Congressionally Directed Medical Research Programs

The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI.

In addition to its well described function as an enzymatic inhibitor of specific caspases, X-linked inhibitor of apoptosis (X-linked IAP or XIAP) can function as a cofactor in Smad, NF-kappaB, and JNK signaling pathways. However, caspases themselves have been shown to regulate the activity of a number of signaling cascades, raising the possibility that the effect of XIAP in these pathways is indirect. Here we examine this question by introducing point mutations in XIAP predicted to disrupt the ability of the molecule to bind to and inhibit caspases. We show that whereas these mutant variants of XIAP lost caspase-inhibitory activity, they maintained their ability to activate Smad, NF-kappaB, and JNK signaling pathways. Indeed, the signaling properties of the molecule were mapped to domains not directly involved in caspase binding and inhibition. The activation of NF-kappaB by XIAP was dependent on the E3 ubiquitin ligase activity of the RING domain. On the other hand, the ability of XIAP to activate Smad-dependent signaling was mapped to the third baculoviral IAP repeat (BIR) and loop regions of the molecule. Thus, the anti-apoptotic and signaling properties of XIAP can be uncoupled.

The early transfusion of plasma is important to ensure optimal survival of patients with traumatic hemorrhage. In military and remote or austere civilian settings, it may be impossible to move patients to hospital facilities within the first few hours of injury. A dried plasma product with reduced logistical requirements is needed to enable plasma transfusion where medically needed, instead of only where freezers and other equipment are available. First developed in the 1930s, pooled lyophilized plasma was widely used by British and American forces in WWII and the Korean War. Historical dried plasma products solved the logistical problem but were abandoned because of disease transmission. Modern methods to improve blood safety have made it possible to produce safe and effective dried plasma. Dried plasma products are available in France, Germany, South Africa, and a limited number of other countries. However, no product is available in the US. Promising products are in development that employ different methods of drying, pathogen reduction, pooling, packaging, and other approaches. Although challenges exist, the in vitro and in vivo data suggest that these products have great potential to be safe and effective. The history, state of the science, and recent developments in dried plasma are reviewed.

The 2014-2015 Ebola epidemic in West Africa has been the deadliest Ebola epidemic to date. In response to this deadly epidemic, the U.S. government declared this a top national security priority and members of the Commissioned Corps of the United States Public Health Service were tasked to provide direct patient care to Ebola virus disease patients. Commissioned Corps nurses provided the highest level of care under the most austere conditions. This article discusses the training, ethical dilemmas, and constant risk for potential exposure while working in an Ebola Treatment Unit.

As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.

INTRODUCTION: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post-traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans. METHODS: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. RESULTS: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia. DISCUSSION: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.

BACKGROUND: This study assessed participant opinions about inclusion of breast cancer survivors as lay representatives in a scientific and technical merit review of proposals for the 1995 Department of Defense Breast Cancer Research Program (DOD BCRP). METHODS: The evaluation employed a prepanel and postpanel survey design, which was intended to elicit feedback about attitudes, perceptions, and beliefs toward collaborative consumer and scientist participation in scientific merit review. Qualitative methods were used to describe the consumers' and scientists' responses, to explore the significance of this interaction, and to gain an understanding of the benefits and disadvantages of bringing these participants together. RESULTS: Both groups were initially troubled about the consumers' lack of scientific background and questioned their qualifications and preparation for participation in a scientific panel. In particular, consumers were concerned that their judgments would not be taken seriously by scientists, a concern somewhat lessened by participation. After the meeting, scientists viewed the consumers as hard-working, dedicated survivors and advocates and endorsed the presence of carefully chosen lay panel members. Scientists were troubled that consumers potentially would have an impact on voting and on the subsequent scoring of proposals, a concern that was not validated by quantitative findings. CONCLUSIONS: As a result of these data, the DOD BCRP continues to embrace clarify the nature of collaborative participation in scientific merit review.

The Drosophila (fs(1)h) gene encodes small (Fs(1)hS) and large (Fs(1)hL) chromatin-binding BET protein transcription factor isoforms. Zygotic mutations cause either lethality or female sterility, whereas maternal mutations cause segmental deletions and thoracic homeotic transformations. Here, we describe novel fs(1)h embryonic phenotypes: homeosis of the head in zygotic mutants and deletion of head and tail regions in maternal mutants, similar to those caused by dominant torso (tor(D)) alleles. tor activates transcription of tailless (tll) and hückebein (hkb) by means of a canonical Ras pathway, through inactivation of Groucho (Gro), Capicua (Cic) and, possibly, Grainy-head (Grh) repressors. Expression of both tailless and hückebein are de-repressed in fs(1)h maternal mutants, as in tor(D), gro, grh, and cic mutant animals, indicating fs(1)h is also necessary for tll and hkb repression. These data link Ras signaling with modulation of a chromatin-binding transcription factor, Fs(1)h, suggesting a novel mechanism by which Ras can modulate gene expression.

