NIH Grants

NIH

Background: Women Veterans often report little or no exercise after leaving military service. Regular exercise contributes to significant benefits in physical and psychological health, including risk reduction for several chronic conditions, such as diabetes and cardiovascular disease. As such, women Veterans’ diminished exercise contributes to their increased risk for significant health conditions and can have a cumulative negative impact on their long-term health (e.g., obesity, cardiovascular disease, hypertension). Women Veterans lack access to effective approaches for increasing exercise, such as behavioral interventions (e.g., goal setting), that are tailored to their needs and can mitigate significant, preventable health conditions among this Veteran population. Psychological skills training (PST) interventions use evidence-based strategies (goal setting, imagery, self-talk, relaxation) to increase exercise participation and satisfaction. In the proposed project, we will adapt evidence-based strategies used in PST interventions to tailor a novel PST intervention known as STRIVE (Skills Training to Increase Veteran Exercise) to increase exercise adoption and adherence among women Veterans from the post-9/11 era. Significance/Impact: The post-9/11 era is the largest cohort of women Veterans and is rapidly growing. To mitigate the impact of significant, preventable health conditions among women Veterans and the subsequent burden on the VA healthcare system, approaches are needed to meet the distinct needs of this Veteran population. This proposal addresses (1) several objectives within the VA's Strategic Plan focused on women Veterans and improving their access to tailored health care and (2) HSR research priorities focused on women Veterans’ health care needs and interventions following military service. The proposed project is also timely and aligned with the recently signed Executive Order prioritizing research on women’s health issues. Findings will contribute to VA’s current exercise initiatives and efforts to tailor women Veterans’ health care. Innovation: Psychological skills training (PST) interventions have been effectively used and implemented in a variety of settings, such as the military, and have been found to increase exercise. PST interventions can also increase self-efficacy, which is one of the strongest determinants of consistent exercise. However, despite the demonstrated effectiveness of PST interventions on increasing exercise and self-efficacy, the application of PST interventions to increase exercise among women Veterans remains largely unexplored. Specific Aims: This study will determine exercise perceptions and support needs among women Veterans, (Aim 1), iteratively tailor a PST-based intervention protocol for exercise among women Veterans (Aim 2), and preliminarily pilot test the PST intervention for exercise to assess feasibility and acceptability (Aim 3). Methodology: This is a multimethod study. In Aim 1 we will use qualitative interviews to elicit perceptions of exercise behaviors from women Veterans (N=30). In Aim 2 we will assemble an advisory group (N=6-8) of VA clinicians and administrators to elicit input on how to tailor a PST-based intervention protocol for exercise for women Veterans. In Aim 3 we will conduct a preliminary pilot test using a sample of women Veterans (N=12) to qualitatively and quantitatively assess the feasibility and acceptability of the intervention developed in Aim 2. Implementation/Next Steps: We will develop implementation strategies in Aim 2 to facilitate broader testing, scalability, and future implementation of the STRIVE intervention. These strategies will be tested and refined in the planned future Merit Award application that will test STRIVE in a randomized controlled trial. More broadly, findings from Aim 1 and the implementation plan in Aim 2 can be used to augment existing services, such as the VA MOVE! Program or Whole Health. Adapted evidence-based strategies to promote exercise among women Veterans can also be implemented into clinical services (e.g., gynecology and primary care visits) and VA services that support women Veterans.

NIH

Partial ophthalmoplegia due to a single cranial nerve palsy are common with an estimated 700,000 cases in the US and 15,000 new cases annually in the VA, with the most common causes being stroke and diabetes. There can also be bidirectional and total ophthalmoplegia due to multiple cranial nerve palsies, for which there is currently no effective treatment. Unresolvable diplopia is common in ophthalmoplegias, resulting in visual confusion, increased risk for falls, and reduced quality of life on par with glaucoma and AMD. Ophthalmoplegias affect many aging Veterans with neurological diseases and younger Veterans with severe polytrauma, making them a priority for VA research. We propose to reanimate the eye in ophthalmoplegias by attaching a NdFeB magnet to the eye and actuating the ocular magnet with a larger magnet fixed externally, on an eyewear temple between the ear and the eye. NdFeB are quite powerful and widely available, as they are commonly used in cell phones and toys, and therefore the safety profile is well-established. In unidirectional cases, such as 6th nerve palsy, a static magnetic force is sufficient and does not require a power source. In bidirectional or total ophthalmoplegias, a small motor will rotate the spectacle magnet to control the eye movements. Prior studies have already made calculations suggesting NdFeB actuation of the eye is possible at clinically feasible component sizes and separations, but the approach has never been pursued beyond this step. This project will move the field forward by creating a realistic eye model, design and optimizing a prototype system, and acquiring feasibility data for methods of fixing the ocular magnet 1) surgically, and 2) non-invasively via a magnetic scleral contact lens.

NIH

Two million Americans—100,000 of whom are Veterans—are living with aphasia, a debilitating communication disorder most commonly caused by stroke. Impaired spoken language comprehension in aphasia has a negative impact on functional outcomes, yet deficits are difficult to treat and there are few efficacious therapy options. One key challenge to rehabilitating spoken language comprehension in aphasia is lack of a mechanistic framework to explain performance. In particular, the role of central auditory processing— a skill critical for spoken language comprehension in other neurological conditions—remains unclear. The goal of this career development award (CDA-1) is to elucidate the role of central auditory processing in spoken language comprehension in aphasia after stroke. We will assess 30 people with chronic aphasia and 30 matched controls using an extensive battery of behavioral and electrophysiological tests. Clinical neuroimaging will also be obtained. Findings will be analyzed using Bayesian multiple linear regression to quantify between-group differences and investigate within-group variation at both behavioral and neural levels. In Aim 1, we will evaluate the unique effect of central auditory processing on spoken language comprehension in aphasia. First, we will quantify differences in performance on a range of speech perception tests in people with aphasia and matched controls. Then, we will evaluate the extent to which performance on the speech perception tests uniquely predicts spoken language comprehension in the aphasia group. Critically, behavioral performance on language and cognitive testing will be included as controlling covariates to account for their known contributions to spoken language comprehension in aphasia. In Aim 2, we will characterize the neural correlates of central auditory processing in aphasia. First, we will quantify differences in latencies and amplitudes from two auditory event-related potentials (N200, P300) in people with aphasia and matched controls. Then, we will evaluate the extent to which performance on the speech perception tests are associated with N200/P300 amplitudes and latencies, and structural damage to key left hemisphere regions in the aphasia group. As with Aim 1, behavioral performance on language and cognitive testing will be controlled for in our analyses. The impact of this CDA-1 will be a brain-behavior framework of spoken language comprehension in aphasia that considers all relevant processes (cognitive, linguistic, central auditory). This framework will allow us to develop novel clinical diagnostic tools and behavioral interventions, the latter of which will be targeted in a CDA-2 proposal. Moreover, this award will support the applicant—a speech-language pathologist with expertise in aphasia and neuroscience—in obtaining auditory research training at the Veterans Affairs National Center for Rehabilitative Auditory Research and developing an independent research program there.

NIH

1 Our ultimate objective is to help Veterans with spinal cord injuries (SCI) regain the ability to stand through 2 peripheral nerve stimulation (PNS), specifically targeting the sciatic nerve (SCN). Traditional standing 3 neuroprostheses aim to selectively activate nerves that control key muscles in the knee, hip, and trunk to 4 maintain standing. Independent activation of muscles in the lower limb with control algorithms paired with 5 sensory feedback further improves standing performance with such neuroprostheses. However, achieving 6 selective activation of the muscles innervated from the upper sciatic nerve has been historically proven to be 7 difficult. The neural fascicles that control multiple major muscle groups are all contained within the proximal SCN 8 (i.e., prior to their distal branching into discrete motor unit components). This makes it more difficult to individually 9 activate the hip extensor muscles, particularly the hamstrings, which are critical in positioning the mass of the 10 head, arms, trunk, and pelvis over the legs. To address this, our SPiRE award project has two main goals. First, 11 we plan to create a 3D model of the SCN fascicles, using microCT and histology techniques. Second, we will 12 characterize nerve and fiber morphology (using Histology) to inform electrode placement and design 13 approaches. This information will ultimately guide the design and surgical placement of new multi-contact nerve 14 cuff electrodes to improve the performance of standing neuroprostheses for SCI patients. During Aim 1, we will 15 develop a 3D model of the fascicles of the SCN, from sciatic notch to the distal branch points, using µCT 16 and histology. The spatial orientation between nerve fibers of the fascicles with respect to neural stimulation 17 electrode placement determines the functional performance of standing neuroprostheses. Hence the 18 development of a 3D model of SCN is crucial to computationally evaluate various electrode designs (electrode 19 geometry, placement, number of contacts and size of contacts) to ultimately achieve increased fiber recruitment, 20 and improved selectivity of fiber recruitment, of the hamstring muscles. During Aim 2, we will complete the 21 most comprehensive histological characterization of the proximal sciatic nerve performed to-date. We 22 will quantify the morphology of the SCN along the nerve at high-resolution. The output of this aim will be used to 23 a) inform the feasibility of invasive electrode approaches, b) validate our fascicle morphology findings from 24 microCT, and c) establish the parameters required to create accurate computational models in the future.

