Use Of Medical Countermeasures Research Articles

Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures.

There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.

Breakthrough SARS-CoV-2 infections among recipients of tixagevimab-cilgavimab prophylaxis: A citywide real-world effectiveness study.

There are limited real-world data on the effectiveness of tixagevimab-cilgavimab as pre-exposure prophylaxis of COVID-19. We describe lessons learned when coordinating data collection and identifying breakthrough SARS-CoV-2 infections among patients across indications and institutions in a major US city. The Chicago Department of Public Health requested patient-level tixagevimab-cilgavimab administration data from all prescribing providers in Chicago, for treatments December 8, 2021 through June 30, 2022. Records were matched to COVID-19 vaccinations and laboratory-confirmed SARS-CoV-2 infections through December 31, 2022. Due to difficulty collecting data from all providers, targeted follow-up was conducted to improve completeness on key variables (demographics, vaccination status, clinical indication for prophylaxis). Over half of reported tixagevimab-cilgavimab administrations were to patients residing outside Chicago. Five hundred forty-four Chicago residents who received at least one dose of tixagevimab-cilgavimab were included in this analysis. Most were age 50 years or older (72%), Black non-Latinx (33%) or White non-Latinx (29%), and fully vaccinated (80%). Seventy-five patients (14%) had laboratory-confirmed COVID-19. Patients with and without breakthrough infections were demographically similar. Clinical indication was missing for >95% of cases, improved to 64% after follow-up; the most frequently specified was hematologic malignancy (10%). Severe outcomes were uncommon: 16% had documented COVID-19-related hospitalizations, one death was identified. Tixagevimab-cilgavimab recipients in Chicago had a lower rate of severe SARS-CoV-2 infection than reported among other untreated high-risk patients, including during predominance of non-neutralizing variants. Improving stakeholder collaboration is essential for generation of real-world effectiveness data, informing pandemic preparedness and optimizing use of medical countermeasures.

Overview of Medical Countermeasures (MCM) for the Treatment of Monkeypox in United States (US) Children During the 2022 Multinational Monkeypox Response

Introduction:During the 2022 Multinational Monkeypox Response, cases of Monkeypox illness reported in children and adolescents in the US were rare. Early in the response, little was known about MCM safety and efficacy for treating monkeypox in children and adolescents. As cases in children and adolescents increased, knowledge about safety and efficacy evolved.Method:Cases of monkeypox in children <18 years of age across the US were reported to CDC. MCM consultations from clinical and regulatory affairs subject matter experts supported clinician administration and management of antiviral and immunoglobulin treatment. Data from the first pediatric cases were collected to help answer some of these questions on the use of MCM in pediatric populations.Results:Across the US, 116 cases of monkeypox in children <18 years of age have been verified through October 2022. Of these cases, 41 occurred in patients twelve years of age or less, with 75 cases in adolescents 13-17 years of age. Ten percent of patients were hospitalized, none required ICU care and no deaths occurred. Children were most commonly hospitalized due to young age, rash near or including the eye, secondary bacterial infections, or pain management. At least eleven patients with confirmed orthopoxvirus were treated with tecovirimat and two with Vaccinia Immune Globulin. Those who received MCM recovered and tolerated treatments well with one patient stopping treatment secondary to development of a drug rash.Conclusion:Data on the safety and efficacy of MCM for monkeypox are limited in pediatric populations. As of November 3, 2022, most cases of monkeypox in the pediatric population in the 2022 monkeypox outbreak were mild and self-limited. Patients who received MCM recovered and tolerated treatments without serious adverse events. These findings can inform clinicians and public health providers about the clinical features of monkeypox in children and provide information about MCM treatment options.

Interim Clinical Treatment Considerations for Severe Manifestations of Mpox - United States, February 2023.

Monkeypox (mpox) is a disease caused by infection with Monkeypox virus (MPXV), an Orthopoxvirus (OPXV) in the same genus as Variola virus, which causes smallpox. During 2022, a global outbreak involving mpox clade IIb was recognized, primarily among gay, bisexual, and other men who have sex with men.* Most affected patients have been immunocompetent and experienced ≤10 rash lesions (1). CDC has recommended supportive care including pain control.† However, some patients have experienced severe mpox manifestations, including ocular lesions, neurologic complications, myopericarditis, complications associated with mucosal (oral, rectal, genital, and urethral) lesions, and uncontrolled viral spread due to moderate or severe immunocompromise, particularly advanced HIV infection (2). Therapeutic medical countermeasures (MCMs) are Food and Drug Administration (FDA)-regulated drugs and biologics that are predominantly stockpiled by the U.S. government; MCMs developed for smallpox preparedness or shown to be effective against other OPXVs (i.e., tecovirimat, brincidofovir, cidofovir, trifluridine ophthalmic solution, and vaccinia immune globulin intravenous [VIGIV]) have been used to treat severe mpox. During May 2022-January 2023, CDC provided more than 250 U.S. mpox consultations. This report synthesizes data from animal models, MCM use for human cases of related OPXV, unpublished data, input from clinician experts, and experience during consultations (including follow-up) to provide interim clinical treatment considerations. Randomized controlled trials and other carefully controlled research studies are needed to evaluate the effectiveness of MCMs for treating human mpox. Until data gaps are filled, the information presented in this report represents the best available information concerning the effective use of MCMs and should be used to guide decisions about MCM use for mpox patients.