BACKGROUND: The ongoing controversy whether mild traumatic brain injury (TBI) can cause chronic sequel is partly due to diagnostic limitations. Diagnosing mild TBI is particularly challenging when assessment is not immediate, and when informed, first responder documentation or witness corroboration is absent. In this common scenario, the diagnosis is made entirely on self-report of an initial period of alteration of consciousness (AOC) associated with a plausible injury mechanism. Yet, there is scant published empirical guidance on methods for accurately detecting historical AOC. OBJECTIVES: To assess the value that recalled AOC symptoms collected via questionnaire have in evaluating individuals exposed to blast during recent military deployment. More specifically, to analyze the concrete AOC items (those signifying unconsciousness and/or posttraumatic amnesia) for their (1) frequency and distribution of positive versus negative responses, (2) interitem agreement, and (3) relation to current neuropsychiatric symptoms including those consistent with postconcussion syndrome (PCS). PARTICIPANTS: Eighty-seven active duty or Veteran subjects who experienced acute effects from a blast within the past 2 years while deployed for Operations Enduring and Iraqi Freedom. RESULTS: : Twenty-nine participants (33.3%) responded positively to at least 1 of 3 concrete AOC items: gap in memory (17.2%), memory not continuous (13.8%), and/or told by observer they had loss of consciousness (20.7%). Alteration of consciousness items were associated with but nondiscriminate of current symptom distress on standardized measures of PCS (Rivermead Postconcussion Symptom Questionnaire), posttraumatic stress disorder (PTSD; PTSD Checklist), depression (Centers for Epidemiological Studies Depression Scale), and pain (Short Form McGill Pain Questionnaire). CONCLUSIONS: The positive association between subjects' questionnaire-based AOC item responses and current symptom complex measures suggests that mild TBI has a role in the development of chronic neuropsychiatric symptoms after blast exposure. The lack of symptom- complex discrimination, and the inconsistencies found in subjects' item responses suggest that a structured interview may improve postacute diagnostic specificity for mild TBI.

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aβ) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aβ42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aβ 42 levels and Aβ oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.

Biopsychosocial and environmental factors play a major role in acute clinical presentation, recovery, and outcome of traumatic brain injury (TBI). As part of the 2024 National Institute of Neurological Disorders and Stroke (NINDS) TBI Classification and Nomenclature Initiative, the Psychosocial and Environmental Modifiers (PEM) Working Group was assembled to perform a narrative review and summary of expert opinions regarding how non-TBI factors influence the presenting features and outcomes of TBI and to make recommendations for incorporating these Modifiers into clinical care and research. With input from working group members and other interested parties, we summarize the membership, methods, and outcomes of the PEM Working Group activities. Modifiers were considered with the NINDS Social Determinants of Health Framework in mind and fall under three broad headings: individual-level variables (e.g., demographics, preinjury health, culture), injury-related variables (e.g., cause and context of injury, second insults), and community-/societal-level factors (e.g., family/community support, socioeconomic position, structural racism). Recommendations include steps to increase awareness of Modifiers in health care encounters, identify Modifier-related disparities in TBI-related care and outcomes, better understand the mechanisms by which Modifiers influence TBI-related clinical presentation and outcomes, and intervene to improve the health and well-being of persons exposed to TBI. These recommendations are intended to be a starting point that will evolve as knowledge grows and additional input is incorporated.

Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem-cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community.

INTRODUCTION: There is a need for investment in manufacturing for vaccine microarray patches (vMAPs) to accelerate vMAP development and access. vMAPs could transform vaccines deployment and reach to everyone, everywhere. AREAS COVERED: We outline vMAPs' potential benefits for epidemic preparedness and for outreach in low- and lower-middle-income countries (LMICs), share lessons learned from pandemic response, and highlight that investment in manufacturing-at-risk could accelerate vMAP development. EXPERT OPINION: Pilot manufacturing capabilities are needed to produce clinical trial material and enable emergency response. Funding vMAP manufacturing scale-up in parallel to clinical proof-of-concept studies could accelerate vMAP approval and availability. Incentives could mitigate the risks of establishing multi-vMAP manufacturing facilities early.