NIH

Career Development and Mentoring: My long-term career goal is to establish an independent laboratory evaluating the inflammatory environment associated with highly prevalent musculoskeletal diseases, to ultimately identify tissue specific therapeutic modalities for regulating inflammation and promoting repair. My prior graduate training included 5-years of focused basic science research where I developed expertise in small animal models of disc degeneration (physical injury & genetically induced), macrophage biology (mechanotransduction, activation, functionality), joint histopathology and image analysis, and biomechanics. This experience in musculoskeletal research has provided me with a strong foundation for success as a postdoctoral fellow. By pursuing the Research Plan described in this proposal, I will further my training in more sophisticated models of musculoskeletal disease (knee OA), high dimensional immunophenotyping, high- resolution imaging, and murine pain-behavior analysis. With direct support from my mentors, Dr. Carla Scanzello MD, PhD and Dr. Robert Mauck PhD, and collaborators, Dr. Karen Hasty, PhD, Dr. De’Broski Herbert, PhD, and Dr. Tristan Maerz, PhD, I will receive mentorship in mechanical overloading models, musculoskeletal mechanobiology, and immunology, in addition to mentorship in career development and scientific collaboration. Research Plan: Injury and overuse introduce aberrant mechanical strains across the knee joint, inducing cellular stresses and a degenerative biological environment thought to contribute to OA. Another biological characteristic of disease pathology, synovial inflammation has been strongly associated with progression of OA (e.g., joint space narrowing and cartilage damage) and pain. When synovitis develops, the synovium acts as a reservoir of local inflammatory bi-products and infiltrating immune cells, of which macrophages are found in the highest frequency. To demonstrate how mechanically activated cartilage drives synovial inflammation and subsequent macrophage activation during OA progression we will utilize a joint overloading model to induce OA with purely mechanically driven inflammation in the murine knee. Combining methods of high dimensional transcriptional (single cell sequencing) and spatial proteomic analysis (imaging mass cytometry) we aim to identify and localize inflammatory cell populations throughout loaded joint tissues. We will first compare differential effects of singular vs. repetitive loading on cartilage and synovial inflammation and combine with histopathology and pain behavior evaluations to identify associations with inflammation and painful OA pathology. We will next develop a co-culture model from previously in-vivo loaded tissue explants (synovium and cartilage), to test the specific hypotheses related to loaded cartilage and synovial driven inflammatory signaling. We will utilize this co-culture model to identify differential tissue specific (cartilage, synovium) effects of loading mediated inflammatory signaling specifically on macrophage activation via functional assays (secretome, phagocytosis, migration, bulk RNA sequencing). Completion of the proposed work will further the understanding of how mechanobiology contributes to joint degeneration via multi joint tissue inflammatory signaling and immune cell activation, ultimately providing new avenues of disease mediating therapeutic targets. Results of this work will provide important insights into disease mechanisms to drive novel therapeutic development and thus will greatly benefit the large population of Veterans and active-duty personnel affected by OA. The proposed research and mentoring plans, collaborative environment, and facilities at the Philadelphia VA Medical Center and the University of Pennsylvania will position me to accomplish my goals of becoming a leading VA-based independent scientist in the fields of musculoskeletal mechanobiology and immunology.

NIH

Approximately 20% of U.S. veterans in wars following 9/11 have experienced one or more traumatic brain injury (TBI), including repetitive mild exposures. The risk of sustaining TBI during military service is doubled in veterans who sustain a TBI prior to enlistment. Repetitive mild TBI (rmTBI) clinical symptoms can emerge years to decades after exposure to injury and include motor and cognitive dysfunction, anxiety, and depression. Furthermore, rmTBI neuropathology is characterized by select neuroinflammatory, vasculature, and degenerative responses in brain regions such as the cortex and hippocampus, contributing to cognitive and emotional alterations. Few treatments are available for rmTBI to address pathological and behavioral outcomes, highlighting the importance of an animal model of rmTBI to allow development of new therapies for the Veteran population. Here, we will first employ a rmTBI model protocol in the mouse and evaluate the ability of therapeutic exposure to stimuli presented at ~40Hz (gamma frequency) to improve rmTBI model-induced pathological and behavioral alterations. Neural gamma band oscillations play a major role in cognition, and exogenous application of simultaneous light and sound stimuli at gamma frequency entrains neural gamma oscillations (referred to as Gamma Entrainment Using Sensory Stimuli; GENUS). GENUS treatment has been shown to alter pathological markers of inflammation and neurodegeneration, as well as improve behavioral/cognitive outcomes, in animal models of Alzheimer’s disease (AD) and in humans with AD. We will apply GENUS daily (or control treatment) in mice starting 6 weeks after rmTBI exposure until a chronic 6-month timepoint, and predict improvement of both pathological and emotional outcomes. Behavioral evaluation (one week following rmTBI model exposure, then every two months until 6-month timepoint) will include measures of motor coordination (rotorod) and mood disturbance, including the elevated plus and open field mazes (anxiety and risk-taking/impulsivity) and tail suspension test (anhedonia/depression). Chronic neuroinflammation seen in rmTBI includes alterations in brain astroglia and microglia, vascular abnormalities, and resulting altered cerebral blood flow which most likely contribute to increased levels of cis-phosphorylated tau and possibly to later neurodegeneration. At the 6-month time point following rmTBI exposure, we will perform immunohistochemistry stains on brain tissue, allowing simultaneous histological labeling of markers including vasculature abnormalities, neurodegeneration, and markers of neuroinflammation. Brain regions to be analyzed include the medial prefrontal cortex (mPFC), hippocampus, and amygdala, which are chief neural players in cognition, anxiety, and mood. GENUS treatment has previously been shown to induce gamma oscillations in several neural structures and improves some of the cognitive dysfunction and histopathological alterations in mPFC and hippocampus in the AD mouse model. We will evaluate here whether GENUS treatment improves the neuropathological changes and behavioral impairments induced by rmTBI in a clinically relevant mouse model. Delaying GENUS treatment until 6 weeks after rmTBI model exposure is translationally significant, modeling the delayed timing from injury to when the Veteran seeks treatment at the VA. If successful, these studies will support the development of a noninvasive therapeutic treatment for rmTBI experienced by Veterans.

NIH

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neuromuscular disease that places extreme financial, physical, and emotional burdens on affected Veterans and their caregivers. Currently, ALS remains without a cure and is commonly diagnosed at advanced disease stages when treatments are ineffective. Though the loss of motor neurons is a disease hallmark, it is now clear that various tissues and cells play a role in the pathogenesis and progression of ALS. As such, multi-factorial therapeutic targeting is an increasingly necessary approach for developing and testing ALS treatments. This therapeutic gap represents an unmet need in ALS. My CDA-2 funding has supported pre-clinical animal studies to assess and optimize the therapeutic potential of the secretome, or conditioned culture medium, from adipose-derived stem cells (ASCs). We and others have determined that systemic mesenchymal stem cell (MSC) secretome therapy, including ASC secretome, imparts neurologic, survival, and other benefits in the mSOD1G93A mouse model of ALS. Preliminary studies have also revealed a significant ASC-CM-mediated reduction in key serum inflammatory biomarkers, which hints at a possible mechanism of its action. However, when given before, through and into late stages of disease, the benefits facilitated by this secretome therapy eventually declines. As such, a clinically relevant adjunctive treatment could enhance the therapeutic benefits of ASC secretome therapy. Trans-spinal direct current stimulation (tsDCS) represents an approach to potentially improve the efficacy of ASC secretome long-term. For the proposed study, we will treat mSOD1G93A ALS mice with ASC secretome derived from ASCs grown using our patented optimized culture approach for neurological disease treatment and test whether regular tsDCS extends the therapeutic benefits in ALS. Our hypothesis is that combining daily systemic ASC secretome therapy and weekly tsDCS beginning at symptom onset will synergistically slow disease progression and extend the therapeutic benefits of ASC secretome. Our long-term goal is to not only extend life, but also improve quality of life for ALS-afflicted Veterans and their families. SPECIFIC AIM 1. Demonstrate whether regular trans-spinal lumbar electrical stimulation supplemented with systemic ASC secretome therapy improves functional and survival outcomes in mSOD1G93A mice. The goal of this Aim is to determine whether weekly tsDCS combined with systemic ASC secretome or control medium therapy ameliorates motor dysfunction and prolongs lifespan in mSOD1G93A mice. As part of a modified Neuroscore we will assess limb extension, grip strength, and locomotor function to assess the onset and progression of symptoms. Overall survival and lifespan from symptom onset will also be analyzed. SPECIFIC AIM 2. Evaluate whether combined tsDCS and ASC serum therapy impart histological motor neuron survival and neuromuscular junction (NMJ) innervation benefits. To test the hypothesis that our proposed therapy could impact the underlying neurodegenerative characteristics differentially from outward behavioral and functional measures such as neurological function, quality of life, and survival, we will perform histologic analysis of lumbar spinal cord and hindlimb muscle to assess MN survival and NMJ innervation. As MN and NMJ are typically fully degenerated at humane end-stage (the endpoint in Aim 1), we will treat a separate cohort of mice with ASC secretome, control medium, and weekly tsDCS between 70-90 days of age, a period we have documented secretome effects on moderate stages of neuromuscular degeneration therapy. Following sacrifice at 90 days, lumbar spinal cord and gastrocnemius muscle will be sectioned and immunolabeled for MN quantification and NMJ innervation, respectively.

