and nuclear incidents. Children are particularly vulnerable in these incidents and may need pharmaceutical countermeasures, including antidotes and cytokines. Searches found no published study comparing pediatric indications and dosing among standard references detailing pediatric medications for these incidents. This study addresses this gap by collecting, tabulating, and disseminating this information to healthcare professionals caring for children. Expert consensus chose the following references to compare their pediatric indications and dosing of medical countermeasures for radiation exposure and internal contamination with radioactive materials: Advanced Hazmat Life Support (AHLS) for Radiological Incidents and Terrorism, DailyMed, Internal Contamination Clinical Reference, Medical Aspects of Radiation Incidents, and Medical Management of Radiological Casualties, as well as Micromedex, POISINDEX, and Radiation Emergency Medical Management (REMM). This is the first study comparing pediatric indications and dosing for medical countermeasures among commonly used references for radiological and nuclear incidents.

Crimean-Congo Hemorrhagic Fever Virus for Clinicians-Diagnosis, Clinical Management, and Therapeutics.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread tickborne viral infection worldwide and has a fatality rate of up to 62%. Despite its widespread range and high fatality rate, no vaccines or treatments are currently approved by regulatory agencies in the United States or Europe. Supportive treatment remains the standard of care, but the use of antiviral medications developed for other viral infections have been considered. We reviewed published literature to summarize the main aspects of CCHFV infection in humans. We provide an overview of diagnostic testing and management and medical countermeasures, including investigational vaccines and limited therapeutics. CCHFV continues to pose a public health threat because of its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, potential for severe and fatal illness, and limited medical countermeasures for prophylaxis and treatment. Clinicians should become familiar with available diagnostic and management tools for CCHFV infections in humans.