The Department of Defense (DOD), Breast Cancer Research Program (BCRP) was established in 1993. Since its inception, Congress has appropriated more than 878 million dollars for the BCRP, a unique public-private partnership between the DOD, consumer advocacy, and scientific communities which has funded approximately 1,800 breast cancer research grants. Through this partnership, the BCRP designed a model program for consumer involvement in scientific peer review. This paper describes the BCRP's approach to the processes of recruitment, selection, and preparation of consumers for this expanded role. Further, factors critical to program implementation, such as effective program management, ongoing process improvement, strong program leadership, and allocation of resources, that led to the BCRP's success in developing the previously undefined role of breast cancer survivors as members of scientific peer review panels are discussed. The BCRP demonstrates the feasibility and unique contributions of consumers in scientific peer review and provides a critical foundation for future efforts to ensure consumer involvement in scientific research programs.

In preparing to support the Army in 2025 and beyond, the Army Blood Program remains actively engaged with the research and advanced development of blood products and medical technology to improve blood safety and efficacy in conjunction with the US Army Medical Research and Materiel Command. National and International Blood Bank authorities have noted that the US Army research and development efforts in providing new blood products and improving blood safety operate on the cutting edge of technology and are transformational for the global blood industry. Over the past 14 years, the Army has transformed how blood support is provided and improved the survival rate of casualties. Almost every product or process developed by or for the military has found an application in treating civilian patients. Conflicts have many unwanted consequences; however, in times of conflict, one positive aspect is the identification of novel solutions to improve the safety and efficacy of the blood supply.

The time from identifying a drug target to a new drug approval is often measured in decades and can take even longer for therapies to treat rare diseases. In fact, 95% of rare diseases do not have a specific therapy approved at all. Coordinated efforts to augment the drug development pipeline along with long-term and comprehensive support that enable scientific breakthroughs for rare diseases are possible, but it requires integration across multiple stakeholders. This article analyzes the coordinated funding efforts of four federal and philanthropic organizations to advance drug development for neurofibromatosis type 1-associated tumors and discusses how these organizations have been collaborating and evolved practices to optimize funding and research support.

Hemorrhage is a leading cause of potentially preventable death in both military and civilian trauma. Current resuscitation approaches minimize crystalloids and emphasize plasma and other blood components to achieve a balanced transfusion as early as possible after injury. Owing to the nature of military operations, military medical systems must contend with great distances, degraded infrastructure, and harsh environments, as well as combat and humanitarian assistance and disaster relief (HADR) scenarios. These factors limit both patient movement and the ability to deliver blood products to the point of need. Current projections are that future military scenarios will have longer times to reach a medical treatment facility than experienced in recent conflicts, increasing the need for logistically efficient blood products. Freeze-dried plasma (FDP) is rapidly available, easy to use, and shelf-stable at room temperature, making it easier to deliver at the point of need in challenging military environments. For the past 30 years, FDP has been available in only a few countries. Where it has been available, it has become the preferred plasma for austere or military expeditionary settings. Recently, a new FDP, OctaplasLG Powder, was approved in 17 countries worldwide and for emergency use by the Canadian and United States militaries. It is expected that FDP will soon become available to many more militaries. This review discusses the importance of plasma, reassesses the potential military uses of FDP across the range of military operations, and provides a brief discussion of OctaplasLG Powder.

Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult Asxl2−/− heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin+ non-cardiomyocytes in Asxl2−/− over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non-cardiomyocytes in the Asxl2−/− heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in Asxl2−/− hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the Asxl2−/− heart due to activation of a population of proliferative cardiogenic non-cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity.

Nearly a billion dollars is spent annually in the Military Health System (MHS) on cancer diagnosis and treatment, with a large portion of that directed toward breast, prostate, and ovarian cancers. Multiple studies have demonstrated the impact of specific cancers on MHS beneficiaries and Veterans, highlighting the fact that active duty and retired military members have a higher incidence than the general public for many chronic diseases and certain forms of cancer. The Congressionally Directed Medical Research Programs have supported research that has contributed to the development, clinical testing, and commercialization of 11 cancer drugs approved by the Food and Drug Administration to treat breast, prostate, or ovarian cancers. In addition to hallmark funding mechanisms that prioritize innovative, groundbreaking ideas, the Congressionally Directed Medical Research Program's cancer programs continue to identify new approaches to fill critical gaps across the full research spectrum, including bridging the translational research gap toward developing new treatments for cancer patients in the MHS and in the general American public.

Abstract The time from target identification to new drug approval is often measured in decades. This can be even more challenging for rare diseases. Indeed, 95% of rare diseases do not have a specific therapy approved. Coordinated efforts to support research along the drug development pipeline can provide long term and comprehensive support to enable scientific breakthroughs for rare diseases. However, this requires coordination across multiple stakeholders. The present article analyzes the funding efforts of four major federal and philanthropic organizations to accelerate the advancement of MEK inhibitors to human clinical trials for NF1-associated tumors.