Monkeypox: An Emerging Global Public Health Emergency.

The virus causing monkeypox, a rare zoonotic viral disease, belongs to the Poxviridae family and the Orthopoxvirus genus. On 23 July 2022, the World Health Organization (WHO) declared the monkeypox outbreak as a Public Health Emergency of International Concern (PHEIC). From May to July 2022, a multi-country outbreak of monkeypox was reported in both endemic and non-endemic regions. Major goals of managing monkeypox are to identify the suspected cases, detect generic orthopoxvirus DNA at a state or commercial laboratory, and establish the Centers for Disease Control and Prevention real-time polymerase chain reaction testing. Currently, there are no approved treatments for monkeypox virus infection. However, a variety of antiviral medications originally designed for the treatment of smallpox and other viral infections could be considered. Pre-exposure prophylaxis for laboratory and health care employees and post-exposure prophylaxis for individuals with high-risk or intermediate-risk exposures are to be considered. The CDC Emergency Operations Center is available for advice on the appropriate use of medical countermeasures, and can help in obtaining antiviral drugs and vaccines from the National Strategic Stockpile. This review gives an overview of the global scenario, clinical presentation, and management of monkeypox in the light of a global public health emergency.

Medical Countermeasures for Children in Radiation and Nuclear Disasters: Current Capabilities and Key Gaps.

Despite children's unique vulnerability, clinical guidance and resources are lacking around the use of radiation medical countermeasures (MCMs) available commercially and in the Strategic National Stockpile to support immediate dispensing to pediatric populations. To better understand the current capabilities and shortfalls, a literature review and gap analysis were performed. A comprehensive review of the medical literature, Food and Drug Administration (FDA)-approved labeling, FDA summary reviews, medical references, and educational resources related to pediatric radiation MCMs was performed from May 2016 to February 2017. Fifteen gaps related to the use of radiation MCMs in children were identified. The need to address these gaps was prioritized based upon the potential to decrease morbidity and mortality, improve clinical management, strengthen caregiver education, and increase the relevant evidence base. Key gaps exist in information to support the safe and successful use of MCMs in children during radiation emergencies; failure to address these gaps could have negative consequences for families and communities. There is a clear need for pediatric-specific guidance to ensure clinicians can appropriately identify, triage, and treat children who have been exposed to radiation, and for resources to ensure accurate communication about the safety and utility of radiation MCMs for children. (Disaster Med Public Health Preparedness. 2019;13:639-646).

Use of Medical Countermeasures in Small-Scale Emergency Responses.

It is well documented that long-standing focus on public health emergency preparedness medical countermeasures (MCMs) distribution and mass dispensing capabilities for mitigation of bioterrorism incidents and a lack of real-world opportunities to test national preparedness for large-scale emergencies has hindered development of a body of evidence-based practices in the United States. To encourage jurisdictions seeking innovative opportunities for continuous improvement, we describe instances when the MCM capabilities were used to address smaller-scale, more-frequent public health emergencies such as disease outbreaks, natural disasters, or routine influenza vaccination. We argue that small-scale events represent a critical opportunity that state, local, tribal, and territorial entities can utilize for greater gains in MCM operational readiness than through exercises or planned reviews. By using and evaluating MCM capabilities during a real response, jurisdictions can advance preparedness science and support the translation of research into practice, thereby increasing their capacity to scale up for larger, rarer, higher-consequence emergencies.

Radiation-Induced Long Noncoding RNAs in a Mouse Model after Whole-Body Irradiation.