NIH

Significance to VA: 110,000 VHA patients have advanced chronic kidney disease (CKD, Stage 4 or 5). These Veterans are mostly older, have multiple chronic conditions, and face a major health transition as they approach the need for chronic dialysis or a kidney transplant to live with kidney failure. Unmet needs include exceptionally high mortality, failure to delay dialysis as long as possible, insufficient preparation for dialysis, and barriers to home dialysis and kidney transplantation (preferred by many over in-center hemodialysis). Our longer-term goal is to improve these outcomes to maximize life participation for Veterans with advanced CKD. Most Veterans receive advanced CKD care at the 120+ VA Medical Centers (VAMCs) with nephrology services. Among Veterans reaching kidney failure, even though 80% transfer to Community Care dialysis, VA nephrology is responsible for assuring access to home dialysis, transplantation, and related services. Though VA/DoD and civilian nephrology practice guidelines recommend coordinated multidisciplinary care for advanced CKD patients, optimal approaches are unknown, and VA offers no national guidance. As such, approaches have evolved differently across VAMCs. Indeed, organized efforts to deliver equitable care within individual VAMCs may be uncommon. As such, strategic intervention to improve coordination of VAMC nephrology care may meaningfully improve the outlook for Veterans facing this life-altering health transition. Innovation & Impact: Our working hypothesis is that, in advanced CKD, a care coordination intervention can be developed that is feasible for VAMC nephrology services to implement, and that doing so will provide more effective care and ultimately improve Veteran-centered outcomes. We follow the Multiteam System (MTS) Framework to work toward a coordination ‘solution’ scoped around optimizing function of the nephrology team so that key services are offered effectively and equitably to highest-risk Veterans. VHA considers improving care coordination a top priority for Veterans with high-intensity, focused, specialty care service needs, such as advanced CKD, yet evidence, approach, and implementation are undeveloped. By addressing this gap, our work will make progress toward improving the outlook for Veterans facing this life-altering health transition. Specific Aims: This pilot project addresses foundational needs by building an evidence base for our hypothesis and gaining stakeholder support for the project’s next phase. Aim 1: Understand variation in VAMC care and outcomes for Veterans with advanced CKD. Obtain a comprehensive understanding of specialty kidney care at the VAMC level. Highlight promising approaches to effective care coordination. Aim 2: Co-Design a bundled care coordination intervention that is acceptable to diverse stakeholders. Methodology: Follows the MTS framework. Aim 1: Describe the current state of care by: (1) VAMC nephrology chief survey (pre-award) and (2) descriptive CDW data, providing an understanding of disparities in resources, care structure and care coordination, and outcomes across VAMCs nationally; (3) exploratory provider interviews, detailing care coordination and delivery at six VAMCs with varied resources and performance; (4) data integration, highlighting and contextualizing findings and inequities. Aim 2: Uses open-ended Co-Design, an evidence-based process that engages stakeholders to co-create solutions to an applied, complex problem. With Aim 1 findings as context, our Design Team (VAMC providers, content leaders, and Veterans) will: (1) identify challenges to providing coordinated care, (2) creative problem-solve to identify potential solutions, (2) assess impact and feasibility, and (4) operationalize into a bundled care coordination intervention for further development. Path to Translation/Implementation: Output will support and guide the next funding submission within 3 months after project end. The follow-on study (2nd phase) will complete pre-implementation activities including formulating a measurement plan, pilot testing at VISN 10 sites, and developing a draft protocol for the project’s 3rd phase, an effectiveness-implementation program incorporating adaptive design as part of a learning health system.

NIH

Project Summary/Abstract Vein graft failure remains a major clinical challenge, with 20–30% of grafts failing within the first year due to neointimal hyperplasia and adverse tissue remodeling. Veterans, in particular, are disproportionately affected by peripheral artery disease (PAD) and coronary artery disease (CAD). Existing interventions such as drug-coated balloons (DCB) or stents and antithrombotic therapies are limited by complications related to permanent metal implants, imprecise drug dosing, and a lack of consideration for patient-specific characteristics. Moreover, no platform currently exists to screen personalized therapies prior to clinical application. To address these limitations, we propose a novel vessel-on-a-chip ex vivo perfusion model using saphenous veins harvested from patients undergoing coronary artery bypass grafting, peripheral bypass, or amputations. This model creates a physiologically relevant microenvironment for studying neointimal hyperplasia progression, predicting vein graft performance, and screening targeted therapies on a patient-specific basis. Our approach utilizes 3D-printed chips that are customized to accommodate variations in human vein size. Each vein segment is sutured into the chip, embedded in a collagen-based extracellular matrix (ECM) for mechanical support, and connected to a peristaltic pump for perfusion. The platform further incorporates pressure sensors and imageable chambers for real-time monitoring of hemodynamic parameters. Notably, each pump can operate up to eight chips simultaneously, offering a higher-throughput alternative to conventional animal models. This high-fidelity ex vivo system will enable real-time tracking of neointimal hyperplasia, correlation of pressure dynamics with disease progression, and efficient drug screening to optimize individualized treatment strategies. By bridging the gap between preclinical testing and clinical application, our platform has the potential to transform personalized vascular medicine and improve long-term graft outcomes.

NIH

Background: Veterans who lack capacity to make their own decisions and do not have a surrogate decision- maker cannot consent to discharge from VA inpatient settings. In these cases, a professional guardian must be court appointed before the Veteran can be discharged from inpatient care to other settings. The guardianship process is complex and time- and resource-intensive. As a result, medically stable, unrepresented Veterans may spend unnecessary months, or even years, in inappropriate inpatient settings awaiting guardianship. These needless delays in discharge: (1) result in inappropriate use of inpatient beds and increased risks of hospital-acquired conditions, (2) conflict with a patient’s right to care in the least restrictive setting and (3) cost VA upwards of $200 Million dollars per year, a figure that is expected to rise as the VA population ages. However, VA does not systematically document or track guardianship processes or outcomes and has no national, standardized approach to guardianship. Research is needed to gauge the scope of the problem, understand the VA guardianship process, and identify ways to improve it. Significance to VA: The US Senate Special Committee on Aging recently called for increased scrutiny of guardianship laws and outcomes, citing the lack of data nationally. According to the VA Social Work Guardianship National Committee, VA lacks national policies and processes for incapacitated Veterans who require transition from inpatient care settings to lower levels of care. The recently updated VA Directive 1004.01 highlights VA’s commitment to provide care for Veterans in the least restrictive setting possible while supporting their right to autonomous, informed participation in their health care decisions. VA must invest in infrastructure to track guardianship in Veterans and support research to enable greater understanding and meaningful improvement of guardianship processes. Innovation and Impact: The proposed study is innovative because it generates new knowledge and creates a foundation for future research on guardianship in VA. Specifically, this work focuses on a unique and underserved population of Veterans who are particularly vulnerable and often excluded from research studies. This mixed methods study is the first of its kind in VA. Our ongoing partnership with the Office of Care Management and Social Work ensures that this work will be used to inform VA policy and practice. Specific Aims: (1) Create a test dataset made up of a national sample of Veterans who have undergone the guardianship process in VA inpatient settings that includes their sociodemographic and clinical factors. (2) Understand key shareholder perspectives of current VA guardianship processes, including workflows, challenges, best practices, and opportunities for improvement. Methodology: (Aim 1): Using retrospective observational methods and an extension of methods developed by our team, we will do searches of VA electronic health record notes and administrative data, followed by manual chart reviews, to create a nationally representative test dataset of Veterans who have guardians. For each case, we will also collect information about their guardianship, health care and demographics. (Aim 2): We will conduct semi-structured interviews with VA staff and leadership who are involved in guardianship policy or practice to understand current guardianship processes, challenges, and ways to improve them at the local VAMC and national levels. We will also conduct interviews with Veterans who have guardians and their guardians to understand their experiences of the process and opportunities for improvement. Path to Translation/ Implementation: We will use the test dataset created in Aim 1 in a future IIR to validate a natural language processing approach to systematically identify Veterans who have guardians. This will facilitate research examining guardianship in VA on a national scale. Findings from Aim 2 will inform future research to develop an intervention improve the guardianship process for future study and dissemination.

NIH

Significance to VA: Post-9/11 Veterans who screen positive for mild traumatic brain injury (mTBI) and do not complete a Comprehensive TBI Evaluation (CTBIE) may be at risk of “falling through the cracks” by not having a mTBI diagnosed and referrals to appropriate health and rehabilitation services. MTBI is associated with increased risk of posttraumatic stress disorder, depression, sleep problems, and substance use. Therefore, it is critical to identify Veterans with mTBI history to intervene and mitigate any negative downstream effects. All Post-9/11 Veterans receiving Veterans Health Administration (VHA) services are screened for previously undiagnosed mTBI at their first VHA visit and offered a referral to a CTBIE if they screen positive. However, about 85,000 (23.4%) of Veterans with a positive TBI screen have not received a CTBIE, leaving their TBI status clinically unknown in VHA. The CTBIE is a pathway to interdisciplinary care for ongoing symptoms regardless of whether they are related to mTBI. Increasing CTBIE completion is a priority. Innovation and Impact: This work is innovative because it (1) integrates administrative data to characterize Veterans who screen positive for TBI with first-hand narratives of these Veterans and the VHA staff responsible for ensuring CTBIE completion and (2) accounts for differences in Veteran characteristics that may otherwise confound analyses of health-related factors by linking to multiple VA and Department of Defense (DoD) datasets. Including DoD data allows us to control for Veterans’ objective (and “pre-VHA”) injury characteristics, the measurement of which might otherwise be biased by limited Veterans’ VHA health services use and diagnoses at time of TBI screening. The result of this work will lead to work that impacts VHA’s delivery of healthcare and rehabilitation services. The synthesized administrative and interview data will identify challenges and, more importantly, best practices for overcoming them that are feasible and acceptable for the CTBIE clinics and acceptable to Veterans. This will inform actionable approaches to developing interventions to increase the CTBIE completion rate for Veterans with a positive TBI screen, a current VHA priority. Specific Aims: (1) Describe and model demographic, military, health, and VHA facility characteristics associated with CTBIE completion status among Veterans who screened positive for mTBI; (2) Identify facilitators and best practices associated with CTBIE completion, from the perspective of VHA staff, (3) Understand Veterans’ perceptions of and experiences with the TBI screening and CTBIE process and assess acceptable ways to improve it. Methodology: This is a 2-year, mixed-methods study. In Aim 1, using VA and DoD administrative data, we will quantify and model Veterans’ CTBIE completion status (CTBIE offer: Agreed vs. Declined; Among agreed: Completed vs. Not Completed) by accounting for sociodemographic, military history, health factors, and VHA facility characteristics. For Aim 2, we will interview 20 VHA staff knowledgeable about the CTBIE scheduling and completion process from VHA facilities that are high- and low-performing for CTBIE completion to understand factors, including facilitators and best practices, associated with CTBIE completion. We will identify current practices that VHA facilities follow when a Veteran screens positive for TBI and the feasibility and acceptability of other practices that could help facilitate CTBIE completion. For Aim 3, we will select 30 Veterans with a positive TBI screen based on their CTBIE completion status from sites where Aim 2 interviews occurred, to identify their perceived facilitators and barriers to CTBIE completion and have them evaluate practices that may increase the likelihood of CTBIE completion. Path to Translation/Implementation: Future research will translate this study’s findings into practical interventions to increase CTBIE completion. In collaboration with VHA TBI leadership, VHA pilot sites will be identified, and interventions will be implemented, monitored, and evaluated in a future study.

NIH

Significance to VA: The proposed research study addresses a critical yet unresolved need in the Veteran and civilian populations and is a high priority within the Veterans Affairs (VA) Health Administration. The prevalence of chronic pain in Veterans with spinal cord injury (SCI) is at a whopping 75%, which is more than triple that of the general population. This is problematic because chronic pain after SCI severely impacts quality of life, physical function, and activities of daily living, with an increased prevalence of poor sleep, disability, and depression. While the causes of chronic neuropathic pain after SCI are not fully understood, research on chronic pain has shown that it is associated with diet, obesity, and systemic inflammation in both SCI and non- SCI literature. Chronic pain has been associated with poor quality diets in the general, non-Veteran population without SCI, as well as in preliminary findings in a non-Veteran SCI sample. Diet quality is a comprehensive diet metric measured with indices such as the 2020 Healthy Eating Index (HEI), which assesses adherence to the 2020-2025 Dietary Guidelines for Americans (0-100, with a higher score indicating greater adherence). Although the diet quality of Veterans with SCI has not been examined yet, nor its association with pain, studies have shown worse diet quality of Veterans compared to their non-Veteran counterparts. Innovation and Impact: The proposed study will be the first to determine diet quality using the novel, validated remote food photography method and assess its relationship with chronic pain in Veterans with SCI. This will be the first step to identify a non-pharmacological and modifiable environmental factor, such as dietary intake, to mitigate chronic pain after SCI. Specific Aims: The proposed observational and cross-sectional pilot study aims to: 1) examine the relationship between diet quality and chronic neuropathic pain and 2) compare the measures of diet quality, pain, and pain-related outcomes across three cohorts: a) Veterans with SCI, b) Veterans without SCI, and c) non-Veterans with SCI. We anticipate a significant inverse correlation between diet quality and pain severity (Aim 1) and worse diet quality, pain, and pain-related psychosocial measures in Veterans with SCI compared to the other study cohorts (Aim 2). Methodology: Veterans with SCI (n=30; ~50% with paraplegia/tetraplegia) will be recruited from the Miami VA Hospital, undergo chronic pain assessments (questionnaires and quantitative sensory testing (QST)), and provide dietary data using food photography. Data from age-, sex- matched Veterans without SCI (n=30), and data from age-, sex-, and injury-level matched non-Veterans with SCI (n=30) will be compared to that acquired for Veterans with SCI to compare across groups. Dietary data will be entered into the Nutrition Data System for Research v.2023 to generate the nutrition analysis reports for diet quality (via HEI) and other diet metrics for exploratory purposes (e.g., individual nutrients). Correlation analyses (Pearson’s or Spearman’s) will be performed to assess the strength of association between diet quality, pain parameters (chronic pain questionnaires, QST measures), and pain-related outcomes (depression, quality of life). Observed associations between diet quality and chronic pain/pain-related outcomes will be compared across the three study cohorts to assess for potential Veteran- and SCI- influence on chronic pain. Path to Translation/Implementation: Completing the proposed CDA-1 pilot study will examine the strength of the association between diet quality and chronic pain in Veterans with SCI, which will then guide the applicant for a more focused mechanism-based (e.g., obesity, inflammatory factors) investigation for future studies (CDA-2, etc.). The long-term goal of this pilot project and future studies is to develop targeted nutrition interventions that could potentially affect chronic pain and maximize Veterans’ functional independence and quality of life after SCI.