Long noncoding RNAs (lncRNAs) are emerging as key molecules in regulating many biological processes and have been implicated in development and disease pathogenesis. Biomarkers of cancer and normal tissue response to treatment are of great interest in precision medicine, as well as in public health and medical management, such as for assessment of radiation injury after an accidental or intentional exposure. Circulating and functional RNAs, including microRNAs (miRNAs) and lncRNAs, in whole blood and other body fluids are potential valuable candidates as biomarkers. Early prediction of possible acute, intermediate and delayed effects of radiation exposure enables timely therapeutic interventions. To address whether long noncoding RNAs (lncRNAs) could serve as biomarkers for radiation biodosimetry we performed whole genome transcriptome analysis in a mouse model after whole-body irradiation. Differential lncRNA expression patterns were evaluated at 16, 24 and 48 h postirradiation in total RNA isolated from whole blood of mice exposed to 1, 2, 4, 8 and 12 Gy of X rays. Sham-irradiated animals served as controls. Significant alterations in the expression patterns of lncRNAs were observed after different radiation doses at the various time points. We identified several radiation-induced lncRNAs known for DNA damage response as well as immune response. Long noncoding RNA targets of tumor protein 53 (P53), Trp53cor1, Dino, Pvt1 and Tug1 and an upstream regulator of p53, Meg3, were altered in response to radiation. Gm14005 ( Morrbid) and Tmevpg1 were regulated by radiation across all time points and doses. These two lncRNAs have important potential as blood-based radiation biomarkers; Gm14005 ( Morrbid) has recently been shown to play a key role in inflammatory response, while Tmevpg1 has been implicated in the regulation of interferon gamma. Precise molecular biomarkers, likely involving a diverse group of inducible molecules, will not only enable the development and effective use of medical countermeasures but may also be used to detect and circumvent or mitigate normal tissue injury in cancer radiotherapy.

Rapid and High-Throughput Detection and Quantitation of Radiation Biomarkers in Human and Nonhuman Primates by Differential Mobility Spectrometry-Mass Spectrometry.

Radiation exposure is an important public health issue due to a range of accidental and intentional threats. Prompt and effective large-scale screening and appropriate use of medical countermeasures (MCM) to mitigate radiation injury requires rapid methods for determining the radiation dose. In a number of studies, metabolomics has identified small-molecule biomarkers responding to the radiation dose. Differential mobility spectrometry-mass spectrometry (DMS-MS) has been used for similar compounds for high-throughput small-molecule detection and quantitation. In this study, we show that DMS-MS can detect and quantify two radiation biomarkers, trimethyl-L-lysine (TML) and hypoxanthine. Hypoxanthine is a human and nonhuman primate (NHP) radiation biomarker and metabolic intermediate, whereas TML is a radiation biomarker in humans but not in NHP, which is involved in carnitine synthesis. They have been analyzed by DMS-MS from urine samples after a simple strong cation exchange-solid phase extraction (SCX-SPE). The dramatic suppression of background and chemical noise provided by DMS-MS results in an approximately 10-fold reduction in time, including sample pretreatment time, compared with liquid chromatography-mass spectrometry (LC-MS). DMS-MS quantitation accuracy has been verified by validation testing for each biomarker. Human samples are not yet available, but for hypoxanthine, selected NHP urine samples (pre- and 7-d-post 10Gy exposure) were analyzed, resulting in a mean change in concentration essentially identical to that obtained by LC-MS (fold-change 2.76 versus 2.59). These results confirm the potential of DMS-MS for field or clinical first-level rapid screening for radiation exposure. Graphical Abstract ᅟ.

Medical Countermeasures for Children in Public Health Emergencies, Disasters, or Terrorism

Significant strides have been made over the past 10 to 15 years to develop medical countermeasures (MCMs) to address potential disaster hazards, including chemical, biological, radiologic, and nuclear threats. Significant and effective collaboration between the pediatric health community, including the American Academy of Pediatrics, and federal partners, such as the Office of the Assistant Secretary for Preparedness and Response, Centers for Disease Control and Prevention, Federal Emergency Management Agency, National Institutes of Health, Food and Drug Administration, and other federal agencies, over the past 5 years has resulted in substantial gains in addressing the needs of children related to disaster preparedness in general and MCMs in particular. Yet, major gaps still remain related to MCMs for children, a population highly vulnerable to the effects of exposure to such threats, because many vaccines and pharmaceuticals approved for use by adults as MCMs do not yet have pediatric formulations, dosing information, or safety information. As a result, the nation's stockpiles and other caches (designated supply of MCMs) where pharmacotherapeutic and other MCMs are stored are less prepared to address the needs of children compared with those of adults in the event of a disaster. This policy statement provides recommendations to close the remaining gaps for the development and use of MCMs in children during public health emergencies or disasters. The progress made by federal agencies to date to address the needs of children and the shared commitment of collaboration that characterizes the current relationship between the pediatric health community and the federal agencies responsible for MCMs should encourage all child advocates to invest the necessary energy and resources now to complete the process of remedying the remaining significant gaps in preparedness.