NIH

Significance to VA: Osteoarthritis (OA) resulting from injury and progressive joint degeneration is a leading cause of disability for which there are no disease modifying drugs. Military service members suffer from OA at higher rates and younger ages than the general population. This massive disease burden from OA is therefore transferred and carried by the VA Healthcare System (VAHCS). Autologous platelet rich plasma (PRP) has been increasingly used clinically for symptomatic treatment of knee OA with variable clinical results. In a program to provide PRP injections to Veterans with symptomatic early knee OA at the VA Palo Alto (VAPA), clinically meaningful improvement in knee pain was achieved in less than 40% of PRP recipients at 6-months follow-up. However, those who improved continued to report better outcomes at 2-years follow-up. Thus, there is critical need for methods to predict clinical responsiveness. Our prior work has shown that PRP from different individuals has differing effects on macrophage inflammatory activity in vitro. We found that PRP from older Veterans with knee OA incited pro-inflammatory differentiation of healthy macrophages while that of young and healthy males did not. These findings underscore that PRP treatment may not be beneficial for all patients and demonstrate a clear need for biological screening. The goal of this pilot project is to explore whether an in vitro macrophage assay has potential to identify patients more likely to benefit from PRP injections for knee OA. Innovation and Impact: There are currently no in vitro assays or tests to predict individual responses to any OA treatment. The ability to predict individual patient responses to PRP injections will directly benefit Veterans and improve clinical care within the VAHCS by directing PRP treatment to those most likely to respond and sparing those unlikely to benefit the risks of undergoing an unnecessary procedure along with delay in referral for alternative care. The Specific Aims are: (Aim 1) To test the hypothesis that a patient’s clinical response to PRP treatment for knee OA can be predicted by the in vitro response of allogenic macrophages to treatment with (1a) patient-specific PRP or (1b) patient-specific platelet poor plasma (PPP); and (Aim 2) To test the hypothesis that a patient’s clinical response to PRP treatment for knee OA can be predicted by the in vitro response of autologous macrophages treated with (2a) patient-specific PRP or (2b) patient-specific PPP. The evaluation of patient- specific PPP (PS-PPP) will evaluate if this readily prepared blood fraction could serve as a surrogate for patient- specific PRP (PS-PRP) thereby facilitating the clinical use of a macrophage assay. Methodology: This pilot study will recruit Veterans receiving PRP injections for clinical treatment of symptomatic knee OA at the VAPA to contribute blood, PRP, and clinical outcomes. Changes in macrophage phenotypical differentiation following treatment with PS-PRP, specifically the ratio of pro-inflammatory M1 to anti-inflammatory M2 macrophages, will be measured using flow cytometry and immunoassays. These in vitro changes will be compared to patient- specific clinical outcomes, including changes in patient-perceived pain and gait function, assessed between baseline and 1-month follow-up as primary and secondary endpoints. Path to Translation/Implementation: This pilot study directly compares in vitro responses with a Veteran patient’s actual clinical response to PRP treatment. Should the proposed macrophage assays show potential to predict the clinical response to PRP, we will advance this work to a full clinical validation trial. This research aligns with the Rehabilitation Research, Development, and Translation (RDT) Broad Portfolio’s goal to improve Veteran mobility through precision medicine. Successful completion of this pilot project followed by broader validation in a full clinical trial could contribute a predictive assay into clinical use to improve the care of Veterans with OA and to support more efficient use of VA clinical resources.

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Significance to the VA: Veterans experience strokes more frequently than non-Veterans. One of the most debilitating consequences of a stroke is aphasia, a chronic language disorder that affects one third of stroke survivors. While individuals experience a degree of spontaneous recovery within the first 6-12 months post- stroke, most individuals do not fully recover. Continued neuroplastic change to the language system is conferred via long-term behavioral speech-language treatment which is most effective at high doses. Unfortunately, Veterans receive considerably less treatment than best-practice guidelines. Motivation is likely a major contributor to this gap in clinical care. In fact, the VA Clinical Practice Guidelines for Management of Stroke Rehabilitation cite motivation as a barrier to post-stroke rehabilitation and recommend that clinicians assess motivation. However, there are no motivation-based measures with validity evidence in the context of aphasia rehabilitation, creating a critical gap in clinicians' ability to assess and ultimately intervene upon motivation to optimize the amount of treatment Veterans with aphasia receive. Innovation and Impact: This proposal aims to address this gap by modifying an existing measurement tool that, with appropriate adaptations, can identify causes of suboptimal motivation in the context of aphasia rehabilitation. The measure is grounded in self-determination theory, a well-studied theory of motivation that finds that optimal motivations (described as “autonomous”) lead to improvements in health behavior and well- being, and bolster cognitive functions associated with aphasia treatment response. Autonomous motivations are driven by contexts that support three basic psychological needs (BPNs). Measures of BPNs can identify underlying causes of suboptimal motivation and guide interventions that improve motivation – a critical variable that can increase the dosage of treatment and enhance cognitive skills key to treatment response. Specific Aims and Methodology: This proposal is guided by state-of-the-art guidelines for measure development. In Aim 1, speech pathologists and researchers (n = 30) will be presented with the unmodified scale via survey and identify irrelevant or missing items. An expert panel will modify or develop items using survey data. In Aim 2, Veterans with aphasia (n = 7-10) will be presented with the scale modified in Aim 1. Via cognitive interviewing, Veterans will identify items they find difficult to understand, irrelevant, or missing. An expert panel will modify or develop items using cognitive interview data. In Aim 3, Veterans with aphasia (n = 25) will complete the modified scale to generate validity evidence that can support its use in future research. Path to Translation/Implementation: This proposal constitutes the initial steps of a productive and programmatic line of research evaluating the effect of BPN-focused motivational interventions on aphasia treatment outcomes in a single-subject investigation (CDA-2) and large-scale efficacy research (MR Award). This work will enable clinicians to assess motivation as advised by VA Clinical Practice Guidelines. Existing frameworks of rehabilitation (e.g., the Rehabilitation Treatment Specification System) can aid researchers in using the scale to identify treatment ingredients that optimize motivation, a variable central to outcomes. Immediate and Long-term Career Goals: The applicant is a speech pathologist and an advanced fellow in geriatrics in the Geriatrics Research, Education, and Clinical Center at VAPHS, with experience in aphasia rehabilitation and research. During the CDA-1, mentorship and structured training in measurement theory, qualitative research, motivational science, and professional development will support the completion of the proposed CDA-1 and the applicant's career goals to become an independent VA clinician-scientist supported by VA Merit Review and NIH/NIDCD award mechanisms. The applicant's long-term research program will (1) identify neurocognitive and psychological mechanisms underlying aphasia recovery and (2) determine how treatment ingredients can be modified to maximize aphasia treatment outcomes at the individual level.

NIH

Significance to VA: There are few treatment options for Veterans with spinal cord injuries (SCI). Recently the Tuszynski lab has developed an approach where neuronal stem cells are implanted into the injury site. These grafted cells differentiate into neurons which extend axons caudally to form synapses with the host; simultaneously, host axons enter the graft and form synapses with graft neurons. This system restores connectivity across the lesion site and improves functional recovery in rodent and primate models. However, recovery is incomplete, in part because of only partial growth of host axons into and within the graft. Innovation and Impact: This CDA-1 proposal will use a new path to enhance the graft by exploiting the existing biology of the graft to enhance its functionality. Specifically, it will explore the role of axonal guidance cues (secreted molecules that attract or repel growing axons) in the graft and manipulate these cues to increase host axon growth into the graft and improve connectivity across the injury site. The Tuszynski lab is currently beginning the process of clinical implementation of our graft system. Success in this project and follow-up work in a CDA-2 award will lead to approaches which can be used to improve the functionality of grafts to improve recovery for SCI patients including Veterans. Specific Aims: This proposal will test the hypothesis that a mismatch of secreted guidance cues may limit host axon regeneration into the graft. This proposal will target mechanisms associated with axon growth into stem cell grafts and test whether modifying guidance cues will increase host axon regeneration into the graft. Aim 1 will focus on reducing the inhibitory effects of the injury site. Injury sites express Wnts which inhibit the growth of corticospinal tract (CST) axons via binding to the Ryk receptor. This aim will test the hypothesis that neutralization of the inhibitory effect of Wnts will increase CST axon growth into the graft. Aim 2 will focus on increasing the attractive environment of the graft. Axons that enter the graft grow towards appropriate interneuronal targets, indicating that some attractive cue exists; however, the relatively short distance of growth within the graft (1-2 mm) suggests that the effects of this cue are limited. A viral labeling and sequencing approach will be used to identify and validate these attractive cues released by the graft. Methodology: Both Aims will be performed in mice using a C4 contusion model of spinal cord injury. Regeneration of host CST axons into the graft will be assessed with histology (N=12 per group). Functional recovery following SCI will be assessed with behavioral performance on a skilled reaching task (N=30 per group). Treated animals will be compared to our current grafting paradigm to determine if these treatments improve the efficacy of the graft in recovery following SCI. Path to Translation/Implementation: Treatments for spinal cord injury are currently limited, and success of this proposal may increase the effectiveness and therapeutic potential of stem cell grafts. While work in this proposal is limited to mouse grafts, future work in a CDA-2 award would test any treatments identified here in human cell grafts which could then be implemented as part of a clinical product to treat Veterans with SCI. The proposed project will provide excellent research training for the applicant including systems neuroscience, spinal cord injury, and human disease. Additionally, he will learn multiple techniques including rodent models of SCI, mouse behavioral assessment, and RNA sequencing. The research environment of the Tuszynski lab is highly collaborative so he will gain exposure to many techniques and subject areas beyond his own research, refine his scientific presentation skills, mentor younger scientists, and network with leaders in the field. Finally, he will directly engage with Veterans by shadowing doctors at the VA San Diego Medical Center while they treat Veterans recovering from SCI. Overall, this CDA-1 grant will provide new insight into novel therapeutic avenues for spinal cord repair and allow the applicant to transition into a career as an independent investigator at the VA.

NIH

Significance to VA: Identifying and assisting Veterans with unmet social needs, like food insecurity and housing instability, is critical to achieve health equity. Recognizing its importance, the Joint Commission recently listed assessment of patients’ social needs and provision of information about resources and support services as a National Patient Safety Goal (NPSG.16.01.01). Effective efforts to assess and assist Veterans with unmet social needs largely do not exist in many VHA clinics. Only a fraction of Veterans experiencing food and/or housing insecurity are being identified. Additionally, Veterans who are identified and provided with a list of resources still struggle to connect with services. A potential solution could exist with nurses. Nurses comprise the largest healthcare workforce in the VA and could be a major force multiplier in reducing gaps in service and care with respect to identifying and assisting Veterans with unmet needs. The proposed study aligns with the updated VA HSR research priorities by: (1) contributing to efforts to address health disparities through development of an intervention to identify and assist Veterans with unmet social needs, (2) employing engagement science, a HSR foundational learning health systems method, through application of human- centered design, (3) engaging Veterans and frontline primary care staff to facilitate study design and intervention development, and (4) responding to the need for research on nursing workforce and practice, specifically the role of nursing to address social drivers of health to improve health equity. Innovation and Impact The proposed research will use human-centered design to empower frontline primary care staff, including nurses- who have been largely overlooked in research- and Veterans to co-design clinical application of pathways to identify and assist Veterans with unmet social needs. Specific Aims are to: 1. Discover the current state of how Veterans with unmet social needs are identified and assisted in VA primary care settings. 2. Co-design and test an intervention to identify and assist Veterans with unmet social needs. Methodology: Aim 1 will use a combination of methods including direct field observations (n=30) of current clinical care as it related to identifying and assisting Veterans with unmet social needs across three primary care clinics. We will also interview Veterans (n=30) whose clinical care we observe to learn their experiences. We will then survey all primary care staff affiliated with the Houston VA and interview 30 to 45 frontline primary care staff (i.e., RNs, LVNs, and MSAs) to learn what supports and hinders their ability to identify and assist Veterans with unmet social needs. In Aim 2, a design team of Veterans (n=6) and primary care staff (n=10-15) will co-design an intervention to identify and assist Veterans with unmet social needs. The co-designed intervention will include education and workflow processes. We will then pilot the intervention at two primary care clinics sequentially to allow for rapid refinement using feedback from focus groups (n=2 per site) with primary care staff/providers and interviews with Veterans (n=15 per site). Path to Translation/Implementation: Products from this research will be shared with the VHA Offices of Health Equity, Nursing Services, and Food Security. Post pilot, the intervention will continue process improvements with operational partners via quality improvement / quality assessment projects. Simultaneously, the research team will prepare for a larger pragmatic trial to evaluate the intervention for effectiveness in identifying and assisting Veterans with unmet social needs in effort to ultimately reduce health inequities.

NIH

For decades, orthopaedic endoprostheses have been manufactured using traditional machining techniques. Specifically, the stem of the endoprostheses would be fabricated using mills and/or lathes, then the osseointegrated (OI) region would be added onto the stem using small metal beads, then sintered for strength. Recently, additive manufacturing, also known as 3-dimensional (3D) printing, has been introduced to provide affordable devices for limited markets. Instead of the traditional multi-step machining process, both the endoprosthetic stem and the OI region are designed to be manufactured in one continuous process, saving valuable resources. While there are FDA-related issues to address before 3D-printed devices become commonplace in the US healthcare system, many short-term implanted medical devices like orthopaedic fixation plates, screws, pins and wires, and even some long-term dental devices like dental fillings, crowns, and dentures are now 3D-printed. However, 3D-printing of many devices, including percutaneous OI endoprosthesis, is not yet widely accepted by the FDA because of the lack of data verifying that the device designed meets the engineering requirements, and validating that the device produced meets the need for which it was designed. Because of this, 3D-printing manufacturers are apprehensive to put their devices directly into humans. Fortunately, our research team has a well-developed sheep forelimb amputation model which has been directly used for this application and has been accepted previously by the FDA as a valid, preclinical model. In this proposed study, we plan to replicate the existing human Percutaneous Osseointegrated Docking Systems (PODS) endoprostheses to develop a 3D-printed version for use in sheep, which we will call sPODS, an acronym for Sheep PODS. The sPODS will be manufactured not only using a 3D-printing process, but also using a traditional machining process to act as a baseline for direct comparison. Both the 3D-printed and the traditionally machined sPODS will have the same external geometry (length, diameters, tapers, etc.), with the only difference being the method used to create the device. Once manufactured, the 3D-printed and the traditionally machined sPODS will be verified through benchtop testing, measuring the amount of bone loss during implantation, the contact area between the bone and the endoprostheses, and the fixation strength post-implantation. This will verify that the device manufactured meets the specified engineering requirements. Next, production quality 3D- printed and traditionally machined sPODS will be surgically implanted into our amputated sheep metacarpal model and validated against our published historical sheep data, confirming that the device produced meets the need for which it was designed. This research project with the following Specific Aims: Specific Aim 1: To quantify the surface, material, and mechanical properties of the 3D-printed sPODS and the traditionally machined sPODS, then to measure and compare the initial tensile and torsional stabilities of devices implanted into sheep carcass metatarsals. Specific Aim 2: To validate that the bone morphology and the tensile and torsional stability of the 3D-printed sPODS are not inferior to traditionally machined sPODS following 6-months in situ in a sheep amputated metacarpal model. Prior to implementing PODS clinically, this study is essential to confirm that device design aligns with engineering and material requirements. Ultimately, these efforts will immediately contribute to enhancing functional independence and quality of life of the Veterans with transhumeral amputations but will also serve as guidance for all teams designing and testing 3D-printed percutaneous OI devices at any anatomic site.

NIH

Background: Traumatic Brain Injury (TBI) is a common problem that affects both military and civilian populations. Although most individuals with TBI recover from the acute cognitive effects of the injury, sensorimotor symptoms often persist. One frequently occurring post-concussive symptom is impairment of near vision. This may manifest as overt diplopia or as new difficulties reading and maintaining focus on near objects. Such symptoms have been attributed to TBI-related convergence insufficiency, but this relationship remains controversial given limited data and the lack of robust and reliable tools to measure vergence function in routine clinical settings. Even when accurately diagnosed, treatment options for convergence insufficiency are limited and generally require direct supervision of a trained optometrist or vision therapist. Moreover, home vision therapy is particularly challenging, because exercises cannot be precisely matched to a particular patient’s vergence deficit, there are few objective measures of functional improvement to judge progress and titrate therapy, and it is difficult to monitor whether a patient is following the therapy plan and performing the exercises correctly. Objective / Hypothesis: This project is based on the overall hypotheses that veterans with TBI and binocular vision symptoms have disturbances of vergence control that can be treated with custom virtual-reality games and that it is feasible to provide this vision therapy in veterans’ homes. Our preliminary data show that many Veterans who have experienced TBI and who report ongoing problems with near vision have impaired static (as measured by a virtual NPC) and dynamic (as measured by responses to abrupt changes in the virtual distance of a fixation target) convergence. The proposed project includes a pilot home VR-based vision therapy trial to test the feasibility of this approach to rehabilitation and to acquire preliminary data for Hypothesis 2 that will support design and powering of a future clinical trial. Specific Aims 1) To investigate the relationship of convergence insufficiency to reading and functional near vision symptoms after TBI. 2) To test the feasibility of custom VR games for home vision therapy of binocular vision and reading impairment after TBI. 3) To assess the effect of custom vision therapy games on binocular vision and reading after TBI Study Design: The first aim will employ a virtual-reality headset with integrated high-speed eye tracking to test static and dynamic vergence and visual function in a group of adults with recent and chronic TBI with and without convergence insufficiency (defined by the near point of convergence, measured in VR). Additional tests will assess cognitive processing related to reading (WIAT reading subscales) and accommodation (for younger participants). Participants with convergence insufficiency will undergo a pilot trial of custom VR games for home vision therapy with a six-week exercise protocol using a crossover design. Aim 2 will examine the feasibility of this home therapy and Aim 3 will provide preliminary efficacy data to support future clinical trial design. Impact: This study will provide critical new information regarding the underpinnings of near vision and reading impairments after TBI, and it will lay the foundation for more precise and accessible home-based vision therapy. If successful, it will provide a novel tool for ameliorating a common and functionally disabling post-concussive symptom that affects many veterans.