Caring for Children After a Radiological Disaster

Children require specialized treatment that differs from adults in nearly every field of medicine, particularly as it relates to emergency response to a large-scale radiation event. Infancy, childhood, and adolescence are distinct stages of growth and development that pose unique vulnerabilities, biological variations, physiological differences, and developmental needs. Screening, decontamination, treatment strategies, and the use of medical countermeasures must occur with respect for these differences. Responding to radiation disasters that impact children requires rapid evaluation and response by health care providers who are equipped with the knowledge, skills, and abilities to appropriately address the physical, emotional, and mental health needs of children.

Regulatory underpinnings of Global Health security: FDA's roles in preventing, detecting, and responding to global health threats.

In February 2014, health officials from around the world announced the Global Health Security Agenda, a critical effort to strengthen national and global systems to prevent, detect, and respond to infectious disease threats and to foster stronger collaboration across borders. With its increasing global roles and broad range of regulatory responsibilities in ensuring the availability, safety, and security of medical and food products, the US Food and Drug Administration (FDA) is engaged in a range of efforts in support of global health security. This article provides an overview of FDA's global health security roles, focusing on its responsibilities related to the development and use of medical countermeasures (MCMs) for preventing, detecting, and responding to global infectious disease and other public health emergency threats. The article also discusses several areas-antimicrobial resistance, food safety, and supply chain integrity-in which FDA's global health security roles continue to evolve and extend beyond MCMs and, in some cases, beyond traditional infectious disease threats.

RAPID RADIATION DOSE ASSESSMENT FOR RADIOLOGICAL PUBLIC HEALTH EMERGENCIES: ROLES OF NIAID and BARDA

A large-scale radiological incident would result in an immediate critical need to assess the radiation doses received by thousands of individuals to allow for prompt triage and appropriate medical treatment. Measuring absorbed doses of ionizing radiation will require a system architecture or a system of platforms that contains diverse, integrated diagnostic and dosimetric tools that are accurate and precise. For large-scale incidents, rapidity and ease of screening are essential. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health is the focal point within the Department of Health and Human Services (HHS) for basic research and development of medical countermeasures for radiation injuries. The Biomedical Advanced Research and Development Authority within the HHS Office of the Assistant Secretary for Preparedness and Response coordinates and administers programs for the advanced development and acquisition of emergency medical countermeasures for the Strategic National Stockpile. Using a combination of funding mechanisms, including funds authorized by the Project BioShield Act of 2004 and those authorized by the Pandemic and All-Hazards Preparedness Act of 2006, HHS is enhancing the nation's preparedness by supporting the radiation dose assessment capabilities that will ensure effective and appropriate use of medical countermeasures in the aftermath of a radiological or nuclear incident.

An Observational Study on Diagnoses of 3,233 Gulf Veterans (Op Granby 1990-91) who attended the Ministry of Defence’s Medical Assessment Programme 1993-2004

This is the result of an observational study on 3,233 Gulf veterans who have attended our medical assessment programme. We wanted to determine as a result of in-depth interviews, full medical examination and appropriate investigations, whether there was any unique Gulf war related medical condition. Over a period of 10 years, 3,233 veterans have been assessed. All diagnoses have been made according to ICD-10 classifications. All psychiatric diagnoses have been confirmed by consultant psychiatrists. 75% of veterans were well. Of the 25% unwell, 83% of ill health was accounted for by a psychiatric disorder. 3% of veterans had organic conditions which could be linked to Gulf deployment. The most common of these were respiratory disorders, followed by digestive disorders, injuries and skin disorders. Only 11 of these cases could be linked to the use of medical countermeasures. A further, 51 cases (41 respiratory disorders, 6 infections, 2 skin disorders and 2 eye conditions) could be linked to environmental conditions. All veterans seen with health problems could be identified as per ICD-10 classification of disease. We did not find any medically unexplained conditions. We found no evidence of a unique 'Gulf War Syndrome'.

Medico-legal Issues Surrounding Medical Countermeasures Used in the Gulf War - Part 2

When the multinational force deployed to the Gulf after Iraq’s invasion of Kuwait in 1990, military intelligence assessed the Iraqis as possessing and being capable of using weapons of mass...

Medico-Legal Issues Surrounding Medical Countermeasures Used in The Gulf War - Part 1

When the multinational force deployed to the Gulf after Iraq's invasion of Kuwait in 1990, military intelligence assessed the Iraqi's as possessing and being capable of using weapons of mass...