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Background: Improving access to high-quality care is a top priority for VHA. In 2018, Congress passed the MISSION Act, which further expanded access to VA-purchased care. The VA is now at a crossroads. Some lawmakers want VA to expand access further, but costs have increased rapidly and are unsustainable. Before the Choice Act, the VA spent about $8 billion on purchased care, or 14% of the 2013 medical care spending. In FY24, VA overspent on VA purchase care, exceeding its budget of $33 billion. VA purchased care now exceeds 25% of VA medical care spending, and VA is facing a >$6 billion deficit. Evaluating the benefit of expanded access is difficult because Veterans that use VA purchased care are different than those that do not. Using causal inference models, our team showed that the Choice Act increased utilization, but did not improve outcomes even among higher risk subgroups. Preliminary research suggests that one explanation for why we are seeing no benefits from the increased use of purchase care is payer shifting. Payer shifting happens when individuals who are covered by more than one insurer, change their payer to make their life easier (e.g., reduce their out-of-pocket expenses, increase convenience). Knee jerk reactions to the preliminary payer shifting data could hurt Veterans. More research on payer shifting is critically needed. This study will fill that gap. Significance: If payer shifting is happening then the VA needs evidence that it can use to address it without harming Veterans. Our proposed study is designed to examine payer shifting among VA enrollees. We will leverage the date at which the MISSION Act was implemented (June 6, 2019) and a difference-in-differences analysis to examine the relative change in utilization over time. This research will conclusively address whether payer shifting is happening, the magnitude of payer shifting, and for which groups of Veterans. Innovation and Impact: Understanding payer shifting is necessary to help VA improve access while simultaneously manage its financial health. We apply novel econometric techniques to take advantage of natural experiments and find the causal effects of increasing access. We will also use subgroup analyses to understand possible mechanisms and equity effects. This research is directly aligned with HSR's priorities on access to care, research related to the MISSION Act, and advancing health services research methods across conditions or care settings. Specific Aims: We have three specific aims. First, we will examine payer shifting among all Veterans in Colorado using a recently acquired all payer claims dataset. Second, we will examine payer shifting among VA enrollees who are age-eligible for Medicare. Finally, we will examine payer shifting among VA enrollees who are disability-eligible for Medicare. Methodology: We will leverage the date at which the MISSION Act was implemented (June 6, 2019) and a difference-in-differences analysis to examine the relative change in utilization over time. Across all three aims, we will also conduct analyses for heterogeneous treatment effects to determine if subgroups differ in their payer-shifting response. The subgroups will include: priority groups, distance, urbanicity, age/service era, length of time with VA, previous VA use intensity, comorbidities, and specific procedures. These subgroups were chosen to inform mechanisms and also address potential equity concerns. Next steps/ implementation: We will work with operational partners to understand payer shifting and its potential impact on Veterans and the VA. If we identify payer shifting, we will work with our operational partners to understand the scope of payer shifting and then design approaches to address it. Evidence of no payer shifting will also be helpful as VA considers expanding access to VA purchased care.

NIH

Background and Innovation: Alcohol use disorder (AUD) accounts for over 88,000 deaths per year in the USA at a health care cost of 250 billion dollars each year. The issue of alcohol dependence and its deleterious consequences including liver disease is a particular burden for veterans, a population that continues experiencing long-standing issues with alcohol abuse. AUD is associated with addiction and behavioral disturbances as well as liver disease, pancreatitis and dementia and current treatments which include psychosocial support and medications are still suboptimal. One of the more prevalent and severe consequences of AUD is the development of liver disease and cirrhosis. Approximately 37% of veterans with cirrhosis had coexisting AUD. Based on these observations, we and others have proposed that treating AUD and ALD simultaneously will be a much better approach than each monotherapy alone. However, there is no treatment for ALD other than abstinence and current FDA-approved drugs for AUD offer variable results and have minimal or no direct effect on adiposity and liver disease. We have identified the purine degradation pathway (PDP) as the most prominent metabolic route preferentially activated in NAc, VTA and hepatocytes of ethanol-preferring (EP) mice as well as in ethanol-exposed human hepatocytes and neurons. The PDP is an enzymatic pathway that regulates energy balance by controlling intracellular levels of phosphonucleotides. It is initiated by the activation of 5’ adenosine monophosphate (AMP) Deaminase (AMPD) and results in the conversion of AMP into uric acid, a metabolite commonly found in liver and plasma of alcoholics. Our pilot data in mice indicate that the genetic or pharmacological blockade of the specific isoform of AMPD in liver and neurons, AMPD2, remarkably reduces consumption and preference of EP mice for ethanol while independently reverses ALD. Significance and Impact to Veterans Healthcare: Alcoholism is a serious problem among veterans, about 11% of veterans presenting for first-time care within the VA healthcare system meet the criteria for substance use disorder including cigarette smoking and consumption of alcohol. This is particularly relevant for young adults (18-25 years old) veterans compared to civilians. To date only three FDA approved medications in the U.S. are available for treatment of alcoholism (disulfiram, naltrexone, and acamprosate) and all show limited and variable responses, particularly among veterans in which discontinuation of these drugs is common when prescribed concurrently with other medications like statins or neuroleptics. Further, there are not specific treatments for alcohol-related deleterious consequences like alcoholic liver disease (ALD) and therefore, new, effective, and safe medications for the treatment of AUD and its consequences are desperately needed. Path to translation/implementation: The goal of this research is to perform proof-of-concept basic studies of the efficiency of targeting AMPD2 in ameliorating alcohol use disorder and alcoholic liver disease in mice. However, besides the genetic manipulations, we propose to conduct studies (Aim 1b) with specific AMPD inhibitors either alone or in combination with an FDA approved drug to prevent relapses in recovered alcoholics, naltrexone. These experiments which include identification of optimal dose (and its potential translation into human doses) as well as toxicity studies will provide good evidence about the potential druggability of this target for such a devastating condition like alcohol use disorder.

NIH

In the United States nearly 91% of prosthetics patient encounters are related to the lower limb, thereby representing the vast majority of delivered device interventions. The Department of Veterans Affairs (VA) is one of the leading providers of prosthetic clinical care in the United States, servicing 380,000 patients with impairments annually across 100 facilities with the aim of restoring function and independence to Veterans. As such, lower limb prostheses are prescribed and custom designed to support the functional mobility and independence of Veterans with limb loss. In accordance with clinical practice, the designs of these devices are personalized to each patient according to individual anatomical characteristics, functional impairments, needs, and goals. These factors are considered when carefully designing and tuning the mechanical function of passive- elastic prosthetic devices to support long-term rehabilitation success, and so a definitive device inherently possesses unique load-bearing mechanical properties (stiffness, damping, and rollover geometry) specific to each Veteran user. There is strong evidence linking these stance-phase mechanical properties to specific rehabilitation outcomes, including limb loading, comfort, and walking economy. While the rigorous component selection and tuning process to personalize each device is responsible for the success of these interventions, clinicians perform this process based on their subjective intuition and skills but without knowledge of the how their design choices influence device mechanical properties. These properties are unknown because: 1) mechanical properties are either not disclosed by manufacturers or are not measured from customized devices; 2) there is no standard, profession-accepted method to measure and communicate these properties; and 3) there is no test system that is accessible in settings with limited resources and expertise, such as clinics. Expanding knowledge of passive-elastic properties of prosthetic devices will help provide objective information on how a device functions for appropriate prescription, identify need for device repair due to degradation, and allow clinical research to correlate device function with Veteran user outcomes to develop our evidence base. The central aim of this project is to develop and evaluate an accessible ‘plug-and-play’ test system that measures mechanical properties of passive-elastic transtibial prostheses (i.e., ankle-feet and pylons) through a user- centered, stage-gate design approach. We will first obtain stakeholder feedback to establish user needs through a focus group involving prosthetics clinicians and researchers/designers. We will seek input on desired functionality, output, and system operation to guide the design of our first-generation prototype. We will develop that prototype with our industry partner, Humotech LLC, who shares the intellectual property with the VA. That prototype will be evaluated for functionality, concurrent validity against measurements from a universal materials test system, and inter-rater reliability by comparing prototype measurements between two stakeholder users (research engineer and prosthetist-orthotist). Feedback from these assessments will be used to design and fabricate the second-generation prototype, which will again be subjected to an evaluation on functionality, validity, and reliability to establish future design improvements. Additionally, data from the second assessment will be entered into our innovative data-driven algorithm to model the non-linear mechanical behavior of these components to establish a novel classification method that can be integrated into a VA data repository on prosthesis characteristics, such as the existing Prosthetics Compendium. The outcome from this project is a mechanical test system that enables VA clinicians and researchers to readily access device mechanical function to help guide clinical decision making on device designs to support user needs and generate accurate, reliable measurements of device mechanical function for communicating these clinically relevant properties.

NIH

Significance to VA. Septic arthritis (SA) of a native knee is a surgical emergency and efficient diagnosis and treatment are critical as delay to treatment risks rapidly progressive arthritis, osteomyelitis, limb loss, and death. Diagnosis is complicated by the existence of other pathologies with similar presentations. There are no clear diagnostic criteria and pre-existing arthritis and crystal arthropathy are common among Veterans, particularly complicating the diagnosis. Evidence-based information at the right time and place will fill a large clinical gap and help reshape underlying assumptions currently driving decision making for knee SA in Veterans. Innovation and Impact. There are no established evidence-based guidelines or tools to accurately diagnose native knee SA. The PI developed a novel multivariable model in a non-Veteran population that demonstrated strong diagnostic characteristics. This model has been validated in a pilot Veteran population with similar performance characteristics. In addition, an on-line risk calculator known as the Septic Arthritis Risk Calculator (SARC) decision support tool (DST) has been developed and undergone usability testing. VA providers have expressed an interest in seeing the model validated in a national VA population and the DST integrated into the VA electronic health record (EHR). If successful, this will be the only tool of its kind and will facilitate decision making for an emergent clinical problem with significant risks of over and under treatment. Specific Aims. (1a): Externally validate the current SARC prediction model in a national VHA patient population while developing and externally validating a second model using predictors that do not require provider assessment to reduce clinical burden; (1b): Compare performance characteristics of the existing SARC model with the newly developed model and determine which model will be most appropriate for converting into the SARC DST (risk calculator) to be integrated into the VHA EHR; (2): Perform necessary programming to integrate the SARC DST into the VHA EHR, working with VA Information Technology specialists and extracting predictors from the CDW to ensure the final tool facilitates auto-population all predictors possible and is available in the VA EHR; (3): Evaluate the content, structure, and usability of the EHR-integrated SARC DST and patient educational handout using a mixed-methods approach, finalizing the tools based on the findings; (4): Identify barriers and facilitators to implementation of the SARC DST through a formative evaluation with clinician participants to identify preferred clinician users, timing of use and methods/vehicles for sharing results with patients, so that it is available for use across VHA. Methodology. We will identify a national sample of Veterans through the VA Corporate Data Warehouse (CDW) and validated through chart notes to validate the current prediction model and develop and validate an enhanced model with alternative predictors that are readily available in the EHR. We will develop the programming infrastructure for the EHR integrated SARC DST by collaborating with VA information technology specialists. This will include leveraging VA secure servers that have the capacity to link directly to the CDW to extract patient data in real time to facilitate auto-population. The tool will undergo usability testing from a national sample of orthopedic, infectious disease, emergency, and hospitalist physicians, as well as Veteran patients previously diagnosed with SA. Key stakeholders will provide feedback on implementation barriers and facilitators. Path to Translation/Implementation. This tool will be considered a “best practice” method to facilitate accurate and timely diagnosis of SA in Veterans. Upon completion of this grant, the tool will be made available VA wide with a planned strategy to champion the tool and to apply multiple vehicles for training and education to ensure uptake and sustainability. Future work will include implementation studies to evaluate the tool's effect on treatment and patient outcomes as well as the potential for initiatives evaluating provider and facility quality of care, the need for which is supported by literature on overuse of surgery.

NIH

Significance to VA. U.S. homeless-experienced Veterans (HEVs) are three times more likely to die by drug overdose than non-homeless Veterans. The use of psychostimulants, such as cocaine and methamphetamine, is the leading risk factor for drug overdose deaths. Beyond overdose, stimulant use disorder (StUD) contributes to marked impairments in social functioning, cognitive deficits, cardiovascular disease, psychosis, suicide, violence, and housing instability. Contingency management (CM), the most effective treatment available for StUD, is significantly underutilized among HEVs with StUD. CM is a psychosocial intervention that consists of providing immediate rewards to reinforce reductions in stimulant use. Permanent supportive housing (PSH), delivered through the VA’s U.S. Department of Housing and Urban Development-VA Supportive Housing (HUD-VASH) program, offers an ideal setting to implement CM due to its structured environment and integrated support services that would facilitate CM engagement. This project focuses on adapting CM for StUD for HEVs in PSH, aligning with the VA’s mission to improve outcomes for HEVs and end Veteran homelessness. Innovation and Impact. This application has potential to reduce stimulant use, increase engagement in substance use disorder services, and enhance HEV’s recovery and social functioning. Currently, no published studies have applied implementation science methods to adapt CM for StUD in homeless service settings, within or outside the VA. This project addresses a critical gap among HEVs in the treatment of StUD, which contributes to significant social, medical, and psychological challenges in an already vulnerable population. Building from available evidence, and engaging with HEVs, VA staff and leadership, and national experts, this application is novel in proposing to design, and in a future CDA-2 application, implement and test a CM intervention tailored to PSH. Adapting CM for PSH may foster new research on how the VA can improve engagement and effectiveness of SUD interventions for HEVs to support recovery and community integration. Specific Aims. 1) To develop a tailored CM intervention for StUD for HEVs in PSH using key informant interviews and an expert panel. 2) To identify a strategy to support the implementation of CM for StUD in PSH in a future trial using implementation mapping methods. Methodology. This project involves qualitative data collection and implementation science methods to guide intervention adaptation. Aim 1 will adapt CM for StUD for HEVs in PSH utilizing key informant interviews with VA staff (n=15), HEVs (n=15), and subject matter experts (n=5), followed by an expert panel (n=6-8). Interviews in Aim 1 will explore facilitators and barriers to CM implementation as well as potential intervention adaptations. Synthesized interview findings will be shared with an expert panel in a single-round modified Delphi process to build consensus around intervention adaptations. While Aim 1 focuses on intervention development, Aim 2 will identify strategies (e.g., staff training, technical assistance resources) that support the implementation of CM in PSH, drawing from the same key informant interviews and expert panel as Aim 1. In addition, Aim 2 will utilize Implementation Mapping, an evidence-based approach to identify implementation strategies, along with a focus group with VA Greater Los Angeles (GLA) PSH and SUD stakeholders to co- design implementation strategies in preparation for a future trial. Path to Translation/Implementation. The findings of this project will inform a future CDA-2 study to evaluate the adapted intervention and implementation strategy in two PSH settings at GLA. This effort represents a critical step toward the ultimate goal of nationwide implementation in VA PSH and other homeless service settings, aiming to enhance recovery and social functioning among HEVs with StUD.

NIH

Project Summary/Abstract Abdominal aortic aneurysms (AAA) are prevalent in the US Veteran population and associate with high morbidity and mortality when dilation occurs to the point of rupture. Monitoring by imaging is the current gold standard for measuring current vessel dimensions for risk stratification and deciding on need for surgical repair. Surgical repair is associated with a high morbidity and mortality, making it unsuitable for routine standard care, and imaging provides information on dilation progression that has already occurred. Understanding mechanisms of growth in humans with AAA, therefore, will allow us to predict which individuals will experience growth before they do, which would greatly improve our management of Veterans with AAA. The goal of this project is to develop and validate a plasma protein interactome map that can inform present and future AAA status clinically and provide mechanistic insight into how aneurysms progressively dilate. We will use the clinical dataset obtained from the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT). N-TA3CT was a randomized, placebo-controlled, double-blind clinical trial that assessed effect of doxycycline (100 mg orally twice a day) on growth of small AAA. Added to this dataset, we have quantified >1,000 proteins from plasma samples for deep proteomic assessment. We hypothesize that constructing a comprehensive AAA interaction network map will reveal plasma protein patterns that signify current and predict future aortic aneurysm growth regulated by neutrophil activation. Aim 1 will map plasma proteins that denote current and predict future aneurysm growth, Aim 2 will determine plasma proteins that reflect neutrophil activation as an indicator of aneurysm status, and Aim 3 will establish and extensively validate an AAA interaction network map that informs aneurysm status. This project will address knowledge gaps regarding how to assess aneurysmal remodeling and how to predict future progression in dilation. The Veteran population is particularly afflicted by AAA, and understanding how to most effectively track our patients will not only improve their care but also refine the need for timely and expensive surveillance monitoring by imaging.